complications of hypertension the heart
Post on 03-Jun-2018
217 Views
Preview:
TRANSCRIPT
8/12/2019 Complications of Hypertension the Heart
http://slidepdf.com/reader/full/complications-of-hypertension-the-heart 1/13
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
8/12/2019 Complications of Hypertension the Heart
http://slidepdf.com/reader/full/complications-of-hypertension-the-heart 2/13
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.
CTION
3APTER
41
H Y P E R T E N S I V E H E A R T
D I S E A S E
542
8/12/2019 Complications of Hypertension the Heart
http://slidepdf.com/reader/full/complications-of-hypertension-the-heart 3/13
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.
8/12/2019 Complications of Hypertension the Heart
http://slidepdf.com/reader/full/complications-of-hypertension-the-heart 4/13
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.
CTION
3APTER
41
H Y P E R T E N S I V E H E A R T
D I S E A S E
544
8/12/2019 Complications of Hypertension the Heart
http://slidepdf.com/reader/full/complications-of-hypertension-the-heart 5/13
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.)
8/12/2019 Complications of Hypertension the Heart
http://slidepdf.com/reader/full/complications-of-hypertension-the-heart 6/13
8/12/2019 Complications of Hypertension the Heart
http://slidepdf.com/reader/full/complications-of-hypertension-the-heart 7/13
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.
8/12/2019 Complications of Hypertension the Heart
http://slidepdf.com/reader/full/complications-of-hypertension-the-heart 8/13
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.
CTION
3APTER
41
H Y P E R T E N S I V E H E A R T
D I S E A S E
548
8/12/2019 Complications of Hypertension the Heart
http://slidepdf.com/reader/full/complications-of-hypertension-the-heart 9/13
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.)
8/12/2019 Complications of Hypertension the Heart
http://slidepdf.com/reader/full/complications-of-hypertension-the-heart 10/13
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.)
CTION
3APTER
41
H Y P E R T E N S I V E H E A R T
D I S E A S E
550
8/12/2019 Complications of Hypertension the Heart
http://slidepdf.com/reader/full/complications-of-hypertension-the-heart 11/13
“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.
8/12/2019 Complications of Hypertension the Heart
http://slidepdf.com/reader/full/complications-of-hypertension-the-heart 12/13
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
CTION
3APTER
41
H Y P E R T E N S I V E H E A R T
D I S E A S E
552
8/12/2019 Complications of Hypertension the Heart
http://slidepdf.com/reader/full/complications-of-hypertension-the-heart 13/13
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
top related