Editorial
Acute Myocardial Infarction in Diabetes Mellitus
Lessons Learned From ACE Inhibition
Richard W. Nesto, MD; Stuart Zarich, MD
iabetes mellitus affects '6% of the US population but is
D
present in as many as 30% of patients hospitalized with
acute coronary syndromes. It has been recognized for
some time that diabetics experience a greater mortality during
the acute phase of myocardial infarction (MI) and a higher
morbidity in the postinfarction period (see recent reviews in
References 1 and 2). Before the advent of coronary care as we
know it today, mortality among diabetic patients in MI was
reported to be as high as 40%3 and at least double the mortality
rate in patients without diabetes. More extensive coronary
artery disease, additional cardiovascular risk factors, and other
end-organ disease were thought to be largely responsible for
this major difference in outcome. Current treatment of acute
MI derived from large clinical trials has dramatically improved
survival in both nondiabetic and diabetic patients. However,
despite these improvements, diabetes still doubles the case-
fatality rate. In the GUSTO-1 angiography substudy report,4
this twofold increase in relative risk of 30-day mortality
persisted even after adjustment for the factors cited above.
What is this “diabetic factor”? It is in this context that new
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information on this topic must be evaluated.
In the December 16, 1997, issue of Circulation, the GISSI-3
investigators compare the effect of early administration (within
24 hours of admission) of lisinopril in patients with and
without diabetes mellitus in MI.5 Compared with placebo,
lisinopril dramatically reduced both 6-week and 6-month
mortality in diabetics versus nondiabetics (6 weeks, 30% versus
5% and 6 months, 20% and 0%, respectively). Furthermore, the
incidence of drug-related adverse effects was similar between
the two groups within the blood pressure and renal function
parameters used in that study. This experience, along with the
subgroup analyses of SAVE6 and TRACE,7 should firmly
establish an ACE inhibitor as part of the regimen for the
diabetic patient with MI. In a recent meta-analysis of ACE
inhibitor trials in acute MI, only a 6% relative mortality
reduction (without regard to the presence or absence of
diabetes mellitus) was found with early drug administration.8
Despite these collective data, ACE inhibitors are generally
withheld on the first day of acute MI to avoid causing
The opinions expressed in this editorial are not necessarily those of the
editors or of the American Heart Association.
From the Cardiovascular Division, Beth Israel Deaconess Medical
Center, Harvard Medical School, Boston, Mass (R.W.N.) and the
Cardiovascular Division, Bridgeport Hospital, Yale University Medical
School, Bridgeport, Conn (S.Z.).
Correspondence to Richard W. Nesto, MD, 110 Francis St, Suite 4B,
Boston, MA 02215.
E-mail rnesto@west.bidmc.harvard.edu
(Circulation. 1998;97:12-15.)
© 1998 American Heart Association, Inc.
12
hypotension. In CONSENSUS II,9 hypotension in the enala-
pril-treated group negated any potential benefit of early ACE
inhibition. This GISSI-3 report also suggests that the diabetic
patient may have far more to gain than the nondiabetic when
an ACE inhibitor is administered within the first day of an
acute MI. The putative mechanisms responsible for the major
benefit of lisinopril in these patients are presented below.
In general, ACE inhibitors are grossly underprescribed in
this setting, despite their recognized benefits.10 The failure to
use them in diabetic patients may be even more prevalent, for
the following reasons: (1) fear of azotemia with or without
preexistent renal disease; (2) fear that they may cause or
contribute to hemodynamic instability, particularly if diabetes-
related autonomic neuropathy is suspected; (3) fear that they
may induce hyperkalemia, because type 4 RTA or bilateral
renal artery stenoses are more common in diabetics; and (4)
preoccupation with the challenge of glycemic control. A
similar paradox relates to the failure to administer b-blockers to
diabetic patients in acute MI.11 Compared with placebo in this
setting, b-blockers provide two to three times the relative
benefit in mortality reduction when diabetes is present com-
pared with when it is absent.12 However, the risk of masking
the warning signs of hypoglycemia and disturbing glycemic
control tends to limit their use. Although these are valid
concerns, insulin-induced hypoglycemia occurs far less com-
monly in type II than in type I diabetic patients, and cardio-
selective b-blockers can be given in doses providing secondary
prevention with less effect on glucose metabolism than non-
selective agents.13,14 Much of the reluctance to administer these
agents stems from warnings issued years ago when only
nonselective b-blockers were available and were typically
prescribed in much higher dosages.
