A. Primary Essential Hypertension
“Essential hypertension” is the term applied to the 95% of hypertensive patients in which elevated blood pressure results from complex interactions between multiple genetic and environmental factors. The proportion regarded as “essential” will diminish with improved detection of clearly defined secondary causes and with better understanding of pathophysiology. Essential hypertension occurs in 10–15% of white adults and 20–30% of black adults in the United States. The onset is usually between ages 25 and 50 years; it is uncommon before age 20 years. The best understood pathways underlying hypertension include overactivation of the sympathetic nervous and renin-angiotensin-aldosterone systems (RAAS), blunting of the pressure-natriuresis relationship, variation in cardiovascular and renal development, and elevated intracellular sodium and calcium levels.
1. Sympathetic nervous system hyperactivity
This is most apparent in younger persons with hypertension, who may exhibit tachycardia and an elevated cardiac output. However, correlations between plasma catecholamines and blood pressure are poor. Insensitivity of the baroreflexes may play a role in the genesis of adrenergic hyperactivity, and polymorphisms in the phosducin gene have been linked to increased blood pressure responses to stress.
2. Abnormal cardiovascular or kidney development
The normal cardiovascular system develops so that elasticity of the great arteries is matched to the resistance in the periphery to optimize large vessel pressure waves. In this way, myocardial oxygen consumption is minimized and coronary flow maximized. Elevated blood pressure later in life could arise from abnormal development of aortic elasticity or reduced development of the microvascular network. This has been postulated as the sequence of events in low birth weight infants, who have an increased risk of hypertension developing in adulthood. Another hypothesis proposes that the association between low birth weight and hypertension arises from reduced nephron number.
3. Renin–angiotensin system activity
Renin, a proteolytic enzyme, is secreted by cells surrounding glomerular afferent arterioles in response to a number of stimuli, including reduced renal perfusion pressure, diminished intravascular volume, circulating catecholamines, increased sympathetic nervous system activity, increased arteriolar stretch, and hypokalemia. Renin acts on angiotensinogen to cleave off the ten-amino-acid peptide angiotensin I. This peptide is then acted upon by angiotensin-converting enzyme (ACE) to create the eight-amino-acid peptide angiotensin II, a potent vasoconstrictor and stimulant of aldosterone secretion. Despite the role of renin in the regulation of blood pressure, it probably does not play a central role in the pathogenesis of most primary (essential) hypertension; only 10% of patients have high renin activity, whereas 60% have normal levels, and 30% have low levels. Black persons with hypertension and older patients tend to have lower plasma renin activity, which may be associated with expanded intravascular volume.
According to the classic Guyton hypothesis, increased salt intake triggers an increase in blood pressure that in turn promotes increased natriuresis, thereby bringing blood pressure back toward basal levels. Salt has long been implicated in the genesis of hypertension, and so-called salt-sensitive hypertension probably arises from a defect in this self-regulating pressure-natriuresis feedback loop.
5. Intracellular sodium and calcium
Intracellular Na+ is elevated in primary (essential) hypertension. An increase in intracellular Na+ may lead to increased intracellular Ca2+ concentration as a result of facilitated exchange and might explain the increase in vascular smooth muscle tone that is characteristic of established hypertension.
Exacerbating factors include obesity, sleep apnea, increased salt intake, excessive alcohol use, cigarette smoking, polycythemia, nonsteroidal anti-inflammatory drug (NSAID) therapy, and low potassium intake. Obesity is associated with an increase in intravascular volume, elevated cardiac output, activation of the renin-angiotensin system, and, probably, increased sympathetic outflow. Lifestyle-driven weight reduction lowers blood pressure modestly, but the dramatic weight reduction following bariatric surgery results in improved blood pressure in most patients, and actual remission of hypertension in 20–40% of cases. In patients with sleep apnea, treatment with continuous positive airway pressure (CPAP) has been associated with improvements in blood pressure. Increased salt intake probably elevates blood pressure in some individuals so dietary salt restriction is recommended in patients with hypertension. Excessive use of alcohol also raises blood pressure, perhaps by increasing plasma catecholamines. Hypertension can be difficult to control in patients who consume more than 40 g of ethanol (two drinks) daily or drink in “binges.” Cigarette smoking raises blood pressure by increasing plasma norepinephrine. Although the long-term effect of smoking on blood pressure is less clear, the synergistic effects of smoking and high blood pressure on cardiovascular risk are well documented. The relationship of exercise to hypertension is variable. Aerobic exercise lowers blood pressure in previously sedentary individuals, but increasingly strenuous exercise in already active subjects has less effect. The relationship between stress and hypertension is not established. Polycythemia, whether primary, drug-induced, or due to diminished plasma volume, increases blood viscosity and may raise blood pressure. NSAIDs produce increases in blood pressure averaging 5 mm Hg and are best avoided in patients with borderline or elevated blood pressures. Low potassium intake is associated with higher blood pressure in some patients; an intake of 90 mmol/day is recommended.
