Discussion

HYPERTENSION
Hypertension is one of the leading causes of the global burden of disease. 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. It often is associated with
additional cardiovascular disease risk factors, and the risk of cardiovascular disease increases with the
total burden of risk factors. Although antihypertensive therapy reduces the risks of cardiovascular and
renal disease, large segments of the hypertensive population are either untreated or inadequately
treated.

Mechanism of Hypertension

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 100–400 μm) and arterioles.

1. Intravascular Volume
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 may initially expand and cardiac output may increase. However, many vascular beds 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. 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. Salt can activate a number of neural, endocrine/paracrine, and vascular mechanisms, all
of which have the potential to increase arterial pressure.
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.
 In each of these situations, a higher arterial pressure may be required to achieve sodium balance.
Conversely, salt-wasting disorders are associated with low blood pressure levels. ESRD is an
extreme example of volume-dependent hypertension.
2. Autonomic Nervous System
The activities of the adrenergic receptors are mediated by guanosine nucleotide-binding
regulatory proteins (G proteins) and by intracellular concentrations of downstream second
messengers. In addition to receptor affinity and density, physiologic responsiveness to
catecholamines may be altered by the efficiency of receptor-effector coupling at a site “distal” to
receptor binding. The receptor sites are relatively specific both for the transmitter substance and
for the response that occupancy of the receptor site elicits. Based on their physiology and
pharmacology, adrenergic receptors have been divided into two principal types: α and β. These
types have been differentiated further into α1, α2, β1, and β2 receptors. Recent molecular cloning
studies have identified several additional subtypes. α Receptors are occupied and activated more
avidly by norepinephrine than by epinephrine, and the reverse is true for β receptors. α1
Receptors are located on postsynaptic cells in smooth muscle and elicit vasoconstriction. α2
Receptors are localized on presynaptic membranes of postganglionic nerve terminals that
synthesize norepinephrine. When activated by catecholamines,
α2 receptors act as negative feedback controllers, inhibiting further norepinephrine release. In
the kidney, activation of α1-adrenergic receptors increases renal tubular reabsorption of sodium.
Different classes of antihypertensive agents either inhibit α1 receptors or act as agonists of α2
receptors and reduce systemic sympathetic outflow. Activation of myocardial β1 receptors
stimulates the rate and strength of cardiac contraction and consequently increases cardiac
output. β1 Receptor activation also stimulates renin release from the kidney. Another class of
antihypertensive agents acts by inhibiting β1 receptors. Activation of β2 receptors by epinephrine
relaxes vascular smooth muscle and results in vasodilation.
3. Renin-angiotensin-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 β1 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 β1 receptor
blockade. In addition, angiotensin II directly inhibits renin secretion due to angiotensin II type 1
receptors on juxtaglomerular cells, and renin secretion increases in response to pharmacologic
blockade of either ACE or angiotensin II receptors. Once released into the circulation, active renin
cleaves a substrate, angiotensinogen, to form an inactive decapeptide, angiotensin I
(Fig. 298-2). A converting enzyme, located primarily but not exclusively in the pulmonary
circulation, converts angiotensin I to the active octapeptide, angiotensin II, by releasing the C-
terminal histidyl- leucine dipeptide. The same converting enzyme cleaves a numberof other
peptides, including and thereby inactivating the vasodilator bradykinin.

4. Vascular Mechanism

Vascular radius and compliance of resistance arteries are important determinants of

arterial pressure. Resistance to flow varies inversely with the fourth power of the radius, and
consequently, small decreases in lumen size significantly increase resistance. In hypertensive
patients, structural, mechanical, or functional changes may reduce the lumen diameter of small
arteries and arterioles. Remodeling refers to geometric alterations in the vessel wall without a
change in vessel volume. Hypertrophic (increased cell size, and increased deposition of
intercellular matrix) or eutrophic vascular remodeling results in decreased lumen size and, hence,
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, whereas in a semirigid vascular system, a small increment in volume induces a relatively
large increment of pressure. Hypertensive patients may have stiffer arteries due to
arteriosclerosis, and high systolic blood pressures and wide pulse pressures are a consequence of
decreased vascular compliance. Due to arterial stiffness, central blood pressures (aortic, carotid)
may not correspond to brachial artery pressures. Ejection of blood into the aorta elicits a pressure
wave that is propagated at a given velocity.