The GISSI-3 authors address only briefly the potential mechanisms
underlying the benefit of lisinopril in diabetic patients. Both in-
hospital and late mortality after acute MI are highly correlated with
the degree of left ventricular dysfunction. A major determinant of this
prognostic variable is left ventricular remodeling, a process involving
expansion of the infarcted segment with subsequent ventricular
dilatation and asynergy of the noninfarcted regions. After adjustment
for the size of infarction, diabetic patients experience more congestive
heart failure than nondiabetic patients, which suggests that the
behavior of the noninfarct zone may be an important determinant in
the outcome between the two groups.1,2 For many years, more
extensive coronary artery disease in the diabetic patient was thought
to explain the greater degree of left ventricular dysfunction. In
GUSTO-1, however, the twofold increase in relative risk of 30-day
mortality conferred by the presence of diabetes remained unaltered
after adjustment for extent of coronary artery disease and a variety of
other clinical factors.4
 Nesto and Zarich
Many conditions specific to the heart in diabetes affect
global myocardial remodeling. Previous silent infarction may
be present in as many as 40% of these patients at the time they
present with their first clinically recognized MI.5,15 Cardiac
autonomic neuropathy may be present in nearly 50% of the
diabetic population with coronary artery disease16 and can
cause both diastolic and systolic dysfunction. Cardiomyopathy
secondary to diabetes is often subclinical, with diastolic dys-
function typically preceding systolic dysfunction.17 Hyperten-
sion and diabetes together result in more cardiac fibrosis than
when either occurs alone.18 Endothelial dysfunction may
impair coronary perfusion at the microvascular level, resulting
in ischemia.19 Although the heart utilizes free fatty acids as its
major source of energy, ischemia results in greater expression
of GLUT4 transporter proteins, facilitating glucose entry and
glycolysis, a major source of myocardial ATP in anaerobic
conditions.20 In diabetes, however, ATP generation is less
efficient, because relative insulinopenia results in increased
lipolysis, elevated plasma levels of free fatty acids, and increased
fatty acid oxidation as glycolysis and glucose oxidation are
suppressed.21 In addition, despite the hyperglycemia most
diabetics experience in acute MI, glucose is unavailable as an
energy source, because myocardial GLUT4 transporter protein
levels may be depressed.22 These metabolic perturbations result
in depressed ATP production, generation of oxygen free
radicals, increased myocardial oxygen consumption, and myo-
cardial contractile dysfunction. It is not surprising that addi-
tional myocardial damage results in heart failure out of pro-
portion to infarct size in patients with diabetes.
