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Prognostic value of left atrial volume in patients who underwent dobutamine stress echocardiography for known or suspected coronary artery disease
Prognostic value of left atrial volume in patients who underwent dobutamine stress echocardiography for known or suspected coronary artery disease Jeane Mike Tsutsui, MD, a, Paulo M. M. Dourado, MD, a Abdou Elhendy, MD, b Sandra N. R. S. Falca ˜o, MD, a Renise M. Goes, MD, a Anto ˆ nio C. P. Chagas, MD, a Prota´sio L. da Luz, MD, a Jose´ A. F. Ramires, MD, a and Wilson Mathias, Jr, MD a São Paulo, Brazil; and Marshfield, WI
Background Left atrial volume indexed (LAVI) has been reported as a predictor of cardiovascular events. We sought to determine the prognostic value of LAVI for predicting the outcome of patients who underwent dobutamine stress echocardiography (DSE) for known or suspected coronary artery disease (CAD). Methods
From January 2000 to July 2005, we studied 981 patients who underwent DSE and off-line measurements of LAVI. The value of DSE over clinical and LAVI data was examined using a stepwise log-rank test.
Results During a median follow-up of 24 months, 56 (6%) events occurred. By univariate analysis, predictors of events were male sex, diabetes mellitus, previous myocardial infarction, left ventricular ejection fraction (LVEF), left atrial diameter indexed, LAVI, and abnormal DSE. By multivariate analysis, independent predictors were LVEF (relative risk [RR] = 0.98, 95% CI 0.95-1.00), LAVI (RR = 1.04, 95% CI 1.02-1.05), and abnormal DSE (RR = 2.70, 95% CI 1.28-5.69). In an incremental multivariate model, LAVI was additional to clinical data for predicting events (χ2 36.8, P b .001). The addition of DSE to clinical and LAVI yielded incremental information (χ2 55.3, P b .001). The 3-year event-free survival in patients with normal DSE and LAVI ≤33 mL/m2 was 96%; with abnormal DSE and LAVI ≤33 mL/m2, 91%; with normal DSE and LAVI N34 mL/m2, 83%; and with abnormal DSE and LAVI N34 mL/m2, 51%. Conclusion
Left atrial volume indexed provides independent prognostic information in patients who underwent DSE for known or suspected CAD. Among patients with normal DSE, those with larger LAVI had worse outcome, and among patients with abnormal DSE, LAVI was still predictive. (Am Heart J 2008;156:1110-6.)
Dobutamine stress echocardiography (DSE) is a widely used technique for diagnosis and prognostic evaluation of patients with known or suspected coronary artery disease (CAD).1-5 The detection of ischemia during DSE has been based on the assessment of transient segmental wall motion abnormalities (WMAs). Other manifestations of myocardial ischemia include diastolic dysfunction, which may result in chronic pressure burden to left atrium.6,7 Left atrial volume is an accurate measurement of left atrial size8,9 and reflects the chronicity and magnitude of the increased left ventricular filling pressure. Left atrial volume indexed (LAVI) by body surface area has been From the aHeart Institute (InCor)-University of São Paulo Medical School, São Paulo, Brazil, and bDepartment of Cardiology-Marshfield Clinic, Marshfield, WI. This study was supported by FAPESP- Fundação de Amparo à Pesquisa do Estado de São Paulo, São Paulo, Brazil. Submitted December 16, 2007; accepted July 21, 2008. Reprint requests: Jeane Mike Tsutsui, MD, Heart Institute (InCor)-University of São Paulo Medical School, Avenida Dr, Enéas Carvalho de Aguiar, 44, Sao Paulo CEP:05403-000, Brazil. E-mails: [email protected], [email protected] 0002-8703/$ - see front matter © 2008, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2008.07.015
associated with cardiovascular risk burden and has been shown to provide prognostic information additional to clinical risk factors in different patient populations.10-14 Other risk factors of CAD such as hypertension, age, and diabetes may result in decreased myocardial compliance and increased filling pressure, with subsequent left atrial enlargement. Recently, normal resting LAVI has been shown to be associated with a normal stress echocardiogram, suggesting that this would be a simple means of identifying patients with low probability of ischemia and low likelihood of severe CAD.15 The long-term prognostic value of left atrial volume measurements in patients who underwent DSE is unknown. Therefore, we aimed to study the prognostic value of LAVI and DSE results for predicting death and nonfatal myocardial infarction (MI) in patients with known or suspected CAD.
