• Prehypertension: systolic pressure of 120–139 mm Hg or diastolic pressure of 80–89 mm Hg.
  
• Stage 1 hypertension: systolic pressure of 140–159 mm Hg or diastolic pressure of 90–99 mm Hg.
  
• Stage 2 hypertension: systolic pressure of at least 160 mm Hg or diastolic pressure of at least 100 mm Hg.

Hypertension is a major public health problem in the United States and many countries worldwide. Prevalence of hypertension in the United States remains unchanged in the past decade at 30%, while prevalence of resistant hypertension (failure to achieve blood pressure [BP] control despite three or more medications) has almost doubled in recent years from 16% to 28%. When the risk is calculated over lifetime, the burden of hypertension in middle-aged men and women is enormous. Eight to nine out of 10 normotensive women or men over the age of 55 are expected to develop hypertension in the next 20 years. Thus, complete understanding of basic pathophysiologic mechanisms and treatment strategies is one crucial step in improving hypertension control.

Pathophysiology of primary hypertension is complex and heterogeneous. At least one or more of the mechanisms involved in BP regulation, such as vascular, neural, renal, and hormonal mechanisms, contribute to development of primary hypertension. Accordingly, therapy often requires more than one antihypertensive agent or approach to tackle hypertension in the majority of patients.

Systemic vascular resistance and cardiac output are two major determinants of BP. Thus, augmented peripheral vasoconstriction at the level of resistance vessels may lead to hypertension in the presence of normal cardiac output. More recently, large arterial stiffness has been shown to contribute to elevated systolic BP. In many epidemiologic studies, systolic BP increases with age both in men and women. However, after the fifth decade of life, systolic BP continues to increase while diastolic BP starts to fall, causing the pulse pressure to widen. Normally, elasticity of aorta helps absorb pressure during systole, and the elastic recoil of the aorta helps maintain BP during diastole. The loss of aortic elasticity causes BP to rise excessively during systole and decrease markedly during diastole. Furthermore, the aortic pulse wave travels at much faster speed in the stiff artery, and the reflected wave from the peripheral sites further amplifies the systolic BP in the central aorta. Although diastolic BP is traditionally thought to be the most important predictor of cardiovascular risk, it is an important risk factor only for the younger population. For hypertensive patients above the age of 60, systolic BP and pulse pressures are much more important in predicting long-term cardiovascular outcomes.

Neural control of BP also plays an important role in development of hypertension. Overactivity of the sympathetic nervous system has been identified in patients with uncomplicated essential hypertension, and many conditions predispose to hypertension such as obesity, renal failure, and obstructive sleep apnea. Sympathetic overactivity contributes to hypertension by stimulating increase in cardiac output while producing peripheral vasoconstriction. Activation of β1-adrenergic receptor by norepinephrine released from the sympathetic nerve terminals further increases BP by increasing renin release, causing renal sodium retention. The major hormones that contribute to hypertension include the renin-angiotensin-aldosterone system (RAAS), which will be discussed later in the section on secondary causes of hypertension. Although RAAS triggers hypertension by promoting renal sodium absorption, a large body of evidence from animal experiments suggests that its direct action on the vascular system and the central nervous system further augments hypertension.

BP Measurement

Proper BP measurement is essential in the diagnosis and treatment of hypertension. BP monitoring should be done both at home and in the clinic.

Clinic BP

In the clinical setting, BP measurement should be performed after patients are sitting quietly for at least 5 minutes with the arm supported at the heart level. The bladder of the cuff should encircle > 80% of the arm, and the width should be about 40% of the arm length. Medical personnel who perform the measurement should avoid talking to the patients during BP measurement because mental stimulation may inadvertently increase BP up to 10–15 mm Hg. Cuff should be inflated 20 mm Hg above systolic BP before deflation, and a minimum of two readings should be obtained at an interval of at least 1 minute. If BP differs by more than 5 mm Hg between the two readings, an additional one or two readings should be taken. During the initial visit, BP should be taken from both arms to exclude subtle stenosis in the subclavian or brachial artery, which could lead to underestimation of actual BP and undertreatment of hypertension. In patients with early onset of hypertension prior to the age of 40, BP should also be obtained from at least one leg to screen for aortic coarctation. In elderly patients and patients with diabetes mellitus or other conditions that predispose to autonomic failure such as Parkinson disease, BP should also be taken after 3 minutes of standing to exclude presence of orthostatic hypotension.

