Asymptomatic Valvular Disease: Who Benefits from Surgery? Naomi F. Botkin, MD, Paula S. Seth, MD, and Gerard P. Aurigemma, MD*

Address *Division of Cardiology, Room S3-860, UMass Memorial Medical Center, 55 Lake Ave North, Worcester, MA 01655, USA. E-mail: [email protected] Current Cardiology Reports 2005, 7:87–93 Current Science Inc. ISSN 1523-3782 Copyright © 2005 by Current Science Inc.

Routine physical examination and noninvasive imaging frequently lead to the diagnosis of valvular heart disease in asymptomatic patients. The decision to proceed to surgical repair or replacement is based on an informed evaluation of the risks of surgery versus those encountered with a nonoperative course. In determining whether symptoms are present, stress testing may be helpful, as many patients with significant valvular lesions have a tendency to limit their daily physical exertion to levels that do not provoke symptoms. The two most feared consequences of conservative management, sudden death and permanent myocardial damage, are rare in asymptomatic patients with severe aortic stenosis or regurgitation. Surgery for asymptomatic aortic stenosis is performed only for certain high-risk subsets of patients, including those with left ventricular dysfunction, ventricular arrhythmia, and critically small valves. Asymptomatic patients with aortic regurgitation and mitral regurgitation should undergo surgery if they have systolic dysfunction or marked ventricular enlargement.

Introduction The aging of the population and the ubiquity of echocardiography have yielded a large number of patients with asymptomatic valvular heart disease. Routine physical examination and noninvasive imaging frequently lead to the diagnosis of aortic stenosis, aortic regurgitation, and mitral regurgitation (MR) in asymptomatic patients. Mild disease is usually managed expectantly, whereas significant disease can raise difficult choices for the cardiologist and patient. When are valve replacement, valve repair, and valvuloplasty indicated in asymptomatic patients? Conversely, when do the risks of intervention outweigh the risks of expectant management? In order to answer these questions, one needs to consider the pathophysiology and natural history of specific valvular lesions as well as the risk of surgery. This article addresses diseases of the aortic and mitral valves in asymptomatic patients.

Aortic Stenosis Aortic stenosis (AS) is one of the most common valvular abnormalities. Although AS may develop in early to mid adulthood, usually as a result of congenitally abnormal (eg, bicuspid or unicuspid) valves or, more rarely, rheumatic heart disease, in contemporary clinical practice, AS is usually a disease of the elderly. Approximately 2% of the population over 65 years of age has AS [1]. Assuming this prevalence, the number of individuals with AS over 65 in the United States in the year 2000 was approximately 700,000 [2]. Until recently, this so-called degenerative AS was thought to be due solely to mechanical valvular damage and calcium deposition. However, examination of valve leaflets in the early stages of AS has revealed inflammation and lipid deposition [3], suggesting that AS results from an atherosclerotic process. Although valvular calcification is the factor that ultimately causes decreased valve opening area, it seems reasonable to speculate that atherosclerosis initiates the process. As valvular stenosis increases in severity, pressure overload develops and alterations in the architecture of the left ventricle (LV) occur. Concentric hypertrophy is the initial ventricular response. Most patients have normal or even hyperdynamic LV ejection fraction (LVEF). Late in the progression of AS, unrelieved afterload excess may lead to a deterioration in LV systolic function. Surgery will often (but not always) result in significant recovery of LV function. The disease progression of AS is quite variable. Most patients with mild AS remain asymptomatic without significant disease progression many years after diagnosis [4]. Smaller valve area and increased calcium burden predict a faster rate of progression [5]. It remains difficult to predict changes in valve severity in individual patients, so regular follow-up is prudent. Patients who do progress to severe AS, defined as aortic valve area less than or equal to 1.0 or mean transvalvular pressure gradient (MPG) greater than or equal to 50 mm Hg [6], often develop symptoms. In two widely quoted studies, the rate of development of symptoms in initially asymptomatic patients with significant aortic stenosis was substantial (Fig. 1). In one series [7], 38% of asymptomatic patients with a peak Doppler velocity exceeding 4 m/sec developed symptoms within 2 years. In a population with moderate to severe AS (average peak Doppler velocity of 3.6 m/sec), 62% of initially asymptomatic patients developed symptoms after 5 years [8].

