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SECTION 3   HYPERTENSIVE HEART DISEASE

chapter 

41  Complications of Hypertension:

The Heart

Chim C. Lang, Henry Krum, and Gregory Y. H. Lip

Definition

n   The clinical cardiac complications of persistently andabnormally increased systemic blood pressure includeincreased left ventricular (LV) mass, with or without chamber 

dilatation, left atrial abnormalities, myocardial ischemia,systolic and diastolic LV dysfunction, atrial and ventricular 

arrhythmias, and sudden death.

Key Findings

n   The cardiac complications of hypertension result from theinteraction of hemodynamic, vascular, cardiac, and

neurohumoral pathogenetic processes, including increased LV wall stress, alterations in myocardial gene expression,endothelial dysfunction, and activation of the adrenergic and

renin-angiotensin systems.

n  Left ventricular hypertrophy (LVH), whether diagnosed by

electrocardiography or by echocardiography, is a major contributor to the major cardiac complications.

n   Heart failure related to hypertension is characterized by

ventricular remodeling and may progress from asymptomaticdiastolic LV dysfunction to symptomatic systolic dysfunction,

according to the degree of blood pressure control and theextent of any myocardial ischemia.

n  Concurrent atherosclerotic coronary heart disease and

hypertension increase the risk of all cardiovascular events and the

likelihood of complications of the acute coronary syndromes.n  Arrhythmias and sudden cardiac death are increased in

hypertensive patients, especially those with LVH and

myocardial ischemia.

Clinical Implications

n   Decreasing blood pressure to optimal levels is paramount.

n   Reducing total absolute cardiovascular disease risk by treating

risk factors, such as diabetes, dyslipidemia, cigarette smoking,and physical inactivity, is a critical component of treatment.

n  Regression of LVH is associated with most antihypertensive

agents (except direct-acting vasodilators). The regression of LVH reduces overall cardiovascular risk and atrial fibrillation and

improves outcomes.

n   Selection of antihypertensive therapy that is also appropriate for the treatment of concomitant cardiac complications (i.e.,

angiotensin-converting enzyme inhibitors and/or angiotensinreceptor antagonists for LV systolic dysfunction; angiotensin

receptorantagonists for LV diastolic dysfunction; betablockers for angina pectoris, post–myocardial infarction, and atrial or 

ventricular arrhythmias) is essential.

The heart is responsible for the pathogenesis of hyperten-

sion, yet it also suffers its consequences. The earliest changes

in cardiac hemodynamics are largely compensatory in

nature, but if a patient’s hypertension is untreated or uncon-

trolled, these invariably lead to compromise of cardiac struc-

ture and function. In particular, it has been well recognized

that the presence of left ventricular hypertrophy (LVH) is an

adverse feature in hypertension, with affected patients having

a substantially greater risk of cardiovascular events, including

mortality and morbidity from heart failure, atrial fibrillation,

sudden death, and stroke. Indeed, LVH is probably the most

visible manifestation of hypertensive target organ damage.

However, hypertension is a complex disease in which several

genetic and demographic factors, comorbid diseases (e.g., dia-betes and obesity), pathophysiologic processes, and environ-

mental influences interact to produce a wide array of target

organ damage. The major clinical consequences of hyperten-

sion stem not only from the effects of increased blood pressure

but also from pathophysiologic, functional, and structural

responses to hypertension (Table 41.1).

PATHOPHYSIOLOGY OF HYPERTENSIVEHEART DISEASE

The presence of hypertension more than doubles the risk for

coronary artery disease, including myocardial infarction and

sudden death, and more than triples the risk of congestiveheart

failure.1-3 Although hypertension, coronary artery disease, andheart failure are separate disease processes with their distinct

natural histories, they are clinically linked and their courses

critically affect one another.4,5 For example, coronary hemo-

dynamics may be altered, with reduced coronary flow reserve,

in hypertension. This may reflect a reduction in the density of 

resistance coronary arterioles, an increase in wall thickness-

to-lumen ratio, a reduction in coronary vasodilator capacity,

and an increase in the systolic impediment to coronary flow

in hypertrophy.6 These coronary alterations may directly con-

tribute to impaired ventricular function. However, in the late

stages of hypertension, there may be marked interstitial fibro-

sis and structural remodeling of the LV chamber, which will

also result in reduced contractile efficiency.These findings underpin the concept of “hypertensive

heart disease” as a distinct entity, which is independent of 

other common associated diseases such as atheromatous

coronary artery disease.4,5 Hypertensive heart disease has

been defined as the response of the heart to the afterload

imposed on the left ventricle by the progressively increasing

arterial pressure and total peripheral resistance produced

by the hypertensive vascular disease.7 Specifically, hyperten-

sive heart disease is characterized by altered coronary

hemodynamics and reserve, cardiac dysrhythmias, LVH and

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enlargement, ventricular fibrosis, diastolic dysfunction, and

cardiac failure.

Hypertensive heart disease develops in response to mutu-

ally shared genetic determinants, environmental risk factors,

and hemodynamic and nonhemodynamic mechanisms

(Fig. 41.1). Because the heart and conduit vessels are integralcomponents of a pulsatile pumping system, the

hemodynamic mechanisms that lead to hypertensive heart

disease include both cardiac elements (myocardial contractility

and wall stress,8 stroke volume9) and vascular factors (periph-

eralresistance and vascularcompliance10), which undergo com-

plex, interrelated adaptive and degenerative changes in

response to the chronic increase in mean and pulsatile hemody-

namic load (Table 41.2).

Although hemodynamic load is the basic initial stimulus to

begin the sequence of biological events leading to thedevelop-

ment of hypertensive heart disease, nonhemodynamic factors

may also influence and contribute to the cascade of molecularchanges that eventually yield the adverse structural remodel-

ing that begets hypertensive heart disease. These nonhemody-

namic factors include age, race, genetic contributions, obesity,

salt intake, insulin resistance,11-13 anda numberof neuroendo-

crine factors (such as angiotensin II, aldosterone, sympathetic

tone, endothelin) and hemorheologic factors (blood viscosity,

plasma volume).14,15 Abnormalities in one or more of these

factors may antedate the development of sustained clinical

hypertension, but may be pathogenetically operative in the

preclinical stages of systemic hypertension.

Indeed, despite blood vessels being exposed to high pres-

sures, the complications of hypertension (e.g., myocardial

infarction and stroke) are paradoxically thrombotic ratherthan hemorrhagic; this is now referred to as the thrombotic

paradox of hypertension or the Birmingham paradox. Cer-

tainly, abnormalities of hemostasis, platelets, and endothelial

damage/dysfunction are present in hypertension, contribut-

ing to a prothrombotic or hypercoagulable state.15 These

abnormalities have also been associated with hypertensive

target organ damage, including LVH; furthermore, they can

be beneficially improved with antihypertensive treatment.

The sequence of events that leads from these multiple

hemodynamic and nonhemodynamic factors to hypertensive

heart disease is only beginning to be elucidated.16 Both

PATHOPHYSIOLOGY OF HYPERTENSIVE HEART DISEASE

Background

Genetic

Age

Sex

Obesity

Salt

Race

Biomechanical stretch [myocyte and nonmyocyte (fibroblast)]

Cellular and subcellular signals

Activation of early proto-oncogenes

Hypertensive heart disease

Altered coronary

reserve

Endothelial

dysfunction

Perivascular fibrosis

LVH

Cardiac dysrhthmias

Myocardial fibrosis

Systolic/diastolic

dysfunction

Clinical consequences

Angina pectoris

Asymptomatic heart

failure

Cardiac dysrhythmias

Acute coronary

syndromes

Symptomatic heart

failure

Sudden death

Myocardial

infarction

Hemodynamic

Blood pressure

Wall stress

Volume load

Arterial stiffness/ 

compliance

Nonhemodynamic

Ang II

Aldosterone

SNS

Insulin resistance

Hemorheologic

Figure 41.1 Pathophysiology of hypertensive heartdisease.  Ang II, angiotensin II; LVH, left ventricular hypertrophy;SNS, sympathetic nervous system.

