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From Left Ventricular Hypertrophy to

Congestive Heart Failure: Management of


Hypertensive Heart Disease
Alan H. Gradman and Fadi Alfayoumi

Although it has been assumed that LVH may lead


Other than age, left ventricular hypertrophy (LVH) is to systolic dysfunction, evidence is lacking that
the most potent predictor of adverse cardiovas- LVH resulting from hypertension is a major risk
cular outcomes in the hypertensive population, factor for systolic heart failure independent of
and is an independent risk factor for coronary coronary artery disease. Treatment of hyperten-
heart disease, sudden death, heart failure and sion greatly attenuates the development of LVH
stroke. Although directly related to systolic blood and significantly decreases the incidence of heart
pressure, other factors including age, sex, race, failure. In patients with established LVH, regression
body mass index and stimulation of the renin- is both possible and desirable and results in a
angiotensin-aldosterone and sympathetic nervous significant reduction in adverse clinical endpoints.
systems play an important role in the pathogene- n 2006 Elsevier Inc. All rights reserved.
sis of LVH. LVH involves changes in myocardial
tissue architecture consisting of perivacular and
myocardial fibrosis and medial thickening of intra- T he course of any case of cardiac hypertrophy may be
myocardial coronary arteries, in addition to myoc- divided into three stages:
tye hypertrophy. The physiologic alterations which The period of development which varies with the nature of
occur as a result of these anatomical changes the primary lesion. . .
include disturbances of myocardial blood flow, The period of full compensation in which the heart’s vigor
the development of an arrhythmogenic myocardial meets the requirements of the circulation. . .
substrate and diastolic dysfunction. The latter is The period of broken compensation which...takes place
directly related to the degree of myocardial fibrosis slowly and results from degeneration and weakening
and is the hemodynamic hallmark of hypertensive of the heart muscle.1
heart disease. When diastolic dysfunction is pres- — William Osler, 1892
ent, left ventricular end-diastolic pressure
increases out-of-proportion to volume and may Structural remodeling of the heart, referred to
be elevated at rest or with exertion leading to as left ventricular hypertrophy (LVH), is a
clinical heart failure. At least one third of heart critical consequence of systemic hypertension
failure patients in the United States can be and the anatomical precursor of a spectrum of
considered to have heart failure related to diastolic cardiovascular abnormalities, which are collec-
dysfunction. Compared to heart failure patients
tively referred to as hypertensive heart disease.1
with systolic dysfunction, diastolic heart failure
In clinical practice, the exact definition of
patients are more likely to be older, female, and
to be hypertensive at the time of presentation. hypertensive heart disease is often elusive as its
manifestations —myocardial ischemia/infarction,
sudden cardiac death, and congestive heart
From the Western Pennsylvania Hospital, Pittsburgh,
failure (CHF) overlap with and frequently
PA, and the Department of Medicine, Temple University
School of Medicine (Clinical Campus), Pittsburgh, PA. coexist with coronary heart disease. Conceptu-
Address reprint requests to Alan H. Gradman, ally, hypertensive heart disease may be thought
MD, Chief, Division of Cardiovascular Diseases, The of as those disease manifestations that can be
Western Pennsylvania Hospital, 4800 Friendship Avenue, directly related to the cardiac anatomical
Suite 3411 N, Pittsburgh, PA 15224. changes, which accompany chronic elevation of
E-mail: gradmanmd@aol.com
0033-0620/$ - see front matter
systolic and diastolic blood pressure (BP).
n 2006 Elsevier Inc. All rights reserved. The comments of Osler1 accurately describe the
doi:10.1016/j.pcad.2006.02.001 clinical development of the most characteristic

