European Heart Journal (2000) 21, 16531665
doi:10.1053/euhj.2000.2339, available online at http://www.idealibrary.com on
Review Article
Hypertensive heart disease
A complex syndrome or a hypertensive cardiomyopathy?
G. Y. H. Lip, D. C. Felmeden, F. L. Li-Saw-Hee and D. G. Beevers
University Department of Medicine, City Hospital, Birmingham, U.K.
Introduction
Hypertension is a major risk factor for cardio-
vascular morbidity and mortality. The presence of
hypertension more than doubles the risk for coronary
heart disease, including acute myocardial infarction
and sudden death, and more than triples the risk of
congestive heart failure as well as strokes[1]. Patients
with high blood pressure frequently have abnor-
malities of cardiac structure or function, including left
ventricular hypertrophy, systolic and diastolic dysfunc-
tion and in extreme cases, overt heart failure. There
may also be concomitant or related coronary heart
disease and an increased risk of arrhythmias and
sudden death.
Many of these factors are inter-related and their
individual contributions are dicult to quantify.
There is, however, some debate as to whether
hypertensive
cardiomyopathy exists as a separate entity specific to
hypertension. The term cardiomyopathy, however,
would normally be reserved for intrinsic myocardial
disease, where underlying causes such as hypertension
and coronary artery disease have been excluded. There-
fore, the preferred term should perhaps be hypertensive
heart disease, and given the many mechanisms by
which the heart may be abnormal in hypertension, the
term hypertensive heart disease is probably not so
controversial.
The purpose of this review is to describe the various
mechanisms whereby the heart is abnormal in hyper-
tension and to discuss the possibility of a discrete entity
called hypertensive cardiomyopathy.
Key Words: Hypertensive heart disease, left ventricular
hypertrophy, regression.
Revision submitted 3 July 2000, accepted 7 July 2000.
Correspondence: Dr G. Y. H. Lip, University Department of
Medicine, City Hospital, Birmingham B18 7QH, U.K.
0195-668X/00/201653 + 13 $35.00/0
Left ventricular hypertrophy
Left ventricular hypertrophy has long been recognised
as an important clinical prognostic entity. Epidemiologi-
cal research has shown that left ventricular hypertrophy
itself is associated with increased mortality and mor-
tality for myocardial infarction, heart failure and stroke.
There is a continuous graded relationship between left
ventricular mass and the development of cardio-
vascular disease with no distinct threshold separating
the postulated compensatory from pathological left
ventricular hypertrophy[2].
In normotensive adults, for example, left ventricular
mass is directly related to the risk of developing later
hypertension[3,4], raising the possibility that left ventricu-
lar hypertrophy may also be involved in the develop-
ment of hypertension in the first place, as well as being a
consequence of raised systemic pressure. There may also
be a continuous graded relationship between left ven-
tricular mass and blood pressure, with no critical
threshold of blood pressure, beyond which left ventricu-
lar hypertrophy develops[24]. Left ventricular hyper-
trophy also has been linked to the development of atrial
fibrillation, ventricular arrhythmias and sudden cardiac
death[57]. Left ventricular hypertrophy is also associated
with a three- to four-fold increase in the risk of stroke,
a two- to three-fold increase in coronary heart disease
(CHD) and a three-fold increase in peripheral arterial
disease. However, the pathophysiological basis link-
ing left ventricular hypertrophy with these adverse
cardiovascular events has not been fully elucidated.
In several epidemiological studies, left ventricular
hypertrophy is an independent risk factor for cardio-
vascular morbidity and mortality[2,8]. The gradient of
risk factor, adjusted for age, of cardiovascular disease in
men was 149 for each 50 g . m 1 (corrected for height)
and in women, 157. This graded correlation between
echocardiographically determined left ventricular mass
and the development of cardiovascular disease appears
to be without a critical mass, separating the sometimes
postulated compensatory from pathological hyper-
trophy[2]. Although a much less sensitive measure for the
2000 The European Society of Cardiology
1654 G. Y. H. Lip et al. Review 1654

presence of left ventricular hypertrophy, the ECG is also diurnal variation in blood pressure, with mean daytime
indicative of increased cardiovascular morbidity and blood pressures being at least 10% higher than mean
mortality. In the Framingham Study, for example, nocturnal blood pressure (dipping). Non-dipping is
ECGleft ventricular hypertrophy increased the risk arbitrarily defined as a nocturnal fall in blood pressure
of cardiovascular disease from three- to seven-fold of less than 10% compared to mean daytime readings[18].
depending on age and sex of the patient[9]. Non-dippers are considered to have a greater 24 h blood
pressure load when compared to dippers, as well as
greater end-diastolic volumes[19] and, in some studies,
more left ventricular hypertrophy [8]. However, one
Types of left ventricular hypertrophy
between average daytime arterial blood pressure and left
There are two common types of left ventricular hyper- ventricular mass[16,17]. In addition, there is normally a
trophy: concentric and eccentric. The thickening of the
left ventricular wall relative to the internal cavity is
referred to as concentric left ventricular hyper-
trophy. Less common is the disproportionate (relative to
the posterior wall) thickening of the intraventricular
septum, referred to as asymmetrical or eccentric left
ventricular hypertrophy. These dierent patterns of left
ventricular hypertrophy have dierent features,
haemo-
dynamic relations, and prognostic implications[10]. For
example, concentric left ventricular hypertrophy is nor-
mally associated with moderate to severe hypertension
and is more common in the middle aged and elderly than
in young patients. Cardiac output is normal or low in
concentric left ventricular hypertrophy, but is high in
eccentric left ventricular hypertrophy. However, some
investigators have reported that these geometric patterns
do not add much additional prognostic information
beyond that oered by the simple degree of left ven-
tricular hypertrophy and traditional cardiovascular risk
factors[8,11].

