Managing Asymptomatic Patients With Chronic Aortic Regurgitation

reviews Managing Asymptomatic Patients With Chronic Aortic Regurgitation* William H. Gaasch, MD; Meena Sundaram, MD; and Thea E. Meyer, MD, PhD

(CHEST 1997; 111:1702-09) Key words: aortic regurgitation; aortic valve replacement; le ft vent1icular volume overfoad; regurgitant volume; vasodilator therapy

Abbreviations: AR=aortic regurgitation ; LV = left ventricular

aortic regurgitation (AR) generally C hronic progresses in a slow and insidious fashion with a very low morbidity during a long asymptomatic phase. Many patients, even those with clinical evidence of a serious regurgitant lesion, remain asymptomatic for decades. Others, particularly those "vith moderate left ventricular (LV) enlargement, show evidence of a gradual progression. Even though they remain asymptomatic, some of these patients can benefit from vasodilator therapy and eventually aortic valve replacement. On occasion, asymptomatic patients present with substantial LV enlargement and evidence of LV systolic dysfunction. Conventional wisdom dictates that these patients undergo aortic valve replacement, even though they are not yet symptomatic. It is readily apparent, therefore, that the treatment of asymptomatic patients with chronic AR requires a knowledge of the pathophysiology and natural history of the disease, comprehension of the therapeutic potential of long-term vasodilator therapy, and an understanding of the potential surgical outcomes. PATHOPHYSIOLOGY OF

AR

AR burdens the LV with a volume load that leads to a series of compensatory myocardial and circula*From the Departments of Medicine (Cardiovascular), the Lahey Hitchcock Medical Center (Drs. Gaasch and Sundaram), Burlington, Mass, and the University of Massachusetts Medical School(Drs. Gaasch and Meyer), Worcester. Manuscript received November 13, 1996; accepted November 14. Reprint requests: William H. Gaasch, MD, Director, Cardiovascular Research, Lahey Hitchcock Medical Center, 41 Mall Rd, Burlington, MA 01805 1702

tory adjustments that can be affected by pharmacologic therapies and reversed by valve replacement_! An understanding of vasodilator therapy requires knowledge of the determinants of regurgitant flow and the variables that affect LV size and function. Likewise, rational selection of patients for aortic valve replacement requires an understanding of the LV response to the regurgitant lesion. The Regurgitant Volume The hydraulic determinants of AR volume are described by solving the standard valve orifice equation for regurgitant volume: ARV=AROAXCXCX

~AOdm- LVdmXTd

where ARV=AR volume, AROA=AR orifice area, C=constant, AOdm=aortic diastolic mean pressure, LVdm=LV diastolic mean pressure, and TJ=time or duration of diastole. In primary disease of the aortic valve, the regurgitant orifice area is generally thought to be fixed and constant. However, experimental and clinical demonstration of a pressuredependent regurgitant area indicates that this assumption may not always be true. 2 •3 For example, in disease of the aortic root (eg, Marfan's syndrome), the distending pressure likely has an effect on regurgitant orifice area. By contrast, the orifice area in calcific disease is constant. The second determinant of regurgitant volume is the transvalvular pressure gradient throughout diastole. An understanding of this variable provides a rationale for treating hypertension in patients with AR, but it should be recognized that most vasodilator therapies reduce the aortic diastolic pressure and the LV diastolic pressure. As a result, there may be little change in the transvalvular pressure gradient. Moreover, the benefit of any reduction in pressure gradient is reduced by the effect of the square root sign in the orifice equation. Manipulation of aortic pressure, therefore, cannot be expected to have a major effect on regurgitant volume. The third determinant of AR volume is the duraReviews

tion of diastole, which is a function of heart rate.4 · 6 Thus, bradycardia will increase and tachycardia will reduce regurgitant volume per b aet. Pacing-induced tachycardia has not been found to be an effective therapy in patients with chronic AR, but clinicians should recognize the potential danger of profound bradycardia. It is apparent, therefore, that the primary determinants of AR volume are the re gurgitant orifice area, the transvalvular pressure gradient, and the duration of diastole. Consideration of these principles places substantial constraints on the potential for achieving a pharmacologic reduction in AR volume (see subsequent text).

