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Epidemiology

Approximately 7.6 million deaths (1315% of the total) and 92 million disability-adjusted life years
worldwide were attributable to high blood pressure in 2001. Hypertension doubles the risk of
cardiovascular diseases, including coronary heart disease (CHD), congestive heart failure (CHF),
ischemic and hemorrhagic stroke, renal failure, and peripheral arterial disease.
Prevalence of hypertension vary among countries and among subpopulations.
In the United States, average systolic blood pressure is higher for men than for women during early
adulthood.
Obesity and weight gain are strong, independent risk factors for hypertension. It has been
estimated that 60% of hypertensives are >20% overweight. Among populations, hypertension
prevalence is related to dietary NaCl intake, and the age-related increase in blood pressure may be
augmented by a high NaCl intake. Low dietary intakes of calcium and potassium also may
contribute to the risk of hypertension. Alcohol consumption, psychosocial stress, and low levels of
physical activity also may contribute to hypertension.
Adoption, twin, and family studies document a significant heritable component to blood pressure
levels and hypertension.

Genetic Considerations
Although specific genetic variants have been identified in rare Mendelian forms of hypertension,
these variants are not applicable to the vast majority (>98%) of patients with essential hypertension. For
most individuals, it is likely that hypertension represents a polygenic disorder in which a combination of
genes acts in concert with environmental exposures to make only a modest contribution to blood pressure.
Further, different subsets of genes may lead to different phenotypes associated with hypertension, e.g.,
obesity, dyslipidemia, insulin resistance.
Current evidence suggests that genes that encode components of the renin-angiotensin-aldosterone
system, along with angiotensinogen and angiotensin-converting enzyme (ACE) polymorphisms, may be
related to hypertension and to blood pressure sensitivity to dietary NaCl. The alpha-adducin gene is
thought to be associated with increased renal tubular absorption of sodium, and variants of this gene may
be associated with hypertension and salt sensitivity of blood pressure. Other genes possibly related to
hypertension include genes encoding the AT1 receptor, aldosterone synthase, and the 2 adrenoreceptor.
Family studies indicate significant heritability of left ventricular mass, and there is considerable individual
variation in the responses of the heart to hypertension.

Mechanisms of Hypertension
Cardiac output and peripheral resistance are the two determinants of arterial pressure. Cardiac output is
determined by stroke volume and heart rate; stroke volume is related to myocardial contractility and to the
size of the vascular compartment. Peripheral resistance is determined by functional and anatomic changes
in small arteries (lumen diameter 100400 m) and arterioles.
Intravascular Volume
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Vascular volume is a primary determinant of arterial pressure over the long term. Sodium is
predominantly an extracellular ion and is a primary determinant of the extracellular fluid volume.
When NaCl intake exceeds the capacity of the kidney to excrete sodium, vascular volume initially
expands and cardiac output increases
However, many vascular beds (including kidney and brain) have the capacity to autoregulate blood
flow, and if constant blood flow is to be maintained in the face of increased arterial pressure,
resistance within that bed must increase.

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The initial elevation of blood pressure in response to vascular volume expansion may be related to
an increase of cardiac output; however, over time, peripheral resistance increases and cardiac
output reverts toward normal.
Nonchloride salts of sodium have little or no effect on blood pressure
As arterial pressure increases in response to a high NaCl intake, urinary sodium excretion increases
and sodium balance is maintained at the expense of an increase in arterial pressure. The
mechanism for this "pressure-natriuresis" phenomenon may involve a subtle increase in the
glomerular filtration rate, decreased absorbing capacity of the renal tubules, and possibly hormonal
factors such as atrial natriuretic factor.
NaCl-dependent hypertension may be a consequence of a decreased capacity of the kidney to
excrete sodium, due either to intrinsic renal disease or to increased production of a salt-retaining
hormone (mineralocorticoid) resulting in increased renal tubular reabsorption of sodium. Renal
tubular sodium reabsorption also may be augmented by increased neural activity to the kidney.

Autonomic Nervous System

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The autonomic nervous system maintains cardiovascular homeostasis via pressure, volume, and
chemoreceptor signals
The three endogenous catecholamines are norepinephrine, epinephrine, and dopamine.
In both normal-weight and obese individuals, hypertension often is associated with increased
sympathetic outflow. Based on recordings of postganglionic muscle nerve activity (detected by a
microelectrode inserted in a peroneal nerve in the leg), sympathetic outflow tends to be higher in
hypertensive than in normotensive individuals. Sympathetic outflow is increased in obesity-related
hypertension and in hypertension associated with obstructive sleep apnea. Pheochromocytoma is
the most blatant example of hypertension related to increased catecholamine production, in this
instance by a tumor.