CARDIAC COMPLICATIONS OF SYSTEMIC HYPERTENSION

Left ventricular Hypertrophy  þ/  Chamber Dilation Left Atrial Abnormalities

Heart failure Diastolic dysfunction

 Asymptomatic left ventricular dysfunction

 Asymptomatic left ventricular dilatation

Symptomatic heart failureCoronary heart disease Angina pectoris

 Acute coronary syndromes

 Arrhythmias and suddendeath

 Atrial arrhythmias Ventricular arrhythmiasSudden cardiac death

Table 41.1  Cardiac complications of systemic hypertension.

PATHOGENETIC PROCESSES UNDERLYING CARDIAC DAMAGEFROM SYSTEMIC HYPERTENSION

Neurohormonal Activation of the renin-angiotensin-aldosterone

systemEnhanced adrenergic activity

Increased production or reduced degradationof biologically active molecules (e.g.,

angiotensin II, cytokines)

Hemodynamic Increased peripheral resistanceIncreased circumferential and meridional wall

stressDecreased coronary reserve

 Vascular Endothelial dysfunction

 Vascular remodelingDecreased vascular complianceExaggerated vascular reactivityCoronary and peripheral vascular 

atherosclerosis

Myocardial Left ventricular remodeling

Fetal gene expressionMyocyte hypertrophy

 Alterations in extracellular matrix

Table 41.2  Pathogenetic processes underlying cardiac damagefrom systemic hypertension.

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myocytes (cardiac and vascular) and nonmyocytes (fibro-

blast) are direct biomechanical sensors of hemodynamic load.

Their activation leads to a series of cellular andsubcellular sig-

nals that regulate the expression of proto-oncogenes and other

genes that regulate cell growth, apoptosis, phenotype, and

matrix turnover. In hypertensive heart disease, tissue homo-

geneity gives way to heterogeneity and a disproportionate

involvement of noncardiomyocyte cells, which accounts for

the adverse structural remodeling of both myocardial and vas-

cular tissue structure.17,18 These alterations in tissue structure

are responsible for the pathologic LVH and medial thickeningof intramural coronary arteries and arterioles of hypertensive

heart disease and contribute to its enhanced risk of adverse

cardiovascular events, including myocardial infarction, dia-

stolic and/or systolic dysfunction, and arrhythmias.

CARDIAC COMPLICATIONS OFHYPERTENSION: LEFT VENTRICULARHYPERTROPHY

Epidemiologic data convincingly show that cardiovascular

and cerebrovascular risk increase with increasing blood pres-

sure, with a “dose-response” relationship (see Chapter 39).

Even though LVH, heart failure, coronary disease, and car-diac arrhythmias occur in the nonhypertensive patient, when

these conditions are accompanied by high blood pressure

they are associated with greater target organ damage,

increased risk of nonfatal cardiac events, premature cardio-

vascular death, and a worse overall prognosis. Simply

decreasing the blood pressure may be inadequate, and a

focus on multiple risk factor modification and reduction in

total cardiovascular disease risk “burden” may be necessary.

Although LVH may be defined by an increase in LV mass,

quantified by measurements of postmortem LV weight, by

electrocardiographic (ECG) criteria, or by echocardiography,

it is complicated by the marked variability in LV size in the

normal adult population. LV mass is strongly related to bodysize, with components attributable to lean body mass and obes-

ity. Criteria for LVH are therefore based on values that

have been indexed to height, weight, or body surface area.

Upper limits of normal LV mass indexed to body surface

area, established using M-mode echocardiography in a

healthy subset of the Framingham   Heart Study population

are 131 g/m2 in men and 100 g/m2 in women (Table 41.3).19

Using these criteria, LVH was present in 12% of men and

14% of women in the Framingham study. In normotensive

adults, LVH is directly related to the risk of developing later

hypertension,20 raising the possibility that LVH may also be

involved in the development of hypertension.

Increased blood pressure greatly increases the risk of having

LVH: there is a 43% increase in the relative risk of havingLVH in men and a 25% increase in women for each 20 mm Hg

increase in systolic pressure.21 The prevalence of LVH in sec-

ondary forms of hypertension owing to renovascular or endocri-

nologic disease is similar to that in essential hypertension.22

Prognostic Implications of LVHLeft ventricular hypertrophy established by ECG or by echo-

cardiography is a strong and independent risk factor for cardio-

vascular morbidity and mortality in the general population, in

hypertensive patients, and in patients with coronary artery

disease.23,24

Echocardiographic LVH predicts an increased riskof cardiovascular morbidity and death, even after adjustment

for other major risk factors (age, blood pressure, pulse pres-

sure, treatment of hypertension, cigarette use, diabetes, obes-

ity, cholesterol profile, and electrocardiographic evidence of 

LVH). LVH significantly increases the risk of coronary artery

disease, congestive heart failure, cerebrovascular accidents,

ventricular arrhythmias, and sudden death. It increases the rel-

ative risk of mortality by twofold in individuals with coronary

artery disease and by fourfold in those with normal epicardial

coronary arteries. In otherwise healthy individuals followed

for 4 years in whom LVH was defined as an LV mass adjusted

for height of 143 g/m in men and greater than 102 g/m in

women, the relative risk of developing cardiovascular disease

was 1.49 in men and 1.57 in women for each increment of 50

g/m in LV mass. Although the ECG is a much less sensitive

measure for LVH, presence of LVH on the ECG increases the

risk of cardiovascular diseases from threefold to sevenfold,

depending on the age and sex of the patient.

It had been suggested that the pattern of LV geometry may

be related to the risk for cardiovascular morbidity and mor-

tality. Four different LV geometric patterns have been iden-

tified: normal LV geometry, concentric remodeling, eccentric

LVH, and concentric LVH. Longitudinal studies have shown

that the risk of cardiovascular disease was highest in patients

with concentric geometry.25,26 However, it should be noted

that the LV mass tends to be greater in concentric LVH. Con-

sequently, the prognostic impact of LV geometry may bereduced or abolished because of the overwhelming prognos-

tic value of LV mass itself.

PathophysiologyGenetic and nongenetic influences on hemodynamic and

nonhemodynamic factors that eventually cause intracellular

stimulation of protein synthesis may influence the develop-

ment of LVH (see Fig. 41.1). There are several lines of evi-

dence that support the genetic influences   on the

development of LVH. Ravogli and colleagues27 found an

ECHOCARDIOGRAPHIC CRITERIA FOR UPPER LIMITS OFLV MASS*

Men Women

Number 347 517

 Age (yr) 42    12 43    12

LV mass, absolute (g) 259 166

LV mass, corrected for BSA (g/m2) 131 100

LV mass, corrected for height (g/m) 143 102

LV mass was calculated using the formula: LVM  ¼  0.8     (1.04    [LVID  þLVPWT  þ   IVST]3  LVID3) where LVID  ¼  LV internal diameter, LVPWT  ¼  LV posterior wall thickness, and IVST  ¼   intraventricular septal thickness.

*Criteria for upper limits of LV mass in adult men and women are set attwo standard deviations above the mean values for healthy populationsderived from the cohort and offspring subjects of the Framingham HeartStudy.