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Several studies support the notion that the structural, func-
tional, and metabolic factors related to diabetes cited above
place the left ventricle at higher risk for maladaptive remod-
eling. One study comparing serial wall motion scores after MI
showed that left ventricular function at discharge and at 6
months remained stable in nondiabetic patients, whereas it
progressively deteriorated in the patients with diabetes.23
Iwasaka and coworkers,24 using radionuclide angiography,
found that regional ejection fraction of the noninfarct zone at
any end-diastolic volume 3 weeks after MI was lower in
patients with diabetes, despite infarct size and extent of
coronary artery disease similar to those in the group without
diabetes. Diabetic patients demonstrated more global and
regional left ventricular dysfunction 4 weeks after inferior MI
than their nondiabetic counterparts in another study that used
radionuclide ventriculography.25
Remodeling of the left ventricle consequent to MI is a time-
dependent phenomenon. Increases in end-diastolic and end-systolic
volumes may be seen within 3 hours of admission26 and serve as
strong predictors of both early and late outcome. In the HEART
study, early ramipril administration in anterior infarction was associ-
ated with substantial recovery of wall motion by 14 days, prompting
the investigators to say that “the major mortality and echocardio-
graphic studies . . . would support early initiation of ACE inhibition
in acute MI, especially in higher-risk individuals in whom this
therapy should be maintained on a long-term basis.”27 In the parent
GISSI-3 report, nearly one half of the lives saved with early lisinopril
use were a result of a reduction in deaths secondary to cardiac rupture
and pump failure.28 Indeed, diabetes is a risk factor for rupture of the
ventricular free wall complicating infarction.29
13
In addition to beneficial effects on ventricular remodeling,
ACE inhibitors can further improve outcomes by reducing
recurrent ischemic events (MI, unstable angina, and revascu-
larization) after MI. ACE inhibition reduced recurrent MI by
25% in the SAVE trial30 and was associated with 37% fewer
ischemic events after infarction in the CATS trial.31 Salutory
effects on neurohumoral activation, oxidative stress, endothe-
lial function, ischemic preconditioning, and fibrinolysis pro-
vide further insight into the preferential effect of ACE inhibi-
tion in diabetic subjects in the postinfarction period.
Epidemiologic studies suggest that enhanced sympathetic
activity is associated with an increased risk for ischemic events
and sudden death. Sympathetic activation increases both the
hemodynamic and hemostatic risk factors, leading to plaque
rupture and thrombosis.32 A substantial number of type I and
type II diabetic patients (with or without clinical signs of
autonomic nervous system dysfunction) have diminished vagal
activity, resulting in relatively higher sympathetic activity
(sympathovagal imbalance) during the day and night.33 Diabet-
ics with autonomic neuropathy are at increased risk of cardiac
events and show an altered circadian pattern of ischemia
compared with diabetics without autonomic dysfunction.34 In
general, sympathovagal imbalance documented by heart rate
variability studies has been associated with a poor prognosis
after MI independent of left ventricular dysfunction.35
In GISSI-3, the diabetic subgroup presented with a higher Killip
classification and higher heart rate, suggesting more pronounced
activation of both the adrenergic and renin-angiotensin systems than
in their nondiabetic counterparts. In general, ACE inhibition is most
effective in patients with the greatest degree of neurohumoral
activation, which helps to explain the magnitude of benefit of ACE
inhibitors in diabetics after infarction in this study.36 ACE inhibitors
increase parasympathetic tone and restore autonomic balance in
congestive heart failure.37 There is increasing evidence that ACE
inhibition may attenuate sympathetic responses. ACE inhibitors may
decrease central sympathetic outflow,38 alter postsympathetic a-ad-
renergic tone,39 and blunt sympathetic coronary vasoconstriction by
decreasing angiotensin II production.40 Altered sympathetic tone may
also be responsible for the potential of ACE inhibitors to reduce
ventricular arrhythmias.41 Although ACE inhibitors may be able to
modify sympathovagal balance, diminishing angiotensin II levels, little
is known regarding their effects on patients with diabetes-related
autonomic neuropathy.