The complex of abnormalities termed the “metabolic syndrome” (upper body obesity, insulin resistance, and hypertriglyceridemia) is associated with both the development of hypertension and an increased risk of adverse cardiovascular outcomes. Affected patients usually also have low high-density lipoprotein (HDL) cholesterol levels and elevated catecholamines and inflammatory markers such as C-reactive protein.
B. Secondary Hypertension
Approximately 5% of patients have hypertension secondary to identifiable specific causes (Table 11–2). Secondary hypertension should be suspected in patients in whom hypertension develops at an early age or after the age of 50 years, and in those previously well controlled who become refractory to treatment. Hypertension resistant to maximum doses of three medications is another clue, although multiple medications are usually required to control hypertension in persons with diabetes. Secondary causes include genetic syndromes; kidney disease; renal vascular disease; primary hyperaldosteronism; Cushing syndrome; pheochromocytoma; coarctation of the aorta and hypertension associated with pregnancy, estrogen use, hypercalcemia, and medications.
Table 11–2.Identifiable causes of hypertension. ||Download (.pdf) Table 11–2. Identifiable causes of hypertension.
Drug-induced or drug-related
Chronic kidney disease
Long-term corticosteroid therapy and Cushing syndrome
Coarctation of the aorta
Thyroid or parathyroid disease
Hypertension can be caused by mutations in single genes, inherited on a Mendelian basis. Although rare, these conditions provide important insight into blood pressure regulation and possibly the genetic basis of essential hypertension. Glucocorticoid remediable aldosteronism is an autosomal dominant cause of early-onset hypertension with normal or high aldosterone and low renin levels. It is caused by the formation of a chimeric gene encoding both the enzyme responsible for the synthesis of aldosterone (transcriptionally regulated by angiotensin II) and an enzyme responsible for synthesis of cortisol (transcriptionally regulated by ACTH). As a consequence, aldosterone synthesis becomes driven by ACTH, which can be suppressed by exogenous cortisol. In the syndrome of apparent mineralocorticoid excess, early-onset hypertension with hypokalemic metabolic alkalosis is inherited on an autosomal recessive basis. Although plasma renin is low and plasma aldosterone level is very low in these patients, aldosterone antagonists are effective in controlling hypertension. This disease is caused by loss of function of the enzyme 11beta-hydroxysteroid dehydrogenase, which normally metabolizes cortisol and thus protects the otherwise “promiscuous” mineralocorticoid receptor in the distal nephron from inappropriate glucocorticoid activation. Glycyrrhetinic acid, found in licorice, causes increased blood pressure through inhibition of 11beta-hydroxysteroid dehydrogenase. The syndrome of hypertension exacerbated in pregnancy is inherited as an autosomal dominant trait. In these patients, a mutation in the mineralocorticoid receptor makes it abnormally responsive to progesterone and, paradoxically, to spironolactone. Liddle syndrome is an autosomal dominant condition characterized by early-onset hypertension, hypokalemic alkalosis, low renin, and low aldosterone levels. This is caused by a mutation that results in constitutive activation of the epithelial sodium channel of the distal nephron, with resultant unregulated sodium reabsorption and volume expansion. Gordon syndrome, or pseudohypoaldosteronism type II, presents with early-onset hypertension associated with hyperkalemia, metabolic acidosis and relative suppression of aldosterone. Inheritance is most often autosomal dominant and the hypertension responds to a thiazide diuretic. The underlying mutations occur in one of several genes encoding proteins that regulate the thiazide-sensitive NaCl co-transporter in the distal nephron, leading to constitutive activation of sodium and chloride reabsorption.