Methods Patients From January 2000 to July 2005, we studied 1,219 consecutive patients from our institutional databank who were referred for
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DSE because of known or suspected CAD. Exclusion criteria were age b18 years, nondiagnostic DSE, treatment with pacemaker implantation, hypertrophic cardiomyopathy, significant mitral valve disease (stenosis or regurgitation more than moderate), severe aortic stenosis, and resting 2-dimensional images not appropriate for retrospective off-line measurements of left atrial size. Diabetes mellitus was defined as a fasting glucose level ≥120 mg/dL or the need for insulin or oral hypoglycemic agents. Hyperlipidemia was defined as a total cholesterol ≥200 mg/dL or treatment with lipid-lowering medications. Hypertension was defined as blood pressure ≥140/90 mm Hg or use of antihypertensive medication. Antiischemic therapy was defined as chronic use of nitrates, β-blockers, or calciumchannel blockers. The study was approved by the Institutional Review Board of the University of São Paulo Medical School (São Paulo, Brazil), and written informed consent was obtained from all patients.
Left atrial size parameters Parameters of left atrial size were left atrial anteroposterior diameter, left atrial volume, left atrial diameter indexed by body surface area (LADI), and LAVI. Measurements were performed off-line from baseline echocardiographic views, obtained before the stress test, by one observer who had no knowledge of stress test results and prognostic data. The anteroposterior diameter of the left atrium was measured by 2-dimensional imaging, and left atrial volume was estimated using area-length formula according to recommendations of the American Society of Echocardiography.9 Single-plane left atrial area was measured at end-ventricular systole, ensuring that there was no foreshortening of the atrium. The area was planimetered with the inferior left atrium border defined as the plane of the mitral annulus, excluding the confluence of the pulmonary veins and the left atrial appendage. Left atrial length was obtained from the middle of the plane of the mitral annulus to the root of left atrium. In patients with atrial fibrillation, it was considered the average of 3 measurements. Interobserver variability of LADI and LAVI measurements were assessed in 30 randomly assigned subjects by 2 independent observers. Intraobserver variability of LADI and LAVI measurements were assessed in 30 randomly assigned subjects by the same observer at least 6 months apart. Left atrial volume indexed was defined as normal when it was ≤28 mL/m2, mildly abnormal when it was 29 to 33 mL/m2, moderately abnormal when it was 34 to 39 mL/m2, and severely abnormal when it was ≥40 mL/m2. On the other hand, left atrium was considered normal when LADI was ≤23 mm/m2, mildly abnormal when it was 24 to 26 mm/m2, moderately abnormal when it was 27 to 29 mm/m2, and severely abnormal when it was ≥30 mm/m2.9
Dobutamine stress protocol All patients underwent DSE with early injection of atropine protocol as previously described.16 Left ventricular ejection fraction (LVEF) was measured using modified Simpson's rule. End points of the tests were achievement of 85% of the maximum predicted heart rate, defined as 220 — age in years, detection of severe or extensive WMA by echocardiography, ST elevation N0.1 mV at an interval of 80 milliseconds after the J point in patients without a previous MI, sustained arrhythmias,
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severe angina, or intolerable side effects.17 Blood pressure, heart rate, and 12-lead electrocardiogram were monitored at each stage of dobutamine infusion. The test was considered diagnostic if the target heart rate was achieved and/or ischemia was detected. The test was considered nondiagnostic when it was prematurely interrupted because of significant adverse effect or did not achieve 85% of the maximum predicted heart rate at the end of protocol without inducible ischemia.17 The stress tests were defined as abnormal if they had new or preexisting WMA in ≥2 contiguous segments. Patients with normal wall motion both at baseline and at peak stress were classified as having a normal DSE. Patients with WMA at baseline without extension observed at peak dobutamine stress were classified as having an abnormal DSE with fixed WMA. Patients with normal wall motion at baseline who developed new WMA with stress, patients with resting WMA with new WMA in other segments, and patients who developed biphasic response were characterized as having abnormal DSE with inducible WMA. The results of DSE were made available to the referring physicians.
Follow-up Follow-up was obtained from review of the patient's hospital chart, electronic records, and telephone interview with the patient. End points of the study were death and nonfatal MI. Cardiac death was defined as death associated with known or suspected MI, life-threatening arrhythmia, or pulmonary edema. Sudden unexpected death occurring without another explanation was included as cardiac death. Nonfatal MI was defined by means of a serial increase in cardiac specific enzymes and/or development of new electrocardiographic changes. Patients who underwent coronary artery bypass grafting surgery or percutaneous coronary intervention were censored at the time of the revascularization. Follow-up was completed in March 2007.