326 Progress in Cardiovascular Diseases, Vol. 48, No. 5 (March/April), 2006: pp 326-341
MANAGEMENT OF HYPERTENSIVE HEART DISEASE 327
consequence of hypertensive heart disease — imaging (MRI). Although not readily available
CHF. In the days before elevations in BP were in most centers, MRI quantification is the most
routinely treated, heart failure was the most accurate and reproducible method of estimating
common cause of death in the hypertensive LVM and is presently favored in research inves-
population.2 Today, hypertension constitutes tigations.4 Echocardiography is widely available
the single most important risk factor for the and clearly superior to the ECG in the sensitivity
development of heart failure in the United States. of LVH detection.5 In patients with moderate to
The type of heart failure it produces includes not severe LVH confirmed by necropsy, Devereux6
only that due to the b weakening Q of the heart reported that the sensitivity of M-mode echocar-
muscle, which Osler observed, but also that diography was 98%, whereas the sensitivity of
related to another aspect of myocardial ECG was 38% in patients with moderate and
bdegenerationQ— diastolic dysfunction. 57% in those with severe LVH.
The contemporary management of hyperten- The exact prevalence of LVH in the hyper-
sive heart disease is directed firstly toward its tensive population is difficult to determine.
prevention through antihypertensive therapy In addition to the problem produced by variable
using pharmacological agents that attenuate or diagnostic criteria, additional difficulties pertain
reverse the remodeling process. When clinical specifically to patients with high BP. These
manifestations of disease including heart failure include uncertainties regarding the severity
are present, treatment is directed toward allevi- and duration of hypertension, the degree to
ation of symptoms and improvement in long- which it has been treated, and the timing and
term prognosis. In this article will be reviewed nature of previous pharmacological therapy. All
the prevalence, risk factor and mechanisms of these factors exert significant effects on LVM
involved in the development of LVH, the path- in the individuals who constitute a given
ways through which the remodeled ventricle hypertensive population.
produces clinical disease, as well as current Studies in untreated populations are particu-
therapeutic perspectives. larly instructive. In an echocardiographic study
of 363 untreated hypertensive patients evaluated
by Gosse et al,7 the prevalence of LVH was
Epidemiology
50%, using a cutoff value of 47 g/m2.7 in women
and 53 g/m2.7 in men. Overall, the prevalence
Incidence and Prevalence
of LVH detected by echocardiography is about
Criteria used to define LVH both by electrocar- 20% to 30% in patients with mild-to-
diogram (ECG) and echocardiography are not moderate and 50% to 60% in patients with more
uniform and vary substantially among studies. severe hypertension.8
Estimates of left ventricular mass (LVM)are con-
ventionally indexed to body size, yielding a value
Left Ventricular Hypertrophy and
for LVM index (LVMI) in grams per square
Cardiovascular Risk
meter if corrected for body surface area or grams
per meter if corrected for height. Hammond et al3 Other than age, LVH is the most potent predictor
has suggested that 134 g/m2 in men and 110 g/m2 of adverse cardiovascular outcomes in the
in women are suitable LVMI threshold values for hypertensive population. Whether detected
defining LVH in a heterogeneous urban popula- by ECG or echocardiography, LVH has been
tion. Factors such as age, race, and physical shown to be an independent risk factor for
activity affect LVM and different threshold coronary heart disease, sudden death, heart
values may be suitable in different populations. failure, and stroke.8-12
The observed prevalence of LVH depends both Although least accurate as a surrogate for
upon its definition and the laboratory method by direct measurement of LVM, ECG evidence of
which it is ascertained. The diagnostic modalities LVH remains the most potent predictor of
currently used to detect LVH and indirectly adverse outcomes in epidemiological stud-
assess LVM include the electrocardiogram, echo- ies.13,14 Reports from the Framingham database
cardiogram, and cardiac magnetic resonance document a 6-fold increase in overall mortality
328 GRADMAN AND ALFAYOUMI

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% LVH. A linear relationship between LVM and
of cardiovascular deaths were preceded by its cardiovascular risk was still present at LVM
development. In men with definite ECG-LVH, values of 105 g/m2 in men and 91 g/m2 in
the incidence of heart failure increased 7-fold to women, independent of other factors including
an annual risk greater than 50 of 1000 patients, age, sex, smoking, serum cholesterol, and
and the risk of sudden cardiac death was 24-hour BP monitoring.
increased 6 times. Although stroke is not usually thought of as a
Echocardiographically determined LVM is manifestation of hypertensive heart disease, it is
also a potent indicator of cardiovascular risk. clear that LVH is an independent risk factor for
In a cohort study of middle-aged patients cerebrovascular events.18 In 2363 untreated
40 years old or older and free of clinically hypertensive patients followed up for 14 years,
apparent cardiovascular disease, each 50-g/m LVH predicted the occurrence of stroke or
increase in LVM was independently associated transient ischemic attack independent of age,
with 1.49 and 1.57 relative risk (RR) for future sex, diabetes, or 24-hour mean ambulatory BP.
cardiovascular events in men and women, ECG-LVH was associated with an increased RR
respectively.15 Left ventricular hypertrophy was of 1.79 and echocardiographic LVH of 1.64. For
associated with up to 2 times the RR for death each increase in LVM of 1 SD (29 g/m2), there
from cardiovascular causes and all-cause mor- was a 31% increase in the risk for cerebrovascu-
tality. In a prospective population-based study of lar events.19
approximately 6000 elderly individuals 65 years
or older, an independent association between
LVM and CHF was observed. Patients in the
Factors in LVH Development
highest LVM quintile exhibited a 2.8 RR for Left ventricular hypertrophy is an adaptive
heart failure development during an average response of the myocardium to increased cardiac
5.5-year follow-up period. workload; its development normalizes wall ten-
As is the case with BP itself, the gradation of sion and is thought to preserve systolic ventric-
risk associated with increasing LVM extends into ular function. The incidence of LVH is directly
the reference range. In the Progetto Ipertensione related to the level of systolic BP.20-24 The
Umbria Monitoraggio Ambulatoriale study,16,17 relationship between the age-adjusted prevalence
previously untreated hypertensive patients were of LVH, as determined by echocardiography and
stratified according to LVM using a value of average systolic BP in the Framingham study, is
125 g/m2 in men and 110 g/m2 in women as shown in Fig 1. Although a linear relationship to
criteria for the echocardiographic diagnosis of BP is observed, BP does not fully account for the
MANAGEMENT OF HYPERTENSIVE HEART DISEASE 329

