Prehypertension

Etiology

Prehypertension, elevated blood pressure, and stage 1 hypertension can have multiple possible causes. The exact pathogenesis of essential or primary hypertension is poorly understood, but several different risk factors have been identified over the past several decades. Age is a major albeit nonmodifiable risk factor for hypertension. Clinical data reveals a high incidence of hypertension with age. The long-term incidence of hypertension was noted to be 0.3% at age 25 years, 6.5% at 45 years, and 37% at 65 years of age.[1] 

Similarly, clinical data reveals a genetic predisposition for hypertension. A family history of hypertension increases the risk of hypertension among individuals. A longitudinal study with a 54-year follow-up revealed that hypertension in both parents was a strong independent predictor of elevated blood pressure levels and incident hypertension.[2] According to the ACC/AHA report, the estimated 40-year risk of hypertension for adults 45 years of age without hypertension was noted to be 93% in African Americans, 92% for Hispanic Americans, 86% for Caucasians, and 84% for Chinese Americans.[1]

Obesity is another major risk factor for the development of hypertension. The relationship between body mass index and blood pressure is linear, direct, and continuous without evidence of a threshold. According to the ACC/AHA report, the relationship between the waist-to-hip ratio and blood pressure is stronger.[1] A recent study from China reported that a high waist circumference was an independent risk factor for new-onset hypertension.[3] The duration of obesity also plays a role, with studies showing that a younger age at the onset of obesity or weight gain is associated with a significantly increased risk of hypertension.[4] 

Excess dietary sodium intake is another significant risk factor for the development of hypertension. It is also independently associated with an increased risk of stroke and adverse cardiovascular events. Similarly, excess alcohol consumption is a known risk factor for hypertension. The ACC/AHA report also highlights that potassium intake is inversely related to blood pressure and appears to blunt the effect of sodium intake on blood pressure. Another protective factor is physical activity, with modest increases in physical activity levels associated with lower BP readings.

Causes of secondary hypertension include medications or substances such as (but not limited to) oral contraceptives, corticosteroids, decongestants (such as phenylephrine and pseudoephedrine), stimulants, atypical antipsychotics, and illicit drugs (such as methamphetamines and cocaine). Medical conditions associated with secondary hypertension include renal failure, hyperaldosteronism, renovascular disease, obstructive sleep apnea, pheochromocytoma, and other endocrine disorders such as hyperthyroidism and Cushing syndrome.[1]

Epidemiology

According to the ACC/AHA, the prevalence of hypertension (≥130/80 mm Hg) among the United States (US) adult population is 46%.[6] In 2010, hypertension was the leading cause of death and disability-adjusted life years worldwide. In the US, hypertension causes more cardiovascular deaths than any other modifiable risk factor and is the second leading cause of preventable deaths for any reason. These outcomes are more concerning when the incidence and prevalence of hypertension among the general population are accounted for. According to the ACC/AHA report, up to 90% of individuals free of hypertension at age 55 or 65 years will develop hypertension during their lifetime. Prevalence estimates vary based on the definition of hypertension. When using the currently recommended ACC/AHA definition of hypertension, the prevalence of hypertension among US adults is reported to be around 46%, compared to 32% when the JNC 7 definition is used.[1]

Global estimates of the prevalence and impact of hypertension are more problematic. According to the World Health Organization (WHO) factsheet on hypertension, an estimated 1.28 billion adults between the ages of 30 and 79 years have hypertension worldwide. Many of these patients live in low- and middle-income countries, with as many as 46% of the adults with hypertension being undiagnosed. The WHO further estimates that on a global scale, only 21% of those diagnosed with hypertension are compliant.

Pathophysiology

The exact molecular pathogenesis of hypertension involves a variety of mechanisms that are not fully understood. Specific pathogenic pathways lead to elevated blood pressure that could benefit from individualized therapy; however, clinical studies have yet to outline clear mechanisms.[7] A complex interplay of hemodynamic, molecular, and stress-induced adaptations is likely involved. Results from a recent study evaluating primary hypertension in children and adolescents concluded that hypertension is not a purely hemodynamic phenomenon. The researchers identified an immune-metabolic syndrome associated with an increased sympathetic drive as playing a key role in the pathogenesis of this disease. They concluded that primary hypertension is a premature vascular aging process associated with neuro-immuno-metabolic abnormalities.[8] 

