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(Circulation. 1997;95:2262-2270.)
© 1997 American Heart Association, Inc.

Articles

Prospective Study of Asymptomatic Valvular Aortic Stenosis

Clinical, Echocardiographic, and Exercise Predictors of Outcome

Catherine M. Otto, MD; Ian G. Burwash, MD; Malcolm E. Legget, MB, ChB; Brad I. Munt, MD; Michelle Fujioka, RDCS; Nancy L. Healy, MS; Carol D. Kraft, RDCS; Carolyn Y. Miyake-Hull, RDCS; Rebecca G. Schwaegler, RDCS

From the Division of Cardiology, Department of Medicine, University of Washington, Seattle.

Correspondence to Catherine M. Otto, MD, Division of Cardiology, Box 356422, University of Washington, Seattle, WA 98115. E-mail cmotto{at}u.washington.edu

	Abstract

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Background Only limited data on the rate of hemodynamic progression and predictors of outcome in asymptomatic patients with valvular aortic stenosis (AS) are available.

Methods and Results In 123 adults (mean age, 63±16 years) with asymptomatic AS, annual clinical, echocardiographic, and exercise data were obtained prospectively (mean follow-up of 2.5±1.4 years). Aortic jet velocity increased by 0.32±0.34 m/s per year and mean gradient by 7±7 mm Hg per year; valve area decreased by 0.12±0.19 cm² per year. Kaplan-Meier event-free survival, with end points defined as death (n=8) or aortic valve surgery (n=48), was 93±5% at 1 year, 62±8% at 3 years, and 26±10% at 5 years. Univariate predictors of outcome included baseline jet velocity, mean gradient, valve area, and the rate of increase in jet velocity (all P.001) but not age, sex, or cause of AS. Those with an end point had a smaller exercise increase in valve area, blood pressure, and cardiac output and a greater exercise decrease in stroke volume. Multivariate predictors of outcome were jet velocity at baseline (P<.0001), the rate of change in jet velocity (P<.0001), and functional status score (P=.002). The likelihood of remaining alive without valve replacement at 2 years was only 21±18% for a jet velocity at entry >4.0 m/s, compared with 66±13% for a velocity of 3.0 to 4.0 m/s and 84±16% for a jet velocity <3.0 m/s (P<.0001).

Conclusions In adults with asymptomatic AS, the rate of hemodynamic progression and clinical outcome are predicted by jet velocity, the rate of change in jet velocity, and functional status.

Key Words: stenosis • aorta • valves • exercise

	Introduction

Top Abstract Introduction Methods Results Discussion References

 
Recent pathological and risk factor studies suggest that valvular aortic stenosis is an active disease process that may be amenable to interventions to slow or prevent disease progression.^{1 2 3 4} Evaluation of potential interventions requires a reliable measure of disease severity as well as knowledge of the rate of hemodynamic progression and predictors of clinical outcome. While Doppler echocardiography (when performed by an experienced laboratory) can provide accurate and reproducible noninvasive measures of stenosis severity,^{5 6 7 8 9 10} there are fewer data on the relationship between hemodynamic progression and clinical outcome or on risk stratification of adults with asymptomatic disease.

Our understanding of the natural history of valvular aortic stenosis initially was based on clinical and autopsy series that did not include hemodynamic data and on small series of patients in whom two cardiac catheterizations were performed for clinical indications,^{11 12 13 14 15 16} with more recent studies utilizing a Doppler echocardiographic approach.^{17 18 19 20 21} Although these data have contributed substantially to our understanding of the disease process, the value of these studies is limited by a retrospective study design in most cases, potential selection bias, the availability of only two data points per patient, and limited clinical, functional, or exercise data. Factors that predict the rate of hemodynamic progression and clinical outcome have not been defined. Other studies focusing on clinical outcome have defined the mortality rates for asymptomatic and symptomatic aortic stenosis^{22 23 24 25 26 27 28 29} ; however, these studies included only limited hemodynamic or echocardiographic data.