Statistical analysis Continuous variables normally distributed were expressed as mean and SD and categorical variables as proportions. Correlation of LAVI and LADI was evaluated using Pearson's coefficient. Comparisons between groups were performed with standard t test, χ2, or analysis of variance, as appropriated. Interobserver agreement was assessed by linear regression. Kaplan-Meier curves were used to estimate the distribution of time to the end point of interest. The Cox model was used to estimate the relative risk of events for each variable. Differences between time-to-event curves were compared with the log-rank test. The Cox hazard model was used to estimate the relative risk (RR) with respective 95% CIs of the combined end points of death and nonfatal MI for each variable including clinical and echocardiographic characteristics. Left atrial size parameters and LVEF were analyzed as quantitative variables, whereas DSE results were analyzed as a qualitative variable (normal or abnormal). The incremental value of LAVI over clinical and echocardiographic data was assessed in 3 modeling steps. The first step consisted of fitting a multivariate model of only clinical data. Left atrial volume indexed was then added to this model, followed by DSE results (normal vs abnormal). The significance of adding additional variables to previous modeling steps was based on
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Table I. Patient characteristics
Table II. Patient characteristics according to LAVI
Variables
N = 981
Age (y) Male gender Cigarette smokers Hyperlipidemia Hypertension Diabetes mellitus Atrial fibrillation Previous MI Previous coronary artery bypass grafting surgery Previous percutaneous coronary intervention Antiischemic medications LADI (mm/m2) LAVI (mL/m2) Left ventricular ejection fraction (%)
61 ± 12 536 (55%) 110 (11%) 583 (59%) 697 (71%) 249 (25%) 35 (4%) 246 (25%) 124 (13%) 160 (16%) 555 (56%) 22 ± 4 31 ± 11 58 ± 13
Data are presented as the mean value ± SD or number (%) of patients.
LAVI categories
Variables Age (y) ⁎ Male sex Hyperlipidemia † Hypertension † Diabetes mellitus Previous CABG Previous PCI Previous MI † Atrial fibrillation † Antiischemic therapy † LVEF (%) ⁎ LADI (mm/m2) ⁎
Abnormal DSE †
Figure 1
Classification of left atrial size according to LAVI (solid bars) and LADI (open bars). There was a significant difference between groups (P b .001).
the change in model-based likelihood statistics with degrees of freedom equal to the number of additional variables. A P value b.05 was considered significant.
Results Among the 1,219 enrolled patients, 122 (10%) were excluded because DSE was nondiagnostic; 57 (5%), because echocardiographic images were not adequate for LAVI measurements; and 59 (5%), because patients were lost to follow-up. Final population consisted of 981 patients. Clinical and echocardiographic characteristics are described in Table I. A total of 348 (35%) patients had known CAD. Categorization of left atrial size according to LADI or LAVI is illustrated in Figure 1. There was significant
_ 28 < mL/m2
29-33 mL/m2
34-39 mL/m2
_ 40 > mL/m2
59 ± 12 268 (58%) 272 (59%) 308 (67%) 115 (25%) 51 (11%) 69 (15%) 95 (21%) 0 235 (51%)
61 ± 11 139 (53%) 170 (65%) 194 (74%) 63 (24%) 36 (14%) 43 (16%) 70 (27%) 7 (3%) 161 (61%)
64 ± 11 72 (48%) 72 (48%) 114 (76%) 44 (29%) 19 (13%) 26 (17%) 40 (27%) 11 (7%) 54 (56%)
64 ± 12 57 (53%) 69 (65%) 81 (76%) 27 (25%) 18 (17%) 22 (21%) 41 (38%) 15 (14%) 75 (70%)
59 ± 13 20 ± 3 134 (29%)
58 ± 12 22 ± 3 89 (34%)
58 ± 14 23 ± 3 58 (39%)
52 ± 16 26 ± 4 49 (46%)
Data are mean ± SD and number (%) of patients. CABG, Coronary artery bypass grafting surgery; PCI, percutaneous coronary intervention. ⁎P b .05 between groups by analysis of variance. †P b .05 between groups by χ2.
positive correlation between left LADI and LAVI (r = 0.48, P = .001). The interclass correlation between the 2 independent observer measurements for LADI was r = 0.93 (95% CI 0.84-0.97), whereas for LAVI, it was 0.90 (95% CI 0.81-0.94). The interclass correlation between the 2 measurements by the same observer for LADI was r = 0.95 (95% CI 0.85-0.99), whereas for LAVI, it was 0.92 (95% CI 0.81-0.96). The percentage of patients with abnormal left atrial size was higher when categorized using LAVI than LADI criteria (53% vs 39%, P b .001). Clinical and echocardiographic features of the study group categorized by LAVI results are presented in Table II.