Renin-Angiotensin-Aldosterone
The renin-angiotensin-aldosterone system contributes to the regulation of arterial pressure
primarily via the vasoconstrictor properties of angiotensin II and the sodium-retaining properties of
aldosterone.
There are three primary stimuli for renin secretion: (1) decreased NaCl transport in the distal portion of the
thick ascending limb of the loop of Henle that abuts the corresponding afferent arteriole (macula densa),
(2) decreased pressure or stretch within the renal afferent arteriole (baroreceptor mechanism), and (3)
sympathetic nervous system stimulation of renin-secreting cells via 1 adrenoreceptors. Conversely, renin
secretion is inhibited by increased NaCl transport in the thick ascending limb of the loop of Henle, by
increased stretch within the renal afferent arteriole, and by 1 receptor blockade.
Renin-secreting tumors are clear examples of renin-dependent hypertension. In the kidney, these
tumors include benign hemangiopericytomas of the juxtaglomerular apparatus and, infrequently, renal
carcinomas, including Wilms' tumors. Renin-producing carcinomas also have been described in lung, liver,
pancreas, colon, and adrenals. Renovascular hypertension is another renin-mediated form of hypertension.
Angiotensinogen, renin, and angiotensin II are also synthesized locally in many tissues, including the brain,
pituitary, aorta, arteries, heart, adrenal glands, kidneys, adipocytes, leukocytes, ovaries, testes, uterus,
spleen, and skin. Excess tissue angiotensin II may contribute to atherosclerosis, cardiac hypertrophy, and
renal failure and consequently may be a target for pharmacologic therapy to prevent target organ damage.
Aldosterone also has effects on nonepithelial targets. Aldosterone and/or mineralocorticoid receptor
activation induces structural and functional alterations in the heart, kidney, and blood vessels, leading to
myocardial fibrosis, nephrosclerosis, and vascular inflammation and remodeling, perhaps as a

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consequence of oxidative stress. Increased activity of the renin-angiotensin-aldosterone axis is not

invariably associated with hypertension.
Vascular Mechanisms
Vascular radius and compliance of resistance arteries are also important determinants of arterial
pressure. Small decreases in lumen size significantly increase resistance. Hypertrophic (increased cell size,
and increased deposition of intercellular matrix) or eutrophic vascular remodeling results in decreased
lumen size and hence contributes to increased peripheral resistance. Apoptosis, low-grade inflammation,
and vascular fibrosis also contribute to remodeling. Lumen diameter also is related to elasticity of the
vessel. Vessels with a high degree of elasticity can accommodate an increase of volume with relatively
little change in pressure. Hypertensive patients have stiffer arteries, and arteriosclerotic patients may have
particularly high systolic blood pressures and wide pulse pressures as a consequence of decreased
vascular compliance due to structural changes in the vascular wall.
Ion transport by vascular smooth muscle cells may contribute to hypertension-associated abnormalities of
vascular tone and vascular growth, both of which are modulated by intracellular pH (pHi). Three ion
transport mechanisms participate in the regulation of pHi: (1) Na+-H+ exchange, (2) Na+-dependent
HCO3-Cl exchange, and (3) cation-independent HCO3Cl exchange. Activity of the Na+-H+ exchanger is
increased in hypertension, and this may result in increased vascular tone by two mechanisms. First,
increased sodium entry may lead to increased vascular tone by activating Na+-Ca2+ exchange and
thereby increasing intracellular calcium. Second, increased pHi enhances calcium sensitivity of the
contractile apparatus, leading to an increase in contractility for a given intracellular calcium concentration.

Pathologic Consequences of Hypertension

1. Heart
o Heart disease is the most common cause of death in hypertensive patients. Hypertensive heart
disease is the result of structural and functional adaptations leading to left ventricular
hypertrophy, CHF, abnormalities of blood flow due to atherosclerotic coronary artery disease
and microvascular disease, and cardiac arrhythmias.
o Both genetic and hemodynamic factors contribute to left ventricular hypertrophy. Individuals
with left ventricular hypertrophy are at increased risk for CHD, stroke, CHF, and sudden death.
o Diastolic dysfunction is an early consequence of hypertension-related heart disease and is
exacerbated by left ventricular hypertrophy and ischemia.
2. Brain
Stroke is the second most frequent cause of death in the world; it accounts for 5 million deaths
each yearElevated blood pressure is the strongest risk factor for stroke.The incidence of stroke rises
progressively with increasing blood pressure levels, particularly systolic blood pressure in individuals >65
years.
Hypertension also is associated with impaired cognition in an aging population. Hypertension-related
cognitive impairment and dementia may be a consequence of a single infarct due to occlusion of a
"strategic" larger vessel or multiple lacunar infarcts due to occlusive small vessel disease resulting in
subcortical white matter ischemia.
Cerebral blood flow remains unchanged over a wide range of arterial pressures (mean arterial pressure of
50150 mmHg) through a process termed autoregulation of blood flow. In patients with the clinical
syndrome of malignant hypertension, encephalopathy is related to failure of autoregulation of cerebral
blood flow at the upper pressure limit, resulting in vasodilation and hyperperfusion. Signs and symptoms of
hypertensive encephalopathy may include severe headache, nausea and vomiting (often of a projectile

