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C 2010, the Authors C 2010, Wiley Periodicals, Inc. Journal compilation DOI: 10.1111/j.1540-8175.2009.01002.x ORIGINAL INVESTIGATIONS Does Left Atrial Size Predict Mortality in Asymptomatic Patients with Severe Aortic Stenosis? Grace Casaclang-Verzosa, M.D., Joseph F. Malouf, M.D., Christopher G. Scott, M.S., Eldyn Marcony Juracan, M.D., Rick A. Nishimura, M.D., and Patricia A. Pellikka, M.D. Mayo Clinic, Rochester, Minnesota Background: We assessed the hypothesis that diastolic function represented by left atrial size determines the rate of development of symptoms and the risk of all-cause mortality in asymptomatic patients with severe aortic stenosis (AS). Methods: From a database of 622 asymptomatic patients with isolated severe AS (velocity by Doppler ≥ 4 m/sec) followed for 5.4 ± 4 years, we reviewed the echocardiograms and evaluated Doppler echocardiographic indices of diastolic function. Prediction of symptom development and mortality by left atrial diameter with and without adjusting for clinical and echocardiographic parameters was performed using Cox proportional-hazards regression analysis. Results: The age was 71 ± 11 years and 317 (62%) patients were males. The aortic valve mean gradient was 46 ± 11 mmHg, and the Doppler-derived aortic valve area was 0.9 ± 0.2 cm2 . During follow-up, symptoms developed in 233 (45%), valve surgery was performed in 290 (57%) and 138 (27%) died. Left atrial enlargement was significantly correlated with symptom development (P < 0.05) but the association diminished after adjusting for aortic valve area and peak velocity (P = 0.2). However, atrial diameter predicted death independent of age and gender (P = 0.007), comorbid conditions (P = 0.03), and AS severity and Doppler parameters of diastolic function (P = 0.002). Conclusion: Diastolic function, represented as left atrial diameter, is related to mortality in asymptomatic patients with severe AS. (Echocardiography 2010;27:105-109) Key words: aortic stenosis, echocardiography, left atrium, valvular heart disease In our previous study of asymptomatic adult patients with peak aortic valve velocity of ≥4 m/sec followed for 5.4 ± 4 years, age, AV velocity, chronic renal failure, and inactivity were independently associated with all-cause mortality.1 However, no criteria or combination of these accurately identified all asymptomatic patients at risk of death. Impairment of diastolic function has been observed to occur frequently as an adverse consequence of severe aortic stenosis (AS).2–5 However, no large study has assessed the impact of diastolic function on the natural history of asymptomatic patients with severe AS. The purpose of the present study was to evaluate the role of echocardiographic parameters of diastolic function on the rate of development of symptoms and the risk of all-cause mortality in asymptomatic patients with severe AS. Address for correspondence and reprint requests: Patricia A. Pellikka, M.D., Mayo Clinic, 200 First Street SW, Rochester, MN 55905. Fax: 507-284-3968; E-mail: pellikka.patricia@ mayo.edu Methods: Two-Dimensional and Doppler Echocardiography: From our previously described cohort of 622 patients with severe, asymptomatic AS and peak AV velocity of ≥4 m/sec,1 we identified patients in whom echo-Doppler parameters of diastolic function, including left atrial size, E and A velocities, E/A ratio, and E deceleration time, had been acquired at the time of echocardiography performed between 1984 and 1995. Left atrial anteroposterior diameter was measured in the parasternal long-axis view by M-mode using the leading edge of the posterior aortic wall to the leading edge of the posterior atrial wall,6 or where M-mode was not feasible, by two-dimensional echocardiography in the same view using the largest diameter during left ventricular end systole. For patients in whom left atrial diameter was not recorded in the database, but had echocardiograms available for the review, off-line measurements were made by a single observer, blinded to the rest of the data. 105 Casaclang-Verzosa, et al. Patient’s clinical history and other Doppler echocardiographic