The relationship of left ventricular

hypertrophy to blood pressure
In patients with normal blood pressure (systolic blood
pressure <140 mmHg) the risk of having left ventricular
hypertrophy is 13%16%, whilst with mild hyper-
tension (systolic blood pressure 140 mmHg160 mmHg)
the risk is 27%56%, and with definite hypertension
(systolic blood pressure >180 mmHg) the risk is 118%
188%[12]. In one series, the prevalence of left ventricular
hypertrophy using the SokolowLyon ECG criteria in
malignant phase hypertension, which is the most severe
form of hypertension, is 756%826%[13].
In the Framingham study, after adjusting for age,
diastolic blood pressure and body mass index, isolated
systolic hypertension was found to be associated with a
26%- to 59-fold risk of developing echocardiographic
evidence of left ventricular hypertrophy. Also increased
wall thickness tended to predominate in women, whilst
left ventricular dilatation predominates in men[14].
However, the correlation between blood pressures
measured in the clinical environment and left ven-
tricular mass is poor[15]. By contrast, 24 h ambulatory
blood pressure monitoring provides a close correlation

Eur Heart J, Vol. 21, issue 20, October 2000 Eur Heart J, Vol. 21, issue 20, October 2000
meta-analysis
1655 G. Y. of H.19 studies
Lip et al. published before 1994 found Review 1655
that the left ventricular mass was only weakly associated
with the daynight blood pressure dierence[21]. It has
also been suggested that nocturnal falls in pressure could
induce myocardial ischaemia in hypertensives with left
ventricular hypertrophy and impaired coronary vaso-
dilator reserve, perhaps contributing to the so-called
J curve, which has been previously observed in some
retrospective studies where diastolic blood pressure was
lowered below 85 mmHg, resulting in increased cor-
onary events[22]. Kario et al.[23] also found that more
magnetic resonance imaging scan evidence of silent
cerebrovascular disease was present in extreme dippers,
whose fall in nocturnal systolic pressure was greater
than 20%. By contrast, the recent large prospective
Hypertension Optimal Treatment (HOT) trial showed
no evidence of a J curve in the short-term amongst
hypertensive patients including those with previous
coronary heart disease[24].

Other variables associated with left

ventricular hypertrophy
The prevalence of left ventricular hypertrophy has been
shown to increase progressively with age[25] and varies
with ethnic group, sex and obesity. African origin
patients have a larger left ventricular mass than com-
parable white patients. In addition, left ventricular
hypertrophy may also precede the development of
hypertension[26]. In general, women have a lower preva-
lence of left ventricular hypertrophy for a given level of
blood pressure than men, even after their left ventricular
mass has been corrected for body surface area or body
weight. However, this gender dierence only
appears
to hold true for pre-menopausal women, raising the
possibility of a preventive role of oestrogens in the
pathogenesis of left ventricular hypertrophy[27].
In left ventricular hypertrophy, increased left ven-
tricular wall thickness causes reduced ventricular com-
pliance (that is, the ventricle is stier) together with
the degree of diastolic dysfunction. This also increases
left
atrial filling pressure, resulting in atrial dilatation, which
can be detected by a biphasic P-wave in lead V1 on
the ECG as well as on the echocardiogram [28]. In the
absence of mitral valve disease and atrial fibrillation, the
left atrial size reflects the duration of increased atrial
pressures as a consequence of left ventricular diastolic
dysfunction[29]. Changes in left atrial function and size
also mirror the regression of left ventricular hypertrophy
in response to antihypertensive treatment[30].

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 1656 G. Y. H. Lip et al. Review 1656

Diagnosis and definitions of left left ventricular mass compared to echocardiography[37]

and post-mortem left ventricular weights[38]. Several
ventricular hypertrophy
Left ventricular hypertrophy is defined by an increase in
left ventricular mass, quantified by measurements of
post-mortem left ventricular weight, by ECG criteria,
by echocardiography or more recently, by magnetic
resonance imaging.

Postmortem
The classic studies from decades ago by Devereux and
Reichek[31] and Jones[32] reported that the normal mean
total ventricular weight is below 250 g; the left ventricle
and the interventricular septum usually weigh less than
190 g; and the right ventricular free wall is below 65 g.
Left ventricular hypertrophy exists when the left ven-
tricular plus septal weight exceeds 225 g[31]. In hyper-
tensive heart disease, in the absence of symptomatic
heart failure, overall heart weight is often greater than
350 g, and in the presence of heart failure, values in
excess of 400 g have been reported[32]. However, this
may be a simplistic viewpoint as individual values for
normal and abnormal are likely to vary by age, sex
and size of the individual.

Echocardiography
For echocardiographic assessment of left ventricular
hypertrophy several upper limits of normal for left
ventricular mass have been suggested. Epidemio-
logical data from the mainly white population of the
Framingham study defined left ventricular hyper-
trophy as left ventricular mass in relation to total body
surface area >131 g . m2 for men and >100 g . m 2
[33]
for women . In a racially mixed normotensive
population, 134 g . m 2 for men and 110 g . m 2 for
women were identified as upper limits of normal[34].
Another way of defining left ventricular hypertrophy
with echocardiography is by indexation of the left
ventricular mass for the power of its relationship to
body height. Thus, the cut-o point for left
ventricular
hypertrophy normalized to height was reported by de
Simone et al.[35] as 126 g . m 1 and 50 g . m 27 for men
and 105 g . m 1 and 47 g . m 27 for women. Despite
diering criteria, the presence of left ventricular hyper-
trophy still remains a powerful predictor of mortality
and morbidity in hypertension[36].

