Aortic stenosis (AS) is incomplete opening of the AV, which restricts blood flow out of the left ventricle during systole.
In developed countries, AS is the most prevalent valvular heart disease in adults. Observational echocardiography studies demonstrate that 2% of people 65 years of age or older have isolated calcific AS, whereas 29% exhibit age-related AV sclerosis without stenosis.12 AS is more common in men and prevalence increases with age. In patients aged 65 to 75 years, 75 to 85 years, and greater than 85 years, the prevalence of AS is 1.3, 2.4, and 4%, respectively.13 The most common causes of AS are acquired degenerative disease, bicuspid AV, and rheumatic heart disease.
The most common cause of AS is degenerative calcification of the AV, which typically occurs in septuagenarians and octogenarians. Progressive calcification, initially along the flexion lines at the leaflet bases, leads to immobilization of the cusps. The characteristic pathologic findings are discrete, focal lesions on the aortic side of the leaflets that can extend deep into the aortic annulus. The deposits may involve the sinuses of Valsalva and the ascending aorta. Although long considered to be the result of years of mechanical stress on an otherwise normal valve, it is now understood that the mechanical stress leads to proliferative and inflammatory changes, with lipid accumulation, upregulation of angiotensin-converting enzyme (ACE) activity, and infiltration of macrophages and T lymphocytes in a process similar to atherosclerosis.13–18 The risk factors for the development of calcific AS are also similar to those for atherosclerosis and include elevated serum levels of low-density lipoprotein (LDL) cholesterol, diabetes, smoking, and hypertension.13 Therefore, coronary artery disease is commonly present in patients with AS. Age-related AV sclerosis is associated with an increased risk of cardiovascular death and myocardial infarction (MI).
Calcific AS is also observed in a number of other conditions, including Paget's disease of bone and end-stage renal disease.19 Ochronosis with alkaptonuria is another rare cause of AS, which also can cause a rare greenish discoloration of the AV.20
A calcified bicuspid AV represents the most common form of congenital AS. Bicuspid AVs are present in approximately 2% of the general population. Gradual calcification of the bicuspid AV results in significant stenosis most often in the fifth and sixth decades of life, earlier in unicommissural than in bicuspid valves and earlier in men than women. The abnormal architecture of the unicommissural or bicuspid AV induces turbulent flow, which injures the leaflets and leads to fibrosis, increased rigidity, leaflet calcification, and narrowing of the AV orifice.21 Bicuspid valves are often associated with dilatation of the ascending aorta related to accelerated degeneration of the aortic media that in some cases may progress to aneurysm formation. Recent work suggests that a DNA transcriptional error in the gene encoding endothelial nitric oxide synthetase may be implicated in the genetic abnormality that leads to bicuspid AV.22 It appears that the microfibrils within the AV and the aortic root are defective in structure in patients with bicuspid AV disease. This leads to a decrease in mechanical support for the valve, thereby contributing to accelerated "wear and tear," and hence degenerative changes in the valve matrix.
Rheumatic Aortic Stenosis
In Western countries, rheumatic AS represents the least common form of AS in adults.23 Rheumatic AS is rarely an isolated disease and usually occurs in conjunction with mitral valve stenosis.24 Rheumatic AS is characterized by diffuse fibrous leaflet thickening with fusion, to a variable extent, of one or more commissures. The early stage of rheumatic AS is characterized by edema, lymphocytic infiltration, and revascularization of the leaflets, whereas the later stages are characterized by thickening, commissural fusion, and scarred leaflet edges.25
In adults with calcific disease, the AV slowly thickens over time. Early, it causes little hemodynamic disturbance as the valve area is reduced from the normal 3 to 4 cm2 to 1.5 to 2 cm2.13 Past this point, hemodynamically significant obstruction of LV outflow develops with a concomitant increase in LV pressure and lengthening of the LV ejection time. The elevated LV pressure increases wall stress. Wall stress is normalized by increased wall thickness and LV hypertrophy (LVH). As it hypertrophies, the left ventricle becomes less compliant and LV end-diastolic pressure (LVEDP) increases without chamber dilatation. This reflects diastolic dysfunction and the ventricle becomes increasingly dependent on atrial systole for filling.26 Hence, if a patient develops an atrial arrhythmia, he or she can rapidly decompensate.
