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Editorial
Indian Heart J 2001; 53: 147154
Management of Coronary Artery Disease in

Patients with Diabetes Mellitus
VK Bahl, Sandeep Seth
Department of Cardiology, All India Institute of Medical Sciences, New Delhi
iabetes mellitus (DM) is a common medical problem

and a major risk factor for the development of
atherosclerotic coronary artery disease (CAD). Worldwide,
more than 100 million people have DM and this figure is
projected to double in the next 20 years. In India alone, it is
estimated that there are more than 20 million diabetics.1
There is no doubt that DM is going to be a major burden on
the health care system in the twenty-first century. DM is
not only associated with increased incidence and prevalence
of CAD, but diabetic patients also have a 2-fold increase in
mortality after acute myocardial infarction (AMI). The
outcome following coronary angioplasty (PTCA) and
coronary bypass grafting (CABG) is also poor. The
Framingham Heart Study data showed that patients with
DM, particularly women, exhibited an increased risk of
cardiovascular events including angina, stroke,
claudication, heart failure, myocardial infarction and
sudden death. 2 Diabetics have the same degree of
cardiovascular risk as non-diabetics who have had a
myocardial infarction (MI). A number of pathophysiological
mechanisms contribute to the development of both
macrovascular and microvascular complications in patients
with DM. The presence of associated risk factors for
atherosclerosis like obesity, advanced age, dyslipidemia and
hypertension, as well as multiple metabolic abnormalities
like hyperglycemia, hyperinsulinemia and abnormalities of
platelet function and coagulation contribute to the
cardiovascular complications.
Control of Risk Factors
In diabetics, coronary risk factors are magnified several
times, and these need to be strictly controlled. Smoking is
an independent predictor of mortality in diabetics and
cessation of smoking should be recommended for all
patients. Weight loss and increased physical activity have
been shown to improve glycemic control, lipid profile and
insulin resistance.
Intense glycemic control is highly effective in preventing
and retarding microvascular and, to some extent,
Correspondence: Dr VK Bahl, Professor of Cardiology, All India Institute
of Medical Sciences, New Delhi, e-mail: vkbahl@satyam.net.in
IHJ-Editorial.p65
147
macrovascular complications in both insulin-requiring DM

(IRDM) and non-insulin requiring DM (NIRDM).
There is no specific trial addressing the effect of lipid
lowering in diabetic patients; however, subgroup analyses
from a number of trials with statins have shown the efficacy
of this therapy. The Scandinavian Simvastatin Survival
Study (4S) trial, which enrolled 202 diabetic patients,
indicated that simvastatin reduced five-year mortality by
43% in diabetic patients with hypercholesterolemia and
CAD, as compared to 29% reduction in non-diabetic
patients.3 The Cholesterol and Recurrent Events Trial
(CARE) enrolled post-MI patients with average cholesterol
levels. Treatment with pravastatin showed a greater
reduction in major coronary event rate during a five-year
follow-up in patients with DM compared to non-diabetics
(37% v. 29%). 4 In the Long-term Intervention with
Pravastatin in Ischemic Disease (LIPID) study (which
enrolled 811 diabetics), pravastatin therapy showed a 19%
reduction in the composite end-point of CAD-related death
and MI during 6 years of follow-up in the subgroup of
diabetics with past history of MI or unstable angina.5 The
data available from studies on the use of fibrate therapy is
limited. The Helsinki Heart Study had suggested a trend
towards decreased coronary events in diabetic patients
treated with gemfibrozil compared to non-diabetics.6
There are a number of studies which have shown that
adequate control of blood pressure markedly reduces major
cardiovascular events. Most of the available data are from
studies using beta-blockers and diuretics and they continue
to be recommended as first-line therapy. There are sufficient
data to show that they reduce mortality and morbidity in
patients with diabetic nephropathy and in NIRDM patients.
Strict control of blood pressure to a mean of 144/82 mmHg
has been shown to significantly reduce strokes, diabetesrelated deaths, heart failure, microvascular complications
and visual loss in UKPDS trial.7 There is a growing amount
of data coming up in support of angiotensin-converting
enzyme (ACE) inhibitors and calcium channel blockers. The
revised guidelines of the Joint National Committee (JNC)
on Prevention, Detection, Evaluation and Treatment of
High Blood Pressure recommended a level of 130/85
mmHg for diabetic patients.
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148 Bahl et al.
Issues in Management
Managing CAD patients with DM requires special attention.
The majority of data on the management of CAD in DM
are based on retrospective subgroup analysis of major
clinical trials, which on an average included 20%30%
diabetic patients. Patients with DM have a number of adverse
clinical, angiographic and metabolic features contributing
to poor prognosis. Diabetic patients with CAD are more often
female, obese and hypertensive. They usually have severe
angina, history of previous MI or CABG and marked left
ventricular failure. They have abnormal endothelial function
with reduced coronary flow reserve. There is platelet
activation with increased thromboxane A2 secretion. The
levels of fibrinogen and Factor VII are higher than normal,
while antithrombin III and plasma fibrinolytic activity are
lower. Angiographically, they have diffuse, extensive
involvement of smaller reference vessels, multivessel
involvement, higher incidence of left main coronary artery
disease, poorer collaterals, lower ejection fraction and more
thrombus formation.
Two important issues need to be considered in the
management of CAD in patients with DMmanagement
of acute myocardial infarction and coronary
revascularization (both surgical and catheter-based).
Management of Acute Myocardial Infarction
Management strategies include the use of thrombolytics,
beta-blockers, ACE inhibitors, nitrates and antiplatelet
agents.
Thrombolytic therapy: Diabetic patients are less likely to
receive thrombolytic therapy as they present late and/or
with atypical symptoms, perhaps due to impaired sensation
of pain. There is also undue concern regarding the adverse
effects of thrombolytic agents, especially ocular
complications. The efficacy of thrombolysis may also be
reduced in DM due to enhanced platelet activity, elevated
procoagulant activity and imparied intrinsic fibrinolysis.
Despite achieving similar patency rates (70%) as nondiabetics, the mortality is higher in diabetics (17.3% v.
10.2%), probably because of impaired endothelial function
and diminished myocardial flow reserve.8 Reocclusion with
recurrent ischemia was also higher in diabetics (9.2% v.
5.3%) in the Global Use of Strategies To Open Occluded
Arteries (GUSTO) study.9 However, in spite of several factors
unfavorable for thrombolysis, they still derive substantial
benefit from it. The Fibrinolytic Therapy Trialists (FTT)
Collaborative Group in an overview of 58 600 patients
including 4529 diabetics, showed that the absolute reduction
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Management of Coronary Disease in Diabetics
148
in the 35-day mortality after thrombolysis in patients with

DM was 3.7% compared with 1.5% in non-diabetics. In
diabetic patients it fell to 13.6% following thrombolysis as
compared to 17.3% in the control group, while in the nondiabetic group, the mortality was reduced to 8.7% versus
10.2% in the control group.8
The fear of increased adverse effects of thrombolytic
therapy in diabetics is not borne out by the available data.
The data from the FTT Collaborative Group showed no
statistically significant increase in hemorrhagic stroke in
patients with DM receiving thrombolytic therapy (0.6% v.
0.4%). In the GUSTO study, the incidence of clinically
evident ocular complications was only 0.02% and there was
no case of intraocular hemorrhage. Stroke rates were
comparable in diabetics and non-diabetics (1.9% v. 1.4%).
Vitreous hemorrhage in diabetic patients was rare.8
There are some data to show the superiority of an
accelerated tissue plasminogen activator (tpa) regimen in
patients with DM. In the GUSTO-1 study, diabetics given
tpa had a 30-day mortality of 8% compared to 10.2% in
the group given streptokinase (STK). The stroke rate was
not significantly different in two groups (1.7% in the tpa
group and 1.4% in the STK group). Thus, the accelerated
tpa regimen appears to be better than STK. However, the
cost-effectiveness of this regimen in our country remains
questionable.
Post-thrombolysis strategies: Whether to follow a
conservative or an invasive approach following
thrombolysis in AMI, is a matter of debate. Clinical variables
collected for the 3339 patients of the Thrombolysis In
Myocardial Infarction (TIMI)-II study were analyzed
retrospectively to identify predictors of clinical events at 42
days, so as to identify the subgroups in which an invasive
or conservative strategy might be superior. Patients with
DM had a higher mortality in the invasive compared to the
conservative strategy group (14.8% v. 4.2%, p<0.001).10
A conservative approach after thrombolysis seems to be a
better option in DM, and angioplasty should be
recommended only in the presence of post-infarction
angina or objective evidence of ischemia.
Primary angioplasty: Primary angioplasty is equally
successful in diabetics and non-diabetics and appears to be
more effective than thrombolytic therapy. The GUSTO-IIb
angioplasty substudy compared the efficacy and relative
benefits of primary angioplasty over thrombolytic therapy
among diabetics.11 Diabetics had worse baseline clinical and
angiographic profiles. Despite more severe stenosis and
poorer flow in the culprit artery, procedural success with
angioplasty was similar for diabetics (70.4%) and non-
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Bahl et al.
diabetics (72.4%). Outcome at 30 days for death, MI and

stroke was better for non-diabetics randomized to
angioplasty versus alteplase (9.3% v. 13.2%) with a similar
trend for diabetics (11.1% v. 16.7%).
Antiplatelet agents: Diabetics have increased platelet
activation and accelerated turnover of platelets. Thus,
theoretically they may need higher doses or higher
frequency of aspirin administration, or need additional
antiplatelet agents like ticlopidine or clopidogrel. The subset
analysis of the Second International Study of Infarct
Survival (ISIS-2) found no benefit of 160 mg per day of
aspirin in diabetic patients. Since this was a subgroup
analysis, it could be a chance finding but it did put a question
mark on the efficacy of low-dose aspirin in diabetic
patients.12 However, a meta-analysis of the Anti-Platelet
Trialists Collaborative Group was done to determine the
effect of antiplatelet therapy on vascular events. It showed
a significant benefit of aspirin therapy in DM with or
without vascular disease, for the combined end-point of
stroke, MI or vascular death. In diabetic patients, the
vascular event rate with aspirin fell to 18.5% as compared
to 22.3% in controls.13 The magnitude of this benefit was
similar in diabetics and non-diabetics. The most widely
tested antiplatelet regimen was medium-dose (75325
mg/day) aspirin. Doses throughout this range seemed to
have a similar effect. There was no appreciable evidence that
either a higher aspirin dose or any other antiplatelet
regimen was more effective than medium-dose aspirin in
preventing vascular events.
Glycoprotein(Gp) IIb/IIIa inhibitors reduce the early and
mid-term incidence of death, MI and recurrent angina in
patients with acute coronary syndrome (ACS). They have
been found to be useful alone and in combination with
thrombolytic agents such as STK and tpa. They are also
useful during percutaneous coronary intervention (PCI).
The data regarding their efficacy in diabetics are based on
subgroup analysis of some of the major trials. In the Platelet
Receptor Inhibition for Ischemic Syndrome Management
in Patients Limited by Unstable Signs and Symptoms
(PRISM-PLUS) study, the reduction in clinical events in the
group receiving tirofiban plus heparin compared to heparin
alone was significant in both the diabetic and non-diabetic
subgroups. The rate of death or MI at 180 days was 11.2%
with tirofiban plus heparin versus 19.2% with heparin
alone.14 In the PURSUIT study (10 948 patients including
20% diabetics), reduction in the 30-day mortality with
eptifibatide was more in diabetic patients than nondiabetics.15 A meta-analysis of 10 recent clinical trials also
showed that diabetics had twice the absolute reduction in
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149
event rates as compared to non-diabetics.16

Anticoagulants: The majority of recent trials of lowmolecular-weight heparins (LMWH) in ACS have shown
their superiority over unfractionated heparin (UFH) in the
30-day incidence of a composite end-point of death, MI or
recurrent angina.17,18 They have been shown to be especially
useful in the high-risk subgroups, i.e. patients with
electrocardiographic changes, positive troponin-T and DM.
The diabetic patients (n=2175) in the randomized GUSTOIIb study (n=12 142) showed a tendency towards a lower
risk of death or reinfarction with hirudin as compared to
heparin at 30 days (12.2% v. 13.9%) and 6 months (17.8%
v. 20.2%). However, they had a higher incidence of major
bleeding and stroke.
Beta-blockers: Clinicians are hesitant to use beta- blockers
for diabetic patients because of their concerns regarding
impaired glucose metabolism and worsening of
dyslipidemia, and the fear that symptoms of hypoglycemia
would be masked. These concerns are only of academic
interest since the benefits outweigh the theoretical risks. A
number of studies evaluating the effect of beta- blockers in
AMI have demonstrated a two-fold reduction in the relative
risk in terms of mortality benefit after MI in diabetics as
compared to non-diabetics. With beta-blockers, the
percentage reduction in mortality was higher in diabetics
(37%) compared to non-diabetics (13%). There were similar
trends for reinfarction rates with a 55% reduction in
patients with DM versus 21% reduction in non-diabetics.20
From a database of 14 417 patients with chronic CAD
who had been screened for participation in the Bezafibrate
Infarction Prevention (BIP) study, 19% had NIRDM. The
total mortality during a 3-year follow-up was 7.8% in those
receiving beta-blockers compared with 14.0% in those who
were not (44% reduction). Multivariate analysis identified
beta-blocker therapy as a significant independent
contributor to improved survival. Within the diabetic
population, the main benefit associated with beta-blocker
therapy was observed in older patients, in those with a
history of MI, those with limited functional capacity, and
those at lower risk. Thus, therapy with beta-blockers
appears to be associated with improved long-term survival
in the high-risk subpopulation of patients with DM and
CAD.21
Angiotension-converting enzyme inhibitors: ACE
inhibition in AMI improves left ventricular remodelling, the
fibrinolytic balance, endothelial function and
sympathovagal balance. It delays renal dysfunction and
improves glycemic control.
A retrospective analysis of the data of the GISSI-3 study
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150 Bahl et al.
revealed a decreased 6-week mortality in diabetic patients

with lisinopril (8.7% v. 12.4%), an effect that was
significantly (p<.025) higher than that observed in nondiabetic patients (5.6% v. 5.9%).22 An analysis from the MI
Collaborative Group comprising the pooled data of
Consensus II, CCS-1 and GISSI-3 trials showed a trend
towards higher benefit of ACE inhibition in diabetic patients
(17.3 lives saved per 1000 diabetics treated v. 3.2 lives saved
per 1000 non-diabetics treated). Even in the CONSESNUSII trial, which showed no overall improvement in mortality
by intravenous enalapril, a 22% reduction in mortality was
seen at 6 months in the diabetic subgroup.23 The Survival
of Myocardial Infarction Long-Term Evaluation (SMILE)
Study revealed 34% cumulative reduction in the risk of
death or severe congestive heart failure (CHF) with
zofenopril at 6 weeks (risk reduction of 61% in diabetics
and 23% in non-diabetics).24 The Trandolapril Cardiac
Evaluation (TRACE) study also showed the benefit of ACE
inhibition following AMI in diabetic patients with severe
left ventricular dysfunction (ejection fraction <35%).25 One
life was projected to be saved in 26 months by treating only
6 diabetics compared to 17 non-diabetics. Thus, the efficacy
of ACE inhibtors in CAD patients with DM is overwhelming
Glucoseinsulin infusion: The long-term results of
Diabetes and InsulinGlucose infusion in the Acute
Myocardial Infarction (DIGAMI) study from Sweden showed
that the mortality in diabetic patients with AMI can be
reduced by 29% with an insulinglucose infusion followed
by multidose insulin therapy. At 1 year, 18.6% patients in
the intervention group had died compared to 26.1% in the
control group. The mortality reduction was particularly
evident in patients who had a low cardiovascular risk profile
and no previous insulin treatment. 26 These observed
benefits from glucoseinsulin infusions may be due to
suppression of free oxidation of fatty acids. Free fatty acids
potentiate ischemic injury by direct toxicity and by
inhibition of glucose oxidation and increased oxygen
demand. Some of these innovative treatments may be useful
in reducing mortality in patients with DM after AMI.
Revascularization in Diabetic Patients
One-third of patients undergoing coronary
revascularization are diabetics and have a poorer prognosis
compared to non-diabetics, partly due to the adverse
baseline variables. The National Heart, Lung, and Blood
Institute (NHLBI) PTCA registry data showed that diabetic
patients were older, had more co-morbid baseline conditions
and triple-vessel disease.
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Balloon angioplasty: PTCA in diabetic patients has a high

angiographic success rate (85%90%) but the risk of inhospital complications is more (MI: 0.4%7%; mortality:
0.6%3.2%), the rate of restenosis is higher (35%41%)
and the long-term outcome is not as good as in non-diabetic
patients with a long-term mortality of 10%40% over 5 to
10 years of follow-up.2731 Overall, 5-year survival is less in
diabetics undergoing PTCA, especially in those with IRDM
(82%) compared to NIRDM (91%).27 The 10-year survival
was 59% in diabetic patients and much higher in nondiabetic patients (83%) following PTCA in the LDCMC
registry data.30 Similarly, 9-year incidence of mortality
(35.9% v. 17.9%), nonfatal MI (29.0% v. 18.5%), repeat
CABG (36.7% v. 27.4%), and repeat PTCA (43.7% v. 36.5%)
was significantly higher in diabetics than in non-diabetics
in the NHLBI Registry. On multivariate analysis, diabetes
remained a significant predictor of decreased 9-year
survival.28 The Emory University Data showed event-free
survival of 36% at 5 years in diabetics compared to 53%
for non-diabetics,27 while it was 46% and 66%, respectively,
in the NHLBI PTCA Registry at 9 years. Diabetics have
higher incomplete revascularization rates as compared to
non-diabetics. However, survival at 10 years may be not
related to completeness of revascularization (72% v. 79%),
as shown by Halon et al.30
In an angiographic study by Rozenman et al., 31 in
addition to the high restenosis rate (41% v. 35%), a
significant finding was the development of new lesions
(22% in diabetics compared to 12% in non-diabetics). PTCA
in DM has additive risk for the development of new
narrowing.
Inability to revascularize all ischemic territories, a high
restenosis rate and progression of atherosclerosis leading
to repeat revascularization procedures are possible reasons
for poor long-term results in CAD patients with DM.
Stents: Coronary stenting has reduced the incidence of inhospital complications and rates of restenosis after
angioplasty. The data on stenting in patients with DM is
mainly based on subgroup analysis of major clinical trials.
The initial angiographic success is similar (92%100%) to
the results in non-diabetic patients. As compared to plain
balloon angioplasty, the restenosis rates are significantly
reduced by stenting. However, the restenosis rates are higher
in DM (24%55%), compared to non-diabetic patients
(17%28%). The higher restenosis in diabetics is due to
exaggerated intimal hyperplasia. Van Belle et al.32 found
restenosis rates to be almost double in diabetic patients (63%
v. 36%) due to greater late loss and a higher rate of late
vessel occlusion. In the data reported by Elezi et al.,33 the
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Bahl et al.
incidence of both restenosis (37.5% v. 28.3%, p<0.001) and

stent vessel occlusion (5.3% v. 3.4%, p=0.037) was
significantly higher in diabetic patients. One-year event-free
survival was significantly lower in patients with DM than
in non-diabetic patients. (73.1 v. 78.5%, p<0.001). The
follow-up was characterized by a higher incidence of death,
myocardial infarction and re-interventions.33 In the series
reported by Abizaid et al.,34 in-hospital mortality was
highest (2%) in the IRDM group compared to the NIRDM
group (0%) and non-diabetics (0.3%). The need for target
vessel revascularization (TVR) was 28% in IRDM, compared
to 18% in NIRDM and 16% in non-diabetics.34 Insulinrequiring diabetics fared worse than non-insulin requiring
diabetics (one-year event-free survival 60% in IRDM, 70%
in NIRDM and 76% in non-diabetics).
In the study by Lau et al.,35 it was shown that diabetics
were more prone to in-stent restenosis, especially in the
small vessels. Follow-up angiography at 5 months revealed
an in-stent restenosis rate of 40.5% in diabetics and 16.7%
in non-diabetic patients. The restenosis rate of 55% was
particularly high in diabetics receiving stents <3 mm in
diameter compared to 27% in diabetics who received larger
stents.
Role of glycoprotein IIb/IIIa receptor antagonists during PCI:
The data available on the role of Gp IIb/IIIa receptor
antagonists during coronary interventions in diabetic
patients are based on subgroup analysis from recent trials.
They suggest that the use of these agents is beneficial in
stented diabetic patients and there are preliminary data to
suggest that they also reduce neointimal proliferation.
The EPIC trial showed a similar reduction (35%) in acute
coronary events by abciximab in both diabetic and nondiabetic patients over a period of one month, but on followup of three years, diabetic patients had more cardiac events
and the initial benefit was lost.36 In the EPILOG trial,
abciximab therapy in diabetics led to a significant reduction
of death and MI at 30 days and 6 months, but the TVR at 6
months was not reduced in diabetics.37
In the EPISTENT study (n=2399), diabetic patients were
a prospectively defined subset with 173 randomized to
stentplacebo, 162 to stentabciximab, and 156 to balloon
angioplastyabciximab. The primary end-point of combined
death, MI or TVR at 6 months was significantly reduced in
the stentabciximab group (13%) compared to the stent
placebo (25.2%) and balloonabciximab (23.9%) groups
(p=0.005). The 1-year mortality rate for diabetics was 4.1%
for stentplacebo and only 1.2% for stentabciximab
patients (p=0.11).38,39
Pooled data from the EPIC, EPILOG and EPISTENT trials
showed that abciximab reduced the 1-year mortality of
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diabetic patients to that of placebo-treated non-diabetic

patients. In the non-diabetics, the placebo group had a oneyear mortality of 2.6% which was reduced to 1.9%. In the
diabetics, abciximab reduced the mortality to 2.5%
compared to 4.5% in placebo group.40
CABG multivessel angioplasty in diabetic patients: DM
is an important predictor of poor outcome after CABG as
well as PTCA. Which strategy is better in patients with
multivessel disease is a subject of much debate initiated by
the Bypass Angioplasty Revascularization Investigation
(BARI) trial results.
In the BARI trial, symptomatic patients with multivessel
disease (n=1829) were randomly assigned to CABG or
multivessel PTCA. Estimates of 7-year survival for the total
population were 84.4% for CABG and 80.9% for PTCA
(p=0.043). This difference could be explained by the 353
patients with treated DM for whom estimates of 7-year
survival were worse for PTCA compared to CABG (55.7% v.
76.4%). Among the remaining 1476 patients, survival was
virtually indentical by the assigned treatment (86.4%
CABG, 86.8% PTCA, p=0.72). The PTCA group also had
substantially higher subsequent revascularization rates
than the CABG group (59.7% v. 13.1%, p<0.001).4143
The BARI study included 4039 patients with multivessel
CAD; 1829 consented to randomization, and 2010 did not,
but were followed up in a registry. In contrast to the
randomized trial, the 7-year mortality rate of treated
diabetics in the registry was equally high (26%) with PTCA
and CABG. Seven-year mortality was higher for patients
undergoing PTCA in the randomized trial than in the
registry (19.1% v. 13.9%, p<0.01) but not for those
undergoing CABG (15.6% v. 14.2%, p=0.57). This
suggested that BARI physicians were able to select patients
for multivessel PTCA who underwent revascularization
without compromising long-term survival either in the
overall population or in treated diabetics.42
Similar results were seen in the Coronary Angioplasty
versus Bypass Revascularisation Investigation (CABRI).
Diabetics randomized to PTCA as well as CABG had higher
mortality than respective non-diabetics; however, the
association reached significance only in the former (RR
2.41, p=0.002). In the CABRI study, diabetics had twice
the long-term mortality compared to non-diabetics; this
difference was statistically significant both for the entire
population and for those randomized to PTCA, but not for
those randomized to CABG.44,45
In contrast, the Emory Angioplasty versus Surgery Trial
(EAST) and Randomized Intervention Treatment of Angina
(RITA)-1 trials, did not show the same benefit of CABG over
multivessel PTCA in diabetic patients.4647 The smaller
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152 Bahl et al.
single-center EAST had 15% drug-treated diabetic patients.

In these patients, the overall 8-year mortality demonstrated
no statistically significant difference relative to the first
revascularization procedure selected. In the RITA-1 trial,
the predefined primary end-point of death or nonfatal MI
occurred in 17% of PTCA patients and in16% of CABG
patients (p=0.64). Diabetics did not fare any differently from
non-diabetic patients.47
Weintraub et al. 29 reported data from the Emory
University showing that angiographic and clinical success
rates after multivessel angioplasty were similar in diabetics
and non-diabetics. In-hospital major complications were
infrequent (3%), with a trend towards higher death or MI
in those with IRDM. The 10-year survival rate in diabetics
after multivessel PTCA was 45% white it was 48% after
CABG. The survival in insulin-requiring diabetics was lower
(31% after PTCA and 48% after CABG).29
The Northern New England Cardiovascular Disease
Study Group has recently reported that patients with DM
treated with percutaneous coronary intervention had
significantly greater mortality relative to those undergoing
CABG (risk-adjusted hazard ratios [HR]=1.49; p=0.037).
The risk of mortality tended to increase further among
patients with three-vessel disease (HR=2.02; p=0.038)
than among patients with two-vessel disease (HR=1.33;
p=0.21).48
The St Luke database49 showed that only 42% of diabetic
patients could achieve complete revascularization by
multivessel PTCA as compared to 79% after CABG. Six-year
survival was 63% after PTCA and 70% after CABG. It
showed that completeness of revascularization rather than
the mode was predictive of late mortality.49 A majority of
trials comparing multivessel plain balloon angioplasty with
CABG revealed that overall long-term survival is better with
CABG and the need for repeat revascularization is less.
The Duke university database (1984 to 1990) included
patients receiving intracoronary stents. At six years, the
cardiovascular mortality was similar with two
revascularization strategies (19% after CABG and 20% after
PTCA in diabetics, and 10% and 8% in non-diabetics).50 The
better results with multivessel PTCA in this database were
attributed to the use of stents in some of the cases.
All these trials with multivessel angioplasty were
initiated when stents had not really become part of routine
coronary interventions. This naturally raises the question
whether multivessel stenting would be better than CABG. The
Arterial Revascularization Therapies Study (ARTS) group
sought to answer this question.51 At one year, there was no
significant difference in terms of the rates of death, stroke or
MI between the patients undergoing multivessel stenting and
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CABG, while the rate of event-free survival was better in the

latter group (73.8% v. 87.8%). However, multivariate Cox
regression analysis showed that presence of DM was the key
predictor of outcome in the stented group. Therefore, even
multivessel stenting may not solve the problems of
percutaneous revascularization in diabetic patients.
Conclusions
The management of CAD in diabetic patients poses a
challenging problem. The risk factors need to be vigorously
controlled with tight management of lipids and blood
pressure. Strict control of hyperglycemia should be ensured.
The benefit of treating diabetics, especially with
thrombolysis and ACE inhibitors, is more in terms of lives
saved. Percutaneous interventions in diabetics are
associated with higher rates of in-hospital complications
and more restenosis as compared to non-diabetics. Longterm results of CABG in diabetics are better than those with
multivessel PTCA. The availability of newer techniques of
angioplasty, better stents and the use of Gp IIb/IIIa
antagonists may improve the prognosis in diabetics.
Intracoronary radiation may reduce neointimal
proliferation. Stents coated with antiproliferation agents like
rapamycin and taxol may be useful. For patients whose
vessels are not suitable for any revascularization procedure,
gene therapy may provide a solution.
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6/5/01, 12:09 PM
Review Article
Indian Heart J 2001; 53: 155162
Percutaneous Coronary Intervention in Patients

with Unstable Angina
Mandeep Singh, David R Holmes Jr
Division of Cardiovascular Diseases and Internal Medicine, Mayo Clinic, Rochester, Minnesota, USA
cute coronary syndrome refers to a constellation of

symptoms that are compatible with acute myocardial
ischemia. It encompasses ST segment elevation, ST segment
depression myocardial infarction, and unstable angina.
Unstable angina and non-ST segment elevation myocardial
infarction (UA/NSTEMI) are components of the acute
coronary syndrome. UA and NSTEMI share common
clinical, pathophysiologic and treatment features, and thus
the 2 entities are often considered together for diagnosis and
management. Patients with UA/NSTEMI account for more
than 1 million hospital admissions annually in the United
States, and 6%8% of patients either die or have nonfatal
myocardial infarction within the first year of diagnosis.1
Pathophysiology
The pathophysiology of UA/NSTEMI has some similarity
with that of Q wave myocardial infarction. Coronary
thrombus after rupture of a vulnerable plaque plays a key
role in the pathogenesis. Autopsy studies have demonstrated
plaque rupture in approximately 60% of cases and plaque
erosion in 30%. 2 The process of atherogenesis, lipid
accumulation and cellular proliferation in UA/NSTEMI is
not linear and is unpredictable. New high-grade lesions
appear in previously mildly diseased segments. In a previous
study of patients undergoing serial angiography, 66% of
patients presenting with myocardial infarction and total
occlusion of an artery on coronary angiography had less
than 50% stenosis, and 97% of patients had less than 70%
stenosis at the time of the initial coronary angiogram
predating the infarction.3 This unpredictable and episodic
progression is most likely a result of plaque rupture and
subsequent intracoronary thrombus. Most plaque ruptures
occur at the shoulder region (junction of the plaque cap
and the adjacent more normal arterial wall). Several factors
contribute to the clinical syndrome of UA/NSTEMI, namely,
platelet aggregation, altered vasomotion, thrombus in the
setting of plaque erosion (endothelial cell denudation),
rupture of a vulnerable plaque (related to the rich lipid core),
macrophage activity and metalloproteinases.46
Correspondence: Dr Mandeep Singh, Division of Cardiovascular
Diseases and Internal Medicine, Mayo Clinic, 200 First Street SW, Rochester,
Minnesota, USA 55905, e-mail: Singh.Mandeep@mayo.edu
IA-004.p65
155
Classification
There is no universally accepted definition for UA/NSTEMI.
It encompasses a range of different clinical presentations.
These clinical variables with different prognostic
implications have been grouped under one diagnosis. In a
proportion of patients admitted with a diagnosis of UA, the
condition evolves into NSTEMI during the hospital stay. This
process makes interpretation of published data difficult. The
Braunwald classification7 has helped, but it is still not widely
used, as ideally should be the case (Table 1). This
classification was recently revised.8 Class IIIB (unstable
angina with rest pain occurring within the preceding 48
hours without a recent myocardial infarction) was divided
into troponin-positive and troponin-negative groups. The
risk of cardiac death or myocardial infarction within 1
month was estimated to be 15%20% in the class IIIB
troponin-positive group and less than 2% in the class IIIB
troponin-negative group. A second sample of troponin was
recommended if the first was negative at admission. The
association between increased troponin levels and increased
mortality was evident in patients with normal creatine
kinase-MB (CK-MB) levels. There was also a significant
increase in mortality with increasing levels of troponin. The
recent American College of Cardiology/American Heart
Association (ACC/AHA) guidelines have stratified patients
with UA/NSTEMI into 3 categories: low, intermediate
and high risk, according to the clinical information,
including history and physical examination, 12-lead
electrocardiogram, and cardiac enzymes values (Table 2).
This stratification is important not only for prognostic
purposes but also for treatment; different treatments may
be offered depending on the risk profile of the patient at
admission or during hospital stay.
Prognosis of Patients with Unstable Angina
Excellent predictive models are available for patients with
UA/NSTEMI. Simple risk scores are available from the
Platelet Glycoprotein IIb/IIIa in Unstable Angina: Receptor
Suppression Using Integrilin Therapy (PURSUIT) data, the
Thrombolysis in Myocardial Infarction (TIMI) risk score
derived from TIMI IIB, and Efficacy and Safety of
Subcutaneous Enoxaparin in Non-Q-Wave Coronary Events
6/5/01, 11:50 AM
156 Singh et al. Coronary Intervention in Unstable Angina

Table 1. Classification of unstable angina
Severity
Class I
New-onset, severe, or accelerated angina
Patients with angina of less than 2 months duration, severe
or occurring 3 or more times per day, or angina that is distinctly
more frequent and precipitated by distinctly less exertion. No
rest pain in the last 2 months
Class II Angina at rest, subacute
Patients with 1 or more episodes of angina at rest during the
preceding month but not within 48 hours
Class III Angina at rest, acute
Patients with 1 or more episodes of angina at rest within the
preceding 48 hours
Clinical circumstances
Class A Secondary unstable angina
A clearly identified condition extrinsic to the coronary vascular
bed that has intensified myocardial ischemia, such as anemia,
infection, fever, hypotension, tachyarrhythmia, thyrotoxicosis,
hypoxemia due to respiratory failure
Class B
Primary unstable angina
Class C
Postinfarction unstable angina (within 2 weeks of documented
myocardial infarction)
Intensity of treatment
1. Absence of treatment or minimal treatment
2. Occurring in presence of standard therapy for chronic stable
angina (conventional doses of oral -adrenergic blockers,
nitrates and calcium antagonists)
3. Occurring despite maximally tolerated doses of all 3 categories
of oral therapy, including intravenous nitroglycerin
Data from Braunwald E7
(ESSENCE) trials.911 The risk factors associated with a

higher risk for death or myocardial infarction in the
PURSUIT trial were older age, faster heart rate, lower blood
pressure, signs of heart failure and ST depression. An
enrollment diagnosis of myocardial infarction was
associated with a 50% increase in 30-day reinfarction.
Therefore, most information about cardiac risk can be
obtained at admission from patients presenting with UA/
NSTEMI. The TIMI score identified that in patients with UA/
NSTEMI, the following factors were associated with a higher
risk for adverse cardiac events: age 65 years or more, at least
3 risk factors for coronary artery disease (such as diabetes,
hypertension, family history of coronary artery disease,
hypercholesterolemia and current smoking), ST segment
elevation (transient) or depression, severe anginal
symptoms (>2 anginal symptoms in past 24 hours), aspirin
use within the past 7 days, and increased values for serum
cardiac markers (CK-MB fraction or cardiac-specific
troponin level). In contrast, similar scores can predict
insignificant coronary artery disease by simple nomograms.
These are important because patients with minimal disease
at coronary angiography do not seem to benefit from
glycoprotein (Gp) IIb/IIIa receptor inhibitors.11 The risk
stratification and prognostication with the available scores
would help identify patients at higher risk for adverse
IA-004.p65
156
Indian Heart J 2001; 53: 155162
cardiac events and would allow cardiologists to stratify these

patients into different plans of management.
Medical Treatment
The medical management of all patients admitted with a
diagnosis of UA/NSTEMI includes bed rest, aspirin,
intravenously administered heparin, nitrates, and adrenergic blockers. Angiotensin-converting enzyme
inhibitors are added in patients with depressed left
ventricular systolic function and diabetes mellitus.
Glycoprotein IIb/IIIa receptor inhibitors have
significantly improved the outcome of patients presenting
with UA/NSTEMI. The 3 agents approved for clinical use
are: (1) the monoclonal antibody abciximab; (2) the peptide
receptor antagonist eptifibatide; and (3) the nonpeptide
receptor antagonist tirofiban. In the Evaluation of c7E3 for
the Prevention of Ischemic Complications (EPIC) study,12
the 2099 patients who had balloon angioplasty or
directional atherectomy had a 35% reduction in the
composite end-points of death, nonfatal myocardial
infarction, refractory ischemia, or urgent revascularization
within 30 days. The benefit of abciximab persisted for up to
3 years after the procedure.13 The Evaluation in PTCA to
Improve Long-term Outcome with Abciximab Gp IIb/IIIa
blockade (EPILOG) trial14 tested the benefits of abciximab
in patients at lesser risk who were given lower doses of
weight-adjusted heparin. In 2972 enrolled patients, those
who received abciximab and low-dose heparin had a 57%
reduction in the composite end-points of death, myocardial
infarction, or urgent revascularization (5.2%), compared
with patients receiving standard heparin therapy (11.7%).
In the Chimeric 7E3 Antiplatelet Therapy in Unstable
Angina Refractory to Standard Treatment (CAPTURE)
trial, 15 patients were randomized after coronary
angiography to either placebo or abciximab. Abciximab
therapy was given for 18 to 24 hours before coronary
intervention and was continued for 1 hour after the
intervention. The CAPTURE trial was prematurely
terminated because the abciximab-treated patients had a
significant reduction in the composite end-points at 30 days.
Also, the progression of myocardial infarction before
coronary intervention was significantly reduced (0.6% v.
2.1%; p=0.03).
The Platelet Receptor Inhibition in Ischemic Syndrome
Management (PRISM), Platelet Receptor Inhibition in
Ischemic Syndrome Management in Patients Limited by
Unstable Signs and Symptoms (PRISM-PLUS),16 and the
Randomized Efficacy Study of Tirofiban for Outcomes and
Restenosis (RESTORE) trials17 evaluated tirofiban. Among
1570 patients who had percutaneous coronary
intervention (PCI) in PRISM-PLUS, there was a 42%
6/5/01, 11:51 AM
Indian Heart J 2001; 53: 155162
Singh et al.
Coronary Intervention in Unstable Angina 157
Table 2. Short-term risk of death or nonfatal myocardial infarction in patients with unstable angina*
Feature
High risk (at least 1 of the following

features must be present)
Intermediate risk (no high-risk feature

but must have 1 of the following
features)
History
Accelerating tempo of ischemic

symptoms in preceding 48 h
Prior MI, peripheral or cerebrovascular

disease, or CABG; prior aspirin use
Character of pain
Prolonged ongoing (>20 min) rest

pain
Prolonged (>20 min) rest angina, now

resolved, with moderate or high
likelihood of CAD
Rest angina (<20 min or relieved with
rest or sublingual NTG)
Clinical findings
Pulmonary edema, most likely

Age >70 years
related to ischemia
New or worsening MR murmur
S3 or new or worsening rales
Hypotension, bradycardia, tachycardia
Age >75 year
ECG findings
Angina at rest with transient ST

segment changes >0.05 mV
Bundle branch block, new or
presumed new
Sustained ventricular tachycardia
T wave inversions >0.2 mV
Markedly elevated (e.g, TnT or TnI

>0.1 ng/mL)
Slightly elevated (e.g. TnT >0.01 but

<0.1 ng/mL)
Cardiac markers
Low risk (no high- or intermediate-risk

feature but may have any of the
following features)
New-onset CCS class III or IV angina

in the past 2 weeks with moderate or
high likelihood of CAD
Normal or unchanged ECG during an

episode of chest discomfort
Pathologic Q waves
Normal
CABG: coronary artery bypass grafting; CAD: coronary artery disease; ECG: electrocardiography; MI: myocardial infarction; NTG: nitroglycerin; TnI: troponin I; TnT: troponinT.
*An estimation of the short-term risks of death and nonfatal cardiac ischemic events in unstable angina is a complex multivariable problem that cannot be fully specified in a
table such as this. Therefore, the table is meant to offer general guidance and illustration rather than rigid algorithms.
From Braunwald E, Antman EM, Beasley JW, Califf RM, Cheitlin MD, Hochman JS, et al. ACC/AHA guidelines for the management of patients with unstable angina and nonST segment elevation myocardial infarction: executive summary and recommendations: a report of the American College of Cardiology/American Heart Association Task
Force on Practice Guidelines (Committee on the Management of Patients With Unstable Angina). Circulation 2000; 102: 11931209. By permission of the American Heart
Association.
reduction in the 30-day incidence of death or myocardial

infarction.16 The RESTORE trial randomized patients to
either percutaneous transluminal coronary angioplasty
(PTCA) or directional atherectomy.17 In 2139 patients, the
study showed a trend for reduction of the combined endpoints of death or myocardial infarction, emergency
coronary artery bypass grafting, unplanned stent
placement for abrupt closure, and recurrent ischemia
compared with placebo at 6 months (24.1% v. 27.1%,
p = 0.11).
In the Integrilin to Manage Platelet Activation to Prevent
Coronary Thrombosis (IMPACT-II) study,18 analysis of
treated patients showed a 24% reduction in the composite
end-points of death, myocardial infarction, or
revascularization (11.6% v. 9.1%). In patients undergoing
PCI in the PURSUIT trial within 72 hours of randomization,
eptifibatide resulted in a 31% reduction in death or
myocardial infarction at 30 days (17.7% v. 11.6%,
p=0.01).19 Meta-analysis of 32 735 patients from 10 major
randomized trials demonstrated a 21% reduction in the
incidence of 30-day death or myocardial infarction in
patients treated with any of the given Gp IIb/IIIa
antagonists.20
IA-004.p65
157
Abciximab is currently approved for treatment of UA/

NSTEMI as an adjunct to PCI or when the intervention is
planned within 24 hours. The longer half-life of abciximab
makes it less suitable in patients likely to need coronary
artery bypass grafting. In this setting, Gp IIb/IIIa inhibitors
with a shorter half-life (eptifibatide) would be optimal.
Tirofiban used in combination with heparin is approved for
use both for medical management and in conjunction with
PCI. Clinical markers that put the patient in the higher-risk
category may guide patient selection. Patients with ST
segment depression or increased cardiac marker values
derive the maximum benefit from this expensive therapy.
These trials indicate that Gp IIb/IIIa receptor inhibitors
are of benefit in patients with UA/NSTEMI, especially if PCI
is planned. Treatment benefits were observed within hours
after intervention and were sustained in the long term. The
clinical trials revealed a greater magnitude of benefit with
abciximab than with the other 2 agents. The effects of two
Gp IIb/IIIa inhibitors were compared in the recent Do
Tirofiban And Reopro Give Similar Efficacy Outcomes Trial
(TARGET) (presented at the American Heart Association 2000
meeting), in which 4812 patients were randomized to
receive either abciximab (n=2414) or tirofiban (n=2398).
6/5/01, 11:51 AM
The 2 groups were matched for the baseline characteristics.

