Valvular Heart Disease

Causes and Prevalence

Valvular aortic stenosis (AS) in older adults is usually due to stiffening, scarring, and calcification of the aortic valve leaflets. The commissures are not fused, as in rheumatic AS. Calcific deposits in the aortic valve are common in older adults and may lead to valvular AS. Aortic cuspal calcium was present in 295 of 752 men (36%), mean age 80 years, and in 672 of 1663 women (40%), mean age 82 years. Of 2358 persons, mean age 81 years, 378 (16%) had valvular AS, 981 (42%) had valvular aortic sclerosis (thickening of or calcific deposits on the aortic valve cusps, with a peak flow velocity across the aortic valve = 1.5 m/sec), and 999 (42%) had no valvular AS or aortic sclerosis. Calcific deposits in the aortic valve were present in 22 of 40 necropsy patients (55%) aged 90 to 103 years. Calcium of the aortic valve and mitral annulus may coexist.

In the Helsinki Aging Study, calcification of the aortic valve was diagnosed by Doppler echocardiography in 28% of 76 persons aged 55 to 71 years, in 48% of 197 persons aged 75 to 76 years, in 55% of 155 persons aged 80 to 81 years, and in 75% of 124 persons aged 85 to 86 years. Aortic valve calcification, aortic sclerosis, and mitral annular calcium (MAC) are degenerative processes, accounting for their high prevalence in older adults.

Otto and colleagues have shown that the early lesion of degenerative AS is an active inflammatory process, with some similarities to atherosclerosis, including lipid deposition, macrophage and T cell infiltration, and basement membrane disruption. In a study of 571 persons, mean age 82 years, 292 (51%) had calcified or thickened aortic cusps or root. A serum total cholesterol of 200 mg/dL, a history of hypertension, diabetes mellitus, and a serum high-density lipoprotein cholesterol level less than 35 mg/dL were more prevalent in older adults with calcified or thickened aortic cusps or root than in older adults with normal aortic cusps and root.

In the Helsinki Aging Study, age, hypertension, and a low body mass index were independent predictors of aortic valve calcification. In 5201 persons older than 65 years in the Cardiovascular Health Study, independent clinical factors associated with degenerative aortic valve disease included age, male gender, smoking, history of hypertension, height, and high lipoprotein(a) and low-density lipoprotein (LDL) cholesterol levels. In 1275 older adults, mean age 81 years, AS was present in 52 of 202 (26%) with 40% to 100% extracranial carotid arterial disease (ECAD) and in 162 of 1073 (15%) with 0% to 39% ECAD. In 2987 older adults, mean age 81 years, symptomatic peripheral arterial disease occurred in 193 of 462 (42%) with AS and in 639 of 2525 (25%) without AS.

In 290 persons, mean age 79 years, with valvular AS, who had follow-up Doppler echocardiography, older adults with MAC had a greater reduction in aortic valve area per year than older adults without MAC. Significant independent risk factors for the progression of valvular AS in 102 older adults, mean age 76 years, who had follow-up Doppler echocardiography were cigarette smoking and hypercholesterolemia. Palta and associates have also shown that cigarette smoking and hypercholesterolemia accelerate the progression of AS. These and other data suggest that aortic valve calcium, MAC, and coronary atherosclerosis in older adults have similar predisposing factors.

A retrospective analysis of 180 older adult patients with mild AS who had follow-up Doppler echocardiography at 2 or more years showed that significant independent predictors of the progression of AS were male gender, cigarette smoking, hypertension, diabetes mellitus, serum LDL cholesterol level equal to 125 mg/dL at follow-up, serum high-density lipoprotein (HDL) cholesterol level less than 35 mg/dL at follow-up, and use of statins (inverse association). A retrospective analysis of 174 older adult patients, mean age 68 years, with mild to moderate AS showed that statin therapy reduced the progression of AS. In a retrospective study of 156 older adult AS patients, mean age 77 years, statin therapy decreased the progression of AS by 54% at 3.7-year follow-up.

In a prospective open-label study of 121 patients with an aortic valve area between 1.0 and 1.5 cm ² , 61 patients with a serum LDL cholesterol level greater than 130 mg/dL were treated with rosuvastatin and 60 patients with a serum LDL cholesterol level less than 130 mg/dL did not receive statins. At 73-week follow-up, patients treated with rosuvastatin had significantly less progression of AS. These data differ from the results reported in 155 patients in the Scottish Aortic Stenosis and Lipid Lowering Trial, Impact on Regression Study, which included patients with extensive aortic valve calcification. Two trials are in progress investigating the effect of statins on AS.