information, including ejection fraction, aortic valve (AV) area, AV mean gradient, and AV peak velocity, were obtained from the original database.1 Two-dimensional and Doppler echocardiographic measurements were obtained according to American Society of Echocardiography recommendations.7 Patients were classified as active or inactive according to whether they required assistance with activities of daily living. Follow-up was obtained as previously described.1 Statistical Analysis: The effects of left atrial diameter (considered separately as a continuous and categorical variable), in addition to the clinical and echocardiographic variables that have been previously tested on the development of symptoms and on mortality, also were analyzed using the same statistical model (Cox proportional-hazards regression analysis) as used in the previous study.1 Using methodology similar to the previous study, follow-up until the time of aortic valve surgery was considered for both endpoints. Univariate and multivariate analysis in the subgroup of patients in whom left atrial diameter was available was performed. The incremental value of left atrial diameter, as a surrogate measure of diastolic function,8,9 on previously reported predictors (age, AV peak velocity, chronic renal failure, and inactivity) on the development of symptoms and death was determined adjusting for age and sex, clinical co-morbidities, and severity of AS. Comparison between groups was performed using 2-tailed Fisher’s test. The Contal and O’Quigley test was used to estimate the optimal value for the single parameter being considered (left atrial diameter) associated with symptom development and death.10 Results: The 513 patients in whom left atrial diameter was measured were included. The mean age was 71 ± 11 years and 318 (62%) were males. The baseline clinical and echocardiographic characteristics are listed in Table I. Development of Symptoms: During the follow-up of 5.4 ± 4.0 years (maximum 15 years), 233 (45%) patients developed symptoms of angina, dyspnea, and syncope. Univariate predictors of symptom development were left atrial diameter, AV area, mean gradient, peak velocity and peak velocity ≥ 4.5 (all P < 0.05). A left atrial diameter of >40 mm was the optimal (P = 0.30) cutoff point for symptom development. Patients with left atrial diameter >40 mm were 1.4 (95% CI, 1.1–1.9, P = 0.007) times more likely to develop symptoms within 5 years than 106 TABLE I Patient Characteristics Age, years ± SD Male sex, n (%) Diabetes mellitus, n (%) Hypertension, n (%)∗ Current/former smoker, n (%) Chronic renal failure, n (%) Inactivity, n (%) Left ventricular hypertrophy, n (%)† Ejection fraction, % ± SD Aortic valve velocity ≥ 4.5, n (%) Aortic valve velocity, m/sec ± SD Aortic valve mean gradient, mmHg ± SD Aortic valve area, cm2 ± SD E-deceleration time, msec ± SD E-deceleration time < 180 msec, n (%) E, m/sec A, m/sec E/A Left atrial diameter, mm ± SD Left atrial diameter ≥ 45mm, n (%) 72 ± 11 317 (62) 621 (12) 220 (43) 193 (38) 20 (4) 37 (8) 85 (17) 64.3 ± 7.3 159 (31) 4.4 ± 0.4 46 ± 11 0.9 ± 0.2 253 ± 63 24 (8) 0.8 ± 0.3 1.0 ± 0.3 0.9 ± 0.3 42.3 ± 7.2 166 (32) ∗ Hypertension was defined as blood pressure ≥ 140/90 mmHg or the use of antihypertensive medication. †Left ventricular hypertrophy based on electrocardiographic criteria. those with smaller left atrial diameter. Patients with left atrial diameter >40 mm had 83%, 66%, and 27% chance of remaining asymptomatic at 1, 2, and 5 years, respectively. In comparison, patients with left atrial diameter ≤40 mm had 84%, 71%, and 42% chance of remaining asymptomatic at 1, 2, and 5 years, respectively. Adjusting for age and sex alone, left atrial diameter was significantly correlated with symptom development (P < 0.05) (Table II). When adjusted for clinical covariates (hypertension, diabetes mellitus, coronary artery disease, chronic renal failure, inactivity, and electrocardiographically diagnosed TABLE II Prediction of Development of Symptoms until Date of Surgery Left Atrial Diameter > 40 mm Unadjusted Age and sex adjusted Adjusted for age, sex, and other clinical variables Adjusted for