BSA, body surface area.Modified with permission from Levy D, Savage DD, Garrison RJ, et al.

Echocardiographic criteria for left ventricular hypertrophy: the FraminghamHeart Study. Am J Cardiol 1987;59:956-960.

Table 41-3  Echocardiographic criteria for upper limits of LV mass.

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increased LV mass in normotensive offspring of hypertensive

parents. Other studies documenting a possible genetic factor

include twin studies28 and racial studies comparing white and

black patients with hypertension. The African American

ancestry has been identified as an independent risk factor for

LVH.29 Finally, a number of candidate genes have been stud-

ied, including angiotensin-converting enzyme (ACE) gene

insertion/deletion   polymorphism and the aldosterone

synthase gene.30,31

Both pressure and volume are implicated in the develop-

ment of LVH. For instance, diastolic blood pressure is moreclosely related to LV wall thickness, and will correspond to

a pure pressure load, whereas systolic blood pressure is more

closely related to LV mass, suggesting an influence of both

pressure and load. Reduced arterial compliance in hyperten-

sion will also increase pulsatile load, and provides a further

stimulus to LVH.32 Some cross-sectional studies have sug-

gested that an increase in blood pressure variability may be

better correlated with the presence of LVH.33 Nonhemody-

namic risk factors for the development of LVH include tro-

phic factors mediated by the renin-angiotensin-aldosterone

system, sympathetic tone, and insulin. Angiotensin II pro-

motes myocyte growth, and aldosterone may increase colla-

gen content and stimulate the development of myocardialfibrosis.17,18 Insulin has trophic effects, and hypertensive

LVH is often associated with high insulin levels and insulin

resistance.34 Obesity, which is associated with increased

plasma volume and cardiac output, is also a determinant of 

LV mass.35

In response to hemodynamic overload and associated

increases in systolic wall stress, specific hypertension-related

growth factors are activated and produced.36 Both myocytes

and nonmyocytes (vascular and fibroblast) may respond as

direct biomechanical sensors of the hemodynamic load. The

biomechanical signal transduction that has been observed in

animal models shows that it is often accompanied by recruit-

ment of the G protein–coupled neurohormones, activation of 

which likely serves to amplify the growth signaling triggered

by the mechanical event itself.  Table 41.4 shows some of the

stimuli of ventricular hypertrophy that have been identified

that are either of a neuroendocrine origin (e.g., catechola-

mines) or are synthesized and released locally by the myo-

cytes and nonmyocytes (e.g., angiotensin II). The signaling

pathways responsible for the hypertrophic growth have been

actively studied, and it is likely that reversible protein phos-

phorylation and dephosphorylation are involved. Three sig-

naling pathways show potential as regulators of the

response: protein kinase C, mitogen-activated protein kinase

cascades, and calcineurin.37 Oxidative stress may also

contribute to LVH.38

Besides myocyte hypertrophy, there is also nonmyocytegrowth in LVH that leads to an adverse structural remodel-

ing of the myocardium and vasculature. An exaggerated

interstitial and perivascular accumulation of collagens   type

I and type III has been found in the hypertensive heart.17,18

Thus it has been suggested that it is not the quantity but

the quality of the myocardium that distinguishes the LVH

in hypertension from adaptive hypertrophy in the athlete.

Structural homogeneity of cardiac tissue is governed by a

balanced equilibrium existing between stimulator and inhib-

itor signals that regulate cell growth, apoptosis, phenotype,

and matrix turnover (Fig. 41.2). Stimulators are normally

counterbalanced by inhibitors (see  Fig. 41.2). Loss of this

reciprocal regulation accounts for connective tissue remodel-

ing in LVH.

The mechanisms by which LVH is associated with the

increased risk of cardiovascular sequelae are not fully under-

stood. The development of LVH is associated with myocar-

dial fibrosis and subsequent diastolic dysfunction, an

important factor in the evolution of congestive heart failure.

The reduced coronary reserve in LVH increases the risk of 

myocardial ischemia—which may in turn promote poten-

tially lethal arrhythmias—and the possibility of suffering

from myocardial infarction. The increase in myocardial

fibrosis may lead to disturbed repolarization of the myocar-

dium, potentially leading to malignant arrhythmias and

subsequent sudden death. Finally, more prothrombotic

abnormalities have been found in association with LVH, con-

tributing to the increased risk of thrombotic complications.15

Clinical Presentation and DiagnosisPathologic hypertrophy may be associated with an absence

of symptoms for many years before the development of con-

gestive heart failure or unexpected sudden death. Thus, in

contemporary clinical practice, the diagnosis depends pre-

dominantly on ECG or echocardiographic measurements.

Nevertheless, physical examination may reveal some clues.

Pulsations lateral to the medioclavicular line are a sensitive

but nonspecific sign. A thrusting apex greater than 2 cm in

STIMULI AND SIGNALS OF VENTRICULAR MYOCYTEHYPERTROPHY

Agonist Type Examples Point of Action

 Vasoactive peptides ET-1, Ang II Gaq/Ga11  !  PIP2

hydrolysis

!  nPKCs

a1-Adrenergicagonists

NorepinephrineEpinephrine

Gaq/Ga11  !  PIP2hydrolysis

! nPKCs?

Direct activators of PKC

Tumor-promotingphorbol esters

nPKCs/cPKCs

Peptide growth

factors

Fibroblast growth

factorsInsulin-like growth

factor 1

Receptor protein

tyrosine kinases

Cytokines Cardiotrophin-1 Gp130/interleukin-6receptor 

 Arachidonatemetabolites

Prostaglandin F2a   JNKs

Mechanical stretch Autocrine/

paracrine factors(ET-1, Ang II)

PIP2 hydrolysis/

PKC?JNKs?

Cell contact Not known Not known

Stimuli and signals of ventricular myocyte hypertrophy. Ang II, angiotensinII; ET-1, endothelin-1; Gaq, Ga11, G proteins; Gp130, glycoprotein 130; JNK,c-Jun N-terminal kinase; PIP2, phosphatidylinositol bisphosphate; cPKC,nPKC, cytoplasmic and nuclear protein kinase C.

 With permission from Sugden PH. Signaling in myocardial hypertrophy.Life after calcineurin? Circ Res 1999;84:633-646.

Table 41.4  Stimuli and signals of ventricular myocyte hypertrophy.

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diameter suggests LV enlargement; if it is more than 3 cm in

diameter in the left cubitus position, it is considered an accu-

rate sign. A chest x-ray is of limited value for the determina-

tion of LVH, as the picture will show the outer contour of the

heart but will not specifically delineate the heart.The ECG is a readily available and specific diagnostic pro-

cedure. A negative P wave in the precordial leads reflects an

increased load on the left atrium. Large QRS amplitude with

deep S in the anterior leads and high R in the lateral leads

reflects an enlarged LV diameter; prolonged ventricular acti-

vation time, such as wide QRS complex, and ST-T changes

reflect altered myocardial depolarization and repolarization

as a result of an increased wall thickness. Furthermore, it

appears that an anterolateral hemiblock in hypertensive

patients is a finding suggestive of LVH. Various combina-

tions of these criteria have been suggested to identify LVH

by ECG. However, a recent systematic review involving  21

studies (n   ¼   5608 patients) by Pewsner and colleagues39

assessed the accuracy of ECG in screening in hypertensive

patients and highlighted the low sensitivity of the ECG in

detecting LVH when compared with the echocardiogram.