Renal parenchymal disease is the most common cause of secondary hypertension, which results from increased intravascular volume and increased activity of the RAAS. Increased sympathetic nerve activity may also contribute.
3. Renal vascular hypertension
Renal artery stenosis is present in 1–2% of hypertensive patients. The most common cause is atherosclerosis, but fibromuscular dysplasia should be suspected in women under 50 years of age. Excessive renin release occurs due to reduction in renal perfusion pressure, while attenuation of pressure natriuresis contributes to hypertension in patients with a single kidney or bilateral lesions. Activation of the renal sympathetic nerves may also be important.
Renal vascular hypertension should be suspected in the following circumstances: (1) the documented onset is before age 20 or after age 50 years, (2) the hypertension is resistant to three or more drugs, (3) there are epigastric or renal artery bruits, (4) there is atherosclerotic disease of the aorta or peripheral arteries (15–25% of patients with symptomatic lower limb atherosclerotic vascular disease have renal artery stenosis), (5) there is an abrupt increase (more than 25%) in the level of serum creatinine after administration of angiotensin-converting enzyme (ACE) inhibitors, or (6) episodes of pulmonary edema are associated with abrupt surges in blood pressure. (See Renal Artery Stenosis, Chapter 22.) There is no ideal screening test for renal vascular hypertension. If suspicion is sufficiently high and endovascular intervention is a viable option, renal arteriography, the definitive diagnostic test, is the best approach. Renal arteriography is not recommended as a routine adjunct to coronary studies. Where suspicion is moderate to low, noninvasive angiography using magnetic resonance (MR) or CT are reasonable approaches. Doppler sonography has good specificity but lacks sensitivity and is operator dependent. Gadolinium, a contrast agent used in MR angiography, is contraindicated in patients with an estimated glomerular filtration rate (eGFR) of less than 30 mL/min because it might precipitate nephrogenic systemic fibrosis in patients with advanced kidney disease. In young patients with fibromuscular disease, angioplasty is very effective, but there is controversy regarding the best approach to the treatment of atheromatous renal artery stenosis. Correction of the stenosis in selected patients might reduce the number of medications required to control blood pressure and could protect kidney function, but the extent of preexisting parenchymal damage to the affected and contralateral kidney has a significant influence on both blood pressure and kidney function outcomes following revascularization. Angioplasty and stenting may prove to be superior to medical therapy in a subset of patients, but identifying this group remains a challenge. A reasonable approach advocates medical therapy as long as hypertension can be well controlled and there is no progression of kidney disease. The addition of a statin should be considered. Endovascular intervention might be considered in patients with uncontrollable hypertension, progressive kidney disease, or episodic pulmonary edema attributable to the lesion. Angioplasty might also be warranted when progression of stenosis is either demonstrated or is predicted by a constellation of risk factors, including systolic blood pressure greater than 160 mm Hg, advanced age, diabetes mellitus, or high-grade stenosis (more than 60%) at the time of diagnosis. However, multiple studies have failed to identify an overall advantage of stenting over medical management in patients with atherosclerotic renal artery stenosis. The CORAL study utilized a distal capture device to prevent embolization into the kidney, but the conclusion was once again that stenting is not superior to medical therapy (incorporating a statin) in the management of atherosclerotic renal artery stenosis. Although drugs modulating the renin-angiotensin system have improved the success rate of medical therapy of hypertension due to renal artery stenosis, they may trigger hypotension and (usually reversible) kidney dysfunction in individuals with bilateral disease.
4. Primary hyperaldosteronism
Hyperaldosteronism should be considered in people with resistant hypertension, blood pressures consistently greater than 150/100 mm Hg, hypokalemia (although this is often absent), or adrenal incidentaloma, and in those with a family history of hyperaldosteronism. Mild hypernatremia and metabolic alkalosis may also occur. Hypersecretion of aldosterone is estimated to be present in 5–10% of hypertensive patients and, besides noncompliance, is the most common cause of resistant hypertension. The initial screening step is the simultaneous measurement of aldosterone and renin in blood in a morning sample collected after 30 minutes quietly seated. Hyperaldosteronism is suggested when the plasma aldosterone concentration is elevated (normal: 1–16 ng/dL) in association with suppression of plasma renin activity (normal: 1–2.5 ng/mL/h). However, the plasma aldosterone/renin ratio (normal less than 30) is not highly specific as a screening test. This is because renin levels may approach zero, which leads to exponential increases in the plasma aldosterone/renin ratio even when aldosterone levels are normal. Hence, an elevated plasma aldosterone/renin ratio should probably not be taken as evidence of hyperaldosteronism unless the aldosterone level is actually elevated.