Home and Ambulatory BP Monitoring

Home BP measurement should be encouraged in all hypertensive patients to guide treatment because 20–40% of hypertensive subjects have elevated clinic BP with normal BP outside the doctor’s office. This phenomenon, known as the white-coat effect (WCE), is more common in older patients, particularly in women with isolated systolic hypertension or diabetes. Accordingly, when home and clinic BP readings provide contradictory results, ambulatory BP monitoring should be considered to verify adequacy of BP control.

It is important to recognize that WCE is not the same as white-coat hypertension (WCH), because the latter is only limited to elevated office BP with normal awake ambulatory BP without any antihypertensive treatment. WCH is not associated with increased cardiovascular risks when compared to the population with normal BP both at home and in the clinic. In contrast, hypertensive patients with WCE during drug treatment experience increased cardiovascular events compared to untreated normotensive controls, but at the same risk observed in patients who achieve BP control both in the clinic and out of office with treatment (ie, treated normalized hypertension).

More recently, another subset of hypertensive patients with clinic BP under 140/90 mm Hg but who have elevated out-of-office BP has been recognized. This condition, termed masked hypertension, has been identified in 20–45% of patients with hypertension. Interestingly, patients with masked hypertension experience increased cardiovascular complications similar to patients with sustained hypertension. Whether treatment of masked hypertension will improve cardiovascular outcomes remains unknown.

Symptoms & Signs

Hypertension is well known as a silent killer because the majority of patients remain asymptomatic until development of target organ damage. However, some patients may have symptoms that could be related to a secondary cause of hypertension. Snoring and daytime somnolence may signify presence of obstructive sleep apnea, whereas episodes of palpitation and paroxysmal hypertension may suggest pheochromocytoma. Presence of muscle weakness, polyuria, and polydipsia might be related to hypokalemia from primary aldosteronism or hypercortisolism. Other symptoms of target organ damage and other coronary risk factors should be assessed because they help to define BP threshold for treatment of hypertension. History taking should also include the onset of hypertension and prior antihypertensive treatment as well as history of side effects from previous medications. The concomitant use of other prescription or nonprescription drugs, such as herbal products, nonsteroidal anti-inflammatory drugs, or decongestant use, which can directly increase BP or interfere with efficacy of antihypertensive medications, should be obtained. In young premenopausal women, method of contraception should be documented because certain antihypertensive medications, such as angiotensin-converting enzyme inhibitors or angiotensin receptor blockers, are teratogenic or fetotoxic. Furthermore, oral contraceptives could cause hypertension in a small number of patients, although the absolute risk is lower than 0.1% with low-dose estrogen preparation. Detailed family history with specific attention to both hypertension and stroke should be obtained because early stroke could be a presenting feature in certain genetic forms of hypertension.

High sodium intake is also a major contributor for uncontrolled hypertension, and detailed dietary assessment should be obtained in patients who fail to achieve BP goals despite multiple medications. Nonadherence to medications is the major cause of apparently resistant hypertension and should be considered in patients on a complex multidrug regimen. Questions related to adherence should not be asked in the manner that sounds judgmental or critical to the patients; otherwise, accurate assessment may not be obtained. Instead of asking, “Do you take medications regularly as the doctors prescribe?”, asking patients if they feel that taking multiple medications is difficult or if they have forgotten to take medications in the past 7 days is more likely to uncover a history of nonadherence.

Physical Examination

Physical examination should focus on signs of target organ damage such as presence of volume overload, laterally displaced apical impulses, S3 and/or S4 gallops, and hypertensive retinopathy. Particular attention should be paid to physical signs that may indicate underlying secondary hypertension. Abdominal bruit may indicate presence of renal artery stenosis. Truncal obesity, dorsocervical fat pads, hirsutism, and abdominal striae may represent cortisol excess. BP gradient between arms and legs and femoral-radial pulse delay may signify coarctation of aorta.