Echocardiography can provide accurate measurements of 

the intraventricular septum, the posterior LV wall thickness,

and the LV diameter in diastole. Echocardiographic determi-

nation of LVH is characterized by high specificity (80% or

greater) and sensitivity (80% or greater). In addition, echo-

cardiography can reveal other reasons for LVH (e.g., valvu-

lar diseases, hypertrophic cardiomyopathy) and can provide

information on the existence of different patterns of LV

geometry and of systolic and diastolic function and the possi-

ble detection of collagen deposition in LVH. Tissue Doppler

imaging is also increasingly used for assessing global ventric-

ular function in systole and diastole.40

New three-dimensional techniques for imaging the heart

include magnetic resonance imaging, advanced computed

tomography techniques, and three-dimensional echocardiog-

raphy.41 All these techniques can measure myocardial mass

more accurately than conventional echocardiographic tech-

niques and may thus offer an advantage. However, their rolein the routine clinical assessment of the hypertensive patient

remains to be established.

ManagementBecause LVH is such an important independent risk factor in

hypertension, there is general agreement that it is beneficial to

prevent and to regress LVH. Regression is associated with such

potential benefits as improved cardiac performance and dia-

stolic filling, enhanced coronary flow reserve, and decreased

ventricular arrhythmias. Many studies have reported reduced

LV mass and wall thickness as a result of antihypertensive treat-

ment. Blood pressure reduction by means of all classes of anti-

hypertensive agents, with the possible exception of purevasodilators such as minoxidil and hydralazine, reduces LVH.

In long-term follow-up, the cumulative incidence of nonfatal

cardiovascular events is significantly greater among treated

hypertensive patients without LVH regression when compared

with those with significant LVH regression.42

Several meta-analyses have suggested that certain classes

of antihypertensive agents may be more effective than

others in promoting regression of LVH.43,44 These analyses

are complicated by inherent demographic, biological, or

pharmacologic variables, because the studies in these anal-

yses included patients of dissimilar sex, race, age, and number

who were treated for varying periods, using unlike doses

and with different compounds of the same therapeutic class

(perhaps having dissimilar physiologic, pharmacodynamic,and pharmacokinetic actions), and who had varying treat-

ment histories (in which past therapeutic effects may be

of extreme importance). It should, however, be noted that

although there have been a number of intervention trials

that have compared the effects of single antihypertensive

agents on LVH, most of these trials have turned out to

be comparisons of combination therapies, because most

patients needed to take more than one drug. Therefore,

we do not know at present whether changes induced

directly by prior pharmacologic treatments or indirectly

by the biological effects of treatment have a prolonged

effect mediated by biologically altered cellular memory.

There is increasing evidence of improved prognosis asso-ciated with LVH regression. Much of this evidence comes

from the LIFE study.43 The Losartan Intervention for

Endpoint Reduction in Hypertension (LIFE) study was the

first double-blind, randomized, parallel-group trial in

patients with essential hypertension and ECG evidence of 

LVH, who were randomly allocated to losartan-based (n  ¼

4605) or atenolol-based (n  ¼  4588) treatment (Fig. 41.3).43

The primary composite endpoint (cardiovascular mortality,

stroke, and myocardial infarction) was in favor of losartan

[11% event rate, compared with 13% for atenolol; adjusted

CARDIAC REMODELING IN HYPERTENSIVE HEART DISEASE

Regulation of structure Stimulators Inhibitors

Growth Apoptosis

Synthesis

Remodelling Reparation

Degradation

Celluar (± phenotype)

ANG II, ET-1,

TGF-BB, ALDO

NO, PG,

bradykinin

Collagen (± Fb phenotype)

Figure 41.2 Cardiac remodeling in hypertensive heartdisease.  Homogeneity in myocardial structure is preserved by abalanced equilibrium between stimulators and inhibitors that

respectively regulate cell growth and death (or apoptosis) andfibroblast (Fb) collagen turnover (and/or cell phenotype). Inhypertensive heart disease, an adverse structural remodeling isrelated to an imbalance in this equilibrium in favor of an absoluteincrease in stimulators or a relative increase secondary to a paucityof inhibitors. ALDO, aldosterone; ANG II, angiotensin II; ET-1,endothelin-1; NO, nitric oxide; PG, prostaglandin; TGF,transforming growth factor. (With permission from Weber KT.Cardioreparation in hypertensive heart disease. Hypertension2001;38:588-591.)

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ventricular pressure, which produces a “suction effect.” This

can lead to an increase in pulmonary capillary pressure that

is sufficient to induce pulmonary congestion. Diastolic dys-

function and the increase in atrial pressure can also lead toatrial fibrillation,51a and in hypertrophied ventricles depen-

dent on atrial systole, the loss of atrial transport can result

in a significant reduction in stroke volume and pulmonary

edema. Exercise-induced subendocardial ischemia can also

produce an “exaggerated” impairment of diastolic relaxation

of the hypertrophied myocardium.

In hypertensive patients, diastolic abnormalities may be the

most common and earliest manifestations of ventricular

dysfunction. Abnormalities of LV diastolic relaxation and com-

pliance usually occur even before evidence of systolic dysfunc-

tion, most often in conjunction with LVH, although the

syndrome can occur even in the absence of LVH. Diastolic dys-

function is commonly clinically silent and may only be recog-

nized during the course of echocardiographic detection of LVH (Fig. 41.5) or as part of the evaluation of ventricular func-

tion. Indeed, diastolic dysfunction may be the sole abnormality

of ventricular hemodynamics detected in approximately 40%

of patients with clinical signs and symptoms of heart failure.

The overall prevalence of normal systolic function in patients

with symptoms of congestive heart failure ranges from 11%

to 83% in hypertensive patients and from 5% to 67% in

patients with coronary artery disease (see Chapter 73).

Hypertension may cause alterations in the major determi-

nants of diastolic function, ventricular relaxation and compli-

ance. Rather than being a passive phenomenon, ventricular

relaxation is an active, energy-requiring process that occurs at

the onset of ventricular diastole when atrial pressure exceedsventricular pressure. Ventricular relaxation is also particularly

sensitive to loading conditions, ischemia, ATP availability,

cytosolic calcium availability, and other alterations in calcium

handling by the sarcoplasmic reticulum. Left ventricular com-

pliance, in contrast, is a more passive process that occurs later

in diastole, and its determinants include increased LV wall

thickness, increased chamber stiffness, and increased total myo-

cardial collagen content. Abnormal arterial compliance may

potentially contribute to the development of LV diastolic

dysfunction in hypertensive heart disease.52

Clinically, diastolic dysfunction can present with all the

typical signs and symptoms of congestive heart failure.

Although the symptoms of heart failure may be exacerbated

by concomitant ischemia and arrhythmias, there is evidence

that hypertension per se can exacerbate diastolic dysfunction

and pulmonary edema. Studying patients hospitalized with

hypertensive pulmonary edema, Gandhi and colleagues53

demonstrated the dramatic acute effects of acute elevations

in systolic blood pressure in reducing diastolic performance.

These patients did not have transient LV systolic dysfunc-

tion. This study emphasizes the role of hypertension in

producing and exacerbating diastolic dysfunction.

Asymptomatic LV Systolic DysfunctionDepressed LV systolic function is the most potent risk factor

for the development of overt congestive heart failure, and in

hypertensive patients this can develop secondary to coronary

artery disease. It is also a risk factor for a late stage of hyper-

tensive heart disease. A reduction in LV systolic performance

predicts the progressive dilatation of the heart and confers a

markedly adverse prognosis. If left untreated, even minimally

depressed systolic function eventually progresses to symptom-

atic heart failure. In the hypertensive patient, accurate assess-ment of ventricular function is therefore essential, and if 

reduced systolic function is confirmed, even in the absence

of symptoms, aggressive therapy is imperative.

