Author + information
- Received January 16, 2007
- Revision received June 15, 2007
- Accepted June 25, 2007
- Published online September 25, 2007.
- Sripal Bangalore, MD, MHA,
- Siu-Sun Yao, MD, FACC and
- Farooq A. Chaudhry, MD, FACC⁎ ()
- ↵⁎Reprint requests and correspondence:
Dr. Farooq A. Chaudhry, Director of Echocardiography, Division of Cardiology, Columbia University College of Physicians and Surgeons, St. Luke’s-Roosevelt Hospital Center, 1111 Amsterdam Avenue, New York, New York 10025.
Objectives The purpose of this study was to evaluate the role of diastolic dysfunction as measured by left atrial (LA) size in patients undergoing stress echocardiography (SE).
Background Left atrial size is a surrogate marker of diastolic function. However, its prognostic value in patients referred for SE is not well defined.
Methods We evaluated 2,705 patients (60 ± 13 years, 47% men) undergoing SE (56% dobutamine). Patients with significant mitral valve disease (mitral stenosis or ≥ moderate mitral regurgitation) were excluded. Enlarged LA was defined as a LA size indexed to body surface area ≥2.4 cm/m2. Follow-up (mean 2.7 ± 1.0 years) for nonfatal myocardial infarction or cardiac death (n = 122) was obtained.
Results A dilated LA was able to further risk-stratify both the normal and abnormal SE groups. In the presence of a dilated LA, an abnormal SE portends a worse prognosis compared with patients with normal LA size. Cox proportional modeling showed that a dilated LA added incremental value over traditional risk factors, stress electrocardiographic, rest echocardiographic, and SE variables for the prediction of hard events (global chi-square increased from 90.4 to 113.1 to 176.1 to 184.4 to 190.5; p < 0.05 all groups). Left atrial size was a significant predictor of events independent of left ventricular systolic dysfunction and ischemia (relative risk = 1.84, 95% confidence interval 1.19 to 2.85; p = 0.006).
Conclusions In patients referred for stress echocardiography, LA size provides independent and incremental value over standard risk factors including left ventricular systolic dysfunction and ischemia. Left atrial size is a powerful prognosticator and should be routinely used in the prognostic interpretation of stress echocardiography.
As measured by M-mode echocardiography, an increase in left atrial (LA) dimension is a risk factor for atrial fibrillation, stroke, and death and is closely related to general cardiovascular risk burden (1,2). Left atrial size is also a marker of left ventricular (LV) diastolic function in patients without significant mitral valve disease or systolic heart failure. Left atrial size reflects the chronicity and magnitude of the increased LV filling pressure (3) and is thus a marker of the severity and duration of diastolic dysfunction (4). It has been suggested (5) that Doppler indexes of diastolic function reflect filling pressures at one point in time, whereas increased LA reflects the cumulative effect of filling pressures over time and hence has been compared to hemoglobin A1c for diabetes.
It has recently been demonstrated (6) that the size of the LA is better described by volume rather than diameter. However, unidimensional measurement is still the most common method worldwide to quantify LA size.
Stress echocardiography is increasingly used for diagnosis, risk stratification, and prognosis of patients with known or suspected coronary artery disease (CAD) (7–11). However, the role of LA size in risk stratification of patients referred for stress echocardiography is not defined. We thus sought to evaluate the role of a routinely measured unidimensional measurement of LA size at further risk stratification of patients with known or suspected CAD referred for stress echocardiography. Our objective was 2-fold: 1) to evaluate the role of LA size as a risk factor for cardiovascular events, and 2) to evaluate the prognostic impact of LA size in risk stratification and prognosis during stress echocardiography.
We identified 3,260 consecutive patients referred for stress echocardiography. Successful prospective follow-up for future cardiac events after testing was obtained in all patients. Patients with acute myocardial infarction (<3 days), hemodynamically significant valvular abnormalities, hemodynamic instability, poor acoustic windows (<13 of 16 segments visualized by echocardiography), pregnancy, and inability to give informed consent were excluded from the study. Patients with significant mitral valve disease (mitral stenosis or moderate to severe mitral regurgitation by color Doppler) were excluded from this analysis (n = 555), leaving a cohort of 2,705 patients. Informed written consent was obtained from all patients, and the study was approved by the institution’s review board.