The frequency of AS increases with age. Valvular AS, as diagnosed by Doppler echocardiography, was present in 141 of 924 older men (15%), mean age 80 years, and in 322 of 1881 older women (17%), mean age 81 years. Severe valvular AS (peak gradient across aortic valve = 50 mm Hg, or aortic valve area < 0.75 cm ² ) was diagnosed in 62 of 2805 older adults (2%). Moderate valvular AS (peak gradient across aortic valve = 26 to 49 mm Hg, or aortic valve area = 0.75 to 1.49 cm ² ) was present in 149 of 2805 older adults (5%). Mild valvular AS (peak gradient across aortic valve =10 to 25 mm Hg, or aortic valve area = 1.50 cm ² ) occurred in 250 of 2805 older adults (9%). In 501 unselected older adults aged 75 to 86 years in the Helsinki Aging Study, critical AS was present in 3% and moderate to severe AS was present in 5% of the 501 older adults.

Pathophysiology

In valvular AS, there is resistance to ejection of blood from the left ventricle into the aorta, with a pressure gradient across the aortic valve during systole and an increase in left ventricular (LV) systolic pressure. The pressure overload on the left ventricle leads to concentric LV hypertrophy, with an increase in LV wall thickness and mass, normalizing systolic wall stress, and maintenance of normal LVEF (LVEF) and cardiac output. A compensated hyperdynamic response is common in older women. Older adults with a comparable degree of AS have more impairment of LV diastolic function than younger persons. Coronary vasodilator reserve is more severely impaired in the subendocardium in patients with LV hypertrophy caused by severe AS.

The compensatory concentric LV hypertrophy leads to abnormal LV compliance, LV diastolic dysfunction with decreased LV diastolic filling, and increased LV end-diastolic pressure, further increased by left atrial systole. Left atrial enlargement develops. Atrial systole plays an important role in diastolic filling of the left ventricle in those with AS. Loss of effective atrial contraction may cause immediate clinical deterioration in those with severe AS.

Sustained LV hypertrophy eventually leads to LV chamber dilation, with reduced LVEF and ultimately congestive heart failure (CHF). The stroke volume and cardiac output decrease, mean left atrial and pulmonary capillary pressures increase, and pulmonary hypertension occurs. Older adults with both obstructive and nonobstructive coronary artery disease have an increased incidence of LV enlargement and LV systolic dysfunction. In a percentage of older adults with AS, the LVEF will remain normal, and LV diastolic dysfunction will be the main problem.

In 48 older adults with CHF associated with unoperated severe valvular AS, the LVEF was normal in 30 of them (63%). The prognosis of those with AS and LV diastolic dysfunction is usually better than that of those with AS and LV systolic dysfunction, but is worse than that of those without LV diastolic dysfunction.

Symptoms

Angina pectoris, syncope or near-syncope, and CHF are the three classic manifestations of severe AS. Angina pectoris is the most common symptom associated with AS in older adults. Coexistent coronary artery disease (CAD) is frequently present in them. However, angina pectoris may occur in the absence of CAD as a result of an increase in myocardial oxygen demand, with a decrease in myocardial oxygen supply at the subendocardial level. Myocardial ischemia in those with severe AS and normal coronary arteries is due to inadequate LV hypertrophy, with increased LV systolic and diastolic wall stresses causing reduced coronary flow reserve.

Syncope in persons with AS may be caused by decreased cerebral perfusion following exertion when arterial pressure falls because of systemic vasodilation in the presence of a fixed cardiac output. LV failure with a reduction in cardiac output may also cause syncope. In addition, syncope at rest may be caused by a marked decrease in cardiac output secondary to transient ventricular or atrial fibrillation or transient atrioventricular block related to extension of the valve calcification into the conduction system. Coexistent cerebrovascular disease with transient cerebral ischemia may contribute to syncope in older adults with AS.

Exertional dyspnea, paroxysmal nocturnal dyspnea, orthopnea, and pulmonary edema may be caused by pulmonary venous hypertension associated with AS. Coexistent CAD and hypertension may contribute to CHF in older adults with AS. Atrial fibrillation may also precipitate CHF in these persons.

CHF, syncope, or angina pectoris was present in 36 of 40 older adults (90%) with severe AS, in 66 of 96 older adults (69%) with moderate valvular AS, and in 45 of 165 older adults (27%) with mild valvular AS.

