From Left Ventricular Hypertrophy to
Congestive Heart Failure: Management of
Hypertensive Heart Disease
Alan H. Gradman and Fadi Alfayoumi
Other than age, left ventricular hypertrophy (LVH) is
the most potent predictor of adverse cardiovas-
cular outcomes in the hypertensive population,
and is an independent risk factor for coronary
heart disease, sudden death, heart failure and
stroke. Although directly related to systolic blood
pressure, other factors including age, sex, race,
body mass index and stimulation of the renin-
angiotensin-aldosterone and sympathetic nervous
systems play an important role in the pathogene-
sis of LVH. LVH involves changes in myocardial
tissue architecture consisting of perivacular and
myocardial fibrosis and medial thickening of intra-
myocardial coronary arteries, in addition to myoc-
tye hypertrophy. The physiologic alterations which
occur as a result of these anatomical changes
include disturbances of myocardial blood flow,
the development of an arrhythmogenic myocardial
substrate and diastolic dysfunction. The latter is
directly related to the degree of myocardial fibrosis
and is the hemodynamic hallmark of hypertensive
heart disease. When diastolic dysfunction is pres-
ent, left ventricular end-diastolic pressure
increases out-of-proportion to volume and may
be elevated at rest or with exertion leading to
clinical heart failure. At least one third of heart
failure patients in the United States can be
considered to have heart failure related to diastolic
dysfunction. Compared to heart failure patients
with systolic dysfunction, diastolic heart failure
patients are more likely to be older, female, and
to be hypertensive at the time of presentation.
From the Western Pennsylvania Hospital, Pittsburgh,
PA, and the Department of Medicine, Temple University
School of Medicine (Clinical Campus), Pittsburgh, PA.
Address reprint requests to Alan H. Gradman,
MD, Chief, Division of Cardiovascular Diseases, The
Western Pennsylvania Hospital, 4800 Friendship Avenue,
Suite 3411 N, Pittsburgh, PA 15224.
E-mail: gradmanmd@aol.com
0033-0620/$ - see front matter
n 2006 Elsevier Inc. All rights reserved.
doi:10.1016/j.pcad.2006.02.001
326 Progress in Cardiovascular Diseases, Vol. 48, No. 5 (March/April), 2006: pp 326-341
Although it has been assumed that LVH may lead
to systolic dysfunction, evidence is lacking that
LVH resulting from hypertension is a major risk
factor for systolic heart failure independent of
coronary artery disease. Treatment of hyperten-
sion greatly attenuates the development of LVH
and significantly decreases the incidence of heart
failure. In patients with established LVH, regression
is both possible and desirable and results in a
significant reduction in adverse clinical endpoints.
n 2006 Elsevier Inc. All rights reserved.
T he course of any case of cardiac hypertrophy may be
divided into three stages:
The period of development which varies with the nature of
the primary lesion. . .
The period of full compensation in which the heart’s vigor
meets the requirements of the circulation. . .
The period of broken compensation which...takes place
slowly and results from degeneration and weakening
of the heart muscle.1
— William Osler, 1892
Structural remodeling of the heart, referred to
as left ventricular hypertrophy (LVH), is a
critical consequence of systemic hypertension
and the anatomical precursor of a spectrum of
cardiovascular abnormalities, which are collec-
tively referred to as hypertensive heart disease.1
In clinical practice, the exact definition of
hypertensive heart disease is often elusive as its
manifestations —myocardial ischemia/infarction,
sudden cardiac death, and congestive heart
failure (CHF) overlap with and frequently
coexist with coronary heart disease. Conceptu-
ally, hypertensive heart disease may be thought
of as those disease manifestations that can be
directly related to the cardiac anatomical
changes, which accompany chronic elevation of
systolic and diastolic blood pressure (BP).
The comments of Osler1 accurately describe the
clinical development of the most characteristic
MANAGEMENT OF HYPERTENSIVE HEART DISEASE
consequence of hypertensive heart disease —
CHF. In the days before elevations in BP were
routinely treated, heart failure was the most
common cause of death in the hypertensive
population.2 Today, hypertension constitutes
the single most important risk factor for the
development of heart failure in the United States.
The type of heart failure it produces includes not
only that due to the b weakening Q of the heart
muscle, which Osler observed, but also that
related to another aspect of myocardial
bdegenerationQ— diastolic dysfunction.
The contemporary management of hyperten-
sive heart disease is directed firstly toward its
prevention through antihypertensive therapy
using pharmacological agents that attenuate or
reverse the remodeling process. When clinical
manifestations of disease including heart failure
are present, treatment is directed toward allevi-
ation of symptoms and improvement in long-
term prognosis. In this article will be reviewed
the prevalence, risk factor and mechanisms
involved in the development of LVH, the path-
ways through which the remodeled ventricle
produces clinical disease, as well as current
therapeutic perspectives.
Epidemiology
Incidence and Prevalence
Criteria used to define LVH both by electrocar-
diogram (ECG) and echocardiography are not
uniform and vary substantially among studies.
Estimates of left ventricular mass (LVM)are con-
ventionally indexed to body size, yielding a value
for LVM index (LVMI) in grams per square
meter if corrected for body surface area or grams
per meter if corrected for height. Hammond et al3
has suggested that 134 g/m2 in men and 110 g/m2
in women are suitable LVMI threshold values for
defining LVH in a heterogeneous urban popula-
tion. Factors such as age, race, and physical
activity affect LVM and different threshold
values may be suitable in different populations.