Increased oxidative stress brought about by hyperglycemia
may be an important link between diabetes and vascular
events.42 Advanced glycosylated end products may quench
nitric oxide through the generation of oxygen free radicals,
leading to impaired endothelial vasodilatation. Angiotensin II
augments oxidative stress by increasing the vascular production
of superoxide radicals,43 which in turn interfere with the
bioavailability of nitric oxide. By increasing free radical pro-
duction, angiotensin II increases leukocyte adhesion to the
endothelium, platelet aggregation, and cytokine expression,
resulting in macrophage infiltration at the site of atherosclerotic
plaques, leading to increased plaque vulnerability. ACE accu-
mulation has recently been demonstrated within inflammatory
regions of atherosclerotic plaque.44 ACE inhibitors improve
endothelial function in atherosclerotic vessels.45
 14 ACE Inhibition for AMI in Diabetes
Diabetes alone or in combination with a variety of risk
factors (hypertension, hypercholesterolemia) can impair endo-
thelial function. ACE inhibitors have recently been found to
normalize endothelial function in type I diabetics via a nitric
oxide–mediated mechanism in the short term, with further
improvements in vasodilatation after 4 weeks of treatment.46
Because bradykinin antagonists have been shown to reverse the
salutory changes of ACE inhibition on endothelium-depen-
dent vasodilatation, accumulation of endogenous bradykinin,
which directly stimulates nitric oxide production, plays a major
role in the vascular effects of ACE inhibition.47 Angiotensin II
can also alter vasomotor tone directly or indirectly by increas-
ing endothelin generation. Because .40% of diabetic patients
studied had previously had angina, ischemic preconditioning
might have mitigated the extent of left ventricular dysfunction.
However, more than three quarters of the study population
had type II diabetes, some of whom were most likely receiving
sulfonylureas, which can block ischemic preconditioning by
inhibition of the potassium-dependent ATP channels.48 Ische-
mic preconditioning can be augmented by a bradykinin-
dependent mechanism that is potentiated by ACE inhibitors.49
In diabetic patients, ACE inhibitors may be particularly ben-
eficial by improving endothelial function and vascular tone and
augmenting ischemic preconditioning.
Impaired fibrinolysis, as reflected by elevated plasminogen
activator inhibitor (PAI)-1 levels, has been associated with an
increased risk of recurrent MI.50 Plasma PAI-1 is increased in
diabetic patients and has been linked to vascular disease.51 The
recent ECAT study documented the association of impaired
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fibrinolysis, parameters of endothelial cell dysfunction, and an
inflammatory state with future adverse coronary events.52
PAI-1 activity and antigen predicted that cardiac events were
related principally to insulin resistance. ACE inhibitors can
suppress plasminogen activator expression experimentally and
improve fibrinolytic capacity in patients after MI.53 ACE
inhibitors also markedly improve insulin sensitivity and glyce-
mic control.54 Acute hyperglycemia can in itself increase
vascular tone, presumably by decreasing nitric oxide availabil-
ity.55 Because improved glycemic control is associated with
improved mortality after MI in diabetic patients receiving
insulin,56 ACE inhibitors may improve survival in this group
by decreasing insulin resistance, improving glycemic control,
and restoring fibrinolytic capacity.
ACE inhibitors counteract many of the established and
putative mechanisms accounting for the increased mortality of
MI in diabetes mellitus. Is the greater relative mortality
reduction in diabetes simply explained by the fact that these
agents defend against mechanisms shared by both groups, or
are there mechanisms specific to diabetes against which ACE
inhibitors might be operative? The authors of this study broach
this question by showing that diabetic patients benefited more
from lisinopril than nondiabetic patients, independent of other
risk factors for elevated mortality. The prevention or retarda-
tion of nephropathy in the diabetic patient is a good example
in which ACE inhibitors act by diabetes-specific (lowering
efferent arteriolar tone) and -nonspecific (lowering systemic
blood pressure) mechanisms. Further elucidation of the role of
the renin-angiotensin system in acute coronary syndromes in
diabetic patients will answer this question.
It appears that the entire benefit of early administration of
lisinopril in GISSI 3,57 as reported initially, could be explained by
the marked effect in patients with diabetes, who composed only
6.5% of the total study population. In a post hoc analysis
conducted in ISIS 2,58 the presence of diabetes was the only
clinical factor that altered the interaction of aspirin and streptoki-
nase on mortality in acute MI. Although the results of these
subgroup analyses are interesting, the implications for practice are
somewhat limited by their post hoc nature. The rewards of
specifying a subgroup for analysis are exemplified in the recent
BARI trial,59 which showed that in the presence of diabetes,
coronary bypass surgery provided a survival benefit over PTCA in
multivessel disease, even though no difference between treatments
was noted for the entire study population. Because diabetes
mellitus profoundly affects the biology of cardiovascular disease,
one could argue that clinical trials in the future with potential
major implications for the care of patients with heart disease
should be specifically designed to evaluate the effect of therapy in
patients with diabetes mellitus.