Therefore, the goal of this prospective study of adults with asymptomatic valvular aortic stenosis was to utilize annual clinical, echocardiographic, and exercise data to (1) determine the rate (and variability) of hemodynamic progression of valvular aortic stenosis, (2) prospectively examine the relationship between hemodynamic severity and symptom onset, and (3) identify clinical, echocardiographic, and exercise predictors of clinical outcome.

	Methods

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Patient Population
Subjects with asymptomatic valvular aortic stenosis were referred by their primary care physician or cardiologist. There were 123 eligible subjects enrolled between September 1989 and April 1995. The study protocol consisted of annual visits that included clinical data collection, a complete Doppler echocardiographic study, a functional status questionnaire, and (if possible) an exercise treadmill stress test. Study visits occurred every year regardless of clinical status. The most recent annual study or the annual study before an end point (death or valve replacement) was considered the final study.

Entry criteria were (1) age 21 years, (2) systolic murmur on auscultation, (3) no symptoms caused by aortic stenosis,(4) aortic valve leaflet thickening with reduced systolic opening on two-dimensional echocardiography, and (5) a maximum aortic jet velocity at rest 2.5 m/s (2 SD >normal). Predefined exclusion criteria were inability to return for follow-up due to severe comorbid disease or distance of hospital from residence, patient refusal, and aortic valve replacement within 3 months of enrollment (n=9). These latter exclusion criteria were used as these subjects most likely had unrecognized symptoms at the time of enrollment. Eligible patients were not excluded for coexisting aortic regurgitation, mitral valve disease, hypertension, coronary artery disease, or comorbid noncardiac disease as the goal was to recruit subjects representative of the clinical spectrum of disease. The protocol was approved by our Institutional Review Board, and all subjects gave written informed consent.

Clinical Data
Clinical data recorded at entry included cardiac symptoms; prior evidence of coronary artery disease (history of myocardial infarction, angioplasty, or coronary artery bypass grafting); a history of hypertension, rheumatic fever, endocarditis, systemic embolic events, smoking, or other chronic diseases (renal disease, diabetes, pulmonary disease); and current medication use. A functional status score was calculated on the basis of a standardized questionnaire³⁰ that yields a score between 0% and 100% with 75% to 100% indicating minimal, 50% to 75% moderate, and <50% severe functional limitation. At each annual visit, interim clinical events were recorded including symptom onset (angina, heart failure, syncope, or near syncope), cardiac events (systemic embolic events, endocarditis, myocardial infarction, percutaneous coronary revascularization procedures, coronary artery bypass graft surgery), and any other hospitalizations.

In the 52 subjects who underwent coronary angiography for clinical indications, the presence of coronary disease and involvement of the left main coronary artery (50% stenosis), left anterior descending, circumflex, or right coronary artery (70% stenosis) were recorded.

Echocardiographic Data
Doppler and echocardiographic data were recorded on videotape on the basis of a standardized examination protocol with the use of a commercially available ultrasound system. All measurements were averaged from 3 to 5 high-quality beats.

On two-dimensional imaging of the valve in parasternal long-axis views, valve anatomy was defined as bicuspid if there was clear identification of two leaflets in systole, rheumatic if there was commissural fusion and mitral valve involvement, and calcific if there was thickening and increased echogenicity of the leaflets with reduced systolic opening.

The maximum aortic jet velocity was recorded using continuous-wave Doppler from that window yielding the highest velocity signal (apical in 62%, high right parasternal or suprasternal in 33%, other in 5%). Left ventricular outflow tract velocity was recorded from an apical approach using pulsed Doppler echocardiography with a 5- to 10-mm sample volume length, taking care to position the sample volume at the aortic annulus but not in the jet or proximal flow convergence region. Left ventricular outflow tract diameter was measured in mid systole from a parasternal long-axis view just proximal to the aortic leaflet insertion into the annulus. Maximum and mean pressure gradients were calculated using the Bernoulli equation, and aortic valve area was calculated with the continuity equation as previously described.^{5 31 32 33} Doppler echocardiographic calculations of stroke volume, cardiac output, and maximum and mean flow rates were performed on the basis of the cross-sectional area of flow and flow velocity data.^{33 34} Interobserver and intraobserver variabilities for these measurements in our laboratory have been published previously.^{31 33}