The LV Response The major change that occurs during the early evolution of chronic AR is an enlargement of the ventricle (Table 1).As a chronic steady-state develops, the normal ventricle is converted into a larger and more compliant chamber that is well suited to deliver a large stroke volume. This comes about through a rearrangement of myocardial fibers with the addition of new sarcomers and th e development of eccentric LV hypertrophy. As a result, preload at the sarcomere level remains normal or near normal and the ventricle retains its preload reserve.7 The enhanced total stroke volume seen in chronic compensated AR is "mediated through a normal performance of each unit of an enlarged circumference."8 Thus, LV contractility, loading conditions, and ejection fraction remain within the range of normal; a form of magnification (ie, physiologic) hypertrophy is present and total stroke volume is high as a r esult of the large end-diastolic volume. During this compensated phase of the disease, most patients remain asymptomatic. Vasodilator therapy may have the

Table !-Functional Adaptations (and Maladaptations) of the LV in AR Adaptations Acute Tachycardia (decreased diastolic regurgitant ti me) Fran k-Starling mechanism Chronic (compensated ) Eccentric (volume overload) hype rtrophy Geometric c hanges (more spheri cal) Rightward shift of diastolic pressure-volum e relation Chronic (decompensated) Inadequate hypertrophy and afterload excess Myocardial slippage and ol ss of Z registry Depression of myocardial contractile sta te Fib rosis and cell loss

potential to reduce the hemodynamic burden, but surgery should be postponed. A most elusive and poorly understood aspect of the pathophysiology of AR is the nature of the transition from a compensated to a d ecompensated state. Such a change may occur as a consequence of progressive increments in the regurgitant volume and/or decrements in LV systolic function. During this transition, most patients remain asymptomatic despite progressive LV enlargement. This transitional phase is an important landmark in the natural history of chronic AR; at this time, vasodilator therapy can b e bene ficial and surgical valve replacement should be considered (see subsequent text). The decompensated stage is characterized b y a substantial and progressive LV enlargement, a more spheiical geometry, elevated LV diastolic pressures, increased systolic wall stress (i e, aH:erload excess), and a d ecline in the ejection fraction. The fall in ejection fraction occurs as a consequence of depressed LV contractility and excessive afterload. Although the transition from a compensated to a decompensated state is frequently heralded by the development of congestive symptoms, an insidious deterioration of ventricular function may occur without clinical signs. This can progress to an extent that can preclude the full benefit of surgical correction of the regurgitant lesion. Because the very nature of this disorder results in LV enlargement, the mere presence of a dilated ventricle cannot be used to identify patients with ventricular dysfunction. For this reason, guidelines that clearly separate patients with compensated AR from those with decompensated disease have been difficult to develop (Table 2).Cardiac catheterization data have generally been the s tandard for characterizing cardiac function in valvular h eart disease, but a variety of echocardiographic descriptors of compen-

Table 2-LV Size and Function in the Three Stages of Chronic AR Compensated Transitional Decompensated Cardiac catheterization End-diastolic volume, mL/m2 End-systolic volume, mU m 2 Ejecti on fraction, % Echocardiography E nd-diastolic dimension, mm End-systolic di mension, mm Fractional shOJtening, %