Sudden death occurs mainly in symptomatic AS older adults. It may also occur in 3% to 5% of asymptomatic older adults with AS. Marked fatigue and peripheral cyanosis in those with AS may be caused by a low cardiac output. Cerebral emboli causing stroke or transient cerebral ischemic attack, bacterial endocarditis, and gastrointestinal bleeding may also occur in older adults with AS.

Signs

A systolic ejection murmur heard in the second right intercostal space, down the left sternal border toward the apex, or at the apex is classified as an aortic systolic ejection murmur (ASEM). An ASEM is commonly heard in older adults, occurring in 265 of 565 unselected older adults (47%). Of 220 older adults with an ASEM and technically adequate M-mode and two-dimensional echocardiograms of the aortic valve, 207 (94%) had aortic cuspal or root calcification or thickening. Of 75 older adults with an ASEM, valvular AS was diagnosed by continuous-wave Doppler echocardiography in 42 of them (56%).

Table 43-1 shows that an ASEM was heard in 100% of 19 older adults with severe AS, in 100% of 49 older adults with moderate AS, and in 95% of 74 older adults with mild AS. However, the ASEM may become softer or absent in persons with CHF associated with severe AS because of a low cardiac output. The intensity and maximal location of the ASEM and transmission of the ASEM to the right carotid artery do not differentiate among mild, moderate, and severe AS. The ASEM may be heard only at the apex in some older adults with AS. The apical systolic ejection murmur may also be louder and more musical than the basal systolic ejection murmur in some older adults with AS. The intensity of the ASEM in valvular AS increases with squatting and by inhalation of amyl nitrite and decreases during the Valsalva maneuver.

Prolonged duration of the ASEM and late peaking of the ASEM best differentiate severe AS from mild AS. However, the physical signs do not distinguish between severe and moderate AS (see Table 43-1 ).

A prolonged carotid upstroke time does not differentiate between severe and moderate AS in older adults. A prolonged carotid upstroke time was palpable in 3% of older adults with mild AS, in 33% of older adults with moderate AS, and in 53% of older adults with severe AS (see Table 43-1 ). Stiff noncompliant arteries may mask a prolonged carotid upstroke time in older adults with severe AS. The pulse pressure may also be normal or wide rather than narrow in older adults with severe AS because of loss of vascular elasticity. An aortic ejection click is rare in older adults with severe AS because of loss of vascular elasticity and because the valve cusps are immobile.

An absent or reduced A ₂ occurs more frequently in older adults with severe or moderate AS than in persons with mild AS (see Table 43-1 ). However, an absent or decreased A ₂ does not differentiate between severe and moderate AS. The presence of atrial fibrillation, reversed splitting of S ₂ , or an audible fourth heart sound at the apex also does not differentiate between severe and moderate AS in older adults. The presence of a third heart sound in older adults with AS usually indicates the presence of LV systolic dysfunction and elevated LV filling pressure.

Diagnosis

Natural History

Ross and Braunwald have demonstrated that the average survival rate was 3 years after the onset of angina pectoris in those with severe AS. They reported that their average survival rate after the onset of syncope was 3 years and that the average survival rate after the onset of CHF in those with severe AS was 1.5 to 2 years.

Persons with symptomatic severe valvular AS have a poor prognosis. At the National Institutes of Health, 52% of those with symptomatic severe valvular AS not operated on were dead at 5 years. At 10-year follow-up, 90% of them were dead.

At 4-year follow-up of older adult patients aged 75 to 86 years in the Helsinki Aging Study, the incidence of cardiovascular mortality was 62% in those with severe AS and 35% in those with moderate AS. At 4-year follow-up, the incidence of total mortality was 76% in those with severe AS and 50% in those with moderate AS.

In a prospective study, at 19-month follow-up (range, 2 to 36 months), 90% of 30 older adult patients with CHF associated with unoperated severe AS and a normal LVEF were dead. At 13-month follow-up (range, 2 to 24 months), 100% of 18 older adult patients with CHF associated with unoperated severe AS and an abnormal LVEF had died.

Table 43-2 shows the incidence of new coronary events in older adults with no, mild, moderate, and severe AS. Independent risk factors for new coronary events in this study were prior myocardial infarction, AS, male gender, and increasing age. In this prospective study, at 20-month follow-up of 40 older adults with severe AS, CHF, syncope, or angina pectoris was present in 36 of 37 (97%) who developed new coronary events and in 0 of 3 (0%) without new coronary events. At 32-month follow-up of 96 older adults with moderate valvular AS, CHF, syncope, or angina pectoris was present in 65 of 77 (84%) who developed new coronary events and in 1 of 19 (5%) without new coronary events. At 52-month follow-up of 165 older adults with mild AS, CHF, syncope, or angina pectoris was present in 40 of 103 older adult patients (39%) who developed new coronary events and in 5 of 62 older adult patients (8%) without new coronary events.