Magnetic resonance imaging

A recently validated method of assessing the left
ventricular mass is by magnetic resonance imaging,
which shows a close correlation between estimated

Eur Heart J, Vol. 21, issue 20, October 2000 Eur Heart J, Vol. 21, issue 20, October 2000
limitations,1657
suchG.
as Y.theH.long
Lip acquisition
et al. time, expense, Review 1657
availability, and unsuitability for critically ill patients,
restrict the use of magnetic resonance imaging in some
patients.

The ECG
Left ventricular hypertrophy can also be assessed by
analysing the electrocardiogram by various means.
Several methods have been evaluated[39]: (i) the
RomhiltEstes Point-Score System of 4 has a sensi-
tivity of 12% and a specificity of 87%; (ii) the more
commonly used SokolowLyon Index (SV1 +SV5 or V6
35 mV) has a sensitivity of 22% and a specificity of
79%, and a SokolowLyon Index (RaVL 11 mV) has
a sensitivity of 18% and a specificity of 92%; (iii) the
Cornell system has a sensitivity of 31% and a specificity
of 87%; and (iv) the Rodrigez Padial system has a
sensitivity of 82% and a specificity of 8%[39].
Thus most forms of interpreting the electrocardio-
gram with regards to left ventricular hypertrophy are
not useful as a screening tool. This can be marginally
improved by multiplying the QRS voltage by the QRS
duration, thus increasing the specificity to 96% and
the sensitivity to about 50%[40]. Crudely speaking, the
features of left ventricular hypertrophy on the ECG
normally mean that true left ventricular hypertrophy is
present, but its absence does not mean that left ventricu-
lar hypertrophy is absent indeed, ECGleft ventricu-
lar hypertrophy is clearly an insensitive measure of left
ventricular hypertrophy, but when present is a powerful
predictor of cardiovascular events[9].

Left ventricular strain

The cardiovascular risk associated with left ventricular
hypertrophy by voltage criteria is further increased when
associated with ST and T wave changes (the so-called
strain pattern). For example in the age group of 6594
years, the risk of cardiovascular disease rose from 74%
in hypertensives without electrocardiogram abnormali-
ties to 302% with ECG changes of left ventricular
hypertrophy and repolarization abnormalities [41]. This
strain pattern is found in approximately two-thirds of
patients with normal coronary arteries and left ventricu-
lar hypertrophy on the ECG. Non-specific ST abnor-
malities, which may be due to relative ischaemia, are
indistinguishable from those of coronary artery disease,
thus potentially reducing the accuracy for the diagnosis
of ischaemia on resting or exercise ECG, if pre-existing
strain is already present[42].

Histopathology of left ventricular

hypertrophy
One area of recent interest has been the study of
the many stimuli for the ultra-structural growth of the

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1658 G. Y. H. Lip et al. Review 1658

myocardium[43], with particular reference to myocyte myocardial scarring can be caused by both hyper-
and fibroblast proliferation[44]. Factors such as angio- tension and aortic valve disease. However, there are
tensin II, endothelin-1 and aldosterone all have eects
on fibroblast proliferation. Growth hormone, thyroxin,
volume and pressure loading are other factors con-
tributing to myocyte proliferation[45]. The relative
increase in fibroblastic activity that occurs in hyper-
tensive heart disease may be an important factor in
pathological rather than physiological left ventricular
hypertrophy.
Cardiac myocytes of the left ventricle are enlarged in
hypertensive heart disease[46] and fibrosis is another
feature of the adverse structural remodelling found
in the myocardium in hypertensive heart disease[47].
Coronary resistance vessels are also remodelled in
hypertensive heart disease, with perivascular fibrosis of
intramyocardial coronary arteries and arterioles,
together with thickening of their media[48]. Furthermore,
fibrosis and myocyte changes are a feature of heart
failure secondary to causes other than hypertension, and
treatments such as the ACE inhibitors can beneficially
aect these abnormalities[49].
Besides contractile disturbance of cardiomyocytes and
interstitial and perivascular fibrosis, cardiomyocyte loss
is now being considered as one of the determinants of
the maladaptive process implicated in the transition
from compensated to decompensated left ventricular
hypertrophy. Involvement of apoptosis in the develop-
ment of left ventricular hypertrophy was first demon-
strated in rats during aortic banding induced cardiac
hypertrophy (even without failure)[50]. Recent reports
have also shown an increase in apoptotic myocytes in
failing hearts, although this did not indicate whether this
was a cause or consequence of heart failure[51,52]. The
increased numbers of apoptotic cells present in the
failing hearts of spontaneous hypertensive rats as com-
pared to non-failing spontaneous hypertensive rats sug-
gests that apoptosis might be the mechanism involved
in the reduction of myocyte mass that accompanies
the transition from compensated left ventricular
hypertrophy to cardiac failure[53].
These observations need to be translated into the
clinical scenario as further work is clearly needed to
assess the contribution of ultra-structural changes to the
morbidity and mortality associated with hypertensive
heart disease and whether they are an independent
feature of hypertensive heart disease rather than simply
being features of associated underlying disease.