Dobutamine stress echocardiography results The mean maximal dose of dobutamine used during DSE was 32 ± 7 μg/kg per minute and atropine was 1.0 ± 0.6 mg. Heart rate increased from 71 ± 13 beats/min at baseline to 137 ± 23 beats/min at peak stress (P b .0001), and the rate-pressure product increased from 9,576 ± 2,389 mm Hg/min to 19,769 ± 5,107 mm Hg/min (P b .0001). Among the 225 patients with ejection fraction b55%, 139 (62%) patients had increased LAVI, whereas among the 756 patients with normal ejection fraction, 411 (54%) had increased LAVI. Dobutamine stress echocardiography was normal in 651 (66%) and abnormal in 330 (34%) patients. Among patients with abnormal DSE, 153 had fixed WMA, 152 with fixed plus inducible WMA, and 25 had inducible WMA. Among the 461 patients with normal LAVI, 327 (71%) had normal DSE and 134 (29%) had abnormal
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Table III. Predictors of death or nonfatal MI Univariate Variables Age (y) Male sex Hyperlipidemia Hypertension Diabetes mellitus Previous CABG Previous PCI Previous MI Antiischemic therapy LVEF (%) LADI (mm/m2) LAVI (mL/m2) Abnormal DSE
RR (95% CI)
Figure 2 Multivariate
P
RR (95% CI)
P
1.01 2.11 0.83 1.84 1.86 1.29 0.89 1.72 0.87
(0.99-1.04) (1.18-3.78) (0.49-1.41) (0.93-3.66) (1.09-3.18) (0.63-2.64) (0.42-1.87) (1.01-2.95) (0.49-1.51)
.2475 .0114 .4946 .0795 .0235 .4837 .7502 .0497 .6104
0.96 3.36 1.03 4.09
(0.94-0.97) (1.78-6.32) (1.02-1.05) (2.35-7.11)
.0001 0.98 (0.95-1.00) .0348 .0002 .0001 1.04 (1.02-1.05) .0001 .0001 2.70 (1.28-5.69) .0093
Data are presented as relative risk (RR) with corresponding 95% CIs.
Kaplan-Meier curves of patients with LAVI. The differences between LAVI ≤28 mL/m2 and 29 to 33 mL/m2 versus LAVI 34 to 39 mL/m2 and ≥40 mL/m2 curves are statistically significant (P = .001).
Table IV. Annual event rates Cumulative event rate at follow-up intervals
DSE Normal DSE Abnormal DSE Fixed WMA Inducible ischemia LAVI Normal LAVI Mildly increased LAVI Moderately increased LAVI Severely increased LAVI Normal DSE and LAVI ≤33 mL/m2 Abnormal DSE and LAVI ≤33 mL/m2 Normal DSE and LAVI N34 mL/m2 Abnormal DSE and LAVI N34 mL/m2
1 year
2 years
3 years
1.1% 4.6% 1.3% 6.0%
2.1% 11.2% 6.1% 10.4%
8.1% 21.0% 11.3% 39.6%
1.9% 0.6% 3.0% 7.9% 1.0% 2.2% 1.5% 9.8%
4.1% 2.0% 7.0% 16.0% 2.0% 5.9% 2.5% 23.1%
4.1% 6.9% 31.8% 27.5% 3.8% 9.2% 17.3% 48.8%
DSE. On the other hand, among the 520 patients with increased LAVI, 324 (62%) had normal DSE and 196 (38%) had abnormal DSE (P b .05 compared with patients with normal LAVI).
Predictors of death or nonfatal MI During a median follow-up of 24 months (range 7 days to 77 months), 56 (6%) patients had events. Events occurred at a median of 17 months (range 7 days to 47 months) after the DSE and included death in 45 patients (cardiac in 28 patients and noncardiac in 17) and nonfatal MI in 11 patients. Coronary revascularization was performed in 74 patients (14 underwent coronary artery bypass grafting surgery, 54 percutaneous coronary intervention, and 6 both procedures), at an average time of 13 months after DSE stress test. These patients were censored at the time of the procedure.
Figure 3
Incremental value (expressed on y-axis as χ2 values with incremental degrees of freedom) of DSE results over clinical variables and LAVI, using a Cox model.
Table III presents the univariate and multivariate predictors of death and nonfatal MI. By univariate analysis, predictors of events were male sex, diabetes mellitus, previous MI, LVEF, LADI, LAVI, and abnormal DSE. By multivariate analysis, the independent predictors of events were LVEF (RR = 0.98, 95% CI 0.95-1.00), LAVI (RR = 1.04, 95% CI 1.02-1.05), and an abnormal DSE (RR = 2.70, 95% CI 1.28-5.69). The cumulative event rates for DSE and LAVI results are demonstrated in Table IV. The 3-year event-free survival was 92% in patients with normal DSE and 79% in those with abnormal DSE (P b .001 between groups). The category of WMA observed during DSE was determinant of prognosis with higher event rates occurring in patients with inducible ischemia.
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Figure 4
Kaplan-Meier curves of patients according to DSE and LAVI results. The differences between curves are statistically significant (P = .0001).
