topics

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Percutaneous Coronary Interventions and Other Interventional Procedures

2071CHAPTER 276

aorta (counterpulsation). This results in an increase in coronary blood

flow and a decrease in afterload. It is contraindicated in patients with

aortic regurgitation, aortic dissection, or severe peripheral artery

disease. The major complications are vascular and thrombotic. Intravenous heparin is given in order to reduce thrombotic complications.

Another support device is the Impella (Abiomed, Danvers,

Massachusetts). The Impella catheter is placed percutaneously from the

femoral artery into the left ventricle. The catheter has a small microaxial

pump at its tip that can pump up to 2.5–5 L/min from the left ventricle

to the aorta. The smaller devices can be placed percutaneously, but

the larger devices need surgical access. Other support devices include

TandemHeart (CardiacAssist, Pittsburgh, Pennsylvania), which involves

placement of a large 21-French catheter from the femoral vein through

the right atrium into the left atrium using the transseptal technique

and a catheter in the femoral artery. A centrifugal pump can deliver

5 L of blood per minute. It may be useful in patients in shock or with

STEMI or very-high-risk PCI. Patients can also be placed on peripheral

extracorporeal membrane oxygenation (ECMO) using large cannulas

placed in the femoral artery and vein. This technique can be performed

emergently or electively in the catheterization laboratory and is useful

for support of patients with acute respiratory failure or cardiac failure.

■ INTERVENTIONS FOR PULMONARY EMBOLISM

The treatment of deep vein thrombosis is intravenous anticoagulation,

with placement of an inferior vena cava filter if recurrent pulmonary

emboli (PE) occur or anticoagulation is not possible. Post-phlebitic

syndrome is a serious condition due to chronic venous obstruction

that can lead to chronic leg edema and venous ulcers. Randomized data

show that mechanical treatments may have a selective role in treatment

of large iliofemoral deep-vein thrombosis.

PE should be treated with fibrinolytic agents if massive and in some

cases if submassive. Surgical pulmonary embolectomy is an option for

the treatment of massive PE with hemodynamic instability in patients

who have contraindications for systemic fibrinolysis or those in whom

it has failed. Catheter-based therapies for submassive and massive PEs

are still evolving, but studies have shown promise. The techniques

employed include the use of aspiration of the clot with a large catheter

(10 French), intraclot infusion of a thrombolytic agent followed by aspiration, ultrasound-assisted catheter-directed thrombolysis, and use of

rheolytic thrombectomy. Success for these techniques has been reported

to be 80–90%, with major complications occurring in 2–4% of patients.

■ INTERVENTIONS FOR REFRACTORY

HYPERTENSION

The recent recognition of the importance of the renal sympathetic

nerves in modulating blood pressure has led to a technique to selectively denervate renal sympathetic nerves in patients with refractory

hypertension. The procedure involves applying low-power radiofrequency treatment via a catheter along the length of both renal arteries.

Despite promising nonrandomized data, in the randomized Symplicity

HTN-3 trial, renal denervation did not significantly reduce blood

pressure compared with medical therapy. Further optimization of the

technique is ongoing with some evidence from small randomized trials

of modest efficacy, with larger scale evaluation ongoing.

CONCLUSION

Interventional cardiology continues to expand its borders. Treatment

for coronary artery disease, including complex anatomic subsets, continues to advance. Technological advances such as drug-eluting stents,

now already in their second generation, are improving the results of

PCI. PCI is the treatment of choice for patients with acute coronary

syndromes. For patients with stable coronary disease, PCI is effective

in symptom alleviation. Use of a Heart Team is the best way to make

decisions concerning which revascularization—PCI or CABG—is best

for an individual patient. Treatment of peripheral and cerebrovascular

disease can be effective with percutaneous techniques. Structural heart

disease is increasingly being treated with percutaneous options, with

interventional approaches such as TAVR becoming preferred over surgical aortic valve replacement. Further growth of invasive procedures

is anticipated in years to come.

■ FURTHER READING

Bhatt DL: Cardiovascular Intervention: A Companion to Braunwald’s

Heart Disease. Philadelphia, Elsevier, 2016.