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Figure 1. Percentage of patients with asymptomatic, severe aortic stenosis who became symptomatic during follow-up. (Data from Pellikka et al. [7] and Otto et al. [8].)

The three cardinal symptoms of aortic stenosis are chest pain, syncope, and congestive heart failure. Chest pain may be due to excessive myocardial oxygen demand or diminished myocardial oxygen supply, both of which may result from LV hypertrophy. Exercise-induced syncope has traditionally been thought to be due to the inability to augment cardiac output. However, neurocardiogenic mechanisms are likely involved as well [9]. Congestive heart failure symptoms may develop due to systolic or diastolic dysfunction of the LV. However, assigning symptoms to the aortic valve obstruction is problematic in many older patients. Coronary disease, autonomic dysfunction, and primary myocardial disease processes may cause similar symptoms in patients with coexistent AS. Deconditioning and other medical problems may also lead to dyspnea, which may be confused with congestive heart failure. It is important to attempt to ascertain, if possible, whether symptoms are due to AS or to an unrelated process, because current guidelines recommend surgical intervention in patients with severe AS who have symptoms attributable to their valvular disease. An exercise treadmill test may clarify symptom status for the clinician. In our experience, some asymptomatic patients with AS are shown to have extremely poor exercise tolerance (eg, inability to complete stage 1 of a standard Bruce protocol) and have likely been gradually limiting their activities, in order to avoid symptoms. Some recent diagnostic developments may be used to assist the clinician in understanding the basis for symptoms. Tissue Doppler techniques now allow estimation of pulmonary capillary wedge pressure in many patients. Preliminary evidence suggests that brain natriuretic peptide levels may correlate with symptom status [10]. Assuming that one is confident that a patient with severe aortic stenosis is asymptomatic, is surgery ever appropriate in such a patient? Rather than alleviation of symptoms, the goal

in this case is to prevent a poor outcome, namely sudden death or irreversible myocardial damage. Sudden death is the most feared complication of aortic stenosis. Fortunately sudden death is rare in asymptomatic patients. In the series by Pellikka et al. [7], no asymptomatic patient experienced sudden death. In fact, overall survival in AS patients was similar to that of age- and sex-matched controls. In the study by Kelly et al. [11] of 51 asymptomatic patients with severe AS followed for 17 months, only two patients died; symptoms preceded death in both cases. In the series of 66 patients followed by Amato et al. [12•], four died suddenly over a mean follow-up period of 15 months. However, although all of the patients in this series were described as having asymptomatic aortic stenosis, 20, including all four patients who died suddenly, had developed either dizziness, precordial chest pain, or both during exercise testing, and thus were not truly asymptomatic. Several other natural history studies have investigated the risk of sudden death in asymptomatic AS; overall, the risk appears to be less than 1% per year. There may be certain patients who are at higher risk, but this has not been well studied. Thus, the prevention of sudden death does not seem to be a compelling argument for proceeding to valve replacement in an asymptomatic patient with severe AS. Is prevention of permanent myocardial damage a reason to perform surgery in asymptomatic AS? It is indeed possible that irreversible myocardial depression may develop during the compensated asymptomatic stage. Such irreversibility has not been proven to be a significant problem, but this concept has been used by some to support early surgery. The risk to asymptomatic patients of sustaining irreversible myocardial damage is difficult to quantify. Certainly not all patients with LV hypertrophy or impaired systolic function have suffered permanent damage; in fact, there is evidence that even severely impaired systolic function can improve significantly after valve replacement