Acknowledgment
The authors wish to acknowledge Murray Mittleman, MD, for
his review of the manuscript.
References
1. Jacoby R, Nesto R. Acute myocardial infarction in the diabetic patient:
pathophysiology, clinical course and prognosis. J Am Coll Cardiol. 1992;20:
736–744.
2. Aronson D, Rayfield E, Cheseboro J. Mechanisms determining course and
outcome of diabetic patients who have had acute myocardial infarction.
Ann Intern Med. 1997;126:296 –306.
3. Partamian J, Bradley R. Acute myocardial infarction in 258 cases of
diabetes. N Engl J Med. 1965;273:455– 461.
4. Woodfield S, Lundergan C, Reiner J, Greenhouse S, Thompson M,
Rohrbeck S, Deychak Y, Simoons M, Califf R, Topol E, Ross A. Angio-
graphic findings and outcome in diabetic patients treated with thrombolytic
therapy for acute myocardial infarction: the GUSTO-I experience. J Am
Coll Cardiol. 1996;28:1661–1669.
5. Zuanetti G, Latini R, Maggioni A, Franzosi M, Santoro L, Tognoni G, on
behalf of the GISSI-3 Investigators. Effect of the ACE-inhibitor lisinopril
on mortality in diabetic patients with acute myocardial infarction: the data
from the GISSI-3 study. Circulation. 1997;96:4239 – 4245.
6. Moye LA, Pfeffer MA, Wun CC, Davis BR, Geltman E, Hayes D,
Farnham DJ, Randall OS, Dinh H, Arnold JMO, Kupersmith J, Hager D,
Glasser SP, Biddle T, Hawkins CM, Braunwald E, for the SAVE Investi-
gators. Uniformity of captopril benefit in the SAVE study: subgroup
analysis. Eur Heart J. 1994;15:2– 8.
7. Torp-Pedersen C, Kober L, Carlsen J, on behalf of the TRACE Study Group.
Angiotensin-converting enzyme inhibition after myocardial infarction: the
Trandolapril Cardiac Evaluation study. Am Heart J. 1996;132:235–243.
8. Latini R, Maggioni AP, Flather M, Sleight P, Tognoni G. ACE inhibitor
use in patients with myocardial infarction. Circulation. 1995;92:3132–3137.
9. The CONSENSUS II Study Group. Effects of the early administration of
enalapril on mortality in patients with acute myocardial infarction. N Engl
J Med. 1992;327:678 – 684.
10. McGovern P, Pankow J, Shahar E, Doliszny K, Folsom A, Blackburn H,
Luepker R, for the Minnesota Heart Survey Investigators. Recent trends in
acute coronary heart disease. N Engl J Med. 1996;334:884 – 890.
11. Viskin S, Kitzis I, Lev E, Zak A, Heller K, Villa Y, Zajarias A, Laniado S,
Belhassen B. Treatment with beta-adrenergic blocking agents after myo-
cardial infarction: from randomized trials to clinical practice. J Am Coll
Cardiol. 1995;25:1327–1332.
12. Kjekshus J, Gilpin E, Cali G, Blackey A, Henning H, Ross J. Diabetic
patients and beta-blockers after acute myocardial infarction. Eur Heart J.
1990;11:43–50.
13. Wright D, Barber S, Kendall M, Poole P. Beta-adrenoceptor-blocking drugs
and blood sugar control in diabetes mellitus. Br Med J. 1979;1:159–161.