Classification of Blood Pressure (JNC 7)

Prehypertension is not a disease category. Rather it is a designation chosen to identify individuals at high
risk of developing hypertension, so that both patients and clinicians are alerted to this risk and encouraged
to intervene and prevent or delay the disease from developing. Individuals who are prehypertensive are
not candidates for drug therapy on the basis of their level of BP and should be firmly and unambiguously
advised to practice lifestyle modification in order to reduce their risk of developing hypertension in the
future
Clinical Disorder of Hypertension

1. PRIMARY HYPERTENSION

Primary hypertension tends to be familial and is likely to be the consequence of an

interaction between environmental and genetic factors. The prevalence of primary hypertension
increases with age, and individuals with relatively high blood pressures at younger ages are at
increased risk for the subsequent development of hypertension

2. Obesity and the Metabolic Syndrome

There is a well-documented association between obesity (body mass index >30 kg/m2)
and hypertension. Further, cross-sectional studies indicate a direct linear correlation
between body weight (or body mass index) and blood pressure. Centrally located body
fat is a more important determinant of blood pressure elevation than is peripheral body
fat. In longitudinal studies, a direct correlation exists between change in weight and
change in blood pressure over time. Sixty percent of hypertensive adults are more than
20% overweight. It has been established that 60–70% of hypertension in adults may be
directly attributable to adiposity. Hypertension and dyslipidemia frequently occur
together and in association with resistance to insulin-stimulated glucose uptake. This
clustering of risk factors is often, but not invariably, associated with obesity, particularly
abdominal obesity. Insulin resistance also is associated with an unfavorable imbalance in
the endothelial production of mediators that regulate platelet aggregation, coagulation,
fibrinolysis, and vessel tone. When these risk factors cluster, the risks for CHD, stroke,
diabetes, and cardiovascular disease mortality are increased further.
3. Renal Parenchymal Disease
Virtually all disorders of the kidney may cause hypertension and renal disease is the most
common cause of secondary hypertension. Hypertension is present in >80% of patients
with chronic renal failure. In general, hypertension is more severe in glomerular diseases
than in interstitial diseases such as chronic pyelonephritis. Conversely, hypertension may
cause nephrosclerosis, and in some instances it may be difficult to determine whether
hypertension or renal disease was the initial disorder. Proteinuria >1000 mg/d and an
active urine sediment are indicative of primary renal disease. In either instance, the goals
are to control blood pressure and retard the rate of progression of renal dysfunction.
4. RENOVASCULAR HYPERTENSION
Hypertension due to an occlusive lesion of a renal artery, renovascular hypertension, is a
potentially curable form of hypertension. In the initial stages, the mechanism of hypertension
generally is related to activation of the renin-angiotensin system. However, renin activity and
other components of the renin-angiotensin system may be elevated only transiently; over time,
recruitment of other pressure mechanisms may contribute to elevated arterial pressure. Two
groups of patients are at risk for this disorder: older arteriosclerotic patients who have a plaque
obstructing the renal artery, frequently at its origin, and patients with fibromuscular dysplasia.
Atherosclerosis accounts for the large majority of patients with renovascular hypertension.
Although fibromuscular dysplasia may occur at any age, it has a strong predilection for young
white women. The prevalence in females is eightfold that in males. There are several histologic
variants of fibromuscular dysplasia, including medial fibroplasia, perimedial fibroplasia, medial
hyperplasia, and intimal fibroplasia. Medial fibroplasia is the most common variant and accounts
 for approximately two-thirds of patients. The lesions of fibromuscular dysplasia are frequently
bilateral and, in contrast to atherosclerotic renovascular disease, tend to affect more distal
portions of the renal artery.
5. Primary Aldosteronism
Excess aldosterone production due to primary aldosteronism is a potentially curable form of
hypertension. In patients with primary aldosteronism, increased aldosterone production is
independent of the renin-angiotensin system, and the consequences are sodium retention,
hypertension, hypokalemia, and low PRA. The reported prevalence of this disorder varies from
<2% to ~15% of hypertensive individuals. In part, this variation is related to the intensity of
screening and the criteria for establishing the diagnosis.
6. CUSHING’S SYNDROME
Cushing’s syndrome is related to excess cortisol production due either to excess ACTH secretion
(from a pituitary tumor or an ectopic tumor) or to ACTH-independent adrenal production of
cortisol. Hypertension occurs in 75–80% of patients with Cushing’s syndrome. The mechanism of
hypertension may be related to stimulation of mineralocorticoid receptors by cortisol and
increased secretion of other adrenal steroids. If clinically suspected based on phenotypic
characteristics, in patients not taking exogenous glucocorticoids, laboratory screening may be
carried out with measurement of 24-h excretion rates of urine free cortisol or an overnight
dexamethasone-suppression test. Late night salivary cortisol is also a sensitive and convenient
screening test. Further evaluation is required to confirm the diagnosis and identify the specific
etiology of cushing’s syndrome
7. Pheocromocytoma
Clinical manifestations, including hypertension, are primarily related to increased circulating
catecholamines, although some of these tumors may secrete a number of other vasoactive
substances. In a small percentage of patients, epinephrine is the predominant catecholamine
secreted by the tumor, and these patients may present with hypotension rather than
hypertension. The initial suspicion of the diagnosis is based on symptoms and/or the association
of pheochromocytoma with other disorders