The Kaplan-Meier curves of event-free survival according to the categories of LAVI are illustrated in Figure 2. Patients with normal or mildly increased LAVI had significantly lower incidence of events than patients with moderately or severely increased LAVI (P = .001). No difference was observed between normal and mildly abnormal LAVI and between moderately and severely abnormal LAVI.
Incremental value of left atrial size parameters and stress echocardiography for predicting death and nonfatal infarction Sequential Cox regression models were fit to test the incremental value of LAVI analysis over clinical and DSE results (Figure 3). When considering the analysis of clinical variables (χ2 17.9), resting LAVI data increased the likelihood of death or nonfatal MI (χ236.8, P b .001). The presence of abnormal DSE added significant incremental value in predicting outcome over clinical and LAVI results (χ2 55.3, P b .001). Figure 4 illustrates the KaplanMeier curves of event-free survival according to DSE results and LAVI, categorized as normal or mildly increased LAVI (LAVI ≤33 mL/m2) and moderately or severely increased LAVI (LAVI N34 mL/m2). Patients with abnormal DSE and LAVI N34 mL/m2 had highest risk for death and MI (RR = 12.58, 95% CI 6.14-25.76, P = .0001).
Discussion Our study shows that LAVI is an independent predictor of death and nonfatal MI in patients who underwent DSE for known or suspected CAD. In these patients, LAVI had incremental prognostic value over clinical variables for predicting events, whereas DSE added significant prognostic information over clinical and resting LAVI data. Among patients with normal DSE, those with larger LAVI
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had worse outcome, and among patients with abnormal DSE, LAVI was still predictive. The left atrium serves as a contractile reservoir and conduit chamber that exert a profound effect on left ventricular filling and overall cardiovascular performance.18 Left atrial enlargement is considered a marker of both the severity and chronicity of systolic and diastolic dysfunction and magnitude of left atrial pressure elevation.10,19 In the setting of CAD, it has been shown that acute MI or infarction produces left atrial dilatation, enhances left atrial preload, and increases its emptying fraction by the Frank-Starling effect, which serves to maintain left ventricular stroke volume despite the reduction in systolic function.20 In patients with acute MI, augmented atrial booster pump function exerts a role for the maintenance of cardiovascular performance.21 Also, in patients with symptomatic CAD, there is an inverse correlation between left atrial stroke volume and left ventricular end-diastolic pressure, as demonstrated by Doppler echocardiography.19 Furthermore, other conditions commonly associated with coronary disease such as hypertension, diabetes mellitus, heart failure, and mitral regurgitation are also associated with elevated left ventricular filling pressures.22 All these factors combine to increase left atrial afterload and produce compensatory left atrial dilatation. Although the prognostic value of left atrial size has been recently investigated, no previous data exist regarding its relationship with prognosis after adjusting for DSE results.
The role of left atrial size in predicting events Several studies have demonstrated that increased left atrial size is associated with adverse cardiovascular outcomes, including stroke, atrial fibrillation, heart failure, and death.10,23-25 In the Strong Heart Study involving 2,804 American Indians free of clinical cardiovascular disease, valvular disease, and atrial fibrillation, left atrial diameter independently predicted incident cardiovascular events after adjustment for established clinical, echocardiographic, and inflammatory risk factors.25 In another study, Tsang et al10 prospectively evaluated 140 patients without a history of atrial arrhythmias or valvular heart disease and demonstrated that LAVI expressed the severity of diastolic dysfunction and provided an index of cardiovascular risk and disease burden. Recently, the same group demonstrated that left atrial volume is a more robust risk marker of future cardiovascular events than diameter or area for patients in sinus rhythm, but the predictive use of left atrial size for cardiovascular events was poor in patients with atrial fibrillation, regardless of the method used for quantitating left atrial size.24 The present study was designed to address the prognostic value of LAVI in patients with known or suspected CAD. It was recently been shown that in patients referred for stress echocardiography, LADI provides independent
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value for predicting death and MI.25 Bangalore et al25 demonstrated in a large group of patients that LADI ≥24 mm/m2 was a significant predictor of events independent of left ventricular systolic dysfunction and ischemia. Anteroposterior diameter of the left atrium is easier to acquire and universally used in clinical practice and research, but its validity has recently been challenged.8 Because of the asymmetrical conformation of this cavity, left atrial size is more accurately reflected by measurement of volume rather than linear dimension.24 In our study, we observed a significant positive correlation between LADI and LAVI. However, a higher percentage of patients were classified as having increased left atrial size using LAVI parameter than LADI. Left atrial diameter indexed was predictor of hard events in univariate analysis but no longer had prognostic value when considering LAVI in multivariate model. Risk was mostly observed with moderate to severe as compared to mild enlargement or normal volume. Although the prognostic value of DSE considering only the wall motion analysis over clinical variables is established in different patient groups, normal wall motion responses to dobutamine were associated with annualized mortality rates up to 8%, and cardiac event rates up to 3.6%.2,5,26-29 Our results are in accordance with previous descriptions, in such a way that DSE results was a strong independent predictor of hard events. However, patients with normal DSE had a 3-year event rate of 8.1%. On the other hand, patients with normal DSE and normal LAVI had a 3-year event rate of 3.8%. Left atrial volume indexed was also an independent predictor as a continuous variable demonstrating that the bigger the left atrial volume is, the higher the probability of the patients to have a future event. The addition of LAVI information significantly increased the prognostic value of DSE for predicting death and MI. The LAVI volume index provided better stratification within each category of stress test results.
