Chronic hypertension

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor-In-Chief: Yazan Daaboul, Serge Korjian, Taylor Palmieri

Arterial blood pressure (BP) is a measure of the force exerted by the blood on the arterial walls. It is the function of both the cardiac output (CO) and the systemic vascular resistance (SVR). The maintenance of a normal blood pressure value is crucial to ensure appropriate blood circulation throughout the cardiovascular system. Arterial BP is considered one of the most important vital signs in the clinical setting.

Hypertension (HTN) is generally defined as an elevated systolic blood pressure (SBP) ≥ 140 mmHg and/or diastolic blood pressure (DBP) ≥ 90 mmHg at each of two or more visits.^[1] However, target BP values are set at a lower threshold in specific populations, such as diabetics and subjects with significant proteinuria and other renal diseases.

In 2004, the Seventh Report of the Joint National Committee (JNC 7) classified blood pressure values into 4 categories: normal, prehypertension, stage I hypertension, and stage II hypertension.^[1] In 2007, the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) classified blood pressure into 7 categories.^[2] This classification remained unchanged in the 2013 ESH/ESC classification.^[3] The ESH/ESC classification excludes JNC 7’s pre-hypertension category, but includes 3 different grades of hypertension in contrast to JNC 7’s two-stage classification of hypertension.

Although the pathophysiology of secondary hypertension has been outlined, there is still much debate about the true pathogenesis of primary (essential) hypertension. It is now conceded that hypertension is caused by multiple genetic and environmental factors with varying roles between individuals.^[1]

The prevalence of primary hypertension is much more common than secondary hypertension, where only 5-10% of hypertension cases are diagnosed as secondary hypertension^[4]. When a full evaluation yields no clear etiology for the hypertension, the latter is thus identified as primary or essential hypertension. It is considered a chronic disease that requires lifetime treatment and management. If an underlying disease is identifiable as the cause of hypertension, the latter is called secondary hypertension. Causes of secondary hypertension include obstructive sleep apnea, hyperaldosteronism, kidney diseases, excess catecholamines, coarctation, cushing syndrome among other diseases.

Before the diagnosis of primary (essential) hypertension, secondary causes of hypertension should be ruled out. Additionally, other conditions that may elevate BP include: White coat hypertension, masked hypertension, and pseudohypertension.

Hypertension is considered an epidemic worldwide. It continues to be one of the most common diseases. In October 2013, CDC data from the 2011-2012 National Health And Nutrition Examination Survey (NHANES) demonstrated that the overall age-adjusted prevalence of hypertension among U.S. adults aged 18 and older was 29.1%.^[5] Similar surveys conducted in Europe estimated the prevalence of hypertension to be 44%.^[6] The prevalence of hypertension increases among older patients and among non-Hispanic black patients, but is similar in both genders.

Established risk factors for essential hypertension include old age, male gender, African American ethnicity, dyslipidemia, diabetes mellitus, smoking, increased salt intake in diet, obesity, and sedentary lifestyle. Studies are currently assessing the role of new emerging factors that might be considered as new risk factors for the development of hypertension.

The age to begin screening for hypertension varies between 13-20 years of age, according to different authorities. Generally, hypertension is defined as SBP > 140 mmHg and/or DBP > 90 mmHg. In specific populations, however, routine follow-up target BP may be different; and initiation of treatment may be considered at even lower BP values than those considered for the normal population.

Hypertension is a well-established risk factor for several serious diseases. Chronic uncontrolled hypertension can be complicated by target organ damage. Most common damaged organs include the cardiovascular system, the brain, the kidneys, and the retina. Even moderate elevation of arterial blood pressure leads to a shortened life expectancy. The risk of cardiovascular complications is significantly increased even with small incremental increases in blood pressures. Blood pressure values should never be regarded as distinct stages or grades, but rather as a continuum of risk. Ultimately, hypertension should never be evaluated in isolation as a cardiovascular risk; it should always be integrated with other risk factors for the decision of optimal management and how aggressive the lowering of blood pressure values must reach.

Thorough history-taking is crucial for the diagnosis and assessment of hypertension. Not only should history-taking be targeted to identify symptoms consistent with high blood pressure, but more importantly it should address risk factors and target organ damage. History-taking alone may be sufficient to diagnose some causes of secondary hypertension, such as drug-induced hypertension, and may guide healthcare providers towards individualized work-up and tailored management.

Physical examination of a patient with isolated hypertension in the absence of target organ damage is usually unimpressive with the exception of high blood pressure. Healthcare providers must nonetheless search thoroughly for findings on physical examination that might suggest target organ damage and associated clinical conditions.

The use of a sphygmomanometer in the clinic to measure blood pressure is the most accurate technique to diagnose hypertension. Blood pressure measurements must be performed appropriately according to a standardized technique that involves adequate device and cuff choice and comfortable positions. Sources of error, involving the sphygmomanometer, the patient, and the technique itself must also be considered and avoided. Other techniques for diagnosis, such as ambulatory and self blood pressure measurements may also be helpful, particularly for the follow-up of patients with hypertension.

Laboratory studies are often undertaken to identify possible causes of secondary hypertension, and seek evidence for end-organ damage to the heart itself or the eyes (retina) and kidneys. Diabetes and raised cholesterol levels being additional risk factors for the development of cardiovascular disease are also tested for as they will also require management.

An electrocardiogram (EKG/ECG) is performed to evaluate for the presence of left ventricular hypertrophy or silent myocardial infarction.

