Etiology

The etiology of hypertensive heart disease is a complex interplay of various hemodynamic, structural, neuroendocrine, cellular, and molecular factors. These factors play integral roles in the development of hypertension and its complications; however, elevated BP itself can modulate these factors. Obesity has been linked to hypertension and LVH in various epidemiologic studies, with as many as 50% of obese patients having some degree of hypertension and as many as 60-70% of patients with hypertension being obese. Elevated BP leads to adverse changes in cardiac structure and function in 2 ways: directly, by increased afterload, and indirectly, by associated neurohormonal and vascular changes. Elevated 24-hour ambulatory BP and nocturnal BP have been demonstrated to be more closely related to various cardiac pathologies, especially in black persons. The pathophysiologies of the various cardiac effects of hypertension differ and are described in this section.

Left ventricular hypertrophy

Of patients with hypertension, 15-20% develop LVH. The risk of LVH is increased 2-fold by associated obesity. The prevalence of LVH based on electrocardiogram (ECG) findings, which are not a sensitive marker at the time of diagnosis of hypertension, is variable.[3, 4] Studies have shown a direct relationship between the level and duration of elevated BP and LVH.[5] LVH, defined as an increase in the mass of the left ventricle, is caused by the response of myocytes to various stimuli accompanying elevated BP. Myocyte hypertrophy can occur as a compensatory response to increased afterload. Mechanical and neurohormonal stimuli accompanying hypertension can lead to activation of myocardial cell growth, gene expression (of which some occurs primarily in fetal cardiomyocytes), and, thus, to LVH. In addition, activation of the renin-angiotensin system, through the action of angiotensin II on angiotensin I receptors, leads to growth of interstitium and cell matrix components. In summary, the development of LVH is characterized by myocyte hypertrophy and by an imbalance between the myocytes and the interstitium of the myocardial skeletal structure. Various patterns of LVH have been described, including concentric remodeling, concentric LVH, and eccentric LVH. Concentric LVH is an increase in LV thickness and LV mass with increased LV diastolic pressure and volume, commonly observed in persons with hypertension; this is a marker of poor prognosis in these patients. Compare concentric LVH with eccentric LVH, in which LV thickness is increased not uniformly but at certain sites, such as the septum. Although the development of LVH initially plays a protective role in response to increased wall stress to maintain adequate cardiac output, it later leads to the development of diastolic and, ultimately, systolic myocardial dysfunction.

Interestingly, findings from a prospective study (The Multiethnic Study of Atherosclerosis [MESA] trial) also indicate a higher risk of developing systemic hypertension among patients in the higher quartiles of the LV mass at baseline.

Left atrial abnormalities

Frequently underappreciated, structural and functional changes of the left atrium are very common in patients with hypertension. The increased afterload imposed on the LA by the elevated LV end-diastolic pressure secondary to increased BP leads to impairment of the left atrium and left atrial (LA) appendage function, plus increased LA size and thickness. Increased LA size accompanying hypertension in the absence of valvular heart disease or systolic dysfunction usually implies chronicity of hypertension and may correlate with the severity of LV diastolic dysfunction. In addition to LA structural changes, these patients are predisposed to atrial fibrillation. Atrial fibrillation, with loss of atrial contribution in the presence of diastolic dysfunction, may precipitate overt heart failure.

Valvular disease
Although valvular disease does not cause hypertensive heart disease, chronic and severe hypertension can cause aortic root dilatation, leading to significant aortic insufficiency. Some degree of hemodynamically insignificant aortic insufficiency is often found in patients with uncontrolled hypertension. An acute rise in BP may accentuate the degree of aortic insufficiency, with return to baseline when the BP is better controlled. In addition to causing aortic regurgitation, hypertension is also thought to accelerate the process of aortic sclerosis and cause mitral regurgitation.