age, sex, and echo Doppler variables Hazard Ratio P Value 1.4 1.4 1.3 0.007 0.009 0.08 1.5 0.08 Clinical variables include hypertension, diabetes mellitus, chronic renal failure, coronary artery disease, inactivity, and left ventricular hypertrophy. Echo Doppler variables include aortic valve area, peak velocity, mean gradient, ejection fraction, E velocity, E/A, and E deceleration time. Left Atrial Size and Mortality in Aortic Stenosis TABLE III Predictors of Overall Mortality until Date of Surgery Figure 1. Survival of patients according to left atrial diameter (LAD) <45 mm and ≥45 mm. Time to death until date of aortic valve surgery. left ventricular hypertrophy) and echo Doppler variables (AV area and AV peak velocity; E, E/A, E deceleration time), left atrial diameter was not a significant predictor of symptom development (Table II). E, E/A, and E deceleration time were also not predictive of symptom development (all P > 0.05) All-Cause Mortality: During follow-up, 138 (27%) patients died; 51 (37%) of deaths were due to cardiac causes. Univariate predictors of death were age (P < 0.0001), male gender (P = 0.01), diabetes mellitus (P = 0.04), coronary artery disease (P < 0.0001), chronic renal failure (P = 0.005), inactivity (P < 0.001), peak AV velocity (P = 0.04), peak AV velocity ≥ 4.5 m/sec (P = 0.009), mean gradient (P = 0.03), AV area (P = 0.02), left atrial diameter (P = 0.0005), left atrial diameter ≥ 4.5 m/sec (P = 0.008), E velocity (P = 0.002), and E deceleration time (P = 0.004). Those who died had more impaired diastolic function (mean left atrial diameter 44 mm vs. 41 mm, P < 0.001; mean EDT, 270 msec vs. 248 msec, P = 0.01) than those who remained alive at 5 years. The relative risk of death increased by 1.04 (95% CI, 1.00–1.08) per one unit increase in the left atrial diameter. The optimal cutoff value for left atrial diameter associated with increased risk of all-cause mortality was ≥45 mm (P = 0.02). All-cause mortality was significantly lower in patients with left atrial diameter <45 mm (Fig. 1). The 1-, 2-, and 5-year probabilities of survival were 92%, 83%, and 51% for those with left atrial diameter ≥45 mm compared to 97%, 90%, and 66% for patients with left atrial diameter <45 mm. In a multivariate analysis, left atrial diameter demonstrated significant independent association with all-cause mortality when adjusted for age and sex alone, and when adjusted for other clinical or echo Doppler variables (Table III). When stratified according to age and Left Atrial Diameter ≥ 45 mm Hazard Ratio P Value Unadjusted Age and sex adjusted Adjusted for age, sex, and other clinical variables Adjusted for age, sex, and echo Doppler variables Left Atrial Diameter (per mm) Unadjusted Age and sex adjusted Adjusted for age, sex and other clinical variables Adjusted for age, sex, and echo Doppler variables 1.6 1.3 1.3 0.008 0.1 0.2 2.6 0.03 1.04 1.03 1.03 0.0005 0.007 0.03 1.1 0.01 Clinical variables include hypertension, diabetes mellitus, coronary artery disease, chronic renal failure, inactivity, and left ventricular hypertrophy. Echo Doppler variables include aortic valve area, peak velocity, mean gradient, ejection fraction, E velocity, E/A, and E deceleration time. inactivity, those who were older (≥ 70 years) and were inactive had higher risk (Fig. 2). The presence of a larger left atrium (LAD ≥ 45 mm) augmented mortality risk across all groups (Fig. 2). Discussion: This study demonstrated that among asymptomatic patients with severe aortic stenosis, those with enlarged left atria (left atrial diameter >40 mm) were more likely to develop symptoms compared with patients who had smaller atria (left atrial diameter ≤40 mm). By the second and fifth year of follow-up, more patients with left atrial diameter >40 mm developed symptoms compared to those with smaller left atrial diameter (second year: 34% vs. 28%; fifth year: 73% vs. 57%; P = 0.007). Left atrial diameter was a strong independent predictor of all-cause mortality after adjusting for age, sex, clinical conditions, AV area, peak AV velocity, and mean gradient. Figure 2. Hazard ratio of all-cause death stratified by age, inactivity, and left atrial diameter (LAD). 