 Nesto and Zarich
14. Waal-Manning H. Metabolic effects of B-adrenoreceptor blockers. ADIS
Press. 1976;1:121–126.
15. Cabin H, Roberts W. Quantitative comparison of extent of coronary
narrowing and size of healed myocardial infarct in 33 necropsy patients
with clinically recognized and in 28 with clinically unrecognized (‘silent’)
previous acute myocardial infarction. Am J Cardiol. 1982;50:677– 681.
16. Toyry J, Niskanen L, Mantysaari M, Lansimies E, Uusitupa M.
Occurrence, predictors, and clinical significance of autonomic neuropathy
in NIDDM. Diabetes. 1996;45:308 –315.
17. Zola B, Vinik A. Effects of autonomic neuropathy associated with diabetes
mellitus on cardiovascular function. Coron Artery Dis. 1992;3:33– 41.
18. van Hoeven K, Factor S. A comparison of the pathological spectrum of
hypertensive, diabetic, and hypertensive-diabetic heart disease. Circulation.
1990;82:848 – 855.
19. Nahser P, Brown R, Oskarsson H, Winniford M, Rossen J. Maximal
coronary flow reserve and metabolic coronary vasodilation in patients with
diabetes mellitus. Circulation. 1995;91:635– 640.
20. Sun D, Nguyen N, DeGrado T, Schwaiger M, Brosius F. Ischemia induces
translocation of the insulin-responsive glucose transporter GLUT4 to the
plasma membrane of cardiac myocytes. Circulation. 1994;89:793–798.
21. Oliver M, Opie H. Effects of glucose and fatty acids on myocardial
ischaemia and arrhythmias. Lancet. 1994;343:155–158.
22. Stanley W, Hall J, Hacker T, Hernandez L, Whitesell L. Decreased myo-
cardial glucose uptake during ischemia in diabetic swine. Metabolism. 1997;
46:168 –172.
23. Azzarelli A, Dini F, Cristofani R, Giaconi A, Rossi A, Volterrani C,
Lundardi M, Bernardi D. NIDDM as unfavorable factor to the postin-
farction ventricular function in the elderly: echocardiography study. Coron
Artery Dis. 1995;6:629 – 634.
24. Iwasaka T, Takahashi N, Nakamura S, Sugiura T, Tarumi N, Kimura Y,
Okubo N, Taniguchi H, Matsui Y, Inada M. Residual left ventricular
pump function after acute myocardial infarction in NIDDM patients.
Diabetes Care. 1992;15:1522–1526.
25. Lomuscio A, Bestetti A, Vergani D, Chiaramello D, Chiti A, Ruffini L,
Pozzoni L, Tarolo G. Radionuclide assessment of left ventricular function
in patients with myocardial infarction and diabetes mellitus. J Intern Med.
Downloaded from http://ahajournals.org by on April 14, 2019
1992;231:73–76.
26. Korup E, Dalsgaard D, Nyvad O, Jensen T, Toft E, Berning J. Comparison of
degrees of left ventricular dilation within three hours and up to six days after
onset of first acute myocardial infarction. Am J Cardiol. 1997;80:449–453.
27. Pfeffer M, Greaves S, Arnold M, Glynn R, LaMotte F, Lee R, Menapace
F, Rapaport E, Ridker P, Rouleau J, Solomon S, Hennekens C, for the
Healing and Early Afterload Reducing Therapy (HEART) Trial Investi-
gators. Circulation. 1997;95:2643–2651.
28. GISSI-3 Investigators. Causes of early in-hospital mortality of patients with
acute myocardial infarction: the impact of ACE-inhibitor treatment. Cir-
culation. 1995;92(suppl I):I-673. Abstract.
29. Kereiakes D. Myocardial infarction in the diabetic patient. Clin Cardiol.
1985;8:446 – 450.
30. Rutherford JD, Pfeffer MA, Moye LA, Davis BR, Flaker GC, Braunwald
E, on behalf of the SAVE Investigators. Effects of captopril on ischemic
effects after myocardial infarction. Circulation. 1994;90:1731–1738.