Exercise echocardiography protocol
Maximal exercise treadmill testing was performed using standard Bruce protocol. Patients exercised to general fatigue, with premature termination for severe angina, ventricular tachycardia, hemodynamically significant arrhythmias, or hemodynamic instability. The maximal degree of ST-segment change at 80 ms after the J point on the electrocardiogram (ECG) was measured. Patients with ≥1 mm ST-segment change after stress were considered to have a positive stress ECG response. After-exercise echocardiographic images were acquired within 30 to 60 s after termination of treadmill exercise.
Dobutamine echocardiography protocol
Dobutamine was administered intravenously beginning at a dose of 5 to 10 μg/kg/min and increased by 5 to 10 μg/kg/min every 3 min to a maximum of 50 μg/kg/min or until a study end point was achieved. The end points for termination of the dobutamine infusion included development of new segmental wall-motion abnormalities, attainment of 85% maximum age-predicted heart rate (MPHR), or the development of significant adverse effects related to the dobutamine infusion. Atropine was administered intravenously in 0.25-mg increments every 3 min to a maximum of 2 mg if a study end point was not achieved at the maximum dobutamine dose.
Beta-blockers were held on the morning of the test, as is the protocol in our laboratory for both types of stress. During both types of stress echocardiography, transthoracic echocardiographic images were obtained with the patient in the left lateral decubitus position using commercially available ultrasound equipment (Acuson Sequoia, Mountain View, California; Hewlett Packard Sonos 5500, Andover, Massachusetts). Four standard echocardiographic views were obtained with each acquisition: parasternal long-axis, parasternal short-axis, apical 4-chamber, and apical 2-chamber views. Echocardiographic images were acquired at baseline, with each increment of dobutamine infusion, and during the recovery phase. Cardiac rhythm was monitored throughout the stress echocardiography protocol, and 12-lead ECGs and blood pressure measurements were obtained at baseline, at each level of stress, and during the recovery phase.
Echocardiographic image analysis
The LV was divided into 16 segments as recommended by the American Society of Echocardiography, and a score was assigned to each segment at baseline, with each stage of stress, and during the recovery phase (12). Each segment was scored as follows: 1 = normal, 2 = mild to moderate hypokinesis (reduced wall thickening and excursion), 3 = severe hypokinesis (marked reduced wall thickening and excursion), 4 = akinesis (no wall thickening and excursion), and 5 = dyskinesis (paradoxical wall motion away from the center of the LV during systole) (9). All echocardiograms were interpreted by consensus agreement of experienced echocardiographers who were blinded to patients’ treatment and outcome.
A normal response to stress was defined as normal wall motion at rest, with an increase in wall thickening and excursion during stress. An abnormal response to stress was defined as: 1) an LV wall segment that did not increase in thickness and excursion during stress (fixed wall motion abnormality); 2) deterioration of LV segment wall thickening and excursion during stress (increase in wall motion score of ≥1 grade); and/or 3) a biphasic response with dobutamine stress. The peak wall motion score index (WMSI) following stress was derived from the cumulative sum score of 16 LV wall segments divided by the number of visualized segments. The stress echocardiogram, with a peak WMSI of 1.0, was considered normal, and those with a WMSI >1.0 were considered abnormal. Maximal severity of ischemia was the score of the LV wall segment(s) with the greatest value (worst wall motion grade) at peak stress (range 0 to 5) (13). Ischemic extent was the number of new (ischemic) wall motion abnormality during stress that increases in wall motion score of ≥1 (range 0 to 16) (13). Resting ejection fraction used in the study analysis was a visual estimation by experienced echocardiographers.