Diagnostic Studies

For patients with mild uncomplicated hypertension, serum electrolytes, urinalysis, and complete blood cell count should be obtained during the initial visit to assess renal function and exclude subtle target organ damage. Electrocardiogram should be obtained to screen for left ventricular hypertrophy and presence of conduction system disturbances, which may prohibit the use of β-blockers or nondihydropyridine calcium channel blockers. Echocardiography should be limited to patients with symptoms and signs of congestive heart failure or patients with syncope to exclude presence of dynamic left ventricular outflow tract obstruction, which has been identified in a subset of hypertensive patients with concentric left ventricular hypertrophy. Fasting lipid panel and plasma glucose should also be obtained to assess overall cardiovascular risks. Microalbuminuria should be tested in diabetic patients and patients with severe hypertension.

In the majority of patients with hypertension, specific etiology cannot be identified, and patients are often labeled as having essential or primary hypertension. However, in approximately 5% of unselected patients with hypertension and 10–20% of all resistant hypertensive cases, causes of hypertension are identifiable and/or potentially reversible. Screening for secondary causes of hypertension is not indicated in every patient with hypertension. Indications for additional workup are as follows:

• Abrupt onset after the age of 55 or before the age of 30
  
• Accelerated or malignant hypertension with grade 3–4 retinopathy
  
• Previously, but not presently, controlled
  
• Poorly controlled hypertension on three or more drugs
  
• Recurrent flash pulmonary edema
  
• Hypertension with unexplained renal insufficiency
  
• Suspected clinical features of secondary causes such as hypokalemia, renal bruits, and truncal obesity

Common secondary causes of resistant hypertension include obstructive sleep apnea, primary aldosteronism, renal parenchymal diseases, and renal artery stenosis. Pheochromocytoma and other endocrine disorders are much less common causes of resistant hypertension.

Obstructive Sleep Apnea

Obstructive sleep apnea (OSA) is a well-established independent risk factor for development of hypertension. Because the majority of the population in the United States is overweight or obese, OSA is now a common condition, affecting 10–20% of the population in the United States. Prevalence of OSA in drug-resistant hypertension is much greater, as high as 83% in some studies. Activation of the sympathetic nervous system via activation of chemoreceptor via repetitive hypoxia and hypercapnia is thought to play an important role in the pathogenesis of hypertension. Patients with a history of loud snoring, insomnia, and/or daytime fatigue should undergo polysomnography. Treatment with continuous positive airway pressure (CPAP) has been shown to reduce BP in hypertensive patients with OSA. However, long-term compliance is very poor; less than 50% of patients still continue to use CPAP after 6 months. Therefore, target BP is rarely achieved with CPAP alone, and further adjustment of antihypertensive medications is often needed to reach target goals.

Primary Aldosteronism

Aldosterone excess, either from idiopathic bilateral adrenal hyperplasia or aldosterone-producing adenoma, is a common cause of resistant hypertension. Primary aldosteronism (PA) has been identified in 5–10% of unselected patients with hypertension in the primary care setting and up to 20% of patients with resistant hypertension referred to a hypertension clinic or a tertiary care center. Aldosterone induces hypertension not only by increasing renal sodium retention, but also by activation of the sympathetic nervous system. Patients with hyperaldosteronism experienced higher cardiovascular event rates than those with essential hypertension, which is out of proportion to the degree of BP elevation. This is likely to be related to direct cardiovascular toxicity of aldosterone. To screen for PA, plasma renin activity (PRA) or levels and serum aldosterone levels should be obtained. However, the screening test should be performed after discontinuation of thiazide diuretics, direct renin inhibitors, angiotensin-converting enzyme inhibitors (ACEIs), and angiotensin receptor blockers (ARBs) for 2–3 weeks and discontinuation of aldosterone antagonists for at least 6 weeks. During the workup period, patients need to be on other antihypertensive agents such as α-blockers or calcium channel blockers. If needed, addition of β-blockers or central sympatholytic drugs may be added, but this may potentially reduce PRA. Patients who are found to have suppressed renin levels or activity in the presence of elevated serum aldosterone levels of 15 ng/dL or greater should undergo a salt loading test or be referred to hypertension specialists. Patients who have insuppressible aldosterone levels after salt loading should undergo adrenal vein sampling because imaging of adrenal glands is not reliable in separating patients with idiopathic hyperplasia from those with aldosterone-producing adenoma. Treatment includes surgical resection of tumor for patients with aldosterone-producing adenoma, which can cure hypertension in 20–60% of patients, depending on duration of hypertension and presence of target organ complications. Mineralocorticoid receptor antagonists (spironolactone or eplerenone) should be used in patients with bilateral hyperplasia or patients with unilateral adenoma in whom surgical risks are prohibitive.