Two-dimensional echocardiographic images in apical four-chamber and two-chamber views were used for calculation of ventricular volumes and ejection fraction by the apical biplane method and mass by the area-length method.³⁵ Left ventricular diastolic inflow was recorded with the pulsed Doppler sample volume positioned at the mitral leaflet tips. Measurements of diastolic filling included E-velocity, A-velocity, E/A ratio, early diastolic deceleration slope, and time to E-peak.³⁶

Aortic regurgitant severity was graded as none to severe (0 to 4+) on the basis of color flow imaging.³⁷ Pulmonary systolic pressures were calculated on the basis of the tricuspid regurgitant jet velocity and the appearance and respiratory variation of the inferior vena cava.^{38 39}

Exercise Treadmill Data
In the 104 subjects (85%) able to exercise, maximal Bruce protocol treadmill testing was performed at each annual visit with the aortic jet velocity, left ventricular outflow tract velocity, and diameter recorded at baseline and immediately after exercise (at an average of 43±35 seconds after exercise), as previously described.³⁴ A 3-lead ECG was monitored continuously with a 12-lead ECG recorded at each exercise stage. Exercise testing was only performed if careful questioning confirmed that the subject had no symptoms of aortic stenosis. The test was stopped if symptoms occurred, if systolic blood pressure fell >10 mm Hg, for >5 mm of flat or downsloping ST depression, or for significant arrhythmias. Exercise duration, rest, and exercise heart rate and blood pressure, ST depression, arrhythmias, and rest and exercise measures of aortic stenosis severity were recorded. Functional aerobic impairment was calculated on the basis of previously validated regression equations based on exercise duration for sedentary men and women.⁴⁰

Clinical Outcome
End points were defined as death or aortic valve surgery. Death was classified as cardiac or noncardiac on the basis of review of the medical records, discussion with the primary care physician, and autopsy (when available). The indication for aortic valve surgery was classified as angina, heart failure, syncope, decreased exercise tolerance, severe asymptomatic stenosis, or valve replacement performed incidental to coronary artery bypass surgery. The decision to refer the subject for valve surgery was made by the patient's own physician. Because it would have been unethical to withhold these data, the primary physician was notified of specific echocardiographic (jet velocity, valve area, and ventricular function) and exercise test (duration, heart rate, blood pressure, ST-segment changes) data, including any complications. The referring physician was not aware of other study data (such as the changes in valve hemodynamics with exercise, functional status score, etc).

Statistical Analysis
Rates of hemodynamic progression were calculated as the difference between the baseline value and at the last visit before valve surgery or death, divided by the time interval in years. Progression rates also were calculated separately for the first year of follow-up. Changes in hemodynamic parameters from rest to immediately after exercise were calculated for each subject. Results are expressed as mean±1 SD and ranges. Baseline and follow-up studies were compared using paired t tests for numerical data and ² for categorical data. Survival without valve replacement was described through the use of Kaplan-Meier life table analysis with the log-rank test to assess differences between groups.

To define potential predictors of outcome, subjects who remained asymptomatic were compared with those who died or underwent valve surgery. Univariate analysis included unpaired t tests and ² analysis. Cox regression models were used for multivariate analysis. For the purposes of data analysis, subjects were divided at entry into three groups on the basis of stenosis severity (aortic jet velocity <3.0 m/s, 3.0 to 4.0 m/s, or >4.0 m/s) as derived from our previous studies.³²

Statistical analysis was performed with the use of dBase VI, version 1.5 (Borland International), and SPSS for Windows, Release 6.0, using default settings and a significance level of .05 both for univariate analysis and for entry into the Cox regression model.