The observed prevalence of LVH depends both
upon its definition and the laboratory method by
which it is ascertained. The diagnostic modalities
currently used to detect LVH and indirectly
assess LVM include the electrocardiogram, echo-
cardiogram, and cardiac magnetic resonance
327
imaging (MRI). Although not readily available
in most centers, MRI quantification is the most
accurate and reproducible method of estimating
LVM and is presently favored in research inves-
tigations.4 Echocardiography is widely available
and clearly superior to the ECG in the sensitivity
of LVH detection.5 In patients with moderate to
severe LVH confirmed by necropsy, Devereux6
reported that the sensitivity of M-mode echocar-
diography was 98%, whereas the sensitivity of
ECG was 38% in patients with moderate and
57% in those with severe LVH.
The exact prevalence of LVH in the hyper-
tensive population is difficult to determine.
In addition to the problem produced by variable
diagnostic criteria, additional difficulties pertain
specifically to patients with high BP. These
include uncertainties regarding the severity
and duration of hypertension, the degree to
which it has been treated, and the timing and
nature of previous pharmacological therapy. All
of these factors exert significant effects on LVM
in the individuals who constitute a given
hypertensive population.
Studies in untreated populations are particu-
larly instructive. In an echocardiographic study
of 363 untreated hypertensive patients evaluated
by Gosse et al,7 the prevalence of LVH was
50%, using a cutoff value of 47 g/m2.7 in women
and 53 g/m2.7 in men. Overall, the prevalence
of LVH detected by echocardiography is about
20% to 30% in patients with mild-to-
moderate and 50% to 60% in patients with more
severe hypertension.8
Left Ventricular Hypertrophy and
Cardiovascular Risk
Other than age, LVH is the most potent predictor
of adverse cardiovascular outcomes in the
hypertensive population. Whether detected
by ECG or echocardiography, LVH has been
shown to be an independent risk factor for
coronary heart disease, sudden death, heart
failure, and stroke.8-12
Although least accurate as a surrogate for
direct measurement of LVM, ECG evidence of
LVH remains the most potent predictor of
adverse outcomes in epidemiological stud-
ies.13,14 Reports from the Framingham database
document a 6-fold increase in overall mortality
328
Fig 1. Prevalence of LVH as a function of 30-year average systolic BP. The Framingham Heart Study. Reprinted
with permission from J Am Coll Cardiol 1991;18(5):1237-1294.
in individuals with definite ECG-LVH, and 45%
of cardiovascular deaths were preceded by its
development. In men with definite ECG-LVH,
the incidence of heart failure increased 7-fold to
an annual risk greater than 50 of 1000 patients,
and the risk of sudden cardiac death was
increased 6 times.
Echocardiographically determined LVM is
also a potent indicator of cardiovascular risk.
In a cohort study of middle-aged patients
40 years old or older and free of clinically
apparent cardiovascular disease, each 50-g/m
increase in LVM was independently associated
with 1.49 and 1.57 relative risk (RR) for future
cardiovascular events in men and women,
respectively.15 Left ventricular hypertrophy was
associated with up to 2 times the RR for death
from cardiovascular causes and all-cause mor-
tality. In a prospective population-based study of
approximately 6000 elderly individuals 65 years
or older, an independent association between
LVM and CHF was observed. Patients in the
highest LVM quintile exhibited a 2.8 RR for
heart failure development during an average
5.5-year follow-up period.
As is the case with BP itself, the gradation of
risk associated with increasing LVM extends into
the reference range. In the Progetto Ipertensione
Umbria Monitoraggio Ambulatoriale study,16,17
previously untreated hypertensive patients were
stratified according to LVM using a value of
125 g/m2 in men and 110 g/m2 in women as
criteria for the echocardiographic diagnosis of
GRADMAN AND ALFAYOUMI
LVH. A linear relationship between LVM and
cardiovascular risk was still present at LVM
values of 105 g/m2 in men and 91 g/m2 in
women, independent of other factors including
age, sex, smoking, serum cholesterol, and
24-hour BP monitoring.
Although stroke is not usually thought of as a
manifestation of hypertensive heart disease, it is
clear that LVH is an independent risk factor for
cerebrovascular events.18 In 2363 untreated
hypertensive patients followed up for 14 years,
LVH predicted the occurrence of stroke or
transient ischemic attack independent of age,
sex, diabetes, or 24-hour mean ambulatory BP.