Faxon DP, Williams DO: Interventional cardiology: Current status

and future directions in coronary disease and valvular heart disease.

Circulation 133:2697, 2016.

Neuman FJ et al: 2018 ESC/EACTS guidelines on myocardial revascularization. Eur Heart J 40:87, 2019.

Vahl TP et al: Transcatheter aortic valve replacement 2016: A modernday “through the looking-glass” adventure. J Am Coll Cardiol

67:1472, 2016.

D E

B C

FIGURE 276-5 Peripheral interventional procedures have become highly effective at treating anatomic lesions previously amenable only to bypass surgery. A. Complete

occlusion of the left superficial femoral artery. B. Wire and catheter advanced into subintimal space. C. Intravascular ultrasound positioned in the subintimal space to

guide retrograde wire placement through the occluded vessel. D. Balloon dilation of the occlusion. E. Stent placement with excellent angiographic result. (Reprinted from A

Almahameed, DL Bhatt: Contemporary management of peripheral arterial disease: III. Endovascular and surgical management. Cleve Clin J Med 2006; 73(suppl 4):S45-S51.

2072 PART 6 Disorders of the Cardiovascular System

Hypertension is one of the leading causes of the global burden of disease. Elevated blood pressure affects more than one billion individuals

and causes an estimated 9.4 million deaths per year. 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 (PAD). 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.

EPIDEMIOLOGY

Blood pressure levels, the rate of age-related increases in blood pressure, and the prevalence of hypertension vary among countries and

among subpopulations within a country. Hypertension is present in all

populations except for small numbers of individuals living in isolated

societies. In industrialized societies, blood pressure increases steadily during the first two decades of life. In children and adolescents,

blood pressure is associated with growth and maturation, and blood

pressure “tracks” over time in children and between adolescence and

young adulthood. In the United States, average systolic blood pressure

is higher for men than for women during early adulthood, although

among older individuals the age-related rate of rise is steeper for

women. Diastolic blood pressure also increases progressively with age

until ~55 years, after which it tends to decrease. The consequence is a

widening of pulse pressure (the difference between systolic and diastolic blood pressure) beyond age 60.

In the United States, based on criteria for defining hypertension prior

to 2018, ~78 million adults have hypertension. Hypertension prevalence is 33.5% in non-Hispanic blacks, 28.9% in non-Hispanic whites,

and 20.7% in Mexican Americans. Among individuals aged ≥60 years,

the prevalence is 65.4%. Recent evidence suggests that the prevalence

of hypertension in the United States may be increasing, possibly as a

consequence of increasing obesity. The prevalence of hypertension and

stroke mortality rates is higher in the southeastern United States than

in other regions. In African Americans, hypertension appears earlier, is

generally more severe, and results in higher rates of morbidity and mortality from stroke, left ventricular hypertrophy, CHF, and end-stage renal

disease (ESRD) than in white Americans. In the United States, hypertension awareness, treatment, and control rates have been improving for

decades. According to National Health and Nutrition Examination Survey (NHANES) data, in 2009–2012, prevalence estimates for men and

women, respectively, were 80.2% and 85.4% for hypertension awareness,

70.9% and 80.6% for treatment (88.4% and 94.4% in those who were

aware), 69.5% and 68.5% for control in those being treated, and 49.3%

and 55.2% for overall control in adults with hypertension.

Both environmental and genetic factors may contribute to variations

in hypertension prevalence. Studies of societies undergoing “acculturation” and studies of migrants from a less to a more urbanized setting

indicate a profound environmental contribution to blood pressure.

Obesity and weight gain are strong, independent risk factors for hypertension. Hypertension prevalence is also 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. The urine sodium-topotassium ratio (an index of both sodium and potassium intakes) is a

stronger correlate of blood pressure than is either sodium or potassium

alone. Alcohol consumption, psychosocial stress, and low levels of

physical activity also may contribute to hypertension.

277 Hypertension

Theodore A. Kotchen*

■ 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 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. Furthermore, different subsets of genes may lead to different

phenotypes associated with hypertension, e.g., obesity, dyslipidemia,

insulin resistance.