107 Casaclang-Verzosa, et al. Furthermore, left atrial dilatation (LAD ≥ 45 mm) augmented the risk of death in asymptomatic patients who were older (≥70 years) and not living independently. Our present study showed an important association between left atrial size and outcome in patients with severe but asymptomatic AS. Our findings are important for several reasons. The course of these patients was not benign. At 5 years, the probability of remaining symptom free for asymptomatic patients with severe AS was only 33% and the probability of remaining free of cardiac events, including cardiac death or AV surgery was only 25%.1 Standard clinical and echocardiographic characteristics are imperfect in identifying patients at risk. For example, although risk was increased in patients with chronic renal failure, there were only 34 (4%) patients with chronic renal failure. Estimates of activity level are approximate. Left ventricular hypertrophy may be secondary to cardiovascular diseases other than AS. Evaluation of diastolic function involves integration of hemodynamic data obtained from Doppler echocardiography and can vary from time to time depending on heart rate, volume status, and rate and depth of breathing.11–15 On the other hand, left atrial diameter is an objective, accurate, and reproducible echocardiographic parameter that is easily obtained in most patients and is relatively preload independent, does not vary with heart rate and respiration, and reflects the severity of diastolic dysfunction.8,9 Left atrial size has recently been identified as a marker for cardiovascular events.9,16–21 Studies have also proven that its enlargement is a marker of both severity and chronicity of diastolic dysfunction and magnitude of left atrial pressure elevation.8,22–26 Left atrial enlargement occurs because of increased wall tension from prolonged elevation of filling pressures.23,27 Impairment of left ventricular diastolic function has been well described in the presence of AS.5,28–30 It has been shown that the presence of diastolic dysfunction increases risk of early and late mortality after AV surgery for severe AS.2,5,31 Early intervention is therefore advocated. However, determination of proper timing for aortic valve surgery in the asymptomatic patient with severe AS remains challenging. The clinical spectrum of AS is broad and patients with the same AV area can differ considerably in New York Heart Association status. Indication for surgical intervention is clear for patients who present with clinical symptoms of decreased cardiac output and concomitant coronary artery disease and other comorbidities.32 However, it is still unclear when to intervene in a patient who has hemodynamically significant AS but is asymptomatic.33,34 It is difficult to predict when the symptoms will occur. 108 Thus, there was a need for more accurate criteria to identify those asymptomatic patients at risk of death. Our findings support the importance of diastolic function in the natural history of patients with severe but asymptomatic AS. We believe that monitoring progression of AS by mean gradient and aortic valve area alone is insufficient. Comprehensive assessment of diastolic function including left atrial size will guide physicians in the management of this high-risk group and evaluate the optimal timing for intervention in asymptomatic patients. Our study contains limitations inherent in a retrospective study. Left atrial diameter was not available in all patients. We did not measure left atrial volume, as it was not routine practice to determine atrial volume during the period of the study (1984–1995). The time period of the study was broad, and Doppler measurements were less often obtained during the earlier part of the study. Detailed classification of diastolic function, including tissue Doppler assessment of the mitral annulus or a grading system of classification, was not available. Our study suggests that diastolic function, represented as left atrial diameter, is related to mortality and development of symptoms in asymptomatic patients with severe AS. 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