ECG-LVH was associated with an increased RR
of 1.79 and echocardiographic LVH of 1.64. For
each increase in LVM of 1 SD (29 g/m2), there
was a 31% increase in the risk for cerebrovascu-
lar events.19
Factors in LVH Development
Left ventricular hypertrophy is an adaptive
response of the myocardium to increased cardiac
workload; its development normalizes wall ten-
sion and is thought to preserve systolic ventric-
ular function. The incidence of LVH is directly
related to the level of systolic BP.20-24 The
relationship between the age-adjusted prevalence
of LVH, as determined by echocardiography and
average systolic BP in the Framingham study, is
shown in Fig 1. Although a linear relationship to
BP is observed, BP does not fully account for the
MANAGEMENT OF HYPERTENSIVE HEART DISEASE
Fig 2. Schematic representation of myocardium and its myocyte and nonmyocyte cells and tissue fluid.
variability in LVM. Using standard criteria, 10%
to 15% of individuals with an average systolic BP
b120 mm Hg— a BP considered optimal by
almost any criteria —were found to manifest
LVH. Statistically, only 10% of the variation in
LVM could be accounted for based on office
systolic BPs averaged over a 30-year period.25
Ambulatory BP monitoring gives a more
accurate estimation of the integrated hemody-
namic load to which the ventricle is subjected
and correlates more closely with LVM calcula-
tions. Twenty-four-hour mean BP and average
daytime systolic BP—in most studies, the best
statistical correlates of LVM—account for about
25% of observed variance in LVM.21 As day-
to-day variability in 24-hour BP is considerable,
it is likely that a better correlation exists between
integrated lifetime hemodynamic burden and
LVM. Maintenance of a normal 24-hour BP
pattern including the normal nocturnal bdipQ in
BP is protective. Despite similar mean BP values,
bnon-dippersQ have increased LVM compared
with individuals displaying the usual circadian
pattern.26-28
Factors other than BP, including age, sex, race,
body mass index, and neurohormonal stimula-
tion, are operative in determining who among
the hypertensive population develops LVH. In
the Framingham study, LVM increase was
329
documented in a much higher percentage of
hypertensive women than men —57% compared
with 31%, a difference which parallels in the
higher contribution of hypertension to overall
heart failure risk in women.8 In African Amer-
icans, the prevalence of LVH is increased 2- to
3-fold compared with whites with similar BP
elevations.29 The prevalence of LVH increases
markedly with age, an effect which is greater in
women compared with men. Controversy exists
as to whether this relationship reflects the
concomitant increase seen in systolic BP or
whether age per se influences LVH development.
Obesity is a major risk factor 30 for LVH
development; a 2 kg/m2 increase in body mass
index correlated with a 50% risk of increased
LVM in a cohort of elderly men and women. In
some studies, obesity was a more important
determinant of LVH development in women
compared with men.
Pathogenesis
Structural Alterations
The myocardium is an elastic network of myocytes
enmeshed in a collagen matrix that connects the
myocytes and supporting coronary vasculature
(Fig 2). 31
330
The cardiac anatomical changes that accom-
pany chronic elevation of systolic and diastolic
BP are commonly referred to by the term left
ventricular hypertrophy. It is important to keep in
mind, however, that the remodeling process,
which accompanies hypertension, consists of a
range of changes in tissue architecture, which
include perivacular and myocardial fibrosis and
medial thickening of intramyocardial coronary
arteries in addition to myocyte hypertrophy. All
of these structural changes and the resulting
alteration in myocardial composition are impor-
tant contributors to the pathogenesis of hyper-
tensive heart disease. The response of the
individual myocardial components and relative
changes in the overall cellular composition of
the myocardium are influenced by both hemo-
dynamic and nonhemodynamic factors. Non-
hemodynamic factors include genetics and
neurohormonal systems, in particular, the sym-
pathetic nervous and renin-angiotensin systems.
The latter are of particular interest because they
are amenable to pharmacological manipulation
by a variety of available drugs, which play a useful
role in the treatment of hypertension and hyper-
tensive heart disease.
Myocytes make up approximately 75% of the
myocardium by weight, and myocyte hypertro-
phy is primarily what is measured when techni-
ques such as echocardiography or MRI are used
to assess LVM. Myocyte hypertrophy occurs
in response to mechanical deformity resulting
from stretch or shear forces and is seen in all
conditions that produce either pressure or
volume overload of the ventricles. Hypertrophy
of cardiac myocytes without accompanying
fibrosis or vascular changes does not appear to
have adverse prognostic implications. Physiolog-
ical LVH seen in athletes performing isometric
exercise (wrestlers and weight lifters) is not
associated with alteration in myocardial compo-
sition and is characterized by normal systolic
and diastolic function. Such hypertrophy is
usually mild and regresses spontaneously when
the physical stimulus is removed.32
In addition to mechanical stress, myocyte
hypertrophy occurs in response to the myocar-
dial stimulator hormones norepinephrine, endo-
thelin, and angiotensin II. Increased activity of
the sympathetic nervous system is correlated
with LVM in young individuals with borderline
GRADMAN AND ALFAYOUMI
hypertension. In animal studies, subpressor
infusions of norepinephrine induce cardiac hy-
pertrophy accompanied by an increase in the
production of cardiac myosin heavy chains
indicative of myocyte hypertrophy.33-35 The
trophic effects of angiotensin II on cardiac
myocytes, mediated by the Angiotensin 1 recep-
tor (AT1) receptor, have been demonstrated in
whole-animal and in vitro models.36 In tissue
culture experiments, phenylalanine incorpora-
tion (a surrogate for protein synthesis) has been
documented after exposure to angiotensin II.