Sixty-three percent had acute coronary syndrome (ST
segment elevation myocardial infarction and patients with
cardiogenic shock were excluded). Ninety-five percent
received intracoronary stents. The primary end-point of
death, myocardial infarction, or urgent target vessel
revascularization was achieved in 7.55% of patients in the
tirofiban group and in 6.01% in the abciximab group
(RR=1.26, p=0.037).
The greater benefit with abciximab is possibly due to
both its longer biological half-life and its effects on non-IIb/
IIIa vitronectin receptors. Dosing issues and
underestimation of platelet inhibition are possible
explanations for the worse outcome with tirofiban than with
abciximab. The current ACC/AHA guidelines recommend
that Gp IIb/IIIa inhibitors be given to patients with
continuing ischemia or with high-risk features and to
patients in whom PCI is planned.
Coronary Angioplasty in Unstable Angina
General considerations: Coronary angioplasty in a
setting of unstable angina differs from that in stable angina
pectoris and may be associated with increased
complications. Angioplasty can aggravate thrombus
formation by endothelial denudation and platelet activation.
The presence of an intracoronary thrombus is an
independent predictor of increased complications with PCI,
especially myocardial infarction.21 The ineffectiveness of
Gp IIb/IIIa inhibitors in a setting of thrombus makes this
option less attractive.21 The setting of UA/NSTEMI also may
exacerbate the dissection at the site of plaque rupture.
Vasoreactivity of the treated vessel can also be a problem
because the thrombus generates vasoactive substances.
Finally, the risk of distal embolization is increased. These
complications are less frequent in a setting of chronic stable
angina. Recently, the introduction of intracoronary stents
and filter and thrombectomy devices, in addition to
improvement in the angioplasty equipment and operator
experience, has led to resurgence of the concept of an early
revascularization strategy in this high-risk subgroup.
Combination therapy: Unfractionated heparin has long
been the main antithrombin agent used in the management
of acute coronary syndromes. The most important
limitation of unfractionated heparin is the variable dose
response relationship in different patients, necessitating
frequent monitoring of the anticoagulation status. It can
also bind to plasma proteins and endothelial cells and
may result in rebound hypercoagulability, induce
thrombocytopenia, and facilitate platelet aggregation.
Low-molecular-weight heparins (LMWHs) have been
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Indian Heart J 2001; 53: 155162
developed to address some of these limitations. These agents

can be administered subcutaneously, and no monitoring is
required. The efficacy of LMWH has been addressed in the
ESSENCE and TIMI IIB trials.22,23 In the ESSENCE trial,23
3171 patients with UA/NSTEMI were randomized to either
subcutaneous enoxaparin or unfractionated heparin.
Therapy was administered for a median of 2.6 days. The
primary end-point of death, myocardial infarction, or
recurrent angina occurred within 14 days of enrollment
in 16.6% of patients receiving enoxaparin and in 19.8% of
patients receiving unfractionated heparin (p=0.02). Similar
results were reported in the TIMI IIB trial comparing
enoxaparin and unfractionated heparin.22 The other trials
with LMWH have not demonstrated their superiority over
unfractionated heparin. In the Fast Revascularization
During Instability in Coronary Artery Disease (FRISC II)
trial,24 dalteparin was given to all patients for a minimum
of 5 days. Subsequently, the patients were randomized to
receive placebo or dalteparin for up to 90 days. There was a
significant reduction in the incidence of death or myocardial
infarction at 30 days but not at 3 months (6.7% v. 8.0%).
The benefits of dalteparin were limited to patients with
increased troponin T levels and those managed medically.
Recently, the National Investigators Collaborating on
Enoxaparin (NICE) 4, in an open-labeled study, compared
the safety and efficacy of enoxaparin used in place of
unfractionated heparin in the setting of acute coronary
syndrome. The preliminary data compared favorably with
the previously published results. Clinical Revascularization
Using Integrilin Simultaneously with Enoxaparin (CRUISE)
is an ongoing randomized trial to address this issue. The
current ACC/AHA guidelines recommend treatment with
either unfractionated heparin or with LMWH to be added
to antiplatelet therapy.
Early invasive versus conservative strategy in
unstable angina (Tables 3 and 4): The 2 strategies for
the treatment of patients with UA/NSTEMI are widely
debated. In the early conservative arm, PCI is reserved for
patients who have recurrent ischemia at rest or minimal
activity or who have a strongly positive stress test despite
maximal medical therapy. The advantage of the early
conservative treatment is that it limits the risks and costs
of the invasive procedure in all patients presenting with UA/
NSTEMI.
In contrast, early revascularization has several potential
advantages that can partially offset the increased hazard
of an early invasive strategy. It defines the coronary
anatomy in patients with UA/NSTEMI. Typically, less than
10% have significant left main coronary artery disease,
multivessel disease is present in 40% to 50%, single-vessel
disease is present in a third, and 10% to 20% have no
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Indian Heart J 2001; 53: 155162
Singh et al.
significant disease.25 The treatment strategy can be decided

on the basis of the clinical profile and the coronary anatomy.
Patients without significant coronary artery disease can be
expeditiously dismissed. The revascularization strategy is
determined by considering several factors: the patients
clinical risk, coronary anatomy, ventricular function,
severity of symptoms, co-morbidities and life expectancy.
The decision for early invasive or conservative treatment
strategies is based on the trials and registries described
below.
In the 1990 TIMI IIIB study, a randomized trial with a

22 factorial design, an early invasive approach in patients
with unstable angina was not found to be superior to early
conservative strategy.25 The primary end-point of death,
myocardial infarction, or an abnormal exercise tolerance
test at 42 days was 16.2% in the early invasive arm and
was not significantly different from that observed in the
early conservative arm (18.1%). However, the number of
patients rehospitalized and the number of days of
hospitalization were significantly lower in the early invasive
Table 3. Recent studies on unstable angina: features

TIMI IIIB (1994)
VANQWISH (1998)
OASIS (1998)
Mayo Clinic (1999)
FRISC II (1999)
Number of patients
Study design
1473
22 factorial design
TPA v. placebo
Early invasive v.
early conservative
920
Randomized trial of
non-Q wave MI
Early invasive v.
conservative strategy
7987
Prospective
registry, studied
the relationship
between rates of
cardiac procedures
and outcomes
7632
Early invasive strategy
in recent years
was compared with
that in earlier years
2433
Randomized trial
Early invasive v.
early conservative
strategy
Primary end-point
Death, nonfatal MI,

positive ETT
Death or nonfatal MI
Death or nonfatal MI
Time from randomization

revascularization
1872 hours
8 days (median)
27 days
Catheterization in
the conservative
group
64%
48%
48% v. 8.5% (7 d)
in hospitals with
and without
cardiac cath lab,
respectively
48% within 6 months
Old study excluded

post-MI patients
No stents or Gp
IIb/IIIa inhibitors
Predominantly male
patients
Mortality in early invasive
strategy after CABG
No deaths after PTCA
Retrospective, singleinstitution experience
Older patients and

patients with prior
CABG excluded
Revascularization
done after 6 days
<20%
50% with 3-vessel or left

main coronary artery
disease
30%
Limitations
Three-vessel
disease
CABG: coronary artery bypass grafting; cath lab: catheterization laboratory; ETT: exercise tolerance test; MI: myocardial infarction; PTCA: percutaneous transluminal
coronary angioplasty; TPA: tissue plasminogen activator
Table 4. Recent studies on unstable angina: results

TIMI IIIB
Result
In-hospital death
MI
Death/MI
Death/MI on F-U
Refractory angina,
readmissions for unstable
angina
Inv
VANQWISH
Inv
Cons
18 (2.5)
42 (5.7)
8.2
133 (18.1)
21
7.7
111
6*
3.3*
85*
5.0
11.0
55 (7.8) 100 (14.1)*
16.1
18 (2.4)
38 (5.1)
7.5
120 (16.2)
Cons
OASIS
C lab +
Mayo Clinic
C lab
199498
199093
Inv
Cons
4.3
9.6
57 (1.8)
24 (0.7)
81 (2.5)
54 (2.4)*
22 (1.0)*
76 (3.4)*
1.9%
9.5%
3.0%
12.0%*
19.3
Cons: conservative; F-U: follow-up; Inv: invasive; MI: myocardial infarction; C lab: cardiac catheterization laboratory
*Significant difference Figures in parentheses are percentages of the cases
IA-004.p65
159
FRISC II
6/5/01, 11:51 AM
arm. Additionally, 64% of patients assigned to the early

conservative arm underwent coronary angiography and
almost half underwent revascularization within 6 weeks
of presentation.
The DANAMI (DANish Trial in Acute Myocardial
Infarction) study26 compared an early invasive strategy of
PTCA or coronary artery bypass grafting with a
conservative strategy in patients with inducible myocardial
ischemia who received thrombolytic therapy for first
myocardial infarction. In 503 patients randomized to an
early invasive strategy, PTCA was performed in 266 (53%)
and coronary artery bypass grafting in 147 (29.2%). In the
conservative arm, only 1.6% of patients were revascularized
2 months after acute myocardial infarction. At a 2.4-year
follow-up, there was no significant difference in mortality
between the invasive and the conservative groups (3.6% v.
4.4%). Patients assigned to an early invasive strategy had a
significant reduction in the incidence of acute myocardial
infarction (5.6% v. 10.5%; p=0.0038) and a lower incidence
of admission for unstable angina (17.9% v. 29.5%;
p<0.00001). There was a significant reduction in the
primary end-points of death, myocardial infarction, or
admission for unstable angina in the early invasive arm
(23.5% v. 36.6% at 2 years; p0.00001).
The Veterans Affairs Non-Q-Wave Infarction Strategies
In Hospital (VANQWISH) trial27 was a randomized trial also
comparing the two strategies of early invasive and early
conservative treatment in 920 patients admitted to the
Veterans Administration hospitals. This trial showed that
patients assigned to early invasive treatment had worse
clinical outcomes during an average follow-up of 23
months. The number of patients with a primary end-point
(death or nonfatal myocardial infarction) at hospital
dismissal was significantly higher in the early invasive group
than in the early conservative group (36 v. 15 patients;
p=0.004) and also at 1 year (111 v. 85; p=0.05). Mortality
was 11.3% in patients who underwent early coronary
artery bypass grafting. In comparison, there was no
mortality in patients who had early angioplasty. The reason
for this difference is unexplained. It did, however, contribute
to the overall conclusions of the trial.
The Organisation to Assess Strategies for Ischaemic
Syndrome (OASIS) registry28 studied the relationship
between the use of cardiac catheterization facilities and
revascularization procedures, and rates of cardiovascular
death, myocardial infarction, stroke, refractory angina and
major bleeding in patients with unstable angina. This was
a prospective registry-based study in 6 different countries
with different approaches to intervention. This study found
no significant difference in the rates of cardiovascular death
or myocardial infarction at 7 days and 6 months in countries
with the highest rates of invasive procedures, but the rates
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Indian Heart J 2001; 53: 155162
of refractory angina and readmission for unstable angina

were significantly lower. Moreover, death and myocardial
infarction rates in 2 countries with high rates of early
angiography and interventions (United States and Brazil)
were different. The incidence of death and myocardial
infarction in the United States was lower. This finding means
that differences in procedural practice alone may be
insufficient to explain the difference in the outcome between
different countries.
A study from Mayo Clinic29 analyzed the in-hospital and
intermediate-term outcomes of 7632 patients with unstable
angina who underwent coronary interventions in the
previous 20 years. The 3 study groups were determined by
the year of intervention. The most recent group represented
the years 1994 to 1998, an era with more experienced
operators, use of effective antiplatelet strategy, and
moderate use of intracoronary stents. The clinical success
(as defined by residual stenosis less than 50% without inhospital death, Q wave myocardial infarction, or coronary
artery bypass grafting) was significantly higher in the recent
period, as was reduction in the in-hospital complications,
including 40% reduction in mortality, 60% decline in
Q wave myocardial infarction, and 85% decrease in the need
for emergency coronary artery bypass grafting (Fig. 1). This
study documented that the results of coronary
interventions had improved in the previous 4 years.
The most recent trial is the Fast Revascularisation during
In Stability in Coronary artery disease (FRISC II).24 This is a
multicenter randomized study (n=3048) from Europe of
early invasive versus conservative strategy. All patients were
treated with dalteparin, an LMWH, for 57 days. There were
1219 patients with unstable angina or non-Q wave
Fig. 1. Improvement in outcome with percutaneous coronary intervention in

patients with unstable angina treated at Mayo Clinic. CABG: coronary artery
bypass grafting; QMI: Q wave myocardial infarction; 1, 19791989; 2,
19901993; 3, 19941998.
6/5/01, 11:51 AM
Indian Heart J 2001; 53: 155162
Singh et al.
myocardial infarction who were randomized to the early

invasive group and 1214 patients in the noninvasive
group. Patients older than 75 years or with previous
coronary artery bypass grafting were excluded. The primary
outcome of death or myocardial infarction at 6 months was
9.5% in the invasive group and 12% in the noninvasive
group (p=0.045). The differences were more pronounced
in men. There was a significant reduction in angina and
hospital admissions in patients with unstable angina.
The mortality at 1 year favored the early invasive strategy
(2.2% v. 3.9%).24
The main drawback of the FRISC II study was a delay of
6 days in achieving revascularization. Second, the highestrisk groups (older patients and patients who had coronary
artery bypass grafting) were excluded. In the recently
presented Treat Angina with Aggrastat+Determine Cost of
Therapy with an Invasive or Conservative Strategy TIMI 18
(TACTICS-TIMI 18) study, 2220 patients with UA/NSTEMI
from 9 countries were randomized to routine early
catheterization (448 hours) or an early conservative
strategy. The primary end-point of death, myocardial
infarction, or early rehospitalization for acute coronary
syndrome at 6 months was 15.9% in the early invasive arm
and 19.4% in the conservative group (p=0.025). Older
patients and patients with prior bypass grafting were not
excluded. This trial extends the benefit of the early invasive
group to early randomization and revascularization and
also to the high-risk groups excluded in the FRISC II trial.
Currently, the ACC/AHA guidelines recommend that
early invasive treatment be considered for patients with the
following findings:
1. Recurrent angina or ischemia at rest or with low-level
activities despite maximal anti-ischemic therapy
2. Recurrent angina or ischemia with symptoms of
congestive heart failure
3. High-risk findings on noninvasive stress testing
4. Depressed left ventricular function (ejection fraction
<0.40)
5. Hemodynamic instability
6. Sustained ventricular tachycardia
7. PCI within 6 months
8. Prior coronary artery bypass grafting
9. Repeated presentations with acute coronary syndrome
despite therapy and without evidence for ongoing
ischemia or high risk
10. Age older than 65 years, presentation with ST segment
depression, and presentation with increased levels of
cardiac markers without contraindications to
revascularization.
The results of some of the early trials comparing invasive
and conservative strategy have been mixed and
IA-004.p65
161
controversial because of different study designs, the

technology used, and the end-points tested. The results of
the Mayo Clinic, FRISC II and TACTICS-TIMI 18 studies
showed that the outcome of coronary interventions
significantly improved in the late 1990s. Management
strategies in these high-risk patients need to be re-examined.
Approach to a patient with UA/NSTEMI: The recent
improved results of coronary interventions, as shown by
the Mayo Clinic experience,29 the FRISC II study,24 and the
TACTICS TIMI18 studies, indicate that our strategy for the
management of patients with unstable angina needs
reorganization. Early coronary angiography allows better
definition of coronary anatomy, including recognition of
the culprit lesion, identification of patients with 3-vessel
disease or left main coronary artery disease, and exclusion
Fig. 2. The acute ischemic pathway, for use in triage for patients with unstable
angina and non-ST segment elevation myocardial infarction. EF: ejection
fraction; LV: left ventricular; Rx: therapy. (From Braunwald E, Antman EM,
Beasley JW, Califf RM, Cheitlin MD, Hochman JS, et al. ACC/AHA guidelines
for the management of patients with unstable angina and non-ST segment
elevation myocardial infarction: executive summary and recommendations: a
report of the American College of Cardiology/American Heart Association Task
Force on Practice Guidelines [Committee on the Management of Patients With
Unstable Angina]. Circulation 2000; 102: 11931209. By permission of
the American Heart Association.)
6/5/01, 11:51 AM
of patients with normal coronary arteries and early hospital

dismissal.
Medical management has improved, and the results of
early PCI are encouraging. Once a patient is admitted with
a diagnosis of UA/NSTEMI, risk stratification by clinical,
electrocardiographic, or biochemical criteria is of
paramount importance. Patients with a low or intermediate
risk can be channeled to early dismissal, or kept under
observation in the chest pain unit. The acute ischemia
pathway outlined by the ACC/AHA guidelines helps triage
a patient to early coronary angiography with or without
percutaneous or surgical revascularization (Fig. 2). In any
decision-making, factors to be considered are the risks for
an acute adverse cardiac event, life expectancy, other comorbid diseases, the experience of the operator and the
institution in doing PCI in the setting of UA/NSTEMI, the
patients and hospital resources, and the countrys policies.
14.
15.
16.
17.
18.
19.
20.
References
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6. Fuster V, Badimon L, Badimon JJ, Chesebro JH. The pathogenesis of
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8. Hamm CW, Braunwald E. A classification of unstable angina
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9. Boersma E, Pieper KS, Steyerberg EW, Wilcox RG, Chang WC, Lee
KL, et al. Predictors of outcome in patients with acute coronary
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10. Antman EM, Cohen M, Bernink PJ, McCabe CH, Horacek T, Papuchis
G, et al. The TIMI risk score for unstable angina/non-ST elevation
MI: A method for prognostication and therapeutic decision making.
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11. Roe MT, Harrington RA, Prosper DM, Pieper KS, Bhatt DL, Lincoff
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randomized trial of brief integrin beta3 blockade with percutaneous
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Umans VA, Kloeg PH, Bronzwaer J. The CAPTURE trial. Lancet 1997;
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Inhibition of the platelet glycoprotein IIb/IIIa receptor with tirofiban
in unstable angina and non-Q-wave myocardial infarction. PRISMPLUS Study Investigators. N Engl J Med 1998; 338: 14881497
The RESTORE Investigations. Effects of platelet glycoprotein IIb/IIIa
blockade with tirofiban on adverse cardiac events in patients with
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angioplasty. Circulation 1997; 196: 14451453
Randomised placebo-controlled trial of effect of eptifibatide on
complications of percutaneous coronary intervention: IMPACT-II.
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Inhibition of platelet glycoprotein IIb/IIIa with eptifibatide in patients
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Vorchheimer DA, Badimon JJ, Fuster V. Platelet glycoprotein IIb/IIIa
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Khan MM, Ellis SG, Aguirre FV, Weisman HF, Wildermann NM, Califf
RM, et al. Does intracoronary thrombus influence the outcome of
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and angiographic outcomes in a large multicenter trial. EPIC
Investigators. J Am Coll Cardiol 1998; 31: 3136
Antman EM, McCabe CH, Gurfinkel EP, Turpie AG, Bernink PJ, Salein
D, et al. Enoxaparin prevents death and cardiac ischemic events in
unstable angina/non-Q-wave myocardial infarction. Results of the
Thrombolysis in Myocardial Infarction (TIMI) IIB trial. Circulation
1999; 100: 15931601
Cohen M, Demers C, Gurfinkel EP, Turpie AG, Fromell GJ, Goodman
S, et al. A comparison of low-molecular-weight heparin with
unfractionated heparin for unstable coronary artery disease.
ESSENCE Study Group. N Engl J Med 1997; 337: 447452
Wallentin L, Lagerqvist B, Husted S, Kontny F, Stahle E, Swahn E.
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Madsen JK, Grande P, Saunamaki K, Thayssen P, Kassis E, Eriksen U,
et al. Danish multicenter randomized study of invasive versus
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in Acute Myocardial Infarction. Circulation 1997; 96: 748755
Boden WE, ORourke RA, Crawford MH, Blaustein AS, Deedwania
PC, Zoble RG, et al. Outcomes in patients with acute non-Q-wave
myocardial infarction randomly assigned to an invasive as compared
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Variations between countries in invasive cardiac procedures and
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Review Article
Indian Heart J 2001; 53: 163166
Failed Thrombolysis: A Continuing Problem

Upendra Kaul, Ranjan Kachru
Batra Heart Centre, Batra Hospital and Medical Research Centre, New Delhi
rials of thrombolysis and primary angioplasty have

shown that coronary artery patency and flow
characteristics following thrombolytic therapy are
independent prognostic predictors of outcome in acute
myocardial infarction (AMI).15 A number of studies suggest
that patency rates with TIMI-3 flow cannot be achieved in
more than 54% of patients even with the best thrombolytic
regimen.1 The timely detection of this failed reperfusion is
very important for the further rational management of
patients with AMI. The need is to diagnose it accurately and
cost-effectively, preferably using noninvasive techniques
(Table 1). This has to be followed by prompt and efficient
attempts to reperfuse the blocked vessels by
pharmacological, catheter-based or combined strategies.
Table 1. Failed thrombolysisnoninvasive diagnosis

1.
Nonresolution of chest pain
2.
Nonresolution of ST segment elevation on ECG (<25%50%

resolution at 90180 min post-thrombolysis)
3.
Enzyme kinetics
Troponin-T or creatinine kinase-MB or myoglobin ratio
post-/pre-thrombolysis
<5 at 60 min
<10 at 90 min
4.
Myocardial contrast echocardiography
Diagnosis of Failed Reperfusion

Cessation of chest pain has been regarded as a clinically
predictive sign of reperfusion though its quantification for
clinical trials is difficult.6 Only complete resolution of chest
pain is a good predictor and this sign has been reported in
only 29% of patients with patent arteries.7 Analgesia, which
is an important part of the management of AMI, can mask
this sign. It is, therefore, necessary to have more objectively
defined markers of reperfusion besides resolution of chest
pain.
Reperfusion arrhythmias: Although observed frequently
Correspondence: Professor Upendra Kaul, Director, Interventional
Cardiology, Batra Hospital and Medical Research Centre, 1, Tughlakabad
Institutional Area, New Delhi 110062
IHJ-136-01.p65
163
after thrombolysis and primary percutaneous transluminal

coronary angioplasty (PTCA), none of the observed
arrhythmias (such as accelerated idioventricular rhythm)
have been shown to add independently to the predictive
value of diagnosing reperfusion.7
Electrocardiography: Nonresolution of ST segment
changes after thrombolysis has been shown to be a predictor
of worse long-term outcome compared with a cohort with
good resolution. However, this analysis is a better predictor
of successful perfusion than of failed reperfusion. Studies
have shown a variety of electrocardiographic (ECG) indices
for reperfusion failure or success. These include 25%
reduction in ST segment elevation, identified in the worst
lead on the 60180 min post-thrombolytic ECG; and a
post- to pre-thrombolysis maximal ST segment elevation
ratio or sum of post- to pre-thrombolysis ST segment
elevation ratio equal to or less than 0.5. All these indices
have been described as having reasonable sensitivity and
specificity, irrespective of the infarct site.8,9 Continuous ST
segment monitoring has also been shown to have a good
predictive value for nonreperfusion in the GUSTO-I study,10
especially when the initial ST segment elevation is more
than 4 mm.
Biochemical markers: Of the numerous markers,
creatinine kinase isoenzymes, troponin-T or I and myoglobin
measurements have been used extensively for the early
diagnosis of AMI. The rapid peaking of myoglobin seems to
be the earliest marker of a successful recanalization, whilst
the rate of rise of troponin-T post-thrombolysis over 3 hours
has revealed very high (94%) sensitivity as well as specificity
(100%) in this situation.11 There is, however, limited evidence
that any of these markers can predict failure to achieve TIMI3 flow at 6090 min with any degree of similar accuracy.12,13
At present, these assays are mostly reserved for post hoc
confirmation rather than direct decision-making so they are
of no help in the triage for patients with failed reperfusion.
Early peaking of levels of these markers, while suggesting
restoration of flow, does not necessarily mean achievement
of reperfusion at tissue level (restoration of microvascular
reperfusion). The lack of accuracy and interpretation makes
their reliable use difficult in the setting of failed reperfusion,
especially in the absence of concomitant ST segment
resolution.14
6/5/01, 11:26 AM
Indian Heart J 2001; 53: 163166
164 Kaul et al. Failed Thrombolysis: A Continuing Problem
There is some evidence to suggest that patients who fail

to achieve detectable fibrinogenolysis following
thrombolysis could benefit from additional thrombolysis.
In one small study, benefit was confined to those patients
whose fibrinogen remained at greater than 1 g/L following
therapy with streptokinase.15 Although fibrinogen assay is
not routinely used, this measurement is potentially
advantageous for distinguishing patients in whom
nonreperfusion is primarily due to nonfibrinogenolysis
rather than due to no reflow. In such cases, further
thrombolysis and/or intensified antiplatelet therapy is more
likely to be beneficial rather than interventional treatment.
Emerging diagnostic strategies: Even though sestamibi
is accurate in assessing patency after systemic thrombolysis,
the need to obtain prethrombolytic scans precludes this
method from wide clinical application. 16 The acute
assessment of microvascular perfusion by myocardial
contrast echocardiography may be the most promising
strategy.17 Contrast agents are currently being tested in
preclinical trials and are likely to become available for
clinical trial assessment shortly.18
Management of Patients in Whom Thrombolysis
has Apparently Failed
Repeat thrombolysis and additional antiplatelet
therapy: Readministering the thrombolytic agent is a
frequently used strategy although the evidence supporting
its utility is limited. Lack of attempts to prove the benefit of
this therapy are surprising, considering the potentially large
impact it could have in most hospitals. White et al.19 and
Verheugt et al.20 showed the advantages of opening the
infarct related artery with systemic or intracoronary tissue
plasminogen activator (tPA) following failure with systemic
streptokinase. Their investigations were, however, made as
nonrandomized trials. In a small group of patients, stratified
on the basis of 25% nonresolution of the ECG, Mounsey et
al.15 also showed the benefit of additional intravenous
alteplase in terms of improvement in the left ventricular
ejection fraction at 6 weeks.
Pathophysiological studies, however, fail to support the
theoretical benefit of repeat thrombolysis. Moreover, there
seems to be little benefit from repeating thrombolysis later
(more than 6 hours) rather than sooner, as the limited
positive impact of late recanalization on reperfusion can be
offset by the small but possibly deleterious effect of increased
risk of bleeding. 21 The issue of the efficacy of repeat
thrombolysis can be sorted out only by a large dedicated
trial but, in view of more recent advances in targeted
IHJ-136-01.p65
164
antiplatelet therapy, the role of repeat thrombolysis may

need to be redefined.
The safety of antiplatelet therapy combined with
thrombolytic therapy will be assessed in GUSTO IV. The TIMI
14 trial22 has shown that a combination of abciximab and
a half dose of tPA is efficacious and gives the best TIMI-3
flow (72%). However, the same was not true for the
combination with streptokinase, which led to higher
bleeding problems, including cerebral bleeds. Data on
combining thrombolytics and antithrombins continue to
suggest that the therapeutic window is narrow. So far,
however, there are no data on the combination of
thrombolytics with glycoprotein IIb/IIIa inhibitors in a
setting of rescue therapy, i.e. when thrombolysis has
failed. For routine use, we will also need information about
its safety, especially with the potential risk of increased
bleeding.
Role of percutaneous coronary intervention (PCI):
It is clear that something needs to be done in patients with
clinical signs of failed reperfusion. However, little is known
regarding the true value of the more costly rescue PCI from
the data of trials that have already been carried out. In the
TIMI IV subgroup analysis,23 no significant benefit was seen
in the intervention group compared to conservative
management. On the other hand, observational studies by
Juliard et al.24 and Kaul et al.25 have shown that rescue PCI
results compare well with the primary PCI in the same
hospital. However, in their reported series, Kaul et al.25 have
used abciximab in all the patients taken up for rescue PCI.
Analysis of the intervention subgroup of the GUSTO I substudy26 has shown a trend towards improved left ventricular
function and 30-day mortality in the PCI group compared
to conservative strategy. The outcome of these patients was,
however, less favorable than that of patients in whom initial
thrombolysis was successful. Failed rescue PCI in the setting
of failed thrombolysis was a significant predictor of high
mortality (30%).
Analysis of the TAMI 5 study27 subgroup of patients with
an occluded artery post-thrombolysis showed no benefit in
patients who underwent early rather than predischarge PCI.
The RESCUE trial28 compared patients with late signs (>8
hours) of occlusion of the left anterior descending artery
post-thrombolysis and the results suggested improvement
in the left ventricular function and composite endpoints.
The relative benefits in these trials, however, have been quite
modest. The benefits could possibly be significant if catheterbased interventions are combined with the use of
glycoprotein IIb/IIIa inhibitors as has been done in the study
reported by Kaul et al.25
Although primary PCI has been shown to be superior to
6/5/01, 11:26 AM
Indian Heart J 2001; 53: 163166
thrombolysis in patients who can be taken up for the

procedure without delay, it has had very little impact on
AMI treatment in a community setting, mainly because of
logistic reasons.
Referring only patients with failed reperfusion to a
cardiac centre with interventional facilities could probably
be both a good and realistic trade-off between additional
expenses and resources and a significant contribution to
cardiac care in the community. Whether the active research
for signs of failed reperfusion in the early stage of AMI is
superior to the strategy of initial conservative treatment
with predischarge risk stratification and selection for late
intervention remains to be seen. The use of intra-aortic
balloon counterpulsation in a setting of failed thrombolysis
can be useful, especially in hemodynamically unstable and
high-risk patients who need transfer for catheter-based
intervention. Data from a few trials do suggest the utility of
this supportive procedure. A dedicated study funded by the
British Heart Foundation, the REACT study (REscue
Angioplasty versus Conservative management of
Thrombolysis), has been planned to answer this important
question.
Newer strategies, which include intracoronary
therapeutic ultrasound or thrombectomy, could be useful
in achieving lysis of an intracoronary thrombus as well as
promoting microvascular reperfusion.2933 There is a good
theoretical basis for these which, if proven in clinical trials,
could add to the present armamentarium as adjunctive
procedures combined with PCI.
Therapeutic options used in failed thrombolysis are listed
in Table 2.
Kaul et al.
Failed Thrombolysis: A Continuing Problem
165
combination of reduced doses of alteplase and abciximab.

Data from the GRAPE study34 suggests that abciximab used
in anticipation of further intervention could recanalize up
to 40% of the occluded vessels. It is, therefore, likely that a
combination of all reperfusion methods (thrombolysis,
antiplatelet agents, intracoronary interventions) could offer
the best reperfusion strategy in AMI. To this end, data from
the SPEED trial35 advances these efforts by demonstrating
that it is safe and efficacious to perform PCI after either
thrombolytic monotherapy or combination therapy (rPA
and abciximab). The study, however, suffers from the
limitation that it is a nonrandomized comparison.
Conclusions
Failed thrombolysis continues to be a significant clinical
problem in the management of patients with AMI. There is
no proven strategy which is clearly superior and can be
recommended as the treatment of choice. In the absence of
sound clinical data, however, it seems logical to recommend
a careful, frequent assessment of the patients clinical status
after instituting systemic thrombolysis. This should include
frequent 12-lead ECG control. A 90120 min recording is
very important since it could form a basis for consideration
of further management, which could be PCI after
administering Gp IIb/IIIa blockers if the option is easily
achievable.
It is likely that patients with failed thrombolysis comprise
a heterogeneous group with different levels of failed lysis,
microvascular no reflow or different degrees of critical
narrowing in the target or infarct related vessel. Careful
evaluation of these factors in individual patients will result
in a more tailored and step-wise approach.
Table 2. Therapeutic options in failed thrombolysis

1.
Repeat thrombolysis (newer agents)
2.
Glycoprotein IIb/IIIa inhibitors (abciximab, eptifibatide,

tirofiban)
3.
Intra-aortic balloon counterpulsation (IABP)
4.
Rescue PTCA
5.
Combination of glycoprotein IIb/IIIa blocker and PCI
Emerging/Combined Strategies
With the advent of new, potent, targeted antiplatelet agents
(abciximab, eptifibatide, etc.) there are some promising data
suggesting that they could be very useful not only as bail
out measures both prior to and during intracoronary
interventions but also as a primary adjunctive treatment.34
In the TIMI 14 study22, thrombolysis was facilitated with a
IHJ-136-01.p65
165
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6/5/01, 11:26 AM
Original Article
A Randomized Study of the Safety and Efficacy of

Reused Angioplasty Balloon Catheters
M Zubaid, CS Thomas, H Salman, I Al-Rashdan, N Hayat, A Habashi,
MT Abraham, K Varghese, L Thalib
Department of Cardiology, Chest Diseases Hospital, Kuwait and
Department of Community Medicine, Faculty of Medicine, Kuwait University
Background: To lower costs, many centers around the world utilize previously used, resterilized balloon catheters
to perform coronary angioplasty. There are no controlled trials regarding their safety and efficacy.
Methods and Results: We performed the first randomized, double-blind, controlled, single-center clinical trial
comparing the safety (clinical success) and efficacy (angiographic success) of reused versus new coronary
angioplasty balloon catheters. A total of 377 procedures were included, 178 in the reused catheter arm and
199 in the new catheter arm. There were no significant differences in clinical or lesion characteristics among
the two arms. The incidence of first balloon failure in the reused catheter arm was similar to that of the new
catheter arm (12 cases [7%] v. 10 cases [5%], respectively). The angiographic success rate was also similar
176 cases (98.9%) in the reused catheter arm and 196 cases (98.5%) in the new catheter arm. The number of
balloon catheters used per lesion, amount of contrast, and procedural and fluoroscopy time were similar in the
two arms. At 30 days, the incidence of major adverse cardiac events was similar in both arms, 8 cases (4.5%) in
the reused catheter arm and 10 cases (5%) in the new catheter arm. The incidence of fever was also similar.
Conclusions: When performing coronary angioplasty, reused catheters are as effective (similar angiographic
success) and safe (similar clinical success) as new catheters. (Indian Heart J 2001; 53: 167171)
Key Words: Angioplasty, Reused balloons, Coronary disease
t is estimated that coronary angioplasty (PTCA) is

performed in more than one million cases worldwide
annually. As the cost of equipment is substantial, several
centers utilize previously used and resterilized balloon
catheters to perform these procedures.1 In the field of
cardiology, ablation catheters and pacemakers are also often
reused. 2,3 Although reuse of expensive materials is a
standard practice in the operating room, according to the
manufacturers these balloon catheters are intended for
single use only.
Observational studies have differed in their assessment
of the safety and efficacy of reused balloon catheters.4,5
According to one observational study, the potential for cost
saving is great; however, much of the costs saved in the reuse
strategy are lost in treating complications.6 Therefore, if
there were no increase in complications, cost savings would
be substantial.
There are no randomized controlled studies looking at
the safety and efficacy of reused balloon catheters. We
Correspondence: Dr Mohammad Zubaid, Department of Medicine,
Faculty of Medicine, Kuwait University, PO Box 24923, Safat 13110, Kuwait
e-mail: zubaid@hsc.kuniv.edu.kw
IHJ-108-01.p65
167
performed the first such study with the aim of

demonstrating the safety (as judged by clinical success) and
efficacy (as judged by angiographic success) of reused
balloon catheters (RC) versus new balloon catheters (NC).
We also measured other relevant factors including volume
of contrast, number of balloons used and fluoroscopy time.
Methods
From February 1999 to February 2000, all patients
undergoing coronary angioplasty at our institute were
considered for enrollment in the study. Exclusion criteria
included total occlusion (Thrombolysis In Myocardial
Infarction, TIMI-0 flow) of unknown duration or longer
than one month, and the presence of cardiogenic shock.
Informed verbal consent was obtained from all patients. To
qualify for enrollment in the trial, the lesion had to be
crossed with a guidewire and the appropriate-size balloon
had to be available (Fig. 1). Once these conditions were met,
the patients were randomized to the reused balloon strategy
or new balloon strategy in a ratio of 1:1. The operator was
blinded to the choice of balloon catheter. If the first
6/5/01, 12:17 PM
168 Zubaid et al.
Indian Heart J 2001; 53: 167171
Safety and Efficacy of Reused Angioplasty Catheters
infarction (MI), death, emergency PTCA or coronary bypass

surgery (CABG). A diseased vessel is defined as one that has
a 50% diameter stenosis and is a major epicardial coronary
vessel or surgically bypassable branch thereof. Procedure
time was always calculated beginning from the time of use
of the guide catheter, and contrast volume was calculated
as the total volume used after cannulation with the guide
catheter. A buccal temperature of >38 C indicated fever.
Catheter preparation for reuse: Immediately after
completion of the angioplasty procedure, the balloon
catheter was inspected for any deformities. If the catheter
had no defects, the shaft and the distal end of the catheter
were cleaned with tap water to remove the blood and
contrast medium, if any. The contrast from the balloon was
sucked out by applying repeated negative pressure with a
10 ml luer lock syringe and the balloon was cleaned several
times with distilled water. The monorail lumen was also
flushed repeatedly and then checked with a guidewire for
patency. The balloon port was left exposed to the air and
the catheter left to dry for 2448 hours. When the balloon
was dry, a small stylet with a cover for the balloon was
inserted and it was packed in its original cover. The balloon
catheter was then sterilized with ethylene oxide.
Statistics: Data are expressed as mean SD. Comparisons
were performed using two-sided Student's t test for
continuous variables. The tests of proportions were carried
out when associated variables were categorical. A statistical
probability of <0.05 was considered to be significant.
Fig. 1. Study flowchart
Results
balloon failed to cross the lesion, then a second smaller

diameter balloon of the same randomization type (i.e. new
or used) was utilized. If this second balloon catheter failed
to cross, then a crossover to the other randomization arm
was allowed. When crossover occurred, a balloon catheter
similar in size was used. When multivessel PTCA was
performed, only one vessel was enrolled in the study, and
when there was more than one lesion in a vessel, only one
lesion was enrolled.
Definitions: Lesion assessment was carried out visually,
and they were classified according to the American College
of Cardiology/American Heart Association lesion
classification as modified by Ellis et al.7 Angiographic
success was defined as a lesion residual stenosis of <50%
by visual estimation. Clinical success was defined as
angiographic success without in-hospital major adverse
cardiac events (MACE), a composite of myocardial
IHJ-108-01.p65
168
A total of 433 patients underwent 452 PTCA procedures

during the study period. Of these, 359 patients (377 lesions)
were enrolled in the study (83% enrollment rate). The
baseline clinical and angiographic characteristics (Tables
1 and 2) indicate that both groups were comparable.
Unstable angina was present in 56% of the study
population. The incidence of diabetes was high in both
groups.
The procedural characteristics (Table 3) showed a high
and similar success rate for crossing the lesion with the first
chosen balloon (93% for reused balloons and 95% for new
balloons). If the first balloon failed, the success of crossing
the lesion with the second chosen balloon was also similar
(4% for both types of balloons). However, the crossover rate
(failure to cross the lesion with the initial chosen strategy)
was higher in the reused arm (3% compared with 0.5% in
the new arm, p=0.04). The angiographic success rate in
both arms (98.9% for reused and 98.5% for new balloons,)
6/5/01, 12:17 PM
Indian Heart J 2001; 53: 167171
Zubaid et al.
Table 1. Clinical characteristics of the patients

Used balloon, n=178
n (%)
199
5511
3187
152 (76)
83 (42)
112 (56)
4 (2)
0
127 (64)
44 (22)
83 (42)
109 (55)
87 (44)
60 (30)
52 (26)
Values are meanSD. All values are statistically not significant
Used balloon
n (%)
Number of lesions
178
Lesions crossed with first balloon
166 (93)
Lesions crossed with second balloon
6 (4)
Lesions crossed over to other strategy
6 (3)
Failure to pass any balloon
0
Lesions stented
125 (70)
Angiographic success
176 (98.9)
Balloon catheters/lesion
1.20.5
Guiding catheters/lesion
1.10.4
Guidewires/lesion
1.00.3
Contrast volume (ml)/per patient
12347
Procedure time (min)
26.812
Fluoroscopy time to cross lesion
2.23
with wire (min)
Fluoroscopy time after lesion crossed
4.63.4
with wire (min)
New balloon
n (%)
199
189 (95)
8 (4)
1 (0.5)
0
137 (69)
196 (98.5)
1.20.5
1.20.6
1.10.4
12453
2913.7
2.84
4.73.3
Values are meanSD

p=0.04
Table 2. Angiographic characteristics
Target vessel
Left anterior descending
Diagonalramus
Circumflexmarginal
Right coronary artery
Graft (Saphenous vein)
PTCA procedure
Multivessel
Single vessel
Single lesion
Multilesion
Elective PTCA
Ad hoc PTCA
Lesion type
De novo
Restenosis
Stent restenosis
Modified ACC/AHA lesion class
A
B1
B2
C
Thrombus
Calcification (moderate or greater)
Tortuosity
% diameter stenosis
Before PTCA
Final result
Left ventricular ejection fraction
169
Table 3. Procedural characteristics
New balloon, n=199

n (%)
Number of lesions
178
Age (years)
5412
Age range (years)
2683
Sex (males)
148 (83)
Clinical presentation
Stable angina
73 (41)
Unstable angina
100 (56)
Acute myocardial infarction 1 (1)
Asymptomatic
4 (2)
Previous myocardial infarction 114 (64)
30 days
44 (25)
>30 days
70 (39)
Diabetes
83 (47)
Extent of CAD
1 vessel
75 (42)
2 vessel
66 (37)
3 vessel
37 (21)
Used balloon, n=178

n (%)
Table 4. Influence of first balloon success on results

New balloon, n=199
n (%)
84 (47)
3 (2)
44 (25)
40 (22)
7 (4)
80 (40)
8 (4)
47 (24)
58 (29)
6 (3)
12 (7)
166 (93)
139 (78)
39 (22)
74 (42)
104 (58)
23 (12)
176 (88)
161 (81)
38 (19)
101 (51)
98 (49)
169 (95)
4 (2)
5 (3)
184 (92)
6 (3)
9 (5)
40 (22)
56 (32)
53 (30)
29 (16)
21 (12)
10 (6)
32 (18)
39 (20)
63 (32)
50 (25)
47 (23)
34 (17)
11 (6)
35 (18)
8810
59
0.550.11
909
615
0.550.13
Number of lesions
Number of balloon catheters/lesion
Contrast volume (ml)
with wire (min)
with wire (min)
MACE
Used balloon
n (%)
New balloon
n (%)
166
165 (99.4)
1.20.4
12146
26.611.9
2.23.1
189
186 (98.4)
1.10.4
12454
28.814.1
2.63.9
4.43.3
4.73.4
8 (4.8)
10 (5.3)

MACE: major adverse cardiac events.
Table 5. Influence of first balloon failure on results
Number of lesions
Number of balloon catheters/lesion
Contrast volume (ml)
with wire (min)
with wire (min)
MACE
Used balloon
n (%)
New balloon
n (%)
12
11 (92)
2.30.5
17146
30.717.5
2.31.8
10
10 (100)
2.30.5
13045
35.46.8
6.64.1
7.73.5
6.33.2
All values are statistically not significant
and the number of balloon catheters used per lesion were

similar. Contrast volume used and procedure and
fluoroscopy time were also similar in both arms, and success
or failure of the first balloon in crossing the lesion did not
IHJ-108-01.p65
169
Values are meanSD. p=0.05, p=0.004

MACE: major adverse cardiac events
affect the success of the procedure or clinical outcome

(Tables 4 and 5) in any of the strategies.
The performance of balloon catheters in certain lesion
6/5/01, 12:17 PM
170 Zubaid et al.
Indian Heart J 2001; 53: 167171
Table 6. Performance of used v. new balloons in different lesion subsets

Modified ACC/AHA class B2
Lesions crossed with first balloon
Used
n=53
New
n=50
49 (92)
1 (2)
Lesions crossed with second balloon

Lesions crossed over to other strategy
Calcification
Stenosis 90%
Tortousity
Used
n=10
New
n=11
Used
n=32
New
n=35
Used
n=118
New
n=149
50 (100)
9 (90)
11 (100)
24 (75)
33 (97)
107 (91)
140 (94)
1 (10)
5 (16)
2 (6)
5 (4)
9 (6)
3 (6)
3 (9)
6 (5)
52 (98)
50 (100)
9 (90)
11 (100)
32 (100)
35 (100)
117 (99)
147 (99)
Balloon catheters/lesion
1.30.4
1.20.4
1.10.3
1.30.5
1.60.6
1.30.4
1.30.4
1.20.4
Fluoroscopy time after lesion

crossed with wire (min)
5.22.1
4.82.4
6.43.6
6.14.0
7.14.0
5.74.2
6.64.6
5.03.1
p value <0.05
p value <0.01
Table 7. In-hospital major adverse cardiac events and

hospital stay
Used balloon, n=178
n (%)
New balloon, n=199

n (%)
Follow-up at 30 days
174 (98)
194 (98)
Fever
MACE
Myocardial infarction
Q wave
Non-Q wave
Emergency PTCA
Emergency CABG
Death
Hospital stay (days)
2 (1)
8 (4.5)
7 (3.9)
2 (1.1)
5 (2.8)
1 (0.6)
2 (1.1)
1 (0.6)
2.44
4 (2)
10 (5)
8 (4)
5 (2.5)
3 (1.5)
3 (1.5)
1 (0.5)
2 (1)
2.32.4

MACE: major adverse cardiac events
subsets was examined (Table 6). In lesions that had 90%

stenosis there were significantly more crossovers, more
balloon catheters were utilized per lesion, and a longer
fluoroscopy time was required in the used balloon arm as
compared to the new balloon arm. In tortuous lesions,
crossing with the first balloon occurred less frequently with
used balloons than with new balloons; 75% v. 97%,
respectively.
The incidence of MACE was similar4.5% for reused
and 5% for new balloon catheters (Table 7). At 30 days of
follow-up, fever was noted in 1% of those in the RC arm
and in 2% of those in the NC arm.
Discussion
To cut costs, the reuse of angioplasty balloon catheters is
common in many countries, though it has not been studied
systematically in the past. 1 It is common for surgical
equipment and certain devices to be sterilized and reused
IHJ-108-01.p65
170
safely.3,8 The concerns relating to balloon reuse include the

risk of bacterial and viral infections, the risk of pyrogenic
reaction, ethical and medicolegal concerns, and the
argument that any cost saving would be offset by a possible
increase in complications. With proper cleaning and
sterilization, and ensuring the patency of the catheter
lumen, the risk of bacterial infections from reused catheters
does not appear to increase.9 There is no strong basis for
concerns of possible transmission of viral diseases such as
hepatitis B, C and HIV, or CreutzfeldtJakob disease. In one
report,10 HIV was not detected by tissue culture technique
after 1 to 3 days of drying.10 In addition, there have not
been any cases reported worldwide of the transmission of
viral diseases due to the reuse of catheters several times
over.11 Fagih et al.12 found no evidence of CreutzfeldtJakob
disease attributable to the reuse of PTCA devices and
recommended that the Quebec health authorities reverse a
previous decision prohibiting the reuse of angioplasty
devices. Although it is documented that chemical residue
of resterilization is left behind on catheters,13,14 this seems
to be of theoretical concern only, as a stringent cleaning
and sterilizing protocol makes the risk of pyrogenic
reactions with reused catheters similar to that of new
catheters.15,16,17
To our knowledge, no randomized clinical trial has been
published comparing catheter reuse strategy with singleuse strategy. Data from observational studies have shown
conflicting results regarding the safety and efficacy of
reused balloons.4,5 Our study sample was representative of
a busy catheterization laboratory as we had a high
enrollment rate (83%). As compared to the published
literature, there was a particularly high prevalence of
diabetes in our series. The safety of PTCA in both strategies
was the same, as judged by a similar rate of MACE and fever.
The efficacy of both strategies was also the same, as reflected
6/5/01, 12:17 PM
Indian Heart J 2001; 53: 167171
Zubaid et al.
by a similar rate of angiographic success, the number of

balloon catheters used per lesion, the amount of contrast
used, and fluoroscopy and procedure time.
The rate of crossing the lesion with the first balloon was
high and similar in the two strategies. This could be due to
the advancements in balloon technology leading to the
creation of small-profile catheters that maintain their low
profile after initial use. However, when the first balloon fails
to cross the lesion, it seems logical that one should switch
to a new balloon of a smaller size. This is supported by our
finding that a second smaller reused balloon failed to cross
the lesion in 6 out of 12 lesions, while a second smaller
new balloon crossed the lesion in 8 out of 9 lesions. Our
study also demonstrated that, regardless of the initial
balloon type, failure to cross with the first balloon will lead
to prolonged procedure and fluoroscopy time and additional
contrast. We examined the performance of used balloons
in lesions with adverse characteristics, e.g. modified ACC/
AHA class B2 lesions, tortuous lesions and lesions with
90% stenosis. The numbers, however, were small in these
subgroups. Although used balloons did not perform as well
as new balloons in these lesion subsets, the angiographic
success rate remained high and was similar in both balloon
types.
This study has demonstrated that there is no evidence
of increased risk with reused balloon catheters. Although
we did not perform a cost analysis, Mak et al. 6 have
suggested that in the absence of increased complications,
the potential for cost savings are tremendous. The ethical
and medicolegal concerns of the patient relate to the
benefits, risks and cost of the procedure. We have
demonstrated that the patient is not subjected to any
procedural risks with reused balloons and there are no
increased complications. Added to this is the fact that
surgical equipment is resterilized and reused widely without
raising any ethical concerns regarding their use.
Conclusions: This study is the first randomized study to
demonstrate that in a wide variety of patients, the results
of reused balloon catheters are similar to those of new
catheters. The potential for cost saving is high.
IHJ-108-01.p65
171
171
References
1. Reuse of disposables in the catheterization laboratory. Report of the
committee appointed by the Cardiological Society of India. Indian
Heart J 1997; 49: 329331
2. Ross DL. Re-use of electrode catheters labelled as single use for clinical
cardiac electrophysiological studies. Aust NZ J Med 1996; 26: 632
635
3. Linde CL, Bocray A, Jonsson H, Rosenqvist M, Rdegran K, Rydn L.
Re-used pacemakersas safe as new? A retrospective case-control
study. Eur Heart J 1998; 19: 154157
4. Plante S, Strauss BH, Goulet G, Watson RK, Chisholm RJ. Reuse of
balloon catheters for coronary angioplasty: a potential cost saving
strategy. J Am Coll Cardiol 1994; 24: 14751481
5. Browne KF, Maldonado R, Telatnik M, Vlietstra RE, Brenner AS. Inital
experience with reuse of coronary angioplasty catheters in the United
States. J Am Coll Cardiol 1997; 30: 17351740
6. Mak KH, Eisenberg MJ, Eccleston DS, Brown KJ, Ellis SG, Topol EJ.
Cost-efficacy modelling of catheter reuse for percutaneous
transluminal coronary angioplasty. J Am Coll Cardiol 1996; 28: 106
111
7. Ellis SG, Vandormael MG, Cowley MJ, DiSciascio G, Deligonul U, Topol
EJ, et al. Coronary morphologic and clinical determinants of
procedural outcome with angioplasty for multivessel coronary
disease. Implications for patient selection. Circulation 1990; 82:
11931202
8. Garner JS, Favero MS. CDC guideline for handwashing and hospital
environmental control, 1985. Infect Control 1986; 7: 231243
9. Mak KH, Eisenberg MJ, Eccleston DS, Cornhill JF, Topol EJ. Reuse of
coronary angioplasty equipment: technical and clinical issues. Am
Heart J 1996; 131: 624630
10. Resnick L, Veren K, Salahuddin SZ, Tondreau S, Markham PD.
Stability and inactivation of HTLV-III/LAV under clinical and
laboratory environments. JAMA 1986; 255: 18871891
11. Woollard K. Reuse of single-use medical devices: who makes the
decision? Medical J Aust 1996; 164: 538
12. Fagih B, Eisenberg MJ. Reuse of angioplasty catheters and risk of
CreutzfeldtJakob disease. Am Heart J 1999; 137: 11731178
13. Aton EA, Murray P, Fraser V, Conaway L, Cain ME. Safety of reusing
cardiac electrophysiology catheters. Am J Cardiol 1994; 74: 1173
1175
14. Grimandi G, Sellal O, Grimandi F, Crochet D. Risks of reusing coronary
angioplasty catheters: results of an experimental study. Cathet
Cardiovasc Diagn 1996; 38: 123130
15. Gensini GG. Reuse in angiography, cardiac catheterization, and
pacing: summary and recommendations. Proceedings of
international conference on the reuse of disposable medical devices
in the 1980s. Washington, DC: Institute of Health Policy Analysis,
1984: 139141
16. Jacobson JA, Schwartz CE, Marshall HW, Conti M, Burke JP. Fever,
chills, and hypotension following cadiac catheterization with singleand multiple-use disposable catheters. Cathet Cardiovasc Diagn 1983;
9: 3946
17. Feldman T. Reuse of coronary angioplasty catheters. Cathet Cardiovasc
Diagn 1996; 38: 131132
6/5/01, 12:17 PM
Original Article
Lipid-Lowering Effect of Simvastatin in Patients of

Type 2 Diabetes Mellitus
Harsh Udawat, RK Goyal
Department of Medicine JLN Medical College & AG Hospitals, Ajmer
Background: Dyslipidemia is an important factor in causation of macrovascular disease in type 2 diabetics.

