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  Disease summary:

  
  
  
  
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    Hypertension is a disease than can be caused by mutations in single genes (monogenic hypertension), nonidentifiable causes (essential hypertension) or secondary to other diseases (secondary hypertension).

    
    
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    Essential (primary) and secondary hypertension: It accounts for 95% of all cases of hypertension, and is traditionally defined as high blood pressure for which an obvious secondary cause cannot be determined. However, several gene variants are claimed to cause essential hypertension. In the remaining 5% of the cases, the cause of hypertension is secondary to conditions such as primary hyperaldosteronism, excess glucocorticoids, pheochromocytoma, or renal disease.

    
    
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    Monogenic hypertension: Most monogenic forms of hypertension have renal origins. The consequence of a defective gene in each of these forms of hypertension is abnormally increased sodium transport in the distal nephron causing an expansion of the circulating plasma volume and increase in cardiac output (Table 16-1). All hereditary forms of hypertension lead to a suppression of the renin-angiotensin system due to plasma volume expansion.

    
    
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    The estimated prevalence of hypertension (in the United States derived from the NHANES 2005-2008) in adults 20 years or older is 33.5% (28.5% ≥18 years) which is approximately 76 million US adults and nearly equal between men (34.1%) and women (32.7%). The prevalence of hypertension varies by age, gender, and race or ethnicity and is also affected by behavior such as the intake of dietary sodium and potassium, weight, waist to hip ratio, alcohol consumption, and physical activity. The prevalence of essential hypertension is highest in non-Hispanic Blacks (43%-46%) and lowest in Asian Americans (30%). Among Americans 65 years and older, more women than men have hypertension.

    
    
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    Blood pressure is regulated by a complex group of interacting genes and essential hypertension is a polygenic disease. About half of the blood pressure variability is thought to be genetically determined but the variation of blood pressure is the result of an interaction among genes and environmental factors.

    
    
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    Early fetal environment may be linked to long-term health and lifespan consequences in the adult, including essential hypertension. Low birth weight babies have higher blood pressures, even after correction for various modifiers such as sex, cigarette smoking, and weight.

    
    
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    Hypertension is strongly associated with major cardiovascular risks such as premature cardiovascular disease, congestive heart failure, left ventricular hypertrophy, stroke, chronic kidney disease, and end-stage renal disease. In 2008, high blood pressure was responsible for about one in six deaths of US adults and was the single largest risk factor for cardiovascular mortality, accounting for about 45% of all cardiovascular deaths.

  
  

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  Differential diagnosis:

  
  
  
  
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    The correct measurement of blood pressure, including the use of an appropriately sized cuff and sphygmomanometer that is properly calibrated and validated is critical.

  
  

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  Family history:

  
  
  
  
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    Blood pressure heritability estimated from family studies is about 20%. The predictive strength of family history as a risk factor is doubled with one hypertensive first-degree relative and increases nearly fourfold with two such relatives.

  
  

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  Twin studies:

  
  
  
  
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    Twin studies showed blood pressure heritability of about 60%. Genome-wide scans for blood pressure in extremely discordant and concordant sib pairs for blood pressure have revealed loci in several genes that are linked to hypertension but the specific gene variants have not been identified.

  
  

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  Environmental factors:

  
  
  
  
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    The most important environmental factors in the development of hypertension at the population level are obesity, high sodium chloride intake, low potassium intake, physical inactivity, heavy alcohol consumption, and psychosocial stress.

  
  

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  Genome-wide associations:

  
  
  
  
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    Genetic studies of essential hypertension have used two approaches: family-based linkage studies and the study of the association of candidate genes in a population-based design. Several chromosomal loci have been linked to hypertension. Common genetic variants associated with blood pressure and hypertension identified through genome-wide association studies (GWAS) in adult populations only account for about 1% to 2% of the variance of blood pressure (Table 16-2). Genome-wide mapping studies have linked loci in several chromosomes to essential hypertension, but these studies have not yet led to the identification of specific gene variants that may be causal. Linkage studies have been successful in the identification of rare and highly penetrant alleles but lack the power to detect alleles conferring moderate risks that may be the case in essential hypertension. Even if a disease risk locus is identified by linkage, the power of linkage disequilibrium to detect an association with a specific variant may be limited if multiple variants at each locus confer disease susceptibility. However, although their individual associations may not reach significance, the combination of variants may explain a substantial proportion of blood pressure variance.