For each patient, LA size was measured as per the recommendation of the American Society of Echocardiography with the use of a leading-edge-to-leading-edge measurement of the maximal distance between the anterior and the posterior LA wall at end-systole (14), and this measurement was done at the time of stress echocardiography. Wade et al. (15) have demonstrated low interobserver (r = 0.97) and intraobserver (r = 0.97) variability in the M-mode measurements of LA dimension using these guidelines. A dilated LA was defined as a LA size ≥3.9 cm in women or ≥4.1 cm in men or LA size indexed to body surface area ≥2.4 cm/m2, as recommended by the American Society of Echocardiography and the European Association of Echocardiography (16). Indexing the size of body surface area accounts for variations in body size and hence for the gender difference (16). Left atrial size measurements were performed by investigators who were blinded to patients’ demographics, stress echocardiography results, and outcomes. Using 2-way random effects model for absolute agreement, there was strong interobserver (interclass correlation [ICC] = 0.977; 95% confidence interval [CI] 0.902 to 0.994) and intraobserver (ICC = 0.980; 95% CI 0.941 to 0.993) correlations for the measurement of LA size. Indexed LA size was used in all of the analyses unless otherwise indicated.
Serial prospective follow-up (mean 2.7 ± 1.0 years) was obtained in all patients by means of a physician-directed telephone interview using a standardized questionnaire. The physicians were blinded to patients’ echocardiography results. If the patient died during follow-up, the closest surviving relative and the patient’s physician were interviewed to determine the cause of death. Cardiac death was confirmed by review of hospital medical record and/or death certificate. Autopsy records were reviewed when available. All patients or relatives were interviewed at least twice during the follow-up period (except for those who were dead at the initial contact).
The primary end point of the study was a composite of nonfatal myocardial infarction (MI) and cardiac death. Nonfatal MI was documented by evidence of an appropriate combination of clinical symptoms, electrocardiographic findings, and cardiac enzyme changes. Adjudication of cardiac death and MI was done by physicians who were blinded to the clinical, stress ECG, and echocardiographic outcome of the patients.
All analysis was carried out using a standard statistical package (SPSS for Windows, version 13.0, SPSS Inc., Chicago, Illinois). Continuous variables were reported as mean value ± SD. Patient groups were compared using the Student ttest (for normally distributed variable) or the Wilcoxon rank-sum test (for other variables) for continuous variables and chi-square test or Fisher exact tests for categorical variables. A p value was considered significant at <0.05.
Univariate analysis was performed to determine the relationship between clinical and echocardiographic variables and cardiac events. Univariate variables that were predictive of cardiac events were considered in the multivariate Cox proportional hazard analysis. Cumulative survival rates as a function of time after stress echocardiography were performed using Kaplan-Meier survival analysis and compared using log-rank analysis. Potential confounders considered included age, gender, standard cardiovascular risk factors, ST-segment depression, %MPHR, wall motion score index, ejection fraction, and number of ischemic segments.
A forward conditional (Wald) Cox proportional hazard model was used to find out the incremental prognostic value of LA size over clinical, stress electrocardiographic, rest echocardiographic, and stress echocardiographic variables. Selection of variables for entry criteria was based on univariate statistical significance. The variables were entered in the order in which they were available to the physicians, with clinical variables (age, gender, diabetes, hypertension, hypercholesterolemia, smoking, family history of premature coronary artery disease, prior MI, and so on) entered first, followed by stress electrocardiographic variables (%MPHR, ST-segment depression, and so on), followed by rest echocardiographic variables (rest WMSI, left ventricular ejection fraction), followed by stress echocardiographic variables (stress WMSI, number of ischemic segments, extent and severity of ischemia, and so on) and finally the LA size variable. p < 0.10 was considered significant for entry and <0.05 for retention in the model. All model assumptions were tested.
To avoid loss of data inherent to dichotomizing a continuous variable (17–19), the LA size (indexed) was considered as a continuous variable for most of the univariate, multivariable, and incremental prognostic value analysis.
In the study cohort of 2,705 patients, 1,286 (47%) were men and 1,419 (53%) were women. There were 1,520 patients (56%) who underwent dobutamine stress and 1,185 patients (44%) who underwent exercise stress echocardiography.
Among the 2,705 patients, 2,061 (76%) had a normal LA size and 644 (24%) had a dilated LA on the basis of LA size (indexed). Their demographics are characterized in Table 1.