Limitations of the study Although the percentage of patients with atrial fibrillation at the time of DSE in our population was low (4%), we have to consider that this could be a possible cause of error in predicting prognosis. Because the history of intermittent atrial fibrillation was not included in the databank, it was not considered as a clinical variable because of the difficulties in determining this data retrospectively. With the relatively small number of events, the multivariable model may be unstable and thus validation of these findings in another dataset would add strength to the conclusions.
Conclusions Left atrial volume indexed provides independent prognostic information for predicting death and nonfatal
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MI in patients who underwent DSE for known or suspected CAD. Among patients with normal DSE, those with larger LAVI had worse outcome, and among patients with abnormal DSE, LAVI was still predictive.
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Background Left atrial volume indexed (LAVI) has been reported as a predictor of cardiovascular events. We sought to determine the prognostic value of LAVI for predicting the outcome of patients who underwent dobutamine stress echocardiography (DSE) for known or suspected coronary artery disease (CAD). Methods
From January 2000 to July 2005, we studied 981 patients who underwent DSE and off-line measurements of LAVI. The value of DSE over clinical and LAVI data was examined using a stepwise log-rank test.
Results During a median follow-up of 24 months, 56 (6%) events occurred. By univariate analysis, predictors of events were male sex, diabetes mellitus, previous myocardial infarction, left ventricular ejection fraction (LVEF), left atrial diameter indexed, LAVI, and abnormal DSE. By multivariate analysis, independent predictors were LVEF (relative risk [RR] = 0.98, 95% CI 0.95-1.00), LAVI (RR = 1.04, 95% CI 1.02-1.05), and abnormal DSE (RR = 2.70, 95% CI 1.28-5.69). In an incremental multivariate model, LAVI was additional to clinical data for predicting events (χ2 36.8, P b .001). The addition of DSE to clinical and LAVI yielded incremental information (χ2 55.3, P b .001). The 3-year event-free survival in patients with normal DSE and LAVI ≤33 mL/m2 was 96%; with abnormal DSE and LAVI ≤33 mL/m2, 91%; with normal DSE and LAVI N34 mL/m2, 83%; and with abnormal DSE and LAVI N34 mL/m2, 51%. Conclusion
Left atrial volume indexed provides independent prognostic information in patients who underwent DSE for known or suspected CAD. Among patients with normal DSE, those with larger LAVI had worse outcome, and among patients with abnormal DSE, LAVI was still predictive. (Am Heart J 2008;156:1110-6.)
Dobutamine stress echocardiography (DSE) is a widely used technique for diagnosis and prognostic evaluation of patients with known or suspected coronary artery disease (CAD).1-5 The detection of ischemia during DSE has been based on the assessment of transient segmental wall motion abnormalities (WMAs). Other manifestations of myocardial ischemia include diastolic dysfunction, which may result in chronic pressure burden to left atrium.6,7 Left atrial volume is an accurate measurement of left atrial size8,9 and reflects the chronicity and magnitude of the increased left ventricular filling pressure. Left atrial volume indexed (LAVI) by body surface area has been From the aHeart Institute (InCor)-University of São Paulo Medical School, São Paulo, Brazil, and bDepartment of Cardiology-Marshfield Clinic, Marshfield, WI. This study was supported by FAPESP- Fundação de Amparo à Pesquisa do Estado de São Paulo, São Paulo, Brazil. Submitted December 16, 2007; accepted July 21, 2008. Reprint requests: Jeane Mike Tsutsui, MD, Heart Institute (InCor)-University of São Paulo Medical School, Avenida Dr, Enéas Carvalho de Aguiar, 44, Sao Paulo CEP:05403-000, Brazil. E-mails: [email protected], [email protected] 0002-8703/$ - see front matter © 2008, Mosby, Inc. All rights reserved. doi:10.1016/j.ahj.2008.07.015
associated with cardiovascular risk burden and has been shown to provide prognostic information additional to clinical risk factors in different patient populations.10-14 Other risk factors of CAD such as hypertension, age, and diabetes may result in decreased myocardial compliance and increased filling pressure, with subsequent left atrial enlargement. Recently, normal resting LAVI has been shown to be associated with a normal stress echocardiogram, suggesting that this would be a simple means of identifying patients with low probability of ischemia and low likelihood of severe CAD.15 The long-term prognostic value of left atrial volume measurements in patients who underwent DSE is unknown. Therefore, we aimed to study the prognostic value of LAVI and DSE results for predicting death and nonfatal myocardial infarction (MI) in patients with known or suspected CAD.
