BLOOD PRESSURE REGULATION

Systemic and local blood pressure must be maintained within a narrow range to prevent
adverse outcomes. Low blood pressure (hypotension) results in inadequate organ perfusion,
organ dysfunction, and sometimes tissue death. Conversely, high blood pressure (hypertension)
causes vessel and end-organ damage and is one of the major risk factors for atherosclerosis
(see later on). Blood pressure is a function of cardiac output and peripheral vascular resistance,
both of which are influenced by multiple genetic and environmental factors (Fig. 9–3). The
integration of the various inputs ensures adequate systemic perfusion, despite regional demand
differences.

• Cardiac output is a function of stroke volume and heart rate. The most important determinant
of stroke volume is the filling pressure, which is regulated through sodium homeostasis and its
effect on blood volume. Heart rate and myocardial contractility (a second factor affecting stroke
volume) are both regulated by the α- and β-adrenergic systems (in addition to their effects on
vascular tone).
-Peripheral resistance is regulated predominantly at the level of the arterioles by neural and
hormonal inputs. Vascular tone reflects a balance between vasoconstrictors (including
angiotensin II, catecholamines, and endothelin) and vasodilators (including kinins,
prostaglandins, and NO). Resistance vessels also exhibit autoregulation, whereby increased
blood flow induces vasoconstriction to protect tissues against hyperperfusion. Finally, blood
pressure is fine-tuned by tissue pH and hypoxia to accommodate local metabolic demands.
Factors released from the kidneys, adrenals, and myocardium interact to influence vascular
tone and to regulate blood volume by adjusting sodium balance (Fig. 9–4). The kidneys filter
170 liters of plasma containing 23 moles of salt daily. Thus, with a typical diet containing 100
mEq of sodium, 99.5% of the filtered salt must be reabsorbed to maintain total body sodium
levels. About 98% of the filtered sodium is reabsorbed by several constitutively active
transporters. Recovery of the remaining 2% of sodium occurs by way of the epithelial sodium
channel (ENaC), which is tightly regulated by the renin–angiotensin system; it is this pathway
that determines net sodium balance.
Kidneys influence peripheral resistance and sodium excretion/retention primarily through the
renin– angiotensin system. The kidneys and heart contain cells that sense changes in blood
pressure or blood volume. In response, these cells release several important regulators that act
in concert to maintain normal blood pressure, as follows:
• Renin is a proteolytic enzyme produced by renal juxtaglomerular cells, myoepithelial cells that
surround the glomerular afferent arterioles. Renin is released in response to low blood pressure
in afferent arterioles, elevated levels of circulating catecholamines, or low sodium levels in the
distal convoluted renal tubules. The latter occurs when the glomerular filtration rate falls (e.g.,
when the cardiac output is low), leading to increased sodium resorption by the proximal tubules
and lower sodium levels more distally.
• Renin cleaves plasma angiotensinogen to angiotensin I, which in turn is converted to
angiotensin II by angiotensin-converting enzyme (ACE) in the periphery. Angiotensin II raises
blood pressure by
(1) inducing vascular smooth muscle cell contraction
(2) stimulating aldosterone secretion by the adrenal gland
(3) increasing tubular sodium resorption.
• The kidney also produces a variety of vascular relaxing substances (including prostaglandins
and NO) that presumably counterbalance the vasopressor effects of angiotensin.
• Adrenal aldosterone increases blood pressure by its effect on blood volume; aldosterone
increases sodium resorption (and thus water) in the distal convoluted tubule while also driving
potassium excretion into the urine.
• Myocardial natriuretic peptides are released from atrial and ventricular myocardium in
response to volume expansion; these inhibit sodium resorption in the distal renal tubules, thus
leading to sodium excretion and diuresis. They also induce systemic vasodilation.
SUMMARY
Blood Pressure Regulation
• Blood pressure is determined by vascular resistance and
cardiac output.
• Vascular resistance is regulated at the level of the arterioles, influenced by neural and
hormonal inputs.
• Cardiac output is determined by heart rate and stroke
volume, which is strongly influenced by blood volume.
Blood volume in turn is regulated mainly by renal sodium
excretion or resorption.
• Renin, a major regulator of blood pressure, is secreted by
the kidneys in response to decreased blood pressure in
afferent arterioles. In turn, renin cleaves angiotensinogen
to angiotensin I; subsequent peripheral catabolism produces angiotensin II, which regulates
blood pressure by
increasing vascular smooth muscle cell tone and by
increasing adrenal aldosterone secretion and, consequently, renal sodium resorption.