Fig 2. Schematic representation of myocardium and its myocyte and nonmyocyte cells and tissue fluid.

variability in LVM. Using standard criteria, 10% documented in a much higher percentage of
to 15% of individuals with an average systolic BP hypertensive women than men —57% compared
b120 mm Hg— a BP considered optimal by with 31%, a difference which parallels in the
almost any criteria —were found to manifest higher contribution of hypertension to overall
LVH. Statistically, only 10% of the variation in heart failure risk in women.8 In African Amer-
LVM could be accounted for based on office icans, the prevalence of LVH is increased 2- to
systolic BPs averaged over a 30-year period.25 3-fold compared with whites with similar BP
Ambulatory BP monitoring gives a more elevations.29 The prevalence of LVH increases
accurate estimation of the integrated hemody- markedly with age, an effect which is greater in
namic load to which the ventricle is subjected women compared with men. Controversy exists
and correlates more closely with LVM calcula- as to whether this relationship reflects the
tions. Twenty-four-hour mean BP and average concomitant increase seen in systolic BP or
daytime systolic BP—in most studies, the best whether age per se influences LVH development.
statistical correlates of LVM—account for about Obesity is a major risk factor 30 for LVH
25% of observed variance in LVM.21 As day- development; a 2 kg/m2 increase in body mass
to-day variability in 24-hour BP is considerable, index correlated with a 50% risk of increased
it is likely that a better correlation exists between LVM in a cohort of elderly men and women. In
integrated lifetime hemodynamic burden and some studies, obesity was a more important
LVM. Maintenance of a normal 24-hour BP determinant of LVH development in women
pattern including the normal nocturnal bdipQ in compared with men.
BP is protective. Despite similar mean BP values,
bnon-dippersQ have increased LVM compared
with individuals displaying the usual circadian
Pathogenesis
pattern.26-28
Structural Alterations
Factors other than BP, including age, sex, race,
body mass index, and neurohormonal stimula-
The myocardium is an elastic network of myocytes
tion, are operative in determining who among enmeshed in a collagen matrix that connects the
the hypertensive population develops LVH. In myocytes and supporting coronary vasculature
the Framingham study, LVM increase was (Fig 2). 31
330 GRADMAN AND ALFAYOUMI