Adoption, twin, and family studies document a significant heritable

component to blood pressure levels and hypertension. Animal models

(including selectively bred rats and congenic rat strains) have identified a number of genetic loci and genes associated with hypertension.

Clinically, although replication has been a challenge, results of candidate gene studies and genome-wide association studies have identified

>25 rare mutations and >100 hypertension-related polymorphisms.

A number of these polymorphisms are involved in pathways that

regulate arterial pressure. However, blood pressure–related polymorphisms account for only ~3.5% of blood pressure variance, whereas

based on family studies, heritability of hypertension is estimated to be

in the range of 30–40%. One hypothesis to account for the “missing

heritability” is that epigenetic modifications of DNA contribute to the

heritability of blood pressure. Epigenetic processes are changes in gene

expression that occur without changes in DNA sequence. In contrast to

DNA sequence, the epigenome is relatively susceptible to modification

by environmental exposures.

Preliminary evidence suggests that there may also be genetic and

epigenetic determinants of target organ damage and vascular disease

attributed to hypertension, including let ventricular hypertrophy and

nephropathy. Specific genetic variants have been linked to CHD and

stroke. Additionally, recent studies have identified specific genomewide epigenetic modifications of DNA associated with hypertension

and with risk of future myocardial infarction and CHD.

MECHANISMS OF HYPERTENSION

To provide a framework for understanding the pathogenesis and

treatment options for hypertensive disorders, it is useful to understand

factors involved in the regulation of both normal and elevated arterial

pressure. Cardiac output and peripheral resistance are the two determinants of arterial pressure (Fig. 277-1). 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.

■ INTRAVASCULAR VOLUME

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. 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. Many vascular beds have the capacity

Arterial pressure

Cardiac output

Peripheral resistance

Stroke volume

Heart rate

Vascular structure

Vascular function

FIGURE 277-1 Determinants of arterial pressure. *

Deceased.

Hypertension

2073CHAPTER 277

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, since

Blood flow Pressure acrossthe vascular bed

Vascularresistance =

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. Whether this hypothesized sequence of events

occurs in the pathogenesis of hypertension is not clear. What is clear is

that salt can activate a number of neural, endocrine/paracrine, and vascular mechanisms, which have the potential to increase arterial pressure. The effect of sodium on blood pressure is related to the provision

of sodium with chloride; non-chloride 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. In individuals with an impaired capacity to excrete sodium, greater increases in arterial pressure are required

to achieve natriuresis and sodium balance.

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.

End stage renal disease (ESRD) is an extreme example of volumedependent hypertension. In ~80% of these patients, vascular volume

and hypertension can be controlled with adequate dialysis; in the other

20%, the mechanism of hypertension is related to increased activity of the

renin-angiotensin system and is likely to be responsive to pharmacologic blockade of renin-angiotensin.

■ AUTONOMIC NERVOUS SYSTEM

Adrenergic reflexes modulate blood pressure over the short term, and

adrenergic function, in concert with hormonal and volume-related

factors, contributes to the long-term regulation of arterial pressure.

Norepinephrine, epinephrine, and dopamine all play important roles

in tonic and phasic cardiovascular regulation.

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. 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.

Circulating catecholamine concentrations may affect the number of

adrenoreceptors in various tissues. Downregulation of receptors may

be a consequence of sustained high levels of catecholamines and provides an explanation for decreasing responsiveness, or tachyphylaxis,

to catecholamines. For example, orthostatic hypotension is frequently

observed in patients with pheochromocytoma, possibly due to the lack

of norepinephrine-induced vasoconstriction with assumption of the

upright posture. Conversely, with chronic reduction of neurotransmitter substances, adrenoreceptors may increase in number or be upregulated, resulting in increased responsiveness to the neurotransmitter.

Chronic administration of agents that block adrenergic receptors may

result in upregulation, and abrupt withdrawal of those agents may produce a condition of temporary hypersensitivity to sympathetic stimuli.

For example, clonidine is an antihypertensive agent that is a centrally

acting α2

agonist that inhibits sympathetic outflow. Rebound hypertension may occur with the abrupt cessation of clonidine therapy, probably

as a consequence of upregulation of α1

receptors.