HYPERTENSIVE HEART DISEASE

As discussed in Chapter 9, hypertension is a common disorder associated with considerable
morbidity and affecting many organs, including the heart, brain, and kidneys. The comments
here will focus specifically on the major cardiac complications of hypertension, which result from
pressure overload and ventricular hypertrophy. Myocyte hypertrophy is an adaptive response to
pressure overload; there are limits to myocardial adaptive capacity, however, and persistent
hypertension eventually can culminate Hypertensive Heart Disease 387 in dysfunction, cardiac
dilation, CHF, and even sudden death. Although hypertensive heart disease most commonly
affects the left side of the heart secondary to systemic hypertension, pulmonary hypertension
also can cause right-sided hypertensive changes—so-called cor pulmonale

Systemic (Left-Sided) Hypertensive Heart Disease

The criteria for the diagnosis of systemic hypertensive heart disease are (1) left ventricular
hypertrophy in the absence of other cardiovascular pathology (e.g., valvular stenosis), and (2) a
history or pathologic evidence of hypertension. The Framingham Heart Study established
unequivocally that even mild hypertension (above 140/90 mm Hg), if sufficiently prolonged,
induces left ventricular hypertrophy. Roughly 25% of the U.S. population suffers from at least
this degree of hypertension.

MORPHOLOGY
As discussed earlier, systemic hypertension imposes pressure overload on the heart and is
associated with gross and microscopic changes somewhat distinct from those caused by
volume overload. The essential feature of systemic hypertensive heart disease is left ventricular
hypertrophy, typically without ventricular dilation until very late in the process (Fig. 10–16, A).
The heart weight can exceed 500 g (normal, 320 to 360 g), and the left ventricular wall
thickness can exceed 2.0 cm (normal, 1.2 to 1.4 cm). With time, the increased left ventricular
wall thickness imparts a stiffness that impairs diastolic filling and can result in left atrial dilation.
Inl ong-standing systemic hypertensive heart disease leading to congestive failure, the ventricle
typically is dilated. Microscopically, the transverse diameter of myocytes is increased and there
is prominent nuclear enlargement and hyperchromasia (“boxcar nuclei”), as well as intercellular
fibrosis.

Clinical Features
Compensated hypertensive heart disease typically is asymptomatic and is suspected only from
discovery of elevated blood pressure on routine physical exams, or from ECG or
echocardiographic findings of left ventricular hypertrophy. In some patients, the disease comes
to attention with the onset of atrial fibrillation (secondary to left atrial enlargement) and/or CHF.
The mechanisms by which hypertension leads to heart failure are incompletely understood;
presumably the hypertrophic myocytes fail to contract efficiently, possibly due to structural
abnormalities in newly assembled sarcomeres and because the vascular supply is inadequate
to meet the demands of the increased muscle mass. Depending on the severity and duration of
the condition, the underlying cause of hypertension, and the adequacy of therapeutic control,
patients can (1) enjoy normal longevity and die of unrelated causes, (2) develop progressive
IHD owing to the effects of hypertension in potentiating coronary atherosclerosis, (3) suffer
progressive renal damage or cerebrovascular stroke, or (4) experience progressive heart failure.
The risk of sudden cardiac death also is increased. Effective hypertension control can prevent
or lead to the regression of cardiac hypertrophy and its attendant risks.

Pulmonary Hypertensive Heart Disease—Cor Pulmonale Cor pulmonale

consists of right ventricular hypertrophy and dilation—frequently accompanied by right heart
failure— caused by pulmonary hypertension attributable to primary disorders of the lung
parenchyma or pulmonary vasculature (Table 10–4). Right ventricular dilation and hypertrophy
caused by left ventricular failure (or by congenital heart disease) is substantially more common
but is excluded by this definition. Cor pulmonale can be acute in onset, as with pulmonary
embolism, or can have a slow and insidious onset when due to prolonged pressure overloads in
the setting of chronic lung and pulmonary vascular disease

MORPHOLOGY
In acute cor pulmonale, the right ventricle usually shows only dilation; if an embolism causes
sudden death, the heart may even be of normal size. Chronic cor pulmonale is characterized by
right ventricular (and often right atrial) hypertrophy. In extreme cases, the thickness of the right
ventricular wall may be comparable with or even exceed that of the left ventricle (Fig. 10–16, B).
When ventricular failure develops, the right ventricle and atrium often are dilated. Because
chronic cor pulmonale occurs in the setting of pulmonary hypertension, the pulmonary arteries
often contain atheromatous plaques and other lesions, reflecting long standing pressure
elevations.