This effect is mediated by several secondary
pathways including the expression of the proto-
oncogenes c-myc, c-fos and c-jun, expression of
growth factors including Egr-1, and production
of cytokines such as transforming growth factor
b.37,38 Mechanical deformity itself induces syn-
thesis of angiotensin II, which is secreted into
the culture medium and stimulates cell growth
in an autocrine fashion. This suggests that the
primary stimulus to hypertrophy—mechanical
stretch —may be angiotensin-mediated.39
The development of myocardial fibrosis dis-
tinguishes pathological from physiological ven-
tricular hypertrophy. Biopsies from patients with
hypertension and LVH demonstrate increased
collagen content and extensive fibrosis com-
pared with normal hearts.40 When there is
parenchymal cell loss, a reparative (replacement)
fibrosis occurs. In addition, there is perivascular-
interstitial fibrosis.
Hormonal influences appear to be particularly
important in the fibrotic process. In the cardiac
muscle, collagen synthesis and degradation are
ongoing, and the equilibrium of these processes
is controlled by a variety of hormones and
cytokines. Profibrotic substances include the
sympathetic nervous system, renin-angiotensin-
aldosterone system, inflammatory cytokines (eg,
transforming growth factor b), and growth
factors such as insulin-like growth factor. In
contrast, bradykinin, nitric oxide, natriuretic
peptides, and glucocorticoids have collagenolytic
effects.37 In experimental studies, both norepi-
nephrine and angiotensin II stimulate fibroblasts
as well as myocytes. In ventricular hypertrophy
induced in rats by infusion of subpressor doses
of norepinephrine,33 hydroxyproline content
increased, and a 37% increase in interstitial
fibrosis was documented. In cultured cardiac
MANAGEMENT OF HYPERTENSIVE HEART DISEASE
fibroblasts, angiotensin stimulates thymidine
incorporation indicative of cellular proliferation
as well as collagen synthesis.
Activation of the renin-angiotensin-aldoste-
rone system also leads to the production of
aldosterone, a hormone that plays a key role
in the development of myocardial fibrosis.41
Aldosterone stimulates deposition of interstitial
collagen and remodeling of the extracardiac
matrix. In rats made hypertensive by aldosterone
infusion, myocyte hypertrophy occurs in the left,
but not the right, ventricle and is a function of
pressure overload (angiotensin levels are normal
in this model). In the same experiment, mRNA
for collagen formation increases and fibrosis
occurs in both the right and left ventricles
indicating that it is the circulating aldosterone
rather than the pressure load that is responsible
for its induction.42,43
Medial thickening of intramyocardial coro-
nary arteries and perivascular fibrosis occur in
pathological LVH. Analogous to ventricular
hypertrophy, vascular hypertrophy constitutes
an adaptive response to chronic BP elevation; the
increased ratio of media thickness to lumen
diameter normalizes elevated wall stress. Tro-
phic hormones, particularly angiotensin II, stim-
ulate smooth muscle cell proliferation and
vascular hypertrophy. In experimental animal
models, angiotensin II infusion also induces
perivascular fibrosis.44
Physiological Changes and Clinical Correlation
The anatomical changes described above are, for
the most part, directly responsible for the
physiological alterations that lead to the clinical
manifestations of hypertensive heart disease.
These changes involve disturbances of myocar-
dial blood flow, the development of an arrhyth-
mogenic substrate, and diastolic dysfunction.
Coronary blood flow
Generalized endothelial dysfunction character-
ized by reduced responses to endothelial-depen-
dent vasodilators is well-documented in
hypertension and is more severe in patients with
LVH. Perticone observed an inverse relationship
between LVM and the magnitude of forearm
blood flow augmentation after acetylcholine
331
infusion. After adjustment for age, systolic/
diastolic BP, sex, and duration of hypertension,
LVM remained an independent predictor of
abnormal endothelial-mediated dilatation.45
Resting coronary blood flow in patients with
LVH is usually normal. However, it is reduced
relative to the increased ventricular mass be-
cause the cross sectional area of the coronary
microcirculation does not increase in parallel
with myocyte growth. Autoregulation of myo-
cardial blood flow in response to changes in
systemic BP is impaired and results in reduced
subendocardial flow, particularly in the presence
of reduced coronary perfusion pressure (diastol-
ic BP), and increased intramyocardial pressures
such as occurs with diastolic dysfunction.
Abnormalities in coronary blood flow are
common in hypertensive patients with or without
LVH but are more severe in the presence of LVH.
Brush et al46 documented angina pectoris in
patients with reduced coronary vasodilator
responses to ergonovine in the absence of either
LVH or epicardial coronary obstruction. Patients
with hypertension and especially with LVH
exhibit significant reduction in coronary flow
reserve, the increase in blood flow, which occurs
after maximal coronary vasodilation. In normal
individuals, coronary blood flow increases 4 to
5 times after administration of dypridamole.
In patients with LVH and ST-segment depression,
this response is reduced by approximately 50%.47
Hamasaki48 reported that endothelium-depen-
dent vasodilatation in the coronary circulation
was normal in hypertensive patients without LVH
but reduced in those in whom LVH was present.
Hypertension/LVH patients with clinical angina
apparently related to abnormal coronary flow
reserve are well described but not common.