On 2D echocardiography, signs of LVH and heart failure are mostly seen in hypertensive patients.

A chest X-ray may show signs of congestive heart failure, such as cardiomegaly, pulmonary edema, and Kirley B lines.

Hypertension is the most common primary diagnosis in America.^[7] Initial treatment for hypertension generally involves lifestyle modifications (nonpharmacologic therapy), which is also critical for prevention of the disease. Modifications encouraged for hypertensive patients include moderate dietary salt restriction, maintain body weight or weight reduction in obese patients, increased intake of fruits and vegetables and low-fat dairy products, limited alcohol intake, and regular aerobic exercise. Although effective control of blood pressure can be achieved in most patients with hypertension, the majority will require 2 or more antihypertensive drugs.^[7]

Medical therapy is considered the most efficient means for the reduction of both systolic and diastolic blood pressure values in patients with hypertension. The two most important approaches for pharmacologic therapy in hypertension are proposed by JNC-7 guidelines in 2004 and more recently by the ESH/ESC guidelines in 2013. With the emergence of recent data, a major shift from the classical use of thiazide-type diuretics as first line therapy for patients with isolated essential hypertension has occurred. Recent guidelines currently encourage the use of any anti-hypertensive agent for isolated essential hypertension. Nonetheless, various conditions warrant the use of specific classes that have been found to have compelling indications in certain diseases and among specific patient populations.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor-In-Chief: Yazan Daaboul, Serge Korjian, Usama Talib, BSc, MD [2]

In 2004, the Seventh Report of the Joint National Committee (JNC 7) classified blood pressure values into 4 categories: normal, prehypertension, stage I hypertension, and stage II hypertension.^[1] In 2007, the Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC) classified blood pressure into 7 categories.^[2] This classification remained unchanged in the 2013 ESH/ESC classification.^[3] The ESH/ESC classification excludes JNC 7’s pre-hypertension category, but includes 3 different grades of hypertension in contrast to JNC 7’s two-stage classification of hypertension.

JNC8(2014) proposes no changes in the blood pressure classification given in JNC7(2004). According to the Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure^[4] blood pressure values were classified as follows:

In Europe, a different classification of blood pressure was introduced in 2007 by The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). According to the 2013 Guidelines for the Management of Arterial Hypertension, blood pressure values were classified as follows: ^[2]

Abbreviations:

ACEI, angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; CCB, calcium channel blocker; CKD, chronic kidney disease; CVD, cardiovascular disease; JNC, Joint National Committee;

RCT, randomized controlled trial.

Adopted from 2014 Evidence-Based Guideline for the Management of High Blood Pressure in Adults. Report From the Panel Members Appointed to the Eighth Joint National Committee (JNC 8).^[5]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor-In-Chief:Yazan Daaboul, Serge Korjian

Although the pathophysiology of secondary hypertension has been outlined, there is still much debate about the true pathogenesis of primary (essential) hypertension. It is now conceded that hypertension is caused by multiple genetic and environmental factors with varying roles between individuals.^[1]

Below is a figure summarizing the pathophysiology of essential hypertension:

• Epidemiological studies suggest that genetic factors account for 30% of blood pressure variations in populations.^[2][3]
• The prevalence of hypertension in patients with family history is almost double than those with no family history.
• Examples of genetic hypertension where specific genetic mutations were identified include, but are not limited to, some forms of primary hyperaldosteronism, pseudohyperaldosteronism, Liddle Syndrome, and syndrome of apparent mineralocorticoid excess.^[1]
• Gene therapy may be a promising novel therapeutic approach to treat hypertension.^[4]

• Patients with hypertension usually have an increased peripheral vascular resistance, which is determined largely by the arterioles with an associated increase in the thickness of smooth muscle cells.
• Intracellular calcium concentrations are increased, contributing to vasoconstriction.
• This vasoconstriction is multifactorial, but the final common pathway is ultimately linked to a sustained increase in intracellular calcium.
• Prolonged constriction leads to a structural damage to arterioles consequently an elevation in blood pressure.

• Notably, the cardiac output in hypertensive patients is generally normal. With age, the decreased compliance of central arteries predominates, causing systolic hypertension in the elderly.

• While the systemic role of RAAS shows little evidence of contribution, local release of renin-angiotensin in the kidneys, heart, and arteries seems to play a much more important role in the pathogenesis of hypertension.^[2]
• Angiotensin II constricts resistance vessels, directly stimulates renal sodium reabsorption, activates aldosterone to increase sodium reabsorption, helps release antidiuretic hormone (ADH), and promotes sympathetic activity of the autonomic nervous system.^[4]
• Aldosterone increases sodium reabsorption by increasing the quantity of open sodium channels in the luminal membrane of the principal cells of the collecting tubules in the kidney.
• Furthermore, aldosterone has a non-genomic effect in increasing fibrosis, collagen deposition, inflammation, and cardiovascular remodeling.^[5]

• The role of sympathetic nervous system in hypertension remains controversial.
• The effectiveness of beta blockers and alpha blockers as anti-hypertensive agents validates that sympathetic nervous system is, at least partially, involved in hypertension.
• There is ample evidence that norepinephrine concentration and rate of norepinephrine spillover from sympathetic nerve terminals are markedly elevated in patients with essential hypertension.^[6]
• Humoral, metabolic, reflex, and central mechanisms of adrenergic activation are all contributory to characterizing hypertension.^[7]

• Pressure natriuresis is the impact of the arterial pressure head on sodium excretion. Experimental evidence has shown that pressure natriuresis is impaired in hypertension even without significant variations in renal blood flow or changes in glomerular filtration rate (GFR).
• In non-hypertensive patients, the increased blood pressure is countered by activation of the renal pressure natriuresis to allow maintenance of normal sodium balance and blood pressure. In hypertensive patients, however, pressure natriuresis seems to be permanently set at a higher BP threshold, whereby an inappropriately normal sodium excretion rate is maintained despite the high blood pressure values.
• Renal damage follows via loss of nephron function leading to a vicious circle of further impairment of pressure natriuresis and elevated BP.