Among clinical characteristics, patients with a dilated LA were older and had a greater number of cardiovascular risk factors (hypertension and those with prior MI, known congestive heart failure, prior percutaneous coronary intervention, and coronary bypass surgery). Among the stress electrocardiographic characteristics, patients with a dilated LA achieved a lower peak heart rate, had a lower 85% MPHR, and had a lower peak systolic blood pressure than the patients with normal LA size. One-third of patients with dilated LA were chronotropically incompetent. For the entire cohort, the mean resting LV ejection fraction was 52%, reflecting the preserved LV function in this cohort. Among stress echocardiographic characteristics, patients with a dilated LA had a relatively lower ejection fraction, higher rest, higher stress WMSI, a greater number of ischemic segments, and a greater extent and severity of ischemia compared with those with a normal LA. Patients with a dilated LA were less likely to exercise than those with a normal LA.
Patients were followed for up to 5 years (mean 2.7 ± 1.0 years) for confirmed nonfatal MI (n = 54) and cardiac death (n = 68). Univariate clinical predictors of cardiac events were older age, hypertension, diabetes, prior MI, and known heart failure. Among stress electrocardiographic variables, lower achieved peak heart rate, inability to exercise, and chronotropic incompetence as defined by failure to achieve 85% MPHR were significant univariate predictors of cardiovascular events. Among echocardiographic variables, a higher rest WMSI, higher stress WMSI, lower ejection fraction, higher number of ischemic segments, and greater extent and severity of ischemia were significant univariate predictors of cardiovascular events (Table 2).
Left atrial size (indexed) was a significant univariate predictor of cardiovascular events (Table 2). For every 10 mm/m2increase in LA size the risk of cardiovascular events increased by 3.15 times. The relationship between LA (indexed) size and cardiovascular events followed an exponential curve (Fig. 1)with a very high correlation (r = 0.98, p < 0.0001) and an exponential increase in event rate beyond a LA (indexed) size of ≥2.4 cm/m2. Using a cutoff of ≥2.4 cm/m2, LA size effectively risk-stratified patients into a normal and abnormal group (Fig. 2).Patients with dilated LA (indexed) had a 2.9 times higher event rate compared with patients with normal LA. Left atrial size risk-stratified patients undergoing stress echocardiography, as shown by early separation of the survival curves. A dilated LA (indexed) has a sensitivity of 42% and specificity of 80% for prediction of future outcomes. Similarly, an unindexed LA size was also a significant predictor of cardiovascular events. The predictive value of the indexed and unindexed measurements of LA size was comparable (Fig. 3).The area under curve for LA (indexed) was 0.70 (95% CI 0.68 to 0.72; p < 0.0001), whereas that for unindexed size was 0.72 (95% CI 0.72 to 0.74; p < 0.0001), p = NS for the difference between the two.
Stress echocardiography and LA size
A dilated left atrium was able to further risk-stratify both the normal and abnormal stress echocardiography cohorts (Fig. 4).Table 3lists the adjusted relative risk of various combinations of LA size and stress echocardiography results for the entire cohort. A normal stress echocardiography in the setting of a dilated LA (indexed) carried a 2.3 times higher risk of a cardiac event when compared with patients with normal stress echocardiography and a normal LA size (event rate 1.7%/year vs. 0.5%/year). A dilated LA (indexed) in the setting of an abnormal stress echocardiography study portended a very high risk for cardiac events (adjusted RR 7.02, 95% CI 4.10 to 12.03, p < 0.0001). A normal stress echocardiography in the setting of a normal LA size portended a benign prognosis (<1% event rate/year). Left atrial size therefore effectively further risk-stratified patients in both normal and abnormal stress echocardiography groups (Fig. 4).
Figure 5depicts quartiles of LA size and event rate. Stress echocardiography risk stratified a normal and abnormal cohort in each of the LA size quartiles. Compared to the first quartile of LA size, the event rate in the subsequent quartiles increased for both normal and abnormal stress echocardiography cohorts (except for the normal group in the third quartile). The prognostic value of both abnormal and normal stress echocardiography was thus further modulated by the LA size. In patients with abnormal stress echocardiography, patients with a LA size in the fourth quartile had a 3.5 times higher event rate compared with patients with a LA size in the first quartile (5.5% vs. 1.6%/year, p < 0.001). Similarly, in patients with normal stress echocardiography, those with a LA size in the fourth quartile had a 4.5 times higher event rate compared with those with a LA size in the first quartile (1.8% vs. 0.4%/year, p < 0.001).