The exact clinical consequences of these
abnormalities in coronary perfusion are far from
clear. Epidemiological studies do not provide
detail on the specific events included under the
category of coronary heart disease. Presumably,
under conditions of increased myocardial oxy-
gen demand with or without large-vessel coro-
nary obstruction, decreased ability to dilate the
microvasculature translates into increased ische-
mia and/or infarction. The observation that
infarct size is increased in animals with hyper-
trophied hearts after experimental coronary
ligation is consistent with this concept.49 A
332
Fig 3. Schematic representation of LV pressure as a function of LV volume during diastolic filling in a normal heart
and in a heart with LVH.
propensity to ischemia may explain some of the
increased risk for coronary events and sudden
cardiac death seen in patients with LVH.
Impaired subendocardial blood flow may con-
tribute to diastolic dysfunction and increase the
risk or severity of heart failure.
Arrhythmogenic substrate
It is generally assumed that sudden cardiac death
is ischemic, arrhythmic, or thrombotic. In these
clinical events are included many cases, which,
no doubt, represent complex interactions of
diminished coronary flow reserve, increased
myocardial oxygen demand, lethal arrhythmias,
and subendocardial ischemia in conjunction
with associated coronary atherosclerosis due to
hypertension. Therefore, it is likely that the
arrhythmic propensity in LVH is multifactorial
in origin.50
There is evidence that the myocardium with
pathological hypertrophy provides a permissive
anatomical substrate for the development and
propagation of ventricular arrhythmia. Myo-
cardial fibrosis impedes the homogenous pro-
pagation of electrical impulses through the
myocardium and facilitates re-entrant arrhyth-
mias. In patients with ventricular tachycardia
and normal left ventricular (LV) function, those
GRADMAN AND ALFAYOUMI
with ventricular late potentials demonstrated a
greater degree of myocardial fibrosis on right
ventricular biopsy. In spontaneously hyperten-
sive rat (SHR) hearts subjected to coronary
ligation, ventricular tachycardia/ventricular fi-
brillation (VT/VF) occurred in more than 60%
compared with b10% of hearts derived from
normotensive rats.51
During ambulatory ECG monitoring, patients
with hypertension and LVH exhibit a greater
prevalence of premature ventricular contractions
and complex ventricular arrhythmias, including
nonsustained ventricular tachycardia, compared
with patients without LVH.52 The Framingham
group reported that the presence of asymptom-
atic ventricular arrhythmias in patients with LVH
was associated with a 2-fold increase in mortal-
ity. Human electrophysiologic studies have
yielded contradictory results regarding induc-
ibility of ventricular tachyarrhythmias. 53,54
There is some evidence that LVH regression is
associated with a diminution in spontaneous
ventricular ectopy.
Diastolic dysfunction
Diastolic dysfunction refers to abnormalities in
LV distensibility, filling, or relaxation, and is the
hemodynamic hallmark of hypertensive heart
MANAGEMENT OF HYPERTENSIVE HEART DISEASE
Fig 4. Pathophysiology of preserved LVEF heart failure.
disease. Normal diastolic function implies that
the volume of ventricular filling is sufficient to
generate an adequate stroke volume while
maintaining normal diastolic pressures. When
diastolic dysfunction is present, LV end-diastolic
pressure increases out of proportion to volume
(Fig 3) and may be elevated at rest or with
exertion. This increased pressure when reflected
into the pulmonary capillaries produces dyspnea
and left-sided CHF. Reduced stroke volume and
cardiac output55 leads to fatigue and decreased
exercise capacity (Fig 4).
Diastolic dysfunction may be symptomatic or
asymptomatic and occurs in hypertensives with
or without LVH. Studies using Doppler echocar-
diography have reported that approximately 20%
of untreated persons with borderline or mild
hypertension have diastolic filling abnormalities
in the absence of LVH.56 In general, however,
the degree of diastolic dysfunction is correlated
with LVM.
Diastole consists of an early rapid filling phase
related to active myocyte relaxation and a late,
passive phase, which is dependent upon the
elastic properties of the left ventricle. Reduced
velocity of relaxation has been described in
hypertrophied myocytes and may contribute to
diastolic dysfunction.56 Myocyte relaxation is an
energy-requiring process, which is impaired in
the presence of ischemia.
The degree of myocardial fibrosis is a critical
determinant of diastolic dysfunction. In SHR,
Brilla et al57 demonstrated normalization of
diastolic stiffness, measured in isolated hearts,
when myocardial fibrosis was eliminated by
treatment with the angiotensin-converting en-
333
zyme (ACE) inhibitor, lisinopril. In aging SHR
with ventricular hypertrophy, animals exhibiting
signs of heart failure were compared with those
without heart failure. Increased passive stiffness
of isolated papillary muscles derived from the
heart failure rats was documented, and this
finding was associated with a higher LV collagen
concentration and degree of interstitial fibrosis
determined histologically. In man, Sugihara
et al58 reported an inverse correlation between
rapid filling volume and % myocardial fibrosis as
assessed by right ventricular endomyocardial
biopsy (Fig 5).
Diastolic function is most accurately charac-
terized by measurement of pressure/volume
relationships, which are impractical in routine
clinical practice. Noninvasive imaging techni-
ques in common use include Doppler echocar-
diography and radionuclide imaging. Several
parameters derived from these techniques are
currently used to describe diastolic function. In
aggregate, these are highly sensitive in detecting
diastolic dysfunction. However, their ability to
distinguish patients with clinical diastolic heart
failure from those with incidental abnormalities
has proved to be highly variable and less than
satisfactory. In clinical practice, diastolic heart
failure remains a clinical diagnosis.