The cardiac anatomical changes that accom- hypertension. In animal studies, subpressor
pany chronic elevation of systolic and diastolic infusions of norepinephrine induce cardiac hy-
BP are commonly referred to by the term left pertrophy accompanied by an increase in the
ventricular hypertrophy. It is important to keep in production of cardiac myosin heavy chains
mind, however, that the remodeling process, indicative of myocyte hypertrophy.33-35 The
which accompanies hypertension, consists of a trophic effects of angiotensin II on cardiac
range of changes in tissue architecture, which myocytes, mediated by the Angiotensin 1 recep-
include perivacular and myocardial fibrosis and tor (AT1) receptor, have been demonstrated in
medial thickening of intramyocardial coronary whole-animal and in vitro models.36 In tissue
arteries in addition to myocyte hypertrophy. All culture experiments, phenylalanine incorpora-
of these structural changes and the resulting tion (a surrogate for protein synthesis) has been
alteration in myocardial composition are impor- documented after exposure to angiotensin II.
tant contributors to the pathogenesis of hyper- This effect is mediated by several secondary
tensive heart disease. The response of the pathways including the expression of the proto-
individual myocardial components and relative oncogenes c-myc, c-fos and c-jun, expression of
changes in the overall cellular composition of growth factors including Egr-1, and production
the myocardium are influenced by both hemo- of cytokines such as transforming growth factor
dynamic and nonhemodynamic factors. Non- b.37,38 Mechanical deformity itself induces syn-
hemodynamic factors include genetics and thesis of angiotensin II, which is secreted into
neurohormonal systems, in particular, the sym- the culture medium and stimulates cell growth
pathetic nervous and renin-angiotensin systems. in an autocrine fashion. This suggests that the
The latter are of particular interest because they primary stimulus to hypertrophy—mechanical
are amenable to pharmacological manipulation stretch —may be angiotensin-mediated.39
by a variety of available drugs, which play a useful The development of myocardial fibrosis dis-
role in the treatment of hypertension and hyper- tinguishes pathological from physiological ven-
tensive heart disease. tricular hypertrophy. Biopsies from patients with
Myocytes make up approximately 75% of the hypertension and LVH demonstrate increased
myocardium by weight, and myocyte hypertro- collagen content and extensive fibrosis com-
phy is primarily what is measured when techni- pared with normal hearts.40 When there is
ques such as echocardiography or MRI are used parenchymal cell loss, a reparative (replacement)
to assess LVM. Myocyte hypertrophy occurs fibrosis occurs. In addition, there is perivascular-
in response to mechanical deformity resulting interstitial fibrosis.
from stretch or shear forces and is seen in all Hormonal influences appear to be particularly
conditions that produce either pressure or important in the fibrotic process. In the cardiac
volume overload of the ventricles. Hypertrophy muscle, collagen synthesis and degradation are
of cardiac myocytes without accompanying ongoing, and the equilibrium of these processes
fibrosis or vascular changes does not appear to is controlled by a variety of hormones and
have adverse prognostic implications. Physiolog- cytokines. Profibrotic substances include the
ical LVH seen in athletes performing isometric sympathetic nervous system, renin-angiotensin-
exercise (wrestlers and weight lifters) is not aldosterone system, inflammatory cytokines (eg,
associated with alteration in myocardial compo- transforming growth factor b), and growth
sition and is characterized by normal systolic factors such as insulin-like growth factor. In
and diastolic function. Such hypertrophy is contrast, bradykinin, nitric oxide, natriuretic
usually mild and regresses spontaneously when peptides, and glucocorticoids have collagenolytic
the physical stimulus is removed.32 effects.37 In experimental studies, both norepi-
In addition to mechanical stress, myocyte nephrine and angiotensin II stimulate fibroblasts
hypertrophy occurs in response to the myocar- as well as myocytes. In ventricular hypertrophy
dial stimulator hormones norepinephrine, endo- induced in rats by infusion of subpressor doses
thelin, and angiotensin II. Increased activity of of norepinephrine,33 hydroxyproline content
the sympathetic nervous system is correlated increased, and a 37% increase in interstitial