The role of simvastatin in the management of dyslipidemia in patients with type 2 diabetes mellitus is not very
well elucidated, particularly in the context of the recent American Diabetes Association criteria 2001. The
American Diabetes Association suggests that aggressive therapy of diabetic dyslipidemia will reduce the risk of
coronary heart disease in diabetics and that optimal levels are serum low-density lipoprotein cholesterol <2.60
mmol/L (<100mg/dl), high-density lipoprotein cholesterol >1.15 mmol/L (>45 mg/dl) and triglycerides <2.30
mmol/L (<200mg/dl).This study was planned to compare the effect of simvastatin together with behavioral
modification and behavioral modification alone, in age, sex and body mass index matched patients with type 2
diabetes mellitus with dyslipidemia, in reaching the target levels of various lipids as suggested by the American
Diabetes Association criteria 2001.
Methods and Results: An open-label, prospective study was conducted on 80 patients with type 2 diabetes
mellitus, who had fair to moderate glycemic control with a total glycated hemoglobin <10%. The patients in the
control group (n=40) were treated with only behavioral modifications like calorie control and daily walking for
30 minutes, and no lipid-lowering agent was given. The lipid profile was re-evaluated after 6 and 12 weeks. The
patients in the test group (n=40) were advised behavioral modification and given simvastatin. The starting dose
was 10 mg at bed time. After 6 weeks of simvastatin therapy, a lipid profile was done. If the goal of low-density
lipoprotein cholesterol <100 mg/dl and/or triglycerides <200 mg/dl and/or high-density lipoprotein cholesterol
>45 mg/dl was not achieved, the dose of simvastatin was increased to 20 mg at bedtime for another 6 weeks. It
was observed that low-density lipoprotein dyslipidemia was most prevalent. In the control group, a favorable
alteration in lipid levels was brought about but none was statistically significant and the American Diabetes
Association goals were not achieved in any of the patients. In the test group, there was a significant and favorable
alteration in all lipid moieties, and the target levels were achieved in 80% of patients after 12 weeks. There was
no significant alteration in glycemic control and liver functions. Myopathy and epigastric pain were seen in 1
patient in each group.
Conclusions: In our study, behavioral modification alone did not achieve the target levels of various lipids in
diabetic dyslipidemia as per the American Diabetes Association guidelines. Hence, pharmacological therapy
with statins should be resorted to in patients with type 2 diabetes mellitus who carry a high risk of coronary
heart disease. Simvastatin is a safe and efficacious lipid-lowering drug. (Indian Heart J 2001; 53: 172176)
Key Words: Lipids, Statins, Diabetes mellitus
he incidence of macrovascular disease is increased twoto five-fold in diabetics as compared to nondiabetic

patients. This is attributed mainly to diabetic dyslipidemia.1
In type 2 diabetes mellitus, dyslipidemia is usually present
in the form of increased serum triglyceride (TG) levels,
Correspondence: Dr Harsh Udawat, c/o Dr MP Udawat, Debi Niwas,
Topdhara, Ajmer 305001
IHJ-101-01.p65
172
decreased high-density lipoprotein cholesterol (HDL-c)

levels, normal or slightly higher low-density lipoprotein
cholesterol (LDL-c) levels as compared to nondiabetics.2
However, the qualitative abnormalities of LDL-c (denser,
smaller, glycosylated and oxidised particles) increase their
affinity towards the endothelium, making them more
atherogenic. Thus, an elevated level of LDL-c is the primary
6/5/01, 11:23 AM
Indian Heart J 2001; 53: 172176
Udawat et al.
risk and prognostic factor for coronary heart disease (CHD)

in patients with type 2 diabetes mellitus.3 Aggressive lipid
optimizing therapy, particularly for LDL-c, reduces cardiac
morbidity and mortality, as well as total mortality.4
The various statins (lovastatin, pravastatin, simvastatin,
fluvastatin, atorvastatin and cerivastatin) not only lower
the lipid levels but also stabilize vulnerable plaque, restore
endothelial function, and have an antithrombotic,
antiplatelet, anti-inflammatory, and antioxidant action.5
The reduction in LDL-c levels achieved by statins is
approximately 30%60%, a dimension never previously
seen with diet control or any other treatment.6
Simvastatin has been shown to reduce the total serum
cholesterol and LDL-c by a mean of 22%32% and 28%
41%, respectively, and to increase HDL-c by a mean of 8%
13%. 7 The role of simvastatin in the management of
dyslipidemia in patients with type 2 diabetes mellitus is not
very well elucidated, particularly in the context of the recent
American Diabetes Association (ADA) criteria 2001.8
The ADA suggests that aggressive therapy of diabetic
dyslipidemia will reduce the risk of CHD in diabetics in
whom the optimal levels are a serum LDL-c level of <2.60
mmol/L (<100 mg/dl), a HDL-c level of >1.15 mmol/L (>45
mg/dl) and a TG level of <2.30 mmol/L (<200 mg/dl)
(Table 1). The primary therapy should be directed mainly
at lowering LDL-c levels. These recommendations are based
not only on the high incidence of CHD in patients with
diabetes but also on the case fatality rate of diabetics with
CHD. Since a large proportion of diabetic patients die before
they reach the hospital, a preventive strategy based solely
on secondary prevention, would not be able to save a large
number of these patients.
Table 1. Category of CHD risk based on various lipid parameters
in adult type 2 diabetics (ADA, 2001)
Risk
LDL-c
HDL-c
Triglyceride
Optimal
<100
>45
<200
100129
3545
200399
>130
<35
>400
Borderline
Higher
Data are given in mg/dl

LDL-c: low-density lipoprotein cholesterol; HDL-c: high-density lipoprotein
cholesterol
This study was, therefore, planned to compare the effect

of simvastatin and behavioral modification together with
the effect of behavioral modification alone, in age, sex and
body mass index (BMI) matched patients with type 2
diabetes mellitus and dyslipidemia, in reaching target levels
of various lipids as suggested by ADA (2001).
IHJ-101-01.p65
173
Lipid-Lowering Effect of Simvastatin
173
Methods
An open-label, prospective study was carried out on 80
patients with type 2 diabetes mellitus. The criteria for
diagnosis of diabetes mellitus and dyslipidemia were based
on those laid down by ADA (2001).8,9 Patients with type 2
diabetes mellitus with a serum level of LDL-c >100 mg/dl
and/or HDL-c <45 mg/dl and/or TG >200 mg/dl were
recruited for this study.
All patients with type 2 diabetes mellitus had been under
a fair or moderate glycemic control with a total glycated
hemoglobin (HbAl) <10%. Blood pressure was maintained
at less than 140/90 mmHg and controlled with only
calcium channel blockers or ACE inhibitors; thiazide
diuretics and -blockers were avoided and the patients were
not given any lipid-lowering drugs. They were asked to avoid
alcohol, smoking and oral contraceptive pills during the
study. Diabetic patients suffering from hypothyroidism,
renal disease, including diabetic nephropathy, and cirrhosis
of liver were not included in the present study.
A detailed history was taken and a thorough physical
examination, including calculation of anthropometric
measurements, carried out in each patient.10 Total cholesterol,
TG and HDL-c levels were measured enzymatically.11,12 Lowdensity lipoprotein cholesterol values were calculated using
the Friedewald equation.13 Two baseline lipid values
separated by an interval of 2 weeks were taken and their
mean calculated. For those subjects in whom the values
differed more than 30 mg%, a third value was taken after 2
weeks and the average calculated.14 Statistical evaluation
was done by determining the p value which was obtained
after calculating the t value by the student's t test. The
0.05 level was used for statistical evaluation. Data were
expressed as meanstandard deviation. The patients were
asked to avoid various drugs like phenytoin, corticosteroids,
amiodarone, vitamin C, vitamin A, erythromycin, isoniazid,
tetracycline, -blockers, etc. which could affect cholesterol
and TG levels during the estimation.15
Patients in the control group (n=40) were treated with
only behavioral modifications like calorie control and a daily
walk for 30 minutes and no lipid-lowering agent was given.
The lipid profile was re-evaluated after 12 weeks. The
desirable body weight was estimated using a heightweight
nomogram. 10 The diabetic subjects were labeled as
underweight (20% below ideal body weight) or obese (20%
above ideal body weight), and the rest as having an ideal
body weight. The recommended daily caloric intake per kg
body weight was 20 kcal/kg for obese patients, 30 kcal/kg
for patients with an ideal body weight and 40 kcal/kg for
underweight patients. The subjects were asked to avoid a
6/5/01, 11:23 AM
174 Udawat et al. Lipid-Lowering Effect of Simvastatin
Indian Heart J 2001; 53: 172176
high fat diet, such as, butter, ghee, cheese, chocolate, cream,
ice-cream, fried foods, cakes, pastries, etc., and to take only
2 tablespoonfuls of whichever oil (except coconut oil) they
consumed. A diet rich in refined carbohydrates like bread,
cake, honey, sugar, sweets, dried fruits, carbonated
beverages, alcoholic and sweetened drinks was also to be
avoided and they were advised to consume green leafy
vegetables and fruits (except the very sweet and very ripe
ones) in plenty. An individualised diet chart of the estimated
caloric intake was given to each subject.
After assessing the risk of exercise, each subject was
encouraged to take a brisk walk (with good footwear) for
3045 minutes everyday and was advised to eat a snack
after exercising to prevent hypoglycemia. The subjects were
interviewed every week regarding their behavioral
modification, and necessary corrections made wherever
required. A close watch was kept on the glycemic control
by testing the fasting and 2-hour postprandial plasma
glucose levels, and monitoring the antidiabetic treatment
by sulfonylureas (glibenclamide, glipizide, gliclazide),
metformin or both.
Patients in the test group (n=40) were advised behavioral
modification and given simvastatin in an initial dose of 10
mg at bedtime. After 6 weeks of simvastatin therapy, the lipid
profile levels were tested. If the goal of serum levels of LDL-c
<100 mg/dl and/or TG <200 mg/dl and/or HDL-c >45 mg/
dl was not achieved, the dose of simvastatin was increased to
20 mg at bedtime for another 6 weeks. The patients were asked
to report any side-effects at every visit. The creatine
phosphokinase (CPK) level was estimated if the patient had
symptoms of myopathy, and if it was more than 10 times
normal, simvastatin therapy was discontinued. The SGOT
and SGPT levels were estimated initially and after every 6
weeks, and the simvastatin therapy discontinued if there
was a three-fold rise above the normal levels.
Table 2. Various parameters at the baseline of both the

groups
Results
Patients with type 2 diabetes mellitus matched in both the
groups with respect to age, sex, waisthip ratio, BMI,
systemic blood pressure and various biochemical
parameters, particularly the lipid levels (Table 2).
The CHD risk stratification depending on lipid levels in
diabetic patients with dyslipidemia was evaluated. It was
observed that LDL dyslipidemia was most prevalent and the
majority of these patients, i.e. 76 (95%) were at a higher
risk of developing CHD. Most of the patients (60%) with TG
dyslipidemia were in the lower risk category, whereas those
with HDL dyslipidemia (57.5%) were at moderate risk of
developing CHD (Table 3).
IHJ-101-01.p65
174
Variable
Control Group
Test Group
p value
Age (years)
Sex (M:F)
Weight (kg)
Waisthip ratio
Body mass index (kg/m2)
Systolic BP (mmHg)
Diastolic BP (mmHg)
Plasma glucose (F)(mg%)
HbAl (%)
SGOT (IU/ml)
SGPT (IU/ml)
BUN (mg%)
Serum creatinine (mg%)
Serum cholesterol (mg%)
Triglycerides (mg%)
LDL-cholesterol (mg%)
HDL-cholesterol (mg%)
53.6510.83
1:1 (10:10)
63.3012.74
0.900.09
28.814.55
130.208.35
82.56.45
148.206.40
8.950.87
22.6012.20
24.815.20
29.482.30
1.070.06
242.1236.19
163.4549.55
170.2834.93
39.216.20
52.159.28
1:1 (10:10)
68.309.68
0.940.10
28.583.72
129.567.54
80.24.52
146.547.20
8.800.72
22.106.27
22.156.49
26.823.12
1.000.18
252.8438.22
180.7650.18
177.3640.59
37.964.71
>0.05 (ns)
>0.05 (ns)
>0.05 (ns)
>0.05 (ns)
>0.05 (ns)
>0.05 (ns)
>0.05 (ns)
>0.05 (ns)
>0.05 (ns)
>0.05 (ns)
>0.05 (ns)
>0.05 (ns)
>0.05 (ns)
>0.05 (ns)
>0.05 (ns)
>0.05 (ns)
HbAl: total glycated hemoglobin; BUN: blood urea nitrogen; LDL: low-density
lipoprotein; HDL: high-density lipoprotein; ns: not statistically significant; SGOT:
serum glutamic oxaloacetic transaminases; SGPT: serum glutamic pyruvic
transaminases
Table 3. Baseline lipid levels in patients with diabetic

dyslipidemia and their stratification based on CHD risk
Test Group
(n=40)
Control Group
(n=40)
Total
(n=80)
66.5257.1
163.4549.55
24(60%)
16 (40%)
0 (0%)
100.0311.00
180.7650.18
24 (60%)
16 (40%)
0 (0%)
48 (60%)
32 (40%)
0 (0%)
109.1279.2
170.2834.93
0 (0%)
2 (5%)
38 (95%)
129.2249.8
177.3640.59
0 (0%)
2 (5%)
38 (95%)
0 (0%)
4 (5%)
76 (95%)
3054.4
39.216.20
6 (15%)
22 (55%)
12 (30%)
31.647.7
37.964.71
2 (5%)
24 (60%)
14 (35%)
8 (10%)
46 (57.5%)
26 (32.5%)
SERUM TG
Range (mg/dl)
MeanSD (mg/dl)
Lower risk n (%)
Moderate risk n (%)
Higher risk n (%)
SERUM LDL-c
Range (mg/dl)
MeanSD (mg/dl)
Lower risk n (%)
Moderate risk n (%)
Higher risk n (%)
SERUM HDL-c
Range (mg/dl)
MeanSD (mg/dl)
Lower risk n (%)
Moderate risk n (%)
Higher risk n (%)
TG: triglycerides; LDL-c: low-density lipoprotein cholesterol; HDL-c: high-density

lipoprotein cholesterol
In the control group (n=40), after 12 weeks of only

behavioral modification, the weight reduced by 2.1 kg and
3.5 kg after 6 and 12 weeks, respectively. There were
favorable alterations in the lipid levels but none were
statistically significant, and the ADA goals were not
6/5/01, 11:23 AM
Indian Heart J 2001; 53: 172176
Udawat et al.
achieved in any of the patients (Table 4). In the test group,

after simvastatin therapy (10 mg per day at bedtime for 6
weeks) along with behavioral modification, the weight
reduced by 1.06 kg and 2.15 kg after 6 and 12 weeks,
respectively. A significant and favorable alteration in all lipid
moieties was achieved; but the target levels were achieved
in only 30% (n=12) of the patients. The remaining 70%
(n=28), received a higher dose of simvastatin (20 mg per
day at bedtime) in continuation for another 6 weeks. A
significant percentage alteration was obtained in lipid
moieties as compared to baseline levels. However, target
levels were not achieved in 8 patients (20%) even after this
higher dosage (20 mg/day) of simvastatin (Table 5).
After 12 weeks of simvastatin therapy, HbAl decreased
from a mean of 8.800.72 g% to 8.430.74 g% (p>0.05);
thus, there was no significant alteration in glycemic control
after the therapy. Similarly, fasting plasma glucose decreased
from 146.547.20 to 141.826.40 mg/dl. The SGOT and
SGPT levels increased from a mean of 22.16.27 IU/ml to
32.858.33 IU/ml (p<0.001) and 22.856.49 IU/ml to
31.569.18 (p<0.001), respectively after 6 weeks, and
values returned to near normal values of 23.244.82 and
24.205.60 IU/ml, respectively after 12 weeks. Jaundice
or other symptoms of deranged liver functions were not
observed in any patient treated with simvastatin.

Only one patient developed epigastric pain after a dose
of 20 mg/day of simvastatin but a dose of 10 mg/day was
well tolerated. In one patient, who developed bilateral
proximal upper limb weakness with CPK values of 1200
IU, simvastatin therapy was discontinued and the CPK
values returned to normal with complete recovery of paresis
within 10 days. Other side-effects like constipation,
flatulence, nausea, dyspepsia, headache, asthenia, sleep
disturbances, fatigue, dizziness, skin rash or myoglobinuria
were not observed in any of the patients.
Lipid-Lowering Effect of Simvastatin
Discussion
The present study revealed that LDL dyslipidemia was the
most prevalent while TG dyslipidemia was the least
prevalent form of dyslipidemia when the ADA (2001)
guidelines for diabetic dyslipidemia and CHD risk were
applied. This is at variance with the common belief that TG
dyslipidemia is the most prevalent in Indian diabetics.
In the present study, the content of the diet prescribed
and exercise chosen was one which is practical for Indian
diabetics, taking into consideration the regional food habits,
life style, and lack of availability of fitness programmes and
Table 4. Effect of behavioral modification alone in diabetic dyslipidemia (Control Group)

Parameters
Baseline
Mean SD
After 6 weeks (n=40)

Mean SD
Change(%)*

Mean SD
Change (%)*
Total Cholesterol
242.1236.19
230.2232.40
4.9
218.3037.20
9.8
Triglyceride
163.4549.55
140.2046.54
14.2
144.9045.30
18.5
LDL-cholesterol
170.2834.93
151.8232.45
10.8
148.8234.90
12.6
HDL-cholesterol
39.216.20
41.485.55
+5.7
42.104.96
+7.37
61.2012.74
61.2010.26
3.37
59.8010.10
5.3
Weight (kg)
The values of lipids are given in mg/dl

*Changes from baseline were not clinically significant (p>0.05)
Table 5. Effect of simvastatin therapy plus behavioral modification in diabetic dyslipidemia (Test Group)
Parameters
Baseline
Mean SD

Mean SD
Change(%)*

Mean SD
Change (%)*
Total Cholesterol
252.8438.22
188.7529.19
25.84
178.7523.97
29.30
Triglyceride
180.7650.18
146.8632.42
18.75
136.6930.03
24.30
LDL-cholesterol
177.3640.59
117.2629.41
33.80
107.2522.80
39.25
HDL-cholesterol
37.964.71
44.995.75
+18.50
45.464.19
+19.80
Weight (kg)
68.309.68
67.248.32
1.55
66.157.28
2.70
The values of lipids are given in mg/dl

* Simvastatin therapy in dosage of 10 mg/day for the initial 6 weeks
* Simvastatin therapy in dosage of 20 mg/day for the next 6 weeks in 28 patients who did not achieve target levels with 10 mg/day
All changes from baseline were clinically significant (p<0.001) except for the change in weight (p>0.05)
IHJ-101-01.p65
175
175
6/5/01, 11:23 AM
176 Udawat et al. Lipid-Lowering Effect of Simvastatin
Indian Heart J 2001; 53: 172176
equipment to calculate a patients oxygen uptake.

Behavioral modification alone did not achieve the target
levels for lipids. However, TG levels were lowered by 18.5%,
similar to the levels obtained by a simvastatin therapy of
10 mg for 6 weeks. Regular exercise has been shown to be
consistently effective in lowering TG levels.7 Low-density
lipoprotein was lowered by only 12.6%, a finding that
implies that even with strict dietary control and rigorous
exercise, which may not be possible for diabetics, LDL-c is
lowered only by 1525 mg/dl.16 The HDL-c was increased
by 7.37%, a finding similar to the ADA's observation that
most studies have failed to demonstrate a significant
improvement in HDL-c levels.
Simvastatin (1020 mg per day) along with behavioral
modification significantly reduced the levels of total
cholesterol (29.3%), LDL-c (41.2%) and TG (24.3%), and
increased the levels of HDL-c (19.80%) with target levels
being achieved in 80% of patients with type 2 diabetes.
Simvastatin did not affect glycemic control in diabetics,
as asessed by fasting plasma glucose and HbAl, like most of
the other studies except that of Daubresse et al. (1994).17
Furthermore, it was well-tolerated by most patients except
for one who developed myopathy and another who
developed gastrointestinal intolerance with a dose of 20 mg
but tolerated 10 mg well. The incidence of myopathy is
<0.2% and gastrointestinal intolerance about 2% in
various studies.18,19 Thus, simvastatin is an effective lipidlowering drug in achieving the goal for lipids, especially
LDL-c, as compared to behavioral modification alone in
patients with type 2 diabetes mellitus with dyslipidemia. It
has no adverse effect on glycemic control.
In the present study, it was found that in diabetic
dyslipidemia, behavioral modification alone does not
achieve lipid levels low enough to reach the target levels as
per the ADA guidelines. Hence, pharmacological therapy
with statins should be resorted to in patients with type 2
diabetes mellitus who carry a high risk of CHD.
The limitations of the present study include a short-term
follow-up and a small number of subjects. Also, there was
no diet and exercise run-in period of 4 weeks prior to
starting simvastatin. The absence of the above-mentioned
run-in period could affect the comparison of lipid levels
lowered by behavioral modification versus simvastatin; but
it does not affect the comparison between the effect of
behavioral modification alone and in conjunction with
simvastatin in achieving the target levels for lipids as per
the ADA (2001).
Since the dysmetabolic syndrome with its serious effects
on mortality and morbidity through macrovascular disease
is prevalent in Indians, aggressive lowering of lipid levels
should be tried. However, long-term randomized follow-up

studies are required to evaluate the efficacy of simvastatin
or other lipid-lowering drugs in Indians with type 2 diabetes
with dyslipidemia.
IHJ-101-01.p65
176
References
1. Stamler J, Vaccaro O, Neaton JD, Wentworth D. Diabetes, other risk
factors, and 12 year cardiovascular mortality for men screened in
the Multiple Risk Factor Intervention trial. Diabetes Care 1993; 16:
434444
2. Barret-Connor, Grundy SM, Holdbrook MJ. Plasma lipids and diabetes
mellitus in an adult community. Am J Epidemiol 1982; 115: 657663
3. Taskinen MR. Quantitative and qualitative lipoprotein abnormalities
in diabetes mellitus. Diabetes 1992; 41 Suppl 2: 1217
4. Pyorala K, Pedersen TR, Kjekshus J, Faergeman D, Olsson AG,
Thorgeirsson G. Cholesterol lowering with simvastatin improves
prognosis of diabetic patients with coronary heart disease. A
subgroup analysis of the Scandinavian Simvastatin Survival Study
(4S). Diabetes Care 1997; 20: 614620
5. Andrews TC, Raby K, Barry J, Naimi CL, Allred E, Ganz P, et al. Effect
of cholesterol reduction on myocardial ischemia in patients with
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6. Oliver MF. Statins prevent coronary heart disease. Lancet 1995; 346:
13781379
7. Haffner SM. Management of dyslipidemia in adults with diabetes.
Diabetes Care 1998; 21: 160178
8. American Diabetes Association. Management of dyslipidemia in
adults with diabetes (Position Statement). Diabetes Care 2001; 24:
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9. Report of the Expert Committee on the diagnosis and classification
of diabetes mellitus. Diabetes Care 1997; 20: 11831197
10. Thomas AE, McKay DA, Cutlip MB. A nomograph method for
assessing body weight. Am J Clin Nutr 1976; 29: 302304
11. Fossati P, Prencipe L. Serum triglycerides determined colorimetrically
with an enzyme that produces hydrogen peroxide. Clin Chem 1982;
28: 2077
12. Grove TH. Effect of reagent pH on determination of high-density
lipoprotein cholesterol by precipitation with sodium
phosphotungstate-magnesium. Clin Chem 1979; 25: 560564
13. Friedewald WT, Levy RI, Fredrickson DS. Estimation of the
concentration of low-density lipoprotein cholesterol in plasma,
without use of the preparative ultracentrifuge. Clin Chem 1972; 18:
499502
14. Farmer JA, Gotto AN. Dyslipidemia and other risk factors for coronary
artery disease. In: Braunwald's Heart Disease. A text book of
cardiovascular disease. 5th ed. Braunwald E (ed). WB Saunders and
Company 1997; p. 11261160
15. Wallach J. Effect of drugs on laboratory test values. In: Interpretation of
Diagnostic tests. 6th ed. Little, Brown and Company 1996: p. 867899
16. Grundy SM, Balady GJ, Criqui MH, Fletcher G, Greenland P, Hiratzka
LF, et al. When to start cholesterol-lowering therapy in patients with
coronary heart disease. Circulation 1997; 95: 16831685
17. Daubresse JC, Machowski R, Pulinx E. Efficacy of simvastatin for
lowering cholesterol in noninsulin dependent diabetic patients with
hypercholesterolemia. Acta Clinica Belg 1994; 49: 6875
18. Bradfold RH, Shear CL, Chremos AN, Dujovne C, Downton M,
Franklin FA, et al. Expanded Clinical Evaluation of Lovastatin (EXCEL)
study results. I. Efficacy in modifying plasma lipoproteins and adverse
event profile in 8245 patients with moderate hypercholesterolemia.
Arch Intern Med 1991; 151: 4349
19. Mitchel YB. The long-term tolerability profile of lovastatin and
simvastatin. Atherosclerosis 1992; 97: S33S39
6/5/01, 11:23 AM
Original Article
Relationship of Xba1 and EcoR1 Polymorphisms of

Apolipoprotein-B Gene to Dyslipidemia and Obesity in
Asian Indians in North India
A Misra, S Nishanth, ST Pasha, RM Pandey, P Sethi, DS Rawat
Department of Medicine and Biostatistics, All India Institute of Medical Sciences, New Delhi and
Division of Biochemistry and Biotechnology, National Institute of Communicable Diseases, New Delhi
Background: Genetic investigation of dyslipidemia and obesity prevalent in the Indian population form the
basis of this study.
Methods and Results: The frequency of restriction fragment length polymorphisms (Xba1 and EcoR1) of the
apolipoprotein-B gene was investigated in a casecontrol study of 30 hyperlipidemic and 40 normolipidemic
subjects. By univariate analysis, old age, higher body mass index, waisthip ratio and sum of four skinfolds were
found to be significantly associated with hyperlipidemia. The frequencies of X- and E+ alleles of the apolipoproteinB gene were significantly higher in North Indians in the state of New Delhi (0.83 and 0.91, respectively) as
compared to the observations made in Caucasians in previous studies, but was similar to the frequency reported
in Indians settled in Singapore and the UK. There were no significant differences in the allele or genotype
frequencies of either Xba1 or EcoR1 polymorphisms between the hyperlipidemic and normolipidemic groups.
On multiple logistic regression analysis considering body mass index, waisthip ratio, percentage body fat and
genotypes as independent variables, no association was observed between the apolipoprotein-B genotypes and
serum lipid components. Further, there were no associations between apolipoprotein-B polymorphisms and
generalized obesity (as assessed by body mass index, sum of four skinfolds, and percentage total body fat) and
abdominal obesity (as measured by waist circumference and waisthip ratio).
Conclusions: We conclude that apolipoprotein-B (Xba1 and EcoR1) polymorphisms do not appear to influence
serum lipid levels and parameters of generalized and regional obesity in the study sample. (Indian Heart J
2001; 53: 177183)
Key Words: Genetics, Obesity, Hyperlipoprotenemia
polipoprotein-B (apo-B) is involved in the assembly and

secretion of chylomicrons from the small intestine and
very low-density lipoprotein cholesterol (VLDL-c) from the
liver.1 Apolipoprotein-B 100, virtually the only protein
component of low-density lipoprotein cholesterol (LDL-c),
functions as a ligand for the LDL-receptor and mediates the
cellular uptake of cholesterol.2 Variants of the apo-B gene
may, therefore, be involved in the pathogenesis of
atherosclerosis. The apo-B gene is located on the short arm
of chromosome 2 (2p23-24).3 Several restriction fragment
length polymorphisms (RFLPs) of the apo-B gene have been
described, including Xba1,4 Ecor1,5 and insertion/deletion
(ins/del) polymorphism of the signal peptide region.6
Correspondence: Dr Anoop Misra, Professor of Medicine, All India
Institute of Medical Sciences, New Delhi 110029,
e-mail: anoopmisra@hotmail.com
IHJ-870-00.p65
177
Epidemiological studies have shown an association

between the apo-B gene polymorphisms and an increase in
various lipoprotein subfractions (total cholesterol [TC],
LDL-c and triglycerides [TG]) and atherosclerosis,719 though
most of these studies have been carried out on Caucasian
subjects. Further, a few studies have also shown a good
correlation between apo-B polymorphisms and generalized
and regional obesity.13,15,17
Asian Indians are prone to develop dyslipidemia and
accelerated atherosclerosis.2024 Genetic investigations of
the Asian Indian populations settled in other countries show
a correlation of apo-B gene polymorphisms with
hyperlipidemia.15,17 The subjects recruited in these studies,
however, were either Indians from the southern states of
India (primarily Tamil Nadu), 17 or from the state of
Punjab.15 No study has been carried out on the Asian
6/5/01, 12:11 PM
178 Misra et al.
population in north India, which may be genetically

different. Environmental and dietary influence, which are
important for the development of a phenotypic profile, may
also be distinctive in this population. Moreover, the
correlation of general and regional obesity with apo-B gene
polymorphisms has never been done on the population of
north India.
We have, therefore, attempted to correlate apo-B gene
polymorphisms (Xba1 and EcoR1) with the lipid profile and
body composition, particularly the percentage body fat
(%BF) of hyperlipidemic and normolipidemic subjects in a
tertiary medical care hospital in north India.
Methods
The study was carried out at the All India Institute of
Medical Sciences, New Delhi, which draws patients from
the northern, central and north-eastern regions of India.
Particular care was taken to select patients residing in the
city or its suburbs. The study was carried out from
September 1997 to March 1999. One hundred consecutive
patients (age range: 2060 years), attending the medicine
outpatient department and lipid research clinic, and healthy
volunteers (recruited by a local advertisement) were
screened for the study. Of these, 74 non-diabetic subjects
were categorized into Group I (entry criteria:
hyperlipidemicsTC >240 mg/dl and/or TG >250 mg/dl)
and Group II (entry criteria: normolipidemicsboth TC and
TG <200 mg/dl). Patients with secondary hyperlipidemia
(e.g. diabetes mellitus, hypothyroidism), definitive familial
hyperlipidemia (e.g. familial hypercholesterolemia), and
those with overt coronary heart disease (CHD) were
excluded from the study. The study population constituted
30 in Group I and 40 in Group II.
Anthropometric measurements: The body mass index
(BMI) was calculated using the formula, BMI=weight/
height2. Weight was measured to the nearest kilogram and
height to the nearest centimeter. Waist circumference was
measured midway between the iliac crest and the lowermost
margin of the ribs and the hip circumference at the
maximum circumference of the buttocks; all measurements
were taken with the subject standing with feet placed
together. A mean of three readings was taken for the
calculation of waisthip ratio (WHR). Biceps, triceps,
subscapular and suprailiac skinfolds were measured using
Lange skinfold calipers. For the biceps skinfold, with the
right arm pendulant, the biceps fat pad was measured at
the level of the nipple line and for the triceps skinfold, the
fat pad was measured midway between the acromion
process of the scapula and the olecranon process. Fat pads
IHJ-870-00.p65
Indian Heart J 2001; 53: 177183
Apolipoprotein-B Gene Polymorphisms in North Indians
178
at the inferior angle of the scapula, and superiorly on the

iliac crest directly in the mid-axillary line were measured
for the subscapular and suprailiac skinfolds. All skinfolds
were measured to the nearest millimeter. A mean of three
readings was recorded at each site. The equation of Durnin
and Womersely was used for the calculation of body fat (BF)
from skinfold thickness.25
Metabolic measurements: All subjects underwent a 75 g
oral glucose tolerance test performed according to standard
WHO guidelines.26 Blood for lipid analysis was collected after
a 12-hour overnight fast. Total cholesterol was estimated
using the ferric chloride method.27 The method described
by Gottfried and Rosenberg28 was used for the determination
of TG. After precipitation of VLDL-c and LDL-c from the
serum by phosphotungstic acid and magnesium chloride,
high-density lipoprotein-cholesterol (HDL-c) was measured
from the supernatant using the method described for TC.
The value of LDL-c was calculated using the Freidwald's
formula,29 LDL-c=TC (HDL-c + TG/5).
DNA analysis: A modification of the procedure employed
by Renges et al.15 was used. A venous blood sample of 2 ml
was collected in an EDTA vial for genetic analysis. Genomic
DNA was isolated using a QIA Amp Blood kit (QIAGEN,
Germany) by following the standard protocol. The
polymorphism detected by Xba1 is due to a neutral
substitution at codon 2488 (Thr2488) of the apo-B gene and
that detected with EcoR1 is due to glutamate/lysine
substitution at codon 4154 (Glu/Lys4154). The genotypes at
Xba1 and EcoR1 polymorphic sites of the apo-B gene were
determined by polymerase chain reaction using restriction
site-specific primers, synthesized on the ABI 392 DNA/RNA
Synthesizer (Perkin-Elmer, Connecticut, USA). The
following primers were used:
For Xba1 site
Forward primer (F) 5' GGA GAC TAT TCA GAA GCT AA 3'
Reverse primer (R) 5' GGA GAG CCT GAA GAC TGA CT 3'
For EcoR1 site

Forward primer (F) 5' CTG AGA GAA GTG TCT TCG AAG 3'
Reverse primer (R) 5' CTC GAA AGG AAG TGT AAT CAC 3'
For PCR, the Gene Amp PCR reagent kit (Perkin-Elmer,

Connecticut, USA) was used and the reaction set up
according to the manufacturers protocol for a final volume
of 50 L. The reaction contents were mixed thoroughly,
centrifuged briefly and placed on a Gene Amp PCR System
2400 (Perkin-Elmer, Connecticut, USA) using a thermal
profile of 94C for 5 s (denaturation), 58C for 10 s
(annealing) and 72C for 30 s (extension) for 50 cycles.
6/5/01, 12:11 PM
Indian Heart J 2001; 53: 177183
Misra et al. Apolipoprotein-B Gene Polymorphisms in North Indians
Overnight restriction enzyme (RE) digestion of the PCR

products was done separately at room temperature with
10 U of Xba1 and 20 U of EcoR1 for a 20 L reaction
volume. Electrophoresis of the reaction mixture of RE
digestion was done on 1.2% agarose gel in a TBE buffer at a
constant voltage of 100 V for 45 minutes. The DNA bands
thus separated on agarose gel were visualized under an
ultraviolet transilluminator (Biometra, GmbH, Germany).
For the Xba1 site, a 710 bp fragment was amplified, which
was digested with Xba1 into two fragments of 433 bp and
277 bp in the presence of the cutting site (X+ allele). For
the EcoR1 site, a fragment of 480 bp was amplified, which
was digested with EcoR1 into two fragments of 253 bp and
227 bp in the presence of the cutting site (E+).
Statistical analysis: The data were recorded on a predesigned proforma and managed with Excel software. Data
entry was double-checked for any human error. The allele
frequencies of DNA polymorphism of the apo-B gene were
estimated by gene counting. After confirming the normality
aspect of the quantitative variable, descriptive statistics were
computed using mean and standard deviation (SD).
Proportions summarized qualitative variables. As age was
statistically different among hyperlipidemics and
normolipidemics, analysis of covariance (ANCOVA) was
applied to compare the meanSD of anthropometric
measurement, adjusting for age. The Students t test was
used to compare the mean values of quantitative
parameters among hyperlipidemic and normolipidemic
groups. Association between hyperlipidemia and other
categorical variables was assessed by the Chi-square test.
At the next stage of analysis, the associations were
quantified by unadjusted odds ratio (OR) and 95%
confidence interval (CI). Stepwise binary logistic regression
analysis was applied to determine a parsimonious model
from candidate variables indentified in the second stage. The
criteria used to decide the candidate variables to be included
in the stepwise multivariate logistic regression analysis were
based on statistical and clinical significance as follows: (i)
all variables showing a statistically significant association
with hyperlipidemia at p<0.2 (age, BMI, WHR and %BF);
and (ii) Xba1 and EcoR1 genotype, though statistically not
significant, were included in the model due to their clinical
importance. Further, hyperlipidemic and normolipidemic
groups were divided according to Xba1 and EcoR1
genotypes. The mean values of BMI, WHR and %BF in the
different genotypes were calculated and compared using the
Student's t test. Any association having p<0.05 was
considered statistically significant. Statistical analysis was
done using the Intercooled STATA version 6.0 (STATA Corp,
Houston, Texas, USA) software package.
IHJ-870-00.p65
179
179
Results
We studied a total of 70 subjects of which 30 (25 males
and 5 females) had hyperlipidemia (Group 1) and 40 (34
males and 6 females) were normolipidemic (Group 2).
Group 1 consisted of 11 (37%) and 13 (43%) subjects
having hypercholesterolemia and hypertriglyceridemia
alone, and 6 subjects (20%) with both raised TC and TG.
While subjects in both the groups were young, the subjects
in Group 1 were significantly older than the subjects in
Group 2 (37 years v. 30.6 years, p<0.009). The mean BMI
in subjects in Group 1 was significantly higher than that in
Group 2 subjects (Table 1). Subjects with a BMI >25 had 5
times higher odds of being hyperlipidemic than subjects
with a BMI <25 (OR 5.35; 95% CI: 1.6417.47).
Abdominal obesity, as defined by WHR, was present in 23
subjects in Group 1 (83%) as compared to 12 subjects in
Group 2 (34%) (p<0.001). Subjects in Group 1 had a higher
mean WHR as compared to Group 2 subjects (Table 1).
The odds of being hyperlipidemic were 7 times higher for a
subject with abdominal obesity (OR 7.12; 95% CI: 2.4
21.13). Sum of the skinfold thickness at four sites (triceps,
biceps, subscapular and suprailiac), termed as total skinfold
thickness (TSFT) and mean %BF, as calculated from TSFT,
were significantly higher in subjects in Group 1 as compared
to Group 2 (Table 1). Subjects with %BF more than 20%
had nearly 3 times higher odds for being hyperlipidemic as
compared to those with lower body fat (OR 2.96; 95% CI:
1.038.53).
Table 1. Demographic and anthropometric profile
Variables
Age (years)
Sex (M:F)
BMI (kg/m2)
WHR
TSFT (mm)
%BF
Hyperlipidemic
subjects
MeanSD
(n=30)
Normolipidemic
subjects
MeanSD
(n=40)
37 (11.5)
25:5
24.92 (3.7)
0.93 (0.07)
75.2 (25.05)
25.85 (6.9)
30.6 (8.5)
34:6
20.8 (3.27)
0.875 (0.06)
52.51 (26.98)
20.65 (8.14)
p value
<0.01
ns
<0.001
<0.01
<0.001
<0.01
BMI: body mass index; WHR: waisthip ratio; TSFT: sum of four skinfolds; %BF:
percentage body fat; ns: statistically not significant
Xba1 polymorphism was analyzed in 29 and 39 subjects

in Groups 1 and 2, respectively; details are given in Table 2.
The difference in genotype frequencies was not statistically
significant in the two groups. The odds of a person with X2
genotype (X+X or X+X+) being hyperlipidemic was 0.58
(95% CI: 0.211.6) as compared to a person with X1
genotype (X X). EcoR1 polymorphisms, analyzed in 28
subjects in Group 1 and 40 subject in Group 2 are given in
Table 2.
6/5/01, 12:11 PM
180 Misra et al.
There was no statistically significant difference between