	Results

Top Abstract Introduction Methods Results Discussion References

 
Clinical Characteristics
Of the 123 subjects, there were 86 (70%) men and 37 (30%) women with a mean age of 63±16 years (range, 22 to 84). The cause of aortic valve disease was rheumatic in 2 (1%), bicuspid in 34 (28%), and calcific in 87 (71%). The cardiac rhythm was normal sinus in 89%, atrial fibrillation in 4%, other irregular rhythm in 2%, and paced in 4%. Left ventricular ejection fraction was >50% in 93%, 40% to 50% in 5%, and <40% in 2% of subjects. Mitral annular calcification was seen in 50% of subjects and regional wall motion abnormalities at rest were noted in 14% of subjects. Coexisting mild aortic regurgitation was present in 73% and moderate to severe regurgitation in 5% of subjects. Coexisting mild mitral regurgitation was present in 89% and moderate regurgitation in 1% of subjects.

There was a history of cerebrovascular event in 12 of 123 (10%) subjects (5 cerebrovascular accidents, 7 transient ischemic attacks), endocarditis in 1 of 123 (1%), diabetes in 7 of 123 (6%), pulmonary disease in 7 of 123 (6%), and renal insufficiency in 2 of 123 (2%). A history of hypertension requiring medical therapy was present in 42 of 123 (34%), with a mean duration of therapy of 7±8 years. A total of 74 of 123 subjects (60%) had a history of cigarette smoking (mean pack-years, 36±23), but 60 of 74 (81%) had quit smoking a mean of 19±14 years before study enrollment. A history of prior myocardial infarction was present in 10 of 123 subjects (8%), percutaneous coronary revascularization in 2 of 123 (2%), and coronary artery bypass grafting in 12 of 123 (10%).

Coronary angiography was performed subsequently in 52 of 123 subjects (42%) and showed significant coronary stenoses in 26 of 52 (50%): left main disease in 7, single-vessel disease in 10, two-vessel disease in 4, and three-vessel disease in 5 subjects.

While 51% of subjects were retired due to age, 37% were working full-time, 7% part-time, 3% were unemployed, and only 2% were unemployed because of health.

Rate of Hemodynamic Progression
The duration of follow-up was 2.5±1.4 years, ranging from 0.3 to 6.3 years (see Table 1). At least two echocardiographic studies were available in 114 (93%) of the 123 subjects; 9 subjects either died or underwent aortic valve surgery within 1 year of enrollment. Over the total follow-up interval, aortic jet velocity increased by 0.70±0.58 m/s, mean transaortic gradient increased by 14±13 mm Hg, and valve area decreased by -0.25±0.28 cm². When normalized for length of follow-up and expressed as an annual rate of change, aortic jet velocity increased by 0.32±0.34 m/s per year (range, -0.4 to 2.0), mean gradient increased by 7±7 mm Hg per year (-5 to 31), and valve area decreased by 0.12±0.19 cm² per year (-0.35 to 1.16). There was marked individual variability in the rate of hemodynamic progression (Fig 1). The rate of change in stenosis severity over the first year of follow-up was no different than the overall annual rate. The rate of hemodynamic progression was not significantly different in those with a bicuspid versus a trileaflet valve (0.24±0.30 versus 0.35±0.34 m/s per year, P=.12).

View this table: [in this window] [in a new window]   Table 1. Echocardiographic Data at Baseline and at Final Study (n=114)

View larger version (19K): [in this window] [in a new window]   Figure 1. Examples of aortic stenosis (AS) jet velocity during prospective annual visits over a 6-year period in 8 patients with asymptomatic AS, demonstrating the marked individual variability in the rate of hemodynamic progression.

The echocardiographic, exercise, and functional status data at baseline and at the most recent follow-up (in those who remain asymptomatic) or the most recent study before death or valve replacement are shown in Table 2.

View this table: [in this window] [in a new window]   Table 2. Univariate Analysis of Predictors of Clinical Outcome

Exercise Test
In the 274 exercise tests performed in 104 subjects, there were no complications in 232 (85%) tests, whereas a fall in systolic blood pressure >10 mm Hg occurred in 25 (9%), and in 4 (2%) there was >2 mm ST-depression persisting >5 minutes into recovery. The treadmill test was stopped for fatigue or shortness of breath in 60%, leg discomfort in 28%, angina in 3%, lightheadedness in 1%, and by the physician (for a fall in blood pressure or arrhythmias) in 8% of all tests. In 87% of the exercise tests, the subject achieved 80% of their maximum predicted heart rate.