Heart failure
Heart failure is a common complication of chronically elevated BP. Patients with hypertension fall into 1 of the following categories:

Asymptomatic but at risk of developing of heart failure - Stage A or B, per the American College of Cardiology (ACC)/American Heart Association (AHA) classification, depending on whether or not they have developed structural heart disease as a consequence of hypertension Suffering from symptomatic heart failure - Stage C or D, per the ACC/AHA classification

Hypertension as a cause of CHF is frequently underrecognized, partly because at the time heart failure develops, the dysfunctioning left ventricle is unable to generate the high BP, thus obscuring the heart failure's etiology. The prevalence of asymptomatic diastolic dysfunction in patients with hypertension and without LVH may be as high as 33%. Chronically elevated afterload and the resulting LVH can adversely affect the active early relaxation phase and the late compliance phase of ventricular diastole. Diastolic dysfunction

Diastolic dysfunction is common in persons with hypertension. It is often, but not invariably, accompanied by LVH. In addition to elevated afterload, other factors that may contribute to the development of diastolic dysfunction include coexistent coronary artery disease, aging, systolic dysfunction, and structural abnormalities such as fibrosis and LVH. Asymptomatic systolic dysfunction usually follows. Systolic dysfunction Later in the course of disease, the LVH fails to compensate by increasing cardiac output in the face of elevated BP, and the LV cavity begins to dilate to maintain cardiac output. As the disease enters the end stage, LV systolic function decreases further. This leads to further increases in activation of the neurohormonal and renin-angiotensin systems, leading to increases in salt and water retention and increased peripheral vasoconstriction. Eventually, the already compromised LV is overwhelmed, and the patient progresses to the stage of symptomatic systolic dysfunction. Decompensation Apoptosis, or programmed cell death, stimulated by myocyte hypertrophy and the imbalance between its stimulants and inhibitors, is considered to play an important part in the transition from compensated to decompensated stage. The patient may become symptomatic during the asymptomatic stages of the LV systolic or diastolic dysfunction, owing to changes in afterload conditions or to the presence of other insults to the myocardium (eg, ischemia, infarction). A sudden increase in BP can lead to acute pulmonary edema without necessarily changing the LV ejection fraction.[6] Generally, development of asymptomatic or symptomatic LV dilatation or dysfunction heralds rapid deterioration in clinical status and a markedly increased risk of death. In addition to LV dysfunction, right ventricular (RV) thickening and diastolic dysfunction also develop as results of septal thickening and LV dysfunction.

Myocardial ischemia
Patients with angina have a high prevalence of hypertension. Hypertension is an established risk factor for the development of coronary artery disease, almost doubling the risk. The development of ischemia in patients with hypertension is multifactorial. Importantly, in patients with hypertension, angina can occur in the absence of epicardial coronary artery disease. The reason for this is 2-fold. Increased afterload secondary to hypertension leads to an increase in LV wall tension and transmural pressure, compromising coronary blood flow during diastole. In addition, the microvasculature beyond the epicardial coronary arteries has been shown to be dysfunctional in patients with hypertension, and it may be unable to compensate for increased metabolic and oxygen demand. The development and progression of arteriosclerosis, the hallmark of coronary artery disease, is exacerbated in arteries subjected to chronically elevated BP. Shear stress associated with hypertension and the resulting endothelial dysfunction cause impairment in the synthesis and release of the potent vasodilator nitric oxide. A decreased nitric oxide level promotes the development and acceleration of arteriosclerosis and plaque formation. Morphologic features of the plaque are identical to those observed in patients without hypertension.

Cardiac arrhythmias
Cardiac arrhythmias commonly observed in patients with hypertension include atrial fibrillation, premature ventricular contractions (PVCs), and ventricular tachycardia (VT).[7] The risk of sudden cardiac death is increased.[8] Various mechanisms thought to play a part in the pathogenesis of arrhythmias include altered cellular structure and metabolism, inhomogeneity of the myocardium, poor perfusion, myocardial fibrosis, and fluctuation in afterload. All of these may lead to an increased risk of ventricular tachyarrhythmias. Atrial fibrillation (paroxysmal, chronic recurrent, or chronic persistent) is observed frequently in patients with hypertension.[9] In fact, elevated BP is the most common cause of atrial fibrillation in the Western hemisphere. In one study, nearly 50% of patients with atrial fibrillation had hypertension. Although the exact etiology is not known, LA structural abnormalities, associated coronary artery disease, and LVH have been suggested as possible contributing factors. The development of atrial fibrillation can cause decompensation of systolic and, more importantly, diastolic dysfunction, owing to loss of atrial kick, and it also increases the risk of thromboembolic complications, most notably stroke. Premature ventricular contractions, ventricular arrhythmias, and sudden cardiac death are observed more often in patients with LVH than in those without LVH. The etiology of these arrhythmias is thought to be concomitant coronary artery disease and myocardial fibrosis.