Inflammation is now being identified as an essential feature in the pathogenesis of hypertension. Elevated inflammatory markers such as cytokines and adhesion molecules were shown to predict hypertension in normotensive patients.[9] From an evolutionary standpoint, hypertension results from maladaptations to increased dietary salt intake and decreased dietary potassium intake. Renal vascular beds that are "programmed" by evolution for a low dietary salt load respond by raising blood pressure to enhance urinary sodium excretion.[10]

History and Physical

Accurately measuring BP is a fundamental medical practice. Validated oscillometric devices are the recommended measurement method because they decrease human errors associated with the auscultatory approach. Fully automated oscillometric devices that obtain multiple readings (even without an observer or clinician) are considered more accurate than auscultatory methods.[11] However, auscultatory methods are still acceptable modes of blood pressure assessment when validated oscillometric devices are unavailable. 

The ACC/AHA provides detailed guidance on accurate measurement and pitfalls to avoid inaccurate readings. One of the most important steps is ensuring the patient is relaxed and resting for 5 minutes or more. Caffeine, exercise, and smoking should be avoided in the 30-minute interval preceding the measurement. The ACC/AHA emphasizes using a validated measurement device calibrated periodically. Accurate measurement also requires accurate cuff size, defined as a cuff with a bladder that encircles 80% of the arm. Estimated radial pulse obliteration pressure by palpation should be obtained first. The cuff should be inflated 20 mm Hg to 30 mm Hg above this level and deflated at 2 mm Hg per second to determine auscultatory BP levels. An average of 2 or more readings obtained on 2 or more occasions should estimate the BP. Care should ensure that the arm is supported during the measurement and is at heart level.

Ambulatory and home BP monitoring should be encouraged and used to supplement data obtained in the office. This practice allows the clinician to identify patients with masked and white-coat hypertension. White coat hypertension is defined as elevated office BP blood measurements but normal readings when measured outside the office using ambulatory or home blood pressure monitoring. Masked hypertension is characterized by normal office readings but elevated blood pressure when measured using ambulatory and home monitoring. The latter entity is critical to identify because the risk of cardiovascular and all-cause mortality in patients with masked hypertension is similar to those with sustained hypertension (elevated home or ambulatory and office readings). In contrast, white-coat hypertension is associated with a minimally increased risk of cardiovascular disease, prompting guidelines to recommend screening.[1] 

Home BP monitoring is recommended routinely in patients with known or suspected hypertension. The monitoring is especially recommended in those who are newly diagnosed and who have elevated BP or stage 1 hypertension (formerly called prehypertension) to help identify masked hypertension.[12]

Ambulatory BP monitoring is the gold standard for out-of-office BP assessment.[11] Ambulatory blood pressure monitoring (ABPM) is measured using a device worn by the patient for a 24 to 48-hour period. The device measures blood pressure every 15 to 20 minutes daily and every 30 to 60 minutes at night. If a 24-hour duration of ABPM cannot be obtained, the period may be shortened to 6 to 8 hours.[12] These devices report averaged BP levels in a diurnal and 24-hour pattern. Hypertension using ABPM is defined as:

• A 24-hour average BP greater than or equal to 125/75 mm Hg or
• Average daytime BP greater than or equal to 130/80 mm Hg or
• An average nighttime BP greater than or equal to 110/65 mm Hg [1]

The preferred location to measure BP is the arm. The BP should be obtained in both arms during initial assessments. Subsequent monitoring should be conducted using the arm with the higher BP reading.[1] In some patients, BP measurements in the arm are not feasible or possible. Alternate locations in these patients are the lower extremity or the wrist. In the lower extremities (calf and ankle), the BP is usually higher than the brachial arteries.[13] However, a high degree of variability prevents accurate translation of lower extremity pressure to that of the arm. Oscillometric BP monitors have not been validated for lower-extremity BP measurements.

Following a diagnosis of elevated BP, sustained hypertension, or masked hypertension, a detailed history should be obtained to help differentiate primary hypertension from secondary hypertension. A gradual rise in BP associated with weight gain, lifestyle factors, physical inactivity, and advancing age is suggestive of primary hypertension. A thorough evaluation of the patient's dietary habits, physical activity, alcohol consumption, and tobacco use should be performed.