• The vascular endothelium plays an important role in releasing vasodilators such as nitric oxide and endothelin.
• Endothelial cell dysfunction and permanent endothelial structural changes may play a role at least in part in the irreversible changes of the vascular bed in chronic hypertension.
• Furthermore, renal microvascular disease is currently hypothesized as an important factor leading to the development of hypertension.^[8]
  • Increased role of vasoconstrive substances:
    • Endothelin: Potent local vasoactive peptide with vasoconstrictor properties. Development of endothelin receptor antagonist for the treatment of systemic hypertension has been discontinued because of teratogenicity, testicular atrophy and hepatotoxicity.^[4]
    • Ouabain: Steroid-like substance that plays a role in sodium and calcium transport.^[2]
  • Defect in vasodilatory substances:
    • Nitric oxide: Potent vasodilator, whose role is diminished in hypertension.^[4]
    • Bradykinin: Potent vasodilator, inhibited by RAAS in hypertensive patients.^[2]
    • Atrial natriuretic peptide (ANP): Hormone secreted by cardiac atria in response to atrial stretch by increased blood volume. Physiologically, it induces natriuresis to decrease blood volume.^[2][4]

• Obesity and metabolic syndrome play a major indirect role in the pathogenesis of hypertension by increasing renal tubular reabsorption, impairment of pressure natriuresis, and activation of sympathetic and RAAS. ^[9]
• Acute emotional stress can cause an immediate, but transient, increase in blood pressure. Although chronic stress, per se, has not been shown to cause hypertension, it has been hypothesized that chronic stress may contribute at least in part or may play an additive role in the context of other risk factors.^[10]
• It remains controversial as to whether depression develops secondary to hypertension or alternatively if it causes hypertension. It is also unclear if antidepressant medications contribute to hypertension in depression.^[11]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor-In-Chief: Yazan Daaboul, Serge Korjian

Secondary hypertension is only responsible for 5% of cases of chronic hypertension whereas primary hypertension (also known as essential hypertension where no identifiable cause is identified) is responsible for 95% of cases.^[1] Common causes of secondary hypertension include obstructive sleep apnea, hyperaldosteronism, kidney diseases, excess catecholamines, coarctation of the arota, cushing syndrome among other diseases.

When a full evaluation yields no clear etiology for the elevated blood pressure, the latter is identified as primary hypertension. Primary or essential hypertension is considered a chronic disease requiring lifelong treatment and follow-up. If an underlying disease is identifiable as the cause, secondary hypertension is diagnosed. Secondary hypertension is a potentially curable condition in most cases.^[2] In comparison, the prevalence of primary hypertension is significantly higher than secondary hypertension, where only 5-10% of patients have a secondary etiology^[1] Classically, the common age range for the presentation of primary hypertension is 30 to 55 years^[3], but age alone should never warrant a diagnosis of primary hypertension without a proper work-up.

It is not cost effective to evaluate all hypertensive patients for secondary hypertension. ^[2] There are certain clinical scenarios, though, that should prompt further evaluation.

Primary hypertension generally first occurs between 30 and 55 years. Onset of hypertension before puberty and before age 30 in the absence of risk factors should raise suspicion for secondary hypertension.

Common causes of secondary hypertension are often memorized by the mnemonic ABCDE:

An accurate assessment and re-assessment of blood pressures is an essential first step when a patient presents with high blood pressure. The accuracy of home BP measurements should be confirmed by calibrating the patient’s measurement technique with that obtained in the doctor’s office.

Obstructive sleep apnea (OSA) is a respiratory disease characterized by repetitive narrowing or collapse of the upper airway during sleep^[6] leading to apnea, hypopnea, and a nocturnal decrease in oxygen tension.^[7] Symptoms and signs that might suggest OSA include daytime somnolence, obesity, snoring, and morning headache.^[8] Patients with sleep apnea also tend to have drug resistant hypertension and may retain sodium. Diagnosis is made by polysomnography. Treatment relies on maintaining airway patency at night and includes, among others, the use of continuous positive airway pressure (CPAP).

Primary (hyporeninemic) and secondary (hyperreninemic) hyperaldosteronism result in excess sodium and water retention with slight hypernatremia along with excretion of potassium resulting in hypokalemia in one half of patients.^[9] Common symptoms of hyperaldosteronism include drug resistant hypertension, fatigue, headache, intermittent paralysis, muscle weakness, and numbness. The most common cause of primary hyperaldosteronism is an aldosterone-producing adenoma (an “aldosteronoma“), i.e. Conn’s Syndrome. Secondary hyperaldosteronism is due to an overactive RAAS, as seen in renin-secreting tumors, renal artery stenosis, pheochromocytoma, and other syndromes. The diagnosis is made by measuring the ratio of plasma aldosterone to plasma renin activity.^[10] It is elevated in primary hyperaldosteronism and decreased/normal with elevated renin in secondary hyperaldosteronism. It should be noted that obesity can also cause aldosterone levels to be elevated. Treatment depends upon the underlying etiology: surgery to resect an adenoma causing primary hyperaldosteronism and spironolactone, an aldosterone antagonist to treat secondary hyperaldosteronism.