EcoR1 genotype frequencies of the two groups. The odds of
an E2 genotype being hyperlipidemic was 0.81 (95% CI:
0.222.98) as compared to the E1 genotype. The frequency
of the more common alleles of each polymorphism (X
allele in case of Xba1 and E+ allele in case of EcoR1) was
calculated by gene counting. The frequencies of X and E+
in all the subjects were 0.79 and 0.92, respectively. The
corresponding values in subjects in Group 1 were 0.81 and
0.91 and in subjects in Group 2 were 0.78 and 0.92. There
was no difference in allele frequencies between subjects in
the two groups (Table 2).
Table 2. Allele frequencies and genotypes in the hyperlipidemic
and normolipidemic subjects
Variables
Allele frequency
X
E+
Xba1 genotype*
XX (%)
X+X (%)
X+X+ (%)
EcoR1 genotype** E+E (%)
E+E+ (%)
Hyperlipidemic
subjects
(n=30)
Normolipidemic
subjects
(n=40)
0.81
0.91
20 (69)
7 (24)
2 (7)
5 (18)
23 (82)
0.78
0.92
22 (56)
17 (43)
0
6 (15)
34 (85)
* Analyzed in 29 hyperlipidemic and 39 normolipidemic subjects

** Analyzed in 28 hyperlipidemic and all normolipidemic subjects
Stepwise logistic regression analysis yielded BMI and

WHR as the two significant predictors of hyperlipidemia.
After adjusting for other covariates, it was found that obese
individuals (BMI>25) had 7 times higher odds of being
hyperlipidemic than nonobese individuals (adjusted OR
7.39; 95% CI:1.4936.69). Subjects with abdominal
obesity (WHR>0.9) were 12 times more likely to be
hyperlipidemic than those without abdominal obesity
(adjusted OR 12.82; 95% CI: 2.9954.98) (Table 3).
Out of a total of 29 subjects in Group 1 in whom Xba1
polymorphism results were available, 20 had X1 genotype
and 9 had X2 genotype (X+X=7, X+X+=2). There was
no statistically significant difference in the body
composition of these two subgroups as measured by BMI
(25.2 v. 24.6), WHR (0.92 v. 0.95) or %BF (26.23 v.
25.67). EcoR1 analysis of 28 subjects in Group 1 was
carried out. Of these, 5 had E1 genotype and 23 had E2
genotype. There was no statistically significant difference
in BMI (26.3 v. 24.7), WHR (0.94 v. 0.92) or %BF (27.20
v. 25.63) between these two subgroups.
In Group 2, Xba1 results were available in 39 subjects.
Twenty-two subjects had X1 genotype and 17 had X2. Body
composition did not differ between the two groups as
measured by BMI (20.93 v. 20.21), WHR (0.86 v. 0.88)
IHJ-870-00.p65
Indian Heart J 2001; 53: 177183
180
Table 3. Unadjusted and adjusted OR (95% CI) for various

parameters using univariate and multivariate stepwise binary
logistic regression
Variables Hyperlipidemic Normolipidemic Unadjusted OR
subjects
subjects
(95% CI)
Age (years)
30
>30
BMI (kg/m2)
25
>25
WHR
0.9
>0.9
TSFT (mm)*
50
>50
%BF*
20
>20
Xba1*
X1
X2
EcoR1
E1
E2
Adjusted OR
(95% CI)
10
20
24
16
1.0
3 (1.128.06)
17
13
35
5
1.0
1.0
5.35 (1.6417.47) 7.39 (1.4936.69)
7
23
28
12
1.0
1.0
7.12 (2.421.13) 12.82 (2.9954.98)
6
24
18
21
1.0
3.43 (1.1510.24)
7
23
18
21
1.0
2.96 (1.038.53)
20
9
22
17
1.72 (0.624.76)
1.0
1.56 (0.475.26)
1.0
5
23
6
34
1.23 (0.334.54)
1.0
2.94 (0.4620)
1.0
BMI: body mass index; WHR: waisthip ratio; TSFT: sum of four skinfolds; %BF:
percentage body fat; X1: XX; X2: X+X or X+X+; E1: E+E; E2: E+E+
*Observation incomplete in one subject.
or %BF (21.23 v. 19.53). Six subjects in Group 2 had E1

genotype and 34 had E2 genotype. There was no statistically
significant difference in BMI (20.10 v. 20.90), WHR (0.86
v. 0.88) or % BF (18.3 v. 21.08) between E1 and E2 groups
in subjects in Group 2.
Discussion
Allele frequency of Apo-B gene polymorphisms (Table 4):
The overall allele frequencies, and those of hyperlipidemic
and normolipidemic subjects in the present study were
similar to those in studies carried out on Indians settled in
other countries. Saha et al.17 recorded a frequency of 0.83
for the X allele of Xba1 polymorphism and 0.9 for the E+
allele of EcoR1 polymorphism in their studies on Indians
Table 4. Relative allelic frequencies of X and E+ alleles in
different ethnic groups
Ethnic groups
Native North Indians
70
0.79
p value
E+
Caucasians (Norway)
56
0.48
<0.001
Caucasians (Sweden)
91
0.44
<0.001 0.81
Asian Indians (UK)
107
0.71
Chinese (Singapore)
221
0.91
Asian Indians (Singapore) 181
0.83
Caucasians (UK)
62
0.50
Sri Lankans
190
0.80
p value
0.92
$
Reference
Present study
Berg et al.7
<0.01 Peacock et al.12
0.89
ns
Renges et al.15
<0.001 0.92
ns
Saha et al.16
ns
ns
0.90
<0.001 0.82
ns
ns
Saha et al.17
<0.01
Talmud et al.18
Mendis et al.30
$: not done; *not available; p value: significance of difference from present study; ns: statistically
not significant from present study
6/5/01, 12:12 PM
Indian Heart J 2001; 53: 177183
settled in Singapore.17 According to Renges et al.,15 a

frequency of 0.71 and 0.89, respectively, was observed in a
South Asian population consisting predominantly of people
from the state of Punjab. The allele frequencies in our study
were also similar to those reported in a population of Sri
Lankans. 30 In the Chinese population, however, the
frequency of X allele was higher but that of E+ allele was
similar to that of our study group.16 A distinct difference is
observed when the allele frequencies in the Caucasian
population (largely European) are compared to those in
Asian populations. Several of these studies reveal that
frequencies of X and E+ were lower in Caucasian
subjects.7,12,18 However, besides ethnic and geographic
differences, age and sex distribution, and the composition
of the population studied by various authors are different.
Saha et al.17 studied a population comparable to the present
study in the age group of 1770 years, with a female
preponderance. Of significance were the allele frequencies
reported by Saha et al.17 and Berg et al.7 from a sample of
the general population while other investigators12,15,30
excluded CHD patients. The frequency reported by Talmud
et al.18 was of normolipidemic individuals.
Association of Apo-B gene and hyperlipidemia:
Table 5 shows that there was no significant difference
in the genotype and allele frequencies of Xba1 and
EcoR1 polymorphisms between hyperlipidemic and
Table 5. Apolipoprotein-B genelipid association studies
Population
Caucasians
(Norway)
Caucasians
(Italy)
Israelis
Caucasians
(USA)
Caucasians
(Sweden)
Caucasians
(Canada)
Asians Indians
(UK)107**
Chinese
(Singapore)
Asian Indians
(Singapore)
Caucasians
(UK)
Sri Lankans
(Sri Lanka)
Caucasians
(USA)
Native North
Indians
Xba1
EcoR1
References
56**
X+high TC, TG
Berg7
55*
119**
536**
84*
84**
87*
91**
56**
X+high TC
None
Corbo et al.8
X+high TC, LDL-c

None
$
None
Friedlander et al.9
Hegele et al.10
X+high LDL-c
None
Peacock et al.12
R high TC
Pouliot et al.13
46*
X+ low HDL-c
None
Renges et al.15
221**
X+ low HDL-c
None
Saha et al.16
181**
X+ high TC, TG; low

HDL-c
X+ high TC, TG
None
Saha et al.17
None
Talmud et al.18
X+ high HDL-c
Mendis et al.30
None
None
Genest et al.31
None
None
Present study
195**
95*
95**
111*
122**
70 #
*patients with coronary heart disease; **normal healthy population; #: selected

hyperlipidemic and normolipidemic subjects; $: Not done; TC: total serum cholesterol; TG:
serum triglycerides; HDL-c: high-density lipoprotein cholesterol; LDL-c: low-density
lipoprotein cholesterol.
IHJ-870-00.p65
181
181
normolipidemic subjects. The findings are similar to the

observations made in a Caucasian population in USA;10,31
however, the authors used Southern blot to study the genetic
polymorphisms and followed a system for the nomenclature
of alleles different from that used currently. Although the
apo-B gene polymorphism did not have any influence on
the lipid levels, there was an association of X1 and R1 alleles
with CHD. Association of the X+ allele and TC,7,8,18 TG,7,8
and LDL-c12 levels in Caucasian populations has been
demonstrated repeatedly. Similar findings were also
demonstrated in Asian Indians settled in Singapore, where
the X+ allele was significantly associated with higher levels
of serum TC, TG and low HDL-c.17 Renges et al.15 showed
that in Asian Indians in the UK, X+ allele was associated
with a low HDL-c level.
There may be several reasons for the differences observed
in the various studies. A simple explanation could be that
the populations studied by Saha et al.16,17 and Renges et al.15
were genetically distinctive, consisting of Indians from the
southern states of India and from the state of Punjab,
respectively. Moreover, geneenvironment interplay may
also account for the differential data since there may be
substantial differences in the diet and lifestyle of Indians
settled in other countries when compared to the north
Indian population studied by us. Further, the sample size
of the current study being small, a larger study would
answer the questions in a more definitive manner. The RFLP
detected with Xba1 is due to substitution in the third wobble
position of a codon, which does not alter the amino acid
sequence of the apo-B. The effect of the substitution on the
lipid levels is probably due to a linkage disequilibrium with
ins/del polymorphism, which causes an amino acid change
in the signal peptide of the apo-B gene. Many other
researchers, including Saha et al.17 simultaneously studied
ins/del polymorphism and showed the existence of a strong
disequilibrium between it and the Xba1 site polymorphism.
Absence of an association between EcoR1 polymorphism
of apo-B and serum lipid levels is, however, similar to the
observations made by Saha et al.17 and Renges et al.15 The
RFLP detected with EcoR1 is due to a single base pair change
in the coding region of the gene, which is known to cause
an amio acid change in the apo-B by itself. This phenomenon
may explain the general concurrence of our findings with
other workers regarding correlation between EcoR1
polymorphism and serum lipids, while correlation with
Xba1 polymorphism was not observed. Indeed, association
of serum lipid levels with the E allele has been rarely
described, except in a study of Canadian population.13
Association of the apo-B gene and body fat: There was
no association of generalized obesity (as measured by BMI
6/5/01, 12:12 PM
182 Misra et al.
and %BF), and abdominal obesity (as measured by WHR)

with the genetic polymorphisms in the current study. Again,
these findings are in variance with those of other workers
and no firm conclusions can be drawn. Renges et al.15
observed an association of X+X+ genotype with low BMI
and WHR, whereas Saha et al.17 in their study found that
the X+ allele was associated with a higher BMI. Pouliot et
al.13 observed an association between the E allele and lower
body and abdominal fat.
In summary, the frequencies of apo-B gene
polymorphisms, as determined with Xba1 and EcoR1 in a
sample of north Indian subjects studied by us were similar
to those reported by previous authors regarding Asian
Indians settled in other countries but were significantly
different from those reported in the Caucasian population.
There was no evidence of association of apo-B
polymorphisms (Xba1 and EcoR1) with serum lipid levels
or generalized and abdominal obesity. In view of the strong
associations reported in some studies, including those on
immigrant Indians, studies are needed with a larger sample
size to study ins/del polymorphisms and its linkage with
Xba1 polymorphism. In addition, association studies should
be performed for other genetic loci, e.g. apolipoprotein-E,
using gene sequencing.
6.
7.
8.
9.
10.
11.
12.
13.
Acknowledgments
14.
The authors would like to express their appreciation to

Dr Arvind Rai, Deputy Director, Division of Biochemistry
and Biotechnology, National Institute of Communicable
Diseases, New Delhi, for his active supervision and
assistance in the genetic studies, analysis of data and the
writing of the manuscript. The authors also express their
appreciation to the staff of SRB Center of Clinical
Pharmacology including Mr Inder Taneja, Mr Giri, Mr Gian
Chand and Mrs Alice Jacob for performing various
investigations, and to Miss Jyoti for typing and editing the
manuscript.
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3. Carlsson P, Darnfors C, Olofsson SO, Bjursell G. Analysis of human
apolipoprotein B gene; complete structure of the B-74 region. Gene
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4. Priestly L, Knott T, Wallis S, Powell L, Pease R, Brunt H, et al. RFLP for
the human apolipoprotein B gene: V; Xba1. Nucleic Acids Res 1985;
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5. Huang LS, Miller DA, Bruns GA, Breslow JL. Mapping of the human
APOB gene to chromosome 2p and demonstration of a two-allele
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Boerwinkle E, Chan L. A three codon insertion/deletion
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apolipoprotein B (APOB) gene directly typed by the polymerase chain
reaction. Nucleic Acids Res 1989; 17: 4003
Berg K. DNA polymorphism at the apolipoprotein B locus is associated
with lipoprotein level. Clin Genet 1986; 30: 515520
Corbo RM, Vilardo T, Mantuano E, Ruggeri M, Gemma AT, Scacchi R.
Apolipoproteins B and E, and angiotensin I converting enzyme (ACE)
genetic polymorphisms in Italian women with coronary artery
disease and their relationships with plasma lipid and apolipoprotein
levels. Clin Genet 1997; 52: 7782
Friedlander Y, Kaufmann NA, Cedar H, Weinberg N, Kark JD. The role
of Xba1 polymorphism of the apolipoprotein B gene in determining
levels and covariability of lipid and lipoprotein variables in a sample
of Israeli offspring with family history of myocardial infarction.
Atherosclerosis 1993; 98: 165177
Hegele R, Huang L, Herbert PN, Blum CB, Buring JE, Hennekens CH,
et al. Apolipoprotein B-gene polymorphisms associated with
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Nieminen MS, Mattila KJ, Aalto-Setala K, Kuusi T, Kontula K,
Kauppinen-Makelin R, et al. Lipoproteins and their genetic variation
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Peacock R, Dunning A, Hamsten A, Tornvall P, Humphries S, Talmud
P. Apolipoprotein B gene polymorphisms, lipoproteins and coronary
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Pouliot M, Despres J, Dionne FT, Vohl M, Moorjani S, Prudhomme D,
et al. Apo B-100 gene EcoR1 polymorphism. Relations to plasma
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Rajput-Williams J, Knott TJ, Wallis SC, Sweetnam P, Yarnell J, Cox N,
et al. Variation of apolipoprotein-B gene is associated with obesity,
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disease. Lancet 1988; 2: 14421446
Renges HH, Wile DB, McKeigue PM, Marmot MG, Humphries SE.
Apolipoprotein B gene polymorphisms are associated with lipid levels
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Saha N, Tay JS, Humphries SE. Apolipoprotein B gene DNA
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Saha N, Tay JS, Heng CK, Humphries SE. DNA polymorphisms of the
apolipoprotein B gene are associated with obesity and serum lipids in
healthy Indians in Singapore. Clin Genet 1993; 44: 113120
Talmud PJ, Barni N, Kessling AM, Carlsson P, Darnfors C, Bjursell G,
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6/5/01, 12:12 PM
Original Article
The Isoprenoid Pathway in Lone Atrial

Fibrillation with Embolic Stroke
A Ravikumar, PA Kurup
Department of Medicine, Medical College Hospital and
Department of Biochemistry, University of Kerala, Trivandrum
Background: The isoprenoid pathway was assessed and compared in patients of lone atrial fibrillation with
embolic stroke as well as in patients with right hemispheric, left hemispheric and bihemispheric dominance to
determine the role of hemispheric dominance in its pathogenesis.
Methods and Results: The activities of hydroxyl methyl glutaryl-CoA reductase and RBC sodiumpotasium
ATPase as well as serum levels of plasma magnesium, digoxin, dolichol and ubiquinone were measured. The
tyrosine/tryptophan catabolic patterns, glycoconjugate metabolism, free radical metabolism and RBC membrane
composition were also assessed. In patients with lone atrial fibrillation with embolic stroke, there was elevated
digoxin synthesis, increased dolichol and glycoconjugate levels, and low ubiquinone and elevated free radical
levels. There was also an increase in tryptophan catabolites and a reduction in tyrosine catabolites; and an
increase in the cholesterol: phospholipid ratio with a reduction in the glycoconjugate levels of the RBC membrane.
The same biochemical patterns were obtained in individuals with right hemispheric dominance whereas the
patterns were reversed in patients with left hemispheric dominance.
Conclusions: Lone atrial fibrillation with embolic stroke is associated with an upregulated isoprenoid pathway
and elevated digoxin secretion from the hypothalamus. This occurs in right hemisphere-dominant individuals.
(Indian Heart J 2001; 53: 184188)
Key Words: Atrial fibrillation, Ions, Isoprenoid pathway
one atrial fibrillation (AF) is considered to represent the

tachycardia phase of the tachycardia bradycardia
syndrome.1 Specific disease states associated with lone AF
include obstruction of the sinus node artery and infiltration
of the atrial myocardium in amyloidosis. Lone AF is the most
important cause of embolic stroke in the elderly. The
presumed stroke mechanism is thrombus formation in the
fibrillating atrium or atrial appendage and its subsequent
embolization.2 Cardiac toxicity of digoxin includes sinus
arrhythmia, sinus bradycardia and all degrees of
atrioventricular block, while premature ventricular
contraction, ventricular bigeminy, ventricular tachycardia
and ventricular fibrillation can also occur. The combination
of supraventricular tachyarrhythmias is highly suggestive
of digoxin toxicity.3 The human hypothalamus is reported
to produce an endogenous membrane sodiumpotassium
ATPase (Na+K+ ATPase) inhibition digoxin.4 Digoxin, being
a steroidal glycoside, is produced by the isoprenoid pathway,5
Correspondence: Dr PA Kurup, Gouri Sadan, T.C. 4/1525, North of Cliff
House, Kattu Road, Kowdiar, Trivandrum, Kerala
IHJ-909-00.p65
184
and it was, therefore, considered pertinent to study this

pathway and endogenous digoxin synthesis in patients with
lone AF. Hemispheric dominance may play a role in the
predisposition to cardiac arrhythmias. As hypothalamic
digoxin can modulate the synaptic transmission of multiple
neurotransmitter systems, the isoprenoid pathway was also
assessed in individuals with differing hemispheric
dominance to determine the role of hemispheric dominance
in the pathogenesis of lone AF. The results are presented in
this paper.
Methods
Three sets of patient populations were chosen for the study.
1. Fifteen cases of lone AF with embolic strokeleft middle
cerebral artery territory and capsular infarct.
2. Fifteen cases of age- and sex-matched bihemispheredominant controls.
3. Fifteen cases each of right hemisphere, left hemisphere
and bihemisphere-dominant individuals diagnosed by
the dichotic listening test.
6/5/01, 11:27 AM
Indian Heart J 2001; 53: 184188
Ravikumar et al.
The age range of the patients as well as the controls was

5070 years. None of the subjects studied was under
medication at the time their blood was tested and those
included in the study were nonsmokers (active or passive).
Informed consent was obtained from the subjects and the
study was approved by the ethics committee of the institute.
Fasting blood samples were collected in citrate tubes from
each of the patients. Red blood cells (RBC) were separated
within one hour of collection of the blood for the estimation
of membrane Na+K+ ATPase. The plasma was used for the
analysis of various parameters. All the biochemicals used
in this study were obtained from M/s Sigma Chemicals, USA.
The activity of hydroxyl methyl glutaryl-CoA (HMG-CoA)
reductase of the plasma was estimated by the method used
by Rao and Ramakrishnan6 which determines the ratio of
HMG-CoA to mevalonate. For the determination of the RBC
Na+K+ ATPase activity of the erythrocyte membrane, the
procedure described by Wallach and Kamath7 was used.
Digoxin in the plasma was determined by the procedure
described by Arun et al. 8 while for the estimation of
ubiquinone and dolichol in the plasma, the procedures
described by Palmer et al. 9 were used. Magnesium in
the plasma was estimated by atomic absorption
spectrophotometry,10 and tryptophan, tyrosine, serotonin
and catecholamines were estimated by the procedures
mentioned in Methods of Biochemical Analysis. 11 The
quinolinic acid content of the plasma was estimated by
HPLC (C18 column micro Bondapak 4.6150 mm),
solvent system 0.01 M acetate buffer (pH 3.0) and methanol
(6:4), flow rate 1.0 ml/min and detection UV (250 mm).
Morphine, strychnine and nicotine were estimated by the
methods described by Arun et al.12 Details of the procedures
used for the estimation of total and individual
glycosaminoglycan (GAG), carbohydrate components of
glycoproteins, the activity of enzymes involved in the
degradation of GAG and the activity of glycohydrolases have
been described earlier.13 Serum glycolipids were estimated
as given in Methods in Enzymology.7 Superoxide dismutase
(SOD) was assayed by the method used by Nishikimi et al.
and modified by Kakkar et al. 14 Catalase, glutathione
peroxidase and glutathione reductase were estimated by
the procedures described in Methods of Enzymatic Analysis.15
Malondialdehyde (MDA), conjugated dienes and
hydroperoxides and reduced glutathione as well as
membrane cholesterol and phospholipids were estimated
by the procedures given in Methods of Biochemical Analysis.11
Nitric oxide (NO) in the plasma was estimated by the method
used by Gabor and Allon.16 Statistical analysis was done by
the Student's t test.
IHJ-909-00.p65
185
Isoprenoid Pathway in Lone AF with Embolic Stroke
185
Results
The results showed that HMG CoA reductase activity, serum
digoxin and dolichol were higher in patients with lone AF
and embolic stroke, indicating upregulation of the
isoprenoid pathway but serum ubiquinone, RBC membrane
Na+K+ ATPase activity and serum magnesium were lower
compared to the control group (Table 1).
Table 1. Concentration of serum digoxin, dolichol,
magnesium and ubiquinone, and RBC membrane Na+K+
ATPase activity in lone AF with embolic stroke
Groups
HMG-CoA Digoxin Dolichol Ubiqui- Na+K+ Magnesium

reductase/ (ng/dl) (g/dl) none
ATPase (mg/dl)
HMG-CoA
(g/dl) (g/pi/mg
mevalonate
protein)
Control (1) 1.15

(0.12)
Lone AF (2) 0.75
(0.06a)
12.80
(1.09)
24.54
(1.47a)
39.1
(2.36)
69.8
(4.19a)
144.2 5.04
(8.65) (0.22)
81.6
1.04
(8.13a) (0.18a)
2.40
(0.24)
1.16
(0.22a)
Mean of the values from 15 samples SD

Group 2 has been compared with Group1
a
p<0.01
The concentration of tryptophan, quinolonic acid,

serotonin, strychnine and nicotine was found to be higher
in the plasma of patients with lone AF and embolic stroke
while that of tyrosine, dopamine, norepinephrine and
morphine was lower (Table 2).
There was an increase in the concentration of serum
total GAG, individual GAG fraction, glycolipids and
carbohydrate components of glycoproteins in patients with
lone AF and embolic stroke. The carbohydrate
componentstotal hexose, fucose and sialic aciddid not
increase to the same extent in all cases, suggesting a
qualitative change in glycoprotein structure. The activity
of GAG degrading enzymes and that of glycohydrolases
showed a significant increase in the serum of patients with
lone AF and embolic stroke (Table 3).
The cholesterol:phospholipid ratio of the RBC
membrane was higher in patients with lone AF and embolic
stroke. The concentration of total GAG, hexose and fucose
content of glycoprotein decreased in the RBC membrane
and increased in the serum of patients with lone AF and
embolic stroke (Table 3).
There was an increase in lipid peroxidation, as evidenced
by the increase in the concentration of MDA, conjugated
dienes, hydroperoxides and NO, with decreased antioxidant
protection as indicated by a decrease in ubiquinone and
reduced glutathione in patients with lone AF and embolic
stroke. The activity of the enzymes involved in free radical
6/5/01, 11:27 AM
Indian Heart J 2001; 53: 184188
186 Ravikumar et al. Isoprenoid Pathway in Lone AF with Embolic Stroke

Table 2. Tyrosine and tryptophan catabolic patterns in lone AF with embolic stroke
Group
Tryptophan
(mg/dl)
Control(1) 1.110.08
Lone AF(2) 2.950.07a
Tyrosine
(mg/dl)
1.140.09
0.810.07a
5HT
(g/dl)
Dopamine
(ng/dl)
20.91.9 12.890.67
48.93.9a 8.430.44a
Norepinephrine
(ng/dl)
Quinolinic acid
(g/dl)
Morphine
(g/dl)
45.152.35
30.541.78a
370.6021.07
655.7348.8a
ND
ND
Strychnine
(g/dl)
Nicotine
(g/dl)
ND
ND
3.540.37a 4.560.02a

a
p<0.01
Table 3. Concentration of plasma glycoconjugates,

lysosomal enzymes and RBC membrane composition in
lone AF with embolic stroke
Groups
Total glycosaminoglycan
(mg uronic acid/dl plasma)
Hyaluronic acid
Heparan sulphate
Heparin (mg uronic acid/dl plasma)
Dermatan sulphate
Chondroitin sulphate
Hexose (mg/g protein)
Fucose (mg/g protein)
Sialic acid (mg/g protein)
Ganglioside (g/dl)
Glycosyl diglyceride (g/dl)
Cerebrosides (g/dl)
Sulphatides (g/dl)
Beta glucuronidase
(g p-nitrophenol/hr/g protein)
Beta N-acetyl hexosaminidase
(g p-nitrophenol/hr/g protein)
Hyaluronidase
(g N-acetyl glucosamine/hr/g protein)
Cathepsin_D (g tyrosine/hr/g protein)
Beta galactosidase
(g of p-nitrophenol/hr/mg protein)
Beta fucosidase
Beta glucosidase
Glycosaminoglycan (g/mg protein)
Hexose (g/mg protein)
Fucose (g/mg protein)
Cholesterol (nmol/mg protein)
Phospholipid (nmol/mg protein)
Cholesterol:Phospholipid
Control (1)
Lone AF (2)
4.570.41
10.380.73a
0.530.41
1.72 0.11a
0.320.02
2.100.11a
0.280.02
2.830.23
1.700.04a
3.920.23a
0.590.04
3.960.15
13.551.26
1.650.15
6.850.62
26.51.2
12.50.72
16.251.10
5.250.61
59.525.26
27.52.48a
2.510.21a
10.270.82a
36.582.1a
20.221.66a
22.521.4a
7.940.63a
114.292.2a
227378.6
322979.5a
62.94.1
2246.8a
90.98.9
52.83.75
316.49.8a
74.253.91a
23.631.65
44.621.32a
27.362.46
43.421.71a
6.620.71
145.0911.85
63.334.60
704.3363.09
727.5767.36
0.970.10
4.030.48
52.654.38a
38.032.37a
824.4733.06b
503.9673.30a
1.640.06a
scavenging, like superoxide dismutase, catalase,

glutathione peroxidase and glutathione reductase, is
decreased in patients with lone AF and embolic stroke,
suggesting reduced free radical scavenging (Table 4).
186
MDA (m/ml RBC)

Hydroperoxide (m/ml RBC)
Conjugated dienes (m/ml RBC)
Nitric oxide (m/g protein)
Gulutathione (g/ml RBC)
Superoxide dismutase (units/mg protein)
Catalase (102 units/mg protein)
GSH peroxide (units/g protein)
GSH reductase (units/g protein)
Control (1)
Lone AF (2)
10.830.43
253.6010.18
49.332.53
2.840.21
256.6010.96
43.141.94
3.490.12
48.101.64
8.370.87
12.630.29a
289.88 8.23a
66.944.81a
3.420.16a
142.2313.99a
32.431.45a
2.120.09a
42.201.32a
6.650.32a
Mean of the values from 15 patients in each group SD

a
p<0.01
The results showed that HMG-CoA reductase activity,

serum digoxin and dolichol were increased and ubiquinone
reduced in left-handed/right hemisphere-dominant
individuals, but the converse was true for right-handed/
left hemisphere-dominant individuals. The concentration
of tryptophan, quinolinic acid, serotonin, strychnine and
nicotine was found to be higher in the plasma of lefthanded/right hemisphere-dominant individuals while that
of tyrosine, dopamine, morphine and norepinephrine
was lower. The results were reversed in the plasma of
right-handed/left hemisphere-dominant individuals
(Tables 5 and 6).
Discussion
Mean of the values from 15 patients in each group SD

a
p<0.01; b between 0.050.01
IHJ-909-00.p65
Table 4. Free radical metabolism in lone AF with embolic

stroke
The increased synthesis of endogenous digoxin, a potent

inhibitor of membrane Na+K+ ATPase, can decrease the
enzyme activity in patients with lone AF with embolic
stroke.4,5 The inhibition of membrane Na+K+ ATPase by
digoxin is known to cause an increase in intracellular Ca++
resulting from an increased Na+Ca++ exchange.17 This
increase in intracellular Ca++, by displacing Mg++ from its
binding site, causes a decrease in the functional availability
of Mg++, which can cause decreased mitochondrial ATP
formation which, along with low Mg++, can result in further
inhibition of membrane Na+K+ ATPase, since the ATP
Mg++ complex is the actual substrate for this reaction. There
6/5/01, 11:27 AM
Indian Heart J 2001; 53: 184188
Ravikumar et al.
187
Isoprenoid Pathway in Lone AF with Embolic Stroke
Table 5. Concentration of serum digoxin, dolichol, magnesium ubiquinone and RBC membrane Na+ K+ ATPase activity/
hemispheric dominance
Groups
HMG-CoA
reductase/
HMG-CoA
mavalonate
Digoxin
(ng/dl)
Dolichol
(g/dl)
Ubiquinone
(g/dl)
Na+K+
ATPase
(g/pi/mg protein)
Magnesium
(mg/dl)
LH Dom (1)
Bihem Dom (2)
RH Dom (3)
1.130.12a
0.820.07
0.460.07a
7.800.06a
14.801.01
30.952.19a
36.12.36a
63.82.96
90.23.63a
142.18.65a
86.45.91
42.82.12a
5.020.22a
3.010.18
1.010.12a
2.900.24a
1.720.13
1.060.11a
Dom: dominance
Group 1 and 3 have been compared with Group2
a
p<0.01; bp between 0.010.05
Table 6. Tyrosine and tryptophan catabolic patterns/hemispheric dominance

Group
Tryptophan
(mg/dl)
Bihem
2.020.05
Dom (1)
LH Dom (2) 1.130.09a
RH Dom (3) 2.960.08a
Tyrosine
(mg/dl)
Serotonin
(g/dl)
Dopamine
(ng/dl)
Norepinephrine
(ng/dl)
Quinolinic acid
(ng/dl)
Morphine
(g/dl)
Strychnine
(g/dl)
Nicotine
(g/dl)
0.840.06
43.91.9
8.720.42
30.561.32
632.5249.42
ND
ND
ND
1.150.08a
0.140.06a
17.91.8a 11.720.62a
52.72.2a 4.920.42a
42.102.30a
21.191.32a
362.2851.63a 7.560.56a
ND
ND
690.2841.32a
ND
0.920.02a 6.280.24a
Dom: dominance
Mean of the values from 15 samples SD.
Groups 2 and 3 have been compared with Group 1
a
p<0.01
is, thus, a progressive inhibition of membrane Na+K+

ATPase activity, first triggered by digoxin.17 Membrane Na+
K + ATPase inhibition thus leads to an increase in
intracellular Ca++ and a decrease in intracellular Mg++
stores. Increased digoxin levels and consequent
hypomagnesemia can affect the atrial conduction, leading
to atrial fibrillation.3 Increase in intracellular Ca++ can
activate the G protein, coupled thrombin receptor and
platelet activating factor, producing the left atrial thrombus
observed in patients with lone AF and embolic stroke.18
There is an increase in tryptophan and its catabolites and
a reduction in tyrosine and its catabolites in the serum of
patients with lone AF and embolic stroke. This could be due
to the fact that digoxin can regulate the neutral amino acid
transport system with preferential promotion of tryptophan
transport over tyrosine. 19 The decrease in membrane
Na+K+ ATPase activity in lone AF with embolic stroke
could be due to the fact that the hyperpolarizing
neurotransmitters (dopamine, morphine and
noradrenaline) are reduced and the depolarizing
neuroactive compounds (serotonin, glutamate, strychnine,
nicotine and quinolinic acid) are increased.
The elevation in the level of dolichol and Mg++ deficiency
can increase the synthesis of structurally abnormal
glycoconjugates.20 Structurally abnormal glycoproteins and
proteoglycans interact between themselves and resist
IHJ-909-00.p65
187
catabolism by lysosomal enzymes leading to their

accumulation and amyloid formation in the conducting
tissue. The cholesterol:phospholipid ratio of the RBC
membrane was increased in patients with lone AF with
embolic stroke, consequent to Mg++ deficiency inhibiting
phospholipid synthesis and an upregulated isoprenoid
pathway increasing cholesterol synthesis. The
incorporation of the glycoconjugates into the membranes
was reduced due to inhibition of membrane trafficking
GTPases and lipid kinases by Mg++ deficiency. The change
in membrane structure can lead to further membrane
Na+K+ ATPase inhibition. Alteration in the membrane of
the conducting tissue can also lead to atrial fibrillation,
while alteration in the left atrial endocardial membrane can
produce platelet adhesion and aggregation, contributing to
the formation of an LA thrombus; and alteration of the
lysosomal membranes can result in defective lysosomal
stability with increased release of lysosomal enzymes,
contributing to the rupture of the thrombus and
embolisation.
In lone AF with embolic stroke, there is mitochondrial
dysfunction and increased generation of free radicals
consequent to: (i) digoxin-induced decreased tyrosine
availability, which leads to inhibition of ubiquinone
synthesis; (ii) increased intracellular Ca++, which induces
NO synthase and liberates NO. There is also reduced free
6/5/01, 11:27 AM
Indian Heart J 2001; 53: 184188
188 Ravikumar et al. Isoprenoid Pathway in Lone AF with Embolic Stroke
radical scavenging owing to: (i) dysfunction of glutathione

synthetase and glutathione reductase induced by Mg++
deficiency; (ii) superoxide dismutase leakage due to opening
of the mitochondrial PT pore by increased intracellular
Ca++; 21 and (iii) catalase dysfunction due to a membrane
peroxisomal defect. Increased generation and reduced
destruction of free radicals, like the superoxide ion and
hydroxyl radical, can produce lipid peroxidation and cell
membrane damage, which can further inactivate Na+K+
ATPase, triggering the cycle of free radical generation once
again. This can lead to membrane Na+K+ ATPase inhibition
of the conducting tissue and AF.
The patterns obtained in right hemispheric dominance
correlated with those obtained in patients with lone AF with
embolic stroke. Right hemisphere-dominant individuals
showed increased digoxin and dolichol levels with reduced
ubiquinone levels. The tryptophan catabolites were
increased and tyrosine catabolites were lowered. In left
hemisphere-dominant individuals, there was a
hypodigoxinemic state and the biochemical patterns were
reversed. Right hemispheric dominance may thus control
the risk for developing lone AF with embolic stroke.
6.
7.
8.
9.
10.
11.
12.
13.
14.
15.
References
16.
1. Zipes DP. Specific arrhythmis: diagnosis and treatment: heart disease.

In: Braunwald E (ed). A Text Book of Cardiovascular Medicine
Philadelphia: Saunders and Company, 1997
2. Atrial fibrillation investigators. Risk factors for stroke and efficacy of
antithrombotic therapy in atrial fibrillation. Analysis of pooled data
from five randomized controlled trials. Arch Intern Med 1994; 154:
14491457
3. Smith TW, Antman EM, Friedman PL, Blatt CM, Marsh JD. Digitalis
glycosides: mechanisms and manifestations of toxicity. Prog Cardiovasc
Dis 1984; 26: 413458
4. Haupert GT. Characteristics of the Na, K-ATPase inhibitor from
hypothalamus. Prog Biochem Pharmacol 1988; 23: 1021
5. Jyothi A. Investigations on Metabolic Derangement in Coronary Artery
17.
IHJ-909-00.p65
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18.
19.
20.
21.
Disease and Neurodegenerative disorders. Trivandrum: University of

Kerala Press, 1998
Rao AV, Ramakrishnan S. Indirect estimation of hydroxyl
methylglutaryl-CoA reductase activity in liver tissue. Clin Chem 1975;
21: 15231528
Wallach DFH, Kamath VB. Methods in Enzymology Colowick SP,
Kaplan O (eds). New York: Academic Press, 1966
Arun P, Ravikumar A, Leelamma S, Kurup PA. Identification and
estimation of endogenous digoxin in biological fluids and tissues by
TLC and HPLC. Indian J Biochem Biophys 1998; 35: 308312
Palmer DN, Anderson MA, Jolly RD. Separation of some neutral lipids
by normal-phase high-performance liquid chromatography on a
cyanopropyl column ubiquione, dolichol and cholesterol levels in
sheep liver. Anal Bioch 1984; 140: 315319
Price WJ. Spectrochemical Analysis by Atomic Absorption. New York:
John Wiley Sons, 1985
Glick D. Methods of Biochemical Analysis. New York: Inter Science,
1971
Arun P, Ravikumar A, Leelamma S, Kurup PA. Endogenous alkaloids
in the brain of rats loaded with tyrosine/tryptophan and in the serum
of patients of neurodegenerative and psychiatric disorders. Ind J Med
Res 1998; 107: 231238
Manoj AJ, Kurup PA. Changes in the glycosaminoglycans and
glycoproteins in the rat brain during protein calorie malnutrition.
J Clin Biochem Nutr 1998; 25: 149157
Kakkar P, Das B, Viswanathan PN. A modified spectrophotometric
assay of superoxide dismutase, Indian J Biochem Biophys 1984; 21:
130132
Bergmeyer HV. Methods of Enzymatic Analysis. New York: Academic
Press, 1978
Gabor G, Allon N. Spectrofluorometric method for NO determination.
Anal Bioch 1994; 220: 1619
Haga H. Effects of dietary magnesium supplementation on diurnal
variations of blood pressure and plasma sodiumpotassium ATPase
activity in essential hypertension. Jpn Heart J 1992; 33: 785800
Lansberg L, Young JB. Physiology and pharmacology of ANS. In:
Fauci AS(ed). Harrison's Principles of Internal Medicine New York:
McGraw Hill, 1998
Hisaka A, Kasamatsu S, Takenaga N, Ohtawa M. Absorption of a novel
prodrug of L-dopa, L-3-alanine DOPA. Drug Metab Dispos 1990; 18:
621625
Jaya P, Kurup PA. Magnesium deficiencey and metabolism of lipids in
rats fed cholesterol-free and cholesterol-containing diet. Indian J
Biochem Biophys 1987; 24: 9295
Green DR, Reed JC. Mitochondria and apoptosis. Science 1998; 281:
13091312
6/5/01, 11:27 AM
Original Article
Prevalence of Coronary Artery Disease in Patients with

Symptomatic Peripheral Vascular Disease
Rajeev Bhardwaj, Neeraj Ganju, Manish Sharma, Sandeep Sud, Sanjeev Asotra
Department of Cardiology, Indira Gandhi Medical College, Shimla
Background: Prevalence of coronary artery disease has been reported to be quite high in patients with peripheral
vascular disease in western literature. Therefore, it is important to study the coronary anatomy in patients with
symptomatic peripheral vascular disease.
Methods and Results: Fifty-three patients presenting with symptoms of peripheral vascular disease underwent
peripheral angiography in our institute during the last 2 years. The total number of vessels involved in these
patients was 117. Fifteen patients had involvement of the upper limb vessels, 46 patients had involvement of the
lower limb vessels and 6 patients had involvement of the carotid/vertebral arteries. Coronary arteriography was
done in all the patients. Only 8 (15%) patients were found to have coronary artery disease with involvement of
11 arteries. Eighty-four (72%) peripheral vessels out of the 117 vessels involved showed total occlusion, whereas
only 2 (18%) coronary arteries out of 11 vessels involved showed total occlusion.
Conclusions: This study shows that the majority of patients with symptomatic peripheral vascular disease
have normal coronaries, the extent of their involvement being low despite severe peripheral vascular disease.
(Indian Heart J 2001; 53: 189191)
Key Words: Peripheral vascular disease, Coronary disease, Angiography
therosclerosis is a systemic disease with the potential

to affect multiple vascular beds. The specific
association of coronary artery disease (CAD) and peripheral
vascular disease (PVD) is well established. The impact of
co-morbid CAD in patients with PVD is two-fold. First, the
prognosis for perioperative morbidity and mortality in
patients undergoing vascular reconstructive surgery is
primarily determined by the presence and extent of the
associated CAD. The specific perioperative events include
myocardial infarction (MI), congestive cardiac failure (CCF)
and arrythmias. Cardiac etiology accounts for 40%60%
of early deaths in patients undergoing vascular
reconstructive surgery.1,2 Late mortality is the second
impact of coronary disease on patients with PVD. It is well
established that in patients who undergo vascular surgery,
there is a decrease in survival if there is presence of
coronary disease. Crawford et al.3 collected extensive longterm survival data on patients who underwent aortic
surgery for either aneurysms or occlusive disease. Actual
survival rates at 5 years were 84%89% for patients without
clinical CAD and only 54% in patients with CAD.4,5 Hence,
Correspondence: Dr Rajeev Bhardwaj, Assistant Professor of Cardiology,
Verma Cottage, Bothwell, Sanjauli, Shimla 171006, Himachal Pradesh
IHJ-900-00.p65
189
determination of the extent and severity of CAD is

important in the management of patients with PVD.
Methods
During the last 2 years, 53 patients presenting with
symptoms of PVD were subjected to peripheral angiography.
Patients with lower limb ischemia presented with
claudication and/or nonhealing ulcer/gangrene. Easy
fatigability was the presenting symptom in patients with
upper limb ischemia and transient ischemic attacks/
syncope in cases with carotid/vertebral artery involvement.
Patients who showed evidence of weakness/absence of at
least one major vessel were subjected to peripheral
angiography. Patients with more than 50% diameter
stenosis were labeled as having PVD and were also subjected
to coronary arteriography (CART). Patients with more than
50% stenosis in one or more coronary arteries were labeled
as having CAD. None of these patients had clinical or
historical evidence of CAD. A right femoral arterial puncture
was used for catheterization, but when the right femoral
artery was not palpable, the left femoral approach was used.
When both femoral pulses were absent, angiography was
done through a left brachial artery puncture.
6/5/01, 1:29 PM
190 Bhardwaj et al.
Indian Heart J 2001; 53: 189191
CAD with Symptomatic PVD
Exclusion criteria: These were: (1) patients with age <40

years; (2) patients with acute arterial embolic occlusion;
and (3) patients fulfilling the criteria for aortoarteritis and
collagen disorders.
Results
Fifty-three patients with symptomatic PVD were subjected
to peripheral and coronary angiography. Six patients had
evidence of gangrene or a nonhealing ulcer on the foot.
Patient characteristics are given in Table 1.
Overall, 15 patients had involvement of the upper limb
arteries, with or without involvement of other regions; 46
had involvement of the lower limb vessels; and 6 had
involvement of the vertebral/carotid arteries, with or
without involvement of other regions. Details of the vessels
involved are given in Table 2.
Coronary arteriography was done in all 53 patients, out
of which 8 patients (15%) showed CAD. Table 2 shows the
details of involvement of CAD in these patients.
Table 1. Patient characteristics

Category
Patients
Total number
Males
Mean age (years)
Smokers
Hypertension
Diabetes mellitus
Family history of CAD
53
44
5411
51
09
02
01
Coronary artery disease

Males
Single vessel disease
Double vessel disease
Triple vessel disease
08
06
06
01
01
Regions involved in PVD

Upper limb arteries
Lower limb arteries
Carotid/vertebral arteries
Upper/lower limb arteries
Upper limb/carotids/vertebral arteries
Upper & lower limb/carotids/vertebral arteries
07
40
00
02
02
04
CAD : coronary artery disease
Table 2. Details of vessels involved