Methods Patients From January 2000 to July 2005, we studied 1,219 consecutive patients from our institutional databank who were referred for
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DSE because of known or suspected CAD. Exclusion criteria were age b18 years, nondiagnostic DSE, treatment with pacemaker implantation, hypertrophic cardiomyopathy, significant mitral valve disease (stenosis or regurgitation more than moderate), severe aortic stenosis, and resting 2-dimensional images not appropriate for retrospective off-line measurements of left atrial size. Diabetes mellitus was defined as a fasting glucose level ≥120 mg/dL or the need for insulin or oral hypoglycemic agents. Hyperlipidemia was defined as a total cholesterol ≥200 mg/dL or treatment with lipid-lowering medications. Hypertension was defined as blood pressure ≥140/90 mm Hg or use of antihypertensive medication. Antiischemic therapy was defined as chronic use of nitrates, β-blockers, or calciumchannel blockers. The study was approved by the Institutional Review Board of the University of São Paulo Medical School (São Paulo, Brazil), and written informed consent was obtained from all patients.
Left atrial size parameters Parameters of left atrial size were left atrial anteroposterior diameter, left atrial volume, left atrial diameter indexed by body surface area (LADI), and LAVI. Measurements were performed off-line from baseline echocardiographic views, obtained before the stress test, by one observer who had no knowledge of stress test results and prognostic data. The anteroposterior diameter of the left atrium was measured by 2-dimensional imaging, and left atrial volume was estimated using area-length formula according to recommendations of the American Society of Echocardiography.9 Single-plane left atrial area was measured at end-ventricular systole, ensuring that there was no foreshortening of the atrium. The area was planimetered with the inferior left atrium border defined as the plane of the mitral annulus, excluding the confluence of the pulmonary veins and the left atrial appendage. Left atrial length was obtained from the middle of the plane of the mitral annulus to the root of left atrium. In patients with atrial fibrillation, it was considered the average of 3 measurements. Interobserver variability of LADI and LAVI measurements were assessed in 30 randomly assigned subjects by 2 independent observers. Intraobserver variability of LADI and LAVI measurements were assessed in 30 randomly assigned subjects by the same observer at least 6 months apart. Left atrial volume indexed was defined as normal when it was ≤28 mL/m2, mildly abnormal when it was 29 to 33 mL/m2, moderately abnormal when it was 34 to 39 mL/m2, and severely abnormal when it was ≥40 mL/m2. On the other hand, left atrium was considered normal when LADI was ≤23 mm/m2, mildly abnormal when it was 24 to 26 mm/m2, moderately abnormal when it was 27 to 29 mm/m2, and severely abnormal when it was ≥30 mm/m2.9
Dobutamine stress protocol All patients underwent DSE with early injection of atropine protocol as previously described.16 Left ventricular ejection fraction (LVEF) was measured using modified Simpson's rule. End points of the tests were achievement of 85% of the maximum predicted heart rate, defined as 220 — age in years, detection of severe or extensive WMA by echocardiography, ST elevation N0.1 mV at an interval of 80 milliseconds after the J point in patients without a previous MI, sustained arrhythmias,
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severe angina, or intolerable side effects.17 Blood pressure, heart rate, and 12-lead electrocardiogram were monitored at each stage of dobutamine infusion. The test was considered diagnostic if the target heart rate was achieved and/or ischemia was detected. The test was considered nondiagnostic when it was prematurely interrupted because of significant adverse effect or did not achieve 85% of the maximum predicted heart rate at the end of protocol without inducible ischemia.17 The stress tests were defined as abnormal if they had new or preexisting WMA in ≥2 contiguous segments. Patients with normal wall motion both at baseline and at peak stress were classified as having a normal DSE. Patients with WMA at baseline without extension observed at peak dobutamine stress were classified as having an abnormal DSE with fixed WMA. Patients with normal wall motion at baseline who developed new WMA with stress, patients with resting WMA with new WMA in other segments, and patients who developed biphasic response were characterized as having abnormal DSE with inducible WMA. The results of DSE were made available to the referring physicians.