Multivariable predictors of cardiac events were older age, hypertension, diabetes, prior MI, lower ejection fraction, LA size (indexed), and ischemia on stress echocardiography (Table 2). Left atrial size (adjusted HR 1.84, 95% CI 1.19 to 2.85, p = 0.006) was an independent predictor of cardiac events even after controlling for clinical risk factors (age, standard cardiovascular risk factors, and so on), stress electrocardiographic variables (%MPHR, ST-segment depression, and so on), and stress echocardiographic variables (stress WMSI, LV ejection fraction, number of ischemic segments, extent and severity of ischemia, and so on). For every 10 mm/m2increase in LA size, the risk of cardiovascular events increased by 1.8 times, even after controlling for baseline cardiovascular risk factors and echocardiographic myocardial ischemia.
Incremental prognostic value
Figure 6shows the incremental prognostic value of LA size (indexed-continuous) over clinical, stress ECG, rest echocardiographic, and stress echocardiography variables (global chi-square increased from 90.4 to 113.1 to 176.1 to 184.4 to 190.5, p < 0.05).
Age-adjusted hazard ratio for an indexed LA size was 2.40 (95% CI 1.42 to 4.08, p = 0.001) for men, whereas it was 2.59 (95% CI 1.46 to 4.60, p = 0.001) for women, illustrating that LA size is a powerful risk stratifier in both men and women and signifies higher risk per 10 mm/m2increase in the size in women compared with men.
This study assessed the role of a simple, widely used, highly reproducible, and routinely used measure of LA size (anteroposterior diameter) in risk stratification of patients with known or suspected CAD referred for stress echocardiography. The results of the present study show that LA size is an independent predictor of cardiovascular outcomes in patients referred for stress echocardiography. Furthermore, there exists an exponential relationship between indexed LA size and cardiovascular events. Left atrial size can further risk-stratify patients undergoing stress echocardiography. A normal stress echocardiography in the setting of a normal LA size portends a benign prognosis (<1% event rate/year). However in the setting of a dilated LA, a normal stress echocardiography study is prognostically less benign, whereas an abnormal stress echocardiogram is prognostically more malignant. Left atrial size provides independent and incremental prognostic value, independent of traditional risk factors, echocardiographic myocardial ischemia, and LV ejection fraction.
LA size and cardiovascular events
Prior studies have explored the role of LA size as a predictor of cardiovascular events in a population-based cohort. Benjamin et al. (1) found that in 3,581 patients in the Framingham cohort who had an echocardiogram, the multivariable adjusted relative risk of death was 1.3 in men and 1.4 in women for every 10-mm increase in LA size. In this study, an increasing LA size was associated with greater number of cardiovascular risk factors, suggesting that a dilated LA may be also be a marker of more severe cardiovascular comorbidities. Our study is concordant with the earlier study, showing that for every 10 mm/m2increase in LA size, the risk of cardiovascular events increased 1.8 times, even after controlling for traditional cardiovascular risk factors and echocardiographic myocardial ischemia. Patients with a dilated LA were sicker, with a greater number of cardiovascular risk factors, thus proving dilated LA to be a marker for other risk factors. But as we and others have shown, LA size is a predictor of events even after controlling for these baseline variables. In patients with hypertropic cardiomyopathy, Kjaergaard et al. (20) found that LA size was a predictor of exercise capacity together with body mass index, heart rate at rest, and LV end-systolic diameter. In the present study, patients with dilated LA were less likely to exercise (23% vs. 50%, p < 0.0001) and more likely to be chronotropically incompetent (30% vs. 16%, p < 0.0001) compared with patients with normal LA size.
LA size and diastolic dysfunction
In patients without significant mitral valve disease, LA size is thought to represent diastolic function (3–5,21). Appleton et al. (3) found a significant correlation between LA size and LV filling pressure (r = 0.70) and found that an enlarged LA has a sensitivity of 82% and specificity of 98% for prediction of an elevated pulmonary wedge pressure (>12 mm Hg). Although Doppler-derived indexes of left ventricular function measure LV loading conditions at one point of time, LA size reflects the chronicity of the loading conditions (5). Left atrial size increases with worsening diastolic dysfunction (4,21), independent of traditional cardiovascular risk factors and independent of LV ejection fraction (21). Left atrial size is thus an index of cardiovascular risk burden and represents the severity of diastolic dysfunction.