Does the left ventricular hypertrophy of

hypertension dier from left ventricular
hypertrophy of aortic stenosis?
The structural changes seen in the myocardium associ-
ated with left ventricular hypertrophy, such as increased
interstitial replacement and perivascular fibrosis, and

Eur Heart J, Vol. 21, issue 20, October 2000 Eur Heart J, Vol. 21, issue 20, October 2000
reasons
1659 G. to believe
Y. H. Lipthatet the
al. left ventricular hypertrophy Review 1659
associated with hypertension may dier from that seen
in association with aortic valve stenosis, with subtle
morphological and histological
dierences[54].
In cases of left ventricular hypertrophy secondary
to aortic valve stenosis, the abnormalities of diastolic
function normalize over time, and a reduction of fibrous
tissue can be observed following aortic valve replace-
ment[54]. However, the left ventricular hypertrophy of
hypertension is not only related to the amount of
afterload, but also to neurohormonal factors, particu-
larly the local and circulating reninangiotensin
aldosterone systems[55]. Furthermore, aldosterone is
one of many potent stimulators of myocardial fibrosis.
Friedrich et al.[56] infused the angiotensin-converting
enzyme inhibitor, enalaprilat, into the left coronary
artery and found an improvement in left ventricular
diastolic distensibility and regional relaxation and filling
in patients with left ventricular hypertrophy due to
aortic valve stenosis. Thus, the cardiac renin
angiotensin system is also involved in patients with
concentric pressure overload hypertrophy, such as aortic
valve stenosis. At the cellular level, the intraventricular
pressure overload of hypertension as well as aortic
stenosis results in myocytic hypertrophy and increased
perimyocytic fibrosis. However, intramyocardial
arteriole wall-thickening and enhanced perivascular
fibrosis are distinctive features of hypertension, but are
not seen in aortic stenosis[48]. These observations are
suggestive of distinct, but important dierences between
left ventricular hypertrophy secondary to hypertension
and aortic stenosis.

Pathophysiology of left ventricular

hypertrophy
The progression from a structurally normal heart to left
ventricular hypertrophy is not solely a consequence of
increased afterload imposed by hypertension, with an
increased total peripheral resistance. Many mechanisms
are now known to be involved in the growth regulation
of the heart, including neurogenic, humoral, autocrine,
paracrine and possibly endocrine factors, all of which
have important therapeutic implications.

Pressure overload
Both aortic stenosis and arterial hypertension lead to
pressure overload of the left ventricle. Therefore if
pressure overload was to be the sole stimulus for left
ventricular hypertrophy the results should be identical.
Nonetheless, dierent models inducing left
ventricu-
lar hypertrophy showed heterogeneity of myocardial
remodelling with varying quantity and distribution of
fibrillar collagen, in addition to varying degrees of
intramyocardial arterial adaptation [57,58]. The intra-
ventricular pressure overload of hypertension as well

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 1660 G. Y. H. Lip et al. Review 1660

as aortic stenosis results in myocytic hypertrophy and
increased perimyocytic fibrosis. However, intramyocar-
dial arteriole wall-thickening and enhanced perivascular
fibrosis are distinctive features of hypertension that are
not seen in aortic stenosis[48].
istration, which are known to cause an increase in
plasma concentrations of renin and angiotensin II[71].
Experimental data also suggest that elevated levels of

Reninangiotensinaldosterone system
Several growth factors have been implicated in initiating
and maintaining myocardial hypertrophy [59,60]. In
particular, the reninangiotensinaldosterone system is
likely to have an important role in hypertensive heart
disease, and both angiotensin-II and aldosterone are
known to cause myocardial fibrosis[55].
Hypertension-induced left ventricular hypertrophy
results in increased myocardial fibrosis, but chronic
pressure overload per se does not cause myocardial
fibrosis, as demonstrated with experiments of infrarenal
aortic banding causing left ventricular hypertrophy
without fibrosis[58]. Only after activation of the renin
angiotensinaldosterone by suprarenal banding would
fibrosis be found in the hypertensive, hypertrophied
left ventricle. Similar changes can be observed after
simulated reninangiotensinaldosterone activation
with intravenous administration of angiotensin II or
aldosterone, suggesting an important role of the renin
angiotensinaldosterone in the development of left
ventricular hypertrophy and fibrosis[61]. Furthermore,
myocardial fibrosis is associated with increased expres-
sion of angiotensin converting enzyme and bradykinin
receptor binding at sites of repair[62]. It is also recognised
that there are both circulating and tissue renin
angiotensin systems. Tissue reninangiotensin
aldosterone components are found in the lungs,
myocardium, brain, kidneys, and testes, and in or
around blood vessels with possible vasoconstriction
eects[63]
.
An important role for the reninangiotensin system is
suggested by the impressive eect of angiotensin-
converting enzyme (ACE) inhibitors, and more recently
the angiotensin II receptor antagonists in causing regres-
sion of hypertensive left ventricular hypertrophy[64,65],
and in preventing remodelling and improving prognosis
after myocardial infarction[66,67]. Furthermore, there is a
close correlation between circulating reninangiotensin
levels and left ventricular mass[68,69].
The reninangiotensinaldosterone may also explain
some clinical observations related to the heart in hyper-
tension. For example, patients with renal artery stenosis
may develop flash pulmonary oedema due to increased
angiotensin-II levels, and correction of the renal artery
stenosis may be curative[70]. The role of angiotensin II in
inducing myocardial necrosis was postulated in dialysis
patients but these cardiac events all occurred during
or shortly after procedures, such as sodium-depleting
dialysis, renal artery surgery, or diazoxide admin-

Eur Heart J, Vol. 21, issue 20, October 2000 Eur Heart J, Vol. 21, issue 20, October 2000
angiotensin1661
II inG.theY. presence
H. Lip etofal.systemic hypertension Review 1661
provokes predominantly left ventricular myocardial
necrotic lesions[72], which may be relevant in some
patients with very high endogenous levels of angiotensin
II[71].