During the workup for hyperaldosteronism, an initial plasma aldosterone/renin ratio can be measured while the patient continues taking usual medications. If under these circumstances the ratio proves normal or equivocal, medications that alter renin and aldosterone levels, including ACE inhibitors, angiotensin receptor blockers (ARBs), diuretics, beta-blockers, and clonidine, should be discontinued for 2 weeks before repeating the plasma aldosterone/renin ratio; spironolactone and eplerenone should be held for 4 weeks. Slow-release verapamil and alpha-receptor blockers can be used to control blood pressure during this drug washout period. Patients with a plasma aldosterone level greater than 16 ng/dL and an aldosterone/renin ratio of 30 or more might require further evaluation for primary hyperaldosteronism.
The lesion responsible for hyperaldosteronism is an adrenal adenoma or bilateral adrenal hyperplasia. Approximately 50% of aldosterone-secreting adenomas arise as a consequence of somatic mutations in genes encoding glomerulosa cell membrane ion transporters, with resultant elevation of intracellular calcium concentration.
Hypertension occurs in about 80% of patients with spontaneous Cushing syndrome. Excess glucocorticoid may act through salt and water retention (via mineralocorticoid effects), increased angiotensinogen levels, or permissive effects in the regulation of vascular tone.
Diagnosis and treatment of Cushing syndrome are discussed in Chapter 26.
Pheochromocytomas are uncommon; they are probably found in less than 0.1% of all patients with hypertension and in approximately two individuals per million population. However, autopsy studies indicate that pheochromocytomas are very often undiagnosed in life. The blood pressure elevation caused by the catecholamine excess results mainly from alpha-receptor–mediated vasoconstriction of arterioles, with a contribution from beta-1-receptor–mediated increases in cardiac output and renin release. Chronic vasoconstriction of the arterial and venous beds leads to a reduction in plasma volume and predisposes to postural hypotension. Glucose intolerance develops in some patients. Hypertensive crisis in pheochromocytoma may be precipitated by a variety of drugs, including tricyclic antidepressants, antidopaminergic agents, metoclopramide, and naloxone. The diagnosis and treatment of pheochromocytoma are discussed in Chapter 26.
7. Coarctation of the aorta
This uncommon cause of hypertension is discussed in Chapter 10. Evidence of radial-femoral delay should be sought in all younger patients with hypertension.
8. Hypertension associated with pregnancy
Hypertension occurring de novo or worsening during pregnancy, including preeclampsia and eclampsia, is one of the most common causes of maternal and fetal morbidity and mortality (see Chapter 19). Autoantibodies with the potential to activate the angiotensin II type 1 receptor have been causally implicated in preeclampsia, in resistant hypertension, and in progressive systemic sclerosis.
A small increase in blood pressure occurs in most women taking oral contraceptives. A more significant increase of 8/6 mm Hg systolic/diastolic is noted in about 5% of women, mostly in obese individuals older than age 35 who have been treated for more than 5 years. This is caused by increased hepatic synthesis of angiotensinogen. The lower dose of postmenopausal estrogen does not generally cause hypertension but rather maintains endothelium-mediated vasodilation.
10. Other causes of secondary hypertension
Hypertension has been associated with hypercalcemia, acromegaly, hyperthyroidism, hypothyroidism, baroreceptor denervation, compression of the rostral ventrolateral medulla, and increased intracranial pressure. A number of medications may cause or exacerbate hypertension—most importantly cyclosporine, tacrolimus, angiogenesis inhibitors, and erythrocyte-stimulating agents (such as erythropoietin). Decongestants, NSAIDs, cocaine, and alcohol should also be considered. Over-the-counter products should not be overlooked, eg, a dietary supplement marketed to enhance libido was found to contain yohimbine, an alpha-2–antagonist, which can produce severe rebound hypertension in patients taking clonidine.