with LVM in young individuals with borderline fibrosis was documented. In cultured cardiac
MANAGEMENT OF HYPERTENSIVE HEART DISEASE 331
fibroblasts, angiotensin stimulates thymidine infusion. After adjustment for age, systolic/
incorporation indicative of cellular proliferation diastolic BP, sex, and duration of hypertension,
as well as collagen synthesis. LVM remained an independent predictor of
Activation of the renin-angiotensin-aldoste- abnormal endothelial-mediated dilatation.45
rone system also leads to the production of Resting coronary blood flow in patients with
aldosterone, a hormone that plays a key role LVH is usually normal. However, it is reduced
in the development of myocardial fibrosis.41 relative to the increased ventricular mass be-
Aldosterone stimulates deposition of interstitial cause the cross sectional area of the coronary
collagen and remodeling of the extracardiac microcirculation does not increase in parallel
matrix. In rats made hypertensive by aldosterone with myocyte growth. Autoregulation of myo-
infusion, myocyte hypertrophy occurs in the left, cardial blood flow in response to changes in
but not the right, ventricle and is a function of systemic BP is impaired and results in reduced
pressure overload (angiotensin levels are normal subendocardial flow, particularly in the presence
in this model). In the same experiment, mRNA of reduced coronary perfusion pressure (diastol-
for collagen formation increases and fibrosis ic BP), and increased intramyocardial pressures
occurs in both the right and left ventricles such as occurs with diastolic dysfunction.
indicating that it is the circulating aldosterone Abnormalities in coronary blood flow are
rather than the pressure load that is responsible common in hypertensive patients with or without
for its induction.42,43 LVH but are more severe in the presence of LVH.
Medial thickening of intramyocardial coro- Brush et al46 documented angina pectoris in
nary arteries and perivascular fibrosis occur in patients with reduced coronary vasodilator
pathological LVH. Analogous to ventricular responses to ergonovine in the absence of either
hypertrophy, vascular hypertrophy constitutes LVH or epicardial coronary obstruction. Patients
an adaptive response to chronic BP elevation; the with hypertension and especially with LVH
increased ratio of media thickness to lumen exhibit significant reduction in coronary flow
diameter normalizes elevated wall stress. Tro- reserve, the increase in blood flow, which occurs
phic hormones, particularly angiotensin II, stim- after maximal coronary vasodilation. In normal
ulate smooth muscle cell proliferation and individuals, coronary blood flow increases 4 to
vascular hypertrophy. In experimental animal 5 times after administration of dypridamole.
models, angiotensin II infusion also induces In patients with LVH and ST-segment depression,
perivascular fibrosis.44 this response is reduced by approximately 50%.47
Hamasaki48 reported that endothelium-depen-
dent vasodilatation in the coronary circulation
Physiological Changes and Clinical Correlation
was normal in hypertensive patients without LVH
The anatomical changes described above are, for but reduced in those in whom LVH was present.
the most part, directly responsible for the Hypertension/LVH patients with clinical angina
physiological alterations that lead to the clinical apparently related to abnormal coronary flow
manifestations of hypertensive heart disease. reserve are well described but not common.
These changes involve disturbances of myocar- The exact clinical consequences of these
dial blood flow, the development of an arrhyth- abnormalities in coronary perfusion are far from
mogenic substrate, and diastolic dysfunction. clear. Epidemiological studies do not provide
detail on the specific events included under the
category of coronary heart disease. Presumably,
Coronary blood flow
under conditions of increased myocardial oxy-
Generalized endothelial dysfunction character- gen demand with or without large-vessel coro-
ized by reduced responses to endothelial-depen- nary obstruction, decreased ability to dilate the
dent vasodilators is well-documented in microvasculature translates into increased ische-
hypertension and is more severe in patients with mia and/or infarction. The observation that
LVH. Perticone observed an inverse relationship infarct size is increased in animals with hyper-
between LVM and the magnitude of forearm trophied hearts after experimental coronary
blood flow augmentation after acetylcholine ligation is consistent with this concept.49 A
332 GRADMAN AND ALFAYOUMI