Systolic dysfunction
It has long been assumed that concentric LVH
with normal ejection fraction (EF) is a precursor
to LV systolic dysfunction and dilated cardio-
myopathy. In many series of patients with
systolic dysfunction heart failure, hypertension
334
Fig 5. Myocardial fibrosis correlates with LV diastolic dysfunction.
is considered to be the most common etiologic
factor, particularly in African Americans.
Patients with hypertension, LVH, and normal
EF frequently exhibit subtle evidence of systolic
dysfunction, including reduced fractional short-
ening of the LV mid wall.59,60 Transition from
concentric hypertrophy to systolic dysfunction is
observed in animal models including SHR,61
aging Harlan-Sprague-Dawley rats, aortic band-
ing62 and transgenic manipulation.63
Nevertheless, it remains unclear if this con-
version is part of the natural history of hyper-
tension-induced LVH in man. The close
epidemiological association between hyperten-
sion, LVH, coronary heart disease, and heart
failure complicates the question. In a published
series, hypertensive patients whose deaths were
attributed to heart failure often had associated
coronary disease. A critical question relates to
the frequency with which patients with concen-
tric LVH develop systolic heart failure in the
absence of coronary artery disease and interval
myocardial infarction (MI).
Two recent studies have addressed this issue.
In a retrospective analysis, Drazner et al65
evaluated 159 middle-aged hypertensive patients
in whom concentric LVH with a normal EF had
been documented on a previous echocardio-
gram. Only 18% developed reduced EF over an
average follow-up period of approximately
4 years. Fifty percent had sustained a MI.64 In
the Cardiovascular Health Study, 3042 partic-
ipants with normal EF underwent echocardio-
GRADMAN AND ALFAYOUMI
graphic evaluation of systolic function and LVM
at baseline and after a 5-year follow-up period.
Statistically, LVH was found to be a risk factor
for development of decreased LVEF independent
of coronary artery disease and MI. However,
most cases of LVH were of eccentric pattern, and
the typical concentric pattern seen in hyperten-
sive heart disease was not shown to be a
predictor for depressed LV systolic function.65
In summary, evidence is lacking that LVH
resulting from hypertension is a major risk
for systolic heart failure independent of coro-
nary artery disease. At present, LVH should
be considered as a direct precursor for clini-
cal heart failure mostly in the form of dia-
stolic dysfunction.
Therapeutic Perspectives
Prevention
Treatment of hypertension greatly attenuates the
development of LVH and heart failure. In a meta-
analysis by Moser and Herbert66 reviewing major
hypertension trials conducted over a 20-year
period and involving more than 48 000 subjects,
ECG-LVH was reduced by about one third and
heart failure by 52%. The type of heart failure —
systolic vs diastolic —was not specified. It is
likely that these figures underestimate the
potential of aggressive antihypertensive therapy.
Target BPs in many of these trials were higher
than those recommended by present guidelines
MANAGEMENT OF HYPERTENSIVE HEART DISEASE
such as Joint National Committee for the
Prevention, Detection, Evaluation and Treatment
of High Blood Pressure 7 (JNC 7).67 For
example, in the Systolic Hypertension in the
Elderly Population (SHEP) study,68 a diuretic-
based trial in patients with isolated systolic
hypertension, heart failure incidence was re-
duced by 51%. According to the treatment
protocol, patients with systolic BPs above
160 mm Hg at baseline were treated to a goal
systolic BP of only 160 mm Hg rather than the
current target of 140 mm Hg.
Left Ventricular Hypertrophy Regression
Left ventricular hypertrophy regression is both
possible and desirable and is an important
intermediate end point in the treatment of
hypertension. Because systolic BP is the primary
stimulus for LVH development, BP reduction by
almost any means produces some degree of LVH
regression. Changes in LVM during treatment
have been correlated with BP reduction par-
ticularly when evaluated using 24-hour moni-
toring. However, this relationship is weak,
emphasizing the contribution of nonhemody-
namic factors.69 The direct acting vasodilators,
hydralazine, and minoxidil, do not cause LV
regression either in experimental animals or in
man despite lowering BP.70 Presumably, this
reflects the finding that both cause sympathetic
activation, illustrating the importance of neuro-
hormonal stimuli.
Multiple meta-analyses have been published
evaluating the comparative effects of antihyper-
tensive drug classes on LVH regression. In an
analysis of 109 published studies, Dahlff et al71
reported that the magnitude of LVM reduction
measured by echocardiography ranged from
7.7% with diuretics to 16.3% with ACE inhib-
itors, the most effective of the classes studied.
The updated meta-analysis by Klingbeil et al72
is consistent with most earlier studies and
extensive animal data. Angiotensin-converting
enzyme inhibitors, AT1 receptor blockers, and
calcium antagonists were found to be more
potent than b-blockers; the efficacy of diuretics
was intermediate.
The results of these meta-analyses should be
interpreted with caution because many of the
studies included were of small size, of short
335
duration, and used nonblinded reading of
echocardiograms. Meta-analyses are also limited
by the fact that they do not represent drug-by-
drug comparisons but aggregate members
of a class, which may have rather different
pharmacological properties. In clinical trials,
head-to-head comparison of antihypertensive
agents is difficult because most patients with
hypertension and LVH require multiple agents
to achieve BP control.