31. Van Den Heuvale AD, Van Gilst WH, Van Veldhuisen DJ, De Vries RJ,
Dunselman PH, Kingma JH. Long-term anti-ischemic effects of angioten-
sin-converting enzyme inhibition in patients after myocardial infarction.
J Am Coll Cardiol. 1997;30:400 – 405.
32. Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onset
of acute cardiovascular disease. Circulation. 1989;79:733–743.
33. Bernardi L, Ricordi L, Lazzari P, Solda P, Calciati A, Ferrari MR, Vandea
I, Finardi G, Fratino P. Impaired circadian modulation of sympathovagal
activity in diabetes. Circulation. 1992;86:1443–1452.
34. Zarich S, Waxman S, Freeman RT, Mittleman M, Hegarty P, Nesto RW.
Effect of autonomic nervous system dysfunction on the circadian pattern of
myocardial ischemia in diabetes mellitus. J Am Coll Cardiol. 1994;24:956–962.
35. Zuanetti G, Neilson J, Latini R, Santoro E, Maggioni A, Ewing D.
Prognostic significance of heart rate variability in post myocardial infarction
patients in the fibrinolytic era. Circulation. 1996;94:432– 436.
36. Cohn JN, Johnson G, Ziesche S, Cobb F, Francis G, Tristani F, Smith R,
Dunkman B, Loeb H, Wong M, Bhat G, Goldman S, Fletcher RD, Doherty
J, Hughes CV, Carson P, Clintron G, Shabeti R, Haakenson C. A comparison
of enalapril and hydralazine-isosorbide dinitrate in the treatment of chronic
congestive heart failure. N Engl J Med. 1991;325:303–310.
37. Binkley PF, Haas GJ, Starling RC, Nunziata E, Hatton PA, Leier CV,
Cody RJ. Sustained augmentation of parasympathetic tone with angioten-
15
sin-converting enzyme inhibition in patients with congestive heart failure.
J Am Coll Cardiol. 1993;21:655– 661.
38. Grassi G, Cattaneo BM, Seravalle G, Lanfranchi A, Pozzi M, Morganti A,
Carugo S, Mancia G. Effects of chronic ACE inhibition on sympathetic
nerve traffic and baroreflex control of circulation in heart failure. Circu-
lation. 1997;96:1173–1179.
39. Lyons D, Roy S, O’Bryne S, Swift CG. ACE inhibition postsynaptic
adrenergic sympatholytic action in men. Circulation. 1997;96:911–915.
40. Saino A, Pomidossi G, Perondi R, Valentini R, Rimini A, Di Francesco L,
Mancia G. Intracoronary angiotensin II potentiates coronary sympathetic
vasoconstriction in humans. Circulation. 1997;96:148 –153.
41. Van Gilst VM, deGraeff PA, Wesseling H, deLangen CDJ. Reduction of
reperfusion arrhythmias in the ischemic isolated rat heart angiotensin con-
verting enzyme inhibitors: a comparison of captopril, enalapril and
HOE498. J Cardiovasc Pharmacol. 1986;8:722–728.
42. Giugliano D, Ceriello A, Paolisso G. Diabetes mellitus, hypertension, and cardio-
vascular disease: the role of oxidative stress? Metabolism. 1995;44:363–368.
43. Laursen JB, Rajagopalan S, Galis Z, Tarpey M, Freeman BA, Harrison DG.
Role of superoxide in angiotensin II-induced but not catecholamine-
induced hypertension. Circulation. 1997;95:588 –593.
44. Diet F, Pratt RE, Berry GJ, Momose N, Gibbons GH, Dzau VJ. Increased
accumulation of tissue ACE in human atherosclerotic coronary artery
disease. Circulation. 1996;94:2756 –2767.