Patient History
Symptoms of hypertensive heart disease depend on the duration, severity, and type of disease. In addition, the patient may or may not be aware of the presence of hypertension, which is why hypertension has been named "the silent killer."

Left ventricular hypertrophy

Patients with LVH alone are totally asymptomatic, unless the LVH leads to the development of diastolic dysfunction and heart failure.

Heart failure
Although symptomatic diastolic heart failure and systolic heart failure are indistinguishable, the clinical history may be quite revealing. In particular, individuals who abruptly develop severe symptoms of CHF and rapidly return to baseline with medical therapy are more likely to have isolated diastolic dysfunction. Heart failure symptoms include exertional and nonexertional dyspnea (New York Heart Association [NYHA] classes I-IV); orthopnea; paroxysmal nocturnal dyspnea; fatigue (more common in systolic dysfunction); ankle edema and weight gain; abdominal pain secondary to a congested, distended liver; and, in severe cases, altered mentation. Patients can present with acute pulmonary edema due to sudden decompensation in LV systolic or diastolic dysfunction. This decompensation can be caused by precipitating factors such as an acute rise in BP, dietary indiscretion, or myocardial ischemia. Patients can develop

cardiac arrhythmias, especially atrial fibrillation, or they can develop symptoms of heart failure insidiously over time.

Myocardial ischemia
Angina, a frequent complication of hypertensive heart disease, is indistinguishable from other causes of myocardial ischemia. Typical symptoms of angina include substernal chest pain lasting less than 15 minutes (vs >20min in infarction). Pain is often described as follows:

A heaviness, pressure, and/or squeezing Radiating to the neck, jaw, upper back, or left arm Provoked by emotional or physical exertion Relieved with rest or sublingual nitroglycerin

However, patients may also present with atypical symptoms without chest pain, such as exertional dyspnea or excessive fatigue, commonly referred to as an angina equivalent. Female patients, in particular, are more likely to present atypically. Patients may present with chronic, stable angina or acute coronary syndrome, including myocardial infarction without ST-segment elevation and acute myocardial infarction with ST elevation. Ischemic ECG changes may be found in individuals presenting with hypertensive crisis in whom no significant coronary atherosclerosis is detectable by coronary angiography. Acute coronary symptoms can be precipitated by a ruptured atherosclerotic plaque; they can also result from an acute and severe rise in BP that leads to a sudden increase in transmural pressure without a change in stability of the plaque.

Cardiac arrhythmias
Irregular or abnormal heart rhythms can cause a variety of symptoms, including the following:

Palpitations Near or total syncope Precipitation of angina Sudden cardiac death Precipitation of heart failure, especially with atrial fibrillation in diastolic dysfunction

Physical Examination
Physical signs of hypertensive heart disease depend on the predominant cardiac abnormality and the duration and severity of the hypertensive heart disease. Findings from the physical examination may be entirely normal in the very early stages of the disease, or the patient may have classic signs upon examination. In addition to generalized findings attributable directly to high BP, the physical examination may reveal clues to a potential etiology of hypertension, such as truncal obesity and striae in Cushing syndrome, renal artery bruit in renal artery stenosis, and abdominal mass in polycystic kidney disease.