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 with ventricular late potentials demonstrated a
increased risk for coronary events and sudden greater degree of myocardial fibrosis on right
cardiac death seen in patients with LVH. ventricular biopsy. In spontaneously hyperten-
Impaired subendocardial blood flow may con- sive rat (SHR) hearts subjected to coronary
tribute to diastolic dysfunction and increase the ligation, ventricular tachycardia/ventricular fi-
risk or severity of heart failure. brillation (VT/VF) occurred in more than 60%
compared with b10% of hearts derived from
normotensive rats.51
Arrhythmogenic substrate
During ambulatory ECG monitoring, patients
It is generally assumed that sudden cardiac death with hypertension and LVH exhibit a greater
is ischemic, arrhythmic, or thrombotic. In these prevalence of premature ventricular contractions
clinical events are included many cases, which, and complex ventricular arrhythmias, including
no doubt, represent complex interactions of nonsustained ventricular tachycardia, compared
diminished coronary flow reserve, increased with patients without LVH.52 The Framingham
myocardial oxygen demand, lethal arrhythmias, group reported that the presence of asymptom-
and subendocardial ischemia in conjunction atic ventricular arrhythmias in patients with LVH
with associated coronary atherosclerosis due to was associated with a 2-fold increase in mortal-
hypertension. Therefore, it is likely that the ity. Human electrophysiologic studies have
arrhythmic propensity in LVH is multifactorial yielded contradictory results regarding induc-
in origin.50 ibility of ventricular tachyarrhythmias. 53,54
There is evidence that the myocardium with There is some evidence that LVH regression is
pathological hypertrophy provides a permissive associated with a diminution in spontaneous
anatomical substrate for the development and ventricular ectopy.
propagation of ventricular arrhythmia. Myo-
cardial fibrosis impedes the homogenous pro-
Diastolic dysfunction
pagation of electrical impulses through the
myocardium and facilitates re-entrant arrhyth- Diastolic dysfunction refers to abnormalities in
mias. In patients with ventricular tachycardia LV distensibility, filling, or relaxation, and is the
and normal left ventricular (LV) function, those hemodynamic hallmark of hypertensive heart
MANAGEMENT OF HYPERTENSIVE HEART DISEASE 333

Fig 4. Pathophysiology of preserved LVEF heart failure.

disease. Normal diastolic function implies that zyme (ACE) inhibitor, lisinopril. In aging SHR
the volume of ventricular filling is sufficient to with ventricular hypertrophy, animals exhibiting
generate an adequate stroke volume while signs of heart failure were compared with those
maintaining normal diastolic pressures. When without heart failure. Increased passive stiffness
diastolic dysfunction is present, LV end-diastolic of isolated papillary muscles derived from the
pressure increases out of proportion to volume heart failure rats was documented, and this
(Fig 3) and may be elevated at rest or with finding was associated with a higher LV collagen
exertion. This increased pressure when reflected concentration and degree of interstitial fibrosis
into the pulmonary capillaries produces dyspnea determined histologically. In man, Sugihara
and left-sided CHF. Reduced stroke volume and et al58 reported an inverse correlation between
cardiac output55 leads to fatigue and decreased rapid filling volume and % myocardial fibrosis as
exercise capacity (Fig 4). assessed by right ventricular endomyocardial
Diastolic dysfunction may be symptomatic or biopsy (Fig 5).
asymptomatic and occurs in hypertensives with Diastolic function is most accurately charac-
or without LVH. Studies using Doppler echocar- terized by measurement of pressure/volume
diography have reported that approximately 20% relationships, which are impractical in routine
of untreated persons with borderline or mild clinical practice. Noninvasive imaging techni-
hypertension have diastolic filling abnormalities ques in common use include Doppler echocar-
in the absence of LVH.56 In general, however, diography and radionuclide imaging. Several
the degree of diastolic dysfunction is correlated parameters derived from these techniques are
with LVM. currently used to describe diastolic function. In
Diastole consists of an early rapid filling phase aggregate, these are highly sensitive in detecting
related to active myocyte relaxation and a late, diastolic dysfunction. However, their ability to
passive phase, which is dependent upon the distinguish patients with clinical diastolic heart
elastic properties of the left ventricle. Reduced failure from those with incidental abnormalities
velocity of relaxation has been described in has proved to be highly variable and less than
hypertrophied myocytes and may contribute to satisfactory. In clinical practice, diastolic heart
diastolic dysfunction.56 Myocyte relaxation is an failure remains a clinical diagnosis.
energy-requiring process, which is impaired in
the presence of ischemia.
Systolic dysfunction
The degree of myocardial fibrosis is a critical
determinant of diastolic dysfunction. In SHR, It has long been assumed that concentric LVH
Brilla et al57 demonstrated normalization of with normal ejection fraction (EF) is a precursor
diastolic stiffness, measured in isolated hearts, to LV systolic dysfunction and dilated cardio-
when myocardial fibrosis was eliminated by myopathy. In many series of patients with
treatment with the angiotensin-converting en- systolic dysfunction heart failure, hypertension
334 GRADMAN AND ALFAYOUMI