< 120

130- 160

> 170

<50

50-60

> 60

> 55

50-55

< 50

< 65

65-75

> 75

<45

45-50

>50

>32

30-31

<29

CHEST I 111 / 6 / JUNE, 1997

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sated and decompensated states have also been developed. 9-15 Markers of a decompensated ventricle include a large end-systolic volume or dimension, and a low ejection fraction or fractional shortening. A very large end-diastolic volume or dimension may also identify the decompensated ventricle, but this is probably less sensitive than a large end-systolic volume or a depressed ejection fraction. A low ratio of regurgitant volume to end-diastolic volume, especially if the ejection fraction is depressed, indicates a cardiomyopathic ventricle.l 6 · 17 Patients who exhibit one or more of these markers of a decompensated ventricle are at high risk of suboptimal response to corrective surgery. An abnormal LV response to exercise may also be useful in identifying early depression of LV function.18·19 However, variations in heart rate and aortic pressure and other hemodynamic adjustments make it difficult to isolate marginal ventricular function as the cause of a subnormal increment in the ejection fraction.20 It is not known whether exercise data have incremental value above that provided by basal measures of LV size and function. It should also be recognized that the prognostic value of the LV response to exercise, in patients being treated with vasodilators, is not known. Patients who are operated on before they enter the decompensated stage generally exhibit salutary changes in LV size and function , and a good clinical result. This is not to say that it is "too late" for corrective surgery if there is evidence of a decompensated ventricle. Rather, the patient is simply less likely to exhibit an optimal clinical result. Indeed, many such patients do quite well despite marked LV enlargement and systolic dysfunction. 21 ·22 While these considerations do not identify the optimum time for aortic valve replacement, they do enable the clinician to predict the LV and clinical response to corrective surgery. 23 ·24 In this fashion, the parameters of LV size and function (Table 2) provide a view of the most likely outcomes associated with medical or surgical therapies- especially if the natural history of chronic AR is considered. Pure AR vvill be emphasized; associated disorders (ie, Marfan's syndrome, coronary artery disease) are beyond the scope of this review.

NATURAL HISTORY

The favorable prognosis of most patients with chronic AR is well documented. The asymptomatic state may be present for decades and even after the onset of symptoms, some patients survive for as long as 30 years. Mean survival was 6.4 years in 1956, 25 but by the 1970s, several clinical investigators re1704

ported a 70% 6-year survivaJ.26 -28 By 1982, the 5-year survival of symptomatic patients exceeded 80%. 29 These reports indicate that most symptomatic patients have a protracted clinical course, despite evidence of severe AR. The outlook in asymptomatic patients is substantially more benign. The natural history of these patients has been defined through echocardiographic measurements of LV size and function. Bonow et aJ3° performed serial echocardiographic studies in 77 asymptomatic patients with moderate to severe AR; most of these patients had LV enlargement and all had normal LV systolic function. During a mean follow-up period of 49 months, there were no deaths, but 12 patients required surgery. By life-table analysis, the percentage of patients not requiring surgery was 90% at 3 years, 81% at 5 years, and 75% at 7 years. Thus, asymptomatic patients with LV enlargement and a normal ejection fraction at baseline require aortic valve replacement at the rate of approximately 4%/yr. These observations were confirmed in 50 patients studied by Siemienczuk et aP 1 During a mean follow-up period of 44 months, 10 patients developed symptoms and/or LV dysfunction; thus, this group of investigators also found that aortic valve replacement was required at the rate of 4%/yr. Bonow and associates 32 later extended their observations by studying a larger number of patients with a longer follow-up period. Compared with their earlier study, the rate of progression seemed to accelerate slightly after 5 years, but the need for surgery was still "less than 5% per year by life table analysis." Low-risk Patients Using measurements of LV chamber size, Bonow et al 30 ·32 were able to define a subgroup that appears to be at particularly low risk of requiring surgery. Virtually all patients with an LV end-systolic dimension (by echocardiography) below 50 mm can expect to remain asymptomatic for the next few years. Over a decade of follow-up, no patient with an end-systolic dimension under 40 mm developed symptoms or LV dysfunction. 30·32 When the end-systolic dimension is between 41 and 49, the need for surgery (ie, development of symptoms and/or LV dysfunction) ranges from 1 to 2%/yr3° to 6%/yr. 32 Siemienczuk et al31 described a similar low-risk ~roup with an enddiastolic volume <150 mUm or an end-systolic volume <60 mUm 2. High-risk Patients These same investigators have also been able to define subgroups of asymptomatic patients who are at a high risk of developing symptoms or LV systolic Reviews