Extent of vessel involvement
Vessels involved
Region
involved
Total
patients
Arteries
involved
Total occlusion
70%99%
<70%
Name
Total
Rt
Lt
Upper
Limb
15
20
15 (75%)
5 (25%)
0 (0%)
Scl
Br
Radial
Ulnar
10
04
02
04
02
01
01
01
08
03
01
03
Lower
Limb
46
87
68 (78%)
16 (18%)
3 (3%)
C Il
E Il
I Il
Fem
Pop
A Tib
P Tib
30
19
03
31
02
01
01
12
11
01
12
00
01
01
18
08
02
19
02
00
00
Carotid
and vertebral
10
1 (10%)
8 (80%)
1 (10%)
Innom
C Car
E Car
I Car
Vert
01
02
01
03
03
0
01
01
01
01
0
01
00
02
02
CAD
11
2 (18%)
8 (72%)
1 (9%)
LAD
LCX
RCA
03
03
05
PVD in
CAD patients
19
13 (68%)
6 (31%)
0 (0%)
PVD in
patients
without
CAD
45
98
71 (72%)
23 (23%)
4 (4%)
Scl: subclavian; Br: brachial; Il: iliac; E:external; I: internal; Fem: femoral; Pop: popliteal; Tib: tibial; A: anterior; P: posterior; Innom: innominate; Car: carotid; C: common; Vert:
vertebral; Rt: right; Lt: left; CAD: coronary artery disease; LAD: left anterior descending; LCX: left circumflex; RCA: right coronary artery; PVD: peripheral vascular disease
IHJ-900-00.p65
190
6/5/01, 1:29 PM
Indian Heart J 2001; 53: 189191
Bhardwaj et al.
If we analyze CAD in relation to the site of involvement

in PVD, 7 out of the 8 patients with CAD had involvement
of only the lower limb vessels, and 1 patient who had single
vessel disease showed involvement of the upper limb vessel.
None of the patients with involvement of two or all three
regions had CAD. The only patient with a three vessel disease
had involvement of the lower limb vessels, type 2 diabetes
mellitus and hypertension. Table 3 shows the risk profile of
CAD patients.
Table 3. Risk profile of CAD patients
Total no. of patients
Patients with CAD
Mean age (years)
Males
Smokers
Diabetes mellitus
Hypertension
Family history of CAD
Dyslipidemia
53
08
569
06
07
01
02
00
02
CAD : coronary artery disease
When we compared patients with and without CAD in

relation to the extent of PVD, 19 peripheral vessels were
found to be involved in 8 patients with CAD as compared to
98 vessels in 45 patients without CAD. Thirteen vessels
(68%) were totally occluded out of the 19 vessels in patients
with CAD, whereas 71 (72%) vessels out of 98 involved
showed total occlusion in patients without CAD (Table 2).
Discussion
Coronary artery disease and PVD are both common diseases
but the symptoms of one usually predominate. The patient
may be incapacitated due to exertional angina so the
symptoms of PVD may not be evident till revascularization
for CAD is done and vice versa. Peripheral vascular disease
usually presents with intermittent claudication. Criqui et
al.6 reported the prevalence of PVD (2.2 % for men and 1.7%
for women) using historical data and noninvasive
measurements of blood flow. A general survey of 5738 men
and 5224 women between the ages of 30 and 59 years was
conducted in Finland. The prevalence of intermittent
claudication increased with age and was similar in men
(2.1%) and women (1.8%). Smoking and an increased
serum cholesterol level were related to increased
prevalence, but high blood pressure and serum triglyceride
levels were not.7
The prevalence of CAD has been reported to be quite high
in patients with PVD. Hertzer2 performed elective coronary
angiography in 1000 consecutive patients considered for
IHJ-900-00.p65
191
CAD with Symptomatic PVD
191
elective peripheral vascular reconstruction. Coronary

artery disease was found in 56% of patients with lower
extremity ischemia (LEI). Only 10% of those with LEI had
normal coronary vessels while 38% had two or three vessel
CAD and 34% had indication of ventricular dysfunction.8
In contrast, our study shows the presence of asymptomatic
CAD in only 15% patients. Our patients had severe PVD
which is evident from the fact that 75% of upper limb
vessels, 78% of lower limb vessels and 10% of
neck vessels had total occlusion. A total of 117 peripheral
vessels were involved in 53 patients. In contrast, only 11
coronary arteries were involved in 8 patients found to have
CAD, and only 2 (18%) of the arteries showed total
occlusion.
Thus, in spite of extensive involvement of PVD in our
patients, CAD is not as common as has been reported in
western studies.2 In another study from South India, a low
incidence of CAD was found in patients with PVD.9 Our data
suggest that some patients with atherosclerosis are prone
to peripheral vessel involvement while others are more
prone to coronary vessel involvement. There may be some
as yet unknown factors that determine the preferential
involvement of a particular vessel.
References
1. Blombery PA, Ferguson IA, Rosengarten DS, Stuchbery KE, Miles CR,
Black AJ, et al. The role of coronary artery disease in complications
of abdominal aortic aneurysm surgery. Surgery 1987; 101:
150155
2. Hertzer NR. Basic data concerning associated coronary artery disease
in peripheral vascular patients. Ann Vasc Surg 1987; 1: 616620
3. Crawford ES, Bomberger RA, Glaeser DH, Saleh SA, Russel WL.
Aortoiliac occlusive disease: factors influencing survival and function
following reconstructive operation over a 25 year period. Surgery
1981; 90: 1055
4. Hertzer NR, Young JR, Beven EG, O'Hara PJ, Graor RA, Ruschhaupt
WF, et al. Late results of coronary bypass in patients with peripheral
vascular disease. Five year survival according to age and clinical
cardiac status. Cleve Clin J Med 1986; 53: 133143
5. Hertzer NR, Young JR, Beven EG, O'Hara PJ, Graor RA, Ruschhaupt
WF, et al. Late results of coronary bypass in patients with peripheral
vascular disease. Five year survival according to sex, hypertension
and diabetes. Cleve Clin J Med 1987; 54: 1523
6. Criqui MH, Fronek A, Barret-Connor E, Klauber MR, Gabriel S,
Goodman B. The prevalence of peripheral vascular disease in a defined
population. Circulation 1985; 71: 510515
7. Reunanen A, Takkunen H, Aromaa A. Prevalence of intermittent
claudication and its effect on mortality. Acta Med Scand 1982; 211:
249256
8. Hertzer NR, Beven EG, Young JR, O'Hara PJ, Rusehhaupt WF, Graor
RA, et al. Coronary artery disease in peripheral vascular patients. A
classification of 1000 coronary angiograms and results of surgical
management. Ann Surg 1984; 199: 223233
9. Premlatha G, Shanthirani S, Deepa R, Markovitz J, Mohan V.
Prevalence and risk factors of peripheral vascular disease in a selected
South Indian population. Diabetes Care 2000; 23: 12951300
6/5/01, 1:29 PM
Original Article
Percutaneous Transseptal Mitral Commissurotomy in

Pregnant Women with Critical Mitral Stenosis
S Mishra, R Narang, M Sharma, A Chopra, S Seth, S Ramamurthy, D Prabhakaran,
KC Goswami, KK Talwar, SC Manchanda, VK Bahl
Department of Cardiology, All India Institute of Medical Sciences, New Delhi
Background: Percutaneous transseptal mitral commissurotomy has been successfully performed in selected
pregnant patients with severe symptomatic mitral stenosis. Its safety and efficacy needs to be evaluated in a
large number of cases.
Methods and Results: Percutaneous transseptal mitral commissurotomy was performed in 85 severely
symptomatic (New York Heart Association functional class III or IV) pregnant women aged 22.74.1 years
(range 1839 years) with critical mitral stenosis at 24.84.7 weeks (range 2034 weeks) of gestation.
Percutaneous valvotomy was performed using a flow-guided Inoue balloon in all the patients. The procedure
was considered successful in 80 (94%) patients. The hemodynamic mean end-diastolic gradient decreased from
26.76.8 mm Hg (range 1635 mmHg) to 4.53.8 mmHg (range 014 mmHg) (p<0.001). The mean diastolic
gradient decreased from 29.19.1 mmHg (range 1838 mmHg) to 7.24.1 mmHg (range 4.118 mmHg)
(p<0.001). The mean mitral valve area assessed by echocardiography increased from 0.750.5 cm2 (range 0.4
1.0 cm2) to 2.00.5 (range 1.02.7 cm2) (p<0.001). The mean fluoroscopy time was 3.63.2 minutes. The
results of the mitral valvotomy were considered suboptimal in 4 patients. Mitral regurgitation increased by 1
grade in 16 patients and more than 2 grades in 2 patients. One patient developed pericardial tamponade during
the procedure and was managed by catheter drainage. Percutaneous mitral valve dilatation was then successfully
performed in this patient. No fetal abortion occurred after the procedure.
Conclusions: The results of this study indicate that percutaneous transseptal mitral commissurotomy is a safe
and effective procedure for severe symptomatic mitral stenosis in pregnancy. (Indian Heart J 2001; 53:
192196)
Key Words: Valvuloplasty, Mitral stenosis, Pregnancy
heumatic mitral valve disease continues to be the most

prevalent organic valve disease encountered in
pregnant women in South Asia.1 Normal pregnancy is
associated with a hyperdynamic circulatory state
characterized by an increase in blood volume, heart rate
and stroke volume, and a decrease in systemic vascular
resistance.25 This increase in cardiac output (usually about
50%) may lead to the unmasking of a previously
asymptomatic valve lesion and worsening of already
symptomatic lesions. In patients with mitral stenosis (MS),
increased blood volume and tachycardia impair left atrial
emptying and can lead to a significant rise in the
venocapillary pulmonary pressure. This hemodynamic
Correspondence: Dr S Mishra, Assistant Professor of Cardiology, All India
Institute of Medical Sciences, New Delhi 110029
IHJ-150-01.p65
192
stress, along with other factors like anemia, atrial fibrillation

and thromboembolism, may precipitate acute pulmonary
edema and cardiogenic shock with unacceptable maternal
and fetal mortality.2,6,7 Thus, pregnancy with mitral stenosis
presents a complex therapeutic problem. Closed or open
surgical commissurotomy can be performed but the
procedure still carries a significant morbidity and
mortality.812
Over the last few years, percutaneous transseptal mitral
commissurotomy (PTMC) has been performed during
pregnancy with excellent short-term results in selected
patients with mitral stenosis.1326 Long-term follow-up
studies have also shown a low risk of complications in the
fetus and a good outcome of these pregnancies.24,25,27
Concerns regarding the risk of radiation exposure still
persist even though some reports have found no harmful
6/5/01, 12:45 PM
Indian Heart J 2001; 53: 192196
Mishra et al. PTMC in Pregnant Women
effects on long-term follow up.28 We report our experience

of PTMC in pregnant women with severe symptomatic
rheumatic MS.
Methods
PTMC was performed in 85 pregnant patients with severely
symptomatic critical MS (New York Heart Association
[NYHA] functional class III or IV) at our center. Clinical
characteristics of these patients are shown in Table 1. All
the patients were NYHA functional class III or IV
symptomaic despite receiving high doses of diuretic therapy,
digoxin and -blockers. Patients were accepted for PTMC if
they fulfilled the following clinical and echocardiographic
critiera: (i) presence of critical MS (absolute mitral valve
area [MVA] <1.0 cm2); (ii) NYHA functional class III or IV;
(iii) absence of more than mild mitral regurgitation; (iv)
absence of left atrial/left atrial appendage thrombus; and
(v) duration of pregnancy greater than 20 weeks. Twenty
patients were in atrial fibrillation with a controlled
ventricular rate. Five patients had mitral restenosis (3 of
these had earlier undergone closed mitral commissurotomy
while 2 were post-balloon valvotomy patients). In 55
patients, a diagnosis of MS had been made prior to the
current pregnancy while in 30 the diagnosis of MS was
made for the first time during the same pregnancy. Twentyfive patients were primigravidae.
Table 1. Clinical characteristics of pregnant patients who
underwent PTMC (n=85)
Age
Duration of pregnancy at
the time of PTMC
Gravida
Primi
Multi
Functional class
NYHA class III
NYHA class IV
Atrial fibrillation
22.74.1 years (1839 years)

24.84.7 weeks (2034 weeks)
25 (29.4%)
60 (70.6%)
46 (54.1%)
39 (45.9%)
20(23.5%)
PTMC : percutaneous transseptal mitral commissurotomy

NYHA : New York Heart Association
Echocardiographic evaluation: Two-dimensional (2-D)

echocardiographic and color Doppler studies were
performed using standard techniques on Hewlett-Packard
Sonos 1500 and 2500 machines before and after PTMC.
The severity of MS and the morphology of the mitral valve
were carefully assessed and transmitral gradients were
measured.29 Planimetry of the mitral valve area was done.
Pulmonary artery systolic pressure was estimated using
tricuspid regurgitation Doppler signal velocity.
IHJ-150-01.p65
193
193
Cardiac catheterization and PTMC: Informed consent

was obtained from all the patients and the risks associated
with the procedure were explained, including potential
harm to the fetus. To limit radiation exposure during the
procedure, the patients abdomen was circumferentially
wrapped from the subcostal margin to the symphysis pubis
with a lead apron. Fluoroscopy was used only when
absolutely essential. Complete right heart study was
avoided. A 6 F pigtail catheter was placed at the root of the
aorta. Left ventriculography was not done in any patient.
PTMC was performed using the conventional Inoue
balloon technique.30 A transseptal puncture of the left
atrium was done using a Brockenbrough needle inserted
via the right femoral vein. Heparin was administered (50
U/kg intravenously) after positioning the Inoue balloon in
the left atrium. The mitral valve mean and end-diastolic
gradients were recorded before and immediately after the
valve dilatation. The step-wise dilatations were done till the
transmitral end-diastolic gradient decreased to less than 5
mmHg, unless a prominent V wave, suggesting significant
mitral regurgitation, appeared on the hemodynamic trace.
The valve area and mitral regurgitation were assessed by
2-D and color-flow Doppler echocardiography after the
procedure. The procedure was considered successful if MVA
was increased by >50% as compared to the baseline and
the final absolute mitral valve area was >1.5 cm2 in the
absence of significant mitral regurgitation.31
Antenatal evaluation: All patients underwent a detailed
obstetric evaluation and follow-up, including ultrasound
(USG) examination, both before and after the procedure.
After PTMC, patients were carefully followed up (including
repeated USG evaluations) for fetal growth and well-being.
Spontaneous labor was awaited in all the patients unless
there was an obstetric reason for induction of labor or
performing cesarean section.
Statistical analysis: All data are expressed as meanSD.
Comparison of data before and after PTMC was performed
using the paired t test. A p value <0.05 was considered
significant.
Results
PTMC was successful in 80 of the 85 (94.1%) patients
studied. All the patients showed an improvement in the
functional class by at least 1 grade when assessed 24 to 48
hours after the procedure. Seventy-six patients were in
NYHA functional class I (89.4%) and 8 were in class II
(9.4%) one month after the procedure. The MVA increased
from 0.750.5 cm2 to 2.00.5 cm2 (p<0.005) and there
6/5/01, 12:45 PM
Indian Heart J 2001; 53: 192196
194 Mishra et al. PTMC in Pregnant Women
was a significant decrease in the transmitral end-diastolic

pressure gradient from 29.19.1 mmHg to 7.24.1 mmHg.
The mean left atrial pressure fell from 34.68.6 mmHg to
14.83.8 mmHg (Table 2). Mean fluoroscopy time was
3.63.2 minutes. The results of the PTMC were considered
suboptimal in 4 patients. Mitral regurgitation increased by
1 grade in 16 patients (18.8%) and by more than 2 grades
in 2 patients (2.3%). One patient with severe mitral
regurgitation (MR) following suboptimal PTMC was
managed medically till term. Elective cesarean section was
performed and the patient underwent a mitral valve
replacement one month later. Another patient, who
developed moderate MR following PTMC, was stabilized on
medical management and continued on medical follow-up
after delivery. One patient developed pericardial tamponade
during PTMC, which was managed successfully by catheter
drainage. Percutaneous mitral dilatation was performed
successfully in this patient. None of the patients developed
any embolic episode or groin complication and there was
no death.
No fetal abortion occurred after the procedure. Although
balloon inflation caused transient maternal hypotension
and a transient decrease in heart rate, these phenomena
were generally well tolerated and both parameters returned
to baseline within a few seconds of balloon deflation.
Table 2. Hemodynamic and echocardiographic data of
pregnant patients undergoing PTMC
MVA (cm2)#
EDG (mmHg)##
MDG (mmHg)##
LA mean (mmHg)##
Pre-PTMC
[MeanSD (range)]
Post-PTMC
[MeanSD (range)]
0.750.5 (0.41.0)
26.76.8 (1635)
29.19.1 (1838)
34.68.6 (22-42)
2.00.5 (12.7)*
4.53.8 (014)*
7.24.1 (4.118)*
14.83.8 (822)*
MVA: mitral valve area; EDG: end-diastolic gradient; MDG: mean diastolic gradient;
LA: left atrium; PTMC: perutaneous transseptal mitral commissurotomy
*p<0.005
# Calculated from echocardiographic 2D-planimetry
## Measured during hemodynamic study
Discussion
Rheumatic valvular involvement remains the commonest
type of heart disease in pregnant patients in many
countries, and up to 75% of these patients have dominant
MS.16 The presence of MS may impair a pregnant womans
ability to generate an increased cardiac output despite an
increase in blood volume, heart rate and decreased systemic
vascular resistance, leading not only to low systemic
perfusion but also pulmonary congestion. Deterioration
may occur in as many as 25% of patients. The maternal
death rate is nearly 1% and varies directly with the NYHA
IHJ-150-01.p65
194
functional class (0.4% for women in class I or II; 6.8% for

those in class III or IV).26 It can reach as high as 17% in
those with atrial fibrillation. The highest risk is during
labour and the delivery period. Ideally, if severe MS is
diagnosed in a nonpregnant woman desiring pregnancy, it
should be treated by PTMC or surgical intervention before
the patient conceives. However, because of several reasons,
this is not always possible. Gupta et al.25 have also reported
that more than half the patients in the group they studied
had been diagnosed before pregnancy but no intervention
had been carried out. After pregnancy, however, severe MS
presents a challenging problem if managed only medically
because of unacceptable fetal and maternal complications.
Thus, in severely symptomatic patients, there is a need to
increase the MVA by some intervention. Surgical
commissurotomy of the mitral valve was first performed in
pregnant patients in 1952.32,33 However, open heart surgery
during pregnancy is attendant with a 15%33% risk of fetal
mortality. The mortality is associated with the establishment
of extracorporeal circulation (with the use of high doses of
heparin and hypotension) and induced hypothermia.34 With
closed mitral commissurotomy, the risk of fetal morbidity
and mortality is lower, although a 5%15% risk of fetal
death is still present.34 Open mitral valvotomy is also
associated with a high maternal mortality.8,12
In this context, PTMC offers an alternative to the surgical
approach. The Inoue technique seems to be particularly
attractive in this setting. A comparison of PTMC with closed
mitral valvotomy (CMV) has shown an equivalent efficacy
of these approaches.35,36 Thus, PTMC seems a practical
approach to these surgically high-risk pregnant patients. It
is a relatively safe procedure which has been performed
widely over the last decade.37 In the last few years, some
large volume centers (Table 3) have offered PTMC to
pregnant women with severe MS.20,21,25,26,28,38,39 The present
study confirms the efficacy and safety of PTMC in pregnant
patients.
No fetal death occurred after the procedure. Only one
fetal death has been reported in about 400 cases of PTMC
performed during pregnancy. No untoward effects of
radiation have been reported.24,25,28 Long-term studies have
confirmed the normal growth of these children.
Our data show that acceptable valve areas can be
achieved with the Inoue single-balloon catheter technique.
This technique is associated with lower complication rates
because of the unique balloon design, flow directed catheter
with blunt tip, adjustable balloon diameter, low inflation
deflation time and less fluoroscopy and procedure time.40
Although the procedure is efficacious, long-term effects
of radiation to the fetus need to be studied. Potentially,
6/5/01, 12:45 PM
Indian Heart J 2001; 53: 192196
Mishra et al. PTMC in Pregnant Women
195
Table 3. PTMC in pregnant patients with mitral stenosis

No.
Study
Year
Patients
Success
n (%)
Severe MR
n (%)
1.
2.
3.
4.
Patel et al.21
Kalra et al.38
Ben Farhat et al.20
Inigo-Riesgo et al.39
1993
1994
1997
1998
19
27
44
7
5.
6.
7.
Martiniz-Reding et al.26 1998

1998
Gupta et al.25
2000
Mangione et al.28
9
40
30
8.
AIIMS study
85
18 (94,.7)
26 (96.2)
40 (90.9)
5 (71.4)
1 (SOR)
8 (88.9)
38 (95)
28 (93.3)
2 (SOR)
80 (94.1)
4 (SOR)
2001
Complications
n
Fluoroscopy
time (min)
1 (5.3)
1 (3.8)
4 (9.1)
0
0
0
1 aortic perforation
9.23.4
5.62.2
16
73
1 (11.1)
1 (2.5)
0 (0)
0
1 PTE
0
Range 1015
7.81.9
-
1 (1.1)
1 tamponade
3.63.2
SOR: suboptimal result; PTE: pulmonary thromboembolism; n: number; MR: mitral regurgitation
radiation exposure during fluoroscopy may pose a hazard

to the unborn child. The fetus receives most of the radiation
dose from scatter and this has been estimated to
be approximately 0.2 rad during balloon mitral
commisurotomy.14 Therapeutic abortion is recommended
when the fetus is exposed to 10 rad or more. Although we
did not measure the actual dose received by the fetus in each
patient, with our short fluoroscopy time the radiation
exposure over the pelvic region should be minimal. Also,
as fetal abnormalities are likely to occur with radiation
exposure before 20 weeks gestation,41,42 we performed
PTMC after 20 weeks of gestation. Taking these factors into
consideration, we believe that the risk to the fetus in our
series was negligible and that the risk of PTMC was much
less than the risk of either surgery or continuing the
pregnancy on medical therapy. A recent study by Mangione
et al.28 showed that over a follow-up of more than 5 years,
all children born to women who had undergone PTMC
during pregnancy showed normal growth and development
without any clinical abnormalities.
Conclusions: Percutaneous transseptal mitral
commissurotomy is a safe and effective method for the
management of pregnant patients with symptomatic,
critical rheumatic MS. The procedure produces consistent
symptomatic and hemodynamic improvement in these
critically ill patients. In experienced hands, this procedure
is quick and safe and should be considered the treatment of
choice.
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6/5/01, 12:45 PM
Original Article
A Meta-analysis of Controlled Clinical Trials Comparing

Low-Molecular Weight Heparins with Unfractionated
Heparin in Unstable Angina
Samir Malhotra, RS Karan, VK Bhargava, P Pandhi, A Grover, YP Sharma, R Kumar
Departments of Pharmacology and Cardiology
Postgraduate Institute of Medical Education & Research, Chandigarh
Background: Unfractionated heparin has been used extensively for the treatment of unstable angina/nonQ wave myocardial infarction but it has several disadvantages. Low-molecular weight heparins are now
recommended although they are 35 times costlier than unfractionated heparin since they are convinient to
administer and do not require activated thromboplastin time monitoring. Whereas enoxaparin, a low-molecular
weight heparin, has been demonstrated to be superior to unfractionated heparin, the results of other lowmolecular weight heparins have not been so convincing.
Method and Results: Through manual, MEDLINE and EMBASE search, we identified five randomized trials
(excluding enoxaparin trials) that compared low-molecular weight heparins with unfractionated heparin in
unstable angina. The prespecified efficacy end point of interest included a composite of death, myocardial
infarction, recurrent angina and urgent revascularization. The safety end point was taken as a composite of
major hemorrhage, minor hemorrhage, thrombocytopenia, allergic reaction and any other adverse event. We
calculated odds ratio (95% confidence interval) for each trial for the composite end point, and the pooled odds
ratio (95% confidence interval) was calculated using two established methods of meta-analysis, the Mantel
HaenszelPeto method and the DerSirmonianLaird method. Both the methods yielded similar odds ratio (95%
confidence interval). Separate odds ratio were calculated for efficacy and safety end points. There was a
nonsignificant reduction in the incidence of the composite efficacy end point; the odds ratio (95% confidence
interval) was 0.83 (0.700.99; p=0.08). The odds ratio (95% confidence interval) for the safety data was 0.78
(0.691.26: p=0.33).
Conclusions: No statistically significant difference was observed when the efficacy and safety of low-molecular
weight heparins were compared with those of unfractionated heparin. A cost-effectiveness analysis of lowmolecular weight heparins versus unfractionated heparin must be done urgently to establish more firmly the
place of low-molecular weight heparins in the management of unstable angina. (Indian Heart J 2001; 53:
197202)
Key Words: Angina, Heparins, Meta-analysis
he role of thrombosis in the pathophysiology of

unstable angina is well established.1 In 1982, the idea
of the administration of intravenous unfractionated
heparin (UFH) for treatment in the acute phase of unstable
angina was introduced.2 Subsequently, several trials35
proved its efficacy and safety alone as well as in combination
with aspirin, and treatment guidelines68 recommended its
use in the routine management of patients with unstable
angina/non-Q wave myocardial infarction.
Correspondence: Dr (Mrs) P Pandhi, Additional Professor of Pharmacology,
PGIMER, Chandigarh 160012
IHJ-892-00.p65
197
Despite its extensive use in clinical practice, UFH has

several disadvantages.9 These include an unpredictable
anticoagulant effect,10 low and variable bioavailability after
subcutaneous administration, 9 a rebound increase in
thrombotic events after cessation of treatment11 and the risk
of thrombocytopenia and thrombosis.12 Low-molecular
weight heparins (LMWHs), however, offer the advantage
of a stable and predictable anticoagulant response to a
given dose, eliminating the need for hematologic
monitoring, and the much simpler subcutaneous
administration route.12,13
6/5/01, 5:23 PM
Indian Heart J 2001; 53: 197202
198 Malhotra et al. Heparins in Unstable Angina
Two Phase III trials of enoxaparin, a LMWH,

demonstrated that it was superior to UFH in reducing the
incidence of a composite end point of death and serious
cardiac ischemic events in patients with unstable angina/
non-Q wave myocardial infarction.14,15 A meta-analysis of
these two trials showed that the incidence of individual end
point was also significantly less with enoxaparin as
compared to UFH.9 The data from the trials comparing other
LMWHs with UFH are less convincing. In a randomized trial
carried out in 1995, nadroparin, a LMWH, was shown to
be significantly better in reducing the incidence of primary
end points than UFH during the acute phase.16 However, a
recent larger trial FRAX.I.S. (FRAxiparine in Ischemic
Syndrome), 17 which enrolled 3468 patients, did not
demonstrate a statistically significant difference with
respect to the primary outcome (cardiac death, myocardial
infarction, refractory angina or recurrence of angina).
Dalteparin, another LMWH, was compared with UFH in the
FRIC (Fragmin In Unstable Coronary artery disease) trial.18
The combined outcome of death, myocardial infarction or
recurrence of angina was observed in 7.6% and 9.3% of
patients treated with UFH and dalteparin, respectively
(p=0.33). In an Indian study by Suvarna et al.,19 which
compared a LMWH, tinzaparine, with UFH, total events
(recurrent angina, acute myocardial infarction, urgent
revascularization) were seen in 45% of patients treated with
UFH and 25% of those treated with tinzaparin. Mattioli et
al. 20 compared another LMWH with UFH in patients
hospitalized with unstable angina. The primary end points
of death, acute myocardial infarction, urgent
revascularization and recurrence of angina were seen in
42% and 23% of patients treated with UFH and LMWH,
respectively.
The last two trials mentioned above 19,20 were not
adequately powered and the evidence from other larger
trials was inconclusive. Keeping this in mind, we decided to
conduct a meta-analysis of five randomized, controlled
trials (excluding enoxaparin trials) of LMWHs in unstable
angina patients, with the objective of detecting a statistically
significant difference between UFH and LMWHs.
Methods
Computerized and manual literature searches are the
recommended methods to gather relevant information from
published studies.21 We searched the literature, MEDLINE
and the EMBASE thoroughly with the key words: LMWHs,
unstable angina, randomized clinical trial. The search was
also carried out by dropping the word clinical from
randomized clinical trial and replacing unstable angina
IHJ-892-00.p65
198
with unstable coronary. Only those trials which compared

LMWHs with UFH were included in the meta-analysis. The
prespecified efficacy end point of interest included a
composite of death, myocardial infarction, recurrent angina
and urgent revascularization. The safety end point was
taken as a composite of major hemorrhage, minor
hemorrhage, thrombocytopenia, allergic reaction and any
other adverse event.
Statistical Analysis: For each individual trial and for the
combination of 5 trials, the odds ratio (OR) for LMWH
versus UFH was estimated along with 95% confidence
interval (CI) for the composite end point between days 6
and 14 (time of ascertainment of the effects of treatment
in the trials). Since it is recommended that two methods be
used22 for assessment of the internal consistency of the
observations on the effect of one treatment versus another,
we used the fixed-effects MantelHaenszelPeto model23,24
and the random-effects DerSirmonianLaird model.22,25
The meta-analysis is presented as OR along with 95% CI
(Figs. 1 and 2). The OR is depicted as a dot, the size of which
is proportional to the quality of the trial, with larger sized
dots indicating large, double-blind, randomized studies and
smaller dots indicating smaller, single-blind or open studies.
The 95% CI are depicted as lines on both sides of the OR.
For each of the 2 methods evaluating the treatment effect
of LMWH, heterogeneity testing was performed to screen
for any important differences between the trials.
A p value <0.05 was considered to be statistically
significant.
Results
All the trials were similar in that they included patients with
unstable angina/non-Q wave myocardial infarction and
excluded those who presented with ST- segment- elevation
myocardial infarction. The trials were similar in design but
differed in the number of patients enrolled (Table 1). In all
the trials, intravenous UFH was adjusted to a similar target
activated thromboplastin time (APTT). The anti-Factor Xa
(antiXa) dose of LMWHs was also similar in all the trials
(Table 1). Aspirin and other conventional therapies were
given to all the patients in all the trials.
The OR (95% CI) for the pooled data on the efficacy end
point and for the individual trials are given in Fig. 1. The
incidence of the composite end point of efficacy was lower
with LMWHs as compared to UFH, but the difference was
not statistically significant. The two methods employed to
calculate the pooled OR yielded similar OR (95% CI); by the
MantelHaenszelPeto method, the OR (95% CI) was 0.81
(0.680.96; p=0.07) and by the DerSirmonianLaird
6/5/01, 5:23 PM
Indian Heart J 2001; 53: 197202
Malhotra et al.
Heparins in Unstable Angina
199
Table 1. Comparison of the five trials of LMWHs in patients hospitalized with unstable angina
Trial characteristic
FRAX.I.S.17
FRIC18
Gurfinkel et al.16
Mattioli et al.20
Suvarna et al.19
Design
Prospective,
randomized,
double-blind,
multicentric
2317
Prospective,
randomized,
double-blind,
multinational
1482
Prospective,
randomized,
single-blind
Prospective,
randomized
Prospective,
randomized,
single-blind
138
120
40
Required
Required
Required
Required
Required
Required
Required
Required
Required
Required
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Corrected cause
of angina
Contraindications to
anticoagulation
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Yes
Outcome measure
Combined
outcome of
cardiac death,
AMI, refractory
angina,
recurrence
of angina
Death,
AMI,
recurrence
of angina
Recurrence
of angina,
AMI,
revascularization,
major bleed
Cardiac death,
AMI, refractory
angina,
recurrence of
angina
Recurrence of
angina, AMI,
revascularization,
bleeding
UFH
1250 IUh-1
preceded by
IV bolus of
5000 IU
5000 IU bolus
followed by
infusion
1000 IUh-1
400 IUkg-1
preceded by
bolus of
5000 IU
5000 IU
bolus followed
by infusion
5000 IU
bolus followed
by 1000 IUH-1
LMWH
Nadroparin,
172 antiXa IUKg-1
SC preceded by
IV bolus of
86 antiXa IUKg-1
Dalteparin,
240 antiXa IUkg-1
SC
Nadroparin,
OP2000,
214 antiXa IUkg-1 150 mg/day
SC
IM
Number
Inclusion criteria
Rest angina within
past 24 hours with ECG
signs compatible with
CAD
Major exclusion criteria
AMI
Planned revascularization
< 24 hours
Dose of study drug in

acute phase
Tinzaparin,
175 antiXa IUkg-1
SC
AMI: acute myocardial infarction; IV: intravenous; IU: International Units; SC: subcutaneous; IM: intramuscular; antiXa IU: anti-Factor Xa activity
method, OR was 0.83 (0.700.99; p=0.08) as shown in

Fig. 1. The heterogeneity test was significant (p=0.04) by
both the methods.
There was also no difference in the safety end point during
the acute phase of treatment with LMWH or UFH (OR 0.78;
95% CI: 0.691.26; p=0.33, by the MantelHaenszelPeto
method; and OR 0.82; 95% CI: 0.551.26; p=0.33, by
the DerSirmonianLaird method) as shown in Fig. 2. In
both the methods, the heterogeneity was not significant.
IHJ-892-00.p65
199
Discussion
Meta-analysis of randomized, controlled trials is an
important method in clinical research.22 Defined as the
quantitative synthesis of data from multiple clinical
experiences, meta-analysis has matured as a scientific
discipline with well developed standards and methods.21,26,27
Several LMWHs are currently available in India and a
recent survey of prescriptions carried out by us on
6/5/01, 5:23 PM
Indian Heart J 2001; 53: 197202
Fig. 1. Meta-analysis of the five trials comparing LMWH with UFH in unstable angina for the combined efficacy end points. The larger dots depict the OR of
large, double-blind, randomized studies and the smaller ones those of smaller, single-blind or open studies.
Fig. 2. Meta-analysis of the three trials comparing LMWH with UFH in unstable angina for the combined safety end points. The larger dots depict the OR of
large, double-blind, randomized studies and the smaller ones those of smaller, single-blind or open studies.
hospitalized unstable angina patients showed that the

utilization of LMWHs and UFH is approximately 70% and
30%, respectively (unpublished data). The recent guidelines
published in March 2000 recommend that LMWH should
replace UFH as the antithrombin of choice.6 However,
different LMWHs have different anti-Factor Xa: antiFactor II ratios, different molecular weights and variable
efficacy in unstable angina12 and, therefore, they may not
be considered equivalent.28 Enoxaparin is the only LMWH
demonstrated to be superior to UFH.12,14,15
The results of our meta-analysis show that the LMWHs
(other than enoxaparin) are equivalent to UFH in efficacy
and safety in patients with unstable angina/non-Q wave
IHJ-892-00.p65
200
myocardial infarction. Although a trend towards better

efficacy of LMWHs was noticed, this failed to reach
statistical significance. Our meta-analysis had enough
power to detect a difference of 5% between the two
treatments. It is possible that if the number of patients was
increased, the results would have shown a statistical
significance. On the other hand, the possibility of a
publication bias cannot be ruled out since negative trials
are more difficult to publish, but this would not have altered
the findings of our meta-analysis. Since a meta-analysis of
two trials of enoxaparin has already been done, we did not
include these studies in our meta-analysis. Moreover, as the
other LMWHs have not been shown to be unequivocally
6/5/01, 5:23 PM
Indian Heart J 2001; 53: 197202
superior to UFH in this setting, the results of our metaanalysis are clinically relevant, especially in developing
countries like India.
The cost of LMWHs is three to five times higher than
that of UFH. However, treatment with UFH requires
additional costs of infusion sets, syringes, nursing time and
the cost of APTT monitoring. A cost-effectiveness analysis
of only enoxaparin has been done, and shown it to be more
cost-effective than UFH,29 but this data has been reported
from developed countries. Similar studies from India and
other developing countries have not been done. However,
our analysis of a recently conducted trial in our hospital
(unpublished data) has shown enoxaparin and UFH to be
equally cost-effective. No such data are available for the
other LMWHs. Only a properly conducted cost-effectiveness
analysis can demonstrate whether the three to five times
more expensive LMWHs can replace UFH in India and other
developing countries. Therefore, there is an urgent need to
carry out this analysis for LMWH and UFH in the Indian
setting.
Till further evidence is available regarding other LMWHs,
it seems appropriate to prescribe enoxaparin to patients with
unstable angina/non-Q wave myocardial infarction. 6
However, if patients are unable to afford enoxaparin (the
costliest LMWH in India), should they be put on another
less expensive LMWH or UFH? The decision has to be made
by the treating physician, but no guidelines are available at
present. The picture in India, where the patient often pays
from his pocket, is different from that in western countries
(whose guidelines we follow) where medical treatment is
covered by insurance companies.
The results of the heterogeneity test, significant for the
efficacy end point, merit further scrutiny. It is established
that a positive heterogeneity test makes a meta-analysis
difficult to interpret; hence, the results must be interpreted
cautiously.30 All the trials were similar in design, inclusion
exclusion criteria and dosages of drugs, and they all used
the same efficacy end points. However, they differed in their
results, with two of the trials showing the superiority of
LMWH over UFH and three not detecting a statistically
significant difference. Even when the same LMWH
(nadroparin) was used in two studies,16,17 it was found to be
superior only in one.16 Regardless of which LMWH is used,
90% of the unstable coronary artery disease patients
clinically stabilize after a few days of treatment;32 therefore,
combining the results from trials carried out for different
LMWHs seems appropriate.
The analysis of the safety end point was conducted from
the data of only three of the trials1618 as no adverse events
were reported in the other two. A statistically significant
IHJ-892-00.p65
201
Malhotra et al.
Heparins in Unstable Angina
201
increase in the incidence of minor hemorrhage and a

nonsignificant increase in major hemorrhage has been seen
with enoxaparin.9 Our results have not demonstrated any
difference in the adverse effects of LMWH and UFH.
Meta-analysis has the potential to eliminate idiosyncrasy
from the evaluation of medical issues, but it is unrealistic
to imagine that it will produce simple statistical answers to
complex clinical problems. A meta-analysis may provide
conclusions about the effect of treatment that could not be
drawn from individual trials because of the small numbers.
Its results are, therefore, directly relevant to the formulation
of medical policies. Meta-analysis cannot tell clinicians how
to treat an individual patient but it can provide information
that can help in decision making.
In conclusion, treatment with LMWHs other than
enoxaparin is as effective as UFH with all the advantages
that LMWHs possess. However, cost-effectiveness analyses
need to be carried out for LMWHs to establish their place
more firmly in the management of unstable angina.
References
1. Fuster V, Badimon L, Cohen M, Ambrose JA, Badimon JJ, Chesebro J.
Insights into the pathogenesis of acute ischemic syndromes.
Circulation 1988; 77: 12131220
2. Telford AM, Wilson C. Trial of heparin versus atenolol in prevention
of myocardial infarction in intermediate coronary syndrome. Lancet
1981; 1: 12251228
3. Theroux P, Quimet H, McCans J, Latour JG, Levy G, Pelletier E, et al.
Aspirin, heparin or both to treat unstable angina. N Engl J Med 1988;
319: 11051111
4. The RISC Group. Risk of myocardial infarction and death during
treatment with low dose aspirin and intravenous heparin in men with
unstable coronary artery disease. Lancet 1990; 336; 827830
5. Cohen M, Adams PC, Parry G, Xiong J, Chamberlain D, Wieorck I, et
al. Combination antithrombotic therapy in unstable rest angina and
non-Q-wave infarction in nonprior aspirin users. Primary end points
analysis from the ATACS trial. Circulation 1994; 89: 8188
6. Antman EM, Fox KM. Guidelines for the diagnosis and management
of unstable angina and non-Q-wave myocardial infarction: proposed
revisions. Am Heart J 2000; 139: 461475
7. Cairns J, Lewis HD Jr, Meade TW, Sutton GC, Theroux P. Antithrombotic
agents in coronary artery disease. Chest 1995; 108: 380S400S
8. Oler A, Whooley MA, Oler J, Grady D. Adding heparin to aspirin
reduces the incidence of myocardial infarction and death in patients
with unstable angina. A meta-analysis. JAMA 1996; 276: 811815
9. Antman EM, Cohen M, Radley D, McCabe C, Rush J, Premmereur J, et
al. Assessment of the treatment effects of enoxaparin for unstable
angina/non-Q-wave myocardial infarction. TIMI 11-ESSENCE metaanalysis. Circulation 1999; 100: 16021608
10. Hirsh J, Fuster V. Guide to anticoagulant therapy. Part I: heparin.
Circulation 1994; 89: 14491468
11. Theroux P, Waters D, Lam J, Juneau M, McCans J. Reactivation of
unstable angina after the discontinuation of heparin. N Engl J Med
1992; 327: 141145
12. Yeghizarians Y, Braunstein JB, Askari A, Stone PH. Unstable angina
pectoris. N Engl J Med 2000; 342: 101114
13. Weitz JI. Low-molecular-weight heparins. N Engl J Med 1997; 337:
688698
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Indian Heart J 2001; 53: 197202

14. Antman EM, McCabe CH, Gurfinkel EP, Turpie AG, Bernink PJ, Salein
D, et al. Enoxaparin prevents death and cardiac ischemic events in
unstable angina/non-Q-wave myocardial infarction. Results of the
Thrombolysis in Myocardial Infarction (TIMI) 11B Trial. Circulation
1999; 100: 15931601
15. Cohen M, Demers C, Gurfinkel EP, Turpie AG, Formell GJ, Goodman
S, et al. A comparison of low-molecular-weight heparin with
unfractionated heparin for unstable coronary artery disease. N Engl
J Med 1997; 337: 447452
16. Gurfinkel EP, Manos EJ, Mejail RI, Cerda MA, Duronto EA, Garcia CN
et al. Low-molecular weight heparin versus regular heparin or aspirin
in the treatment of unstable angina and silent ischemia. J Am Coll
Cardiol 1995; 26: 313318
17. The FRAX.I.S Study Group. Comparison of two treatment durations
(6 days and 14 days) of a low-molecular weight heparin with a 6day treatment of unfractionated heparin in the initial management
of unstable angina or non-Q wave myocardial infarction: FRAX.I.S
(FRAxiparine in Ischemic Syndrome). Eur Heart J 1999; 20: 1553
1562
18. Klein W, Buchwald A, Hillis SE, Monrad S, Sanz G, Turpie G, et al.
Comparison of low-molecular weight heparin with unfractionated
heparin acutely and with placebo for 6 weeks in the management of
unstable coronary artery disease. Fragmin in unstable coronary
artery disease study (FRIC). Circulation 1997; 96: 6168
19. Suvarna TT, Parikh JA, Keshav R, Pillai MG, Pahlajani DB, Gandhi
MJ. Comparison of clinical outcome of fixed-dose subcutaneous low
molecular weight heparin (tinzaparin) with conventional heparin in
unstable angina: a pilot study. Indian Heart J 1997; 49: 159162
20. Mattioli AV, Castellani ET, Goedecke L, Sormani L, Sternieri S, Mattioli
G. Efficacy and tolerability of a very low molecular weight heparin
compared with standard heparin in patients with unstable angina: a
pilot study. Clin Cardiol 1999; 22: 213217
IHJ-892-00.p65
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21. L'Abbe KA, Detsky AS, O'Rourke K. Meta-analysis in clinical research.