Several well-designed comparisons of specific
agents in larger populations have recently been
reported. In Prospective Randomized Enalapril
Study Evaluating Regression of Ventricular
Enlargement trial,73 enalapril and nifidipine
Gastrointestinal Therapeutic System (GITS) (ex-
tended release) were compared in 303 patients
with hypertension and LVH using M-mode
guided 2D echocardiography to calculate LVM
at baseline and after 24 and 48 weeks of
treatment. At 48 weeks, comparable reductions
in BP, echocardiographic dimensions, and LVM
were observed in the 2 treatment groups. Left
ventricular mass index was reduced into the
reference range in 56% of enalapril-treated
and 48% of nifidipine GITS –treated patients.
Most of the decrease in mass was seen during the
first 6 months. There was a significant but
weak correlation between BP reduction and
LVM regression.
Two other large studies illustrate the impor-
tance of study duration, combination therapy,
and BP reduction in evaluating treatment effects.
In one trial,74 the diuretic, indapamide sus-
tained release was found to be superior to
enalapril in 505 hypertensive men and women
with LVH. Interestingly, the results with these 2
agents were similar after 24 weeks but diverged
over the subsequent 24 weeks, perhaps indicat-
ing the importance of longer-term studies to
evaluate treatment effects. In a well-conducted
study using MRI to estimate LVM, the combi-
nation of 2 renin-angiotensin system blockers,
the aldosterone antagonist, eplerenone, and
enalapril, was found to be superior to either
alone. Interpretation of the study is complicated
by the small but statistically significant differ-
ence in systolic BP favoring the combination
therapy group.75
The Losartan Intervention For Endpoint re-
duction in hypertension (LIFE) trial76 was the
336
first clinical trial in patients with LVH to
compare the effects of specific drugs not only
on LVM regression but also on clinical end
points. The study randomized 9193 hypertensive
patients with definite ECG evidence of LVH to
receive losartan or atenolol as first-line therapy
for hypertension. Most patients in both treat-
ment groups received additional antihyperten-
sive agents including hydrochlorothiazide
(HCTZ). After 4.8 years of follow-up, BP
reduction in the 2 groups was nearly identical.
The composite primary end point of cardiovas-
cular death, MI or stroke was reduced by 13% in
losartan-treated compared with atenolol-treated
patients. The difference in the primary end point
was entirely driven by a 25% reduction in stroke
in the losartan group.
To determine the prognostic significance of
LVM reduction during treatment, a prospective
echocardiographic substudy was conducted in
941 patients in whom LVM was measured at
baseline and annually during the follow-up
period. Reduction in LVM was found to be
significantly greater in the losartan group (mean
reduction 21.7g/m2 vs 17.7 g/m2 ( P = .021).
Reduction in LVM continued for 2 full years after
randomization. Cox regression analysis showed
that lower LVM during antihypertensive therapy
was associated with lower rates of clinical end
points independent of the BP, treatment assign-
ment, other risk factors, and various comorbid-
ities.77 Reduction in LVMI by 1 SD (25.3 g/m2)
was associated with a calculated 22% reduction
in the primary end point and a 28% reduction in
total mortality additional to that predicted by BP
reduction alone.
The results of the LIFE echo substudy validate
earlier,78 less definitive reports indicating that
LVH regression is associated with improved
long-term clinical outcome and is a desirable
target for therapy. These results also point to
limitations in the use of LVM regression as a
clinical end point when comparing drug treat-
ments. In the LIFE study, cardiovascular mor-
tality, which, in epidemiological studies, is
directly correlated with LVM, was not different
between the losartan and atenolol treatment
groups despite the large sample size and the
documented superiority of losartan with regard
to LVM regression. Presumably, this relates to
pharmacological properties of the 2 agents,
GRADMAN AND ALFAYOUMI
which are independent of than their effect
on LVM.
Diastolic Dysfunction and Heart Failure
More than 4.6 million people in the United
States have chronic heart failure; at least one
third of these patients can be considered to have
diastolic heart failure.79 Because of the relative
lack of clinically useful measures of diastolic
function, diastolic heart failure is usually defined
as the presence of typical heart failure signs/
symptoms and preserved systolic function (LVEF
N 40%-50%). In Acute Decompensated Heart
Failure National Registry (ADHERE), a contem-
porary database of more than 52 000 patients
hospitalized with acute heart failure, 46% had
preserved systolic function.80
In general, the older the population studied,
the higher the prevalence of normal EF among
patients with heart failure. More than 50% of
participants in large population-based studies of
patients older than 65 years hospitalized for
CHF demonstrated an EF exceeding 45% on a
baseline echocardiogram.65 Compared with
patients with heart failure with systolic dysfunc-
tion, patients with diastolic heart failure are
more likely to be female and to have an elevated
BP at the time of presentation. Most have a
history of hypertension, and LVH is common. In
a recent series of hospitalized urban patients,
82% were found to have increased LVM.81
Diastolic heart failure is associated with
increased mortality compared with an age-
matched control group,82 although survival is
improved relative to patients with heart failure
based on systolic dysfunction. The mortality rate
ranges from 4% to 8% annually, as compared
with 10% to 15% in patients with systolic heart
failure. Morbidity, however, is approximately
equal. The 1-year hospital readmission rate can
approach 50%.83 In the Candesartan in Heart
failure: A Assessment of Reduction in Mortality
and morbidity (CHARM)-Preserved study,82
which included less severely symptomatic (most-
ly New York Heart Association class II patients),
18% in the placebo group required hospital
admission over a 3.5-year follow-up period;
4.2% had more than 3 admissions.