45. Mancini GB, Henry GC, Macaya C, O’Neill BJ, Puccilo AL, Carere RG,
Wargovich TJ, Mudra H, Luscher TF, Klibaner MI, Haber HE, Uprichard
AC, Pepine CJ, Pitt B. Angiotensin-converting enzyme inhibition with
quinapril improves endothelial vasomotor dysfunction in patients with
coronary artery disease. Circulation. 1996;94:258 –265.
46. O’Driscoll G, Green D, Rankin J, Stanton K, Taylor R. Improvement in
endothelial function by angiotensin converting enzyme inhibition in
insulin-dependent diabetes mellitus. J Clin Invest. 1997;100:678 – 684.
47. Hornig B, Kohler C, Drexler H. Role of bradykinin in mediating vascular
effects of angiotensin-converting enzyme inhibitors in humans. Circulation.
1997;95:1115–1118.
48. Cleveland JC, Meldrum DR, Cain BS, Banerjee A, Harken AH. Oral
sulfonylurea hypoglycemic agents prevent ischemic preconditioning in
human myocardium. Circulation. 1997;96:29 –32.
49. Paratt JR, Vegh A, Zeitlin IJ, Ahmad M, Oldroyd K, Kaszala K, Papp JG.
Bradykinin and endothelial-cardiac myocyte interactions in ischemic pre-
conditioning. Am J Cardiol. 1997;80:124A–131A.
50. Hamsten A, Walldius G, Szamosi A, Blomback M. Plasminogen activator
inhibitor in plasma: risk factor for recurrent myocardial infarction. Lancet.
1987;3:3–9.
51. McGill JB, Schneider DJ, Arfken CL, Lucore CL, Sobel BE. Factors
responsible for impaired fibrinolysis in obese subjects and NIDDM patients.
Diabetes. 1994;43:104 –109.
52. Juhan-Vague I, Pyke SD, Alessi MC, Jespersen J, Haverkate F, Thompson
SG. Fibrinolytic factors and the risk of myocardial infarction or sudden
death in patients with angina pectoris. Circulation. 1996;94:2057–2063.
53. Vaughan DE, Rouleau JL, Ridker PM, Arnrold JM, Menapace FJ, Pfeffer
MA. Effects of ramipril on plasma fibrinolytic balance in patients with acute
anterior myocardial infarction. Circulation. 1997;96:442– 447.
54. Torlone E, Britta M, Rambotti AM, Perriello G, Santeusanio F, Brunetti
P, Bolli GB. Improved insulin action and glycemic control after long-term
angiotensin-converting enzyme inhibition in subjects with arterial hyper-
tension and type II diabetes. Diabetes Care. 1993;16:1347–1355.
55. Giugliano D, Marfella R, Coppola L, Verrazzo G, Acampora R, Giunta R,
Nappo F, Lucarelli C, D’Onofrio F. Vascular effects of acute hyperglycemia in
humans are reversed by L-arginine. Circulation. 1997;95:1783–1790.
56. Malmberg K, Ryden L, Efendic S, Herlitz J, Nicol P, Waldenstrom A, et al.
Randomized trial of insulin-glucose infusion followed by subcutaneous insulin
treatment in diabetic patients with acute myocardial infarction (DIGAMI
study): effects on mortality at 1 year. J Am Coll Cardiol. 1995;26:57–65.
57. Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico.
GISSI-3: effects of lisinopril and transdermal glyceryl trinitrate singly and
together on 6 week mortality and ventricular function after myocardial
infarction. Lancet. 1994;343:1115–1122.
58. ISIS-2 Collaborative Group. Randomized trial of intravenous strep-
tokinase, oral aspirin, both or neither among 17,187 cases of suspected
acute myocardial infarction: ISIS-2. Lancet. 1988;2:349 –360.
59. The Bypass Angioplasty Revascularization Investigation (BARI) Investi-
gators. Comparison of coronary bypass surgery with angioplasty in patients
with multivessel disease. N Engl J Med. 1996;335:217–225.
KEY WORDS: diabetes mellitus n myocardial infarction