Ann Intern Med 1987; 107: 224233
22. Lau J, Antman EM, Jimenez-Silva J, Kupelnick B, Mosteller F, Chalmers
TC. Cumulative meta-analysis of therapeutic trials for myocardial
infarction N Engl J Med 1992; 327: 248254
23. Robins J, Breslow N, Greenland S. Estimators of the MentelHaenszel
variance consistent in both sparse data and large-strata limiting
models. Biometrics 1986; 42: 311323
24. Antiplatelet Trialists Collaboration. Collaborative overview of
randomized trials of antiplatelet therapyI: prevention of death,
myocardial infarction, and stroke by prolonged antiplatelet therapy
in various categories of patients. BMJ 1994; 308: 81106
25. DerSirmonian R, Laird N. Meta-analysis in clinical trials. Control Clin
Trials 1986; 7: 177188
26. Sacks HS, Berrier J, Reitman D, Ancona-Berk VA, Chalmers TC. Metaanalysis of randomized controlled trials. N Engl J Med 1987; 316:
450455
27. Thacker SB. Meta-analysis: a quantitative approach to research
integration. JAMA 1988; 259: 16851689
28. Fareed J, Jeske W, Hoppensteadt D, Clarizio R, Walenga JM. Lowmolecular-weight heparins: pharmacologic profile and product
differentiation. Am J Cardiol 1998; 82: 3L10L
29. Mark DB, Cowper PA, Berkowitz SD, Davidson-Ray L, DeLong ER,
Turpie AG, et al. Economic assessment of low-molecular-weight
heparins (enoxaparin) versus unfractionated heparin in acute
coronary syndrome patients: results from the ESSENCE randomized
trial. Circulation 1998; 97: 17021707
30. Thompson SG, Pocock SJ. Can meta-analysis be trusted? Lancet 1991;
338: 11271130
31. Wallentin L. New trials of LMW heparinslights and heavy weight
as good on short but what about longer distances? Eur Heart J 1999;
20: 15221524
6/5/01, 5:23 PM
Brief Report
Brugada Syndrome with Monomorphic Ventricular

Tachycardia in a One-Year-Old Child
BKS Sastry, C Narasimhan, B Soma Raju
CARE Hospital and CARE Foundation, Hyderabad
A one-year-old child with a structurally normal heart presented with monomorphic ventricular tachycardia.
Electrocardiogram in sinus rhythm showed right bundle branch block with ST segment elevation suggesting a
diagnosis of Brugada syndrome. At a later date, when the ST segment was isoelectric, intravenous procainamide
caused ST elevation typical of Brugada syndrome. (Indian Heart J 2001; 53: 203205)
Key Words: Tachyarrhythmias, Syncope, Brugada syndrome
entricular tachycardia (VT) in a structurally normal

heart is a distinctly uncommon disease, especially in
children. We report the case of a one-year-old female child
with Brugada syndrome1 who presented with rapid VT and
syncopal attacks.
Case Report
Baby N, a one-year-old female child born of a
nonconsanguineous marriage is the youngest of three
siblings. While the first child is healthy, the second died of
sudden cardiac arrest during a febrile illness. Our patient
had a mild nonspecific febrile illness of one days duration
for which she was given paracetamol. On the second day,
the child suddenly developed multiple syncopal episodes and
was brought to the hospital.
The 12-lead electrocardiogram (ECG) showed VT (Fig.1)
that degenerated intermittently into spontaneously
terminating ventricular fibrillation (VF). Her blood
chemistry, including magnesium levels, was normal. Her
echocardiogram was unremarkable with good left
ventricular (LV) and right ventricular (RV) function and no
abnormality in wall motion. There was no response to
intravenous lidocaine, magnesium and amiodarone. After
a few hours, she regained sinus rhythm, but the ECG during
sinus rhythm showed right bundle branch block (RBBB)
with ST segment elevation in leads V1V2 (Fig. 2). Over the
next few days, she did not have any further episodes of VT
and the ST segment in the right precordial leads became
Correspondence: Dr BKS Sastry, CARE Hospital, Exhibition Road,
Nampally, Hyderabad, Andhra Pradesh 500001
e-mail: bkssastry@hotmail.com
IHJ-116-01.p65
203
isoelectric (Fig. 3). After a few days, when the ST segment

was still isoelectric, she was given intravenous procainamide
which led to a prompt and marked elevation of the ST
segment (Fig. 4). She was diagnosed to be suffering from
Brugada syndrome. Interestingly, her father, who is
asymptomatic, also has RBBB with an isoelectric ST
segment. He did not give his consent for an intravenous
procainamide challenge.
Discussion
Differential diagnosis of VT in children includes long QT
syndrome, ventricular pre-excitation, fascicular VT,
myocarditis and arrhythmogenic right ventricular dysplasia
(ARVD). The first three conditions can be safely excluded
after taking into account the ECG tracings. Good ventricular
function and the type of serial ECG changes seen make the
diagnosis of myocarditis unlikely. ST segment elevation in
early repolarization syndrome is usually localized to leads
V2V4 and has an upward concavity with positive T wave
polarity accompanied by a notched J point,2 and is seldom
associated with VT. ST segment elevation in Brugada
syndrome is limited to the right precordial leads, slowly
down sloping and followed by negative T waves. It is often
associated with conduction delay in the RV, thereby
producing varying degrees of RBBB.3
The differentiation between Brugada syndrome and
ARVD is controversial. Brugada syndrome may represent a
functional abnormality of the electrical activity of the heart,
i.e. a primary electrical disease, 4 whereas ARVD is
characterized by myocardial atrophy with adipose tissue or
fibro-fatty infiltration of the dilated RV, often involving the
conducting tissue. Though identified genetic loci and the
6/5/01, 1:27 PM
Indian Heart J 2001; 53: 203205
204 Sastry et al. Brugada Syndrome with Monomorphic VT
Fig. 1. Fast ventricular tachycardia with RBBB morphology at admission.
Fig. 2. Sinus rhythm with RBBB, ST segment elevation and T wave inversion
in leads V1V2.
Fig. 3. Sinus rhythm with RBBB, isoelectric ST segment in leads V1V2.
inheritance pattern seem to be different, it is premature to

draw definitive conclusions about the existence or lack of
relationship between the two conditions.5 A definitive
diagnosis of ARVD is based on the histological
demonstration of transmural fibro-fatty displacement of the
RV myocardium at either necropsy or surgery.6 However,
this was not possible in our patient. The Task Force of the
Working Group of Myocardial and Pericardial Disease of
the European Society of Cardiology suggested certain
criteria to diagnose ARVD7 but our patient does not fulfil
these criteria.
Brugada syndrome is classically associated with
polymorphic VT or VF. Monomorphic VT is distinctly
uncommon. However, as in our patient, there are case
reports where monomorphic VT, which could be induced,
is well documented.811 This further raises the question as
to whether Brugada syndrome is indeed a part of the
spectrum of ARVD.
The mean age of affected individuals is in the mid to latethirties, but ranges from 4 to 70 years. Our patient seems
to be the youngest among those reported so far to have this
syndrome.3
Electrical heterogeneity within the RV epicardium leads
to phase 2 re-entry and thence to VT and VF.12 Because the
ECG changes can be transient and sodium channel blockers
can shorten phase 2 of the action potential, their use has
been suggested to unmask the ECG changes of Brugada
syndrome.13 This is amply demonstrated in our patient
(Fig. 4). In addition to procainamide, ajmaline and
flecainide can also be used. Conversely, antiarrhythmic
agents that selectively block transient outward current (Ito)
could prove effective in Brugada syndrome. The incidence
of arrhythmic events appears to be the same in patients
receiving implantable cardioverter-defibrillator (ICD),
amiodarone and -blockers. However, only patients on ICD
are protected from sudden death.
Our patient was empirically started on amiodarone and
is now doing well, nearly 18 months later. A repeat
evaluation did not show any change in her clinical
condition.
References
Fig. 4. Sinus rhythm with RBBB, ST segment elevation and T wave inversion
in leads V1V2 after intravenous procainamide.
IHJ-116-01.p65
204
1. Brugada P, Brugada J. Right bundle branch block, persistent ST

segment elevation and sudden cardiac death: a distinct clinical and
electrocardiographic syndrome. A multicenter report. J Am Coll
Cardiol 1992; 20: 13911396
2. Gussak I, Antzelevitch C, Bjerregaard P, Towbin JA, Chaitman BR.
The Brugada syndrome: clinical, electrophysiologic and genetic
aspects. J Am Coll Cardiol 1999; 33: 515
3. Wasserburger RH, Alt WJ, Lloyd CJ. The normal RST segment
elevation variant. Am J Cardiol 1961; 8: 184192
6/5/01, 1:27 PM
Indian Heart J 2001; 53: 203205

4. Brugada P, Brugada J, Brugada R. Brugada syndrome: a structural
cardiomyopathy or a functional electrical disease? In: Ravieli A (ed).
Cardiac Arrhythmias. Berlin: Springer-Verlag, 1997: p. 323332
5. Corrado D, Nava A, Buja G, Martini B, Fasoli G, Oselladore L, et al.
Familial cardiomyopathy underlies syndrome of right bundle branch
block, ST segment elevation and sudden death. J Am Coll Cardiol 1996;
27: 443448
6. Lobo FV, Heggtveit HA, Butany J, Silver MD, Edwards JE. Right
ventricular dysplasia: morphological findings in 13 cases. Can J Cardiol
1992; 8: 261268
7. McKenna WJ, Theine G, Nava A, Fontaliran F, Blomstrom-Lundqvist
C. Diagnosis of arrhythmogenic right ventricular dysplasia/
cardiomyopathy. Br Heart J 1994; 71: 215218
8. Boersma LV, Jaarsma W, Jessurun ER, Van Hemel NH, Wever EF.
Brugada syndrome: a case report of monomorphic ventricular
tachycardia. Pacing Clin Electrophysiol 2001; 24: 112115
9. Pinar Bermudez E, Garcia-Alberola A, Martinez Sanchez J, Sanchez
IHJ-116-01.p65
205
Sastry et al. Brugada Syndrome with Monomorphic VT
10.
11.
12.
13.
205
Munoz JJ, Valdes Chavarri M. Spontaneous sustained monomorphic

ventricular tachycardia after administration of ajmaline in a patient
with Brugada syndrome. Pacing Clin Electrophysiol 2000; 23: 407
409
Vanpee D, Blommaert D, Gillet JB, De Roy L. A young man with
recurrent syncopes, right bundle branch block and ST segment
elevation. Am J Emerg Med 1999; 17: 601603
Shimada M, Miyazaki T, Miyoshi S, Soejima K, Hori S, Mitamura H, et
al. Sustained monomorphic ventricular tachycardia in a patient with
Brugada syndrome. Jpn Circ J 1996; 60: 364370
Lukas A, Antzelevitch C. Phase 2 re-entry as a mechanism of
initiation of circus movement re-entry in canine epicardium exposed
to simulated ischemia. Cardiovasc Res 1996; 32: 593603
Miyazaki T, Mitamura H, Miyoshi S, Soejima K, Aizawa Y, Ogawa S.
Autonomic and antiarrhythmic drug modulation of ST segment
elevation in patients with Brugada syndrome. J Am Coll Cardiol 1996;
27: 10611070
6/5/01, 1:27 PM
Brief Report
Valvuloplasty Balloon Detaching From the Stem of

A Catheter
D Prabhakar, P Thirumalai, R Alagesan
Department of Cardiology, Madras Medical College, Chennai
A 12-year-old boy underwent pulmonary balloon valvotomy for isolated critical pulmonary stenosis. Following
valvotomy, blood was found to be drawn into the syringe during deflation of the balloon, so a provisional diagnosis
of a burst balloon was made. However, when the balloon catheter was withdrawn, the balloon got detached
from the stem of the catheter at the level of the right atrium and was retained over the exchange guidewire. The
balloon, when retrieved with a snare, was found to be intact. The balloon may have been partially detached at
the junction of the proximal end of the balloon and the catheter; hence, blood was drawn from the catheter
during deflation. In our institution balloons are reused following sterilization with ethylene oxide gas. We conclude
that any balloon presumed to have burst inside the heart must be removed with great caution. In a third world
country like India, where cost is an important factor, balloons can be reused, but with caution, keeping in mind
complications such as in this case. (Indian Heart J 2001; 53: 206207)
Key Words: Valvuloplasty, Balloon, Pulmonary stenosis
ulmonary balloon valvotomy (PBV) is one of the

simplest interventional procedures, producing very good
results with rare occurrence of complications.1,2 We report a
case of PBV in which the valvuloplasty balloon was detached
from the stem of the catheter and trapped at the level
of the right atrium, after the balloon was presumed to have
burst.
Case Report
A 12-year-old boy presented with dyspnoea on moderate
exertion and one episode of exertional giddiness. He was
clinically diagnosed as a case of pulmonary stenosis.
Echocardiography using a Vingmed CFM 725 machine
revealed right ventricular free wall hypertrophy, severe
valvar pulmonary stenosis with a peak systolic gradient of
200 mmHg and a pulmonary annulus size of 16 mm with
no other associated anomalies.
The case was taken up for elective PBV. Right heart
catheterization, using the right femoral vein approach,
showed a peak systolic gradient of 264 mmHg across the
pulmonary valve. An angiogram of the right ventricle
revealed doming of the pulmonary valve, with a thin central
Correspondence: Dr D Prabhakar, Assistant Professor of Cardiology,

AA Block 27, Annanagar, Chennai 600040, e-mail: prabhud@vsnl.com
IHJ-123-01.p65
206
jet from the valve during systole, but no significant tricuspid

regurgitation.
A 0.032 inch guidewire was anchored through the left
inferior pulmonary artery in a good wedge position and a
23 mm 4 cm pulmonary valvuloplasty balloon was
positioned across the pulmonary valve and inflatedthere
was disappearance of the waist at the level of the pulmonary
valve. A second inflation did not show any waist but blood
was drawn into the syringe on deflationand a provisional
diagnosis of a burst balloon was made.
The balloon catheter was then withdrawn from the
pulmonary position. At the level of the right atrium, the
balloon encountered mild resistance and the catheter
suddenly seemed to move freely. Fluoroscopy revealed that
both the proximal and distal markers of the balloon were
at the level of the right atrium but as the stem of the catheter
was separate from the balloon (Fig. 1), the guidewire was
left in situ and the stem of the catheter removed. A snare
was passed over the wire and the balloon was pulled over
the wire. It was then retrieved to the level of the right
femoral vein, which was exposed and the balloon extricated
(Fig. 2). Examination of the balloon following retrieval
revealed that the balloon was intact.
On post-procedure echocardiography residual gradient
across the pulmonary valve was 20 mmHg. The tricuspid
valve was intactthere was no evidence of tricuspid valve
tear or regurgitation.
6/5/01, 1:26 PM
Indian Heart J 2001; 53: 206207
Prabhakar et al. Detachment of Balloon From the Catheter
Fig. 1. The proximal and distal markers are seen at the level of the right atrium.
The balloon is still on the guidewire.
Fig. 2. The balloon and the stem of the catheter after removal.
Discussion
Pulmonary balloon valvotomy is a relatively safe procedure.
Apart from rare cases of embolic manifestations,
pulmonary regurgitation and valve tear, no other
complications are reported following PBV.24 Infective
endocarditis following PBV is also rare.2 MEDLINE search
did not reveal any instance of a balloon getting entrapped
at the level of the right atrium.
The present case was peculiar in many ways: while it is
rare for a balloon to be detached from the stem of a catheter,
balloon entrapment at the right atrium is not reported in
the literature; an entrapped balloon being retrieved with a
snare percutaneously and a presumably ruptured balloon
found intact following retrieval are rarer still. Balloons are
not reused outside developing nations and, hence, there is
a paucity of literature on the topic.
Normally, the balloon and the catheter stem are attached
firmly at the proximal and distal points. The central portion
is free and expands during inflation. In the present case,
the balloon may have detached partially from the catheter
during inflation at the junction of the proximal end of the
IHJ-123-01.p65
207
207
balloon and the catheter; hence, blood was drawn from the
catheter during deflation. When the catheter was in the
right atrium, the balloon and catheter were totally
detachedboth at the proximal and distal attachments.
Since the entire procedure was done over the wire, the
balloon stayed in position and was successfully retrieved
with a snare.
Our institution provides free health care to patients and
balloons are reused following sterilization with ethylene
oxide gas. In a developing country like India, where cost is
a major constraint for providing health care, reuse of
balloons has been found to be very economical.
During reuse of balloons, two questions arise, namely,
the precautions to be taken and the use of a larger sheath
to prevent an arteriotomy. As a precautionary measure, we
propose that the balloon must be inflated before the
procedure and the proximal and distal ends carefully
inspected for any signs of leakage. Normally, air is not drawn
into the syringe on deflation of the balloon; however, if air
is drawn into the syringe, it could provide a clue to partial
detachment. A bigger percutaneous sheath to prevent an
arteriotomy was not successful because the balloon
collapsed and folded on itself as seen in Fig. 1, wherein both
the proximal and distal markers are seen close to each other.
It is important to note that a burst balloon may or may not
necessarily detach from the catheter. The possibility of a
manufacturing defect being the cause of detachment is
unlikely since balloons are intended for single use.
We conclude that any balloon presumed to have burst
inside the heart should be removed with extreme caution.
Herein, a provisional diagnosis of partial detachment of the
balloon from the catheter should be considered. It is
important to have a guidewire in position to facilitate
retrieval of such a balloon. In a developing country like
India, where cost is an important factor, balloons can be
re-used, but with extreme caution.
References
1. Lazaro Castillo JL, Munayer Calderon J, Aldana Perez T, San Luis
Miranda R, Maza Juarez G, Ramirez Reyes H, et al. Pulmonary
valvuloplasty. Long-term results at the Centro Medico la Raza. Arch
Inst Cardiol Mex 1999; 69: 338343
2. Beghetti M, Oberhansli I, Friedli B. Short and long-term results of
pulmonary balloon valvuloplasty in children. Schweiz Med Wochenschr
1988; 128: 491496
3. Kuhn MA, Mulla NF, Dyar D, Cephus C, Larsen RL. Valve perforation
and balloon pulmonary valvuloplasty in an infant with tetralogy of
Fallot and pulmonary atresia. Cathet Cardiovasc Diagn 1997; 40: 403
407
4. Berman W Jr, Fripp RR, Raisher BD, Yabek SM. Significant pulmonary
valve incompetence following oversize balloon valvuloplasty in small
infants: a long-term follow-up study. Catheter Cardiovasc Interv 1999;
48: 6166
6/5/01, 1:26 PM
Brief Report
Adenosine-Induced Ventricular Fibrillation

Chetan P Shah, Anoop K Gupta, Ranjan K Thakur, Oliver W Hayes,
Avanti Mehrotra, Yash Y Lokhandwala
KEM Hospital, Mumbai, India and
Thoracic and Cardiovascular Institute, Michigan State University, Lansing, Michigan, USA
The use of adenosine has been suggested as a diagnostic tool in the evaluation of wide QRS complex tachycardia.
However, adenosine shortens the antegrade refractoriness of accessory atrioventricular connections and may
cause acceleration of the ventricular rate during atrial fibrillation. We observed ventricular fibrillation in 2
patients who presented to the emergency department with pre-excited atrial fibrillation and were given 12 mg
of adenosine. (Indian Heart J 2001; 53: 208210)
Key Words: Adenosine, Ventricular fibrillation, Tachyarrhythmias
udden arrhythmic death in patients with the Wolff

ParkinsonWhite (WPW) syndrome usually occurs as
a result of atrial fibrillation (AF) with an extremely rapid
ventricular response.1,2 In these patients, AF generally
presents as an irregular wide QRS complex tachycardia
(WQRST). This, in general, represents a diagnostic challenge
and adenosine has been advocated by ACC/AHA guidelines
in 1992 as an ideal pharmacological agent to distinguish
WQRSTs of ventricular origin from those of
supraventricular origin with bundle branch block
aberrancy.3 In addition, because of its presumed safety,
adenosine is used widely in emergency departments.
Adenosine, however, has been associated with proarrhythmic effects in several patient populations,46 can
precipitate AF in some patients,7 and has been associated
with ventricular fibrillation (VF) in patients with pre-excited
AF.8 We report two cases of adenosine-induced VF and
discuss strategies to prevent this lethal outcome.
an irregular WQRST with the shortest RR interval of

160 ms. Supraventricular tachycardia (SVT) with
aberrancy was suspected and the patient was administered
12 mg of adenosine intravenously followed by a saline bolus.
Within 5 seconds, he developed VF (Fig. 2). Electrical
defibrillation was performed to convert his heart beat to
sinus rhythm. The ECG now showed pre-excitation
suggestive of left posteroseptal accessory pathway (AP),
which was subsequently ablated using radiofrequency
energy.
Case 2: A 35-year-old man with a long-standing history
of paroxysmal palpitations, diagnosed as WPW syndrome,
presented with palpitations of sudden onset to the
emergency department. He had been treated with digoxin
and -blockers in the past, but had not been on any
Case Report
Case 1: A 24-year-old man, with a long-standing history
of palpitations, presented to the emergency department for
the first time. His past history was unremarkable and he
was not on any medication. Physical examination revealed
a heart rate of 200 beats/min with an irregularly irregular
pulse. Blood pressure was 100/68 mmHg and
electrocardiogram (ECG) on presentation (Fig. 1) showed
Correspondence: Yash Y Lokhandwala, Associate Professor of Cardiology,
KEM Hospital, Parel, Mumbai 400012
e-mail: yashlokhandwala@hotmail.com
IHJ-129-01.p65
208
Fig. 1. Fast broad irregular QRS complexes suggestive of pre-excited atrial

fibrillation. The shortest RR interval is 160 ms.
6/5/01, 1:25 PM
Indian Heart J 2001; 53: 208210
Fig. 2. Electrocardiogram monitor strips of the same patient. Panel A shows

pre-excited atrial fibrillation. Adenosine 12 mg, denoted by the arrow, was
administered in the emergency department. Panel B shows development of
ventricular fibrillation after adenosine administration.
medication for a few months. On examination, his blood

pressure was 100/72 mmHg and heart rate was 204 beats/
min. The ECG was interpreted as SVT with aberrancy in a
case of WPW syndrome and the patient was administered
12 mg of adenosine intravenously. Immediately following
this bolus dose, the patient developed VF. Sinus rhythm was
restored subsequently by electrical defibrillation. An
electrophysiological study demonstrated a left lateral AP,
which was successfully ablated using radiofrequency
energy.
Discussion
The most common arrhythmia in patients with WPW
syndrome is orthodromic paroxysmal supraventricular
tachycardia (PSVT) which may present either as a narrow
QRS complex tachycardia or WQRST (SVT with aberrancy).
Antidromic tachycardia is considerably less common and
may resemble a regular ventricular tachycardia because of
the wide QRS complexes resulting from ventricular
activation via the AP.2 Prognostically, the most dangerous
arrhythmia in a patient with WPW syndrome is AF with
rapid ventricular response as a result of conduction
proceeding over the AP. Atrial fibrillation may precipitate
VF if the AP allows sufficiently rapid conduction. Atrial
fibrillation with an extremely rapid ventricular response is
usually the cause of sudden death due to arrhythmia in
patients with the WPW syndrome.1,2
Wide QRS complex tachycardia represents a diagnostic
challenge in the emergency department.9 Adenosine has
been proposed to be an ideal pharmacological agent to help
distinguish wide QRS complex supraventricular tachycardia
from ventricular tachycardia because: (i) most SVT circuits
encompass the AV node; (ii) adenosine blocks transmission
at the AV node; and (iii) the pharmacological effect of
IHJ-129-01.p65
209
Shah et al.
209
adenosine is short-lived.10 Adenosine, however, has been

associated with pro-arrhythmic effects in several distinct
patient populations and has been implicated in precipitating
AF.4 Pause-dependent venticular tachycardia has also been
described in women with a normal heart.5 It has been
associated with the induction of pause-dependent
polymorphic ventricular tachycardia in patients with a
structurally normal heart and a normal QT interval.6
The patients described above presented to the emergency
department with an irregular WQRST. A fast, broad and
irregular tachycardia must bring to mind the strong
possibility of AF with the WPW syndrome.11 The type of
tachycardia was AF as evidenced by the irregularly irregular
QRS complexes as well as occasional conduction via
the AV node, resulting in narrow QRS complexes. The wide
QRS complexes were due to ventricular activation through
the AP rather than the AV node. Thus, the AV node
was not involved in the development or maintenance
of the tachycardia. Since predominant pharmacological
effect of adenosine is at the AV node, it predictably
would not terminate these tachycardias. Adenosine also
produces marked vasodilatation and a rebound sympathetic
surge.
The mechanism of development of VF following
adenosine administration in these patients may be
multifactorial.
(i) First, adenosine could favor conduction through the
AP by slowing conduction over the AV node and decreasing
the concealed retrograde conduction into the AP by
normally conducted beats.2 However, it is unlikely that
slowing of AV conduction is an important factor in patients
who have a rapid ventricular response during AF with most
complexes conducted through the AP.
(ii) Second, adenosine may shorten the AP effective
refractory period (APERP) directly, leading to an increased
ventricular rate.
(iii) Third, adenosine may shorten the APERP as a result
of a reflex increase in adrenergic tone brought about by its
peripheral vasodilatory effect. 12 This observation is
supported by the uniform observation of a decrease in
systolic blood pressure after administration of adenosine.
(iv) Finally, ventricles are more arrhythmogenic under
catecholamine stimulation.
We conclude that adenosine may cause VF when
administered during pre-excited AF. This phenomenon is
seen in patients with rapidly conducting APs with short
effective refractory periods. Adenosine may be safely used
as a diagnostic aid for regular WQRST but should be avoided
for irregular WQRST.
6/5/01, 1:25 PM
210 Shah et al.
References
1. Dreifus LS, Haiat R, Watanabe Y, Arriaga J, Reitman N. Ventricular
fibrillation: a possible mechanism of sudden death in patients with
WolffParkinsonWhite syndrome. Circulation 1971; 43: 520527
2. Klein GJ, Bashore TM, Sellers TD, Pritchett EL, Smith WN, Gallagher
JJ. Ventricular fibrillation in the WolffParkinsonWhite syndrome.
N Engl J Med 1979; 301: 10801085
3. Guidelines for cardiopulmonary resuscitation and emergency cardiac
care: recommendations of the 1992 national conference. JAMA
1992; 268: 21992241
4. Slade AKB, Garratt CJ. Pro-arrhythmic effect of adenosine in a patient
with atrial flutter. Br Heart J 1993; 70: 9192
5. Romer M, Candinas R. Adenosine-induced non-sustained
polymorphic ventricular tachycardia. Eur Heart J 1994; 15: 281
282
6. Smith JR, Goldberger JJ, Kadish AH. Adenosine induced polymorphic
ventricular tachycardia in adults without structural heart disease.
IHJ-129-01.p65
Indian Heart J 2001; 53: 208210
210
Pacing Clin Electrophysiol 1997; 20: 743745

7. Nunain SO, Garratt C, Paul V, Debbas N, Ward DE, Camm AJ. Effect
of intravenous adenosine on human atrial and ventricular
repolarization. Cardiovasc Res 1992; 26: 939943
8. Exner DV, Muzyka T, Gillis AM. Proarrhythmia in patients with the
WolffParkinsonWhite syndrome after standard doses of
intravenous adenosine. Ann Intern Med 1995; 122: 351352
9. Stewart RB, Brady GH, Greene HL. Wide QRS tachycardia:
misdiagnosis and outcome after emergent therapy. Ann Intern Med
1986; 104: 766771
10. Sharma AD, Klein GJ, Yee R. Intravenous adenosine triphosphate
during wide QRS complex tachycardia: safety, therapeutic efficacy
and diagnostic utility. Am J Med 1990; 88: 337343
11. Gupta AK, Thakur RK. Wide QRS complex tachycardia: a clinical
approach. Med Clin North Am 2001; 85: 245266
12. Biaggioni I, Olafsson B, Robertson RM, Hollisters AS, Robertson D.
Cardiovascular and respiratory effects of adenosine in conscious man.
Evidence for chemoreceptor activation. Circ Res 1987; 61: 779786
6/5/01, 1:25 PM
Brief Report
Isolated Congenital Left Ventricular

Diverticulum in Adults
D Vaidiyanathan, D Prabhakar, K Selvam, R Alagesan,
N Thirunavukarasu, D Muthukumar
Department of Cardiology, Madras Medical College, Chennai
Isolated congenital ventricular diverticulum or aneurysm is rare and usually arises from the left ventricle. The
presentation of this condition is diverse. We report three cases of isolated congenital left ventricular diverticula.
The age range was 1730 years. Chest X-ray provided the earliest clinical suspicion in these three cases of a
cardiac anomaly which was diagnosed by echocardiography and confirmed by angiocardiography. The location
of the congenital left ventricular diverticulum was the left ventricular apex in two cases and basal in the other.
We conclude that congenital left ventricular diverticulum is a disease of protean presentations. A high index
of suspicion is necessary while interpreting chest X-rays and echocardiographs to diagnose congenital left
ventricular diverticulum. A contractile accessory chamber of the left ventricle with a narrow neck with or without
midline defects and an electrocardiogram without Q waves is consistent with the diagnosis of congenital left
ventricular diverticulum. (Indian Heart J 2001; 53: 211213)
Key Words: Echocardiography, Aneurysm, Congenital heart defects
ongenital left ventricular diverticulum (CLVD) or

aneurysm is uncommon and is reported from time to
time, either as an isolated case report or as a small series of
retrospective analyses, whereas ventricular aneurysms due
to acquired coronary artery disease are well documented.1,2
Congenital left ventricular diverticulum or aneurysm may
present in adulthood with the findings of abnormal chest
X-ray, tachyarrhythmia, abnormal electrocardiogram
(ECG), or cardiac failure. 1 We present three cases of
isolated CLVD seen over a period of 3 years between 1998
and 2000.
apex of the left ventricle (LV) through a narrow neck, with

systolic flow from the diverticulum to the LV (Fig. 1). In
addition, there was rheumatic mitral stenosis with a
mitral valve orifice of 1.8 cm2 by planimetry. Selective
coronary angiography was normal. Left ventricular
angiocardiography confirmed the location of the accessory
chamber at the apex and its contraction during systole
(Fig. 2). At surgery, external morbid anatomy revealed a
large contracting outpouch with a connection to the apex
of the LV. Longitudinal opening of the outpouch showed a
narrow neck connected to the LV cavity. The outpouch was
excised and the narrow neck defect was closed with a
synthetic patch adopting the Dor procedure.
Case Reports
Case 2: A 17-year-old male patient presented with an

episode of palpitation of sudden onset. Clinical examination
was unremarkable except for tachycardia. A 12-lead ECG
showed regular wide QRS tachycardia with a rate of 200
per minute, and the patient was hemodynamically stable.
Attempts at pharmacological conversion were unsuccessful
and electrical cardioversion was performed, following which
the 12-lead ECG was within normal limits and clinical
examination revealed mild mitral regurgitation. Chest Xray PA view was normal and echocardiography showed an
accessory chamber communicating with the basal part of
the LV with a narrow neck, with systolic flow from the
Case 1: A 30-year-old female patient presented with

features of cardiac failure which had progressed over the
last six months. A 12-lead ECG showed complete right
bundle branch block (RBBB) while chest X-ray PA view
revealed an abnormal apical shadow and evidence of grade
II pulmonary venous hypertension. Echocardiography
showed an accessory chamber communicating with the
Correspondence: Professor D Vaidiyanathan, Professor of Cardiology,
Madras Medical College, No. 7, Sylvan Lodge Colony, Kilpauk, Chennai
600010, e-mail: prabhud@vsnl.com
IHJ-119-01.p65
211
6/5/01, 11:31 AM
Indian Heart J 2001; 53: 211213
212 Vaidiyanathan et al. Isolated Congenital LV Diverticulum
Fig. 1. Echocardiography of case 1apical four-chamber view showing the

diverticulum at the LV apex.
Fig. 3. Left ventricular angiogram of case 2left anterior oblique view

showing the diverticulum at the posterobasal wall of the LV.
Fig. 2. Left ventricular angiogram of case 1anteroposterior view showing

the diverticulum at the LV apex.
Fig. 4. Left ventricular angiogram of case 3anteroposterior view showing

the multiple sacs of the diverticulum at the LV apex.
accessory chamber to the LV on color flow mapping and

mild mitral regurgitation. Selective coronary angiography
was normal. Left ventricular angiocardiography confirmed
the presence and location of the LV accessory chamber at
the posterobasal segment of the LV (Fig. 3).
continuity with each other arising from the LV apex and

extending upward along the left border of the heart (Fig. 4).
At surgery, a large contracting outpouch communicating
with the LV apex was excised and the defect closed with a
synthetic patch adopting the Dor procedure.
Case 3: A 25-year-old male patient presented with a

nonanginal type of chest pain. Clinical examination was
unremarkable. A 12-lead ECG showed ST depression in leads
V5 and V6. Chest X-ray PA view showed an abnormal
shadow along the left border of the heart above the apex.
Echocardiography revealed an accessory chamber
communicating with the LV apex through a narrow neck,
and systolic flow was documented from the accessory
chamber to the LV by color flow mapping. Selective coronary
angiography was normal. Left ventricular angiography
showed the LV accessory chamber with three sacs in
IHJ-119-01.p65
212
Discussion
Several authors have attempted to classify and differentiate
a congenital aneurysm from a diverticulum. 1,2 An
aneurysm may be defined as a localized enlargement or
dilatation involving all the tissue layers of the wall
secondary to a mechanical weakness caused by a
developmental defect or an acquired abnormality. A
ventricular aneurysm is classified as congenital in origin
when no known causes of acquired aneurysm are found.3
A diverticulum, on the other hand, is usually defined as a
6/5/01, 11:31 AM
Indian Heart J 2001; 53: 211213
Vaidiyanathan et al. Isolated Congenital LV Diverticulum
pouch or sac created by herniation of an internal layer of a

tubular organ through a defect in the muscular coat.3
Diverticula of the LV are extremely rare among all forms
of diagnosed congenital heart diseases. The age of our
patients ranged from 17 to 30 years. Cardiac failure and
tachyarrhythmia are the usual modes of presentation1 as
seen in cases 1 and 2. Chest pain can occur as it did in case
3, but the causeeffect relationship is not conclusively
proved. Several nonspecific ECG findings have been
described, of which Q waves are considered to favor
aneurysm but none of our patients showed Q waves in their
ECG. 2 Right bundle branch block (seen in case 1),
ventricular tachycardia (seen in case 2) and ST depression
in leads V5V6 (seen in case 3) have also been documented
by other authors.2,3 Routine X-ray chest PA view may show
an abnormal cardiac silhouette which provides the earliest
clue for diagnosis. 1 In a series of 9 patients with
diverticulum studied by Baltaxe et al,2 all had normal chest
X-ray as seen in case 2. On echocardiogram, the
diverticulum is seen as a small, circular, echo-free space
communicating with the LV cavity via a short neck which
is akin to the appearance in pseudoaneurysm. The neck is
defined as narrow if its diameter is less than 40% of the
maximal diameter of the aneurysm. This has been well
described in pseudoaneurysms but its application in the case
of a diverticulum is unclear. However, Doppler flow mapping
in the diverticulum shows systolic flow from the
diverticulum to the LV while in a pseudoaneurysm it is in
the reverse direction.4 All the cases reported here follow the
systolic flow pattern described for diverticulum. Our cases
had an accessory chamber communicating with the LV
through a narrow neck, and the sites were apical in two
patients and basal in one.
Three general types of LV diverticula have been
recognized in the literature. The first type, described by
Cantrell et al5 in 1958, comprises CLVD which are large,
muscular, commonly located at the apex and are part of a
syndrome of cardiac anomalies and midline defects. In the
second type, the LV diverticula are usually subvalvular and
basal, and intimately related to the mitral and aortic valves
producing regurgitation, but are occasionally apical. The
second type has been described as congenital fibrous
diverticula of the LV and, since the walls of these diverticula
are fibrous, they are usually classified as aneurysms. First
described by Hoeffel et al, 6 an isolated muscular
diverticulum has been designated as the third type and
IHJ-119-01.p65
213
213
about 13 cases have been reported in the literature.

To differentiate between congenital muscular
diverticulum and aneurysm of the LV, the connection to
the LV cavity and thoracoabdominal defects are considered.
If the connection to the LV cavity is narrow with associated
thoracoabdominal defects, the lesion is thought to be a
congenital muscular diverticulum.7 In aneurysm of the LV,
the point of connection is wide and there are no midline
defects.7 During LV angiography, diverticula contract during
systole and are best seen during diastole, in contrast to
aneurysms which are hypokinetic or dyskinetic during
systole.2 However, there is disagreement over this. Singh
et al.1 characterized diverticula as being noncontractile and
congenital aneurysms as contractile. In our series, the
accessory chamber in all the patients contracted in systole
and had a narrow connection to the LV; hence, we classified
them as diverticula. As there are no midline defects in any
of our patients, we believe they belong to the isloated type
of diverticula first described by Hoeffel et al.6 We operated
on 2 patients and the presence of a narrow neck was
confirmed. Histologically, they showed features consistent
with muscular diverticulum.
We conclude that CLVD is a disease of protean
manifestations and, for diagnosis, a high index of suspicion
is required during interpretation of chest X-ray and
echocardiography. A contractile accessory chamber of the
LV with a narrow neck, with or without midline defects,
and an ECG without Q waves is consistent with the diagnosis
of CLVD.
References
1. Singh A, Katkov H, Zavoral JH, Sane SM, McLeod JD. Congenital
aneurysms of the left ventricle. Am Heart J 1980; 99: 2532
2. Baltaxe HA, Wilson WJ, Amiel M. Diverticulosis of the left ventricle.
Am J Roentgenol 1979; 133: 257261
3. Tecklenberg PL, Alderman EL, Billingham ME, Shumway NE.
Diverticulum of the left ventricle in hypertrophic cardiomyopathy.
Am J Med 1978; 64: 707714
4. Franco-Vazquez S, Sutherland RD, Fowler M, Edwards JE. Congenital
aneurysm of left ventricular base. Chest 1970; 57: 411415
5. Cantrell JR, Haller JA, Ravitch MM. A syndrome of congenital defects
involving the abdominal wall, sternum, diaphragm, pericardium of
the heart. Surg Gynaecol Obstet 1958; 107: 602614
6. Hoeffel JC, Henry M, Pernot C. Heart diverticula in children: radiological aspects. Ann Radiol 1974; 17: 411415
7. Gueron M, Hirsch M, Opschitzer I, Mogel P. Left ventricular
diverticulum and mitral incompetence in asymptomatic children.
Circulation 1976; 53: 181186
6/5/01, 11:31 AM
Brief Report
Stenting for SVC Obstruction in an Infant Operated for

Total Anomalous Pulmonary Venous Return
Atul Khasnis, Bharat Dalvi
Glenmark Cardiac Centre and Jaslok Hospital, Mumbai
Superior vena cava obstruction following corrective repair of total anomalous pulmonary venous return has
rarely been described in the literature. A one-month-old boy who underwent corrective surgery for obstructive
supracardiac total anomalous pulmonary venous return with consequent symptomatic superior vena cava
obstruction in the immediate postoperative period, is reported. This was treated by balloon dilatation followed by
stenting of the superior vena cava. The immediate postoperative result was satisfactory and the infant continued
to remain asymptomatic at six months follow up. We suggest that this intervention could prove to be a viable
alternative to a repeat surgical procedure for such complex cases. (Indian Heart J 2001; 53: 214217)
Key Words: Angioplasty, Superior vena cava syndrome, Stents
otal anomalous pulmonary venous return (TAPVR)

comprises approximately 2.6% of all congenital heart
diseases.1 Almost all types of TAPVR become symptomatic
during the first year of life and present with shortness of
breath, cyanosis, or both. The mortality rate of TAPVR
in the first year of life is 80%.2 Surgical correction of
TAPVR entails ligation of the abnormal connection
between the pulmonary and systemic veins, re-routing
the pulmonary veins into the left atrium and closing the
interatrial communication. Following this procedure,
obstruction to the pulmonary venous flow has been
reported, especially during infancy.3 However, superior vena
cava (SVC) obstruction due to neoseptation is an extremely
uncommon complication. There are very few reports of SVC
obstruction following repair of TAPVR. Balloon dilatation
and stenting of the SVC baffle has been described for the
SVC syndrome following the Mustard and Senning
procedures.4,5 We report the case of an infant who was
operated for TAPVR and developed symptomatic SVC
obstruction in the postoperative period. He was subjected
to balloon angioplasty with stent implantation, resulting
in immediate clinical and hemodynamic improvement. The
child continues to remain asymptomatic with good
hemodynamic results at the end of six months.
Correspondence: Dr Bharat Dalvi, Flat No. 10, Nandadeep,

209-D, Dr Ambedkar Road, Matunga(E), Mumbai 400019
e-mail: bharatdalvi@hotmail.com
IHJ-104-01.p65
214
Case Report
A one-month-old boy weighing 5 kg presented with a
history of shortness of breath and dusky appearance of the
lips and nails. Clinical examination revealed mild cyanosis,
a respiratory rate of 60 per minute, with subcostal and
intercostal retraction. Cardiac examination revealed an
active precordium, with a short systolic murmur located in
the pulmonary area. Both the components of the second
heart sound were well heard and did not vary with
respiration. There was a mid-diastolic murmur in the
tricuspid area. Chest X-ray revealed cardiomegaly
(cardiothoracic ratio 70%) with increased pulmonary
vascularity. The electrocardiogam (ECG) showed normal
sinus rhythm with a monophasic R in lead V1. A twodimensional (2-D) echo and color Doppler evaluation
showed nonobstructive supracardiac type of TAPVR with
the pulmonary veins draining into the left vertical vein, and
then via the left innominate vein and the right SVC into the
right atrium. The peak systolic pulmonary artery pressure
was 40 mmHg. There was a large ostium secundum atrial
septal defect (ASD) with an obligatory right-to-left shunt.
There was no other intracardiac defect or extracardiac
shunt seen. The child was subjected to intracardiac repair
under cardiopulmonary bypass, during which the right SVC
was cannulated with a 12 F Pacifico cannula. The left
vertical vein was ligated and the common confluence
incorporated into the left atrium. The ASD was closed with
a pericardial patch in such a way that the pulmonary veins
6/5/01, 12:35 PM
Indian Heart J 2001; 53: 214217
were re-routed into the left atrium. The child withstood the
procedure well. He was discharged after an uneventful postoperative course. He was asymptomatic for six weeks after
which the parents noticed puffiness of the face and upper
half of the body, including the upper limbs. The puffiness
increased progressively and breathlessness set in a fortnight
after the onset of edema. The weight of the child was 6 kg
at this time. A chest X-ray was done which showed a rightsided pleural effusion. A pleural tap revealed a chylothorax
on the right side. The child was treated conservatively for a
week but the effusion recurred and the intercostal tube
continued to drain 120150 ml of chyle every 24 hours. A
repeat 2-D echo and color Doppler evaluation revealed
severe obstruction to the SVC flow with a peak gradient of
15 mmHg and a mean gradient of 7 mmHg. The child was
taken up for cardiac catheterization with a view to dilate
and stent the SVC. The procedure was performed under
general anesthesia. Under sterile conditions, the right
femoral artery and vein were accessed percutaneously. A
6 F and a 4 F Hemaquit were placed in the right femoral
vein and artery, respectively and 100 U/kg of heparin was
administered. A JR 3 catheter was placed in the right atrium
and a 0.032" Crosswire guidewire (Terumo Inc., Japan)
was used to cross the obstruction. The mean pressures
recorded in the right atrium and SVC above the obstruction
were 5 mmHg and 12 mmHg, respectively. The JR 3 catheter
was exchanged for a 6 F cut pigtail catheter. A jugular and
superior vena cavagram were performed, which revealed a
tight stenosis of the SVC at the SVCRA junction (Fig. 1).
There were well-developed collaterals which drained into
the azygos system. A 0.035" exchange wire was introduced
through the pigtail catheter and positioned in the right
jugular system. The pigtail catheter was exchanged for a
103 mm Tyshak balloon catheter (NuMed, Cornwall,
Ontario, Canada). The balloon was inflated three times, till
the waist disappeared (Fig. 2). Although the waist
disappeared during the first balloon inflation, it reappeared
during subsequent inflations, indicating recoil. Hence, it
was decided to stent the SVC to obtain satisfactory
hemodynamic results. A 812 mm long Palmaz stent
(Cordis, Warren, NJ) was crimped on a 103 mm Tyshak
balloon and, after changing the femoral sheath to a 7 F long
Hemaquit, the balloon-mounted stent was positioned at the
site of maximum stenosis which was confirmed by a test
angiogram. The stent was deployed by inflating the balloon
(Fig. 3). The post-stent angiogram revealed excellent flow
through the SVC with no evidence of any narrowing, no
pressure gradient across the stenosis, and the disappearance
of collaterals (Fig. 4). A central venous catheter was inserted
through the right internal jugular vein for a period of three
IHJ-104-01.p65
215
Khasnis et al. Stenting for SVC Obstruction
215
Fig. 1. Superior vena cavagram showing the site of obstructed SVC flow
(arrow) with extensive venous collaterals (also indicated with an arrow).
Fig. 2. Balloon dilatation of the SVC obstruction.
6/5/01, 12:35 PM
216 Khasnis et al.
Indian Heart J 2001; 53: 214217
Stenting for SVC Obstruction
days in the postoperative period. There was no evidence of

blockage of this catheter at any time and, on removal, there
was no clot at the catheter tip. The child was put on oral
aspirin 5 mg/kg/day. At follow-up after six months, the child
weighs 9 kg and is asymptomatic. On examination, his
development is normal with no evident cardiovascular
abnormality. A 2-D echo showed the stent in position at the
right atriumSVC junction with a part protruding into the
right atrium. On color Doppler evaluation, the peak and
mean gradients across the stented portion were 4.2 mmHg
and 1.5 mmHg, respectively. The flow was biphasic with
evidence of respiratory pressure variations.
Discussion
Fig. 3. Deployment of stent after balloon dilatation.
Fig. 4. Post-stent venogram showing position of the stent (arrow) with

complete relief of SVC obstruction and disappearance of venous collaterals.
IHJ-104-01.p65
216
Balloon dilatation and stenting for venous obstruction has

been well documented in the literature.6,7 Superior vena
cava baffle obstruction following the repair of transposition
of great arteries (TGA) using the Mustard and Senning
procedures has been described. The incidence of the SVC
syndrome is 4%40% following the Mustard procedure, and
10% following the Senning procedure.8 Superior vena cava
obstruction following intracardiac repair of TAPVR has
rarely been described in the literature. The patient described
in the case above required relief of the SVC obstruction in
view of the persistent drainage of chyle from the right
pleural cavity and worsening edema, in spite of medical
management. The exact cause of SVC narrowing in this
patient is not certain; it could be related to the cannulation
of the SVC during cardiopulmonary bypass or to the
placement of the central line through the right internal
jugular vein in the postoperative period; the former seems
to be the more likely explanation. Percutaneous venous
angioplasty with or without stenting provides an effective
nonsurgical treatment for the SVC syndrome following
repair of TGA.4,5,9 By avoiding the extensive operative
dissection associated with traditional surgical techniques,
angioplasty with or without stent placement significantly
reduces morbidity and mortality in these often complicated
cases. In our patient, simple angioplasty did not result in a
drop in the gradients. Moreover, reappearance of the waist
with every dilatation was an indicator of recoil. In view of
this, it was decided to implant a stent. Placement of stents,
which is frequently used in conjunction with angioplasty
to treat the SVC syndrome in adults, is not recommended
in children as SVC growth could lead to stent migration and
would necessitate a repeat dilatation of the stent.10 However,
in our case, we were left with very little choice, in view of
the suboptimal results with angioplasty alone. Angioplasty
may suffice and can be repeated, if necessary, to maintain
6/5/01, 12:35 PM
Indian Heart J 2001; 53: 214217
SVC patency until the patient reaches maturity, at which

time stent placement may be advisable. Angioplasty may
also be used as a bridge to definitive surgical repair. By
relieving the SVC obstruction, the collaterals get
decompressed, thereby reducing the size and number of
vessels that bypass the obstructed SVC, thus providing for a
greater safety margin during the operative dissection for
surgical relief of the SVC syndrome. Whether as a bridge
or as an independent treatment modality, angioplasty of
the SVC in pediatric patients with congenital heart disease
is safe and effective and should be considered an important
part of the existing treatment modalities in these patients.
References
1. Fyler DC, Buckley LP, Hellenbrand WE, Cohn HE. Report of the New
England Registry Infant Cardiac Program 1980. Pediatrics 1980; 65
(Suppl): 376461
2. Van Praagh R, Harken AH, Delisle G, Ando M, Gross RE. Total
anomalous pulmonary venous drainage to the coronary sinus: a
revised procedure for its correction. J Thorac Cardiovasc Surg 1972;
64: 132135
IHJ-104-01.p65
217
Khasnis et al. Stenting for SVC Obstruction
217
3. Sano S, Brawn WJ, Mee RB. Total anomalous pulmonary venous

drainage. J Thorac Cardiovasc Surg 1989; 97: 886892
4. Abdulhamed JM, Khan MA, al Yousef S, Mullins C. Balloon dilatation
of complete obstruction of the superior vena cava after Mustard
operation for transposition of great arteries. Br Heart J 1994; 72:
482485
5. Benson LN, Yeatman L, Laks H. Balloon dilatation for superior vena
cava obstruction after the Senning procedure. Cathet Cardiovasc Diagn
1985; 11: 6368
6. Ward CJ, Mullins CE, Nihill MR, Grifka RG, Vick GW. Use of
intravascular stents in the systemic venous and systemic venous
baffle obstruction. Short-term follow up results. Circulation 1995; 91:
29482954
7. O Laughlin MP, Perry SB, Lock JE, Mullins CE. Use of endovascular
stents in congenital heart disease. Circulation 1991; 83: 19231939
8. Marx GR, Hougen TJ, Norwood WI, Fyler DC, Castenada AR, Nadas
AS. Transposition of great arteries with intact ventricular septum:
results of Mustard and Senning operation in 123 consecutive
patients. J Am Coll Cardiol 1983; 1: 478483
9. MacLellan-Tobert SG, Cetta F, Hagler DJ. Use of intravascular stents
for superior vena caval obstruction after the Mustard operation. Mayo
Clin Proc 1996; 71: 10711076
10. Cox T, Moore CW, James Beyer A, Seigel EL. Percutaneous angioplasty
for treatment of superior vena cava syndrome after correction of total
anomalous pulmonary venous return. MIRS-IR 1999; III: 7
6/5/01, 12:35 PM
Brief Report
Pulmonary Embolism with Isolated Right