Diseases of the Pulmonary Parenchyma

Chronic obstructive pulmonary disease
Diffuse pulmonary interstitial fibrosis
Pneumoconiosis
Cystic fibrosis Bronchiectasis
Diseases of the Pulmonary Vessels
Recurrent pulmonary thromboembolism
Primary pulmonary hypertension
Extensive pulmonary arteritis (e.g., Wegener granulomatosis)
Drug-, toxin-, or radiation-induced vascular obstruction
Extensive pulmonary tumor microembolism
Disorders Affecting Chest Movement
Kyphoscoliosis
Marked obesity (pickwickian syndrome)
Neuromuscular diseases
Disorders Inducing Pulmonary Arterial Constriction
Metabolic acidosis
Hypoxemia Obstruction to major airways
Idiopathic alveolar hypoventilation
SUMMARY
Hypertensive Heart Disease
• Hypertensive heart disease can affect either the left ventricle or the right ventricle; in the latter
case, the disorder is called cor pulmonale. Elevated pressures induce myocyte hypertrophy and
interstitial fibrosis that increases wall thickness and stiffness.
• The chronic pressure overload of systemic hypertension causes left ventricular concentric
hypertrophy, often associated with left atrial dilation due to impaired diastolic filling of the
ventricle. Persistently elevated pressure overload can cause ventricular failure with dilation.
• Cor pulmonale results from pulmonary hypertension due to primary lung parenchymal or
vascular disorders. Hypertrophy of both the right ventricle and the right atrium is characteristic;
dilation also may be seen when failure supervenes.

HYPERTENSIVE VASCULAR DISEASE

Hypertension is a major health problem in the developed world. Although it occasionally
manifests in an acute aggressive form, high blood pressure is much more often asymptomatic
for many years. This insidious condition is sometimes referred to as benign hypertension, but it
is in fact far from harmless. Besides increasing the risk of stroke and atherosclerotic coronary
heart disease, hypertension can lead to cardiac hypertrophy and heart failure (hypertensive
heart disease), aortic dissection, multi-infarct dementia, and renal failure. While the molecular
pathways of blood pressure regulation are reasonably well understood, the mechanisms leading
to hypertension in the vast majority of affected persons remain unknown. The accepted wisdom
is that such “essential hypertension” results from the interplay of genetic polymorphisms (which
individually might be inconsequential) and environmental factors, which conspire to increase
blood volume and/or peripheral resistance.

Epidemiology of Hypertension
Like height and weight, blood pressure is a continuously distributed variable, and the
detrimental effects increase continuously as the pressure rises; no rigidly defined threshold
reliably predicts who will suffer ill effects. Nevertheless, sustained diastolic pressures greater
than 90 mm Hg, or sustained systolic pressures in excess of 140 mm Hg, are associated with
an increased risk of atherosclerosis and are therefore used as cutoffs in diagnosing
hypertension in clinical practice. By these criteria, some 25% of persons in the general
population are hypertensive. As noted however, these values are somewhat arbitrary, and in
patients with other cardiovascular risk factors (e.g., diabetes), lower thresholds may be
applicable. The prevalence of pathologic effects of high blood pressure increases with age and
is also higher in African Americans. Without appropriate treatment, some 50% of hypertensive
patients die of ischemic heart disease (IHD) or congestive heart failure, and another third
succumb to stroke. Reduction of blood pressure dramatically reduces the incidence and clinical
sequelae (including death) of all forms of hypertension-related disease. Indeed, detection and
treatment of asymptomatic hypertension constitute one of the few instances in which “preventive
medicine” has a major demonstrated health benefit. A small percentage of hypertensive patients
(approximately 5%) present with a rapidly rising blood pressure that, if untreated, leads to death
within 1 to 2 years. Such malignant hypertension usually is severe (i.e., systolic pressures over
200 mm Hg or diastolic pressures over 120 mm Hg) and associated with renal failure and retinal
hemorrhages, with or without papilledema. It can arise de novo but most commonly is
superimposed on preexisting benign hypertension.