Fig 5. Myocardial fibrosis correlates with LV diastolic dysfunction.

is considered to be the most common etiologic graphic evaluation of systolic function and LVM
factor, particularly in African Americans. at baseline and after a 5-year follow-up period.
Patients with hypertension, LVH, and normal Statistically, LVH was found to be a risk factor
EF frequently exhibit subtle evidence of systolic for development of decreased LVEF independent
dysfunction, including reduced fractional short- of coronary artery disease and MI. However,
ening of the LV mid wall.59,60 Transition from most cases of LVH were of eccentric pattern, and
concentric hypertrophy to systolic dysfunction is the typical concentric pattern seen in hyperten-
observed in animal models including SHR,61 sive heart disease was not shown to be a
aging Harlan-Sprague-Dawley rats, aortic band- predictor for depressed LV systolic function.65
ing62 and transgenic manipulation.63 In summary, evidence is lacking that LVH
Nevertheless, it remains unclear if this con- resulting from hypertension is a major risk
version is part of the natural history of hyper- for systolic heart failure independent of coro-
tension-induced LVH in man. The close nary artery disease. At present, LVH should
epidemiological association between hyperten- be considered as a direct precursor for clini-
sion, LVH, coronary heart disease, and heart cal heart failure mostly in the form of dia-
failure complicates the question. In a published stolic dysfunction.
series, hypertensive patients whose deaths were
attributed to heart failure often had associated
Therapeutic Perspectives
coronary disease. A critical question relates to
the frequency with which patients with concen-
Prevention
tric LVH develop systolic heart failure in the
absence of coronary artery disease and interval Treatment of hypertension greatly attenuates the
myocardial infarction (MI). development of LVH and heart failure. In a meta-
Two recent studies have addressed this issue. analysis by Moser and Herbert66 reviewing major
In a retrospective analysis, Drazner et al65 hypertension trials conducted over a 20-year
evaluated 159 middle-aged hypertensive patients period and involving more than 48 000 subjects,
in whom concentric LVH with a normal EF had ECG-LVH was reduced by about one third and
been documented on a previous echocardio- heart failure by 52%. The type of heart failure —
gram. Only 18% developed reduced EF over an systolic vs diastolic —was not specified. It is
average follow-up period of approximately likely that these figures underestimate the
4 years. Fifty percent had sustained a MI.64 In potential of aggressive antihypertensive therapy.
the Cardiovascular Health Study, 3042 partic- Target BPs in many of these trials were higher
ipants with normal EF underwent echocardio- than those recommended by present guidelines
MANAGEMENT OF HYPERTENSIVE HEART DISEASE 335
such as Joint National Committee for the duration, and used nonblinded reading of
Prevention, Detection, Evaluation and Treatment echocardiograms. Meta-analyses are also limited
of High Blood Pressure 7 (JNC 7).67 For by the fact that they do not represent drug-by-
example, in the Systolic Hypertension in the drug comparisons but aggregate members
Elderly Population (SHEP) study,68 a diuretic- of a class, which may have rather different
based trial in patients with isolated systolic pharmacological properties. In clinical trials,
hypertension, heart failure incidence was re- head-to-head comparison of antihypertensive
duced by 51%. According to the treatment agents is difficult because most patients with
protocol, patients with systolic BPs above hypertension and LVH require multiple agents
160 mm Hg at baseline were treated to a goal to achieve BP control.
systolic BP of only 160 mm Hg rather than the Several well-designed comparisons of specific
current target of 140 mm Hg. agents in larger populations have recently been
reported. In Prospective Randomized Enalapril
Study Evaluating Regression of Ventricular
Left Ventricular Hypertrophy Regression
Enlargement trial,73 enalapril and nifidipine
Left ventricular hypertrophy regression is both Gastrointestinal Therapeutic System (GITS) (ex-
possible and desirable and is an important tended release) were compared in 303 patients
intermediate end point in the treatment of with hypertension and LVH using M-mode
hypertension. Because systolic BP is the primary guided 2D echocardiography to calculate LVM
stimulus for LVH development, BP reduction by at baseline and after 24 and 48 weeks of
almost any means produces some degree of LVH treatment. At 48 weeks, comparable reductions
regression. Changes in LVM during treatment in BP, echocardiographic dimensions, and LVM
have been correlated with BP reduction par- were observed in the 2 treatment groups. Left
ticularly when evaluated using 24-hour moni- ventricular mass index was reduced into the
toring. However, this relationship is weak, reference range in 56% of enalapril-treated
emphasizing the contribution of nonhemody- and 48% of nifidipine GITS –treated patients.
namic factors.69 The direct acting vasodilators, Most of the decrease in mass was seen during the
hydralazine, and minoxidil, do not cause LV first 6 months. There was a significant but
regression either in experimental animals or in weak correlation between BP reduction and
man despite lowering BP.70 Presumably, this LVM regression.
reflects the finding that both cause sympathetic Two other large studies illustrate the impor-
activation, illustrating the importance of neuro- tance of study duration, combination therapy,
hormonal stimuli. and BP reduction in evaluating treatment effects.
Multiple meta-analyses have been published In one trial,74 the diuretic, indapamide sus-
evaluating the comparative effects of antihyper- tained release was found to be superior to
tensive drug classes on LVH regression. In an enalapril in 505 hypertensive men and women
analysis of 109 published studies, Dahlff et al71 with LVH. Interestingly, the results with these 2
reported that the magnitude of LVM reduction agents were similar after 24 weeks but diverged
measured by echocardiography ranged from over the subsequent 24 weeks, perhaps indicat-
7.7% with diuretics to 16.3% with ACE inhib- ing the importance of longer-term studies to
itors, the most effective of the classes studied. evaluate treatment effects. In a well-conducted
The updated meta-analysis by Klingbeil et al72 study using MRI to estimate LVM, the combi-
is consistent with most earlier studies and nation of 2 renin-angiotensin system blockers,
extensive animal data. Angiotensin-converting the aldosterone antagonist, eplerenone, and
enzyme inhibitors, AT1 receptor blockers, and enalapril, was found to be superior to either
calcium antagonists were found to be more alone. Interpretation of the study is complicated
potent than b-blockers; the efficacy of diuretics by the small but statistically significant differ-
was intermediate. ence in systolic BP favoring the combination
The results of these meta-analyses should be therapy group.75
interpreted with caution because many of the The Losartan Intervention For Endpoint re-
studies included were of small size, of short duction in hypertension (LIFE) trial76 was the
336 GRADMAN AND ALFAYOUMI