Some signs and symptoms may suggest secondary causes of hypertension and should be elicited at the time of diagnosis. Historical features to consider in this regard include:

• Lability of BP and episodic dizziness/pallor (pheochromocytoma)
• Snoring, hypersomnolence (obstructive sleep apnea)
• Muscle cramps, weakness, and other signs suggestive of hypokalemia (primary or secondary aldosteronism)
• Weight loss, palpitations, heat intolerance (hyperthyroidism)
• Edema, fatigue, frequent urination (kidney disease or failure)
• Central obesity, facial rounding, easy bruising (Cushing syndrome)[1]

Evaluation

According to the World Health Organization (WHO) guidelines for the pharmacological treatment of hypertension, laboratory testing is indicated in patients with elevated blood pressure to screen for comorbidities and secondary causes.[14] The WHO recommends obtaining the following tests as long as it is feasible and does not delay treatment for hypertension:

• Serum electrolytes and creatinine
• Lipid panel
• Hemoglobin A1c or fasting glucose level
• Urinalysis
• Electrocardiogram

The WHO acknowledges the added cost burden of this testing. They state that it is unknown if this testing is cost-effective in low-resource areas and if initiation of therapy is warranted.[14] 

The WHO report also recommends cardiovascular risk assessment at or after the initiation of pharmacological treatment in patients with hypertension, so long as it does not delay therapy. This is particularly important in patients with elevated blood pressure and stage 1 hypertension, as the management strategy would change if these patients had higher cardiovascular risk estimation.[14]

The ACC/AHA has made similar recommendations regarding testing. They recommend laboratory measurements for all patients with a new diagnosis of hypertension to determine cardiovascular risk profile and screen for secondary causes.[1] They recommend routine testing for fasting blood glucose level, complete blood count, lipid profile, serum creatinine with glomerular filtration rate, serum electrolytes (sodium, potassium, and calcium), thyroid-stimulating hormone, urinalysis, and an electrocardiogram.[1] Optional testing recommended by the ACC/AHA guidelines includes an echocardiogram, uric acid, and urinary albumin to creatinine ratio.[1]

An electrocardiogram is useful in screening for left ventricular hypertrophy (LVH) and has been shown to independently predict cardiovascular complications in these patients. Moreover, a reduction in LVH can predict decreased cardiovascular risk independent of a change in blood pressure levels.[1]

Treatment / Management

The WHO recommends initiation of pharmacological treatment in all individuals with hypertension, defined as a BP of ≥140/90 mm Hg.[14] This corresponds to stage 2 hypertension according to the ACC/AHA classification.[1] Patients with a systolic BP of 130 to 139 mm Hg (prehypertensive according to JNC 7 or stage 1 hypertension by the ACC/AHA classification) and underlying cardiovascular disease should also be started on pharmacologic therapy. Patients with a systolic BP of 130 to 139 mm Hg who do not have any cardiovascular disease but have high cardiovascular risk due to underlying diabetes or chronic kidney disease should also be started on pharmacotherapy. The recommended pharmacologic agents for those who require treatment are thiazide, angiotensin-converting enzyme inhibitors, angiotensin-receptor blockers, and/or long-acting dihydropyridine calcium channel blockers alone or in combination.[14] (A1)

Similar recommendations are given by the ACC/AHA guidelines regarding patients who fall into the elevated blood pressure or stage 1 hypertension categories.[1] The ACC/AHA guidelines recommend estimating 10-year atherosclerotic cardiovascular disease risk in patients in this category. Pharmacologic therapy should be initiated if the 10-year risk is 10% or higher. This risk is estimated using validated assessment tools. The ACC/AHA assessment tool is validated for adults in the US aged 40 to 79 years. For patients older than 79 years, the 10-year risk is estimated to be greater than 10%. (A1)

According to the ACC/AHA, prehypertensive patients, ie, those with elevated BP or stage 1 hypertension who have an estimated 10-year risk of less than 10%, should receive nonpharmacological therapy with a repeat blood pressure evaluation within 3 to 6 months.[1] Patients with stage 1 hypertension who have an estimated 10-year risk of 10% or higher should receive combination therapy with nonpharmacological and antihypertensive drug therapy with a repeat blood pressure evaluation in 1 month. Patients with stage 2 hypertension (ie, those with blood pressure greater than or equal to 140/90 mm Hg) should be treated with a combination of nonpharmacological therapy AND dual antihypertensive drug therapy (with 2 agents of different classes).(A1)