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Table 1. Indications for valve replacement surgery for aortic stenosis in asymptomatic patients Class Severe AS, having concomitant heart or aortic surgery Moderate AS, having concomitant heart or aortic surgery LV systolic dysfunction Abnormal response to exercise Ventricular tachycardia Marked LV hypertrophy (> 15 mm) Valve area < 0.6 cm2

I IIa IIa IIa IIb IIb IIb

AS—aortic stenosis; LV—left ventricle. Class I: there is evidence or general agreement that the treatment is useful and effective. Class IIa: conflicting evidence, but weight of evidence/opinion is in favor of usefulness. Class IIb: usefulness/efficacy is less well established. (Adapted from Bonow et al. [6].)

[13,14]. It may be possible to detect irreversible changes in myocardial architecture with a dobutamine challenge; the absence of contractile reserve—that is, an inability to augment stroke volume in response to dobutamine—portends a poor prognosis after surgery [15]. Among patients with impaired systolic function, another possible clue to permanent damage is the size of the LV at end-systole, because patients with a larger LV end-systolic volume have a poorer outcome after surgery [16]. These clues help physicians avoid recommending surgery to patients who are unlikely to benefit, but they are not helpful in predicting which patients—and in particular which asymptomatic patients— are at risk for developing permanent damage. However, because patients with significant myocardial disease are rarely asymptomatic [6], it is likely that the risk of irreversible myocardial damage in asymptomatic patients is low. Aortic valve replacement (AVR) is not without significant risk. The overall operative mortality is approximately 3.6% [17] and increases with age. The severity of symptoms influences mortality, with New York Heart Association (NYHA) class I patients having a low operative mortality relative to class IV patients. AVR is also associated with complications including valve thrombosis, thromboembolism, major bleeding, valve incompetence, and endocarditis. The yearly incidence of complications is 2% to 5.5% [18,19], and long-term mortality related directly to valve complications appears to be 1.8% to 2.7% per year [20]. Thus, although operative mortality in asymptomatic patients is low, long-term mortality and morbidity are not insignificant. The current American College of Cardiology/American Heart Association Guidelines for the Management of Patients with Valvular Heart Disease [6] describe situations in which valvular replacement surgery is recommended or acceptable for asymptomatic patients with severe AS (Table 1). Patients with LV systolic dysfunction or an abnormal response to exercise were felt by the expert panel to probably benefit from AVR. Those with ventricular tachycardia (due to their increased risk of sudden death), might also benefit from surgery. Critically small valves and excessive LV hypertrophy are other potential indications for AVR. The basis for this latter

recommendation is not clear. In fact, some studies have shown that excessive hypertrophic remodeling, seen often in elderly women with concomitant hypertension, is associated with poor outcome after surgery [21]. Though there are few data on this issue, it is likely that increased recognition of the syndrome of cardiac collapse in such patients following AVR has led to better postoperative outcome in these patients, thanks in part to reliance on transesophageal echocardiography for perioperative management [22]. Patients with severe AS who are undergoing coronary artery bypass grafting (CABG), aortic surgery, or other heart valve surgery should undergo concomitant AVR due to the high risk of needing reoperation for symptoms due to AS soon thereafter. This principle may apply to patients with moderate AS (MPG ≥ 25 mm Hg) as well, but patients with milder AS do well with watchful waiting, particularly as the operative mortality of reoperative AVR following CABG has diminished in recent years [23]. Balloon valvuloplasty is an alternative to surgery in severe AS. Unfortunately, this procedure has a high mortality and morbidity in adults [24] and is reserved for symptomatic patients who have a contraindication to surgery. Percutaneous AVR is an emerging technique that is still investigative. In the past, replacement of the aortic valve was thought to be the only effective therapy for AS. However, the atherosclerotic etiology of AS suggests a potential role for HMG CoA reductase inhibitors (statins) in delaying the progression of the disease. Recent retrospective studies demonstrated that statin therapy is associated with a lower rate of aortic valve calcium accumulation as detected by electronbeam computed tomography [25] and a smaller increase in transvalvular gradient as measured by Doppler echocardiography [26]. A prospective, nonrandomized study provided further evidence for the benefit of statins in AS [27••]. O’Brien et al [28] have discovered that angiotensin-converting enzyme and angiotensin II are present in AS and aortic sclerosis lesions (thus the supporting connection between AS and atherosclerotic coronary disease). Whether drugs that affect the renin-angiotensin system might have an impact on the progression of AS remains to be seen.