PATHOGENESIS
Table 9–2 lists the major causes of hypertension, but most cases (95%) are idiopathic (essential
hypertension). This form is compatible with long life unless a myocardial infarction, stroke, or
another complication supervenes. Most of the remaining cases (secondary hypertension) are
due to primary renal disease, renal artery narrowing (renovascular hypertension), or adrenal
disorders. Several relatively rare single-gene disorders cause hypertension (and hypotension)
by affecting renal sodium resorption. Such disorders include
• Gene defects in enzymes involved in aldosterone metabolism (e.g., aldosterone synthase,
11β-hydroxylase, 17α-hydroxylase), leading to increased aldosterone secretion, increased salt
and water resorption, and plasma volume expansion
• Mutations in proteins that affect sodium resorption (as in Liddle syndrome, which is
caused by mutations in ENaC, leading to increased distal tubular resorption of sodium induced
by aldosterone)

Mechanisms of Essential Hypertension

Although the specific triggers are unknown, it appears that both altered renal sodium handling
and increased vascular resistance contribute to essential hypertension.
• Reduced renal sodium excretion in the presence of normal arterial pressure probably is a
key pathogenic feature; indeed, this is a common etiologic factor in most forms of hypertension.
Decreased sodium excretion causes an obligatory increase in fluid volume and increased
cardiac output, thereby elevating blood pressure (Fig. 9–3). At the new higher blood pressure,
the kidneys excrete additional sodium. Thus, a new steady state of sodium excretion is
achieved, but at the expense of an elevated blood pressure.
• Increased vascular resistance may stem from vasoconstriction or structural changes in
vessel walls. These are not necessarily independent factors, as chronic vasoconstriction may
result in permanent thickening of the walls of affected vessels.
• Genetic factors play an important role in determining blood pressure, as shown by familial
clustering of hypertension and by studies of monozygotic and dizygotic twins. Hypertension has
been linked to specific angiotensinogen polymorphisms and angiotensin II receptor variants;
polymorphisms of the renin-angiotensin system also may contribute to the known racial
differences in blood pressure regulation. Susceptibility genes for essential hypertension in the
larger population are currently unknown but probably include those that govern renal sodium
handling, pressors, and smooth muscle cell growth.
• Environmental factors, such as stress, obesity, smoking, physical inactivity, and high levels
of salt consumption, modify the impact of genetic determinants. Evidence linking dietary sodium
intake with the prevalence of hypertension in different population groups is particularly strong.

Essential Hypertension Accounts for 90% to 95% of all cases

Secondary Hypertension
Renal : Acute glomerulonephritis
 Chronic renal disease
Polycystic disease
Renal artery stenosis
Renal vasculitis Renin-producing tumors
Endocrine: Adrenocortical hyperfunction (Cushing syndrome, primary aldosteronism,
congenital adrenal hyperplasia, licorice ingestion)
Exogenous hormones (glucocorticoids, estrogen [including pregnancy induced
and oral contraceptives], sympathomimetics and tyramine containing foods,
monoamine oxidase inhibitors)
Pheochromocytoma
Acromegaly
Hypothyroidism (myxedema)
Hyperthyroidism (thyrotoxicosis)
Pregnancy-induced (pre-eclampsia)
Cardiovascular : Coarctation of aorta
Polyarteritis nodosa
Increased intravascular volume
Increased cardiac output
Rigidity of the aorta
Neurologic : Psychogenic
Increased intracranial pressure
Sleep apnea Acute stress, including surgery

MORPHOLOGY
Hypertension not only accelerates atherogenesis but also causes degenerative changes in the
walls of large and medium sized arteries that can lead to aortic dissection and cerebrovascular
hemorrhage. Two forms of small blood vessel disease are hypertension-related: hyaline
arteriolosclerosis and hyperplastic arteriolosclerosis (Fig. 9–5).
Hyaline arteriolosclerosis is associated with benign hypertension. It is marked by
homogeneous, pink hyaline thickening of the arteriolar walls, with loss of underlying structural
detail, and luminal narrowing (Fig. 9–5, A). The lesions stem from leakage of plasma
components across injured endothelial cells, into vessel walls and increased ECM production by
smooth muscle cells in response to chronic hemodynamic stress. In the kidneys, the arteriolar
narrowing caused by hyaline arteriosclerosis leads to diffuse vascular compromise and
nephrosclerosis (glomerular scarring). Although the vessels of elderly patients (normo- or
hypertensive) show the same changes, hyaline arteriolosclerosis is more generalized and
severe in patients with hypertension. The same lesions also are common in diabetic
microangiopathy; in this disorder, the underlying etiology is hyperglycemia associated
endothelial cell dysfunction.
Hyperplastic arteriolosclerosis is more typical of severe hypertension. Vessels exhibit
“onionskin,” concentric, laminated thickening of arteriolar walls and luminal narrowing (Fig. 9–5,
B). The laminations consist of smooth muscle cells and thickened, reduplicated basement
membrane. In malignant hypertension these changes are accompanied by fibrinoid deposits
and vessel wall necrosis (necrotizing arteriolitis), which are particularly prominent in the kidney