Although adaptive, the concentric hypertrophy that develops has adverse consequences. LVH, increased systolic pressure, and prolonged ejection time all contribute to an increase in myocardial oxygen consumption. Increased diastolic pressure increases endocardial compression of the coronary arteries, reducing coronary flow reserve (or maximal coronary flow).27 Prolonged ejection also results in decreased time in diastole and therefore reduced myocardial perfusion time. The increased demand of the hypertrophied ventricle and decreased delivery capacity can yield subendocardial ischemia with activity. This can result in angina and LV dysfunction. LVH also makes the heart more susceptible to ischemic injury. Severe LVH is only partly reversed by AV replacement (AVR) and is associated with decreased long-term survival even after initially successful surgery.28
In late stages of severe AS, the left ventricle decompensates with resulting dilated cardiomyopathy and heart failure. Cardiac output (CO) declines and the pulmonary artery pressure rises, leading to pulmonary hypertension.
Myocardial hypertrophy in patients with AS is characterized by increased gene expression for collagen I and II, and fibronectin that is associated with activation of the renin-angiotensin system.22 Reduction in renin-angiotensin parallels regression of hypertrophy after AVR.29 Experimental studies have indicated a role of apoptotic mechanisms in the progression to LVH and heart failure in patients with AS.30 For 50% of patients who present with symptoms of congestive heart failure (CHF), mean survival is less than 1 year.31
The severity of AS can be assessed by measuring the AV orifice area (AVA), mean pressure gradient, and peak jet velocity. AVA is calculated by using CO, heart rate (HR), systolic ejection period (SEP), and mean pressure gradient in the Gorlin formula, which describes the fundamental relationships linking the area of an orifice to the flow and pressure drop across the orifice. The Gorlin formula is:
CO can be measured using the Fick or thermodilution technique. SEP is the time from AV opening to closure. The normal AVA is 2.6 to 3.5 cm2 in adults. Valve areas of less than 1.0 cm2 represent severe AS. In low-output states, the Gorlin formula may systematically predict smaller valve areas than are actually present. Several reports also indicate that the AVA from the Gorlin formula increases with increases in CO.32
In patients with AS, the transvalvular pressure gradient can be measured by simultaneous catheter pressure measurements in the left ventricle and proximal aorta. The peak-to-peak gradient, measured as the difference between peak LV pressure and peak aortic pressure, is used commonly to quantify the valve gradient.
Invasive measurements of AS severity have been largely replaced by echocardiographic measurements, which are currently the clinical standard. The Doppler acquired jet velocity is converted to a gradient using the Bernoulli equation, which is:
Gradient = 4 × (velocity)2
Transesophageal echocardiography (TEE) is an alternative method for assessment of AVA that uses planimetry of the systolic short-axis view of the AV (Fig. 31-6).33 Planimetry of the valve area is challenging because the valve orifice is a complex, three-dimensional shape, and area measurements assume the valve orifice lies entirely within the image plane.
Transesophageal echocardiographic image of aortic stenosis resulting from severe degenerative calcification. Transverse section of the aortic root at the level of the aortic valve orifice showing the aortic ring (arrow), the sinuses of Valsalva (asterisks), and a significantly reduced aortic valve orifice area of 0.44 cm2 (dotted line).
The cardinal symptoms of AS are angina pectoris, syncope, and symptoms of CHF (dyspnea, orthopnea, and paroxysmal nocturnal dyspnea).34 Although the mechanisms of angina and heart failure are well understood, the mechanism of syncope is less clear. A common theory is that the augmented stroke volume that usually accompanies exercise is limited by the narrowed outflow orifice. With exercise-induced reduction in peripheral arterial resistance, blood pressure drops, leading to cerebral hypoperfusion and syncope.35 Syncope also may be the result of dysfunction of baroreceptor mechanisms and a vasodepressor response to the increased LV systolic pressure during exercise. Besides these cardinal symptoms, patients also commonly present with more subtle symptoms, such as fatigue, decreased exercise tolerance, and dyspnea on exertion.36
Another rare presentation of AS is gastrointestinal bleeding secondary to angiodysplasia occurring predominantly in the right colon as well as the small bowel or stomach. This complication arises from shear-stress–induced platelet aggregation with reduction in high-molecular-weight multimers of von Willebrand factor and increases in proteolytic subunit fragments. These abnormalities correlate with the severity of AS and are correctable by AVR.37 Other late manifestations of severe AS include atrial fibrillation and pulmonary hypertension. Infective endocarditis can occur in younger patients with AS; it is less common in elderly patients with a severely calcified valve.
Patients who develop severe AS have a long period of asymptomatic progression in which morbidity and mortality is relatively low (Fig. 31-7). Sudden death from AS before the onset of symptoms is estimated to be approximately 1% per year.38 With the onset of symptoms, survival is dramatically reduced without surgical intervention. Of the 35% of patients who present with angina, 50% survive for 5 years. Of the 15% who present with syncope, 50% survive for 3 years, and mean survival for those who present with CHF is 2 years.34
Natural history of aortic stenosis. (From Ross J, Braunwald E. Aortic stenosis. Circulation 1968; 38(suppl 5):61-67.)