Aldosterone
Aldosterone, apart from the retention of sodium, loss of
potassium, and sympathetic activation, causes baro-
receptor dysfunction, impaired arterial compliance,
myocardial and vascular fibrosis[73]. There are syner-
gistic eects of angiotensin II and aldosterone
with
regards to perivascular and interstitial fibrosis of
the ventricle, but an angiotensin-independent eect of
aldosterone on myocardial fibrosis in hypertension
has been demonstrated in various animal models, as well
as the protective eect of spironolactone [74]. Aldoster-
one, therefore, plays an important role in the
pathophysiology of left ventricular hypertrophy.
Aldosterone may be involved in the transition from
compensated to decompensated left ventricular hyper-
trophy. Initially, the increase of interstitial and peri-
vascular fibrosis enhances the likelihood of diastolic
dysfunction and signs/symptoms of heart failure.
Cardiomyocyte loss, which can be induced by chronic
aldosterone administration, may further accelerate
this maladaptive process[75]. The recent RALES
(Randomized Aldactone Evaluation) Study further sup-
ports a role of aldosterone in heart failure which may be
independent of renin and angiotensin, as the blockade of
aldosterone receptors by spironolactone, in addition to
standard therapy (including ACE inhibitors), substan-
tially reduced the risk of both mortality and morbidity
in patients with severe heart failure[76]. Whilst the trial
data suggest an additional benefit of aldosterone antag-
onists when given in combination with ACE inhibitors
in heart failure, aldosterone plays an important part in
myocardial fibrosis associated with hypertension and
possibly in the transition from left ventricular hyper-
trophy to cardiac failure. Theoretically, therefore,
aldosterone antagonists may oer additional benefits
to ACE inhibition in the treatment/prevention of left
ventricular hypertrophy and hypertensive heart disease.
In patients with Conns syndrome, where there is a
chronic excess of aldosterone, the ratio of ischaemic
heart disease is similar to cerebrovascular disease;
nevertheless in this age group ischaemic heart disease
should be 24 times commoner than stroke, suggesting
either an excess of cerebrovascular disease or a reduction
in the incidence of ischaemic heart disease in Conns
syndrome[77]. It is therefore possible that some adverse
eects of aldosterone on the heart require an excess of
angiotensin II levels, which are clearly suppressed in
Conns syndrome.

Catecholamines
The sympathetic activation present in hypertension con-
tributes to the rise in blood pressure, but also seems to

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1662 G. Y. H. Lip et al. Review 1662

have adverse metabolic eects, such as insulin resistance, However, the relationship between insulin resistance
hyperinsulinaemia and hyperlipidaemia [78,79]. There and hypertensive heart disease has some inconsistencies.
have been animal studies suggesting that sympathetic
influences may exert cardiotrophic eects, thus favour-
ing the development of myocardial hypertrophy[80].
Similar results on the sympathetic nervous system
activity facilitating the development of left ventricular
hypertrophy in essential hypertension in man have been
observed[81]. Not surprisingly, patients with phaeo-
chromocytoma frequently have left ventricular hyper-
trophy, and congestive heart failure is often one of the
first presenting clinical symptoms. Antihypertensive
agents that stimulate the sympathetic nervous system,
such as direct vasodilators (hydralazine and minoxidil)
also fail to reduce left ventricular hypertrophy despite
their well-documented antihypertensive eect[82].
If a relationship between hypertensive left ventricular
hypertrophy and sympathetic activation is postulated,
this raises the possibility that heart failure may be part
of this syndrome, especially since neuroendocrine acti-
vation is found in heart failure, with activation of the
reninangiotensinaldosterone and the sympathetic sys-
tem. Indeed sympathetic activation is well-recognised to
be associated with the severity of heart failure and
prognosis[83].

Sodium
Left ventricular mass is influenced by dietary salt
ingestion. Studies in hypertensive rats have demon-
strated left ventricular hypertrophy following high
dietary salt intake[84]. This correlation has been con-
firmed in several trials with hypertensive patients[8587].
Data from the TOHMS study also clearly indicate a
blood pressure independent eect of sodium restriction
on left ventricular mass regression[88]. Possible under-
lying mechanisms for the relationship between salt and
left ventricular hypertrophy include: (i) salt-induced
volume overload; (ii) increased sensitivity of cardiovas-
cular system to noradrenaline; and (iii) angiotensin II[89].

Insulin resistance
Hypertension is commonly associated with the insulin
resistance syndrome and diabetes. Indeed, insulin resist-
ance has been identified as a blood pressure-independent
determinant of left ventricular hypertrophy[9092].
Hypertensive patients with glucose intolerance also have
a higher degree of left ventricular hypertrophy and left
ventricular diastolic dysfunction than those with normal
glucose tolerance[93,94]. For example, diabetes is found
in 5% to 25% of hypertensives, especially in African
origin[95]. This combination substantially increases
overall cardiovascular risk in hypertensive patients,
and diabetes is also commonly associated with atrial
fibrillation, coronary artery disease and heart failure.

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Drugs
1663 which
G. Y.worsen
H. Lipinsulin
et al. resistance, such as thiazides, Review 1663
lower blood pressure and prevent more heart attacks
than other antihypertensive agents, but appear less
eective at left ventricular hypertrophy
regression.
Other agents, which improve insulin resistance, such as
the biguanides, do not lower blood pressure and barely
prevent cardiovascular problems in non-insulin dia-
betics[96]. Diabetic cardiomyopathy probably repre-
sents a cardiac disorder with involvement of myocardial,
interstitial, coronary and neural structures and it is
postulated that it is due to underlying small vessel
or microvascular disease with reduced coronary flow
reserve[97].