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Table 2. Angiographic and echocardiographic characteristics of chronic aortic regurgitation Compensated Cardiac catheterization End-diastolic volume, mL/m2 End-systolic volume, mL/m2 Ejection fraction Echocardiography End-diastolic dimension, mm End-systolic dimension, mm Fractional shortening, %

Transitional

Decompensated

< 120 < 50 > 55

130–160 50–60 50–55

> 170 > 60 < 50

< 65 < 45 > 32

65–75 45–50 30–31

> 75 > 50 < 29

(Data from UpToDate. Table by W. Gaasch. Edited by Rose BD. Wellesley, MA: UpToDate; 2004; with permission. For more information visit www.uptodate.com.)

Table 3. Indications for aortic valve replacement in asymptomatic, chronic, severe aortic regurgitation Class Mild to moderate LV dysfunction (EF 25%–49%) Undergoing other heart or aortic surgery Normal LV systolic function (EF > 50%) but severe dilatation (EDD > 75 mm or ESD > 55) Severe LV dysfunction (EF < 25%) Normal systolic function and progressive LV dilatation when the degree of dilatation is moderately severe (EDD 70–75 mm, ESD 50–55 mm)

I I IIa IIb IIb

EDD—end-diastolic dimension; EF—ejection fraction; ESD—end-systolic dimension; LV—left ventricle. Class I: there is evidence or general agreement that the treatment is useful and effective. Class IIa: conflicting evidence, but weight of evidence/opinion is in favor of usefulness. Class IIb: usefulness/efficacy is less well established. (Adapted from Bonow et al. [6].)

Aortic Regurgitation Aortic regurgitation (AR) can result from abnormalities of the valve leaflets (bicuspid valve, calcification, rheumatic heart disease, diet-drug valvulopathy, endocarditis) or the aortic root (Marfan syndrome, aneurysm, aortitis, systemic lupus erythematosus, and other causes). AR is considerably less common than AS. When AR is chronic and severe, the LV is faced with both pressure and volume overload; as a result, increases in both wall thickness and chamber dilation occur. This adaptation permits generation of large stroke volume at normal or higher pressure without systolic dysfunction. When systolic dysfunction does occur, it tends to develop after a long latency period but may be reversible if surgery is performed promptly (eg, within weeks to months) after symptom recognition. Table 2 demonstrates the changes in cardiac dimensions seen during the progression of aortic regurgitation. Chronic AR is generally associated with low morbidity during the (long) asymptomatic phase. Some patients with mild AR remain asymptomatic for decades and usually do not require medical treatment beyond endocarditis prophylaxis. Fewer than 5% of asymptomatic or mildly symptomatic patients progress to LV dysfunction or symptom development each year [6], although once LV dysfunction has developed, symptoms usually follow. As in the case of AS, the appropriate timing of surgery depends on weighing the risk of surgery