In asymptomatic patients with abnormal LV systolic func-

tion, progression to ventricular dilatation appears to be

slower and clinical events, including death, less common.

Nonetheless, in asymptomatic patients with LV systolic dys-

function, survival at 2 years is significantly reduced (15% to

18%), compared with patients who have normal systolic

function.54,55

PROGRESSION OF LV MORPHOLOGY IN

HEART FAILURE

Eccentric

LVH

LV failure

Systolic LVD

Concentric

LVH

Hypertrophy Dilatation

Concentric

LV remodelling

Normal

LV

Figure 41.4 Progression of LV morphology in heartfailure.  LVD, left ventricular dysfunction; LVH, left ventricular hypertrophy. (Modified from Lopez-Sendon J. Regional myocardialischemia and diastolic dysfunction in hypertensive heart disease.Eur Heart J 1993;14(Suppl J):110-113.)

PRESSURE–VOLUME CURVES IN DIASTOLIC

AND SYSTOLIC DYSFUNCTION

40

80

120

Diastolic

dysfunction

Systolic

dysfunction

   P  e  r  c  e  n   t   d  e  v  e   l  o  p   i  n  g

   f   i  r  s   t  e  v  e  n   t

Left ventricular volume (mL/m2 body surface area)

50

Normal pressure–volume curve

Shift of curve to right, in systolic dysfunction

Shift of curve to upwards, with highter

end-diastolic pressures in diastolic dysfunction

100 150

Figure 41.5 Pressure-volume curves in diastolic and systolicdysfunction.

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Asymptomatic Left Ventricular DilatationLeft ventricular dilatation is a precursor of heart failure and

an indication of increased risk of major cardiac events and

death.56,57 In the hypertensive patient, the presence of 

LVH may lessen LV wall stress, but at the expense of dia-

stolic function, systolic function is often preserved. How-

ever, the development of ventricular dilatation in the

hypertensive patient with LVH, even if asymptomatic, is an

ominous sign, indicating that LVH is no longer able to main-

tain normal wall stresses. It may be hypothesized that, with

loss of the mechanical advantage conferred by LVH, ventric-ular dilatation is the next compensatory response (through

the Frank-Starling mechanism), which is invoked in an effort

to restore normal ventricular systolic function. Any func-

tional benefit derived, however, is at the cost of increased

myocardial oxygen consumption, greater ventricular wall

stress, and afterload mismatch.

Symptomatic Heart Failure The transition from asymptomatic to symptomatic heart fail-

ure is accompanied by further deterioration of LV systolic

function, increased activation of compensatory mechanisms,

and more rapid progress along the path to cardiac decompen-

sation, resulting in a decline in the ability of the heart todeliver enough oxygen to enable tissues to function opti-

mally. In the hypertensive patient, it is unclear whether

neurohormone-induced increases in peripheral vascular

resistance initially exceed a threshold of afterload mismatch

and cause a decline in cardiac pumping capacity, or whether

the factors that lead to increases in peripheral resistance also

exert an independent parallel effect on the heart, leading

to remodeling of the LV, microvascular dysfunction, and a

decline in pumping capacity.

The compensatory mechanisms (i.e., activation of the

renin-angiotensin-aldosterone system, catecholamines, cyto-

kines, and molecular vasodilatory systems) become more

maladaptive, with fluid retention, vasoconstriction, progres-

sive cardiac dilatation, and further impairment. Myocyte

hypertrophy, cellular contractile dysfunction, apoptosis, and

associated changes in collagen composition, extracellular

matrix, and chamber geometry have long-term deleterious

effects on cardiac energy balance and contractile function.

Clinical PresentationsAlthough useful in understanding pathophysiology, categori-

zation of the clinical features of heart failure according to dia-

stolic or systolic dysfunction is inappropriate, because both

these mechanisms may be active in an individual patient.

The signs and symptoms of heart failure in the hypertensive

patient are similar to those of patients with heart failure of 

other etiology (Table 41.5). Dyspnea is the most consistentsymptom, whether heart failure is due primarily to systolic

or to diastolic dysfunction. The hypertensive patient may

present with a combination of symptoms, some classically

attributable to systolic dysfunction, such as fatigue, exercise

intolerance, and muscle weakness; and others typical of dia-

stolic dysfunction and pulmonary congestion, including breath-

lessness, persistent cough, and pulmonary edema. Exacerbation

of pulmonary symptoms by tachycardia or loss of sinus rhythm

(with the development of atrial fibrillation) may suggest

diastolic dysfunction.

Diagnostic TechniquesThe diagnostic approach to hypertensive heart failure is no

different from that of congestive heart failure, in general (see

Chapter 42). The history and physical examination may pro-

vide important clues in clinical differential diagnosis, but are

of limited value in establishing a definitive pathophysiologic

diagnosis. Because coronary disease often coexists with

hypertension, a careful clinical history, physical examination,

or laboratory evidence of myocardial ischemia or infarction

may be important in establishing the underlying cause(s) of 

heart failure. Physical findings, including jugular venous dis-

tention, third or fourth heart sound, pulmonary rales or pedal

edema, would not reliably differentiate heart failure caused

by diastolic dysfunction from that caused by systolic dysfunc-

tion. Indeed, diastolic dysfunction may lead to decreased car-

diac output (a cardinal finding in systolic dysfunction), and

systolic dysfunction may lead to increased LV filling pressures

(a cardinal finding in diastolic dysfunction) (Fig. 41.6).

The ECG and chest radiograph may provide important infor-

mation, but do not differentiate diastolic from systolic dysfunc-tion. Echocardiography58 and radionuclide ventriculography

are useful for documentation of the presence, type, and severity

of LV dysfunction and mayplay a crucial role in the differential

diagnosis, staging, and management of heart failure. In addition

to assessing LV function, the echocardiogram with Doppler is

COMMON PRESENTING SYMPTOMS AND SIGNS OFCONGESTIVE HEART FAILURE IN HYPERTENSION

Symptoms Signs

Dyspnea at rest Resting tachycardia

Dyspnea with exertion Third heart sound

Effort intolerance Vascular congestion

Fatigue and weakness Peripheral edema

Orthopnea Hypotension

Paroxysmal nocturnal dyspnea Organomegaly

Impaired mentation Pleural effusion

Gastrointestinal complaints Cachexia

Table 41.5   Common presenting symptoms and signs of congestiveheart failure in hypertension.

COMMON CLINICAL FINDINGS IN HYPERTENSIVE PATIENTS

WITH DIASTOLIC OR SYSTOLIC HEART FAILURE

Exercise intolerance

Exertional dyspnea

Pulmonary edema

↑PCWP

Diastolic dysfunction Systolic dysfunction

Figure 41.6 Common clinical findings in hypertensive patientswith diastolic or systolic heart failure.   PCWP, pulmonary capillarywedge pressure.

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helpful in excludingthe presence of valvular, pericardial, infiltra-

tive, or congenital heart disease. A recent consensus statement

supports the use of B-type natriuretic peptide (BNP) determina-tion, and tissue Doppler imaging should be used in the diagnosis

of diastolic heart failure (Fig. 41.7).59

Magnetic resonance imaging (MRI) has recently emerged as

a useful imaging modality that can provide an extremely accu-

rate assessment of LV chamber dimensions and function.60

ManagementThe approach to management of heart failure in the hyper-

tensive patient should, in general, follow principles similar

to those for congestive heart failure. High blood pressure

should be treated and controlled. Concomitant cardiac ische-

mia and arrhythmias should be managed accordingly. As

regards treatment of acute heart failure, little is to be gainedby differentiating diastolic from systolic dysfunction; in

chronic heart failure, aggressive blood pressure control,

rate/rhythm control, and LVH regression are important aims

in diastolic heart failure. In addition to relief of symptoms,

therapeutic approaches should aim to slow the course of ven-

tricular remodeling and prevent progression of cardiac and

vascular damage (Fig. 41.8).