Diastolic dysfunction and stress echocardiography
Stress echocardiography is a very valuable tool for risk stratification and prognosis of patients with known or suspected CAD and has traditionally risk-stratified patients into a normal group with a benign prognosis and an abnormal group with worse prognosis (7–9,11). Though the importance of diastolic dysfunction has been well recognized, there are limited data in the stress echocardiography literature regarding incorporation of indexes of diastolic dysfunction during interpretation of stress echocardiography results. Recent studies have looked at global diastolic function Doppler indexes using mitral inflow pattern for prediction of ischemia during stress echocardiography with variable results (22–24). This variable result has in part been due to the load-dependent nature of these flow Doppler indexes. Other recent studies (25) have evaluated tissue Doppler measures of regional diastolic function with good prediction of ischemia on stress echocardiogram. Alsaileek et al. (26) evaluated the role of normal LA volume index during stress echocardiography and showed a good negative predictive value (94%) at predicting abnormality on stress echocardiography. However, none of these studies evaluated the role of diastolic dysfunction for prognostication.
In this study of patients without significant mitral valve disease and relatively preserved LV function, we have shown that LA size further risk stratifies both a normal and abnormal stress echocardiography cohorts. The interpretation of stress echocardiography results should incorporate the valuable data obtained from LA size measurements. In the setting of a normal stress echocardiography study, patients with dilated LA have 1.8 times the event rate compared with those with a normal LA. Similarly, in patients with an abnormal stress echocardiography study, patients with dilated LA have a 2.1 times the event rate as that of a normal LA size cohort. On the basis of previous studies, LA size represents chronicity and severity of diastolic dysfunction, and this study shows that it is an independent and strong predictor of cardiovascular events independent of traditional risk factors, LV function, and echocardiographic myocardial ischemia.
Recent studies have shown that LA volumes may be a better indicator of diastolic function compared with the LA diameter (27). The echocardiographic evaluation of the LA size in this study was limited to M-mode/2-dimensional measurement of the diameter, which may have resulted in some misclassification of LA size. However, this measurement is still the simplest, most highly reproducible, and most widely used measure of LA size.
As in other studies with stress echocardiography, though the stress echocardiography was interpreted by 2 experienced observers, it is subjective, and extrapolation of our results to those of other centers may be limited. As in other echocardiography studies, patients with an abnormal stress echocardiography tend to proceed to angiography and revascularization, thereby decreasing the outcomes from an abnormal test. Given the limited number of events (only 23 events in the 1,185 patients undergoing exercise stress echocardiography), we were unable to develop a regression model for the exercise group alone and hence could not take into consideration exercise capacity or workload, which have been shown to be important predictors of events in prior studies. Given limited data, we were not able to account for medical therapy and the effects of revascularization, which could have influenced the results. Because patients can be effectively risk-stratified by either exercise or dobutamine stress echocardiography, we have used the regression modeling for the entire group.
In this group of patients without significant mitral valve disease and relatively preserved LV ejection fraction, a simple, universally used measure of LA size further risk-stratifies both the normal and abnormal stress echocardiography cohorts. A normal stress echocardiography in the setting of a normal LA size portends a benign prognosis (<1% event rate/year). However, in the setting of a dilated LA, a normal stress echocardiography study is prognostically less benign, whereas an abnormal stress echocardiogram is prognostically more malignant. Left atrial size provides independent and incremental prognostic value, independent of traditional risk factors, LV ejection fraction, and echocardiographic myocardial ischemia. Left atrial size should be routinely incorporated in prognostic interpretation of stress testing.
Further studies using LA volumes are needed to elucidate the role of diastolic dysfunction in patients undergoing stress echocardiography and to further evolve the concept of “diastolic stress echocardiography.”
This work was presented in part at the 2006 Annual Scientific Session of the American Society of Echocardiography, June 3–7, 2006, Baltimore, Maryland.
- Abbreviations and Acronyms
- coronary artery disease
- interclass correlation
- left atrial/atrium
- left ventricular
- myocardial infarction
- risk ratio
- wall motion score index
- Received January 16, 2007.
- Revision received June 15, 2007.
- Accepted June 25, 2007.
- American College of Cardiology Foundation
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