Exercise tests were not performed in 19 subjects due to arthritis (4), paraplegia (1), prior cerebrovascular event (1), pulmonary disease (2), nonspecific debility (4), or patient refusal (7). Compared with the remainder of the study group, subjects who did not exercise were older (71±12 versus 62±16 years, P=.02) and had a lower ejection fraction (36±14% versus 66±10%, P<.001) and functional status score (82±18 versus 96±7%, P<.001) but had no differences for valve area, mean gradient, or jet velocity. On univariate analysis, subjects who did not exercise were more likely to have a clinical end point (74% versus 40%, P=.007), but this factor did not enter into the multivariate Cox regression model.

In the 274 exercise tests, asymptomatic flat or downsloping ST depression (>1 mm) was common, occurring in 188 of 274 (69%) of all tests. The ST segments were abnormal on resting ECG in 51% of subjects (left bundle branch in 4%, right bundle branch in 10%, left ventricular hypertrophy with strain in 33%, nonspecific in 52%). Exercise ST depression was seen in 119 of 141 (85%) of those with an abnormal resting ECG and in 69 of 133 (52%) of those with a normal resting ECG. Flat or downsloping ST depression averaged 1.8±1.5 mm in inferior, 0.7±1.4 mm in anterior, and 2.2±1.7 mm in lateral ECG leads. The presence or absence of ST depression did not correlate with the presence of coronary artery disease at subsequent angiography.

In the 62 subjects with paired exercise tests at baseline and at the final annual visit, exercise duration decreased from 8.7±3.8 to 8.2±3.8 minutes (P=.005), functional aerobic impairment decreased slightly (-10±33% to -6±35%, P=.02), and there was a fall in the exercise change in systolic blood pressure (27±18 to 20±26 mm Hg, P=.03), but there were no changes in the exercise change in valve area, cardiac output, or stroke volume.

Clinical Outcome
Of the 123 subjects, 8 (7%) died and 48 (39%) underwent aortic valve surgery. The 8 deaths occurred at a mean of 32±13 months (range, 8 to 49) after enrollment. The cause of death was noncardiac in 4 (2 gastrointestinal bleeding, 1 brain tumor, 1 diverticulitis with peritonitis). The 4 cardiac deaths were all due to congestive heart failure: 2 of these subjects had coexisting coronary artery disease with reduced left ventricular systolic function (ejection fraction <40%); the other 2 had severe aortic stenosis and had refused valve replacement. All 4 of these subjects had been hospitalized 1 or more times for heart failure. There were no sudden deaths.

The primary indication for valve replacement was decreased exercise tolerance in 18 of 48 (38%), heart failure in 11 of 48 (23%), angina in 7 of 48 (15%), syncope or near syncope in 6 of 48 (12%), severe asymptomatic aortic stenosis in 3 of 48 (6%), and incidental valve replacement for moderate stenosis at the time of coronary artery bypass grafting to avoid subsequent reoperation in 3 of 48 (6%). Kaplan-Meier event-free survival (ie, without valve surgery) was 93±5% at 1 year, 62±8% at 3 years, and 26±10% at 5 years (Fig 2).

View larger version (8K): [in this window] [in a new window]   Figure 2. Kaplan-Meier life-table analysis showing survival without valve replacement for 123 subjects with initially asymptomatic valvular aortic stenosis.

Interim events included coronary artery bypass surgery without valve replacement in 2 subjects (2%), percutaneous revascularization in 3 (2%), myocardial infarction in 4 (3%), endocarditis in 1 (1%), and a systemic embolic event in 7 (6%).

Predictors of Outcome
Univariate analysis of potential predictors of outcome are shown in Table 2. There were no significant differences between those who remained asymptomatic versus those who had an end point for age, sex, or cause of aortic stenosis, although functional status at entry was associated with clinical outcome. Aortic jet velocity, mean gradient, and valve area (measures of aortic stenosis severity) were all significantly different, whereas left ventricular mass and ejection fraction, the severity of coexisting aortic and mitral regurgitation, pulmonary artery pressures, and parameters of diastolic dysfunction showed no differences. In addition, a more rapid rate of change in aortic jet velocity and gradient was related to clinical outcome. Of note, despite significant group differences for measures of aortic stenosis severity and the rate of change in severity, there was substantial overlap in individual values as shown for aortic jet velocity and valve area in Fig 3.

