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Heart failure (HF) is a clinical syndrome in which an abnormality of cardiac structure or function is

responsiblefortheinabilityoftheheart to eject orfill with blood ata


ratecommensuratewiththerequirements of the metabolizing tissues

Dyspnea (Chap. 29) In early HF, dyspnea is observed only during exertion, when it may simply represent
an aggravation of the breathlessness that occurs normally. As HF advances, dyspnea occurs with
progressively less strenuous activity and ultimately it is present even at rest. The principal difference
between exertional dyspnea in normal persons and in patients with HF is the degree of exertion
necessary to induce this symptom. Cardiacdyspnea is observed most frequently in patients with
elevations of pulmonary venous and capillary pressures who have engorged pulmonary vessels and
interstitial accumulation of interstitial fluid. The activation of receptors in the lungs results in the rapid,
shallow breathing characteristic of cardiac dyspnea. The oxygen cost of breathing is increased by the
excessiveworkoftherespiratorymusclesrequiredtomoveairinto and out of the congested lungs. This is
coupled with the diminished delivery of oxygen to these muscles, a consequence of a reduced
cardiacoutput.Thisimbalancemaycontributetofatigueoftherespiratory muscles and the sensation of
shortness of breath.

ROLE OF RENIN Renin is an enzyme secreted by the juxtaglomerular cells of the kidney and linked with
aldosterone in a negative feedback loop (Chap. 321). While a variety of factors can modify its rate of
secretion, the primary determinant is the volume status of the individual, particularly as related to
changes in dietary sodium intake. The end product of the action of renin on its substrate is the
generation of thepeptideangiotensinII.Theresponseoftargettissuestothispeptide is uniquely determined
by the prior dietary electrolyte intake. For example, sodium intake normally modulates adrenal and
renal vascular responses to angiotensin II.Withsodiumrestriction,adrenalresponses are enhanced and
the renal vascular responses reduced. Sodium loading has the opposite effect. The range of plasma renin
activities observed in hypertensive subjects is broader than in normotensive individuals. In
consequence, some hypertensive patients have been defined as having low-renin and others as having
high-renin essential hypertension. Low-Renin Essential Hypertension Approximately 20% of patients
who by all other criteria have essential hypertension have suppressed plasma renin activity. Low-renin
essential hypertension describes a widely recognized classification validated by clinical
features,including salt-sensitivity of blood pressure and diuretic responsiveness.This situation is more
common in individuals of African descent than in white patients, and in diabetics and the elderly.
Though these patients are not hypokalemic, they have been reported to have expanded extracellular
fluid volumes, and one unproven suggestion is that they have sodium retention and renin suppression
due to excessiveproduction of an unidentified mineralocorticoid. There are data to suggest that the low-
renin state confers a beneficial natural history compared to that in patients with normal- or high-renin
hypertension. Nonmodulating Essential Hypertension Another subset of hypertensive patients who are
also salt-sensitive has a reduced adrenal response to sodium restriction. In these individuals, sodium
intake does not modulate either adrenal or renal vascular responses to angiotensin II. Hypertensives in
this subset have been termed nonmodulators becauseof the absence of the sodium-mediated
modulation of target tissue responses to angiotensin II. These individuals make up 25 to 30% of the
hypertensivepopulation,haveplasmareninactivitylevelsthatarenormal to high if measured when the
patient is on a low-salt diet, and have hypertension that is salt-sensitive because of a defect in the
kidney’s ability to excrete sodium appropriately. They also are more insulin-resistant than other
hypertensive patients, and the pathophysiologic characteristics can be corrected by the administration
of an angiotensin-converting enzyme (ACE) inhibitor. Nonmodulation is