Several reflexes modulate blood pressure on a minute-to-minute

basis. One arterial baroreflex is mediated by stretch-sensitive sensory

nerve endings in the carotid sinuses and the aortic arch. The rate of

firing of these baroreceptors increases with arterial pressure, and the

net effect is a decrease in sympathetic outflow, resulting in decreases

in arterial pressure and heart rate. This is a primary mechanism for

rapid buffering of acute fluctuations of arterial pressure that may

occur during postural changes, behavioral or physiologic stress, and

changes in blood volume. However, the activity of the baroreflex

declines or adapts to sustained increases in arterial pressure such that

the baroreceptors are reset to higher pressures. Baroreflex control of

blood pressure deteriorates with advancing age, hypertension, and

atherosclerosis. The consequences are increased blood pressure variability and an increased incidence of orthostatic hypotension. Patients

with autonomic neuropathy and impaired baroreflex function may

have extremely labile blood pressures with difficult-to-control episodic

blood pressure spikes associated with tachycardia.

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. Baroreceptor

activation via electrical stimulation of carotid sinus afferent nerves

lowers blood pressure in patients with “resistant” hypertension. Drugs

that block the sympathetic nervous system are potent antihypertensive

agents, indicating that the sympathetic nervous system plays a permissive, although not necessarily a causative, role in the maintenance of

increased arterial pressure.

Pheochromocytoma is the most blatant example of hypertension

related to increased catecholamine production, in this instance by a

tumor. Blood pressure can be reduced by surgical excision of the tumor

or by pharmacologic treatment with an α1

receptor antagonist or with

an inhibitor of tyrosine hydroxylase, the rate-limiting step in catecholamine biosynthesis.

■ 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.

Renin is an aspartyl protease that is synthesized as an enzymatically

inactive precursor, prorenin. Most renin in the circulation is synthesized in the renal afferent renal arteriole. Prorenin may be secreted

directly into the circulation or may be activated within secretory cells

2074 PART 6 Disorders of the Cardiovascular System

and released as active renin. 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 the angiotensin-converting enzyme or angiotensin II receptors.

Once released into the circulation, active renin cleaves a substrate,

angiotensinogen, to form an inactive decapeptide, angiotensin I

(Fig. 277-2). 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 histidylleucine dipeptide. The same converting enzyme cleaves a number

of other peptides, including and thereby inactivating the vasodilator

bradykinin. Acting primarily through angiotensin II type 1 receptors

(AT1

R) on cell membranes, angiotensin II is a potent pressor substance

and is the primary trophic factor for the secretion of aldosterone by

the adrenal zona glomerulosa. Utilizing various signal transduction

cascades, the AT1

R is believed to mediate most functions of angiotensin

II, resulting in hypertension, cardiovascular remodeling, and endorgan damage. The angiotensin II type 2 receptor (AT2

R) has the

opposite functional effects of the AT1

R. The AT2

R induces vasodilation,

sodium excretion, and inhibition of cell growth and matrix formation.

The AT2

R may improve vascular remodeling by stimulating smooth

muscle cell apoptosis and contributes to the regulation of glomerular

filtration rate. AT1

R blockade induces an increase in AT2

R activity.

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. Obstruction of the renal artery leads to decreased renal

perfusion pressure, thereby stimulating renin secretion. Over time,

possibly as a consequence of secondary renal damage, this form of

hypertension may become less renin-dependent.

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. Angiotensin II in tissues may be formed by

the enzymatic activity of renin or by other proteases, e.g., tonin, chymase, and cathepsins. In addition to regulating local blood flow, tissue

angiotensin II is a mitogen that stimulates growth and contributes

to modeling and repair. 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.

Angiotensin II is the primary tropic factor regulating the synthesis

and secretion of aldosterone by the zona glomerulosa of the adrenal

cortex. Aldosterone synthesis is also dependent on potassium, and

aldosterone secretion may be decreased in potassium-depleted individuals. Although acute elevations of adrenocorticotropic hormone

(ACTH) levels also increase aldosterone secretion, ACTH is not an

important trophic factor for the chronic regulation of aldosterone.