View larger version (19K): [in this window] [in a new window]   Figure 3. Aortic jet velocity (top) and aortic valve area (bottom) in subjects who developed symptoms requiring aortic valve replacement or died (AVR/Died) are compared with those who remained asymptomatic for the baseline and final studies (P<.001 for asymptomatic vs those with an end point for both baseline and final values). Data are shown using box plots where the median is indicated by the dark line, 25th and 75th percentiles by the box, largest and smallest nonoutlier values by the lines at the ends of the box, and outliers by the circles.

Although exercise duration was not predictive of outcome, there were significant group differences for estimated functional aerobic impairment and for the change in valve area, stroke volume, cardiac output, and blood pressure with exercise. Again, despite significant group differences, there was substantial overlap between groups for individual values for the exercise change in blood pressure and valve area.

Multivariate Cox regression analysis considered baseline clinical and echocardiographic variables: jet velocity, valve area, ejection fraction, left ventricular mass, age, sex, cause of aortic stenosis, and functional status score; and the rate of change in jet velocity, valve area, ejection fraction, and left ventricular mass. Only aortic jet velocity at baseline (P<.0001), baseline functional status score (P=.002), and the rate of change over time in jet velocity (P<.0001) were identified as predictors of clinical outcome. Adding the exercise data to the model, including the changes in hemodynamics and blood pressure with exercise, did not change the variables included in the final Cox model.

Kaplan-Meier survival curves for subgroups defined by aortic jet velocity at entry are shown in Fig 4. For those with a jet velocity >4.0 m/s at entry, the likelihood of remaining alive without valve replacement at 2 years was only 21±18%; for a jet velocity 3.0 to 4.0 m/s, event-free survival was 66±13%, whereas for a jet velocity <3.0 m/s, 2-year event-free survival was 84±16% (P<.0001).

View larger version (12K): [in this window] [in a new window]   Figure 4. Cox regression analysis showing event-free survival in groups defined by aortic jet velocity at entry (P<.0001 by log- rank test).

If only cardiac deaths and valve replacement for symptomatic aortic stenosis are considered end points, overall Kaplan-Meier event-free survival was 93±5% at 1 year, 67±10% at 3 years, and 34±15% at 5 years. Using this stricter end point, multivariate Cox regression again identifies baseline aortic jet velocity, baseline functional status score, and the rate of change in jet velocity (all P<.0001) as predictors of clinical outcome. In addition, baseline aortic valve area (P<.0001) enters the multivariate model. For this analysis, data for subjects with noncardiac death (n=4) and those with valve replacement incidental to coronary surgery (n=3) or for asymptomatic severe stenosis (n=3) were censored at the time of the clinical event.

	Discussion

Top Abstract Introduction Methods Results Discussion References

 
This prospective study of adults with initially asymptomatic valvular aortic stenosis has defined the rate and variability of hemodynamic progression and has provided insight into the relationship between hemodynamic severity (at rest and with exercise) and clinical symptoms. The strongest predictor of clinical outcome in this study was stenosis severity at baseline. In addition, functional status and the rate of hemodynamic progression were strong predictors of clinical outcome.

Rate of Hemodynamic Progression
There is substantial variability in the rate of hemodynamic progression among adults with valvular aortic stenosis. However, for a cohort of subjects, the overall rate of increase in aortic stenosis severity is predictable with an average annual increase in aortic jet velocity of 0.3 m/s and a decrease in aortic valve area of about 0.1 cm². Over the relatively short time period of this study (mean follow-up, 2.5 years), there were few changes in parameters of left ventricular geometry, mass, and systolic or diastolic function.