Renovascular hypertension is due to decreased blood supply to the kidneys secondary to renal artery stenosis and it is the most common correctable cause of secondary hypertension. Atherosclerosis of the renal artery (renal artery stenosis) in older patients above 50 years of age^[11] and fibromuscular dysplasia in younger patients are the most common etiologies.

According to the 2013 ACC/AHA Guidelines for the Management of PAD^[12], diagnostic work-up for renal artery stenosis is indicated in the following conditions:

• Hypertension of any stage before the age of 30
• Stage II hypertension (severe hypertension systolic blood pressure > 180 mm Hg or diastolic blood pressure > 120 mm Hg) in patients older than 55 years. If only mild hypertension is present, then renal artery stenosis is the underlying cause in only 1% of patients ^[13], but if the blood pressure is markedly elevated, then the risk of renal artery stenosis goes up 10 to 50 fold.
• Accelerated condition of previously controlled hypertension
• Resistant hypertension
• Malignant hypertension
• New azotemia (50% rise in creatinine that is sustained) within one week after administration of an Angiotensin Converting Enzyme (ACE)inhibitor or ARB
• Unexplained atrophic kidney or asymmetric kidneys that differ by > 1.5 cm. If the kidney is < 9 cm in size, there is a 75% chance that renal artery stenosis is present.
• Severe hypertension, impaired renal function, and recurrent flash pulmonary edema

• Unexplained renal failure including patients starting renal replacement therapy

• Presence of multi vessel CAD and no clinical clues of ARAS or PAD
• Unexplained CHF or refractory angina

• Severe hypertension in the presence of polyvascular disease (coronary artery disease or peripheral arterial disease)
• A unilateral systolic-diastolic abdominal bruit. Although a bruit is infrequent in documented renal artery stenosis (the sensitivity is only 40% percent) if it is auscultated, it is associated with a very high specificity of 99%.^[14]
• The association of race with renal artery stenosis is not clear. Reports that it is observed more often in white patients may be due to reporting bias.^[15]

Definitive diagnosis is made by magnetic resonance angiography (MRA) and renal arteriography.^[16] Other diagnostic methods include duplex ultrasound scanning^[17], and captopril-augmented radio-isotopic renogram^[18]. Treatment is based upon the underlying etiology.

Renal parenchymal disease blunts the kidney’s physiological ability to maintain appropriate blood pressure. Notably, hypertension is both a cause and a consequence of renal parenchymal disease; the two are closely associated and may potentiate each other.^[19] The diagnosis is made by demonstration of a decreased GFR. The mechanisms by which renal parenchymal disease leads to the development of hypertension are numerous and include activation of the local RAAS, release of vasoconstrictor cytokines, and inappropriate natriuresis for any given blood pressure.

Catecholamine excess occurs in several non-disease states, such as acute stress, the administration of medications with sympathomimetic activity, and illicit drug use such as cocaine and these conditions can be ruled out by thorough history taking. Pheochromocytoma, a tumor of the adrenal gland leading to excess secretion of epinephrine, should be considered in young patients with the triad of intermittent hypertensive episodes causing headache, sweating, and tachycardia. However, pheochromocytoma in older adults or a presentation with sustained hypertension is not uncommon. Diagnostic studies to evaluate pheochromocytoma include measurement of plasma free metanephrines and urinary fractionated metanephrines. The diagnostic value of plasma and urinary catecholamines is of limited value given the very short half-life of catecholamines. Treatment is usually by surgical resection of the secreting tumor with appropriate adrenergic blockade.^[20]

Coarctation of the aorta is a congenital heart defect, caused by a narrowing in a segment of the ascending or descending aorta. The diagnosis is often made in a neonate or an infant as a result of a weak femoral pulse or asymmetric brisk brachial pulses. Hypertension occurs as a result of a reduction in the effective circulation at the level of the kidneys which respond by increasing plasma volume which in turn causes hypertension in the upper extremities. Diagnosis is by CT angiography, but can also be made in neonates and infants by ultrasound of the heart and the great vessels. Definitive treatment is by surgical correction and or stenting.

Cushing’s syndrome is an endocrine disorder caused by prolonged exposure to high endogenous or exogenous cortisol levels. Hypertension in Cushing’s syndrome has been classically attributed to the mineralocorticoid effects of cortisol. It manifests as an absent fall of nocturnal blood pressure physiologically seen in normotensive subjects with associated disturbance in the adrenocorticotropic hormone-glucocorticoid system.^[21] Symptoms of Cushing’s syndrome include rapid weight gain, particularly of the trunk and face with sparing of the limbs (central obesity), a round face often referred to as a “moon face” along with central obesity, excess sweating, proximal muscle weakness, ecchymoses, insomnia, reduced libido, impotence, amenorrhoea, infertility and psychological disturbances, ranging from euphoria to psychosis. Depression and anxiety.^[22] Although an ideal diagnostic test is not considered yet available, clinicians often assess the 24-hour urinary cortisol excretion^[23], a low-dose dexamethasone suppression test^[24], late evening serum or salivary cortisol^[25], and a CRH a following a dexamethasone suppression test to establish the diagnosis.^[26]