dysfunction. Thus, the yearly rate of developing symptoms or LV dysfunction and requiring surgery is approximately 15% when the baseline end-diastolic volume is > 150 mUm 2 or the end-systolic volume is >60 mUm 2 .3 1 The risk is almost 20%/yr when the end-systolic dimension exceeds 50 mm; 30·32 the risk exceeds 25% when the end-systolic dimension exceeds 55 mm. 33 These natural history data are consonant with the large literature on pathophysiology and they are of signal importance in the development of a rational approach to treating the asymptomatic patient with chronic AR. 30-35 Although most patients seem to develop symptoms before they exhibit LV systolic dysfunction,30·32 it appears that LV dysfunction tends to precede the development of symptoms in patients treated with vasodilators. 36 Therefore, clinical evaluations, including an assessment of exercise tolerance, are at least as important as echocardiographic studies. In an attempt to identify progressive changes in LV size and function, most clinicians obtain an echocardiogram every year. This approach is based on the observation that a good surgical result can be expected (even in patients with LV dysfunction) if the duration of LV dysfunction is <14 months.34,35 Annual studies, while necessary in high-risk patients, may not be approp1iate in low-risk patients. In this subgroup, 100 echocardiograms are required to identify the few patients who might need surgery.

VASODILATOR THERAPY

Vasodilator therapy is designed to optimize LV loading conditions and achieve favorable remodeling of the ventricle through a systolic unloading, a reduction in regurgitant volume, or possibly nonspecific vasodilator effects. Certainly it is possible to reduce the hemodynamic burden of the regurgitant lesion in many patients. 37 Those with the largest hearts, the lowest ejection fractions, and the most disabling symptoms are the most likely to exhibit salutary effects, but selected asymptomatic patients can also benefit from vasodilator therapy. In the largest (to our knowledge) randomized, placebo-controlled, double-blind trial of hydralazine, Greenberg et al38 found a significant reduction in LV volume in 45 largely asymptomatic patients. These salutary effects were not apparent in a randomized, double-blind trial comparing enalapril and hydralazine therapy in 76 patients reported by Lin et al;39 in this study, the patients receiving enalapril exhibited a significant reduction in LV volume while there were no changes in the hydralazine group. Wisenbaugh et al40 could find no effect on LV dimensions or ejection fraction after 6 months of captopril

therapy in 23 patients. By contrast, Schon et al41 found significant reduction in LV volume and a small increase in ejection fraction in 12 patients treated with quinapril for 1 year. Some of these disparate results can be explained by differences in patient characte1istics and hemodynamic responses. For example, Lin et aJ3 9 and Schon et al41 found that angiotensin-converting enzyme inhibitor produced a decrease in a1terial pressure with salutary effects on LV size and function, while Wisenbaugh et al40 did not achieve a reduction in arterial pressure. It would appear, therefore, that if vasodilator therapy is to be effective, a predefined dose should not be used. Rather, the dosage should be adjusted to achieve a decrease in arterial pressure. Scognamiglio et al 42 studied the effect of longterm nifedipine therapy in a randomized, doubleblind, placebo-controlled trial in 72 asymptomatic patients with severe AR. Nifedipine produced a significant fall in arterial pressure and reduction in LV volume. All 72 patients remained asymptomatic during this 12-month study; none of them required aortic valve replacement. In a subsequent study, the same investigators reported the course of 143 asymptomatic patients who were randomized to receive either nifedipine or digoxin. 36 During the first 12 months of the study, 5% of the digoxin-treated group required aortic valve replacement, while none in the nifedipine group needed surgery. By the end of 6 years, 34% of the patients assigned to digoxin treatment and 15% of those assigned to the nifedipine group had undergone aortic valve replacement. These and other studies of vasodilator therapy in patients with chronic AR indicate that such therapy can be effective in reducing the hemodynamic burden on the LV, in producing a favorable remodeling of the ventricle, and probably even in effecting a delay in the need for surgical replacement of the valve. It should be recognized, however, that most patients exhibiting a favorable response to vasodilator therapy had significant LV chamber enlargement. Indeed, they had ventricular volumes or dimensions that are typically seen in the transitional stage; virtually none of them had dimensions characteristic of compensated AR (Table 2) . Thus, to our knowledge, there are no published data that can be used to support the use of vasodilator therapy in asymptomatic patients with only minimal LV enlargement and a normal ejection fraction (ie , most patients in the compensated stage).