Aldosterone is a potent mineralocorticoid that increases sodium

reabsorption by amiloride-sensitive epithelial sodium channels (ENaC)

on the apical surface of the principal cells of the renal cortical collecting duct (Chap. 309). Electric neutrality is maintained by exchanging

sodium for potassium and hydrogen ions. Consequently, increased

aldosterone secretion may result in hypokalemia and alkalosis. Cortisol also binds to the mineralocorticoid receptor but normally functions as a less potent mineralocorticoid than aldosterone because

cortisol is converted to cortisone by the enzyme 11 β-hydroxysteroid

dehydrogenase type 2. Cortisone has no affinity for the mineralocorticoid receptor. Primary aldosteronism is a compelling example of

mineralocorticoid-mediated hypertension. In this disorder, adrenal

aldosterone synthesis and release are independent of renin-angiotensin,

and renin release is suppressed by the resulting volume expansion.

Mineralocorticoid receptors are expressed in a number of tissues

in addition to the kidney, and mineralocorticoid receptor activation

induces structural and functional alterations in the heart, kidney,

and blood vessels, leading to myocardial fibrosis and left ventricular

hypertrophy, nephrosclerosis, and vascular inflammation and remodeling, perhaps as a consequence of oxidative stress. These effects are

amplified by a high salt intake. In animal models, spironolactone

(an aldosterone antagonist) prevents aldosterone-induced myocardial

fibrosis. In patients with CHF, low-dose spironolactone reduces the

risk of progressive heart failure and sudden death from cardiac causes

by 30%. Due to a renal hemodynamic effect, in patients with primary

aldosteronism, high circulating levels of aldosterone also may cause

glomerular hyperfiltration and albuminuria.

Increased activity of the renin-angiotensin-aldosterone axis is not

invariably associated with hypertension. In response to a low-NaCl diet

or to volume contraction, arterial pressure and volume homeostasis

may be maintained by increased activity of the renin-angiotensinaldosterone axis. Secondary aldosteronism (i.e., increased aldosterone

secondary to increased renin-angiotensin), but not hypertension, also

is observed in edematous states such as CHF and liver disease.

■ VASCULAR MECHANISMS

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

Angiotensinogen

Angiotensin I

Angiotensin II

AT1 receptor AT2 receptor

Renin

Aldosterone

Bradykinin

Inactive

peptides

ACE-kininase II

FIGURE 277-2 Renin-angiotensin-aldosterone axis. ACE, angiotensin-converting

enzyme.

Hypertension

2075CHAPTER 277

the vessel. Vessels with a high degree of elasticity can accommodate an

increase of volume with relatively little change in pressure, whereas in

a semi-rigid vascular system, a small increment in volume induces a

relatively large increment of pressure.

An association between arterial stiffness and hypertension is well

established. A stiffened vasculature is less able to buffer short-term

alterations in flow. Although it has been assumed that arterial stiffness

is a manifestation of hypertension, recent evidence suggests that vascular stiffness may also contribute to elevated arterial pressure. Clinically,

noninvasive determination of elevated pulse wave velocity between the

carotid and femoral arteries is often interpreted as an indicator of arterial stiffness. 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. The forward traveling wave generates a reflected wave that

travels backward toward the ascending aorta. Although mean arterial

pressure is determined by cardiac output and peripheral resistance,

pulse pressure is related to the functional properties of large arteries

and the amplitude and timing of the incident and reflected waves.

Increased arterial stiffness results in increased pulse wave velocity of

both incident and reflected waves. The consequence is augmentation

of aortic systolic pressure and a reduction of aortic diastolic pressure,

i.e., an increase in pulse pressure. The aortic augmentation index, a

surrogate index of arterial stiffening, is calculated as the ratio of central

arterial pressure to pulse pressure. However, wave reflections are also

influenced by left ventricular structure and function. Central blood

pressure may be measured directly by placing a sensor in the aorta

or noninvasively by radial tonometry. Central blood pressure and the

aortic augmentation index are independent predictors of cardiovascular disease and all-cause mortality. Central blood pressure also appears

to be more strongly associated with preclinical organ damage than

brachial blood pressure.