Ventricular Infarction
SR Mittal, Hemant Arora
Department of Cardiology, JLN Medical College, Ajmer
Concomitant occurrence of pulmonary embolism and right ventricular infarction is rare. It poses important
diagnostic and therapeutic implications. A case of pulmonary embolism with isolated right ventricular anterior
wall infarction presented with ventricular tachycardia. One pathology could have led to the other. Twodimensional echocardiography was useful in documenting pulmonary artery hypertension as well as regional
wall motion abnormality of the right ventricle. Thrombolytic therapy and dobutamine infusion were useful.
Nitrates, fluid infusion and diuretics should be used cautiously. (Indian Heart J 2001; 53: 218220)
Key Words: Echocardiography, Myocardial infarction, Tachyarrhythmias
he importance of right ventricular (RV) infarction in

patients with pulmonary embolism is not widely
appreciated, and there are few case reports in the
literature.13 We report a case of sub-massive pulmonary
embolism with isolated infarction of the RV anterior wall
who presented with sustained ventricular tachycardia (VT).
Case Report
A 52-year-old male was admitted with complaints of
sudden onset of palpitation and breathlessness ten days
prior to admission. There was no previous history of chronic
lung disease. Clinical examination revealed orthopnea, a
pulse rate of 200/min (regular), blood pressure of 100/70
mmHg and raised jugular venous pressure with irregularly
occurring cannon waves. The electrocardiogram (ECG)
(Fig. 1) revealed a broad QRS tachycardia with
atrioventricular (AV) dissociation. The mean frontal plane
QRS axis was +105 with monomorphic negative QRS
complexes in the precordial leads (left bundle branch block
morphology). The patient did not respond to intravenous
lignocaine but the VT reverted to sinus rhythm with a
synchronized DC shock of 50 Joules. The ECG in sinus
rhythm revealed T wave inversion in leads V1 to V4, without
loss of R wave in these leads. There was no right bundle
branch block (RBBB) or any other remarkable abnormality.
Correspondence: Professor SR Mittal, 101/XI, Brahampuri,

Ajmer 305001, Rajasthan
IHJ-102-01.p65
218
An X-ray of the chest revealed bilateral mild-to-moderate

pleural effusion. Computerized axial tomography of the
chest revealed pulmonary embolism in the posterobasal
parts of both lungs (Fig. 2), together with consolidation and
loss of volume in the lower portion.
On echocardiographic evaluation, all walls of the left
ventricle, including the interventricular septum, showed
normal thickness and mobility. The RV was dilated with a
thin and akinetic anterior wall (Fig. 3). The inferior wall
showed normal thickness and movement in a subcostal
four-chamber view. MB isoenzyme of creatinine kinase (MBCK) was 19 IU, and a Doppler evaluation of the lower limb
veins did not reveal any thrombus.
The patient was treated with intravenous heparin,
intravenous dobutamine, oral warfarin, amiodarone and a
small dose of frusemide. He gradually improved and was
asymptomatic at the time of discharge. The patient did not
agree to undergo any invasive evaluation.
Discussion
Sub-massive pulmonary embolism results in an acute
increase in RV afterload. Right ventricular oxygen demand
is further increased if there is RV failure with dilatation.
Both these factors, along with hypoxia, can contribute to
isolated RV infarction. This can happen even if there is no
significant coronary artery disease.13 In some cases, RV
infarction could be a primary event, and pulmonary
embolism could be secondary to a thrombus dislodged from
the RV or congested systemic veins.
6/5/01, 11:45 AM
Indian Heart J 2001; 53: 218220
Fig. 1. ECG showing broad QRS tachycardia with atrioventricular dissociation

and negative QRS complexes in leads V1 to V6.
Fig. 2. Computerized axial tomograph of the chest showing bilateral

pulmonary embolism.
Fig. 3. M-mode echocardiograph showing a dilated right ventricle with akinesia

of the right ventricular anterior wall. Left ventricular cavity size and movement
of the interventricular septum and left ventricular posterior wall are normal.
IHJ-102-01.p65
219
Mittal et al.
Pulmonary Embolism with RV Infarction
219
Ventricular tachycardia in our patient could be

secondary to concomitant RV infarction. Negative QRS
deflections in the precordial leads suggest a focus in the RV
anterior wall with the dominant vector directed posteriorly.
Right axis deviation suggests that the origin of VT was
probably close to the RV outflow tract.
Clinical diagnosis of concomitant RV infarction in a case
of pulmonary embolism can be difficult because pulmonary
embolism by itself can produce gross RV failure and
hypotension.
Pulmonary embolism produces ST segment elevation
and T wave inversion in the right-sided chest leads and leads
V2 V4.4,5 Infarction of the RV anterior wall also produces
similar changes in these leads.6 Therefore, an ECG is not
helpful in diagnosing additional RV infarction in a case of
pulmonary embolism but elevation of MB-CK in a case of
pulmonary embolism could be suggestive of the above.7
Serum levels of MB-CK start rising after six hours of
infarction and return to baseline within three days.
Estimation of this isoenzyme, therefore, may not be helpful
in patients presenting very early or those presenting after
three days. This could be the reason for normal values of
MB-CK in our patient. Echocardiography can reveal RV
enlargement with diffuse hypokinesia in patients with
massive or sub-massive pulmonary embolism.8 Regional
wall motion abnormality without diffuse hypokinesia can
help in diagnosing additional RV infarction.3
Concomitant occurrence of pulmonary embolism and
RV infarction has some therapeutic implications.
Thrombolytic therapy is useful in pulmonary embolism
irrespective of whether or not there is concomitant RV
infarction. Dobutamine infusion is helpful in patients
presenting with hypotension and/or right-sided failure.
Nitrates should, however, be used cautiously. These
drugs can produce severe hypotension by reducing the
filling pressure of the infarcted RV which is already subject
to increased afterload due to pulmonary embolism. Fluid
infusion is usually recommended for patients of RV
infarction with hypotension, though it may not be helpful
in cases with concomitant RV infarction and pulmonary
embolism. Unlike patients with RV infarction without
pulmonary embolism, fluid infusion may not translate into
an increased RV output due to a significant increase in
afterload. On the contrary, volume overload of an already
pressure overloaded and failing RV may cause a further
shift of the interventricular septum to the left. This will
result in further elevation of left ventricular filling pressure
and decrease in its output. Diuretics, when used cautiously,
may be helpful in patients with raised jugular venous
pressure.
6/5/01, 11:46 AM
220
References
1. Jerjes Sanchez C, Gutierrez-Fajardo P, Ramirez-Rivera A, GarciaMollinedo Md, Hernadez Chavez G. Acute infarction of right ventricle
secondary to a massive thromboembolism. Arch Inst Cardiol Mex
1995; 65: 6573
2. Goldhaber SZ. Contemporary pulmonary embolism thrombolysis. Int
J Cardiol 1998; 65: S91S93
3. Mittal SR, Jain S, Maheshwari S. Pulmonary embolism with isolated
right ventricular infarction. Indian Heart J 1996; 48: 704706
4. Sreeram N, Cheriex EC, Smeets JL, Gorgels AP, Wellens HJ. Value of
12-lead electrocardiogram at hospital admission in diagnosis of
IHJ-102-01.p65
Indian Heart J 2001; 53: 218220
Mittal et al. Pulmonary Embolism with RV Infarction
220
pulmonary embolism. Am J Cardiol 1994; 73: 298303

5. Chia BL, Tan HC, Lim YT. Right-sided chest lead electrocardiographic
abnormalities in acute pulmonary embolism. Int J Cardiol 1997; 6:
4346
6. Mittal SR, Tiwari D. Electrocardiographic diagnosis of infarction of
right ventricular anterior wall. J Electrocardiol 1996; 29: 119122
7. Adams JE, Siegel BA, Goldstein JA, Jaffe AS. Elevations of CK-MB
following pulmonary embolism. A manifestation of occult right
ventricular infarction. Chest 1992; 101: 12031206
8. Pavan D, Nicolosi GL, Antonini-Canterin F, Zanuttini D.
Echocardiography in pulmonary embolism disease. Int J Cardiol 1998;
65: S87S90
6/5/01, 11:46 AM
Brief Report
Secondary Lymphoma of the Heart Presenting as

Recurrent Syncope
Rohit Manojkumar, Anurag Sharma, Anil Grover
Department of Cardiology, Post Graduate Institute of Medical Education and Research, Chandigarh
A 12-year-old male child presented with recurrent syncope. Ventricular tachycardia was noted on the
electrocardiogram. Transthoracic echocardiogram revealed a homogeneous tumor mass in the right ventricular
cavity with extension into the outflow region. Left cervical lymph node biopsy confirmed the diagnosis of nonHodgkins lymphoma. The tumor resolved completely with chemotherapy without surgical intervention. (Indian
Heart J 2001; 53: 221223)
Key Words: Non-Hodgkins lymphoma, Ventricular tachycardia, Syncope
he most common secondary tumors in pediatric

patients are non-Hodgkins lymphoma, leukemia and
neuroblastoma.1 Cardiac involvement from non-Hodgkins
lymphoma can present with pericardial effusion,
arrhythmia and congestive heart failure.2 Ventricular
tachycardia (VT) as a presentation is rare.3,4 We describe a
case of metastatic non-Hodgkins lymphoma presenting
with syncope due to recurrent VT.
and configuration, and normal lung fields. Blood

investigations revealed a hemoglobin level of 10.1 g/dl, total
leucocyte count of 3000/cmm with a normal differential
count, and a platelet count of 21000/cmm. Peripheral
smear did not reveal any blast cells. Computed tomogram
(CT) showed mild hepatomegaly with a focal hypodense area
in the right lobe of the liver, small multiple lymph nodes in
the retroperitoneal area with normal spleen and kidneys.
Case Report
GS, a 12-year-old boy was admitted to the medical
emergency department with recurrent syncope. He had four
episodes of syncope in the past month. During the present
admission, his pulse was not recordable and the
electrocardiogram (ECG) showed VT with a heart rate of
280/minute (Fig. 1). He was successfully resuscitated with
a DC shock and started on amiodarone. On examination
after resuscitation, his pulse rate was 100/minute and his
supine blood pressure in the right upper limb 106/64
mmHg. Cardiac examination revealed the apical impulse
in the left fifth intercostal space within the midclavicular
line. Heart sounds were normal and there was a grade II/
IV ejection systolic murmur in the second left intercostal
space. His left mandibular region was swollen and the left
cervical region revealed multiple lymph nodes. Abdominal
examination showed hepatomegaly.
Standard ECG revealed sinus rhythm with a QTc interval
of 0.36 seconds. The chest X-ray showed normal heart size
Correspondence: Dr Rohit Manojkumar, House No. 400, Sector 9,
Panchkula, Haryana, e-mail: dr.manoj.k@usa.net
IHJ-109-01.p65
221
Fig. 1. 12-lead ECG showing ventricular tachycardia.
6/5/01, 12:15 PM
222 Manojkumar et al. Secondary Lymphoma Presenting as Recurrent Syncope
Indian Heart J 2001; 53: 221223
Fig. 3a. Parasternal short axis view of an echocardiogram showing a mass in

the right ventricular outflow tract measuring 2627 mm.
Fig. 2. CT scan (head) showing a metastatic tumor in the left mandibular region.
CT scan of the head revealed a mass in the left mandibular

region (Fig. 2). Echocardiography showed a homogeneous
mass in the right ventricular (RV) cavity with extension into
the outflow region (Fig. 3a). On Holter analysis, multiple
episodes of ill-sustained polymorphic VT were noted which
correlated with the diary event of syncope. Aspiration
cytology from the left cervical lymph node showed a
monomorphic population of lymphoid cells with a few
mature lymphocytes and many lymphoglandular bodies. A
lymph node biopsy confirmed the findings, and
immunostaining for alpha-fetoprotein and chromogranin
were negative. Metastatic non-Hodgkins lymphoma was
diagnosed.
The patient was started on systemic chemotherapy
(CHOPcyclophosphamide, adriamycin, vincristine and
prednisolone). He completed six cycles of chemotherapy and
showed complete disappearance of the tumor mass from
the RV, as shown in Fig. 3b. For VT, he was initially started
on amiodarone in addition to chemotherapy. After
disappearance of the tumor from the RV, amiodarone was
discontinued as the patient was asymptomatic.
Discussion
Primary cardiac lymphoma is rare, but secondary
involvement of the heart by a lymphoma is not uncommon.5
IHJ-109-01.p65
222
Fig. 3b. Parasternal short axis view of an echocardiogram showing complete

disappearance of a mass in the right ventricular outflow tract after chemotherapy
(compare with Fig. 3a).
Huh et al.6 have described three cases of lymphoma in a

series of 8 cases of secondary cardiac tumors in children.
Patients may present with pericardial involvement in the
form of an effusion and cardiac tamponade, while
myocardial involvement may result in heart failure or
arrhythmia.7,8 Ventricular tachycardia due to a lymphoma
is uncommon. Miyashita et al.3 from Japan reported the case
of a 70-year-old woman with sustained VT in a primary
cardiac lymphoma. In their patient, the lymphoma was
localized to the RV outflow tract and there was no evidence
of extracardiac involvement. Ventricular tachycardia was
successfully terminated with intravenous disopyramide.
In our case, we used electrical cardioversion followed by
amiodarone for the treatment of VT. Amiodarone has been
successfully used for the control of VT secondary to cardiac
6/5/01, 12:15 PM
Indian Heart J 2001; 53:221223
Manojkumar et al. Secondary Lymphoma Presenting as Recurrent Syncope 223
metastasis as reported by Leak.9 Danbauch et al.4 reported

VT in a 19-year-old student with metastatic non-Hodgkins
lymphoma. Agarwala et al.10 reported the case of a 5-yearold child with non-Hodgkins lymphoma localized to the
right and left atria, whose ECG showed paroxysmal
supraventricular tachycardia. Unlike our patient, in their
case the tumor was in both atria, and there was no episode
of VT. The tumor resolved with chemotherapy alone.
References
1. Chan HS, Sonley MJ, Moes CA, Daneman A, Smith CR, Martin DJ.
Primary and secondary tumors of childhood involving the heart,
pericardium and great vessels. Cancer 1985; 56: 825836
2. Ancalmo N, King TD, Mills NL, Willis G. Lymphoma with large
intracavitary metastasis to the heart. Report of a case. J Cardiovasc
Surg 1976; 17: 136139
3. Miyashita T, Miyazawa I, Kawaguchi T, Kasai T, Yamaura T, Ito T, et
al. A case of primary cardiac B-cell lymphoma associated with
ventricular tachycardia, successfully treated with systemic
IHJ-109-01.p65
223
4.
5.
6.
7.
8.
9.
10.
chemotherapy and radiotherapy: a long-term survival case. Jpn Circ

J 2000; 64: 135138
Danbauch SS, Okpapi JU, Maisaka MM, Ibrahim A. Ventricular
tachycardia in a patient with non-Hodgkins lymphoma. Cent Afr J
Med 1995; 41: 169171
Chim CS, Chan AC, Kwong YL, Liang R. Primary cardiac lymphoma.
Am J Hematol 1997; 54: 7983
Huh J, Noh CI, Kim YW, Choi JY, Yun YS, Shin Hy, et al. Secondary
cardiac tumor in children. Pediatr Cardiol 1999; 20: 400403
Tanaka T, Sato T, Akifuji Y, Sakamoto M, Shio H, Ueki J, et al.
Aggressive non-Hodgkins lymphoma with massive involvement of
with the right ventricle. Intern Med 1996; 35: 826830
Aleksic I, Herse B, Busch T, Lotfi S, Sirbu H, Dalichau H. Third degree
atrio-ventricular-block caused by malignant non-Hodgkins
lymphoma: an unusual indication for epicardial pacing. Cardiovasc
Surg 1999; 7: 378380
Leak D. Amiodarone for control of recurrent ventricular tachycardia
secondary to cardiac metastasis. Tex Heart Inst J 1998; 25: 198
200
Agarwala B, Rubin CM. Intracardiac lymphoma in a child: successful
treatment with chemotherapy alone. Pediatr Cardiol 2000; 21:
401402
6/5/01, 12:15 PM
Point of View
Indian Heart J 2001; 53: 224230
Does Moderate Alcohol Intake Protect Against

Coronary Heart Disease?
Dharam P Agarwal, Lalit M Srivastava
Institute of Human Genetics, University of Hamburg, Hamburg, Germany
Department of Biochemistry, Sir Ganga Ram Hospital, New Delhi, India
here is abundant epidemiological and clinical evidence

to show that light-to-moderate drinking is associated
with a reduced risk of coronary heart disease (CHD), total
and ischemic stroke, and total mortality in middle-aged and
elderly men and women. The evidence suggests a J- or Ushaped relationship between alcohol and CHD. Alcohol
reduces the risk of coronary heart disease both by inhibiting
the formation of atheroma and by decreasing the rate of
blood coagulation. It appears that for most conditions, other
than cardiovascular diseases and cholelithiasis, moderate
alcohol consumption has either none or only an
intermediate type of risk as compared with the risk of either
abstinence or excessive drinking. It is now fully recognized
and accepted that drinking alcohol regularly for years is
toxic to almost every tissue of the body. However, most
people who choose to drink alcohol have little or no problem
limiting their consumption to amounts that do not generally
cause serious health or social consequences. Moreover, a
given dose of alcohol may affect different people differently.
It is, therefore, imperative that a critical evaluation, based
on the observations made hitherto, be done of both the
harmful and the protective effects of alcohol consumption
on various organs/systems of the body. This article reviews
epidemiological evidence for the protective effects of alcohol
on the cardiovascular system and discusses how alcohol
might lower the risk of CHD.
Health Risks of Alcohol Consumption
Many of the toxic effects of alcohol are due to disturbances
of a wide variety of metabolic functions and organ
damage.13 Alcohol is a depressant that is absorbed into the
bloodstream and transmitted to all the systems in the body.
Light-to-moderate doses can reduce physical coordination
and mental alertness, making activities such as sports and
driving dangerous. Even moderate doses of alcohol can
Correspondence: Dr Dharam P Agarwal, Professor of Human Genetics,
Institute of Human Genetics, University of Hamburg, 22529 Hamburg,
Butenfeld 42, Germany, e-mail: agarwal@uke.uni-hamburg.de
IHJ-113-01.p65
224
cause staggering, slurred speech, double vision, mood

swings and unconsciousness. Persistent impotence and loss
of libido as well as hepatitis, esophagitis and pancreatitis
may occur with heavy alcohol use. Long-term alcohol use
increases the risk of liver disease, heart disease, peptic ulcer,
certain types of cancer, complicated pregnancies, birth
defects, and brain damage. Heavy or binge drinking may
even result in respiratory depression and death. Use of
alcohol can also cause mood changes and loss of inhibition
as well as violent or self-destructive behavior. Alcohol tends
to produce a strong psychological dependence and can
create physiological addictions. It is also a potent
contributing factor to many accidents and tragedies.
Alcohol-related effects on organs and tissues based on data
published on the health risks and benefits of alcohol
consumption are summarized in Table 1. While alcohol in
Table 1. Health effects related to alcohol drinking
Effect
Type of
drinking
Protective
effect
Risk/
damage
Heavy
Moderate
Light
No
*
Yes2
Yes1
No
No
Heavy
Moderate
No
*
Yes3
*
Heavy
No
Yes4
Heavy
Moderate
No
Yes
Yes5
*
Neurological
Gastrointestinal (stomach,
oesophagus, pancreas,
liver, colon, rectum)
Fetal
Cardiovascular
Heavy: >80g/day; Moderate: 3080 g/day; Light: <30 g/day

* Indicates either no effect or that it has not been studied in detail
1
Examples of cognitive deficits: dementia, WernickeKorsakoff syndrome, cerebral
degeneration
2
Decreases the risk for ischemic stroke by reducing atherothrombotic phenomenon
3
Examples: alcoholic liver cirrhosis, pancreatitis, cancers of the colon and the
rectum
4
Alcohol-related birth defects: include craniofacial abnormalities and growth
deficiency and deficits in intellectual functioning, leading to difficulties in learning,
memory, problem-solving and attention
5
Causes damage to heart muscle, increases risk of congestive heart failure and/or
sudden death
6/5/01, 12:26 PM
Indian Heart J 2001; 53: 224230
Agarwal et al. Does Moderate Alcohol Protect Against CHD?
light and moderate doses does not exert any significant risk
or benefit on most organs, it certainly has a protective effect
on the cardiovascular system.
225
CHD is supported by a number of epidemiological

studies.
Protective Effects of Alcohol Intake
What is Moderate Drinking?

It is difficult to specify moderate intake quantitatively as
alcohol intake is frequently expressed in drinks or units
that vary with the beverage type, culture and era. Heavier
drinking usually indicates a daily intake of 3 or more
standard-sized drinks per day of wine, liquor or beer;
moderate drinking usually indicates an intake of 3 or
fewer drinks per day. Low-to-moderate alcohol intake is
usually defined as an average consumption of 1 to 2 drinks
a day. Thus, based upon recent publications, alcohol
drinking maybe divided into heavy, moderate and
light categories depending upon the amount of alcohol
consumed in terms of pure ethanol per day.4 Generally, daily
consumption of 80 g and more of pure alcohol is considered
as heavy drinking. Amounts of pure alcohol consumed
ranging between 30 to 80 g per day are accepted as
moderate drinking and that of below 30 g per day are taken
as light drinking.
Alcohol and the Cardiovascular System
Disparities in the relationship between alcohol consumption
and various cardiovascular disorders are now evident, with
complex interrelationships between the conditions.5 It is
best to consider the relationship of alcohol consumption
with various disorders separately:
1. evidence continues to mount that susceptible persons
may suffer heart muscle damage following the intake
of large amounts of alcohol, leading to alcoholic
cardiomyopathy;6
2. consistent epidemiological data support a close
relationship between heavy drinking and
hypertension;7 intervention studies show a pressor
effect of alcohol which appears and regresses within
several days, but the mechanism has not yet been
established;
3. heavy, and possibly moderate, drinking is related to a
higher risk of hemorrhagic stroke,8,9 but moderate
drinking is associated with a lower risk of ischemic
stroke, particularly among women;10
4. heavier drinking, especially binge drinking, is related
to cardiac rhythm disturbances;11
5. a 20% to 40% lower incidence of CHD has been
reported among drinkers compared to nondrinkers.
This inverse relationship of moderate alcohol use to
IHJ-113-01.p65
225
Several epidemiological investigations have shown that a

low-to-moderate level of alcohol intake has a definitive,
protective role against CHD and stroke. 1216 Such
conclusions have been based upon epidemiological studies
on the risks for heart disease, coronary artery disease and
death in individuals with low or moderate alcohol intake
when compared with the corresponding risks in persons
who do not consume alcohol at all.9,1517 The doseresponse
curve is usually found to be U- or J-shaped, i.e., the risk is
higher when alcohol consumption is high, lower when
alcohol consumption is low or moderate and tends to go up
again in individuals who do not consume any alcohol.1820
As compared to people who do not drink alcohol, the risk
of CHD in persons who take low or moderate amounts of
alcohol seems to be reduced (between a third and a fifth).16,21
The level of alcohol consumption that has been associated
with a lower risk for CHD ranges widelyfrom 1 drink to
about 3 drinks per day.12,1622 Studies have found that
individuals who consume 1 alcoholic drink every 1 to 2 days
have a lower risk of a first acute myocardial infarction (AMI)
than abstainers or heavy drinkers but the effect of prior
drinking on mortality after AMI is uncertain.23
When all cohort data of the above mentioned studies are
combined, there appears to be a decline in the risk for
myocardial infarction at doses up to 1 drink a day, with little
further change in the risk associated with increased alcohol
intake.16 Berger et al. 9 showed that light-to-moderate
alcohol consumption reduced the risk of an ischemic stroke
in men. The benefit was apparent with as little as 1 drink
per week. Greater consumption, up to 1 drink per day, did
not increase the observed benefit. Rimm et al.16 reported
that an intake of 30 g of alcohol a day is causally related to
a lower risk of CHD through changes in lipids and
lipoproteins. At this dose, an increase in high-density
lipoprotein (HDL) by 3 mg/dl, apolipoprotein AI by 8.82
mg/dl, triglycerides by 5.69 mg/dl and a modest increase
in the hemostatic factor related to the thrombolytic profile
was observed.
Putative Mechanisms Underlying
the Protective Effects of Alcohol
One of the most obvious possibilities could be that the effect
of alcohol is associated with other confounding factors
affecting the risk of cardiovascular diseases such as age,
6/5/01, 12:26 PM
226 Agarwal et al.
sex, high serum cholesterol and triglyceride levels, smoking,

a sedentary life style, and an over-enthusiastic approach to
day-to-day living. Most of the prospective cohort studies,
taking these factors into consideration, have consistently
shown that moderate alcohol intake has a protective effect
on CHD.1416,2022 Several factors have been proposed as
explanation for the beneficial effects of moderate alcohol
consumption on the development of CHD and
atherosclerosis.24,25 These include the effects of alcohol on
high-density lipoprotein cholesterol (HDL-c), low-density
lipoprotein cholesterol (LDL-c), prostaglandin release and
synthesis, platelet aggregability, blood fibrinolytic activity
and estrogen levels2539 (Table 2).
Increase in HDL mediating the protective effect of
alcohol: It is amply and unequivocally accepted that
alcohol intake is linked to high levels of HDL-c and
apolipoproteins AI and AII.2529 When HDL-c levels were
taken into account in a multivariate analysis, the protective
alcoholCHD relationship was quite apparent, supporting
the contention that the effect was mediated through
HDL.16,2527 As, it is well accepted that HDL-c is inversely
related to CHD and, hence, it has been justifiably proclaimed
that the effect of alcohol is mediated through HDL.2527
However, in a large prospective cohort study, only part of
the effect of alcohol was mediated through HDL and other
lipid factors.16 Experimental studies have shown that
alcohol intake inhibits the transfer of cholesterol esters from
HDL to other lipoproteins. The transfer of cholesterol esters
between lipoproteins is facilitated by cholesteryl ester
transfer protein. A low transfer rate may reduce the reverse
transport of cholesterol since much of the HDL-c is taken
up by the liver in the form of LDL.
In fact, plaque regression has been demonstrated
angiographically in those persons who received drugs that
lower cholesterol and increase HDL, indicating that reverse
cholesterol transport can be enhanced by raising HDL levels
and thereby overcoming the inhibitory effects of oxidized
LDL upon the atherogenic process.40 While it was thought
earlier that alcohol increased only HDL-3 and not HDL-2,
recent observations have shown that both classes contribute
equally and additively to the overall efficiency of the reverse
transport of cholesterol.25,41 In addition, an increase in
paraoxonase activity was strongly correlated with
concomitant increase in the concentration of HDL-c and
apolipoprotein AI.42 Hence, alcohol intake may raise plasma
HDL levels either by altering the synthesis or clearance of
HDL or by an effect on the enzymes and proteins influencing
HDL metabolism.43
Antioxidative effects of alcohol: Antioxidative effects
IHJ-113-01.p65
Indian Heart J 2001; 53: 224230
Does Moderate Alcohol Protect Against CHD?
226
Table 2. Possible biological mechanisms by which alcohol

may protect against CHD
Effect of alcohol
Reference
Alcohol improves blood lipid profile

Increases protective HDL
Inhibits oxidation of harmful LDL
2527
2629
Alcohol decreases thrombosis

Reduces platelet aggregation
Reduces fibrinogen
Increases fibrinolysis
30,31
32,33
34
Other positive effects of alcohol drinking

Increases coronary blood flow
Reduces blood pressure (<12 drinks per day)
Increases blood insulin sensitivity
Increases estrogen levels
Reduces stress
35
36
37
38
39
of alcohol, especially wine, have been frequently proposed

as the mode of action of alcohol. It is known that wine
contains antioxidants which could slow down the oxidation
of unsaturated fatty acids to saturated fatty acids.44 In fact,
the antioxidative effect of alcohol is, in all probability,
exerted by affecting the oxidation of LDL, thereby
hampering the atherosclerotic plaque formation.45 Indeed,
polyphenolic antioxidants present in red wine have been
shown to inhibit the oxidation of human LDL.4648 It has
been shown recently that distilled alcohol on wood ageing
does acquire a significant amount of antioxidants which
could be different from those present in red wine.49 These
findings indicate that there might not be a large difference
between the capabilities of wine (red wine especially) and
distilled alcohol in the protection/and or lowering the risk
of heart disease.50
Antioxidant effects of alcohol on LDL: Many
observational studies have established that dense LDL-c is
a major risk factor for CHD. Oxidation of LDL-c is supposed
to play a major role in the generation of atherosclerotic
lesions.48 The atherogenic potential of LDL in the majority
of individuals arises from an increase in the number of small
dense LDL particles and not from its cholesterol content per
se. Studies have shown that a diet high in saturated fatty
acids (SFAs) and cholesterol and low in polyunsaturated
fatty acids (PUFAs) and monounsaturated fatty acids
(MUFAs) increases LDL-c.44
Role of paraoxonase in LDL peroxidation: The human
serum HDL-linked paraoxonase enzyme limits LDL
peroxidation by preventing the transformation of LDL into
biologically active atherogenic particles. Paraoxonase
serum activity varies among individuals due to a Gln/Arg
polymorphism with low (A phenotype) and high
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Indian Heart J 2001; 53: 224230
Agarwal et al.
(B phenotype) activity. Recent studies have implicated

paraoxonase in providing protection against LDL oxidation,
thus affecting the risk of CHD in the general population.
Van der Gaag et al.42 examined the effects of moderate
consumption of red wine, beer and spirits in comparison
with mineral water on paraoxonase activity in serum.
Fasting paraoxonase activity was higher after intake of
wine, beer and spirits than after consumption of water but
did not differ significantly between the 3 alcoholic
beverages. Similar effects were observed pre- and
postprandially. These findings, and those from other recent
studies,51 suggest that increased serum paraoxonase may
be one of the biological mechanisms underlying the reduced
risk of CHD in moderate alcohol consumers.
Increased production and altered clearance of
apolipoproteins: Apolipoprotein AI is distributed within
HDL between different types of particles, one containing
both apolipoprotein AI and apolipoprotein AII (LpAI:AII),
the other containing no apolipoprotein AII (LpAI). Branchi
et al.52 demonstrated a significant increase in plasma
concentrations of apolipoprotein AI and apolipoprotein AII
in men drinking more than 30 g of alcohol a day as
compared to nondrinkers. Gottrand et al.53 found that
increase in the plasma concentration of apolipoprotein AII
was due to the reduced plasma clearance of apolipoprotein
AII as well as an increase in its production. Hence, alcohol
drinking increased the plasma concentrations of
apolipoprotein AI and apolipoprotein AII, the main
components of HDL particles. Based upon epidemiological
data, it has been estimated that an average individual
consuming 30 g of alcohol per day would show an 8 mg/dl
increase in the plasma apolipoprotein AI concentration,
primarily due to its increased synthesis in the liver.16
The effect of alcohol on Lp(a): The protein component
of this lipoprotein consists of apolipoprotein-B covalently
linked to a series of kringles homologous with those
comprising plasminogen. Recent observational studies
confirm and extend previous evidence that Lp(a) plays a
significant role in atherosclerosis and is one of the major
risk factor for cardiovascular diseases.54,55 Epidemiologically,
Lp(a) is a strong positive risk factor for CHD, the presumed
mechanism being the inhibition of fibrinolysis by reduced
plasminogen levels due to elevated Lp(a) levels.56 These
levels have been found to be significantly higher in ischemic
stroke patients and in those with carotid plaques than in
controls.57 A number of intervention studies in human
subjects support the notion that alcohol consumption
reduces plasma Lp(a) concentrations.58,59 Most convincing
are the finding of Kervinen et al.60 in which the cessation
IHJ-113-01.p65
227
227
or reduction in beverage alcohol was accompanied by a

significant increase in plasma Lp(a). Our group was
amongst the first to demonstrate that coronary artery
disease patients had higher levels of Lp(a) and those who
were alcohol drinkers showed significantly low Lp(a)
levels.61 Further, Paassilta et al.62 have shown that social
drinking, i.e. <39 g alcohol/week is associated with low
Lp(a) lipoprotein concentration in middle-aged men and
thus concluded that low Lp(a) lipoprotein concentration
maybe one factor explaining low mortality and retarded
progression of coronary artery disease in social drinkers.
However, a number of studies have yielded conflicting
results, some apparently demonstrating a negative
association between Lp(a) and alcohol consumption58-62
while others failed to find any such relationship.63,64
Additional Factors Contributing to the
Protective Effect of Alcohol
Platelet aggregation and blood clotting: Recent studies
have shown HDL-c levels can account for only 50% of the
protective effect of alcoholic beverages.16 The other 50%
may be partly related to decreased platelet activity.30,31 The
antiplatelet activity of wine is explained not only by ethanol
but also by the polyphenolic components with which red
wines are richly endowed. It has been suggested that wine
phenolics could reduce platelet activity mediated by nitric
oxide. Moreover, wine phenolics increase vitamin E levels
while decreasing the oxidation of platelets subjected to
oxidative stress. However, a rebound phenomenon of
hyperaggregability is observed after acute alcohol
consumption but not after the consumption of wine. This
protection afforded by wine has been duplicated in animals
with grape phenolics added to alcohol. It appears that wine,
and wine phenolics in particular, could significantly inhibit
platelet aggregation and that this could explain, at least in
part, the protective effect of red wine against atherosclerosis
and CHD.
Excessive alcohol consumption clearly affects platelet
function. Moderate alcohol consumption may affect several
hemostatic factors, including fibrinogen concentration,
platelet aggregability and the fibrinolytic factors tissuetype plasminogen activator and plasminogen activator
inhibitor. Plasma fibrinogen concentrations are decreased
by moderate alcohol consumption.32,33 Hence, alcohol has
been shown to reduce coagulation of blood.3034
Role of homocysteine: Recent studies suggest that high
plasma homocysteine concentrations are an independent
risk factor for coronary, cerebral and peripheral arterial
occlusive diseases.65,66 Its effect appears to depend upon its
6/5/01, 12:26 PM
228 Agarwal et al.
direct toxicity for endothelial cells. Endothelial dysfunction

is associated with atherogenesis and oxidative stress in
humans. Serum homocysteine increases after moderate
consumption of red wine and spirits, but not after moderate
consumption of beer.67 These authors argue that vitamin
B6 in beer prevents the alcohol-induced rise in serum
homocysteine. One of several routes for metabolism of
homocysteine involves methylation using betaine as the
methyl donor. Betaine is often added to less expensive wine
when beet sugar is used to increase alcohol content. In
France, a diet high in saturated fat and cholesterol is
associated with low coronary artery disease mortality and
drinking wine is commonly believed to be protective against
ischemic heart disease. Recently, Mar and Zeisel68 found that
many commercial wines contain betaine an average glass
of wine contains approximately 3 mg of betaine. This
small amount is less than the dose used to lower the
homcysteine level in patients with genetic forms of
hyperhomocysteinemia. However, whether humans with
modest elevations of homocysteine would be influenced by
this dose is not known.
Conclusions
As reviewed in detail in this article, alcohol may directly
increase the hepatic production and secretion of
apolipoproteins and lipoprotein particles, increase
triglyceride lipase concentrations, and decrease the removal
of circulating HDL-c. Lipolysis of triglyceride-rich particles
increases the flow of cholesterol to HDL particles from the
circulating very low density lipoprotein remnants and raises
the overall HDL concentration. Although speculative,
alcohol may also interfere with the activity of cholesteryl
ester transfer protein and reduce the transfer of cholesteryl
esters in HDL particles to more atherogenic particles. The
effect of alcohol on the thrombolytic and coagulation
processes are not well understood. The mechanism by which
alcohol decreases fibrinogen concentration is not known,
although the effect has been documented in several large
cross-sectional studies as well as the small experimental
studies described. Alcohol inhibits induced platelet
aggregation in several in vitro systems.
Taken together, results from many observational studies
provide strong evidence that moderate alcohol intake lowers
the risk of CHD. This has given rise to what is now popularly
termed the French paradox. 68,69 This relationship has
been observed in both men and women and in different age,
ethnic and geographic groups. It is independent of dietary
and other known risk factors for heart disease, such as
smoking and obesity. Moreover, short-term trials of alcohol
IHJ-113-01.p65
Indian Heart J 2001; 53: 224230
228
intake show significant changes in concentrations of lipids

and clotting factors. The evidence that moderate alcohol
consumption is healthful is ample and consistent. Should
physicians, therefore, recommend such consumption to
their patients? Looking at the benefits of moderate
consumption of alcohol to the cardiovascular system,
especially atherosclerosis, it may be worthwhile to accept
moderate drinking. While there is no consensus among
physicians on whether to inform their patients of the
beneficial effects of moderate alcohol consumption, most
concur with the notion A little is good, but a lot is not
better.
Acknowledgments
This study was supported by the Alexander von Humboldt
Foundation, Bonn, Volkswagen Foundation, Hanover and
DLR, Bonn, Germany.
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Current Perspective
Indian Heart J 2001; 53: 231234
Communications in Cardiology: Why Digital?