AS is frequently first diagnosed before symptom onset by auscultation of a murmur on physical exam. Classically, AS causes a systolic crescendo-decrescendo murmur, heard loudest at the right upper sternal border. Another sign of AS is a delayed second heart sound (S2) because of prolongation of the systolic ejection time. S2 also may be single when the aortic component is absent, and if the aortic component is audible, this may give rise to a paradoxical splitting of S2.
The classic pulsus parvus (small pulse) is a sign of severe AS or decompensated AS and occurs when stroke volume and systolic and pulse pressures fall. A wide pulse pressure is also characteristic of AS. Prolongation of the ejection phase with slow rise in the arterial pressure also gives rise to the pulsus tardus (late pulse). Pulsus parvus et tardus is diagnosed by palpation.
LVH is evident as a sustained apical thrust or heave. This sign is present only when failure occurs because until failure occurs, the hypertrophy is not accompanied by dilatation, and the apical impulse is not displaced. Conversely, absence of an apical thrust (except in muscular patients, or those with emphysema or adiposity) suggests mild or moderate AS. Other physical findings of significant AS include a prominent atrial kick and prominence of the jugular venous a wave secondary to decreased right ventricular compliance caused by right ventricular hypertrophy.39
Most patients with severe AS present with QRS complex or ST-T interval abnormalities reflecting LVH. Patients with a higher gradient are more likely to show a "strain" or "systolic overload" pattern. The conduction abnormalities may result from septal trauma secondary to high intramyocardial tension from hypoxic damage to the conducting fibers or from extension of valvular calcifications into the fibrous septum.
The roentgenographic characteristics of compensated AS include concentric hypertrophy of the left ventricle without cardiomegaly, poststenotic dilatation of the aorta, and calcification of the valve cusps. With decompensation, there is cardiomegaly in the posteroanterior projection and pulmonary venous congestion. It is important to recognize that a routine chest x-ray may be within normal limits in patients with hemodynamically compensated AS. The rounding of the lower-left heart border may be subtle, the poststenotic aortic dilatation may be equivocal, and the valvular calcification may be invisible on the posteroanterior view. Of equal importance, the presence of cardiomegaly in a normotensive patient with isolated AS indicates decompensated AS.
Echocardiography is the diagnostic tool of choice for confirming the diagnosis of AS and quantification of disease severity. Echocardiography is used to define: (1) the severity and etiology of AS; (2) coexisting valvular abnormalities; and (3) cardiac chamber size and function.
The development of diastolic dysfunction in patients with AS can lead to symptom development, and may increase late mortality after AVR.28,40 Hence, the quantification of diastolic dysfunction is important in the assessment of AS. LV filling pressures can be assessed by combining transmitral flow velocity and annular velocity obtained at the level of the mitral annulus with tissue Doppler (E/E').41 In patients with normal LV function (LVF), stress echocardiography is used to determine if symptom development during exercise is due to diastolic dysfunction.42 Diastolic dysfunction in patients with normal LVF may cause exercise intolerance for several reasons: (1) elevated LV diastolic and pulmonary venous pressures increase the work of breathing and cause dyspnea; (2) patients with LVH exhibit a limited ability to use the Frank-Starling mechanism during exercise, resulting in a decrease in CO during exercise; and (3) elevated LV diastolic and pulmonary venous pressures result in abnormalities in the diastolic properties of the ventricle.
When AS is suspected, an initial Doppler echocardiogram can confirm the diagnosis and assess the severity. Periodic re-examination, every 5 years for mild AS, every 2 years for moderate AS, and annually for severe AS, is recommended to identify worsening stenosis, LV dysfunction, LVH, and mitral regurgitation.43 Although AS is best understood as a disease continuum, severity can be graded by echocardiographic evaluation of hemodynamics. The current guidelines use definitions based on the AVA, mean pressure gradient, and peak jet velocity (Table 31-1).