Nonpharmacological interventions are highly recommended in patients with elevated blood pressure or stage 1 hypertension. These interventions include weight reduction, following a heart-healthy diet, reduction in sodium consumption, increased dietary potassium consumption (unless contraindicated due to underlying renal dysfunction), and increased physical activity. Future cardiovascular and cerebrovascular risk benefits are mediated by the multisystem physiological adaption to lifestyle/dietary changes and exercise. Alcohol cessation or significantly limiting alcohol consumption is also advised. Of the dietary interventions studied, only the DASH (Dietary Approaches to Stop Hypertension) diet has robust proof of efficacy and is endorsed by the ACC/AHA. 

Other nonpharmacological interventions have been shown to decrease blood pressure; however, the evidence supporting their efficacy in lowering blood pressure is less robust and unsupported by the current guidelines. Interventions with limited evidence that the ACC/AHA does not endorse include:

• Consumption of probiotics, garlic, dark chocolate, coffee
• Increased intake of protein, flaxseed, or fish oil
• Supplementation with calcium or magnesium
• Dietary patterns other than the DASH diet (such as low-carbohydrate, vegetarian, and Mediterranean diets)
• Stress reduction
• Behavioral therapies (such as guided breathing, yoga, transcendental meditation, and biofeedback)

The blood pressure-lowering effect of weight loss in patients with elevated blood pressure (prehypertensive) is similar to that of the weight loss effect in patients with established hypertension. A linear relationship corresponding to a 1 mm Hg improvement in blood pressure per kilogram of weight loss is seen in these patients. The DASH diet is high in fruits, vegetables, and low-fat dairy, reducing systolic blood pressure in hypertensive and normotensive patients. The blood pressure-lowering effect of the DASH diet is greatly enhanced with sodium reduction and behavioral changes that include increased physical activity, leading to weight loss.[1](A1)

Differential Diagnosis

Acute and transient elevation in blood pressure may be due to the following:

• Acute drug toxicity/intoxications such as amphetamines, cocaine, stimulants
• Stroke
• Myocardial infarction
• Withdrawal syndromes from sedatives such as benzodiazepines
• Alcohol withdrawal

Other diagnoses to consider in the differential of high blood pressure include secondary causes of hypertension such as:

• Renal failure
• Hyperthyroidism
• Hyperaldosteronism
• Cushing syndrome
• Renovascular disease
• Obstructive sleep apnea
• Pheochromocytoma
• Mineralocorticoid excess syndromes [1] 

Genetic disorders that have singular defects leading to hypertension are exceedingly rare and include:

• Liddle syndrome
• Gordon syndrome [1] 

Prognosis

Prehypertension or elevated blood pressure and stage 1 hypertension confer increased morbidity and mortality in patients. After adjusting for underlying cardiovascular risk factors other than elevated blood pressure, these mild elevations in blood pressure were associated with higher stroke morbidity, even in those with low-range prehypertension.[15] A recent study evaluating the prognosis of prehypertension in patients without progression to hypertension reported that prehypertensive individuals who avoid developing hypertension have a lower cardiovascular risk of morbidity and mortality relative to those who develop hypertension.

The lower risk is maintained if prehypertension develops early (before the age of 55 years) in life.[16] This underscores the importance of identifying individuals with elevated blood pressure and stage 1 hypertension and implementing strategies to avoid conversion to higher-stage hypertension requiring pharmacotherapy. A recent study from China evaluating prehypertensive individuals in a rural cohort reported an increased incidence of major adverse cardiovascular events (hazard ratio, HR 1.337), cardiovascular mortality (HR 1.331), and stroke (HR 1.424) when compared to normal blood pressure.[17] 

Complications

Untreated and uncontrolled blood pressure elevations can lead to hypertension and multiple cardiovascular complications, including stroke, heart failure, and cardiovascular mortality.[1] In addition, patients with prehypertension are at an increased risk of complications during pregnancy,[18] a decline in global cognition and memory,[19] and preclinical end-organ damage (such as increased left ventricular mass and impaired diastolic function).[20] Well-established complications of uncontrolled hypertension include myocardial infarction, left ventricular hypertrophy, congestive heart failure, aneurysms, ischemic or hemorrhagic strokes, chronic renal failure, and hypertensive eye disease or retinopathy.[21]