The New England Journal of Medicine -- August 31, 2000 -- Vol. 343, No. 9
Aortic Stenosis -- Listen to the Patient, Look at the Valve
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Over the past 15 years, the increasing use of echocardiography has dramatically changed our understanding of the prevalence and progression of aortic-valve stenosis. Aortic stenosis may be due to rheumatic disease or to calcification of a congenitally bicuspid or normal trileaflet valve. However, in the United States and Europe, calcific valvular disease is by far the most common cause of aortic stenosis.
We now recognize that calcific valvular disease is not simply a degenerative condition associated with aging but, instead, represents the end stage of an active disease process. In the early stages, the aortic side of the valve contains focal lesions characterized by thickening of the subendothelium and adjacent fibrosa (the central, collagenous layer of the leaflet). These lesions contain low density-lipoprotein, Lp(a) lipoprotein, macrophages, and T lymphocytes. (1,2,3) Areas of microscopic calcification form within regions of lipoprotein accumulation, and some macrophages within lesions produce osteopontin, a protein that modulates tissue calcification. (4)
This stage of the disease process is evident on echocardiography as mild, irregular leaflet thickening without obstruction of ventricular outflow and is termed aortic sclerosis. In population-based studies, the prevalence of aortic sclerosis increases with age; it is present in approximately 25 percent of adults over the age of 65 years. (5,6) As the disease progresses, calcification and fibrosis increase leaflet stiffness and reduce systolic opening, eventually leading to a reduction in the area of the valve and an increase in forward velocity. Clinically significant obstruction of flow through the valve is present in about 1 to 2 percent of adults over the age of 65 years, and it is likely that most of these patients will ultimately have symptoms necessitating valve replacement.
Obstruction of left ventricular outflow results in pressure overload, with compensatory hypertrophy to maintain normal wall stress (stress is directly related to intracavitary pressure and chamber size and inversely related to wall thickness). Unlike the situation in patients with aortic regurgitation, in whom chronic volume overload leads to progressive dilatation and asymptomatic left ventricular dysfunction, systolic function is typically preserved in patients with aortic stenosis. (7) Furthermore, even if the ejection fraction is depressed late in the course of the disease, systolic function improves after valve replacement, thanks to the resultant decrease in afterload. (8) In adults with aortic stenosis, in contrast to those with aortic regurgitation, clinical outcome is most closely related to the presence or absence of symptoms.
Once symptoms occur, the clinical outcome is extremely poor, with two-year survival rates below 50 percent. It is well established that this dismal prognosis can be reversed by valve replacement with acceptable levels of operative mortality and morbidity and postoperative survival similar to that of age-matched normal adults. (9) In adults with symptoms that may be due to aortic stenosis who have a systolic murmur on auscultation, echocardiography is essential to identify those who are likely to benefit from surgical intervention. Although the decision has to be individualized, surgery should be considered even for very elderly persons and those with left ventricular dysfunction, since these groups of patients often benefit substantially from the relief of outflow obstruction. (8,10)
In contrast, adults with asymptomatic aortic stenosis have an excellent clinical prognosis. The condition is often diagnosed in such patients when a systolic murmur is found on physical examination, with a subsequent echocardiogram showing aortic-valve disease. The simplest measure of the extent of stenosis is the forward velocity across the valve. This velocity is about 1.0 m per second in normal valves and increases to 2.5 to 2.9 m per second in cases of mild stenosis, 3.0 to 4.0 m per second in cases of moderate stenosis, and more than 4.0 m per second in cases of severe stenosis. Measurement of the area of the valve is also useful for distinguishing mild disease (with an area above 1.5 cm2), moderate disease (1.0 to 1.5 cm2), and severe disease (less than 1.0 cm2). The average rate of hemodynamic progression of aortic stenosis is characterized by an increase in aortic-jet velocity of 0.3 m per second per year and a decrease in aortic-valve area of 0.1 cm2 per year, but there is wide individual variation in the rate of progression. (11) Interestingly, there also is substantial variation in the degree of stenosis associated with the onset of symptoms; as a result, many asymptomatic patients with hemodynamically severe obstruction are now identified by echocardiography. These patients and their physicians are often uncertain about the expected course of the disease and about whether valve replacement should be considered before symptoms appear.