SURGICAL TREATMENT

Surgical correction of chronic AR has almost always required replacement of the diseased valve CHEST I 111 I 6 I JUNE, 1997

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with a prosthesis. Thus, the patient is exposed to the risks of surgery and the long-term complications of a prosthetic valve. Surgical mortality of aortic valve replacement is reportedly 2.4 to 4.9%. 43 - 4 5 However, these recent mortality rates include patients with associated coronary artery disease and coronary artery bypass grafts. If patients with coronary disease are excluded, early mortality is probably well under 3%. This conclusion is supported by the results of isolated aortic valve replacement at the Lahey Hitchcock Medical Center, Burlington, Mass. During a recent 5-year period (1990 to 1995), isolated elective or urgent aortic valve replacement was performed in 120 patients; there were no 30-day or in-hospital deaths. The long-term complications of prosthetic valves should also be considered. A variety of prosthetic valves are available, but the most widely used is the St. Jude Medical valve. In the aortic position, it has an excellent hemodynamic profile and has been remarkably free of structural failure. Unfortunately, even this valve is associated with a variety of complications that occur at the rate of approximately 3%/yr (Table 3). It should be recognized, however, that not all of these complications produce serious disability. For example, thromboembolism may occur as often as 2.4/100 patient-years, but the incidence is only 0.33 for "major events." 43 Event-free survival at 10 years is 75%;43 .44 freedom from valverelated death is 85%. 43 .45 Thus, the incidence of serious complications of prosthetic aortic valves is likely well under 3%/yr-especially if anticoagulation is carefully monitored. Death related to prosthetic valve complications can be as low as 1%/yr. The occurrence of prosthetic valve complications has stimulated the development of alternative surgical procedures, such as repair of the diseased native valve46 A7 or replacement of the diseased valve with a homograft or pulmonary autograft. 48 -50 These proce-

Table 3-Complications of Prosthetic Aortic Valves Aoyagi et al43 Ibrahim et al 44 Khan et al45 No. of patients Type of valve Early mortality, % Complications* Thromboembolism Hemolysis Hemorrhage Structural failure Paravalvular leak Endocarditis Reoperation

178 St. Jude 3.9 1 0 0.4 0 0.4 0.4 0.6

*Events per 100 patient-years. 1 Approximate value.

1706

578 St. Jude 2.4 2.4 0 1.7 0 0.3 0.1 0.2

471 St. Jude 4.9 2.5 0 2.0 0 0.2 1 0.4 ' 0.2 1

dures are technically difficult and experience is limited, but in selected patients, they may have advantages over prosthetic valves. For example, patients with aortic aneurysm and preserved leaflets can benefit from repair and leaflet resuspension at the time of aortic root replacement.51 A pulmonary autograft may be the procedure of choice in some children. 52 The development of these specialized procedures, however, is unlikely to affect our approach to most asymptomatic patients with chronic AR.

CONCLUSIONS

Most clinicians are reluctant to consider surgical replacement of the aortic valve in a truly asymptomatic patient. Such early surgery exposes the patient to perioperative morbidity and mortality and the longterm complications of a prosthetic valve. However, waiting for the patient to experience exercise intolerance or dyspnea may allow time for the development of irreversible depression of LV function. If this occurs, the patient may be deprived of the full benefit of corrective surgery and the long-term results will be suboptimal. Based on the data presented herein, it is possible to develop guidelines for treating the asymptomatic patient with chronic AR (Table 4). AR in asymptomatic patients is most often discovered during routine clinical examinations. Echocardiography is then used to evaluate further the disorder. An estimate of the severity can be made with Doppler echocardiography and a quantitative mea-

Table 4-Guidelines for Treating Asymptomatic Patients With Chronic AR Guidelines l. Patients with only minimal LV enlargement and normal systolic function are treated conservatively. These patients rarely require corrective surge1y. 2. (a) When the LV diastolic dimension (echocardiography) exceeds 60 mm , periodic clinical evaluations and annual echocardiograms are indicated. (b) Patients who show evidence of moderate LV enlargement (LV diastolic dimension > 65 mm ) and normal systolic function should be treated \vith a vasodilator and followed up closely. (c) Surgery should be considered in patients who show progressive ventricular enlargement, especially if the LV diastolic dimension exceeds 70 mm , the systolic dimension is approaching 50 mm, and the ejection fraction is approaching 50%. 3. Reliable evidence of LV systolic dysfunction (ie low ejection fraction , not merely LV enlargement) indicates that the patient is entering a decompensated stage. Vasodilator therapy can reduce the hemodynamic burden, but aortic valve replacement is indicated in most such patients.

