Hypertension

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]

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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]

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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.

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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.

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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]

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