Despite its frequency, there are no definitive
clinical trial data available to direct the therapy
MANAGEMENT OF HYPERTENSIVE HEART DISEASE
for patients with diastolic dysfunction heart
failure and hypertension. Diuretics are generally
required to reduce ventricular preload and
relieve dyspnea and edema. Various authors have
recommended the use of drugs that reduce heart
rate and prolong diastolic filling time, including
b-blockers and verapamil. There are no human
data evaluating the efficacy of b-blockers. In
1 small study, verapamil was compared with
placebo in 20 patients and was associated with
prolongation of exercise duration on a stationary
bicycle after a 5-week treatment period.84
Based upon favorable results in animal mod-
els, renin-angiotensin system blockers have
undergone clinical evaluation in man. Using
serial LV biopsy and echocardiographic exami-
nations, Brilla et al85 compared lisinopril and
HCTZ in 35 hypertensive patients with symp-
toms of either dyspnea or angina and evidence of
diastolic dysfunction by echocardiogram. After
6 months of treatment, morphometric studies of
biopsy specimens documented regression of
myocardial fibrosis in lisinopril-treated patients,
but not those receiving HCTZ. A parallel
improvement in diastolic functional parameters
relative to the diuretic was also noted. In another
study, diastolic heart failure was evaluated in
21 patients randomized to receive enalapril or
placebo. The enalapril group had significant
reduction in BP and LVM; these findings were
associated with improvement in heart failure
symptoms and in diastolic function evaluated by
Doppler echocardiography.86
Angiotensin receptor blockers are the best
studied drug class in diastolic heart failure. In a
cross-over study comparing losartan and place-
bo, 20 patients with dyspnea and exercise-
induced hypertension (systolic BP N200 mm
Hg) were recruited.87 Losartan treatment signif-
icantly reduced exercise systolic BP. While
receiving losartan, patients were able to exercise
for a longer period and had improved quality
of life. All patients in the study had echocar-
diographic evidence of diastolic dysfunction,
although only 25% had LVH.
The CHARM-Preserved trial82 is the only large
scale clinical trial, which has been completed in
patients with diastolic heart failure. In this study,
the angiotensin receptor blocker candesartan
cilexitil, titrated to a dose of 32 mg/d, was
compared with placebo in 3031 patients with
337
heart failure and LVEF above 40%. After a
median follow-up period of 37 months, there
was an 11% reduction in the primary end point
of cardiovascular death or heart failure hospital-
ization, a result which did not reach statistical
significance. There was no effect on mortality.
The reduction in hospitalization was of bor-
derline significance. Several large clinical
trials with other Angiotensin receptor blockers
are ongoing.
A major set of unanswered questions relates to
the effectiveness of antihypertensive therapy per
se in the treatment of diastolic heart failure.
There are theoretical reasons to postulate that
such treatment may be effective. The left ventri-
cle generally compensates for increased systolic
pressure load through an often small increase in
end-diastolic volume. It is possible that these
increases could cause significant elevation of
end-diastolic pressure in patients with severe
diastolic dysfunction. Proof of this concept or
recommendations regarding optimal BP targets
are not possible with present evidence. Certain-
ly, BP should be treated aggressively to JNC
7 goals. These are systolic BP below 140 mm Hg
for hypertensives in general and below 130 mm
Hg in persons with diabetes. Diabetes is
known to exert an independent adverse effect
on diastolic function and, in both the ADHERE80
and New York Heart Failure Registries,81 consti-
tuted 45% of patients with diastolic heart failure.
Summary
Left ventricular hypertrophy is an adaptive
response of the heart to hypertension, which
results in changes in myocardial structure that
greatly increase the risks of cardiovascular
mortality, sudden death, coronary heart disease,
heart failure, and stroke. Ischemia, ventricular
arrhythmias and diastolic dysfunction are the
functional components of hypertensive heart
disease. Myocardial fibrosis appears to be the
most important structural alteration in its
development. Although elevated BP is the
initiating stimulus, neurohormonal factors, par-
ticularly the renin-angiotensin system, play a
key role in determining who among hyper-
tensives will develop LVH. Aggressive antihy-
pertensive therapy is critical in preventing the
development of hypertensive heart disease,
338
LVH, and CHF. Achieving LVH regression is a
desirable and achievable goal and is associated
with improved prognosis. Antihypertensive
agents exhibit variable effectiveness in inducing
LVH regression, with renin-angiotensin system
blocking agents the most effective. In patients
who have developed diastolic heart failure, the
most characteristic manifestation of hyperten-
sive heart disease, current evidence favors the
use of diuretics, ACE inhibitors, and angioten-
sin receptor blockers as preferential antihyper-
tensive agents.
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