An extensive list of drugs can be associated with hypertension. The most common agents include immunosuppressive agents, non-steroidal anti-inflammatory drugs, oral contraceptive pills, some weight loss agents, stimulants, monoamine oxidase inhibitors, triptans, ergotamines, and sympathomimetics.^[1]

In addition to the association of obesity with hypertension, the 2001 study “Effects on Blood Pressure of Reduced Dietary Sodium and the Dietary Approaches to Stop Hypertension (DASH) Diet” concluded that a high sodium diet above the recommended 100 mmol per day (2.4 g of sodium or 6 g of sodium chloride salt) is associated with hypertension. As a result, reduction of sodium levels below 100 mmol per day and following the DASH diet (rich in vegetables, fruits, with low-fat dairy products) can significantly lower BP.^[27] Ingestion of excessive amounts of liquorice can lead to elevation in the blood pressure.

Elevated erythropoietin is typically seen in COPD patients who have functional anemia due to chronic hypoxia and in hematologic disorders such as polycythemia. The pathogenesis of erythropoietin-induced hypertension includes increased hematocrit and blood viscosity, altered sensitivity to vasopressors, dysregulated vasodilatory factors, and vascular cell growth causing arterial remodeling and changes in arterial smooth musculature.^[28] Diagnosis and treatment are etiology-dependent.

In addition to the more common endocrine causes of hypertension such as hyperaldosteronism, Cushing’s syndrome, and pheochromocytoma, several other endocrine changes can cause hypertension. Both hypothyroidism and hyperthyroidism can cause hypertension by volume retention and by increased cardiac output, respectively. Also, hyperparathyroidism and hypovitaminosis D can cause hypertension due to poorly understood mechanisms, where parathyroidectomy seems to significantly decrease blood pressure in patients with parathyroid disease and elevated BP.^[29] Acromegaly can also be a cause of hypertension.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor-In-Chief: Yazan Daaboul, Serge Korjian, Taylor Palmieri

Before the diagnosis of primary (essential) hypertension is established with certainty, secondary causes of hypertension (secondary hypertension) should be considered as well as other conditions that may elevate the blood pressure which include white coat hypertension, masked hypertension, and pseudohypertension.

Although it is not practical to rule out secondary hypertension in every hypertensive patient, secondary hypertension should be considered if there is early onset of hypertension before the age of 30, if there is the abrupt onset of hypertension, if there rapid progression of hypertension, and if there is a hypertensive urgency or hypertensive emergency. The evaluation of secondary hypertension is discussed in detail here.

White coat hypertension, more commonly known as white coat syndrome, is a phenomenon in which patients exhibit elevated blood pressure in a clinical setting but not in other settings.^[1] The prevalence of white coat hypertension is approximately 13%.^[2] Risk factors for white coat hypertension in observational studies include age, female sex, and being a non-smoker. The higher the blood pressure in the clinical setting, the lower the probability of white coat hypertension.^[1] Ambulatory blood pressure monitoring and patient self-measurement using a home blood pressure monitoring device are being increasingly used to differentiate patients with white coat hypertension from patients with true hypertension. Ambulatory monitoring has been found to be a more practical and reliable method in detecting patients with white coat hypertension and for the prediction of target organ damage. The 2013 ESC/ESH recommendations recommend that white coat hypertension be confirmed within 3-6 months of initial diagnosis and that close follow-up and periodic out-of-office BP measurements be obtained.^[1] The treatment of white coat hypertension remains controversial.^[3] Finally, the risk of target organ damage and prognosis among patients with white coat hypertension is still unknown. Although white coat hypertension was initially considered intermediate in risk between normal blood pressure and hypertension, larger subsequent meta-analyses have not demonstrated a significant difference in outcomes between patients with white coat hypertension and those with normal blood pressure levels.^[2][4][5]

The term “masked hypertension” can be used to describe a contrasting phenomenon from that of white coat hypertension, where blood pressure is elevated during daily living, but not in an office setting.^[6] The prevalence of masked hypertension is approximately 13% and tends to be more likely when the office blood pressure values are high-normal.^[7][8] Risk factors for masked hypertension include young age, male gender, smoking, alcohol, physical exercise, anxiety and stress, obesity, diabetes, chronic renal insufficiency, and family history of hypertension. In contrast to white coat hypertension, patients with masked hypertension are at a two-fold increased risk of cardiovascular events and target organ damage, especially when BP levels are elevated at night.^[9][10]

Pseudohypertension is defined as marked arterial stiffness associated with calcification of brachial arteries that requires much higher cuff-inflating pressures to occlude the artery leading to falsely elevated blood pressures.^[1] Pseudohypertension is more common among elderly patients.^[1]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor-In-Chief: Yazan Daaboul, Serge Korjian, Taylor Palmieri

Hypertension is considered an epidemic worldwide. It continues to be one of the most common diseases. In October 2013, CDC data from the 2011-2012 National Health And Nutrition Examination Survey (NHANES) demonstrated that the overall age-adjusted prevalence of hypertension among U.S. adults aged 18 and older was 29.1%.^[1] Similar surveys conducted in Europe estimated the prevalence of hypertension to be 44%.^[2] The prevalence of hypertension increases among older patients and among non-Hispanic black patients, but is similar in both genders.