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nature), focal neurologic signs, and alterations in mental status. Untreated, hypertensive encephalopathy
may progress to stupor, coma, seizures, and death within hours.
3. Kidney
The kidney is both a target and a cause of hypertension. Primary renal disease is the most common
etiology of secondary hypertension. Mechanisms of kidney-related hypertension include a diminished
capacity to excrete sodium, excessive renin secretion in relation to volume status, and sympathetic
nervous system overactivity. Conversely, hypertension is a risk factor for renal injury and end-stage renal
disease. Glomerular injury also may be a consequence of direct damage to the glomerular capillaries due
to glomerular hyperperfusion.
With progressive renal injury there is a loss of autoregulation of renal blood flow and glomerular filtration
rate, resulting in a lower blood pressure threshold for renal damage and a steeper slope between blood
pressure and renal damage. The result may be a vicious cycle of renal damage and nephron loss leading to
more severe hypertension, glomerular hyperfiltration, and further renal damage. Glomerular pathology
progresses to glomerulosclerosis, and eventually the renal tubules may also become ischemic and
gradually atrophic. Clinically, macroalbuminuria (a random urine albumin/creatinine ratio >300 mg/g) or
microalbuminuria (a random urine albumin/creatinine ratio 30300 mg/g) are early markers of renal injury.
These are also risk factors for renal disease progression and cardiovascular disease.
4. Peripheral Arteries
In addition to contributing to the pathogenesis of hypertension, blood vessels may be a target organ for
atherosclerotic disease secondary to long-standing elevated blood pressure. Hypertensive patients with
arterial disease of the lower extremities are at increased risk for future cardiovascular disease.
Approach to the Patient: Hypertension
1. History
Most patients with hypertension have no specific symptoms referable to their blood pressure elevation.
Although popularly considered a symptom of elevated arterial pressure, headache generally occurs only in
patients with severe hypertension. Characteristically, a "hypertensive headache" occurs in the morning
and is localized to the occipital region. Other nonspecific symptoms that may be related to elevated blood
pressure include dizziness, palpitations, easy fatigability, and impotence. When symptoms are present,
they are generally related to hypertensive cardiovascular disease or to manifestations of secondary
hypertension.
2. Measurement of Blood Pressure
3. Physical Examination
o Body habitus, including weight and height, should be noted. At the initial examination, blood
pressure should be measured in both arms and preferably in the supine, sitting, and standing
positions to evaluate for postural hypotension.
o The neck should be palpated for an enlarged thyroid gland.
o Auscultation for bruits over the carotid and femoral arteries, and palpation of femoral and pedal
pulses.
o The retina is the only tissue in which arteries and arterioles can be examined directly.
o Examination of the heart may reveal a loud second heart sound due to closure of the aortic
valve and an S4 gallop attributed to atrial contraction against a noncompliant left ventricle.
o Kidneys of patients with polycystic kidney disease may be palpable in the abdomen.
4. Laboratory Testing

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Repeat measurements of renal function, serum electrolytes, fasting glucose, and lipids may be
obtained after the introduction of a new antihypertensive agent and then annually or more frequently if
clinically indicated.

Patient's Relevant History

Duration of hypertension
Previous therapies: responses and side effects
Family history of hypertension and cardiovascular disease
Other risk factors: weight change, dyslipidemia, smoking, diabetes, physical inactivity
Evidence of secondary hypertension: history of renal disease; change in appearance; muscle weakness; spells of
sweating, palpitations, tremor; erratic sleep, snoring, daytime somnolence; symptoms of hypo- or hyperthyroidism; use
of agents that may increase blood pressure
Evidence of target organ damage: history of TIA, stroke, transient blindness; angina, myocardial infarction, congestive
heart failure; sexual function Other comorbidities