first clinical trial in patients with LVH to which are independent of than their effect
compare the effects of specific drugs not only on LVM.
on LVM regression but also on clinical end
points. The study randomized 9193 hypertensive
Diastolic Dysfunction and Heart Failure
patients with definite ECG evidence of LVH to
receive losartan or atenolol as first-line therapy More than 4.6 million people in the United
for hypertension. Most patients in both treat- States have chronic heart failure; at least one
ment groups received additional antihyperten- third of these patients can be considered to have
sive agents including hydrochlorothiazide diastolic heart failure.79 Because of the relative
(HCTZ). After 4.8 years of follow-up, BP lack of clinically useful measures of diastolic
reduction in the 2 groups was nearly identical. function, diastolic heart failure is usually defined
The composite primary end point of cardiovas- as the presence of typical heart failure signs/
cular death, MI or stroke was reduced by 13% in symptoms and preserved systolic function (LVEF
losartan-treated compared with atenolol-treated N 40%-50%). In Acute Decompensated Heart
patients. The difference in the primary end point Failure National Registry (ADHERE), a contem-
was entirely driven by a 25% reduction in stroke porary database of more than 52 000 patients
in the losartan group. hospitalized with acute heart failure, 46% had
To determine the prognostic significance of preserved systolic function.80
LVM reduction during treatment, a prospective In general, the older the population studied,
echocardiographic substudy was conducted in the higher the prevalence of normal EF among
941 patients in whom LVM was measured at patients with heart failure. More than 50% of
baseline and annually during the follow-up participants in large population-based studies of
period. Reduction in LVM was found to be patients older than 65 years hospitalized for
significantly greater in the losartan group (mean CHF demonstrated an EF exceeding 45% on a
reduction 21.7g/m2 vs 17.7 g/m2 ( P = .021). baseline echocardiogram.65 Compared with
Reduction in LVM continued for 2 full years after patients with heart failure with systolic dysfunc-
randomization. Cox regression analysis showed tion, patients with diastolic heart failure are
that lower LVM during antihypertensive therapy more likely to be female and to have an elevated
was associated with lower rates of clinical end BP at the time of presentation. Most have a
points independent of the BP, treatment assign- history of hypertension, and LVH is common. In
ment, other risk factors, and various comorbid- a recent series of hospitalized urban patients,
ities.77 Reduction in LVMI by 1 SD (25.3 g/m2) 82% were found to have increased LVM.81
was associated with a calculated 22% reduction Diastolic heart failure is associated with
in the primary end point and a 28% reduction in increased mortality compared with an age-
total mortality additional to that predicted by BP matched control group,82 although survival is
reduction alone. improved relative to patients with heart failure
The results of the LIFE echo substudy validate based on systolic dysfunction. The mortality rate
earlier,78 less definitive reports indicating that ranges from 4% to 8% annually, as compared
LVH regression is associated with improved with 10% to 15% in patients with systolic heart
long-term clinical outcome and is a desirable failure. Morbidity, however, is approximately
target for therapy. These results also point to equal. The 1-year hospital readmission rate can
limitations in the use of LVM regression as a approach 50%.83 In the Candesartan in Heart
clinical end point when comparing drug treat- failure: A Assessment of Reduction in Mortality
ments. In the LIFE study, cardiovascular mor- and morbidity (CHARM)-Preserved study,82
tality, which, in epidemiological studies, is which included less severely symptomatic (most-
directly correlated with LVM, was not different ly New York Heart Association class II patients),
between the losartan and atenolol treatment 18% in the placebo group required hospital
groups despite the large sample size and the admission over a 3.5-year follow-up period;
documented superiority of losartan with regard 4.2% had more than 3 admissions.
to LVM regression. Presumably, this relates to Despite its frequency, there are no definitive
pharmacological properties of the 2 agents, clinical trial data available to direct the therapy
MANAGEMENT OF HYPERTENSIVE HEART DISEASE 337
for patients with diastolic dysfunction heart heart failure and LVEF above 40%. After a
failure and hypertension. Diuretics are generally median follow-up period of 37 months, there
required to reduce ventricular preload and was an 11% reduction in the primary end point
relieve dyspnea and edema. Various authors have of cardiovascular death or heart failure hospital-
recommended the use of drugs that reduce heart ization, a result which did not reach statistical
rate and prolong diastolic filling time, including significance. There was no effect on mortality.
b-blockers and verapamil. There are no human The reduction in hospitalization was of bor-
data evaluating the efficacy of b-blockers. In derline significance. Several large clinical
1 small study, verapamil was compared with trials with other Angiotensin receptor blockers
placebo in 20 patients and was associated with are ongoing.
prolongation of exercise duration on a stationary A major set of unanswered questions relates to
bicycle after a 5-week treatment period.84 the effectiveness of antihypertensive therapy per
Based upon favorable results in animal mod- se in the treatment of diastolic heart failure.
els, renin-angiotensin system blockers have There are theoretical reasons to postulate that
undergone clinical evaluation in man. Using such treatment may be effective. The left ventri-
serial LV biopsy and echocardiographic exami- cle generally compensates for increased systolic
nations, Brilla et al85 compared lisinopril and pressure load through an often small increase in
HCTZ in 35 hypertensive patients with symp- end-diastolic volume. It is possible that these
toms of either dyspnea or angina and evidence of increases could cause significant elevation of
diastolic dysfunction by echocardiogram. After end-diastolic pressure in patients with severe
6 months of treatment, morphometric studies of diastolic dysfunction. Proof of this concept or
biopsy specimens documented regression of recommendations regarding optimal BP targets
myocardial fibrosis in lisinopril-treated patients, are not possible with present evidence. Certain-
but not those receiving HCTZ. A parallel ly, BP should be treated aggressively to JNC
improvement in diastolic functional parameters 7 goals. These are systolic BP below 140 mm Hg
relative to the diuretic was also noted. In another for hypertensives in general and below 130 mm
study, diastolic heart failure was evaluated in Hg in persons with diabetes. Diabetes is
21 patients randomized to receive enalapril or known to exert an independent adverse effect
placebo. The enalapril group had significant on diastolic function and, in both the ADHERE80
reduction in BP and LVM; these findings were and New York Heart Failure Registries,81 consti-
associated with improvement in heart failure tuted 45% of patients with diastolic heart failure.
symptoms and in diastolic function evaluated by
Doppler echocardiography.86
Summary
Angiotensin receptor blockers are the best
studied drug class in diastolic heart failure. In a Left ventricular hypertrophy is an adaptive
cross-over study comparing losartan and place- response of the heart to hypertension, which
bo, 20 patients with dyspnea and exercise- results in changes in myocardial structure that
induced hypertension (systolic BP N200 mm greatly increase the risks of cardiovascular
Hg) were recruited.87 Losartan treatment signif- mortality, sudden death, coronary heart disease,
icantly reduced exercise systolic BP. While heart failure, and stroke. Ischemia, ventricular
receiving losartan, patients were able to exercise arrhythmias and diastolic dysfunction are the
for a longer period and had improved quality functional components of hypertensive heart
of life. All patients in the study had echocar- disease. Myocardial fibrosis appears to be the
diographic evidence of diastolic dysfunction, most important structural alteration in its
although only 25% had LVH. development. Although elevated BP is the
The CHARM-Preserved trial82 is the only large initiating stimulus, neurohormonal factors, par-
scale clinical trial, which has been completed in ticularly the renin-angiotensin system, play a
patients with diastolic heart failure. In this study, key role in determining who among hyper-
the angiotensin receptor blocker candesartan tensives will develop LVH. Aggressive antihy-
cilexitil, titrated to a dose of 32 mg/d, was pertensive therapy is critical in preventing the
compared with placebo in 3031 patients with development of hypertensive heart disease,
338 GRADMAN AND ALFAYOUMI

LVH, and CHF. Achieving LVH regression is a tive heart failure, and mortality in an elderly cohort
(the Cardiovascular Health Study). Am J Cardiol
desirable and achievable goal and is associated
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