Clinical factors that might predict the rate of hemodynamic progression were not identified in this study. Although there was a trend toward more rapid progression in those with a trileaflet compared with bicuspid valve, this difference was not statistically significant and may relate to other clinical factors (such as age). Risk factor studies suggest that progression of degenerative valvular aortic stenosis may be related to clinical factors not examined in this study (such as serum lipid levels) and other factors (such as smoking) that may require a larger sample size to establish a relationship.^{3 4 41 42 43 44}

Predictors of Clinical Outcome
Overall, there was a very high rate of clinical events, defined as death or aortic valve surgery for aortic stenosis, in these adults with initially asymptomatic aortic stenosis. On life table analysis, while only 7% had an event at 1-year follow-up, by 3 years 38% had a clinical end point and by 5 years, 74% had undergone valve replacement or died. These prospective results show an even higher event rate in initially asymptomatic patients than previous studies.^{25 26 27 28 29} While the decision to perform aortic valve replacement was made by each subject's physician rather than on the basis of strict criteria, indications for valve replacement are reasonably standard in our community, typically including definite symptoms of aortic stenosis as well as evidence of significant obstruction at the valvular level. In any case, it would have been unethical to require or withhold valve surgery as part of the current study. It should be emphasized that there were no sudden cardiac deaths in these prospectively followed subjects²⁷ and that deaths classified as cardiac were due to associated coronary disease with ventricular dysfunction or to severe aortic stenosis in subjects who refused surgery.

Univariate analysis identified several clinical, echocardiographic, and exercise parameters that differed in the groups of subjects remaining asymptomatic over the study period compared with those who died or underwent valve replacement. The only baseline clinical variable associated with outcome was functional status score. There were no differences observed for age, sex, cause of aortic stenosis, comorbid disease (hypertension, renal disease, diabetes), smoking history, or coexisting coronary artery disease.

The echocardiographic severity of aortic stenosis at baseline was a strong predictor of outcome, whether expressed as aortic jet velocity, mean gradient, or valve area. In addition, the annual rate of change in aortic jet velocity and mean gradient was higher in the group with a clinical end point. Similar differences are present for alternate measures of stenosis severity such as valve resistance and the velocity ratio, although these measures provided no incremental value.

On multivariate analysis, only baseline aortic jet velocity, functional status score, and the rate of change in aortic jet velocity were predictive of clinical outcome. To some extent, this result reflects the fact that different measures of stenosis severity all relate to the same underlying disease process so that any one of these measures is predictive of clinical outcome. The advantages of jet velocity as a measure of stenosis severity are that it is recorded directly on Doppler examination, requires no calculations, and has a low interobserver variability in experienced laboratories. The potential disadvantage of aortic jet velocity is that poor technique (as with any approach to evaluation of stenosis severity) may lead to erroneous results. The importance of searching for the highest jet velocity, with a parallel intercept angle between the Doppler beam and aortic jet, cannot be overemphasized.⁴⁵

Relationship Between Hemodynamic Severity and Clinical Symptoms
Although there were statistically significant group mean differences for several rest and exercise measures of aortic stenosis severity, there was substantial overlap in individual exercise hemodynamic values as illustrated in Fig 3. The individual data for other measures of stenosis severity (including indexed valve areas) are similar to these examples.

This observed overlap in hemodynamic severity between symptomatic and asymptomatic patients contradicts the traditional view, derived from theoretical considerations, that symptom onset occurs only when stenosis severity reaches a specific numerical value. Instead, the careful clinical observations in this and other studies^{25 26 27 28} support the concept that symptom onset in an individual patient depends on the interaction between stenosis severity at the valvular level, left ventricular systolic function, and the peripheral circulation. Symptom onset then occurs when the heart is unable to pump an adequate cardiac output to meet peripheral demands, especially under conditions of stress or exercise. Of course, comorbid disease, as well as patient expectations, modulate this balance.

Exercise Testing in Asymptomatic Aortic Stenosis
The hypothesis that symptom onset depends on the interaction between stenosis severity, ventricular function, and the periphery is supported by the exercise hemodynamics observed in those remaining asymptomatic versus those with an clinical end point. While both groups had a similar increase in heart rate with exercise (to age-predicted maximums), there was a greater fall in stroke volume in the end point group, resulting in a smaller increase in cardiac output with exercise. The increase in aortic valve area with exercise seen in our subjects has been observed in other studies.^{34 46 47 48 49} As has been hypothesized in these previous studies, there was a greater increase in valve area with exercise in the group that remained asymptomatic compared with those with a clinical end point. One possible mechanism for this phenomenon is greater leaflet stiffness in patients with more severe disease, resulting in an inability to increase the degree of opening with an increased flow rate. Another possible mechanism is that those with an end point had decreased leaflet opening due to the lower maximum flow rate across the valve.