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sure of LV size and function can be made v.rith two-dimensional echocardiography. With rare exception, hemodynamically significant chronic AR is not present unless the LV end-diastolic dimension exceeds 6 em. It can also be important to confirm the asymptomatic nature of the disorder by performing an exercise tolerance test. Having confirmed the presence of a serious hemodynamic burden and preserved exercise tolerance, various medical and surgical options must be considered. Asymptomatic patients with only minimal LV enlargement (end-diastolic dimension <60 mm) and normal systolic function rarely, if ever, need aortic valve replacement. Moreover, to our knowledge, there are no published data to support the use of vasodilator therapy in such patients. Conservative follow-up, including bacterial endocarditis prophylaxis, is indicated. Patients with larger ventricles (end-diastolic dimension=60 to 65 mm) may be approaching a transitional stage, but it should be recognized that the vast majority of such patients remain in stable condition for years. These patients may benefit from vasodilator therapy; corrective surgery is not yet indicated. To detect a decline in systolic function, annual echocardiography should be performed. Patients who show evidence of progressive LV enlargement (end-diastolic dimension exceeding 65 mm) appear to have entered a transitional stage. While many such patients remain in stable condition for years, two options should be considered. First, vasodilator therapy certainly can reduce the hemodynamic burden. If hydralazine, 38 angiotension-converting enzyme inhibitors, 39 or nifedipine 40 are used, it is important to achieve a reduction in arterial pressure. It is also necessary to continue the serial echocardiographic studies of LV size and function. Alternatively, corrective surgery might be recommended- especially if there is a tendency for the ejection fraction to be declining. Under such circumstances, a radionuclide study and/or cardiac catheterization should be performed to confirm the echocardiographic assessment of LV size and function. If there is definite and reliable evidence of marginal systolic function (ie, the ejection fraction is approaching 50% and/or the end-systolic dimension is approaching 50 mm), many clinicians would recommend surge~y. Thus, aortic valve replacement should be considered before the decompensated stage. As always, the risk of surgery and the potential longterm complications of prosthetic valves should be considered. The patient's wishes and expectations are also an important consideration. Finally, it should be recognized that borderline or even frank LV systolic dysfunction of a relatively short duration (ie, < 1 year) does not carry the same ominous prognosis

as a prolonged period of LV dysfunction. 34 •35 Thus, it is rarely, if ever, necessary to perform urgent surgery in a patient with AR who shows evidence of progression toward the decompensated stage. Asymptomatic patients who have entered the decompensated stage of chronic AR regurgitation are at risk of a suboptimal response to surgery and a poor clinical result. The status of the LV should be confirmed with radionuclide and/or cardiac catheterization data, and if there is reliable evidence of LV dysfunction, corrective surgery is indicated. If, because of patient preference or some other reason, surgery is postponed, vasodilator therapy should be instituted. These guidelines and recommendations are largely based on the concept of compensated, transitional, and decompensated stages that are defined on the basis of quantitative measures of LV chamber size at end-diastole and end-systole, and the ejection fraction. The stages are not based on qualitative or semiquantitative assessments of the severity of AR that are obtained from aortic root cine angiography and Doppler echocardiography. 53 Recognizing that these three stages and their clinical utility have not been validated statistically in a prospective fashion , they should be used only as general guidelines in a decision analysis that includes all other clinical data, including patient preferences. ACKNOWLEDGMENT: The authors are indebted to Dr. Lars Svensson for providing the surgical-results data. from the Lahey Hitchcock Medical Center, and to Pam Amico for her assistance in the preparation of this manuscript.

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