Approaches to Patient with Hypertension

History Taking:

Physical Exam
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. Even if the femoral pulse is normal to palpation, arterial pressure should be
measured at least once in the lower extremity in patients in whom hypertension is discovered before age
30. Heart rate also should be recorded. Hypertensive individuals have an increased prevalence of atrial
fibrillation. The neck should be palpated for an enlarged thyroid gland, and patients should be assessed
for signs of hypo- and hyperthyroidism. Examination of blood vessels may provide clues about underlying
vascular disease and should include funduscopic examination, auscultation for bruits over the carotid and
femoral arteries, and palpation of femoral and pedal pulses. The retina is the only tissue in which arteries
and arterioles can be examined directly. With increasing severity of hypertension and atherosclerotic
disease, progressive funduscopic changes include increased arteriolar light reflex, arteriovenous crossing
defects, hemorrhages and exudates, and, in patients with malignant hypertension, papilledema.
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. Left ventricular
hypertrophy may be detected by an enlarged, sustained, and laterally displaced apical impulse. An
abdominal bruit, particularly a bruit that lateralizes and extends throughout systole into diastole, raises
the possibility of renovascular hypertension. Kidneys of patients with polycystic kidney disease may be
palpable in the abdomen. The physical examination also should include evaluation for signs of CHF and a
neurologic examination.

Management:

Treatment:
Lifestyle Modification
Mechanism of Action:

1. Diuretics Thiazides inhibit the Na+/Cl− pump in the distal convoluted tubule and hence increase
sodium excretion. In the long term, they also may act as vasodilators.
2. ACEIs decrease the production of angiotensin II, increase bradykinin levels, and reduce
sympathetic nervous system activity. ARBs provide selective blockade of AT1receptors, and the
effect of angiotensin II on unblocked AT2 receptor may augment their hypotensive effect.
3. Aldorsterone Antagonist Spironolactone is a nonselective aldosterone antagonist that may be
used alone or in combination with a thiazide diuretic. It may be a particularly effective agent in
patients with low-renin primary hypertension, resistant hypertension, and primary
aldosteronism.
4. β-Adrenergic receptor blockers lower blood pressure by decreasing cardiac output, due to a
reduction of heart rate and contractility. Other proposed mechanisms by which beta blockers
lower blood pressure include a central nervous system effect and inhibition of renin release
5. α-Adrenergic Blockers Postsynaptic, selective α-adrenoreceptor antagonists lower blood pressure
by decreasing peripheral vascular resistance
6. Sympatholytic Agents Centrally acting α2 sympathetic agonists decrease peripheral resistance by
inhibiting sympathetic outflow.
7. Calcium antagonists reduce vascular resistance through L-channel blockade, which reduces
intracellular calcium and blunts vasoconstriction
 Cerebrovascular Disease
Stroke is the second leading cause of death worldwide, causing 6.2 million deaths in 2011, and is
double the rate of heart disease in China. Strokes cause ~200,000 deaths each year in the United
States and are a major cause of disability. The incidence of cerebrovascular diseases increases
with age. A stroke, or cerebrovascular accident, is defined as an abrupt onset of a neurologic
deficit that is attributable to a focal vascular cause. Thus, the definition of stroke is clinical, and
laboratory studies including brain imaging are used to support the diagnosis. The clinical
manifestations of stroke are highly variable because of the complex anatomy of the brain and its
vasculature. Cerebral ischemia is caused by a reduction in blood flow that lasts longer than several
seconds. Neurologic symptoms are manifest within seconds because neurons lack glycogen, so
energy failure is rapid. If the cessation of flow lasts for more than a few minutes, infarction or
death of brain tissue results. When blood flow is quickly restored, brain tissue can recover fully
and the patient’s symptoms are only transient: this is called a transient ischemic attack (TIA).