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) cationindependent HCO3

–

-Cl–

exchange. Based on measurements in cell

types that are more accessible than vascular smooth muscle (e.g., leukocytes, erythrocytes, platelets, skeletal muscle), 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.

Additionally, increased Na+-H+ exchange may stimulate growth of vascular smooth muscle cells by enhancing sensitivity to mitogens.

Vascular endothelial function also modulates vascular tone. The

vascular endothelium synthesizes and releases several vasoactive

substances, including nitric oxide, a potent vasodilator. Endotheliumdependent vasodilation is impaired in hypertensive patients. This

impairment often is assessed with high-resolution ultrasonography

before and after the hyperemic phase of reperfusion that follows

5 min of forearm ischemia. Alternatively, endothelium-dependent

vasodilation may be assessed in response to an intra-arterially infused

endothelium-dependent vasodilator, e.g., acetylcholine. Endothelin is

a vasoconstrictor peptide produced by the endothelium, and orally

active endothelin antagonists may lower blood pressure in patients

with resistant hypertension.

■ IMMUNE MECHANISMS, INFLAMMATION, AND

OXIDATIVE STRESS

Low-grade inflammation and uncontrolled activation of the immune

system have been implicated in the pathogenesis of vascular injury and

hypertension for at least four decades. Both thymus-derived cells (T

cells) and bone marrow– or bursa-derived cells (B cells) are involved.

Activation has been attributed to increased sympathetic nervous system activity, mechanical forces in the vascular wall, interstitial sodium

concentration, and a high salt intake. Inflammatory cytokines and

free radicals secreted by activated immune cells may contribute to

vascular and target organ injury. Inflammation and exudative injury

are closely coupled. Inflammation, vascular stretch, angiotensin II, and

salt have all been shown to result in the generation of reactive oxygen

species (ROS), which modify T-cell function and further enhance

inflammation. ROS also attenuate the effects of endogenous smallmolecule vasodilators. Preliminary evidence suggests that hypertension is blunted and vascular endothelial function is preserved in

experimental models that lack both T cells and B cells. In animal

models of salt-sensitive hypertension, salt-related increases in renal

perfusion pressure induce the infiltration of immune cells into the kidney. The infiltrating cells release cytokines and free radicals that may

contribute to renal injury. Additionally, ROS within the renal medulla

may disrupt pressure-natriuresis and thereby potentiate the development of hypertension.

Clinically, patients with primary hypertension have increased circulating levels of autoantibodies, and markers of oxidative stress have

been described in both hypertensive and prehypertensive individuals.

Increased numbers of activated immune cells (either in the circulation

or tissue biopsies) and the inflammatory cytokines they produce also

occur in patients with preeclampsia, resistant hypertension, malignant

hypertension, and renal allograft rejection.

PATHOLOGIC CONSEQUENCES OF

HYPERTENSION

■ HEART

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, increased

atrial size, CHF, atherosclerotic coronary artery disease, microvascular

disease, and cardiac arrhythmias, including atrial fibrillation. Independent of blood pressure, individuals with left ventricular hypertrophy

are at increased risk for CHD, stroke, CHF, and sudden death. Control

of hypertension can regress or reverse left ventricular hypertrophy and

reduce the risk of cardiovascular disease. Coronary artery calcium

score provides a noninvasive estimate of target organ injury and is

associated with cardiovascular events. However, there is currently relatively little information regarding the impact of improvement of this

subclinical marker on prognosis.

CHF may be related to systolic dysfunction, diastolic dysfunction,

or a combination of the two. Abnormalities of diastolic function that

range from asymptomatic heart disease to overt heart failure are common in hypertensive patients. Approximately one-third of patients with

CHF have normal systolic function but abnormal diastolic function.

Diastolic dysfunction is an early consequence of hypertension-related

heart disease and is exacerbated by left ventricular hypertrophy and

ischemia. Cardiac catheterization provides the most accurate assessment of diastolic function. Alternatively, diastolic function can be

evaluated by several noninvasive methods, including echocardiography

and radionuclide angiography.