Hypertension is considered an epidemic worldwide. It continues to be one of the most common diseases. In October 2013, CDC data from the 2011-2012 National Health And Nutrition Examination Survey (NHANES) demonstrated that the overall age-adjusted prevalence of hypertension among U.S. adults aged 18 and older was 29.1%.^[1] Similar surveys conducted in Europe estimated the prevalence of hypertension to be 44%.^[2] Worldwide data currently estimates that hypertension currently affects approximately 972 million people with yearly incidence rates ranging between 3% and 18%.^[3] Data from the 1990s suggested a decrease in the prevalence of hypertension; however, recent data has in fact revealed that hypertension is on the rise again.^[3] Despite the high prevalence of hypertension, NHANES reports that there is a significant increase in awareness, treatment, and control among hypertensive patients over the last 10 years.^[4]

The prevalence of hypertension varies according to age, gender, and ethnicity which has been underlined by data collected by the NHANES 2011-2012:^[1]

Age
The prevalence of hypertension was found to be 7.3% among those aged 18-39, 32.4% among those aged 40-59, and 65.0% among those aged 60 and over. A global rise in systolic blood pressure with age is likely the principle etiology for the increased incidence and prevalence of hypertension among older individuals.

Gender
The age-adjusted prevalence on hypertension doesn’t vary significantly by gender with a prevalence of 29.7% among men and similarly a prevalence of 28.5% among women.

Ethnicity
The age-adjusted prevalence is significantly higher among non-Hispanic blacks at 42.1% in contrast to 28.0% among white non-Hispanic, 26.0% among Hispanic, 24.7% among Asian individuals.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor-In-Chief:Yazan Daaboul, Serge Korjian

Established risk factors for essential hypertension include old age, male gender, African American ethnicity, dyslipidemia, diabetes mellitus, smoking, increased salt intake in diet, obesity, and sedentary lifestyle. Studies are currently assessing the role of new emerging factors that might be considered as new risk factors for the development of hypertension.

Several factors have been robustly associated with hypertension, particularly cardiovascular risk factors. Nonetheless, other emerging factors have been linked to an increased risk of developing hypertension in select studies.

• Age: Men > 55 years, women > 65 years^[1]
• Ethnicity: African American^[2]
• Smoking: Cigarettes ^[3]
• Alcohol: Excessive intake of more than 2 alcoholic drinks per day^[4]
• Dyslipidemia: Elevated total cholesterol > 190 mg/dL and/or LDL > 115 mg/dL and/or HDL < 40 mg/dL for men and 45 mg/dL for women and/or triglycerides > 150 mg/dL^[1]
• Insulin resistance: Fasting plasma glucose 102-125 mg/dL, and/or abnormal glucose tolerance test^[1]
• Known cardiovascular diseases^[5]
• Known kidney diseases^[5]
• Family history of hypertension: Paternal or maternal^[6]
• Family history of CVD: Men < 55 years and/or women < 65 years^[1]
• Diet: Low in fruits and vegetables; excessive sodium intake^[7]
• Obesity and recent weight gain: BMI ≥ 30 kg/m2^[8] or waist circumference for men > 102 cm or for women > 88 cm (in Caucasian adults)
• Sedentary lifestyle^[5]

• Vitamin D insufficiency^[9]
• Low ionized serum calcium^[10]
• Hyperinsulinemia^[11]
• Preterm birth^[12]
• Neurofibromatosis Type II^[13]
• Plasma reactive carbonyl species^[14]
• Hyperuricemia^[15]
• Major depression^[16]

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]: Associate Editor(s)-in-Chief: Yazan Daaboul, Serge Korjian

The age to begin screening for hypertension varies between 13-20 years of age, according to different authorities. Generally, hypertension is defined as SBP > 140 mmHg and/or DBP > 90 mmHg. In specific populations, however, routine follow-up target BP may be different; and initiation of treatment may be considered at even lower BP values than those considered for the normal population.

The age to start screening for hypertension varies according to different authorities:

• If SBP < 120 mmHg and DBP < 80 mmHg: Screening is recommended every 2 years
• If SBP = 120-139 mmHg and/or DBP = 80-89 mmHg: Screening is recommended yearly
• If SBP = 140-159 mmHg and/or DBP = 90-99 mmHg: Confirmation of BP values within 2 months is required
• If SBP = 160-180 mmHg and/or DBP > 110 mmHg: Evaluation or referral to source of care within 1 month
• If SBP > 180 mmHg: Evaluation and treatment immediately or within 1 week. Clinical situation and complications are to be taken into major consideration.

Template:WH Template:WS

Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Assistant Editor-In-Chief: Yazan Daaboul, Serge Korjian

Hypertension is a well-established risk factor for several serious diseases. Chronic uncontrolled hypertension can be complicated by target organ damage. Most common damaged organs include the cardiovascular system, the brain, the kidneys, and the retina. The risk of cardiovascular complications is significantly increased even with small incremental increases in blood pressures. Blood pressure values should never be regarded as distinct stages or grades, but rather as a continuum of risk. Ultimately, hypertension should never be evaluated in isolation as a cardiovascular risk; it should always be integrated with other risk factors for the decision of optimal management and how aggressive the lowering of blood pressure values must reach.

The overnight blood pressure may be the most predictive^[1].

Earlier, an article that was retracted found that the 24-hour blood pressure monitoring better predicts complications that the office blood pressure^[2].