Angiotensin-converting enzyme inhibitors are the first-line

treatment of chronic heart failure61,62; they prevent or slow

the progression of heart failure, decrease the risk of major

THE DIAGNOSIS OF HEART FAILURE WITH NORMAL

LEFT VENTRICULAR-EJECTION FRACTION

Symptoms or signs of heart failure

Normal or mildly reduced left ventricular systolic function

LVEF > 50%

andLVEDVI < 97 mL/m2

 

Evidence of abnormal LV relaxation, filling, diastolic

distensibility, and diastolic stiffness

Invasive hemodynamic measurements

mPCW > 12 mm Hg

or

LVEDP > 16 mm Hg

orr > 48 ms

or

b >0.27

TD

Biomarkers

NT-proBNP > 220 pg/mL

or

BNP > 200 pg/mL

Echo – blood flow Doppler

E/A50 yr < 0.5 and DT50 yr > 280 ms

or

Ard-Ad > 30 ms

or

LAVI > 40 mL/m2

or

LVMI > 122 g/m2 ( ), > 149 g/m2 ( )

or

Atrial fibrillation

TD

E/E′ > 8

Biomarkers

NT-proBNP > 220 pg/mL

or

BNP > 200 pg/mL

HFNEF

E/E′ > 15 15 > E/E′ > 8

Figure 41.7 The diagnosis of heart failure with normal left ventricular ejection fraction (LVEF).  As recommended by the HeartFailure and Echocardiography Associations of the European Society of Cardiology. (From Paulus WJ, Tschope C, Sanderson JE, et al.How to diagnose diastolic heart failure: a consensus statement on the diagnosis of heart failure with normal left ventricular ejectionfraction by the Heart Failure and Echocardiography Associations of the European Society of Cardiology. Eur Heart J 2007;28:2539-2550.)

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cardiac events, and improve the quality of life, in both asymp-

tomatic and symptomatic patients with heart failure. In patients

intolerant of ACE inhibitors, the angiotensin receptor blockers

are a viable alternative, with increasingly more evidence of 

their efficacy becoming available. Although agents of this class

do not relieve acute symptoms, they do limit the vascular and

ventricular remodeling that accompanies heart failure.

In addition to their role in the management of systolic dys-

function, drugs that target the renin-angiotensin-aldosterone

system may have a role in the chronic management of dia-stolic dysfunction, by reducing myocardial collagen content

and improving compliance and relaxation, especially in the

presence of LVH. Indeed, drugs of this class are the best stud-

ied drug class in diastolic dysfunction. The CHARM-Pre-

served study63 is the first large scale clinical trial in diastolic

dysfunction. In this study, candesartan cilexitil (titrated to a

dose of 32 mg/day) was compared with placebo in 3031

patients with heart failure and LVEF  >40%. After a median

follow-up period of 37 months, there was a 11% reduction

in the primary endpoint of cardiovascular death or heart fail-

ure hospitalization, a result that did not reach statistical signif-

icance (Fig. 41.9). The reduction in hospitalization was of 

borderline significance. The PEP-CHF trial examined the

potential benefits of perindopril in elderly patients with heart

failure and echocardiographic evidence of diastolic dysfunc-

tion.64 Although there was no effect on any outcome over

the full study duration, there was a trend to a reduction in

the primary outcome of death or heart failure–related hospi-

talization at 1 year. It should be noted that low event rates

and low recruitment rate resulted in a considerable loss of sta-

tistical power to show an effect of perindopril. There are two

ongoing large trials in diastolic dysfunction, one involving

another angiotensin receptor blocker65 and the other will

investigate the potential beneficial effects of spironolac-

tone.66 In patients in whom ACE inhibitors (or angiotensin

receptor blockers) are not well tolerated or are contraindi-

cated, the combination of hydralazine and isosorbide dini-trate may be a suitable alternative, although the survival

benefit is greater with ACE inhibitors.67 This combination

may have particular benefits for hypertensive Afro-Carib-

bean patients with heart failure.68 The addition of incremen-

tal doses of loop diuretics to ACE inhibitors is required for

the management of fluid retention, edema, or pulmonary con-

gestion, but is symptomatic rather than diagnostic.

Beta blockers have proved to be effective antihyperten-

sive agents; they also slow heart rate and are effective in

treating myocardial ischemia, in addition to improving LV

function and prolonging survival in patients with heart fail-

ure.69 The SENIORS study suggested a survival/cardiovascular

hospitalization benefit for the third-generation beta blocker,

nebivolol, in elderly patients with heart failure and preserved

systolic function.70

In the hypertensive patient with diastolic dysfunction, the

nondihydropyridine calcium channel blockers may not only

decrease blood pressure and heart rate, but may also

improve relaxation. Although verapamil and diltiazem may

have a direct “relaxation-enhancing” effect, it is uncertain

whether their benefit is independent of their effect on heart

rate, blood pressure, and anti-ischemic properties. However,

these drugs should be avoided in LV systolic dysfunction.

CORONARY ARTERY DISEASE ANDHYPERTENSION

There is a close relationship between hypertension and risk

of coronary artery disease. The risk for development of a

cardiovascular event is approximately doubled in the hyper-

tensive patient, and this is irrespective of sex or age, or

whether systolic or diastolic blood pressure is increased.71

Indeed, there is almost a “dose-response” relationship

between coronary heart disease risk and increasing bloodpressure, greater blood pressures being associated with

greater risk (see Chapter 39). In a study of 5000 patients

with chronic angina pectoris, more than 50% had history of 

hypertension.72 In one study evaluating the effects of normal

blood pressure (BP), prehypertension, and hypertension on

progression of coronary atherosclerosis by intravascular

ultrasound, uncontrolled blood pressures contributed to

greater disease progression and atheroma volume, whereas

the most favorable rate of progression of coronary athero-

sclerosis was observed in patients whose BP fell within the

ACUTE AND CHRONIC TREATMENT GOALS IN

DIASTOLIC DYSFUNCTION

Acute treatment Chronic treatment

Reduce filling pressures

Eliminate venous congestion

Reverse abnormal diastolic

  properties

Cause regression of hypertrophy

Figure 41.8 Acute and chronic treatment goals in diastolicdysfunction.

THE CHARM-PRESERVED STUDY PRIMARY OUTCOME

CV DEATH OR CHF HOSPITALIZATION

30

25

20

15

10

5

0

1514

1509

0

1458

1441

1

1377

1359

2

833

824

3

182

195

3.5

     %

HR 0.89 (95% Cl, 0.77-1.03), P =0.118Adjusted HR 0.86, P =0.051

CandesartanPlacebo

Number at risk

CandesartanPlacebo

Years

366 (24.3%)

333 (22.0%)

Figure 41.9 The CHARM-Preserved study.  (With permissionfrom Yusuf S, Pfeffer MA, Swedberg K, et al. Effects of candesartanin patients with chronic heart failure and preserved left ventricular 

ejection fraction: the CHARM-Preserved Trial. Lancet2003;362:777-781.)

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“normal” range (i.e., systolic BP  <120 mm Hg and diastolic

BP  <80 mm Hg).73

Furthermore, patients with hypertension have an increased

incidence of unrecognized myocardial infarction, a greater

likelihood of complications from acute coronary syndromes,

and, compared with normotensive patients, worse acute and

5-year survival after myocardial infarction (Fig. 41.10).