Pulses
The arterial pulses are normal in the early stages of hypertensive heart disease. The cardiac rhythm is regular if the patient is in sinus rhythm; it is irregularly irregular if the patient is in atrial fibrillation. The heart rate is as follows:

Normal in patients in sinus rhythm Not normal in decompensated heart failure Tachycardic in patients with heart failure and in patients with atrial fibrillation and a rapid ventricular response

The pulse volume is usually normal, but it is decreased in patients with LV dysfunction. Additional findings may include radial-femoral delay if the etiology of hypertension is coarctation of the aorta

Blood pressure
Systolic and/or diastolic BP is elevated (>140/90mm Hg). Mean BP and pulse pressure are also elevated generally. The BP in the upper extremities may be higher than that in the lower extremities in patients with coarctation of the aorta. BP may be normal at the time of evaluation if the patient is on adequate antihypertensive medications or if the patient has advanced LV dysfunction and the LV cannot generate enough stroke volume and cardiac output to produce an elevated BP.

Veins
In patients with heart failure, the jugular veins may be distended. The predominant waves depend on the severity of the heart failure and any other associated lesions.

Heart
The apical impulse is sustained and nondisplaced in patients without significant systolic LV dysfunction but with LVH. A presystolic S4 may be felt. Later in the course of disease, when significant systolic LV dysfunction supervenes, the apical impulse is displaced laterally, owing to LV dilatation. In the right ventricle, a lift is present late in the course of heart failure if significant pulmonary hypertension develops. S1 is normal in intensity and character. S2 at the right upper sternal border is loud because of an accentuated aortic component (A2); it can have a reverse or paradoxical split due either to increased afterload or to associated left bundle-branch block (LBBB). S4 is frequently palpable and audible, implying the presence of a stiffened, noncompliant ventricle due to chronic pressure overload and LVH. S3 is not typically present initially, but it is audible in the presence of heart failure, either systolic or diastolic. An early decrescendo diastolic murmur of aortic insufficiency may be heard along the midparasternal to left parasternal area, especially in the presence of acutely elevated BP, frequently disappearing once the BP is better controlled. In addition, an early systolic to midsystolic murmur of aortic sclerosis is commonly audible. A holosystolic murmur of mitral

regurgitation may be present in patients with advanced heart failure and a dilated mitral annulus.

Lungs
Findings upon chest examination may be normal or may include signs of pulmonary congestion, such as rales, decreased breath sounds, and dullness to percussion due to pleural effusion.

Abdomen
The abdominal examination may reveal a renal artery bruit in patients with hypertension secondary to renal artery stenosis, a pulsatile expansile mass of abdominal aortic aneurysm, and hepatomegaly and ascites due to CHF.

Extremities
Ankle edema may be present in patients with advanced heart failure.

Central nervous system and ophthalmologic system

Central nervous system (CNS) examination findings are usually unremarkable unless the patient has had previous cerebrovascular accidents with residual deficit. CNS changes may also be seen in patients who present with hypertensive emergency. Examination of the fundi may reveal evidence of hypertensive retinopathy, the severity of which depends on the duration and severity of the patient's hypertension, or earlier signs of hypertension, such as aStaging

of Hypertension

Although hypertensive heart disease typically is not described in various stages, the disease usually progresses in the following sequence:

Increased wall stress leads to LVH Which leads to diastolic LV dysfunction Which can be followed by systolic LV dysfunction

The risks of ventricular ectopy, ventricular arrhythmias, sudden cardiac death, and cardiovascular mortality are increased in patients once LVH develops and are also increased in patients with heart failure. Table 1, below, shows the division of BP and hypertension into stages. Table 1. Stages of Elevated BP and Hypertension According to The Seventh Report of the Joint National Committee (JNC7) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure[12] (Open Table in a new window) Systolic BP, Diastolic BP, Category

mm Hg

mm Hg

Optimal < 120 Prehypertension 120-139 Stage I 140-159 Stage II >160 rteriovenous nicking

< 80 80-89 90-99 >100

Laboratory Studies
Laboratory studies are helpful in establishing the etiology of hypertension, quantitating the severity of target organ damage, and monitoring the adverse effects of therapy. The tests to be ordered depend on clinical judgment regarding the etiology of hypertension. Recommendations from the Seventh Report of the Joint National Committee (JNC7) on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure include carrying out the following baseline laboratory workup before initiating treatment for hypertension[12] :

Electrocardiogram Urinalysis Blood glucose and hematocrit levels Serum potassium, creatinine (or the corresponding estimated glomerular filtration rate [GFR]), and calcium measurements Lipid profile after a 9- to 12-hour fast - Includes high density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, and triglycerides Optional tests - Include measurement of urinary albumin excretion or albumin/creatinine ratio

Evaluating the renal system

Blood urea nitrogen (BUN) and creatinine levels are elevated in patients with renal failure. Other studies include the above-mentioned urinalysis, GFR, and urinary albumin excretion or albumin/creatinine ratio measurements.