Because patients with hypertension usually have other concomitant cardiovascular risk factors, such as dyslipidemia and diabetes mellitus, the isolated effect of hypertension on cardiovascular outcomes may be difficult to assess. However, the Framingham Heart Study and other trials and observational studies well-established that hypertension has an additive effect, among other risk factors, in its contribution to cardiovascular disease and events.^[3][4][5][6] While some risk factors are directly induced by hypertension and its vascular effects, such as renal insufficiency, stroke, and heart failure, the mechanism of other complications, such as dyslipidemia, insulin resistance, and atherogenesis, is not as straightforward.^[7] These complications are not only worsened by hypertension, but also may predispose to hypertension and together are risk factors for cardiovascular disease, events, and mortality.^[7]

Almost half of all deaths in the USA are attributed to cardiovascular diseases, such as coronary artery disease and stroke. Hypertension is considered a strong risk factor for the development of cardiovascular events in target organs, such as the heart, the brain, the kidneys and within the arterial system.^[8] Even more recent data has shown that the 11-year all-cause mortality risk increases with higher SBP and DBP even in the non-hypertensive ranges: compared to men with SBP < 110 mmHg, those with SBP between 120 and 129 had a 1.16 risk of cardiovascular death. The risk increases gradually with increased blood pressure values to reach almost 1.6 times when SBP is only between 140 and 149 mmHg. The risk exceeds two-folds when SBP is > 150 mmHg and exceeds three-folds when SBP > 180 mmHg.^[9] The risk of diastolic blood pressures is also significantly associated with cardiovascular disease and death.^[9] While higher SBP and DBP have been found to be risk factors for cardiovascular disease, too much lowering of both SBP and DBP is currently under further investigation with the recent introduction of the J-curve phenomenon, defined as increased risk at very high and very low systolic and diastolic blood pressures.^[10][11] Whether very low diastolic blood pressures are a cardiovascular risk per se or due to their association with an increased systolic blood pressure and high pulse pressure, the real mechanism remains poorly understood.^[12][13][10] When followed for 10 years, patients with hypertension had a 20% risk of fatal and non-fatal cardiovascular events.^[14][15]

Newer studies confirm similar findings for non-hypertensive patients who are older than 65 years and fall in the high-normal blood pressure category.^[3] In fact, the recent introduction of a pre-hypertension category in clinical practice to non-hypertensive patients was only an emphasis of the association of high blood pressure levels, even among those with high normal blood pressure values, with fatal and non-fatal cardiovascular complications.^[16][17] In 2001, Vasan and colleagues^[3] compared 2967 men and 3892 women, most of whom were white and whose blood pressures were categorized as optimal (SBP<120 mmHg, DBP<80 mmHg), normal (SBP at 120-129 mmHg, DBP at 80-84 mmHg), or high-normal (SBP at 130-139 mmHg, DBP at 85-89 mmHg). They noted the following associated cardiovascular outcomes during a 12-year follow-up in these patients based on the time-dependent progression of blood pressures: death from a cardiovascular etiology, myocardial infarction, stroke, and congestive heart failure. Using subjects with optimal blood pressure values as controls, the study showed that more cardiovascular end-points were associated with worse categories of blood pressure.^[3] High-normal blood pressures had a 1.6- and a 2.5-fold hazard ratio for cardiovascular disease in male and female patients, respectively. Similar but attenuated associations were also concluded even when blood pressure values and co-variants were modeled as time-dependent variables during follow-up.^[3] In the study, crude event rates increased remarkably between patient categories and age groups. Among patients older than 65 years with high-normal blood pressures, the crude event rate was 28.1 and 19.5 events per 1000 person-years among male and female patients, respectively; whereas it was only 9.2 and 4.7 events per 1000 person-years in male and female patients younger than 65 years. While the five-year cardiovascular complications are significantly reduced by 25% in elderly patients when blood pressure values are appropriately lowered.^[18] it is currently unknown whether patients with high-normal blood pressure values similarly benefit from blood pressure lowering,^[3]

Finally, it is important to emphasize that the risks of cardiovascular complications are significantly increased even with small incremental increases in blood pressures. Blood pressure values should never be regarded as distinct stages or grades, but rather as a continuum of risk. Ultimately, hypertension should never be evaluated in isolation as a cardiovascular risk. It should always be integrated with other risk factors for the decision of optimal management and how aggressive the lowering of blood pressure values must reach.

Hypertensive heart disease is defined as the development of left ventricular hypertrophy, atherogenic coronary artery disease, and/or heart failure due to hypertension.^[6] Coronary artery disease is perhaps the most common hazard of long-standing hypertension.^[19] It equally affects males and females, all ethnicities, and ages.^[9] Hypertensive patients are at two to three-fold increased risk of all clinical forms of atherosclerotic heart disease, including angina, myocardial infarctions, and sudden death.^[7] According to the MRFIT trial (Cohort of Men Screened for the Multiple Risk Factor Intervention Trial) that studied more than 300,000 White men between 35 and 57 years for more than 10 years, both high systolic and diastolic blood pressures were significantly associated with coronary artery disease in a continuous and graded fashion.^{[20][21][22][23][17]} Elevated systolic blood pressure levels in patients older than 45 years was particularly notorious.^[22] The Framingham Heart Study showed that unrecognized myocardial infarctions were also significantly higher in patients with hypertension vs. those who are not, even when adjusting for use of anti-hypertensive therapy, diabetes, and left ventricular hypertrophy.^[18]