against the risk of conservative management. Sudden death occurs in asymptomatic and mildly symptomatic patients with AR at a rate of less than 1% per year [29,30]. There are few data available regarding the risk of irreversible myocardial damage, but several studies have shown that only 1% of patients with severe AR develop LV systolic function each year without also developing symptoms [29]. Echocardiography is necessary for the optimal management of patients with AR, because LV size and function changes may not necessarily be associated with symptoms. In a recent study, a comparable percentage of patients with preserved and impaired LV systolic function were asymptomatic (37% vs 28%) [31]. Because numerous studies have shown that patients with LV systolic dysfunction or dilatation have a poorer postsurgical survival regardless of the presence of preoperative symptoms [32], these parameters are seen as indications for surgery. An end-diastolic dimension of less than 65 mm and an LVEF greater than 55% generally indicate a compensated stage. An end-systolic dimension greater than 50 mm, or an LVEF less than 50% usually indicates a decompensated state. Severe dilatation is defined as an enddiastolic dimension greater than 75 mm or an end-systolic dimension greater than 55 mm. Recommendations regarding the appropriate timing of surgery in asymptomatic AR are outlined in Table 3. Surgery

Asymptomatic Valvular Disease: Who Benefits from Surgery? • Botkin et al.

should be considered in asymptomatic patients who show progressive LV enlargement, particularly if the end-diastolic dimension exceeds 75 mm, the systolic dimension approaches 55 mm, or the LVEF approaches 50%. Many clinicians prescribe vasodilators in patients with chronic, severe AR. Vasodilators are currently recommended for asymptomatic patients only if there is concomitant hypertension, LV dilatation, or systolic dysfunction [6]. Even though vasodilators may not often decrease regurgitant volumes [33]; nonetheless, these drugs can improve LVEF, as shown in two studies by Scognamiglio et al. [34,35]. These randomized studies involving asymptomatic patients with severe AR showed that nifedipine was associated with improved blood pressure, LV volume, and clinical outcome. Vasodilators other than nifedipine have not been investigated but are often utilized. Patients with only minimal LV enlargement and normal EF have not been shown to benefit from chronic vasodilator therapy.

Mitral Regurgitation Mitral regurgitation is a common valvular lesion with diverse etiologies. Primary MR is due to abnormalities of the mitral valve apparatus (mitral valve prolapse, rheumatic heart disease, infective endocarditis, ruptured chordae or papillary muscle, diet-drug valvulopathy, and collagen vascular diseases). Functional MR is caused by conditions that alter the LV architecture; these include the many causes of dilated cardiomyopathy as well as some types of restrictive cardiomyopathy. As the incidence of rheumatic heart disease has increased, myxomatous valvular changes have become the most common cause of significant MR [36]. Severe MR presents a volume load to the LV. The ventricle enlarges to accommodate the increased volume of blood and eccentric LV hypertrophy develops. During the compensated phase, LV function is normal and the overall stroke volume is increased so that forward stroke volume can be preserved. Patients are usually asymptomatic but may have dyspnea on exertion or easy fatigability. A feared complication of chronic, severe MR is LV systolic decompensation. This decompensation is related to both the increase in wall stress from ventricular dilatation and the reduction in myocardial myosin content [37]. In many instances the LVEF may remain near normal despite significant contractile dysfunction, but eventually it will fall below normal levels. Symptoms of congestive heart failure may develop at any point during the decompensation process, due to elevated left atrial pressures and decreased cardiac output. Atrial fibrillation is a common occurrence. Some patients remain asymptomatic even with considerable myocardial dysfunction. Do patients with severe MR sustain irreversible myocardial damage? Fortunately, not all myocardial dysfunction in these patients is permanent. However, at this time, LV contractile dysfunction in chronic MR is incompletely understood. MR with chamber dilatation may be associated with