In this issue of the Journal, Rosenhek and colleagues (12) report on a prospective study conducted to identify predictors of clinical outcome in adults with severe asymptomatic aortic stenosis. In their patients, all of whom had an aortic-jet velocity of more than 4.0 m per second, the proportion in whom symptoms developed approximated that in a previous study from my institution, (11) in which similar groups of patients were compared. In our study, which included patients with a range of degrees of stenosis, from mild to severe, aortic-jet velocity was a strong predictor of outcome; a velocity of more than 4.0 m per second was associated with a mean (±SD) event-free survival of only 21±18 percent at 2 years. (11) In both studies, a faster rate of hemodynamic progression was associated with a higher likelihood of the development of symptoms; in the study by Rosenhek et al., (12) an increase in aortic-jet velocity of at least 0.3 m per second per year identified a high-risk group.
It is noteworthy that the extent of valve calcification was the only independent predictor of clinical outcome in the study by Rosenhek et al. (12) Although aortic-valve calcification was not considered in the study by my colleagues and me, (11) this finding corroborates my clinical experience and is congruent with our understanding of the disease process at the tissue level. The study by Rosenhek et al. included a relatively high percentage of patients with rheumatic disease, and these patients accounted for the bulk of those with only mild calcification of the valve. Despite the association of clinical factors such as hypertension, diabetes, smoking, and hyperlipidemia with calcific aortic-valve disease, (5,13) these factors did not predict either the rate of hemodynamic progression or the clinical outcome in either of these prospective studies. (11,12) One possible explanation is that there were too few patients for an effect to be clearly demonstrated; alternatively, these factors may become less important once leaflet mobility is impaired.
Although some clinicians have suggested that valve replacement be performed in patients with severe aortic stenosis before the onset of symptoms, I agree with Rosenhek et al. that the optimal time for surgical intervention, in nearly all cases, is when symptoms develop. (14) The risk of sudden death in asymptomatic patients appears to be low, probably less than 1 percent per year. This risk is substantially lower than published rates of mortality associated with valve-replacement surgery. Although the hypothesis that earlier intervention will prevent ventricular hypertrophy and diastolic dysfunction is plausible, there are no studies to support this approach, and it is unlikely that the postulated benefits would exceed the risk entailed by earlier surgery and placement of a prosthetic valve. Of course, there are occasional patients with severe aortic stenosis for whom it is appropriate to consider surgery before the onset of symptoms. For example, early surgery is reasonable for patients with severe progressive disease in whom symptoms are expected to develop within the next year and who prefer to schedule surgery at a convenient time -- so long as the patients understand the factors involved in this decision. Other examples include patients who live in areas remote from medical care and cases in which there is a long waiting list for elective surgery.
What are the clinical implications of the recent studies? First, it is critical for primary care physicians to consider the diagnosis of aortic stenosis in evaluating adults with a systolic murmur and symptoms that may be due to outflow obstruction. Instead of the classic end-stage symptoms of angina, heart failure, and syncope, most patients present with milder symptoms earlier in the course of the disease. (11) It is difficult to rule out aortic stenosis completely by auscultation; a very soft (grade 1/6) murmur or a physiologically split second heart sound are the only reasonably reliable indicators of the absence of aortic stenosis. (15) In general, echocardiography can visualize the valvular anatomy and make clear the severity of obstruction. When aortic stenosis is present, the prognosis depends on the extent of calcification of the valve, the base-line flow velocity, and the rate of increase in the aortic-jet velocity over time; periodic echocardiography is therefore appropriate.
Most important, we need to educate patients with aortic stenosis about the expected course of the disease. Once symptoms supervene, prompt valve-replacement surgery is indicated. The lack of a direct relation between hemodynamic severity and clinical outcome emphasizes the importance of obtaining a careful history in order to elicit information about any symptoms each time the patient visits the physician. In this slowly progressive disease, the onset of symptoms can be insidious, and patients may incorrectly ascribe a decrease in exercise tolerance to other causes, such as "getting older" or "the flu," when in fact, it is time for valve replacement.
As always, we need to listen to our patients. We also need to look directly at the valve on the echocardiogram. These two simple approaches are the keys to optimal clinical decision making in the care of adults with valvular aortic stenosis.
Catherine M. Otto, M.D.
University of Washington School of Medicine
Seattle, WA 98195