Other hormones
Both atrial and brain natriuretic peptides are raised in
the presence of left ventricular hypertrophy. In particu-
lar, brain natriuretic peptide appears to be a better index
of left ventricular hypertrophy than atrial natriuretic
peptide for the detection of altered left ventricular
structure and function in a patient population at risk for
cardiovascular disease[98].
It has also been postulated that left ventricular hyper-
trophy associated with insulin resistance and a hyper-
insulinaemic state is associated with the presence of
insulin-like growth factor-I receptors, implicating the
role of growth hormones[92]. The role of the vaso-
constrictor endothelin in the pathogenesis of left
ventricular hypertrophy and its interaction with the
reninangiotensin system and atrial natriuretic peptide
still remains to be elucidated [99].
Recently, there has been some interest in myocardial
osteopontin, which is thought to contribute to the
angiotensin II-induced remodelling process in cultured
cardiomyocytes. Human myocardium with extensive
fibrosis and cardiomyocyte hypertrophy obtained from
explanted hearts was found to contain high immuno-
reactivity for osteopontin, suggesting induction of
osteopontin expression is strongly associated with
left ventricular hypertrophy[100]. Laviades and co-
[101]
workers recently found that systemic extracellular
degradation of collagen type I (as indicated by the
measurement of metalloproteinses and tissue inhibitors
of metalloproteinasess) is abnormal in patients with
essential hypertension. The abnormal collagen proteo-
lytic activities were normalized after 1 year of treatment
with an ACE inhibitor, lisinopril[101]. Whilst more data
are needed, these abnormalities may perhaps facilitate
organ fibrosis in hypertensive patients, namely those
with left ventricular hypertrophy.
Finally, other studies have shown a correlation
between left ventricular hypertrophy and parathyroid
hormones and between left ventricular hypertrophy and
growth hormone[102,103]. These findings clearly attest to
the role of various hormonal systems and the multi-
factorial pathogenesis of left ventricular hypertrophy
and in particular, the hypertensive heart disease
syndrome.

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 1664 G. Y. H. Lip et al. Review 1664

ACE genes high pressures, the complications associated with hyper-

tension (heart attacks, stroke) are paradoxically mainly
As illustrated above, the reninangiotensinaldosterone
plays an essential part in the pathophysiology of left
ventricular hypertrophy. ACE is responsible for the
generation of angiotensin II, which is closely related to
left ventricular mass. Indeed the insertion/deletion poly-
morphism of the ACE gene has been shown to account
for up to 50% of the variance in the plasma ACE
concentration[104,105]. Not surprisingly, there is also a
close relationship between left ventricular hypertrophy
and a deletion polymorphism of the ACE gene.
For example, the DD genotype, which increases
plasma ACE activity, is associated with the development
of left ventricular hypertrophy[106]. In hypertensive
patients without any additional risk factors, the risk of
left ventricular hypertrophy increased 38-fold with
homozygosity for the D allele of the ACE gene[107].
Another study showed increased left ventricular mass in
hypertensive males with non-insulin-dependent diabetes
mellitus, indicating that the ACE gene polymorphism
is crucial in the pathophysiology of left ventricular
hypertrophy[108].

Thyroid disease
Thyroid disease causes significant changes in the
cardiovascular system, particularly the heart. Thyroid
hormones interrelate with the sympathetic nervous sys-
tem by modifying the sensitivity to sympathetic stimuli.
There is now also increasing evidence of direct eects
of thyroid hormones on the myocardium, causing an
increase of protein synthesis. Therefore, the association
of hyperthyroidism with left ventricular hypertrophy
may be related to either thyroxin-induced increase of
cardiac workload or to direct thyroid hormone-induced
stimulation of the myocardial cells[109].

Microproteinuria
Microalbuminuria, a subclinical increase in urinary
protein excretion, is established as an indicator of target
organ damage in hypertension. Recent studies have
shown a positive correlation between urinary albumin
excretion and thickness of the left ventricular wall,
which was independent of blood pressure[110].

Hypercoagulability
There is increasing evidence that patients with hyper-
tension demonstrate abnormalities of haemostasis,
platelets and endothelial function, in keeping with a
hypercoagulable or prothrombotic state[111]. This may
explain why despite the blood vessels being exposed to

Eur Heart J, Vol. 21, issue 20, October 2000 Eur Heart J, Vol. 21, issue 20, October 2000
thrombotic rather
1665 G. Y.than haemorrhagic.
H. Lip et al. In addition, Review 1665
patients with hypertension and left ventricular hyper-
trophy have higher plasma fibrinogen levels, when com-
pared to those without left ventricular hypertrophy[112].
Nevertheless, the processes of thrombogenesis and
atherogenesis are intimately related. Many patients
with atherosclerotic vascular disease demonstrate simi-
lar abnormalities, where they may have independent
prognostic implications. For example, in patients with
hypertension, some markers such as prothrombin
fragment F1 + 2[113] and von Willebrand factor[114] are
associated with subsequent adverse cardiovascular
outcomes.