much more frequent among males and postmenopausal females. Furthermore, the nonmodulation
characteristic appears to be genetically determined (associated with a certain allele of the
angiotensinogen gene). Thus, nonmodulators are probably the most completely characterized
intermediate phenotype in the hypertensive population. High-Renin Essential Hypertension
Approximately 15% of patients with essential hypertension have plasma renin
activitylevelsabovethenormal range. It has been suggested that plasma renin plays an important role in
the pathogenesis of the elevated arterial pressure in these patients. However, most studies have found
that saralasin (a substance that, like losartan, acts as a competitive antagonist of angiotensin II)
significantly reduces blood pressure in fewer than half of these patients. This finding has led some
investigators to postulate that the elevated renin levels and blood pressure may both be secondary to
an increase in adrenergic system activity. It has been proposed that in patients with angiotensin-
dependent high-renin hypertension whose arterial pressures are lowered by an angiotensin II
antagonist, the mechanism responsible for the increase in renin and, therefore, forthe hypertension is
the nonmodulating defect. SODIUM ION VERSUS CHLORIDE OR CALCIUM Most studies assessing the role
of salt in the hypertensive process have assumed that it is the sodium ion that is important. However,
some investigators have suggested that the chloride ion may be equally important. Thissuggestion is
based on the observation that feeding chloride-free sodium salts to salt-sensitive hypertensive animals
fails to increase arterial pressure. Calcium has also been implicated in the pathogenesis of some forms
of essential hypertension. A low-calcium intake has been associated with an increase in blood pressure
in epidemiologic studies; an increase in leukocyte cytosolic calcium levels has been reportedinsome
hypertensives. Finally, calcium entry blockers are effectiveantihypertensive agents. Several studies have
reported a potential link between the salt-sensitive forms of hypertension and calcium. It has been
postulated that salt loading in combination with a defect in the kidney’s ability to excrete salt may lead
to a secondary increase in circulating natriuretic factors. One of these factors, the so-called digitalis-
likenatriureticfactor,inhibitsouabain-
sensitiveNa ,K -ATPaseandthereby leads
to intracellular calcium accumulation and a hyperreactive vascular smooth muscle. CELL MEMBRANE
DEFECT Another postulated explanation for salt-sensitive hypertension is a generalized cell membrane
defect. This hypothesisderivesmostofitsdatafromstudiesoncirculatingbloodelements, particularly red
blood cells, in which abnormalities in the transport of sodium across the cell membrane have been
documented. Since both increases and decreases in the activity of different transport systems have been
reported, it is likely that some abnormalities are primary and some are secondary. It has been assumed
that an abnormality in sodium transport reflects an undefined alteration in the cell membrane and that
this defect occurs in many, perhaps all, cells of the body, particularly the vascular smooth-muscle cells.
The defect leads to an abnormal accumulation of calcium in vascular smooth muscle, resulting in a
heightened vascular responsiveness to vasoconstrictor agents. This defect has been proposed to be
present in 35 to 50% of essential hypertensive persons on the basis of studies using red cells. Other
studies suggest that the abnormality in red cell sodium transport is not fixed but can be modified by
environmental factors. The common final pathway in all these hypotheses is an increase in cytosolic
calcium resulting in increased vascular reactivity. However, as described above, several mechanisms
might produce this calcium accumulation. INSULIN RESISTANCE Insulin resistance and/or
hyperinsulinemia have been suggested as being responsible for the increased arterialpressure in some
patients with hypertension. This feature is now widely recognized as part of syndrome X, or the
metabolic syndrome (Chap. 225),markedalsobycentralobesity,dyslipidemia(especiallyelevated
triglycerides), and high blood pressure. While it is clear that a substantial fraction of the hypertensive
population has insulin resistance

230 Hypertensive Vascular Disease 1465

TABLE 230-3 Genesis Hypothesized to be Involved in Essential Hypertension

Gene

Statistical Approacha Linkage

/ Association

Renin-angiotensin-aldosterone system/sodium-volume Angiotensin-converting enzyme 0/1 12/14


Angiotensinogen 3/4 12/9 Aldosterone synthase 1/1 5/7 -Adducin 0/1 5/3 AT1 receptor 4/6 Atrial
natriuretic peptide 2/5 Human natriuretic peptide receptor (A) 1/1 Human natriuretic peptide receptor
(B) 1/2 Renin 3/2 2/2 Adrenergic

2-Adrenergic receptor 3/4

3-Adrenergic receptor 3/1 Dopamine D2 receptor 2/0 2-Adrenergic receptor 1/1 Vascular Endothelin-1
3/1 Nitric oxide synthase, endothelial (NOS3) 0/2 5/10 Nitric oxide synthase, inducible (NOS2A) 1/1
Metabolic Glycogen synthase 1/1 Insulin receptor 0/1 3/0 Lipoprotein lipase 1/2 Apolipoprotein C-III 1/1
Miscellaneous G protein

3 subunit 3/5

a Number of pertinent positive ( ) and negative


(

) published studies in humans.