Renal Parenchymal Disease

Renal parenchymal disease could be a cause or a consequence of hypertension. Hypertension is very common in chronic kidney disease (CKD) but is much more difficult to control. Despite requirement for larger numbers of antihypertensive medications, the hypertension control rate in the United States in CKD patients is less than 30% compared with 50% in non-CKD patients. Hypertension related to renal parenchymal disease has traditionally been viewed as being largely volume dependent, due to the failing kidney’s inability to excrete salt and water. However, increased systemic vascular resistance from overactivation of the sympathetic nervous system has also been identified in the majority of patients.

Renovascular Hypertension

Renovascular hypertension is another common cause of secondary hypertension, accounting for 5–7% of hypertension in patients over the age of 60. Atherosclerosis is the major form of renal artery pathology in the elderly, as fibromuscular dysplasia is seen predominantly in young adults. Screening for renovascular hypertension should be considered in patients with (1) onset of hypertension at < 30 years of age or abrupt onset of hypertension after 55 years of age; (2) accelerated or malignant hypertension; (3) unexplained atrophic kidney or size discrepancy of more than 1.5 cm between each kidney; (4) sudden, unexplained pulmonary edema; (5) unexplained renal dysfunction, including individuals starting renal replacement therapy; and (6) development of new azotemia or worsening renal function after administration of an ACEI or ARB. Imaging of renal arteries with computed tomography (CT) angiography or magnetic resonance angiography should also be obtained in patients with suspected renal artery stenosis. Unfortunately, no currently available invasive or noninvasive studies are sufficiently sensitive or specific in assessing functional significance of a given stenotic lesion or in predicting BP pressure control after revascularization. Renal artery revascularization leads to significant and sustained reduction in BP in patients with fibromuscular dysplasia, but effects on BP control in patients with atherosclerotic renal artery stenosis are much less consistent. Therefore, revascularization should be considered in most patients with fibromuscular dysplasia and selected patients with atherosclerotic renal artery stenosis plus one or more of the following features: (1) bilateral disease or stenosis of the unilateral functioning kidney; (2) rapid decline in renal function; (3) resistant hypertension despite three or more antihypertensive medications; or (4) recurrent pulmonary edema.

Pheochromocytoma

Although a screening test for pheochromocytoma is often done in patients with labile hypertension or resistant hypertension, it accounts for < 1% of patients with unselected hypertension. Patients may present with paroxysmal hypertension, palpitation from sinus tachycardia or supraventricular arrhythmia, and panic/anxiety sensation from catecholamine excess. Myocardial infarction, congestive heart failure, and Takotsubo-like cardiomyopathy may be the presenting symptoms, along with hypertension in some patients. Diagnosis requires demonstration of elevated plasma/urinary metanephrines (metanephrine and/or normetanephrine) above 3–4 times the upper limit of normal without other identifiable causes. Patients with paraganglioma or extra-adrenal tumor may have isolated elevation in plasma dopamine, and thus, a plasma catecholamines panel (epinephrine, norepinephrine, and dopamine) should be obtained in patients with suspected pheochromocytoma in the absence of adrenal mass. Borderline elevation in plasma metanephrines or catecholamines is common in hypertensive patients with underlying conditions that cause sympathetic overactivity such as OSA, congestive heart failure, or CKD. These levels may return to normal after correction of the underlying problems. A clonidine suppression test should be obtained in patients with persistent but borderline (less than twofold) elevation in plasma metanephrines or catecholamines to confirm diagnosis. CT or magnetic resonance imaging (MRI) of the abdomen should be used to localize tumor after biochemical confirmation. Metaiodobenzylguanidine scan should be used when CT or MRI fails to reveal tumor.