Coronary heart disease

Epidemiological data have shown a strong association
between hypertension and atherosclerosis, but only a
quarter of the risk for development of coronary artery
disease can be attributed to hypertension[115]. Neverthe-
less, some of the features attributed to hypertensive
heart disease may simply be attributable to associated
myocardial ischaemia. The reduction in coronary
reserve seen with left ventricular hypertrophy makes
the heart more susceptible to ischaemia when demand
increases or when the perfusion pressure drops[116].
Furthermore, hypertension is associated with other
factors that accelerate coronary artery disease, such
as acceleration of atherosclerosis of larger coronary
arteries[117] and impaired endothelium-dependent
vasodilatation[118]. Indeed, specific associations have
also been noted between left ventricular hypertrophy
and other atherothrombotic disease, such as carotid
atherosclerosis [119] and stroke[120].
Underlying coronary artery disease in a patient with
hypertensive heart disease may be dicult to distinguish
from left ventricular hypertrophy with the so-called
strain pattern with ST depression on the ECG. The
diagnostic accuracy of the ST segment response in
patients with baseline ECG abnormalities due to left
ventricular hypertrophy of 59% compared to 90% in
patients without resting ECG changes is poor[121]. These
ST changes particularly reduce the specificity of an
exercise tolerance test in hypertensive patients with
chest pain, whereas the sensitivity is only marginally
aected[122]. Alternative methods such as stress echo-
cardiography or thallium perfusion scanning have been
shown to be more accurate in assessing hypertensive
patients with abnormalities of their baseline ECG than
the exercise tolerance test[123].
Hypertension is also associated with myocardial
perfusion abnormalities even in the absence of sympto-
matic coronary heart disease[124]. Indeed, myocardial
ischaemia may result from the left ventricular hyper-
trophy itself because of an associated increase in
coronary vascular resistance, a reduction in the number
of capillaries per gram of muscle tissue and a rise in
coronary vascular resistance[125,126]. Left ventricular

Eur Heart J, Vol. 21, issue 20, October 2000 Eur Heart J, Vol. 21, issue 20, October 2000
1666 G. Y. H. Lip et al. Review 1666

hypertrophy is also associated with impaired coronary
reserve even in the absence of epicardial coronary dis-
ease. Underlying causes of impaired coronary reserve
include arteriolar rarefaction, medial wall thickening of
arterioles, perivascular fibrosis, endothelial dysfunction,
and myocyte hypertrophy[127]. The presence of under-
lying cardiac ischaemia may also explain the increased
incidence of atrial fibrillation, ventricular arrhythmias,
myocardial infarction and sudden cardiac death, which
have otherwise been simply attributed to hypertensive
heart disease.
left ventricular hypertrophy[137,138]. This is of signifi-
cance as the transition from sinus rhythm to atrial
fibrillation in a patient with left ventricular hypertrophy
and diastolic dysfunction may result in loss of stroke
volume and heart failure consequent upon the loss of
atrial transport. Furthermore, the presence of atrial
fibrillation and hypertension are additive to the risks of
stroke and thromboembolism. Left atrial dilatation also
occurs in association with left ventricular hypertrophy,
which may predispose to atrial fibrillation. Finally,
alcohol also contributes to both hypertension and atrial
fibrillation.

Alcoholic heart disease

It has been shown that left ventricular hypertrophy is
more common in patients with essential hypertension
who regularly drink 50 g or more of alcohol per day,
where the left ventricular mass index is proportional to
the amount of alcohol[128]. This is important, as patients
with alcohol-induced hypertension and left ventricular
hypertrophy are at particularly high risk of develop-
ing supraventricular arrhythmias, particularly atrial
fibrillation[129,130]. Indeed, hypertensive patients with
marked left ventricular hypertrophy should be carefully
questioned on their alcohol intake, particularly if it
seems inappropriate to the height of the blood pressure.
Heart failure
Hypertension, according to Framingham data, is the
commonest cause of heart failure. In recent community-
and hospital-based studies, however, coronary artery
disease was the number one cause of heart failure in
Western countries and indeed the importance of hyper-
tension as an underlying cause has been declining[139].
Hypertension still increases the risk of heart failure four-
to eight-fold when associated with ECG defined-left
ventricular hypertrophy [140], but many of these patients
Supraventricular arrhythmias such as atrial fibril-
lation are commonly associated with hypertension and

Arrhythmias and sudden cardiac death

The increased risk for sudden cardiac death in hyper-
tensive heart disease has been attributed to increased
ventricular ectopic activity[131]. However, Pringle and
co-workers[132] argued that the presence of left ventricu-
lar hypertrophy did not cause an increased propensity
for re-entrant arrhythmias but rather the arrhythmias
are simply markers of myocardial ischaemia. Studies in
cats showed increased vulnerability to inducible poly-
morphic ventricular fibrillation after aortic banding
induced left ventricular hypertrophy; these abnor-
malities disappeared with left ventricular hypertrophy
regression after removal of the aortic band, whereas cats
with persistent left ventricular hypertrophy remained
vulnerable to arrhythmias[133]. The role of hypokalae-
mia, due to thiazide diuretic therapy for hypertension, in
the causation of arrhythmias remains controversial [134].
Indeed, most studies showed that diuretics are very
eective in [135]
preventing coronary heart disease in
hypertension .
Nevertheless, it is known that electrophysiological
changes associated with left ventricular hypertrophy are
not uniform throughout the hypertrophied tissue and
this could form a substrate for cardiac arrhythmias[136].
Alternatively, myocardial fibrosis could cause local
variations in the conduction velocities precipitating
ventricular arrhythmias.