and hyperinsulinemia, it is less certain that this is more than an association. Insulin resistanceis
commoninpatientswithdiabetesmellitus type 2 and in obesity; both of these conditions are more
common in hypertensive than in normotensive subjects. However, several studies have found that
hyperinsulinemia and insulin resistance are present even in lean hypertensive patients without type 2
diabetes, suggesting that this relationship is more than a coincidence. As noted earlier, these individuals
seem to be concentrated in the nonmodulation phenotype. Hyperinsulinemia can increase arterial
pressure by one or more of fourmechanisms. An underlyingassumptionineachcaseisthatsome, but not
all, of the target tissues of insulin are resistant to its effects. Specifically, tissues involved in glucose
homeostasis are resistant (thereby producing the hyperinsulinemia), while tissues involved in the
hypertensive process are not. First, hyperinsulinemia produces renal sodium retention (at least acutely)
and increases sympathetic activity.Eitherorbothoftheseeffectscouldleadtoanincreaseinarterial pressure.
Another mechanism is vascular smooth-muscle hypertrophy secondary to the mitogenic action of
insulin. Third, insulin also modifies ion transport across the cell membrane, thereby potentially
increasing the cytosolic calcium levels of insulin-sensitive vascular or renal tissues. This mechanism
would increase arterial pressureforreasons similar to those described above for the membrane-defect
hypothesis. Finally, insulin resistance may be a marker for another pathologic process, e.g.,
nonmodulation, which could be the primary mechanism increasing blood pressure. It is important to
point out, however, that the role of insulin in controlling arterial pressureis only vaguely understood,
and, therefore, its potential as a pathogenicfactor in hypertension remains unclear. Few of the features
of hypertension discussed above remain constant in a given patient. Some may be a reflection of the
current metabolic and hormonal status of the patient rather than a permanent feature of the disease
process. For example, at one point a patient might have insulin resistance secondary to obesity, which
could lead to sodium retention, intravascular volume expansion, and renin suppression. This patient
would be labeled as having “low-renin essential hypertension.” If the patient lost weight, however, the
salt-retaining tendency would be reversed. If the blood pressure did not normalize, the patient might
then have “normal- or high-renin essentialhypertension.” Thus, the features reviewed above should not
be considered mutually exclusive orpermanent characteristicsinagivenpatientwith hypertension.

GENETIC CONSIDERATIONS Hypertensionisoneofthemostcommon complex genetic disorders, with


genetic heritability averaging 30%. Data supporting this view emerge from animal studies as well as in
population studies in humans. One approach has been to assess the correlation of blood pressure in
families (familial aggregation). From these studies, the minimum size of the genetic factor can be
expressed by a correlation coefficient of 0.2. However, the variation in the size of the genetic factor in
different studies reemphasizes the probably heterogeneous nature of the essential hypertensive
population. In addition, most studies support the concept that the inheritance is probably multifactorial
or that a number of different genetic defectseachhaveanelevatedbloodpressureasoneoftheirphenotypic
expressions. However, genes responsible for three distinct but rare monogenic hypertensive syndromes
have been identified, two of which are inherited in a dominant fashion. Patients with glucocorticoid-
remediable hypertension (GRA) have characteristically early-onset hypertension with increased
frequency of strokes and evidence of hyperaldosteronism.
Plasmaaldosteroneconcentratesarehigh,plasmareninactivity is low, and hypokalemia is frequent. A
chimeric gene containing the promoter of the 11

-hydroxylase gene and the coding sequence for the aldosterone synthase gene has been identified in
these patients, resulting in the ectopic production of aldosterone, which is corticotropin-dependent. The
second dominant form is also a rare familial syndrome in which patients also appear to have elevated
aldosterone

activity, with suppressed plasma renin activity and hypokalemia. In these patients, however, plasma
aldosterone is normal. Mutations in the epithelial amiloride-sensitive sodium channel located in the
collecting cortical tubule are responsible. The third monogenicsyndrome is also a low-renin state,
termed the syndrome of apparent mineralocorticoid excess (AME), caused by a defect in renal 11

-hydroxysteroid dehydrogenase. In these patients, the protective conversion of cortisol to the inactive
cortisone does not occur, and local cortisol binds to the renal mineralocorticoid receptor. In addition to
these monogenic syndromes, susceptibility genes have now been reported which have as one of their
consequences an increased arterial
pressure(seebelowandChap.321).Themostpromisingoftheseisthegeneforreninsubstrate,angiotensinogen
,inwhich a substitution of threonine for methionine at codon 235 has been associated with
hypertension. Also, in patients with low-renin essential hypertension, an association with the G460W
polymorphism of the adducin gene has been demonstrated. One of the hints of the genetic heritability
of the low-renin state has emerged from studies revealing the familial aggregation of low-renin
hypertension. Morethan50geneshavebeenexaminedinassociationstudieswith hypertension, and the
number is constantly growing. As can be seen in Table 230-3, most studies of likely genes have failed to
document linkage or consistent association with hypertension. However, uncertainty exists as to
thevalidity ofthesenegativeconclusions.Apositive relationship between hypertension and a gene could
be obscured by the high probability of a false-negative result because of the heterogeneity of the
hypertensive population. Thus,intermediatephenotypes in the hypertensive population need to be
identified to differentiate patients into more homogeneous subgroups; the role of a specific candidate
gene can then be more readily assessed. Such an approach is illustrated in Table 230-4.