Evaluating the endocrine system

Hypokalemia is found in patients with primary hyperaldosteronism and in patients with secondary hyperaldosteronism, Cushing disease, and Bartter syndrome. Hypokalemia is most useful in leading to further diagnostic studies if the patient has not received diuretics. Plasma renin activity is generally depressed and serum aldosterone level is elevated in patients with primary hyperaldosteronism. Twenty-four hour urinary catecholamine and metanephrine levels are elevated in patients with pheochromocytoma.

Elevated 24-hour urinary free cortisol and failure to suppress an early morning serum cortisol level after an overnight dexamethasone suppression test are observed in patients with Cushing disease. Thyrotropin levels may be elevated in patients with hypothyroidism and depressed in patients with hyperthyroidism.

Transthoracic Echocardiography
Transthoracic echocardiography (TTE) may be very useful for identifying features of hypertensive heart disease. TTE is more sensitive and specific then electrocardiography for diagnosing the presence of LVH (57% for mild and 98% for severe LVH). LVH is symmetrical, whereas the hypertrophy of hypertrophic cardiomyopathy is asymmetrical. The definition of the LVH based on echocardiography findings is somewhat controversial in the absence of any criterion standards. (See the images below.)

Two-dimensional echocardiogram (parasternal long axis view) from a 70-year-old woman showing concentric left ventricular hypertrophy and left atrial

enlargement. Two-dimensional echocardiogram (parasternal short axis view) from a 70-year-old woman showing concentric left ventricular hypertrophy.

M-mode echocardiogram from a 70-year-old woman showing

concentric left ventricular hypertrophy. Two-dimensional echocardiogram (parasternal short axis view at the aortic valve level) from a 70-year-old woman showing mild aortic sclerosis.

Calculating LV mass
On 2-dimensional (2-D) and M-mode examination, the interventricular septum is thickened, as is the posterior wall (>1.1cm). LVH is defined quantitatively as an increase in the LV mass or the LV mass index (LVMI), which is defined as LV mass divided by body surface area. Various formulas have been used to calculate LV mass, each with inherent drawbacks. The Troy formula was used in the Framingham Heart study. The American Society of Echocardiography (ASE)recommended formula for estimation of LV mass from LV linear dimensions (validated with necropsy) is based on modeling the LV as a prolate ellipse of revolution: LV mass = 0.8 {1.04[(LVIDd + PWTd + SWTd)3 - (LVIDd)3]} + 0.6g, where LVIDd is the internal dimension of the left ventricle at end diastole, PWTd is posterior wall thickness at end diastole, and SWTd is septal wall thickness at end diastole. This formula is appropriate for evaluating patients without major distortions of LV geometry (eg, patients with hypertension).[13] In various studies, LVH has been defined either as LV mass greater than 215g or greater than 225g. Because LV mass is affected by height, weight, and body surface area, LVMI more accurately sets the limits for LV mass. Framingham Heart Study data indicated that abnormal LVMI limits are 134g/m2 for men and 110g/m2 for women.

Flow velocity pattern

The transmitral flow velocity pattern, characterized by abnormally prolonged isovolumic relaxation time, a reversed "E:A" ratio (ie, reversed velocity of early diastole to peak flow velocity of atrial contraction), and a prolonged deceleration time, is abnormal. The patient may exhibit a pseudonormal pattern during the transition from the impaired relaxation to the restrictive filling phase. The tissue Doppler indices are abnormal. The tissue Doppler profile shows a reversed E:A ratio, which is especially helpful in patients who have a pseudonormal pattern on transmitral flow velocity Doppler studies.