  
  

Diagnostic Criteria of Hypertension

In adults aged 18 years and older normal blood pressure is defined as systolic blood pressure less than 120 mm Hg and diastolic blood pressure less than 80 mm Hg measured, at least twice, in the sitting position with feet on the floor, after at least a 5-minute rest. Hypertension is defined as systolic blood pressure equal to or greater than 140 mm Hg or diastolic blood pressure equal to or greater than 90 mm Hg. Systolic blood pressure from 140 to 159 mm Hg or diastolic blood pressure 90 to 99 mm Hg is considered stage 1 hypertension. Systolic blood pressure equal to or greater than 160 mm Hg or diastolic blood pressure equal to or greater than 100 mm Hg is considered stage 2 hypertension. Systolic blood pressure from 120 to 139 mm Hg or diastolic blood pressure from 80 to 89 mm Hg systolic is prehypertension.

Subjects with hypertension have blood pressure greater than 135/85 mm Hg when awake and more than 120/75 mm Hg when asleep. Hypertension that is not observed in the clinic or doctor’s office is called masked hypertension while hypertension observed only in the clinic or doctor’s office is called white coat hypertension.

In children and adolescents, hypertension is defined as repeatedly (≥3) measured systolic or diastolic blood pressure (fifth Korotkoff sound) at or greater than the 95th percentile adjusted for age, height, and sex. Systolic or diastolic blood pressures from the 95th percentile to 5 mm Hg about the 99th percentile is stage 1 hypertension while blood pressures greater than 5 mm Hg above the 99th percentile is stage 2 hypertension. Prehypertension in children is defined as systolic or diastolic blood pressure equal to or greater than the 90th percentile but less than the 95th percentile, adjusted for height, weight, and sex.

Clinical Characteristics

There are no signs or symptoms in uncomplicated hypertension.

Screening

Blood pressure measurement in parents and relatives may give a clue as to the genetic pattern of hypertension.

Counseling

Lifestyle modification, similar to those used in the Dietary Approaches to Stop Hypertension (DASH), appropriate weight and waist to hip ratio, limitation of dietary sodium chloride intake, moderate alcohol intake of no more than two drinks per day and increased physical activity are recommended. Additionally, smoking cessation is also recommended to improve cardiovascular health. The benefits of these interventions include lowering of blood pressure, enhancement of antihypertensive efficacy, and reduction of cardiovascular risks.

The primary goal of antihypertensive therapy is to reduce cardiovascular and renal morbidity and mortality using the least intrusive means possible. The Joint National committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure (JNC 7) and US national guidelines recommend systolic blood pressure below 140 mm Hg and diastolic blood pressure below 90 mm Hg in all hypertensive patients. However, there may be a J-shaped curve, in which blood pressure below a critical level (which remains to be determined) may be associated with increased cardiovascular risk.

In patients with hypertension and diabetes or chronic kidney disease, the recommended blood pressure goal is less than 130/80 mm Hg.

The JNC 7 recommends that low-dose thiazide-type diuretics should be used as initial therapy for most patients with hypertension either alone in stage 1 hypertension, or in combination with other agents such as angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), calcium channel blockers (CCBs) or beta-blockers in stage 2 hypertension. However, the use of thiazide-type diuretics, because of toxic effects, in the treatment of essential hypertension has been questioned.

Pharmacogenetics/Pharmacogenomics

Genotyping for certain gene variants may aid in the diagnosis of salt sensitivity (Table 16-2). Genetic screening may be an effective mechanism to identify salt-sensitive normotensive and hypertensive subjects. As an example, genotyping for GRK4 variants has a 70% predictive value for hypertension in Ghanaians and 94% predictive accuracy for salt sensitivity in Japanese. Pharmacogenomics of essential hypertension is in its early stages. Patients with adducin (ADD1) G460T may respond better to ouabain antagonists. Patients with NEDD4L rs4149601 G allele may be more responsive to beta-adrenergic blocker or diuretic monotherapy. In South African black patients with mild-to-moderate hypertension, carriers of GRK4 R65 and GRK4 R65L or GRK4 A142 and GRK4 A142V may have a good response to low-sodium diet.