Eur Heart J, Vol. 21, issue 20, October 2000 Eur Heart J, Vol. 21, issue 20, October 2000
may
1667haveG.underlying
Y. H. Lip coronary
et al. heart disease, which may Review 1667
be asymptomatic. The presence of cardiomegaly, as
defined by the chest X-ray in hypertensive patients
(usually related to left ventricular hypertrophy), also
significantly increases the risk of heart failure[140]. How-
ever, it is often dicult to dissect out the
unique
influence of hypertension on the myocardium and car-
diac function per se in the absence of age, as well as
accompanying obesity, coronary disease and diabetes.
Hypertension may lead to heart failure due to systolic
dysfunction, in association with underlying coronary
heart disease and heart attacks, but in hypertensive left
ventricular hypertrophy, heart failure due to diastolic
dysfunction may also occur. The latter is related to
delayed ventricular relaxation and impaired filling,
associated with the ultrastructural changes of left ven-
tricular hypertrophy[141]. Indeed the normal concen-
tration of fibrillar collagen in the myocardium is an
important determinant of its stiness[142]. A two- to
threefold increase in collagen concentration is associated
with an increase in diastolic stiness, whilst resting
systolic stiness and ejection fraction are pre-
served[143,144]. A further rise in myocardial collagen
raises the diastolic stiness even further, eventually
leading to systolic dysfunction[145]. left ventricular
hypertrophy is also associated with an impaired cor-
onary reserve, which may lead to myocardial ischaemia,
even in the absence of epicardial coronary artery disease,
leading to impaired left ventricle relaxation[127].
However, diastolic dysfunction is also commonly
associated with coronary artery disease, valve disease
and increasing age. Therefore the development of heart
failure in hypertension is less likely to be related to
hypertensive heart disease per se in many patients,

Eur Heart J, Vol. 21, issue 20, October 2000 Eur Heart J, Vol. 21, issue 20, October 2000
 1668 G. Y. H. Lip et al. Review 1668

especially in elderly hypertensives with underlying To address these unresolved questions, there are now
coronary artery disease. It should be noted that whilst several large observational studies underway, as well as
well-trained athletes develop physiological left ventricu-
lar hypertrophy, the parameters of diastolic and systolic
function are be within normal range[146].

Regression of left ventricular

hypertrophy
There is now evidence both from experimental animal
studies and from clinical studies that left ventricular
mass can be reduced with control of blood pressure via
pharmacological or non-pharmacological means[147,148].
Problems encountered in earlier studies include inad-
equate number of patients with left ventricular hypertro-
phy and lack of standardization of the techniques
for measurement of left ventricular mass in dierent
laboratories[149].
Recent recommendations by Devereux and
Dahlof[149] state that a minimum of 40 subjects are
needed when investigating the underlying pathophysiol-
ogy of left ventricular hypertrophy; however, 300400
subjects should be studied for the detection of left
ventricular mass reduction between dierent agents (for
at least a year); and for long-term prognosis in left
ventricular hypertrophy regression studies, 1200 subjects
or more should be followed over a period of at least
4 years. This raised several issues over whether pre-
viously published studies, some of which were smaller
and of shorter follow-up, were adequate to answer the
question(s) posed.
The published meta-analyses suggest that ACE inhibi-
tors promote the greatest amount of regression of left
ventricular hypertrophy, followed by calcium antagon-
ists[82,150,151]. The evidence for beta-blockers and diuret-
ics are variable, but in a recent meta-analysis, there are
few little dierences between diuretics and beta-blockers
in left ventricular hypertrophy regression, although
diuretics tended to do so by reducing left ven-
tricular internal dimensions[152]. Recently published
data also suggest that antihypertensive treatment with
angiotensin-II antagonists results in significant regres-
sion of left ventricular hypertrophy, perhaps greater
than that seen with the beta-blockers[153].
Does treatment of hypertensive heart disease by the
regression of left ventricular hypertrophy (if present)
confer a benefit on the patient, which is independent of
blood pressure reduction? As yet there are only limited
data with regard to morbidity and mortality available.
One observational study showed a reduction in cardio-
vascular events in the group with a decrease in left
ventricular mass as compared to the group with an
increase in left ventricular mass[8]. During the observa-
tional period there were no fatal cardiovascular end-
points, presumably due the short duration of follow-up
and the fairly low cardiovascular risk of the patients.

Eur Heart J, Vol. 21, issue 20, October 2000 Eur Heart J, Vol. 21, issue 20, October 2000
outcome 1669
trials G.
comparing
Y. H. Lipdierent
et al. antihypertensive Review 1669
treatment regimes investigating the possible prog-
nostic implications of left ventricular hypertrophy
regression[154158].
In the absence of major end-point data, it is necessary
to consider surrogate end-points that may indicate a
benefit to patients in terms of regression of left ven-
tricular hypertrophy. For example, there is now evidence
that systolic ventricular function is maintained and
diastolic ventricular function, both at rest and during
exercise, improves with regression of left ventricular
hypertrophy[159161]. Furthermore, Iriarte et al.[162]
found that regression of left ventricular mass through
antihypertensive treatment with enalapril appeared to
reduce microvascular ischaemia and the subsequent
development of angina pectoris, with associated
improvement in exercise tolerance. Finally, there is also
good experimental animal evidence that treatment (with
ACE inhibitors) causes a parallel regression both in
myocytes and in fibrous tissues[163].

Conclusion
Hypertensive heart disease is probably part of a (very)
wide syndrome that includes underlying left ventricular
hypertrophy, coronary artery disease, neuroendocrine
activation and possibly the insulin resistance syndrome.
Many of the features associated with hypertensive heart
disease, such as heart failure, may be explained by
activation of the reninangiotensinaldosterone system,
catecholamine excess, diastolic dysfunction and cor-
onary artery disease. The combination of the variety of
underlying mechanisms in hypertension results in car-
diac abnormalities, which are comparable to those seen
in other pathophysiological circumstances. Nonetheless,
distinctive dissimilarities in hypertension, particularly
when comparing with aortic stenosis, require a dier-
entiation as a separate entity, which can perhaps be
referred to as a hypertensive cardiomyopathy.
Dr Li-Saw-Hee is supported by a non-promotional project grant
from Merck Sharpe and Dohme. We acknowledge the support
of the City Hospital NHS Trust Research & Development
Programme.

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