PathophysiologyHypertension not only contributes to the development of 

atherosclerosis in the epicardial arteries, but is also impor-

tant in the genesis of structural and functional abnormalities

of the microvascular endothelium (atheromatous plaques do

not occur in the microvasculature).

There is growing evidence that the atherosclerotic process is

a response to injury of the vascular endothelium and to conse-

quential changes in the production and release of vasodilator

and vasoconstrictor substances. Nitric oxide, the most impor-

tant of the endothelium-derived relaxing factors, is integral to

the modulation of the atherogenic process. Other processes,

such as platelet aggregation and adhesion, proliferation of 

smooth muscle cells, and leukocyte adhesion, are also impor-

tant.74 Whether abnormalities in endothelial structure and

function (and associated atherogenesis?) that occur in hyper-

tension are the cause or the consequence of increased blood

pressure remains an area of active investigation.75

Increasing evidence suggests that patients with hyperten-sion also demonstrate (Fig. 41.11) abnormalities of 

n   vessel walls (endothelial dysfunction or damage);n   blood constituents (abnormal concentrations of hemo-

static factors, platelet activation and fibrinolysis); andn   blood flow (rheology, viscosity, and flow reserve).

The fulfillment of the three components of Virchow’s triad

for thrombogenesis suggests that hypertension confers a

prothrombotic or hypercoagulable state, which appears to

be related to the degree or severity of target organ damage.

These abnormalities can be related to long-term prognosisand, in addition, may be altered by antihypertensive treat-

ments. As the process of thrombogenesis is intimately

related to atherogenesis, the prothrombotic state in hyper-

tension may contribute to the increased risk of (atheroscle-

rotic) coronary artery disease and thrombus-related

complications, such as unstable angina and myocardial

infarction.76,77 Additional myocardial ischemia can be

caused by reduction in coronary blood flow in the large

conduit arteries or reduced coronary reserve resulting from

an inadequate coronary blood flow response to increased

myocardial oxygen demand (often related to microvascular

dysfunction).15

Finally, hypertension may also result in changes in

mechanical and hemodynamic forces that can influence

plaque composition, the potential for plaque erosion, and

the likelihood of plaque disruption. Hypertension-related

increases in transmural pressure, wall tension, and shear

stresses induce excess proliferation, hypertrophy, and hyper-

plasia of vascular smooth muscle cells; increased vascular

wall thickness; reduced vascular dilatory capacity; and accel-

erated plaque formation. Perivascular fibrosis may also con-

tribute to impaired coronary flow reserve. Schwartzkopff 

and colleagues78 demonstrated that perivascular collagen

volume formation correlated inversely with coronary flow

reserve in hypertensive individuals. Indeed, myocardial

ischemia caused by abnormalities in endothelial function

and coronary vascular reactivity has also been reported inhypertensive patients, independent of coronary atherosclero-

sis or LVH and hypercholesterolemia.

Clinical PresentationsThe spectrum of clinical presentations of coronary artery

disease and hypertension, with angina, acute coronary syn-

dromes and myocardial infarction, are discussed in detail in

Chapter 40.

Chronic angina pectoris is related to myocardial ischemia sec-

ondary to luminal encroachment by one or more atherosclerotic

PREVALENCE OF CHD AND HYPERTENSION

Men Women

n =331 n =321

30%

40%

19%

11%

37%

40%

7%

15%

Hypertension alone

Coronary heart disease alone

No HTN or CHD

CHD + HTN

Figure 41.10 Prevalence of coronary heart disease (CHD) andhypertension (HTN), alone and in combination, amongFramingham Heart Study patients with congestive heart failure.

VIRCHOW’S TRIAD OF THROMBOGENESIS

Blood constituents

Blood flow

Abnormalities of all three components of Virchow’s

triad are present in hypertension

Hypertension confers a prothrombotic state

Blood vessel

abnormalities

Figure 41.11 Virchow’s triad of thrombogenesis: theBirmingham paradox.

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plaques in an epicardial artery. However, in the hypertensive

patient there also appear to be functional and structural altera-

tions in the coronary microvasculature, resulting in an imbalance

between myocardial oxygen supply and demand. This may

occur even in the absence of atherosclerotic coronary vascular

disease and independent of other risk factors.79,80 This syn-

drome, often referred to as syndrome X, includes atypical chest

pain, female predominance, occasional abnormal noninvasive

tests, reduced coronary reserve, and benign prognosis—which

has been described in hypertensive patients with and without

LVH. In the presence of LVH, endothelial functional abnormal-ities also occur and are linked to structural changes in the myo-

cardium, such as increased myocyte hypertrophy, excess

interstitial collagen, reduced microvascular density and external

compression of intramyocardial arterioles. In the hypertensive

patient without LVH, myocardial ischemia may be attributed

to endothelial damage produced by increased blood pressure

alone, by concomitant hypercholesterolemia, or by basic

abnormalities in the neurohumoral control of vascular tone.

Hypertension, especially in the presence of LVH, increases

the risk of complications after myocardial infarction, including

infarct expansion, reinfarction, and cardiac rupture.

In hypertensive patients with LVH, the clinical manifestations

of atherosclerotic epicardial coronary disease may overlapwith the clinical features of nonatherosclerotic vascular dys-

function and ventricular remodeling, such as arterial vaso-

spasm, impaired ventricular performance, reduced coronary

reserve, and electrical instability.

Diagnostic TechniquesIn the hypertensive patient, it may be difficult to distinguish

the secondary ST-T wave changes (ST segment depression

and T wave inversion) that is associated with LVH or micro-

vascular disease from the primary ST-T wave depression that

is associated with unstable angina and non–Q wave infarction.

These differences may be difficult to distinguish, even during

exercise stress testing, as the baseline ST-T changes associatedwith LVH and hypertension may limit the specificity of these

findings. Detailed diagnosis and investigations for coronary

artery disease are summarized in Chapters 19 and 20.

ManagementManagement of the patient with hypertension and either

documented or suspected coronary disease requires

n   control of hypertension;n   avoidance of symptoms of myocardial ischemia;n  prevention of coronary complications (unstable angina,

infarction, heart failure, or death); andn  prevention of other cardiovascular disease through man-

agement of risk factors.

Blood pressure reduction is the critical element of manage-

ment. The purported superiority of specific drug classes is

still debated.81 Irrespective of the differences, combination

of drugs   is frequently required to achieve blood pressure

targets.82

In choosing an antihypertensive medication for a patient

with possible or confirmed coronary disease, it is important

to consider not only the blood pressure–decreasing efficacy

of the drug, but also its value or limitations in reducing myo-

cardial ischemia and limiting total cardiovascular disease

risk.83 Some antihypertensive agents may aggravate myocar-

dial ischemia even though blood pressure is decreased.

Direct-acting vasodilators (hydralazine and minoxidil) may

cause marked vasodilatation and stimulation of barorecep-

tors, with resulting increases in heart rate and myocardial

stroke work. Hydralazine may directly stimulate the heart,

in addition to its potent peripheral vasodilatory properties,

increasing contractility and oxygen demand.