Other cardiac complications of hypertension include ventricular hypertrophy, which acts as a consequence and as a predictor of future cardiovascular disease.^{[24][25][26][27][28][29][30]} More than 70% of patients with heart failure have a past history of hypertension.^[31][19] According to the first National Health and Nutrition Examination Survey (NHANES I) in 2001, hypertension comprised 10% of the population attributable risk of heart failure.^[32] Although the pathophysiology of heart failure in hypertension is complicated, it is believed that it may be caused by both the mechanical chronic pressure that overloads the left ventricle, and causes fibrosis of the myocardium and dysfunctional filling during diastole^[33] along with neuro-hormonal alterations that are not usually seen in non-hypertensive subjects.^[34] Electrocardiography (ECG) findings consistent with left ventricular hypertrophy (LVH) were independently associated with up to 3.7 times and 1.9 times risk of coronary artery disease among 40-64 year old men and women, respectively.^[25][28] Relevant ECG abnormalities, such are premature ventricular beats, increased voltages or repolarizations, were significantly increased as systolic and diastolic blood pressures increased.^{[7][35][28][36]} Finally, ejection fraction may or may not be preserved in heart failure. The frequencies of systolic and diastolic left ventricular dysfunction are approximately the same.^[32][37]

When adjusting for confounding factors, such as smoking, diabetes, and dyslipidemia, the risk of fatal stroke remained significantly high, reaching up to 3-fold in patients with systolic prehypertension values and progressively worsened to reach approximately 20-fold increase in fatal stroke in patients with SBP > 180 mmHg.^[17] Although SBP was more associated with stroke than DBP, both are still considered significant factors in the development of stroke in both genders in patients of all ethnicities above the age of 35.^[17] While earlier reports hypothesized that hypertensive patients are at higher risk of hemorrhagic strokes compared to atheroembolic strokes, the Framingham Heart Study showed that paradoxically, both mild and severe hypertension were in fact significantly much more associated with more atheroembolic stroke at a rate of 70% and 56%, respectively.^[38]

A significant relationship between elevated blood pressure values and the 12-year risk of death from renal etiology was made in 1993.^[39] Renal disease due hypertension is called nephronagiosclerosis or hypertensive nephropathy. It is attributed to small and medium-size renal arteriolopathy that cause characteristic intimal hyperplasia, hyalinosis, and smooth muscle hypertrophy in the arteriolar media.^[40] The mechanism of nephroangiosclerosis and vascular modifications have been poorly identified, but involvement of inflammatory cascades are proposed.^[40] Nephroangiosclerosis was shown to be responsible for approximately 25-33% of new cases of end-stage renal disease (ESRD), according to data collected from the End-Stage Renal Disease Program.^[40][41] Additionally, the HDFP trial in 1989^[42] demonstrated that both higher SBP and DBP were also associated with higher creatinine levels, with a frequency of 8% of elevated creatinine in patients with SBP > 200 mmHg vs. only 2% in patients with SBP between 120 and 139 mmHg. Hypercreatininemia at baseline, defined in the study as serum creatinine levels more than 1.7 mg/dL, was associated with approximately a three-fold increase in mortality. Accordingly, kidney function was considered an independent predictor of mortality.^[42] The study enrolled 10940 black and white patients and measured creatinine periodically for 5 years.^[42] Creatinine increase was significantly higher in blacks and in older patients.^[42] In another trial that assessed renal outcome following anti-hypertensive therapy, DBP < 95 mmHg was associated with stable kidney function.^[43]

In hypertension, the microvasculature in the retina constricts and undergoes intimal thickening, medial hyperplasia, and subsequent hyaline degeneration.^[44] As such, hypertensive retinopathy is a common complication among patients with long-standing hypertension and may be the earliest manifestation.^[45] In fact, hypertension has a range of eye manifestations that lead to vision less, especially among adults above the age of 40 years. Ischemic and non-ischemic occlusion of the retinal vein and artery in central and peripheral vessels, retinal emboli, ischemic optic neuropathy, glaucoma, and age-related macular degeneration are also common ophthalmic manifestations significantly associated with hypertension.^[45][46] According to Cugati and colleagues, central vein occlusion was seen in 0.4% of the cases, whereas branch retinal vein occlusion was seen in 1.2% among 3654 patients aged 49 and older when followed-up for 10 years.^[47] Studies have confirmed that eye involvement in hypertension heralds stroke, heart failure, and other cardiovascular events and mortality.^[45][46] Ophthalmic complications of hypertension are significantly reduced with the use of appropriate anti-hypertensive medications and optimal blood pressure control. There are currently 3 grades of retinopathy: mild retinopathy is defined as generalized and focal arteriolar narrowing, arterial wall opacification, and arteriovenous nipping. Moderate retinopathy is defined as flame-shaped or blot-shaped hemorrhages with cotton-wool spots, hard exudates, and/or microaneurysms. Finally, severe retinopathy is defined as signs of mild or moderate retinopathy with optic disc swelling.^[45][46]

Blood pressure is also consistently and independently associated with the development of peripheral vascular disease (PVD) in the young and the elderly.^[8] High SBP by only 20 mmHg and DBP by only 10 mmHg was associated with more claudication in both men and women at all ages.^[8] At the time of diagnosis of hypertension, up to 5% of patients, especially among the elderly, have symptomatic peripheral arterial disease (PAD), such as intermittent claudication.^[48] The converse is also true; where approximately half of patients diagnosed with PAD were also found to have hypertension.^[48] Patients with PAD are at further increased risk of future cardiovascular events.

Template:WS Template:WS