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increased afterload [38] and therefore LV function may improve once the regurgitant lesion is removed. Experimental data suggest that contractile dysfunction can improve after mitral valve surgery or β-blocker administration [37]. However, postoperative survival is poor when surgery is performed on patients with moderate to severe LV dysfunction, suggesting that beyond a certain point, LV dysfunction is permanent. Subnormal LVEF, ventricular dilatation, and large left atrial diameter are parameters that predict poor outcome and failure of systolic function to improve postoperatively [39–41]. Mitral valve operations that do not spare the chordal apparatus are associated with a postoperative drop in LVEF [38]. It is unclear how closely symptoms are related to irreversible myocardial damage in chronic MR. The ideal timing for mitral valve surgery is prior to the development of debilitating symptoms and significant myocardial dysfunction. However, if surgery is performed too early, the risks of the procedure may outweigh the benefits. The risks of surgery depend on which procedure is performed. Mitral valve repair has the best operative mortality [42] and an excellent long-term outcome [43], but is more difficult to perform than valvular replacement, and is limited to patients without significant valvular calcification. This procedure is more likely to be successful in posterior leaflet prolapse or with ruptured chordae tendinae, and less likely with anterior leaflet involvement, rheumatic disease, or ischemic disease [6]. Mitral valve repair with chordal sparing is the next best choice. Mitral valve repair without chordal preservation is the least preferred alternative, because it has been associated with a reduction in LVEF which is not observed when the chordal apparatus is preserved. As is the case with AR, management decisions and the indications for surgery in chronic severe MR depend on the echocardiographic assessment of LV size and function [6]. Mild to moderate chamber enlargement alone does not mandate surgery, because some degree of LV and left atrial enlargement are to be expected in severe chronic MR. There is, however, some lack of agreement about the indications for surgery in an asymptomatic patient. As a result, the general guidelines presented here should be modified depending upon local experience and outcomes from surgery. Figure 2 may serve as a guideline to decision making. In the asymptomatic patient with normal EF (eg, ≥ 60%), conservative (nonoperative) management is justifiable. By contrast, patients with progressive left atrial enlargement, AF, or pulmonary hypertension (defined as pulmonary artery systolic pressure > 50 mm Hg at rest or > 60 mm Hg with exercise) should be considered for early surgery, particularly if valve repair can be achieved. In addition, surgery is indicated in asymptomatic patients if LV systolic dysfunction is demonstrable. This has been defined by the American College of Cardiology/American Heart Association and the Working Group on Valvular Heart Disease of the European Society of Cardiology (ESC) as an LVEF less than 60% or an end-systolic LV diameter greater then 45 mm [6]. Those with near normal EF (eg, 55%–59%) may

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Figure 2. Decision algorithm for treatment of asymptomatic patients with severe mitral regurgitation. *If the anatomy suggests MVR is feasible, patients with preserved LV function may undergo surgery (class IIb indication). AF—atrial fibrillation; LVEF—ejection fraction; ESD—end-systolic dimension; MVR—mitral valve repair or replacement; PHTN—pulmonary hypertension. Class I: there is evidence or general agreement that the treatment is useful and effective. Class IIa: conflicting evidence, but weight of evidence/opinion is in favor of usefulness. Class IIb: usefulness/efficacy is less well established. (Data from Bonow et al. [6].)

prefer medical management, and this may be appropriate, because it is possible that some of these patients may remain asymptomatic and stable for years. In such patients, surgical decisions often depend upon other issues such as atrial size, the presence or absence of AF, evidence of pulmonary hypertension, and the preferences of the patient. Among those who are treated medically, any trend indicating a further decline in LVEF can be taken as an indication for surgery. Patients with MR who are not yet surgical candidates are sometimes given vasodilating medications in an effort to decrease the severity of MR. There is little evidence that this approach is beneficial, particularly in asymptomatic patients without systemic hypertension [6].

Conclusions The majority of asymptomatic patients with significant disease of the aortic or mitral valve may be managed expectantly, with periodic physical examination and echocardiography, as well as prophylaxis for bacterial endocarditis. Surgery is sometimes indicated when the risks of permanent myocardial damage or sudden death outweigh the risk of surgery. The challenge to the clinician is to determine when patients have reached this point. It is possible that improvements in surgical technique and perhaps the development and refinement of percutaneous valve

replacement in the future may lead to a lowering of the threshold for interventions on asymptomatic patients.

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