After the clinical diagnosis of stroke is made, an orderly process of evaluation and treatment should
follow. The first goal is to prevent or reverse brain injury. Attend to the patient’s airway, breathing, and
circulation (ABCs), and treat hypoglycemia or hyperglycemia if identified. Perform an emergency
noncontrast head CT scan to differentiate between ischemic stroke and hemorrhagic stroke; there are no
reliable clinical findings that conclusively separate ischemia from hemorrhage, although a more depressed
level of consciousness, higher initial blood pressure, or worsening of symptoms after onset favor
hemorrhage, and a deficit that is maximal at onset, or remits, suggests ischemia. Treatments designed to
reverse or lessen the amount of tissue infarction and improve clinical outcome fall within six categories:
(1) medical support, (2) IV thrombolysis, (3) endovascular revascularization, (4) antithrombotic treatment,
(5) neuroprotection, and (6) stroke centers and rehabilitation.
Pathogenesis of Cerebral Ischemia

Acute occlusion of an intracranial vessel causes reduction in blood flow to the brain region it supplies. The
magnitude of flow reduction is a function of collateral blood flow, and this depends on individualvascular
anatomy (which may be altered by disease), the site of occlusion, and systemic blood pressure. A decrease
in cerebral blood flow to zero causes death of brain tissue within 4–10 min; values <16–18 mL/100 g tissue
per minute cause infarction within an hour; and values <20 mL/100 g tissue per minute cause ischemia
without infarction unless prolonged for several hours or days. Focal cerebral infarction occurs via two
distinct pathways (Fig. 446-2): (1) a necrotic pathway in which cellular cytoskeletal breakdown is rapid,
due principally to energy failure of the cell; and (2) an apoptotic pathway in which cells become
programmed to die. Ischemia produces necrosis by starving neurons of glucose and oxygen, which in turn
results in failure of mitochondria to produce ATP. Without ATP, membrane ion pumps stop functioning
and neurons depolarize, allowing intracellular calcium to rise. Cellular depolarization also causes
glutamate release from synaptic terminals; excess extracellular glutamate produces neurotoxicity by
activating postsynaptic glutamate receptors that increase neuronal calcium influx. Free radicals are
produced by degradation of membrane lipids and mitochondrial dysfunction. Free radicals cause catalytic
destruction of membranes and likely damage other vital functions of cells.

Treatment of Acute Ischemic Stroke

• Intravenous Thrombolysis
 • Endovascular mechanical thrombectomy

Endovascular mechanical thrombectomy has been studied as an alternative or adjunctive

treatment of acute stroke in patients who are ineligible for, or have contraindications to,
thrombolytics or in those who failed to achieve vascular recanalization with IV
thrombolytics

• Antithrombotic Treatment

Aspirin is the only antiplatelet agent that has been proven effective for the acute
treatment of ischemic stroke; there are several antiplatelet agents proven for the
secondary prevention of stroke (see below).

Etiology

• Cardioembolic stroke (20%)

Cardioembolism is responsible for ~20% of all ischemic strokes. Stroke caused by heart
disease is primarily due to embolism of thrombotic material forming on the atrial or ventricular
wall or the left heart valves. These thrombi then detach and embolize into the arterial circulation.
The thrombus may fragment or lyse quickly, producing only a TIA. Alternatively, the arterial
occlusion may last longer, producing stroke. Embolic strokes tend to occur suddenly with
maximum neurologic deficit present at onset. With reperfusion following more prolonged
ischemia, petechial hemorrhages can occur within the ischemic territory. These are usually of no
clinical significance and should be distinguished from frank intracranial hemorrhage into a region
of ischemic stroke where the mass effect from the hemorrhage can cause a significant decline in
neurologic function.