Beta Blockers 

Although beta blockers are no longer recommended as rou-tine initial therapy,84 they are the agents of choice for the

management of patients with concurrent hypertension and

coronary artery disease or heart failure. Anti-ischemic

effects of beta blockers are comparable in all racial groups,

although effective control of blood pressure may require

increased doses or duration of treatment in blacks. Beta

blockers are also recommended for secondary prevention

after myocardial infarction because they have been shown

to reduce infarct size, decrease mortality after infarction,

decrease the incidence of nonfatal ischemic complications,

and reduce arrhythmias and sudden death.85

Nitrates Glyceryl trinitrate and other organic nitrates, administered

sublingually, transdermally or orally, have long been a main-

stay of treatment for angina pectoris. However, although

nitrates may variably decrease blood pressure through veno-

dilatation and reductions in arteriolar tone, they have no use

in the management of chronic systemic hypertension and are

used primarily for the management of acute anginal episodes

(administered sublingually) and for chronic angina pectoris

(long-acting preparations).

Angiotensin-Converting Enzyme Inhibitors Evidence from clinical trials has established this class of 

agent as effective for the treatment of hypertension and

heart failure and for the prevention of renal insufficiency indiabetic patients. Recent studies of ACE inhibitors in humans

with chronic ischemic coronary disease have not shown that

these drugs have substantial anti-ischemic action, and they

are of limited value in the treatment of angina or the acute

coronary syndromes. They have also been shown to prevent

myocardial remodeling and heart failure and to decrease

death rates in patients with myocardial infarction and LV

dysfunction.

Calcium Channel Blockers The impact of dihydropyridine calcium channel blockers  on

myocardial infarction had been the subject of controversy.86

However, these drugs have been shown to be effective in thetreatment of acute severe coronary spasm and Prinzmetal’s

variant angina. There is data that long-acting dihydropyri-

dine calcium channel blockers, such as nifedipine GITS in

the ACTION trial, are safe in patients with stable angina.87

Although it had no effect on major cardiovascular mortality,

it reduced the need for coronary angiography and coronary

interventions. After myocardial infarction, the dihydropyri-

dine calcium channel blockers have been shown to have a

negative impact on reinfarction and mortality rates, and are

not recommended in the management of acute myocardial

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infarction, especially with LV dysfunction. In contrast, non-

dihydropyridine calcium channel blockers may be of consid-

erable utility in patients with hypertension and active

ischemic heart disease. The INVEST study demonstrated

equal efficacy of a verapamil-based regimen in comparison

to a beta blocker–based regimen in such patients.88

In patients who cannot tolerate beta blockers, ivabradine

may provide an alternative antianginal agent that lowers

heart rate exclusively by selectively inhibiting the I(f) chan-

nel.89 This agent has no negative inotropy, unlike calcium

channel blockers, and is currently being investigated inpatients with active ischemia and systolic LV dysfunction.90

Drug Combinations for Hypertension and Coronary Artery Disease Although available data are limited, combination therapy

may prove advantageous in selected circumstances. For

example, low-dose combinations of beta blockers and dihy-

dropyridine calcium channel blockers may effectively con-

trol both angina and hypertension with reduced adverse

side effects. Because of their negative inotropic and chrono-

tropic effects, beta blockers should not be combined with

nondihydropyridine calcium channel blockers in patients at

risk for bradycardia (e.g., long PR interval, atrioventricularnodal disease) or with ventricular dysfunction with dilata-

tion. Calcium channel blockers (e.g., amlodipine or felodi-

pine) may be added to ACE inhibitors and diuretics for

more effective control of angina and blood pressure.

 ARRHYTHMIAS AND SUDDEN DEATH

Hypertensionis an important risk factor for the development of 

atrial and ventricular arrhythmias and sudden cardiac death.4,91

Hypertension may play a direct part in the development of 

these rhythm disturbances by contributing to the development

of LVH, atherosclerotic disease, and microvascular dysfunc-

tion. The risk of arrhythmias is greatest with evidence of LVH

and/or left atrial abnormality on echocardiography and ECG,

even in patients with no clinical history of coronary disease.92

Hypertensive individuals are predisposed to arrhythmias even

with normal cardiac chamber size.93

Atrial ArrhythmiasAtrial fibrillation is the most common and most serious of 

the atrial tachyarrhythmias because of its   association with

fatal and nonfatal stroke and heart failure.94 Indeed, hyper-

tension accounts for more atrial fibrillation in the population

than does any other risk factor,95 especially if associated

hypertensive LVH is present.96 Other than diabetes, hyper-

tension is the only cardiovascular risk factor that indepen-

dently predicts the development of atrial fibrillation, evenafter adjustment for age and associated comorbidity. A high

pulse pressure is a particularly strong predictor of subsequent

atrial fibrillation.97

The presence of hypertension adds to the risk of stroke

and thromboembolism in atrial fibrillation, which is reduced

by anticoagulation; among anticoagulated atrial fibrillation

patients, good blood pressure   control reduces the risk of 

stroke and thromboembolism.98

The evaluation and management of the hypertensive

patient with atrial fibrillation should include

n   appropriate selection of antihypertensive drug;

n   identification of prognostic markers;n   exclusion of intrinsic cardiac disease;n   maintenance of sinus rhythm; andn   anticoagulation if there is persistent atrial fibrillation.

The use of renin-angiotensin blocking antihypertensive

agents in ameliorating atrial fibrillation is attracting much

interest. For example, Madrid and colleagues99 have shown

that agents such as angiotensin receptor blockers prolong

the atrial effective refractory period and this translates intobeneficial clinical effects. A large-scale clinical trial is cur-

rently evaluating whether these beneficial effects may result

in fewer major cardiac events.100

Ventricular ArrhythmiasPremature ventricular ectopy and complex ventricular

tachyarrhythmias are common in hypertensive individuals,

but are more prevalent in patients with hypertension and

LVH than in those without hypertrophy or in normotensive

individuals.101 The arrhythmic risk of hypertensive patients

has been shown to markedly increase if microvolt level T wave

alternans is present.102 Arrhythmias in hypertensive patients

have been shown to be related to LVH, but are independentof coexisting coronary artery disease or LV dysfunction.

Increased risk of sudden death appears to be due primarily to

coincident myocardial ischemia and concomitant subendocar-

dial fibrosis and collagen deposition, with impaired coronary

vasodilator reserve, subendocardial ischemia, and cellular elec-

trophysiologic abnormalities related to cardiac hypertrophy.

In the treatment of ventricular arrhythmias, the use of beta

blockers as antihypertensive agents is desirable because of 

their role as anti-ischemic and antiarrhythmic agents. Low-

dose diuretic treatment also reduces cardiovascular events

in hypertensive patients. Conversely, use of high-dose diure-

tics and hypokalemia or hypomagnesemia during drug treat-

ment of hypertension must be avoided because of the

increased risk of arrhythmias in the presence of electrolyte

imbalance.

Sudden Cardiac DeathHypertension-induced LVH is a risk factor for spontaneous

ventricular arrhythmias and is associated with a greater risk

of sudden cardiac death.103 Some 80% of individuals who

experience sudden cardiac death have coronary heart dis-

ease.104 It should be remembered that not all sudden death

is arrhythmia-related, as autopsy studies confirm the pres-

ence of thrombus in the left main coronary artery, in keeping

with the prothrombotic state seen in hypertension.15

Although hypertension, LVH, hypercholesterolemia, glucose

intolerance, smoking, and excess weight are risk factors for cor-onary artery disease, these factors also identify individuals at

risk for sudden cardiac death. Advanced LV dysfunction is also

an independent predictor of sudden cardiac death in patients

with ischemic and nonischemic cardiomyopathy.

For patients who have suffered myocardial infarction and

for those with heart failure, beta blockers are the drugs of 

choice. However, the implantable cardioverter-defibrillator

appears to be the best current therapeutic modality for pro-

phylaxis against sudden   cardiac death, and should be used

in high-risk populations.105