While the exercise changes provide intriguing insight into the pathophysiology of symptom onset and were predictors of outcome on univariate analysis, exercise parameters did not add to the multivariate model. In addition, exercise Doppler hemodynamics are unlikely to be useful in management of individual patients because of the substantial overlap between groups, the inherent measurement variability of this data, and the difficulty in recording Doppler velocities quickly and accurately immediately after exercise. Perhaps the most helpful variable in the clinical setting is simply to record the increase in systolic blood pressure with exercise. A failure to increase or a fall in blood pressure connotes a poor prognosis. Given the potential risks of exercise testing even in asymptomatic patients with valvular aortic stenosis, testing should be undertaken only after careful consideration of the clinical situation and evaluation of stenosis severity. Exercise testing should be stopped for any fall in blood pressure, excessive ST-segment depression, or significant arrhythmias.

Clinical Implications
As the Cox regression model shows, the likelihood of a clinical event in asymptomatic valvular aortic stenosis is predicted by aortic jet velocity at baseline, the rate of change in aortic jet velocity, and baseline functional status. Baseline jet velocity alone provides useful prognostic information, as shown in Fig 4. Subjects with a jet velocity <3.0 m/s are unlikely to develop symptoms due to aortic stenosis over the next 5 years, whereas those with a jet velocity >4.0 m/s have a >50% likelihood of symptom onset or death within 2 years. Those with a jet velocity between 3 and 4 m/s have an intermediate likelihood of symptom onset.

These data can be used to educate asymptomatic patients about their short- and long-term prognosis and can be used to tailor the frequency of clinical and echocardiographic follow-up based on stenosis severity at each visit. In addition, with advances in surgical options for aortic valve surgery, these data may allow consideration of elective intervention in patients with progressive disease at the first evidence of clinical symptoms rather than waiting for severe symptomatic deterioration. In the patient with mild to moderate aortic valve stenosis undergoing coronary artery bypass surgery, an estimate of the time course of disease progression will aid in the decision to perform "prophylactic" aortic valve replacement to avoid a repeat sternotomy in the near future.

Research Implications
Until recently, progressive thickening and obstruction of a bicuspid or trileaflet aortic valve in the absence of commissural fusion was thought to be a nonspecific "degenerative" process related to aging.^{41 50 51} Instead, current studies^{1 52 53} suggest that although the initiating factor may be related to mechanical and shear stress forces,^{54 55 56 57} leaflet changes are due to an active disease process characterized by subendothelial lesions on the aortic side of the leaflets that consist of intracellular and extracellular lipid accumulation (apo B, apo(a), and apo E); inflammatory cells (non–foam cell and foam cell macrophages, occasional T-cells); and fine, stippled mineralization in association with the active production of osteopontin by a subset of lesion macrophages.^{1 52 53} Other investigators have demonstrated accumulation of T-cells (with expression of interleukin-2 receptors) and fibroblasts (with expression of smooth muscle cell characteristics and HLA-DR antigen) in abnormal regions of the leaflets.^{2 58}

These studies, in combination with identification of potential risk factors for valvular aortic stenosis, suggest that either risk factor interventions or interventions directed at specific cellular and molecular mechanisms of disease might slow or prevent disease progression in adults with mild aortic valve stenosis. Doppler echocardiographic measures of stenosis severity can provide noninvasive, sensitive indicators of disease progression. The data from the current study will be useful in determining appropriate sample size estimates and risk stratification for future randomized intervention trials.

	Acknowledgments

 
This study was supported in part by a Grant-in-Aid from the American Heart Association (#91007520).

Received August 22, 1996; revision received December 9, 1996; accepted December 14, 1996.

	References

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