In a prospective study of 981 older adults, mean age 82 years, with aortic sclerosis and of 999 older adults, mean age 80 years, without valvular aortic sclerosis, older adults with aortic sclerosis at 46-month follow-up had a 1.8 times higher chance of developing a new coronary event than those without valvular aortic sclerosis. Otto and colleagues also reported that AS and aortic sclerosis increased cardiovascular morbidity and mortality in 5621 men and women aged 65 years.

Kennedy and associates followed 66 older adults with moderate AS diagnosed by cardiac catheterization (aortic valve area, 0.7 to 1.2 cm ² ). In 38 older adults with symptomatic moderate AS and 28 older adults with minimally symptomatic moderate AS, the probabilities of avoiding death from AS were 0.86 and 1.0 for those with minimally symptomatic moderate AS at 1-year follow-up, 0.77 for those with symptomatic AS and 1.0 for those with minimally symptomatic AS at 2 years, 0.77 for those with symptomatic AS and 0.96 for those with minimally symptomatic AS at 3 years, and 0.70 for those with symptomatic AS and 0.90 for those with minimally symptomatic AS at 4 years. During the 35-month mean follow-up in this study, 21 older adults underwent aortic valve replacement.

The Veterans Administration Cooperative Study on Valvular Heart Disease followed 106 older adults with unoperated AS for 5 years. During follow-up, 60 of 106 older adults (57%) died. Multivariate analysis has demonstrated that measures of the severity of the AS, presence of CAD, and presence of CHF were the important predictors of survival in unoperated older adults.

Studies have shown that patients with asymptomatic severe AS are at low risk for death and can be followed until symptoms develop. Turina and colleagues followed 17 older adults with asymptomatic or mildly symptomatic AS. During the first 2 years, none died or had aortic valve surgery. At 5-year follow-up, 94% were alive and 75% were free of cardiac events. Kelly and associates followed 51 asymptomatic older adults with severe AS. During 17-month follow-up, 21 (41%) of them became symptomatic. Only 2 of 51 (4%) died of cardiac causes. In both of them, death was preceded by the development of angina pectoris or CHF. Pellikka and coworkers showed that 113 of 143 older adults (79%), mean age 72 years, with asymptomatic severe AS were not initially referred for AVR or percutaneous aortic balloon valvuloplasty. During 20-month follow-up, 37 of 113 of them (33%) became symptomatic. The actuarial probability of remaining free of cardiac events associated with AS, including cardiac death and aortic valve surgery, was 95% at 6 months, 93% at 1 year, and 74% at 2 years. No asymptomatic older adult with severe AS developed sudden death while asymptomatic.

Rosenhek and colleagues followed 126 older adults with asymptomatic severe AS for 22 months. Eight of them died and 59 of them developed symptoms necessitating aortic valve replacement. Event-free survival was 67% at 1 year, 56% at 2 years, and 33% at 4 years. Five of the six deaths from cardiac disease were preceded by symptoms. Of those with moderately or severely calcified aortic valves whose aortic jet velocity increased by 0.3 m/sec or more within 1 year, 79% underwent AVR or died within 2 years of the observed increase.

However, other studies have demonstrated that those with asymptomatic severe AS should be considered for AVR (AVR). Of 338 older adult patients with severe asymptomatic AS, mean age 71 years, 99 (29%) had AVR during a mean follow-up of 3.5 years. Survival at 1, 2, and 5 years in the nonoperated patients was 67%, 56%, and 38%, respectively, compared with 94%, 93%, and 90%, respectively, in those who underwent AVR ( P < .0001). In this study, unoperated patients had a 48% significant reduction in mortality if they were treated with statins and a significant 48% reduction in mortality if they were treated with β-blockers.

Data were analyzed for 622 older adult patients, mean age 72 years, with asymptomatic severe AS at the Mayo Clinic. After the initial diagnosis, 166 (27%) developed chest pain, shortness of breath, or syncope and had AVR. Another 97 older adult patients (16%) had AVR in the absence of symptoms. The operative mortality was 2% for the symptomatic patients and 1% for the asymptomatic patients. The survival of the 263 older adult patients who had AVR was not significantly different from an age- and gender-matched population. The 10-year survival was 64% for symptomatic patients and 64% for asymptomatic patients who had AVR. At 3 years after the diagnosis of severe AS, 52% of the 622 older adult patients had had symptoms develop, had undergone AVR, or had died. Absence of AVR was an independent risk factor for mortality, with a hazard ratio of 3.53.