G Vijayaraghavan
Department of Cardiology, Welcare Hospital, Dubai, United Arab Emirates
olygraph, introduced towards the end of the last

century, was probably the first cardiac investigation to
become popular. This instrument recorded heart rate,
rhythm, arterial pulse, venous pulse and respiration. Later,
other investigations like chest X-rays, electrocardiogram,
vectorcardiogram, ballistocardiogram, etc. were introduced.
During the early part of the latter half of this century,
cardiac catheterization and angiography became the last
word in cardiac investigations and cine film was the
standard format in which angiograms were recorded and
stored. With the introduction of echo and Doppler
techniques, video recording became popular and highquality Super VHS was the best format available. Nuclear
cardiology was probably the first discipline to introduce total
digital technology for imaging, image processing and
archiving. As coronary angiography and angioplasty
became popular, cardiologists wanted cine pictures to be
re-run immediately after the procedure. Cine fluoroscopy
pictures were recorded and replayed from videotapes.
However, permanent video archiving with adequate image
quality in a cost-effective manner posed a problem! Hence,
cine film continued to be used as the only medium of storage
for angiograms.
During the 1980s, equipment vendors developed digital
imaging techniques for the cath lab which provided superior
image quality over standard video fluoroscopy. Even though
video fluoroscopy became popular, image acquisition and
archiving was on videotapes and cine films, the analog
format dominating the field.1 Analog imaging is a method
of representing data using continuously varying
information. Video/analog images displayed on a television
monitor consist of 625 lines where every line of video is a
continuous wave form representing the brightness of the
image. Digital imaging is a method of representing
information or data using discrete or sample
(noncontinuous) information. Images are represented by
discrete picture elements called pixels. Each pixel represents
the brightness of the image sample in quantum steps. For
example, the brightness of a pixel can range from 0 to 255
levels of intensity. A value of 0 corresponds to black and
255 represents white.
Correspondence: Dr G Vijayaraghavan, Department of Cardiology, Welcare
Hospital, PO Box 31500, Dubai, UAE
IHJ-144-01.p65
231
Limitations of Analog Imaging

Analog imaging systems are expensive to maintain and
often require custom adjustment and calibration.
Quantitative analysis or postprocessing of recorded images
is not possible and exact duplication of these images is
virtually impossible. Recorded images lose their quality
significantly. Image quality is extremely difficult to control
and maintain over a period of time.
Advantages of Digital Imaging
Digital imaging enables image quality to be measured and
quantified using software tools. These systems are less
expensive to maintain. Recorded images could be used for
off-line measurement and quantification using software
tools. Digital X-ray angiographic images enable the user to
measure the diameter of the coronary artery or the cardiac
chambers in actual millimeters/centimeters. This format
facilitates exact image reproduction without losing any
information or clarity. Image quality can be altered by
postprocessing and, as the quality is quantifiable, data
management is software dependent and precise.
Digital Angiography
Normally, an angiographic image is created by a complex
process involving at least 5 phases. The X-ray tube emits
the incident beam which after passing through the patient
falls on the the image intensifier, which then converts it into
a visible light signal. An optical system consisting of two
very fast, highly corrected lenses projects this image onto
the pick-up tube of a television camera and, finally, the
television signal is displayed on a television monitor. Video
fluoroscopic images are also connected to the digital image
processor for digitalization and necessary image
manipulation. Computer techniques offer superior image
quality over standard video fluoroscopy. Optimal image
quality depends on the proper integration of the X-ray
generator, the image intensifier system, optical coupling,
video image detectors, monitors and the configuration of
the whole system. In the new totally digital imaging system,
the entire analog image intensifier-based imaging chain is
replaced by a flat panel, amorphous silicon detector.
6/5/01, 12:31 PM
232 Vijayaraghavan
In most digital systems, image processing is done in a

sequential manner. Images are acquired and then processed
by an image processor commonly called the digital
pipeline. Multiple simultaneous operations can be applied
to the image. For medical imaging, the most commonly used
digital processing elements in the digital pipeline are as
follows.
(i) Anti-blooming (Extended Dynamic Range)
enhancement is a technique for equalizing the
brightness of an image.
(ii) Subtraction processing removes unwanted data and
increases the contrast of anatomical objects of interest.
The difference between two images is calculated pixel
by pixel for removing extraneous structures such as
bones and soft tissues.
(iii) Edge enhancement/filtering improves the sharpness
and contrast on any structure containing distinct
edges, like coronary arteries.
(iv) Zoom and pan technique is used to expand areas of
interest and to bring such images to the center of the
monitor.
(v) Upscan interpolation improves the perceived resolution
of an image. It is another form of the zoom filter.
(vi) Brightness and contrast enhancement modifies the
brightness and/or contrast of images.
Image Archiving
Cardiac cine-angiographic study generates a large volume
of digital data so that special care is required to select only
the desired data for archiving. Angiograms use a matrix of
at least 512512 pixels with 8 bits/pixel providing 256 grey
levels. One frame of 5125128 bits consists of 256 000
bytes (0.25 MB). One second of digital angiogram consists
of 7.5 MB of digital data and each angiogram lasts for 6 to
8 seconds. A patient study consisting of 9 to 10 injections
requires 450 to 500 MB of storage space. At the
conventional angio speed of 30 frames/s for coronary
angiography, transfer rates of at least 7.5 MB/s will be
required. We should remember that if we decide to buy an
equipment with a 10241024 matrix, the transfer rate of
data has to be 4 times faster. Archiving of such a large
volume of data can be done cost effectively on a compact
disk (CD). However, we will need standard formats for data
compression and storage which are acceptabe to all
equipment vendors and users.
Digital Echocardiography
Echo Doppler study enables one to view dynamic pictures
of cardiac anatomy, physiology and hemodynamic
IHJ-144-01.p65
Indian Heart J 2001; 53: 231234
Communications in Cardiology
232
parameters. Some rudimentary digital image storage and

retrieval systems were in place in some echo labs as early as
1970. These systems allowed a snapshot of a video field
from a videotape and the resultant storage on a floppy disk.
With the advent of stress echocardiography, the ability to
digitize loops of videotapes was achieved. Now, with the new
generation echo Doppler equipment, digital acquisition,
storage, retrieval and transmission are a reality.2
Echocardiography is in transition today; changing from
a modality in which most images are stored in analog
fashion on videotape into one where most data are stored
digitally.3 This transformation was helped by three factors.
(1) Widespread recognition of the value of digital storage
of echocardiograms, allowing random review of
current and prior studies on split screen on the same
monitor, easier quantification and remote transmission
without image degradation.
(2) Ongoing revolution in the computer industry, doubling
the priceperformance ratio of computers every 18
months, makes all-digital storage of echocardiograms
both feasible and affordable.
(3) Widespread acceptance in the industry of the Digital
Communication in Medicine (DICOM) image
formatting standard for echocardiography.
Digital file format: The echocardiographic image has to
be broken down into discrete bits of information that can
be recorded in a binary code on floppy disk, optical disk, CD
or computer tape. A single full-screen of the video image in
color may take close to 1 MB of storage space. Concurrent
storage of calibration data will allow linear and area
measurements as well as direct quantification from spectral
and color Doppler studies. Video recordings allow 5 to 10
cardiac cycles for each imaging plane to be recorded and
stored. However, this is not possible with the digital format.
One beat loop for each imaging plane has to be stored and
grabbing these best cardiac cycles needs some practice.
During the learning curve, this may increase the scanning
time by 50%. But this will be more than compensated by
saving time for queuing up tapes, searching for old studies,
filing tapes, etc.2
Digital Storage of Medical Images
From 1983, the American College of Radiology and the
National Electrical Manufacturers Association (ACR/
NEMA) were trying to develop common standards for
exchange of digital medical images. DICOM was originally
developed for black and white still images in radiology. The
current version DICOM 3.0 permits color and moving
images with encoding specified for cardiac cine-
6/5/01, 12:31 PM
Indian Heart J 2001; 53: 231233
angiography, diagnostic ultrasonography, nuclear medicine

and numerous other investigations. For the first time,
DICOM 3.0 specifies a file format for actual storage of
images rather than simply exchange protocols for data over
a network, and part of this specifically sanctions the use of
a data compression scheme in disk storage. In 1996,
Thomas and Nissen4 from Cleveland Clinic reported that
approximately one quadrillion bytes (or one million
gigabytes, also called one pedabyte) had to be stored in
one year from the echo Doppler and angiographic
laboratories of that center.
The resolution of a digital image is determined by the
number of pixels, typically ranging from 256256 (64 000
pixels) to 10241024 (1 million pixels). For grey scale
images (angiography), 8 bits per pixel (256 levels) whereas
for color imaging up to 24-bits per pixel (16.7 million hues)
are required. For moving images, the storage requirement,
naturally, is enormous. Echocardiography typically requires
a 512512 pixel matrix with 24-bit color at 30 frames /s,
i.e. 24 MB/s, while angiography requires only 7.5 MB/s.4 A
recordable 5.25 inch CD was found to be the ideal device
for storing angiographic images. This CD, commonly used
for multimedia applications, has a capacity of 680 MB. This
format for recording angiograms was accepted at the annual
session of the 1995 Amercian College of Cardiology and
the European Society of Cardiology, and adopted by all
leading equipment vendors. The CD-R storage capacity of
680 MB permits a recording of nearly 2400 frames per disk.
This will be insufficient to archive all cardiovascular
examinations on a single disk. An average echocardiographic
study, lasting 10 minutes, would exceed 14 GB of storage,
which is completely impractical in clinical practice at
present. Most hospital networks use the ethernet standard,
allowing data transmission at about 10 megabits/s, which
is too slow to allow real-time transmission and viewing of
echocardiographic images over the network. Data
transmission at a speed of 189 megabits/s is required for
transmission of moving color echo Doppler pictures.
Digital data compression will allow us to store a large
amount of digital information in less space. The techniques
available are either lossless or lossy compression algorithms.
Lossless compression is fully reversible or bit preserving and
allows 3:1 data compression by techniques like run-length
encoding. Large areas of homogeneous pixel intensity like
the black screen surrounding the echocardiographic sector
are compresssed to two bytes, one giving the number of
encoded pixels and the other giving the grey value for those
pixels. The images are identical, pixel for pixel when
reconstructed, to the original. Lossy compression enables
significant space saving without much degradation of
IHJ-144-01.p65
233
Vijayaraghavan
233
image quality. This technique, as recommended by the Joint

Photographic Expert Group (JPEG), is being accepted
internationally. It is simple to implement for coding
(compressing) and decoding (decompression). With a
compression ratio of up to 20:1 there is no image
degradation. Image degradation becomes significant with
compression ratios higher than 25:1. Increase of
compression ratio results in an increase in the scatter in
pixel intensity and a decrease in the signal to noise ratio.
The image quality of Super VHS video replay produces an
image degradation equivalent to 26:1 digital compression.
We should remember that degradation of endocardial
borders and myocardial texture is far worse in videocassette
replay images. When a digitally compressed image is
decoded for display and then manipulatedcropped,
edge enhanced, etc.and then re-encoded through
JPEG compression, progressive degradation of the image
may occur. Hence, digital compression must be used only
once and all image processing should be done before
archiving.
The clinician can conserve archiving space by: always
using single loops and four images in quad screens; reducing
play back speed from 30 to 15 frames/s; storing in 256256
matrix rather than 512512 and recording with fewer grey
levels, from the current 256 to 64. An 8 cell loop may be
used instead of a 32 cell loop. By these measures, an original
1 second loop requiring 7.86 MB could be stored in 0.18
MB. Such a compromised archival technique may not be
the ideal solution but it facilitates storage of studies on
floppy disks (1.44 MB) and ordinary PC stations may be used
for storage and viewing. While recording stress echo
pictures, one should store the data as a pair of quad screen
loops with 256256 rasterization and save only the systolic
frames. This will allow storage of each patients data
without compression in a single floppy disk, as the space
required will be only 1 MB.
The Ad Hoc Standards committee5 suggested digital data
compression to increase the storage capacity of the CD-R
so that complete patient files could be stored in a single disk.
Archiving and storage in a CD jukebox will facilitate random
access to data as well as access from any workstation in a
hospital network. However, one should ensure a data
transmission speed of at least 189 megabits/s through
fiberoptic cabling within the hospital building. It is also
advisable that workstation monitors should have a very high
image resolution. Once proper archiving and hospital
networks are established, it is easy to expand the utility of
this facility by establishing hospital to hospital data
transmission as well as tele-medicine consultations with
remote centers.
6/5/01, 12:31 PM
234 Vijayaraghavan
Indian Heart J 2001; 53: 231234
DICOM Standard for Nuclear Cardiolgoy

Nuclear cardiology evolved with a totally digital imaging
format. However, it is often difficult or impossible to transfer
nuclear cardiology images from one computer system to
that with a different configuration. All companies write data
using proprietary software and media. Most of the
equipment vendors have now accepted that their system
will provide the capability to format and exchange data
according to the DICOM 3.0 standard. Necessary software
will be provided to record nuclear cardiology studies
(images, regions of interest, time activity curves, etc.) on a
CD-R. The same CD could have echo or angio images on it
and could be replayed on stand-alone stations or even on
home PCs.
from different places such as doctors offices, hospitals,

laboratories and pharmacies. Delivery of integrated data
will be the facilitator of improved health care delivery.
Patient histories, clinical reports, medical records,
physiological waveforms and various imaging data are now
available in digital format. All this information could be
integrated, displayed, shared, archived and transmitted to
any part of the world. In the future, a patients records could
be stored in a card that may be kept in a pocket, information
could be accessible through a secure internet connection
at the doctors home, office or even by a portable computer.
However, to achieve this goal, we have to overcome many
obstacles. Once these problems are solved, paperless offices,
laboratories and hospitals will be the order of the day.
References
Strategy for the Next Millennium

The percentage of medical specialists using electronic
patient records is still low but many general practitioners
and pharmacists have moved over to the electronic era in
the last few years. Many hospitals have automated patients
registration and appointments, pharmacies, laboratories as
well as hospital finances and administration. Laboratory
results are also processed, reported and stored using
computer systems. Institutions are developing internet sites
with public information on local health services and there
are attempts to develop building blocks for a virtually
distributed electronic patient record. This will facilitate data
storage in a central location although it has been collected
IHJ-144-01.p65
234
1. Condit P. Comparative imaging technology in the cardiac

catheterization laboratory. J Cardiovasc Manag 1993; 4: 1923
2. Adams DB. Digital echo lab. In: Digital Cardiac Imaging in the 21st
Century. A Primer. 1997: p. 128
3. Thomas JD, Khanderia BK. Digital formatting standards in medical
imaging: a primer for echocardiographers. J Am Soc Echocardiogr
1994; 7: 100104
4. Thomas JD, Nissen SE. Digital storage and transmission of
cardiovascular images: what are the costs, benefits and timetable for
conversion? Heart 1996; 76: 1317
5. American College of Cardiology, American College of Radiology and
Industry Developed Standards for Digital Transfer of Angiographic
Images. ACC/ACR/NEMA Ad Hoc Group. J Am Coll Cardiol 1995; 25:
800802
6/5/01, 12:31 PM
Cardiovascular Images
Indian Heart J 2001; 53: 235236
Pulmonary Vein Varix in Association with

Bilateral Pulmonary Vein Stenosis
Bhanu Duggal, Sandeep Seth, Anita Saxena
Department of of Cardiology, All India Institute of Medical Sciences, New Delhi
Fig. 1. Computerized tomography of the chest showing pulmonary vein

varix (arrow) in the posterior segment of the right lower lobe.
Fig. 2. Computerized tomography showing soft tissue thickening in the

perivascular space in the left hilar region.
Fig. 3. Pulmonary artery angiogram (AP view) showing pulmonary varix

in the venous phase.
Fig. 4. The varix draining normally into the left atrium.
blood) just prior to admission. His general physical

examination was unremarkable. Chest X-ray revealed an
oval-shaped 23 cm retrocardiac shadow in the right lower
zone. Echocardiography revealed no gross intracardiac
abnormality. However, the pulmonary venous drainage was
36-year-old male presented with dyspnoea which had

progressively increased in the last six months. He had
one episode of significant hemoptysis (200 ml of fresh
Correspondence: Professor Anita Saxena, Department of Cardiology, All
India Institute of Medical Sciences, New Delhi 110029
IHJ-155-00.p65
235
6/12/01, 10:49 AM
236 Duggal et al.
not clearly visualized because of the suboptimal parasternal

window. Computerized tomography (CT) of the chest
revealed a dilated tortuous vascular structure in the
posterior segment of the right lower lobe abutting on the
inferior vena cava but draining into the left atrium (Fig. 1).
It had smooth, well-defined margins with no evidence of
extravasation of blood. There was soft tissue thickening in
the perivascular space in the left hilar region (Fig. 2) with a
suggestion of narrowing of the left pulmonary vein at its
opening into the left atrium, probably of inflammatory
etiology. Cardiac catheterization revealed severe pulmonary
arterial hypertension (65/30 mmHg). An unexpected
finding was the high pulmonary artery wedge pressure
36 mmHg on the left side and 22 mmHg on the right. Since
the mitral valve and left atrium were normal on
echocardiography and the left ventricular end-diastolic
pressure was 6 mmHg, the pulmonary vascular resistance
was located between the pulmonary capillary bed and the
left atrium. Selective right pulmonary artery angiography
in the venous phase showed a large globular tortuous
opacity in the right lower zone (Fig. 3), sluggishly emptying
into the left atrium (Fig. 4). Selective left pulmonary artery
angiogram showed markedly delayed filling of the
pulmonary veins on the left side. A diagnosis of right lower
zone pulmonary varix with bilateral pulmonary venous
obstruction was made.
The hemoptysis could have been due to rupture of
bronchopulmonary collaterals secondary to pulmonary
venous hypertension, as seen in patients with mitral
stenosis. As the patients problem seemed to be due to an
obstruction of the pulmonary veins, for which surgical
correction would be difficult, it was decided to keep him on
close medical follow-up. The patient remained stable during
hospitalization with no recurrence of hemoptysis. At follow-
IHJ-155-00.p65
Indian Heart J 2001; 53: 235236
Pulmonary Vein Varix
236
up after six months, he is doing well with no recurrence of

hemoptysis.
A pulmonary vein varix is an innocuous lesion, usually
picked up on routine chest X-ray as a coin lesion or a
mediastinal mass. It may be congenital or acquired. The
former is usually asymptomatic1 while the latter presents
with symptoms of the associated disease. Acquired
pulmonary vein varix is the result of sustained pulmonary
venous hypertension and is usually reported with mitral
valve disease. These varices sometimes regress after mitral
valve replacement2 or balloon valvuloplasty. Its association
with pulmonary venous stenosis, which itself is a rare
disorder, has not been reported. Pulmonary venous stenosis
may be congenital or secondary to pulmonary venoocclusive disease, thrombosis, constrictive pericarditis,
mediastinal fibrosis and mediastinal tumour.3 We speculate
that the slow progression of stenosis by a chronic
inflammatory disorder (mediastinal fibrosis) led to the
development of the varix.4 Usually, patients of pulmonary
varix are managed conservatively. Surgical resection is
advised if the size of the lesion increases significantly or if
there is recurrent hemoptysis.
References
1. Hipoma FA, Jamhidi A. Observations on the natural history of
varicosity of pulmonary veins. Circulation 1967; 35: 471475
2. Shida T, Hidetaka O, Nakamura K. Pulmonary varices associated with
mitral valve disease: a case report and survey of literature. Ann
Thoracic Surg 1982; 34: 452456
3. Nasser WK, Feigenbaum H, Fisch C. Clinical and hemodynamic
diagnosis of pulmonary venous obstruction due to sclerosing
mediastinitis. Am J Cardiol 1967; 20: 725729
4. Yoshida S, Akiba H, Tamakawa M, Takeda M, Yama N, Hareyama M,
et al. Acquired anomalous intrapulmonary venous connection
secondary to pulmonary venous stenosis. Br J Radiol 2000; 73:
211213
6/12/01, 10:49 AM
Selected Summaries
Indian Heart J 2001; 53: 237240
Effects of Atorvastatin on Early Recurrent Ischemic Events in

Acute Coronary Syndromes. The MIRACL Study
Gregory G Schwartz et al. JAMA 2001; 285: 17111718
Summary
Myocardial Ischemia Reduction with Aggressive Cholesterol
Lowering (MIRACL) was a multicentric, randomized,
double-blind trial that compared the effect of atorvastatin
80 mg/day, initiated 24 to 96 hours after acute coronary
syndrome (ACS), with a placebo and followed up these
patients for 16 weeks. A total of 3086 adults aged 18 years
or older with unstable angina or non-Q wave acute
myocardial infarction (AMI) were enrolled in the study. The
primary end-point events were death, nonfatal myocardial
infarction (MI), cardiac arrest with resuscitation, or
recurrent symptomatic myocardial ischemia with objective
evidence and requiring emergency rehospitalization. The
primary end-point event occurred in 228 patients (14.8%)
in the atorvastatin group and 269 patients (17.4%) in the
placebo group (relative risk [RR], 0.84; 95% confidence
interval [CI]: 0.701.00; p=0.048). However, despite
significantly lower rates of readmission (6.2% v. 8.4%; RR
0.74; 95% CI: 0.570.95; p=0.02), reduction in mortality
(4.0% v. 4.4%) and nonfatal MI (6.6% v. 7.3%) was not
significant. Reduction of primary ischemic events by
atorvastatin did not appear to depend on the baseline level
of LDL cholesterol. There was no significant difference in
the incidence of secondary outcomes of coronary
revascularization procedures, worsening heart failure or
worsening angina, although there were fewer strokes in the
atorvastatin group (12 v. 24 events; p=0.045). Elevation
of liver transaminases (>3 times the upper limit of normal)
were more common in the atorvastatin group (2.5% v.
0.66%; p<0.001).
Comments
Numerous trials have demonstrated the efficacy of lipid
lowering in both primary prevention (Helsinki Heart Study
and WOSCOPS Study) and secondary prevention (Post
CABG, 4S, LIPID and CARE) of coronary artery disease
(CAD). Lowering of lipids leads to reduction of nonfatal MI
and reduces cadiovascular and overall mortality. Statins are
the most effective lipid-lowering agents. Conventionally,
they have been used for secondary prevention only in
patients with stable CAD. The studies excluded patients who
had an ACS within 36 months of enrollment. These
patients were excluded because it was believed that
determination of total cholesterol levels during the acute
phase may be fallacious and factors which are important
IHJ-Selected Summary.p65
237
during the acute phase like left ventricular dysfunction,

ventricular arrhythmias, and mechanical complications
were unlikely to be affected by lowering the lipid levels.
Furthermore, as per lipid-lowering studies in stable CAD, it
took at least 12 years before a significant reduction in
cardiovascular events occurred and therefore lipid lowering
was not considered to be of immediate importance. As the
highest risk of death and recurrent ischemic events is within
the first few weeks of ACS, any therapeutic strategy during
this period is likely to provide more benefit. The nonlipidlowering effects of statins like plaque stabilization,
improvement in endothelial function, antithrombotic and
anti-inflammatory activities are well known. However,
whether these effects are operative in an acute coronary
syndrome setting and lead to an additional reduction in
cardiovascular events have not been addressed by a large
prospective randomized study. In an observational study
by the Swedish Registry of Cardiac Intensive Care, the use
of statins at or before discharge after AMI was associated
with 25% reduction in relative risk for mortality at 1 year.
The MIRACL study is the first prospective randomized study
which shows that potent lipid-lowering therapy
(atorvastatin 80 mg) started within 96 hours of ACS could
reduce event rate as early as 16 weeks after initiation of
therapy even in patients with nearly normal baseline
cholesterol levels (mean LDL cholesterol 124 mg/dl).
However, the MIRACL study was not empowered to detect
small differences in mortality. The reduction in stroke rate
in the MIRACL study appears to be an additional benefit of
statin therapy. However, data from the MIRACL study
requires careful interpretation. The positive findings in this
trial are not very definitive. The p value of 0.048 is
marginally significant. The MIRACL study lost 11 patients
to follow-up, 8 of them from the atorvastatin group. If these
patients were lost to follow-up because of death or severe
stroke, the result would no longer be statistically significant.
Thus, the possibility of a type I statistical error cannot be
ruled out. Secondly, a fixed dose of atorvastatin 80 mg/day
was used. This high dose may not be necessary because the
beneficial effects may be due to effects other than lipid
lowering. However, limitations notwithstanding, the results
of the MIRACL study are optimistic and, given the potential
for short-term benefit, the definite longer-term benefit and
absence of harm, it may be prudent as of now to include
statins as an integral part of therapy in ACS. Several other
trials including A to Z, PRINCESS and PACT are also
evaluating the role of statins in acute coronary syndromes.
6/5/01, 11:57 AM
Indian Heart J 2001; 53: 237240
238 Selected Summaries
Unprotected Left Main Coronary Artery Stenting: Immediate and Medium-Term

Outcomes of 140 Elective Procedures
Marc Silvestri et al.
Summary
This study evaluated immediate and medium-term
outcomes after stenting in 140 consecutive unselected
patients with unprotected left main coronary artery (LMCA)
disease. Patients were divided into two groups. Group I
included 47 patients categorized as poor surgical candidates
because of a contraindication to cardiopulmonary bypass
by one or more surgeons or the presence of any of the
following factors : age more than 75 years, history of heart
surgery, left ventricular ejection fraction lower than 35%,
renal failure, inadequate coronary distal run-off or severe
respiratory failure. Group II included 93 patients with no
such contraindication (low-CABG-risk patients). Nearly
half the cases (49%) presented with unstable angina
whereas 11% patients had silent ischemia. Besides the
LMCA, the right coronary artery was occluded in 14% of
patients and another 33% showed significant stenosis.
Overall, 47% of patients had triple-vessel disease. The site
of the LMCA lesion was the ostium in 10%, midportion of
the artery in 38% and the distal portion in 52%. The mean
number of lesions treated per patient was 1.8 and complete
revascularization was achieved in 70% of cases. Procedural
success was obtained in 100% of cases with a very low local
complication rate (0.7%). One-month mortality was 9% in
Group I and 0% in Group II. Among the 4 deaths that
occurred in Group I patients, 2 were due to subacute
thrombosis, 1 due to terminal left ventricular failure and 1
due to aortic prosthesis thrombosis. No stent thrombosis was
observed in Group II. A follow-up angiography was obtained
in 82% of cases, and target lesion revascularization (TLR)
was required in 17.4% (10.5% in Group I and 21% in Group
II). Medium-term results showed a restenosis rate of 23%.
One-year acturial survival was 89% in Group I patients and
97.5% in Group II patients. The authors attribute the
excellent immediate results to the absence of acute
thrombosis, probably because of the large size of the LMCA,
optimal deployment of stents (with kissing balloon inflation
for bifurcation) and perfect compliance with ticlopidine
therapy. The problem of distal LMCA dilatation could be
overcome to a great extent after the introduction of a
simultaneous double balloon dilation of the LAD and
circumflex arteries at the end of the procedure. This
probably brought down the overall restenosis rate (similar
to that seen after stenting at other coronary sites). The low
rate of complications could be ascribed to the use of
ticlopidine and 6 F or 7 F guiding catheters. Stenting reduces
238
J Am Coll Cardiol 2000; 35: 15431550
the need for hemodynamic assistance (IABP, circulatory

support), which is a well known source of local morbidity.
Comments
Conventionally, CABG has been considered to be the
treatment of choice in patients with LMCA disease. Results
of medical stabilization have been disappointing. Plain
balloon angioplasty was associated with several problems.
There was a substantial perioperative mortality, restenosis
rates were high, and long-term survival rates were
unsatisfactory. In patients in whom the LMCA was
unprotectedthat is, lacking a patent graft to either the
left anterior descending or circumflex artery the one-year
mortality after left main angioplasty was 30%, and hence
not much better than that for medical therapy. However,
the explosive growth of coronary stenting and the
availability of potent antithrombotic agents like ticlopidine
have prompted new attempts at LMCA dilatation.
Karnowski et al. have shown that stenting is superior to
balloon angioplasty in the LMCA. There was higher
procedural success (98% v. 92%), lower procedural
complications (0% v. 5.4%), lower TLR (15% v. 18%) and a
higher 1-year event-free survival (78% v. 76%). More
recently, several workers (Kosuga et al., OKeefe et al., Eldar
et al., Park et al., Wong et al., Tamura et al.) have published
their own series. The angiographic success rate is generally
high (>95%) but in-hospital mortality has been variable
(0%40%) depending on the type of patients enrolled. The
incidence of TLR varied from 20% to 40%. In a study by
Park et al. who reported results in 42 patients with normal
left ventricular function, the angiographic success rate
was 100%, there were no in-hospital complications, the TLR
was 17% and 1-year mortality was 2.5%. A recent study
by Fajadet and his group has also confirmed the same
findings in 92 consecutive patients of unprotected LMCA
disease. The procedural success rate was 100%. The inhospital mortality was 4%, overall mortality was 3.8% in
the low surgical-risk group and 20.5% in the high-risk
group. Although all these studies suggest that LMCA
stenting is a safe and efficacious alternative to CABG, the
data should be interpreted with caution as there might have
been a publication bias in favor of positive studies.
Unprotected LMCA stenting should be used only in selected
patients and that too by an experienced operator in highvolume centers.
6/5/01, 11:57 AM
Indian Heart J 2001; 53: 237240
Selected Summaries 239
Arterial Revascularization Therapies Study (ARTS)

PW Serruys et al. N Engl J Med 2000; 314: 11171124
Summary
The Arterial Revascularization Therapies Study (ARTS) was
a prospective randomized trial conducted to compare the
clinical outcome and costeffectiveness of multivessel
stenting and bypass surgery in 1205 patients with
multivessel disease, in whom an equivalent degree of
revascularization was achievable with both techniques
(patients with left main coronary artery disease, recent
transmural myocardial infarction (MI) and left ventricular
ejection fraction (LVEF) <30% were excluded). The primary
end-point of freedom from death, major cardiac or
cerebrovascular event or repeat revascularization at 12
months was significantly better in the surgery group
compared to the stent group (87.8% v. 73.8%, p<0.001),
primarily due to a lesser need for repeat revascularization
(3.5% v. 16.8%), while there was no difference in the rate
of death, stroke or MI. Thrombosis occurred in 1.1% of
stents (2.8% patients). Throughout the 12-month period
of observation, more patients were free from angina after
surgery than after stenting (90% v. 79%). Multivariate Cox
regression analysis revealed that the only predictor of
outcome was an elevation in postoperative creatine kinase
(CK-MB) in the surgery group and diabetes mellitus in the
stent group. Eight major adverse cardiac events occurred
during the waiting period in the surgery group while only
1 event occurred in the stent group as the waiting period
was nearly 2.5 times longer in the surgery group (2739
days v. 1116 days). At 1 year, there was still a substantial
costbenefit (2973 dollars per patient) in the stent group
despite the higher re-intervention rate with a calculated
additional cost of approximately 21000 dollars for every
patient-year free of events with surgery. This led the
investigators to conclude in favour of percutaneous coronary
intervention (PCI) in such patients, with the caveat that the
patient and the physician should weigh the possible need for
further procedures prior to taking the final decision.
Comments
The results of this trial are consistent with the available
data on the role of these strategies in patients with
multivessel disease, wherein PCI is found to be cheaper (in
western countries) and less invasive with earlier recovery,
but with a much higher need for repeat revascularization.
239
Most of the previous studies, including the BARI, GABI,

EAST, CABRI, ERACI-1 and RITA-1, however, compared
surgery with PCI without the use of stents or glycoprotein
(Gp) IIb/IIIa inhibitors. ARTS is different in that each patient
received at least 2 stents, though coated stents and Gp IIb/
IIIa inhibitors were not used, which might have significantly
reduced the stent thrombosis rates and thus the adverse
events. The only other study with contrasting results is
the ERACI-II, where PCI compared to surgery in a
population of patients with predominantly unstable angina
(92%) with multivessel disease was associated with a
significantly better survival (96.9% v. 92.5%) and freedom
from MI (97.7% v. 93.4%) at a mean follow-up of 18.56.4
months. However, ERACI-II has been said to be biased
against surgery, with the mortality being nearly twice as
high as expected in a group with equivalent risk factors.
The perioperative mortality was 3.3% in the New York
Cardiac Surgery and Angioplasty Case Registry. The adverse
implications of diabetes mellitus in patients undergoing
multivessel angioplasty bears out the results in the BARI
subgroup, in which treated diabetics undergoing multivessel
balloon angioplasty had a higher mortality (5-year survival
of 65.5% v. 80.6% in the surgery group, p=0.003). Even
though Gp IIb/IIIa inhibitors, which have been shown to
improve the outcome of stenting in diabetics to levels
comparable to nondiabetics, were not used in both studies,
this highlights the prognostic significance of diabetes and
thus the need for serious thought prior to attempting PCI
in these patients. As the waiting period is much longer for
surgery, it can be associated with an increased risk of major
adverse cardiac events while awaiting surgery. Both
strategies are thus acceptable in an individual patient
provided they are feasible, the decision being based on
patient preference. Of note, however, is the fact that only
<10% of multivessel disease patients were finally
randomized in these trials, emphasizing the fact that
surgery remains the preferred modality in most of them.
The situation is somewhat different in our country, where
the initial cost of multivessel stenting is usually higher than
surgery, and the need for Gp IIb/IIIa inhibitors and repeated
revascularization procedures make it costlier still. Such an
approach becomes extremely expensive in our setting,
where only a patient with no financial constraints and
wishing to avoid the more invasive surgical option is a
suitable candidate for multivessel stenting.
6/5/01, 11:58 AM
Indian Heart J 2001; 53: 237240
240 Selected Summaries
One-year Survival Following Early Revascularization for Cardiogenic Shock (SHOCK trial)
JS Hochman et al. JAMA 2001; 285: 190192
Summary
Should We Emergently Revascularize Occluded Coronaries
for Cardiogenic Shock (SHOCK) trial was an unblinded,
randomized, controlled trial involving 302 patients with
acute myocardial infarction (AMI) and cardiogenic shock
(CS), mostly due to left ventricular failure. The trial was
designed to compare the utility of early revascularization
with aggressive medical management. The initial medical
stabilization (IMS) group of 150 patients received
thrombolysis (63%), intra-aortic balloon counterpulsation
(IABP) (86%) and subsequently (after 54 hours or more)
revascularization (25%). The early revascularization (ERV)
group of 152 patients underwent angioplasty (PTCA) (55%)
or coronary bypass surgery (CABG) (38%) within 6 hours
of randomization. There was a non-significant
improvement in survival in the ERV group at 1 month (56%
v. 47%) but at 1 year (a prespecified secondary end-point)
the survival was significantly better in the ERV group
(46.7%) than in the IMS group (33.6%) (p<0.03, with a
relative risk [RR] of death 0.72, 95% CI: 0.540.95). Age
was the only factor out of 10 prespecified variables that
interacted significantly with the treatment, the 1-year
survival being better only in patients <75 years of age
(51.6% in the ERV group v. 33.3% in the IMS group,
p<0.03). The investigators thus recommend early transfer
of AMI patients with CS to centers with facilities for early
revascularization, especially in those <75 years of age.
Comments
Cardiogenic shock (CS) in the setting of AMI is associated
with a high mortality regardless of the management
strategy. Previous nonrandomized trials and retrospective
studies have shown that thrombolysis, IABP use and early
revascularization using either PTCA or CABG reduced
mortality. Survival was distinctly better in patients
undergoing coronary angiography (signifying a low-risk
subgroup), as well as in those who underwent successful
PTCA compared to those who had a failed PTCA in previous
nonrandomized studies and the prospective SHOCK
Registry. The only other randomized trial was SMASH,
240
which was limited by the small number of patients enrolled

(32 in the invasive and 23 in the medical strategy group)
and did not show any difference in mortality (69% v. 78%,
p=ns). Even the SHOCK trial failed to demonstrate the
benefit of an early revascularization strategy over aggressive
medical management in 30-day mortality (primary endpoint of trial 56% v. 47%, p=0.11), though there was a
significant benefit at 6 months (50.3% v. 63.1%, p=0.027),
which persisted till 1 year. The late survival benefit achieved
is expected, as the early hazard of surgery is more than offset
only after long periods of follow-up in this high-risk cohort.
Previous studies have shown that thrombolytic therapy (TT)
and IABP are used less often than indicated in CS patients
(German 60 minute MI Project and GUSTO-1), but when
used, they improve survival significantly despite the efficacy
of thrombolysis being lower in these patients (42%48%).
The SHOCK Registry also reveals a lower mortality in
thrombolysed patients versus those not thrombolysed (54%
v. 64%, p=0.005) and in those in whom IABP was used
versus those in whom it was not used (50% v. 72%,
p<0.0001). There was a graded rise in mortality in subjects
in whom these measures were not used, from 47% in both
the TT and IABP groups, to 52% in IABP alone, 63% in TT
alone and 77% in those in whom neither was used
(p<0.0001). However, survival correlated best with early
revascularization, where the mortality was 39% compared
to 78% in those not revascularized (p<0.0001). Thus, a
combination of these aggressive measures helps to stabilize
patients till they are taken up for intervention (25% in the
IMS group of SHOCK), leading to a similar 30-day survival
as in the ERV group. However, the improved 6- and 12month outcome of the ERV group forces one to think that
the intermediate-term outcome is better in patients offered
ERV, possibly due to more myocardial salvage and thus lesser
events over follow-up. The net 39% reduction in 1-year
mortality translated into an absolute benefit of 132 lives
saved per 1000 treated, which is a major gain. Hence, it
would be prudent to offer these patients aggressive therapy
right from the onset, and all patients with CS (especially
those <75 years of age) should be referred to centers with
facilities for urgent revascularization.
6/5/01, 11:58 AM
Letters to the Editor
Indian Heart J 2001; 53: 241
Can We Eradicate Rheumatic Fever

in the 21st Century?
4. Adam D, Scholz H, Helmerking M. Short-course antibiotic treatment of 4782 culture-proven cases of group A streptococcal
tonsillo-pharyngitis and incidence of poststreptococcal sequelae.
J Infect Dis 2000; 182: 509516
he review article on rheumatic fever (RF) 1 was

interesting. However, the guidelines for secondary
prevention need reconsideration. This is now relevant as
excellent echocardiographic techniques for visualization of
the valves are available.
The blanket long-term prophylaxis2 recommended for all
cases of RF is unjustifiable. It causes much physical and
psychological pain to the patient and his/her family. The
main aim of secondary prophylaxis for RF is to prevent valve
disease. In the case of RF, the mitral valve is the most
commonly affected. The moot point is whether a recurrence
of RF will have any effect on a badly damaged valve, and if
so, what greater damage would it cause? In such cases,
should the cumbersome prophylaxis be continued if the
valve is already badly damaged?
Echocardiography can provide the answer. In a patient
with a history of RF, the mitral valve should be checked for
fibrosis or calcification. If these are absent or minimally
present, then aggressive RF prophylaxis needs to be
instituted, which can even be lifelong. Such a strategy is
worth the effort because it will, hopefully, prevent valve
damage. However, the lenient strategy adopted in the USA
for patients without rheumatic heart disease (RHD), as
mentioned in the article, would sometimes be enough for
such patients. As a corollary, effective prophylaxis should
also be adopted for patients who have undergone balloon
valvotomy.
In patients with a badly damaged fibrotic or calcified
valve, continuation of the prophylaxis would not be worth
the effort. Similarly, some authorities have recommended
prophylaxis for patients with a prosthetic valve.3 Here again,
I see no reason why RF would affect a biologically inert
structure. In all these cases, the probable theoretical benefits
would be protection of the other valves, especially the aortic
valve, and prevention of fulminant forms of carditis.
Fortunately, these are rare in this age of widespread use of
antibiotics.4 The basis of any treatment is to weigh the
benefits against the harm that could be done. Each patient
should be optimally treated according to individual
circumstances. It is time we had a thorough re-look at
secondary prevention of RF.
References
1. Stollerman GH. Can we eradicate rheumatic fever in the 21st
century? Indian Heart J 2001; 53: 2534
2. ACC/AHA guidelines for the management of patients with
valvular heart disease. J Am Coll Cardiol 1998; 32: 14861588
3. Dajani AS. Rheumatic Fever. In: Eugene Braunwald (ed). Heart
DiseaseA Textbook of Cardiovascular Medicine. 5th ed. Bangalore: Prism Books; 1997: p. 1774
Letter to Editor.p65
241
Dr George Thomas
Department of Cardiology
Indira Gandhi Co-operative Hospital
Gandhi Nagar, Kochi 682020, India
Reply
ertainly blanket recommendations for secondary

prophylaxis of RF are made with reservations that
consider the judgment of clinicians concerning individual
patients in various geographical and socioeconomic
settings. As Dr George Thomas suggests, The main aim of
secondary prophylaxis for RF is to prevent valve disease
and therefore, where the greatest damage to the heart has
already occurred, e.g. advanced mitral stenosis, prevention
of further damage is unlikely. Were every RHD patient to
have the benefit of expert echocardiography to diagnose
irreparable mitral valve damage (not likely to be available
in all settings in which RF is rampant), and to have the
further benefit of expert valve replacement in such cases
(also unlikely to be available or affordable in all settings),
they might indeed be able to survive repeated attacks of
acute RF, even when such recurrences may be accompanied
by pancarditis with pericardial effusion and myocarditis,
and possible further damage to the aortic valve. Should one
gamble on that assumption?
I would welcome reference to some reliable data,
however, on just how well patients with advanced mitral
valvular disease, with and without valve replacements, fare
from recurrent acute rheumatic attacks. I recall that even
in the days before echocardiography, some patients with
advanced rheumatic valvular disease (well diagnosed by
competent clinicians), were lost due to recurrent rheumatic
attacks valvular surgery notwithstanding. If secondary
prophylaxis recommendations are to be further modified,
so that patients with advanced RHD no longer require
prophylaxis because of the benefits of expert modern
cardiology and cardiovascular surgery, we need to see the
data on which such modifications should be based. Does
the alleged suffering from continued use of antibiotic
prophylaxis by patients with advanced RHD exceed their
potential suffering from repeated attacks of RF? Perhaps, if
the risk of rheumatic recurrences no longer exists.
Professor Gene H Stollerman
# 21, The Courtyard, Hanover
New Hampshire 03755, USA
e-mail: gstollerman@valley.net
6/5/01, 12:28 PM
Calendar of Conferences
June 2427, 2001, 4th International Meeting on
Interventional Cardiology, Tel Aviv, Israel
Contact: The Secretariat, 4th International Meeting on
Interventional Cardiology
P.O. Box 50006, Tel Aviv 61500, Israel
Fax: 972 3 517 5674,
e-mail: intercard4@kenes.com
June 2730, 2001, American Society of
Echocardiography: 12th Annual Scientific Session,
Washington State Convention Center, USA
Contact: The Secretariat, Washington State Convention
Center, Seattle, WA, USA
Website: www.asecho.org
July 611, 2001, XVII World Congress of the
International Society for Heart Research, Winnipeg,
Manitoba, Canada
Contact: Institute of Cardiovascular Sciences, St. Boniface
General Hospital Research Centre, University of
Manitoba, Faculty of Medicine, 351 Tache
Avenue, Winnipeg, Manitoba R2H 2A6, Canada
Fax: 1 204 233 6723,
e-mail: ishr@cc.umanitoba.ca
July 29Aug 10, 2001, 27th 10-Day Seminar on the
Epidemiology and Prevention of Cardiovascular
Diseases, Granlibakken Conference Centre, Tahoe, CA
Contact: David C Goff Jr, Seminar Director, c/o American
Heart Association, 7272 Greenville Avenue,
Dallas, Texas 75231, USA
Fax: 1 214 373 3406
September 15, 2001, XXIII Congress of the
European Society of Cardiology, Stockholm, Sweden
Contact: European Congress Organization (ECOR), The
European Heart House, Stockholm, Sweden,
Fax: 33 4 9294 7620,
e-mail: scientific@escardio.org
October 36, 2001, 13th Asia-Pacific Congress of
Cardiology, Manila, Philippines
Contact: Dr Noe A Babilonia, Chairman, Organizing
Committee, 13th APCC, Suite 1108, 11th Floor,
East Tower, PSE Centre, Exchange Road, Ortigas
Commercial Complex, Pasig City, Manila 1605,
Philippines, Fax: 632 634 7441
Cal of Conference.p65
242
Indian Heart J 2001; 53: 242
October 1316, 2001, VII Asian-Pacific Symposium

on Cardiac Pacing and Electrophysiology, Beijing, China
Contact: Dr Hu Da Yi, Secretary-General, VII APSPE,
Beijing Red Cross Chaoyang Hospital
8 Baijiazhang Road, Chaoyang District, Beijing
100020, Peoples Republic of China
Fax: 86 10 6593 7858,
e-mail: heart@bme-cspe.org
November 1114, 2001, 74th Scientific Session,
American Heart Association, Anaheim, California, USA
Contact: American Heart Association, 7320, Greenville
Avenue, Dallas, Texas 75231, USA
Fax: 1 214 373 3406
February 810, 2002, VIth World Congress of
Echocardiography and Vascular Ultrasound,
New Delhi, India
Contact: Dr (Col) SK Parashar, Secretary General,
C-144, Sarita Vihar, New Delhi 110044,
Fax: 6 942222,
e-mail: parashar@del6.vsnl.net.in
March 1720, 2002, 51st Annual Scientific Sessions,
American College of Cardiology, Atlanta, Georgia, USA
Contact: American College of Cardiology, 9111 Old
Georgetown Road, Bethesda, MD 20814, USA
Fax: 1 301 897 9745
May 59, 2002, XIV World Congress of Cardiology,
Sydney, Australia
Contact: The Congress Secretariat, QVB Post Office Locked
Bag Q4002, Sydney, NSW 1230, Australia,
Fax: 61 2 9290 2400,
e-mail: wcc@icms.com.au
July 1721, 2002, 14th Asean Congress of Cardiology
Kuala Lumpur, Malaysia
Contact: Dr David KL Quek, Chairman, Organizing
Committee, c/o Letter Box 1, 15th Floor, Menara
Merais, 1 Jal Petaling Jaya 46300, Selangor, Ma
Fax: 60 3757 8363
August 31September 4, 2002, XXIV Congress of the
European Society of Cardiology, Berlin, Germany
Contact: European Society of Cardiology (ECOR), B.P. 174,
Sophia Antipolis Cedex F-06903, France
Fax: 33 49244 7601
6/5/01, 5:22 PM

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Editorial

Indian Heart J 2001; 53: 147154

Management of Coronary Artery Disease in

iabetes mellitus (DM) is a common medical problem

macrovascular complications in both insulin-requiring DM

148 Bahl et al.

Indian Heart J 2001; 53: 147154

Management of Coronary Disease in Diabetics

in the 35-day mortality after thrombolysis in patients with

Indian Heart J 2001; 53: 147154

diabetics (72.4%). Outcome at 30 days for death, MI and

Management of Coronary Disease in Diabetics

event rates as compared to non-diabetics.16

150 Bahl et al.

revealed a decreased 6-week mortality in diabetic patients

Indian Heart J 2001; 53: 147154

Management of Coronary Disease in Diabetics

Balloon angioplasty: PTCA in diabetic patients has a high

Indian Heart J 2001; 53: 147154

incidence of both restenosis (37.5% v. 28.3%, p<0.001) and

Management of Coronary Disease in Diabetics

diabetic patients to that of placebo-treated non-diabetic

152 Bahl et al.

single-center EAST had 15% drug-treated diabetic patients.

Indian Heart J 2001; 53: 147154

Management of Coronary Disease in Diabetics

CABG, while the rate of event-free survival was better in the

Indian Heart J 2001; 53: 147154

8. Fibrinolytic Therapy Trialists (FTT) Collaborative Group. Indications

Management of Coronary Disease in Diabetics

23. Swedberg K, Held P, Kjekshus J. Rasmussen K, Rydeat L, Wedel H,

154 Bahl et al.

EPILOG Investigators. Circulation 1998; 97: 19121920

Indian Heart J 2001; 53: 147154

Management of Coronary Disease in Diabetics

in the mortality of the CABRI diabetic and non-diabetic population

Indian Heart J 2001; 53: 155162

Percutaneous Coronary Intervention in Patients

cute coronary syndrome refers to a constellation of

156 Singh et al. Coronary Intervention in Unstable Angina

(ESSENCE) trials.911 The risk factors associated with a

Indian Heart J 2001; 53: 155162

cardiac events and would allow cardiologists to stratify these

Indian Heart J 2001; 53: 155162

Coronary Intervention in Unstable Angina 157

High risk (at least 1 of the following

Intermediate risk (no high-risk feature

Accelerating tempo of ischemic

Prior MI, peripheral or cerebrovascular

Prolonged ongoing (>20 min) rest

Prolonged (>20 min) rest angina, now

Pulmonary edema, most likely

Angina at rest with transient ST

T wave inversions >0.2 mV

Markedly elevated (e.g, TnT or TnI

Slightly elevated (e.g. TnT >0.01 but

Low risk (no high- or intermediate-risk

New-onset CCS class III or IV angina

Normal or unchanged ECG during an

reduction in the 30-day incidence of death or myocardial

Abciximab is currently approved for treatment of UA/

158 Singh et al. Coronary Intervention in Unstable Angina

The 2 groups were matched for the baseline characteristics.