Table 31-1 Classification of Aortic Stenosis Severity ||Download (.pdf)
Table 31-1 Classification of Aortic Stenosis Severity
|Aortic valve area (cm2)||>1.5||1.0–1.5||<1.0|
|Aortic valve area index (cm2 per m2)||<0.6|
|Mean pressure gradient (mm Hg)||<25||25–40||>40|
|Peak jet velocity (m/sec)||<3.0||3.0–4.0||>4.0|
Traditionally, severe AS has been regarded as a relative contraindication to exercise testing. Exercise testing should be avoided in symptomatic patients with AS as well. Recent studies have indicated that quantitative exercise Doppler echocardiography can be performed safely in asymptomatic patients and may be useful for identifying patients who at higher risk of becoming symptomatic and/or requiring AVR. Several studies have shown that asymptomatic patients with severe AS who become symptomatic on exercise stress testing, have a higher rate of cardiac death or progression to AVR.44,45 Dobutamine stress echocardiography is occasionally used in severe AS, specifically to assess contractile reserve in patients with moderate to severe AS with a low AV gradient and depressed LVF.46,47
Although Doppler echocardiography is well validated, cardiac catheterization remains the gold standard for measuring the transvalvular gradient. Because coronary artery disease is common in patients with AS, coronary angiography is usually performed in patients with severe AS to assess coronary anatomy and evaluate the need for combined AVR and myocardial revascularization. Right-sided heart catheterization is also used to calculate the AVA based on the Gorlin equation, as described earlier. Cardiac catheterization can also provide an assessment of ejection fraction (EF) through ventriculography and also may provide information about the presence or absence of other valve lesions.
Computed tomography (CT) can be used to assess progression of AS. Electrocardiographically gated multidetector row CT has shown high accuracy and reproducibility in quantifying AV calcification and its progression48 and estimating AVA by planimetry.49 The quantification of calcification may develop into clinical applications with respect to the prognostic relevance of AV sclerosis, as well as the problem of calcification of bioprostheses after surgery.
Magnetic Resonance Imaging
Cardiac magnetic resonance imaging (MRI) has emerged as an alternative noninvasive imaging modality for AS.50 Similar to echocardiography, cardiac MRI records images throughout the cardiac cycle. Cardiac MRI uses a range of pulse sequences to assess structural heart disease. The steady-state free precession (SSFP) cine pulse sequence is commonly used in cardiac MRI and provides detailed images of AV leaflet number, leaflet thickening, valve calcification, and commissural fusion. This sequence is also useful for assessing the effects of AS, including LVH and LVF.51 MRI is useful when acoustic windows in the echocardiogram are poor or there are discordant imaging and catheterization results.52,53 MRI has also been used to demonstrate improvement in LVF, myocardial metabolism, and diastolic function, as well as reduced hypertrophy after AVR for AS.54
There is no effective medical therapy for AS. Given the biologic similarity of the calcific lesions of AS to atherosclerosis, there has been substantial effort to investigate the role of lipid-lowering agents in slowing the progression of AS, but to date prospective randomized trials have not found any benefit.55,56 Prophylactic antibiotics are recommended before any dental or surgical procedures as a prevention strategy for endocarditis.43 Management of CHF from AS has traditionally consisted of diuretics and ionotropes. Beta-blockers are avoided as reduced inotropy may lead to decreased CO in an overloaded ventricle. Classically, vasodilators are avoided in AS because their administration can lead to hypotension, syncope, and reduced coronary perfusion.
Percutaneous balloon valvuloplasty (valvotomy) is effective in congenital AS, but in adults the valve tends to re-stenose, and the procedure has no effect on long-term mortality.17 Currently, valvuloplasty is recommended only as a possible bridge to surgical intervention or a palliative measure.43 AV repair for AS has yielded poor results compared with AVR.57
The definitive treatment for severe AS is AVR, and onset of symptoms is the primary indication for AVR. As the risk of asymptomatic severe AS is perceived to be low, symptom onset remains the primary indication. Survival after successful AVR is reduced in younger patients but mimics that of the normal population in older patients.28,58,59
Percutaneous AVR represents a novel, less invasive approach to the treatment of AS. This approach has been applied successfully in high-risk patients with severe symptomatic AS who were not deemed candidates for conventional surgery.60
AVR in asymptomatic patients is currently controversial. Current guidelines recommend AVR for patients with symptomatic AS, for patients with asymptomatic moderate or severe AS who also require coronary revascularization or surgery of the aorta, and for patients with severe AS and reduced EF.43 As AVR has become a safer procedure and technology for assessing disease severity has improved, it is likely that an identifiable high-risk subset of asymptomatic patients with severe AS could benefit from AVR. Studies show that asymptomatic patients with an aortic jet velocity greater than 4 m/sec,36 patients with high rates of aortic jet velocity progression and valve calcification,61 and those with small AVAs and LVH38 progress to symptom development quickly and will soon require AVR. Exercise stress testing, as described earlier, is also useful to stratify high-risk patients.
A number of recent studies have explored the potential benefit of AVR in asymptomatic patients. In studies of propensity matched cohorts of asymptomatic patients with severe AS, those who had AVR had significantly improved survival.62,63 It has also been shown that, among patients undergoing AVR for severe AS, LVH is only partly reversed and is associated with decreased long-term survival even after initially successful surgery. This suggests that intervening before development of LVH may improve outcomes.28 In summary, there is increasing evidence that AVR can be beneficial in a subset of asymptomatic patients with severe AS.