■ BRAIN

Stroke is the second most frequent cause of death in the world; it

accounts for 5 million deaths each year, with an additional 15 million persons having nonfatal strokes. Elevated blood pressure is the

strongest risk factor for stroke. Approximately 85% of strokes are due

to infarction, and the remainder are due to either intracerebral or subarachnoid hemorrhage. The incidence of stroke rises progressively with

increasing blood pressure levels, particularly systolic blood pressure in

individuals aged >65 years. Treatment of hypertension decreases the

incidence of both ischemic and hemorrhagic strokes.

Hypertension is also associated with impaired cognition in an aging

population, and longitudinal studies support an association between

midlife hypertension and late-life cognitive decline. Vascular dementia

and Alzheimer’s disease often coexist. Hypertension is associated with

beta amyloid deposition, a major pathologic factor in dementia. In

addition to actual blood pressure level, arterial stiffness and visit-to-visit

2076 PART 6 Disorders of the Cardiovascular System

blood pressure variability may be independently related to subclinical

small vessel disease and subsequent cognitive decline. Hypertension-related cognitive impairment and dementia may also 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. Several clinical trials suggest that

antihypertensive therapy has a beneficial effect on cognitive function.

Cerebral blood flow remains unchanged over a wide range of arterial

pressures (mean arterial pressure of 50–150 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 nature), focal neurologic signs, and

alterations in mental status. Untreated, hypertensive encephalopathy

may progress to stupor, coma, seizures, and death within hours. It

is important to distinguish hypertensive encephalopathy from other

neurologic syndromes that may be associated with hypertension, e.g.,

cerebral ischemia, hemorrhagic or thrombotic stroke, seizure disorder,

mass lesions, pseudotumor cerebri, delirium tremens, meningitis,

acute intermittent porphyria, traumatic or chemical injury to the brain,

and uremic encephalopathy.

■ KIDNEY

Hypertension is a risk factor for renal injury and ESRD. The increased

risk associated with high blood pressure is graded, continuous, and

present throughout the distribution of blood pressure above optimal

pressure. Renal risk appears to be more closely related to systolic than

to diastolic blood pressure, and black men are at greater risk than white

men for developing ESRD at every level of blood pressure.

Atherosclerotic, hypertension-related vascular lesions in the kidney

primarily affect preglomerular arterioles, resulting in ischemic changes

in the glomeruli and postglomerular structures. 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, 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. The renal lesion

associated with malignant hypertension consists of fibrinoid necrosis

of the afferent arterioles, sometimes extending into the glomerulus,

and may result in focal necrosis of the glomerular tuft.

Clinically, macroalbuminuria (a random urine albumin/creatinine

ratio >300 mg/g) and microalbuminuria (a random urine albumin/

creatinine ratio 30–300 mg/g) are early markers of renal injury. They are

also risk factors for renal disease progression and cardiovascular disease.

■ PERIPHERAL ARTERIES

Blood vessels are a target organ atherosclerotic disease secondary to

long-standing elevated blood pressure. Independent of blood pressure,

arterial stiffness (measured as carotid-femoral pulse wave velocity or

carotid pulse pressure) is associated with target organ disease, including stroke, heart disease, and renal failure. Hypertensive patients with

arterial disease of the lower extremities are also at increased risk of

future cardiovascular disease. Clinically, PAD may be recognized by

the symptom of claudication. The ankle-brachial index (ratio of ankle

to brachial systolic blood pressure) is a useful approach for evaluating

peripheral arterial disease. An ankle-brachial index <0.90 is considered

diagnostic of PAD and is associated with >50% stenosis in at least one

major lower limb vessel. An ankle-brachial index <0.80 is associated

with elevated blood pressure, particularly systolic blood pressure.

Whether arterial stiffness and vascular remodeling are primary

alterations or secondary consequences of elevated arterial pressure

remains to be established. Limited evidence suggests that vascular compliance and endothelium-dependent vasodilation may be

TABLE 277-1 Blood Pressure Classification in Adults

BLOOD PRESSURE

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