Systolic dysfunction
Evidence of LV systolic dysfunction includes a dilated LV, low LV fractional shortening, low LV ejection fraction, and the presence of systolic dysfunction, which is commonly associated with some degree of diastolic dysfunction.

Aortic dilatation
LA dilatation may be demonstrated by evidence of right-sided dilatation (right-sided chambers may be dilated with some degree of pulmonary hypertension) and evidence of valvular abnormalities, such as aortic sclerosis (on 2-D TEE) and aortic and mitral insufficiency (on color flow and Doppler examination).

dditional Imaging Studies

Chest radiographs may show notching of the undersurface of the ribs from the development of collateral circulation in coarctation of the aorta; cardiomegaly in late stages of the disease, due to LV dilatation; cephalization of pulmonary blood flow, Kerley B lines, and alveolar infiltrates in the presence of elevated LV end-diastolic pressure and pulmonary congestion; and blunting of the costophrenic angle in the presence of pleural effusion. Computed tomography (CT) scanning, and magnetic resonance imaging (MRI) of the heart, although not used routinely, have been shown in experimental studies to quantify LVH. CT scanning, MRI, and magnetic resonance angiography (MRA) of the abdomen and chest show the presence of adrenal masses, renal artery stenosis, or evidence of coarctation of aorta. Nuclear imaging may be useful in screening for the presence of coronary artery disease.

Electrocardiography
A 12-lead ECG may show a variety of abnormalities. For example, ischemic ECG changes may be found in individuals presenting with hypertensive crisis in whom no significant coronary atherosclerosis is detectable by coronary angiography. Evidence of LA enlargement includes broad P waves in the limb leads and a prominent and wide, delayed negative deflection in V1. (See the images below.)

Electrocardiogram from a 47-year-old man with a longstanding history of uncontrolled hypertension showing left atrial enlargement and left

ventricular hypertrophy. Electrocardiogram from a 46-yearold man with long-standing hypertension showing left atrial abnormality and left ventricular hypertrophy with strain. In one series, among patients with left anterior fascicular block on ECG, 50% had hypertension. As many as 70-80% of patients with LBBB have hypertension.

LVH criteria
Various criteria, differing in sensitivity and specificity, have been used to diagnose LVH. Note that the specificities and sensitivities of the different approaches are far less than those of echocardiography. The frequency of LVH on ECG at the time of initial diagnosis varies from 10% to 100%; in one trial, for example, the frequency was 13%. The sensitivity of ECG for diagnosing LVH is limited, approximately 30-57% in patients with severe LVH.

The Cornell criteria (most sensitive) are (1) R wave in aVL plus an S wave in V3 of greater than 2.8 mV in men and greater than 2mV in women. The Cornell and Cornell voltage duration (Cornell voltage multiplied by QRS duration) criteria have a sensitivity as high as 95% and a specificity as high as 50-60%. A Cornell voltage duration of greater than 2440mV/ms-1 particularly identifies the highest-risk patients. The Sokolow-Lyon criteria are an S wave in V1 plus an R wave in V5 or V6 of greater than 3.5mV or an R wave in V5 or V6 of greater than 2.6mV. The sensitivity of these criteria is 25%, with a specificity of close to 95%. The Gubner-Ungerleider criteria are an R wave in I plus an S wave in III of greater than 2.5mV. Another set of LVH criteria, the Romhilt-Estes criteria, are summarized in Table 2, below. Table 2. Romhilt-Estes Criteria (A Point Score System*) (Open Table in a new window) Voltage Criteria R wave or S wave in any limb lead >0.2mV or S wave in lead V1 or V2 or R wave in V5 or V6 >0.3mV LV strain (ST and T waves in direction opposite to QRS direction) without digitalis LV strain (ST and T waves in direction opposite to QRS direction) with digitalis LA enlargement (terminal negativity of P waves in V1 >0.1mV deep and 0.04 seconds wide) Left-axis deviation greater than -30 QRS duration greater than 0.09 seconds Intrinsicoid deflection in V5 or V6 >0.05 seconds * Probable LVH is 4 points; definite LVH is 5 points. The sensitivity of these criteria is 50%, with a specificity of close to 95%. Points 3 3 1 3 2 1 1