Treatment

Causes and Prevalence

Acute aortic regurgitation (AR) in older adults may be due to infective endocarditis, rheumatic fever, aortic dissection, trauma following prosthetic valve surgery, or rupture of the sinus of Valsalva and causes sudden severe LV failure. Chronic AR in older adults may be caused by valve leaflet disease (secondary to any cause of AS, infective endocarditis, rheumatic fever, congenital heart disease, rheumatoid arthritis, ankylosing spondylitis, following prosthetic valve surgery, or myxomatous degeneration of the valve) or by aortic root disease. The cause of aortic root disease causing chronic AR in older adults includes association with systemic hypertension, syphilitic aortitis, cystic medial necrosis of the aorta, ankylosing spondylitis, rheumatoid arthritis, Reiter disease, systemic lupus erythematosus, Ehler-Danlos syndrome, and pseudoxanthoma elasticum. Mild or moderate AR was also diagnosed by Doppler echocardiography in 9 of 29 persons (31%) with hypertrophic cardiomyopathy.

The prevalence of AR increases with age. Margonato and colleagues linked the increased prevalence of AR with age to aortic valve thickening. In a prospective study of 450 unselected older adults, mean age 82 years, AR was diagnosed by pulsed Doppler echocardiography in 39 of 114 men (34%) and in 92 of 336 women (27%). Severe or moderate AR was diagnosed in 74 of 450 older adults (16%). Mild AR was diagnosed in 57 of 450 older adults (13%). In a prospective study of 924 men, mean age 80 years, and 1881 women, mean age 82 years, valvular AR was diagnosed by pulsed Doppler recordings of the aortic valve in 282 of 924 men (31%) and in 542 of 1881 women (29%).

Pathophysiology

The primary determinants of AR volume are the regurgitant orifice area, transvalvular pressure gradient, and duration of diastole. Chronic AR increases LV ventricular end-diastolic volume. The largest LV end-diastolic volumes are seen in those with chronic severe AR. LV stroke volume increases to maintain the forward stroke volume. The increased preload causes an increase in LV diastolic stress and the addition of sarcomeres in series, which results in an increase in the ratio of the LV chamber size to wall thickness. This pattern of LV hypertrophy is termed eccentric left ventricular hypertrophy .

Primary myocardial abnormalities or ischemia due to coexistent CAD decrease the contractile state. LV diastolic compliance decreases, LV end-systolic volume increases, LV end-diastolic pressure rises, left atrial pressure increases, and pulmonary venous hypertension result. When the LV end-diastolic radius-to-wall thickness ratio rises, LV systolic wall stress increases abnormally because of the preload and afterload mismatch. Additional stress then decreases the LVEF response to exercise. Eventually, the LVEF, forward stroke volume, and effective cardiac output are decreased at rest. My colleagues and I have demonstrated that an abnormal resting LVEF occurs in 8 of 25 older adults (32%) with CHF associated with chronic severe AR.

In those with acute severe AR, the left ventricle cannot adapt to the increased volume overload. Forward stroke volume falls, LV end-diastolic pressure increases rapidly to high levels, and pulmonary hypertension and pulmonary edema result. The rapid rise of the LV end-diastolic pressure to exceed the left atrial pressure in early diastole causes premature closure of the mitral valve. This prevents backward transmission of the elevated LV end-diastolic pressure to the pulmonary venous bed.

Symptoms

Persons with acute AR develop symptoms due to the sudden onset of CHF, with marked dyspnea and weakness. Persons with chronic AR may remain asymptomatic for many years. Mild dyspnea on exertion and palpitations, especially on lying down, may occur. Exertional dyspnea, orthopnea, paroxysmal nocturnal dyspnea, fatigue, and edema are common clinical symptoms when LV failure occurs. Syncope is rare. Angina pectoris occurs less often in older adult patients with AR than in older adult patients with AS and may be due to coexistent CAD. However, nocturnal angina pectoris, often accompanied by flushing, diaphoresis, and palpitations, may develop when the heart rate slows and arterial diastolic pressure falls to very low levels. Most of those with severe AR who do not have surgery die within 2 years after CHD develops.