• Artery to Artery Embolic Stroke

Thrombus formation on atherosclerotic plaques may embolize to intracranial arteries

producing an artery-to-artery embolic stroke. Less commonly, a diseased vessel may
acutely thrombose. Unlike the myocardial vessels, artery-to-artery embolism, rather than
 local thrombosis, appears to be the dominant vascular mechanism causing large-vessel
brain ischemia. Any diseased vessel may be an embolic source, including the aortic arch,
common carotid, internal carotid, vertebral, and basilar arteries

Carotid Atherosclerosis

Atherosclerosis within the carotid artery occurs most frequently within the common
carotid bifurcation and proximal internal carotid artery. Male gender, older age, smoking,
hypertension, diabetes, and hypercholesterolemia are risk factors for carotid disease, as
they are for stroke in general.

Primary and Secondary Prevention

A number of medical and surgical interventions, as well as lifestyle modifications, are available for
preventing stroke. Some of these can be widely applied because of their low cost and minimal risk; others
are expensive and carry substantial risk but may be valuable for selected high-risk patients. Identification
and control of modifiable risk factors, and especially hypertension, is the best strategy to reduce the
burden of stroke, and the total number of strokes could be reduced substantially by these mean.

Older age, diabetes mellitus, hypertension, tobacco smoking, abnormal blood cholesterol (particularly,
low high-density lipoprotein [HDL] and/or elevated low-density lipoprotein [LDL]), and other factors are
either proven or probable risk factors for ischemic stroke, largely by their link to atherosclerosis.
Hypertension is the most significant of the risk factors; in general, all hypertension should be treated to a
target of less than 140– 150/90 mmHg. However, many vascular neurologists recommend that guidelines
for secondary prevention of stroke should aim for blood pressure reduction to 130/80 mmHg or lower.
The presence of known cerebrovascular disease is not a contraindication to treatment aimed at achieving
normotension. Lowering blood pressure to levels below those traditionally defining hypertension appears
to reduce the risk of stroke even further. Data are particularly strong in support of thiazide diuretics and
angiotensin-converting enzyme inhibitors. Also, several trials have confirmed that statin drugs reduce the
risk of stroke even in patients without elevated LDL or low HDL.

Platelet antiaggregation agents can prevent atherothrombotic events, including TIA and stroke, by
inhibiting the formation of intraarterial platelet aggregates. These can form on diseased arteries, induce
thrombus formation, and occlude or embolize into the distal circulation. Aspirin, clopidogrel, and the
combination of aspirin plus extended-release dipyridamole are the antiplatelet agents most commonly
used for this purpose. Ticlopidine has been largely abandoned because of its adverse effects but may be
used as an alternative to clopidogrel.

 Aspirin is the most widely studied antiplatelet agent. Aspirin acetylates platelet
cyclooxygenase, which irreversibly inhibits the formation in platelets of thromboxane A2,
a platelet aggregating and vasoconstricting prostaglandin.
 Ticlopidine and clopidogrel block the adenosine diphosphate (ADP) receptor on platelets
and thus prevent the cascade resulting in activation of the glycoprotein IIb/IIIa receptor
that leads to fibrinogen binding to the platelet and consequent platelet aggregation.
Ticlopidine is more effective than aspirin; however, it has the disadvantage of causing
diarrhea, skin rash, and, in rare instances, neutropenia and thrombotic thrombocytopenic
purpura (TTP).
 Dipyridamole is an antiplatelet agent that inhibits the uptake of adenosine by a variety of
cells, including those of the vascular endothelium, dipyridamole also potentiates the
antiaggregatory effects of prostacyclin and nitric oxide produced by the endothelium and
acts by inhibiting platelet phosphodiesterase, which is responsible for the breakdown of
cyclic AMP. The resulting elevation in cyclic AMP inhibits aggregation of platelets.
Dipyridamole is erratically absorbed depending on stomach pH, but a newer formulation
combines timed-release dipyridamole, 200 mg, with aspirin, 25 mg, and has better oral
bioavailability