Follow-up Follow-up was obtained from review of the patient's hospital chart, electronic records, and telephone interview with the patient. End points of the study were death and nonfatal MI. Cardiac death was defined as death associated with known or suspected MI, life-threatening arrhythmia, or pulmonary edema. Sudden unexpected death occurring without another explanation was included as cardiac death. Nonfatal MI was defined by means of a serial increase in cardiac specific enzymes and/or development of new electrocardiographic changes. Patients who underwent coronary artery bypass grafting surgery or percutaneous coronary intervention were censored at the time of the revascularization. Follow-up was completed in March 2007.
Statistical analysis Continuous variables normally distributed were expressed as mean and SD and categorical variables as proportions. Correlation of LAVI and LADI was evaluated using Pearson's coefficient. Comparisons between groups were performed with standard t test, χ2, or analysis of variance, as appropriated. Interobserver agreement was assessed by linear regression. Kaplan-Meier curves were used to estimate the distribution of time to the end point of interest. The Cox model was used to estimate the relative risk of events for each variable. Differences between time-to-event curves were compared with the log-rank test. The Cox hazard model was used to estimate the relative risk (RR) with respective 95% CIs of the combined end points of death and nonfatal MI for each variable including clinical and echocardiographic characteristics. Left atrial size parameters and LVEF were analyzed as quantitative variables, whereas DSE results were analyzed as a qualitative variable (normal or abnormal). The incremental value of LAVI over clinical and echocardiographic data was assessed in 3 modeling steps. The first step consisted of fitting a multivariate model of only clinical data. Left atrial volume indexed was then added to this model, followed by DSE results (normal vs abnormal). The significance of adding additional variables to previous modeling steps was based on
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Table I. Patient characteristics
Table II. Patient characteristics according to LAVI
Variables
N = 981
Age (y) Male gender Cigarette smokers Hyperlipidemia Hypertension Diabetes mellitus Atrial fibrillation Previous MI Previous coronary artery bypass grafting surgery Previous percutaneous coronary intervention Antiischemic medications LADI (mm/m2) LAVI (mL/m2) Left ventricular ejection fraction (%)
61 ± 12 536 (55%) 110 (11%) 583 (59%) 697 (71%) 249 (25%) 35 (4%) 246 (25%) 124 (13%) 160 (16%) 555 (56%) 22 ± 4 31 ± 11 58 ± 13
Data are presented as the mean value ± SD or number (%) of patients.
LAVI categories
Variables Age (y) ⁎ Male sex Hyperlipidemia † Hypertension † Diabetes mellitus Previous CABG Previous PCI Previous MI † Atrial fibrillation † Antiischemic therapy † LVEF (%) ⁎ LADI (mm/m2) ⁎
Abnormal DSE †
Figure 1
Classification of left atrial size according to LAVI (solid bars) and LADI (open bars). There was a significant difference between groups (P b .001).
the change in model-based likelihood statistics with degrees of freedom equal to the number of additional variables. A P value b.05 was considered significant.
Results Among the 1,219 enrolled patients, 122 (10%) were excluded because DSE was nondiagnostic; 57 (5%), because echocardiographic images were not adequate for LAVI measurements; and 59 (5%), because patients were lost to follow-up. Final population consisted of 981 patients. Clinical and echocardiographic characteristics are described in Table I. A total of 348 (35%) patients had known CAD. Categorization of left atrial size according to LADI or LAVI is illustrated in Figure 1. There was significant
_ 28 < mL/m2
29-33 mL/m2
34-39 mL/m2
_ 40 > mL/m2
59 ± 12 268 (58%) 272 (59%) 308 (67%) 115 (25%) 51 (11%) 69 (15%) 95 (21%) 0 235 (51%)
61 ± 11 139 (53%) 170 (65%) 194 (74%) 63 (24%) 36 (14%) 43 (16%) 70 (27%) 7 (3%) 161 (61%)
64 ± 11 72 (48%) 72 (48%) 114 (76%) 44 (29%) 19 (13%) 26 (17%) 40 (27%) 11 (7%) 54 (56%)
64 ± 12 57 (53%) 69 (65%) 81 (76%) 27 (25%) 18 (17%) 22 (21%) 41 (38%) 15 (14%) 75 (70%)
59 ± 13 20 ± 3 134 (29%)
58 ± 12 22 ± 3 89 (34%)
58 ± 14 23 ± 3 58 (39%)
52 ± 16 26 ± 4 49 (46%)
Data are mean ± SD and number (%) of patients. CABG, Coronary artery bypass grafting surgery; PCI, percutaneous coronary intervention. ⁎P b .05 between groups by analysis of variance. †P b .05 between groups by χ2.
positive correlation between left LADI and LAVI (r = 0.48, P = .001). The interclass correlation between the 2 independent observer measurements for LADI was r = 0.93 (95% CI 0.84-0.97), whereas for LAVI, it was 0.90 (95% CI 0.81-0.94). The interclass correlation between the 2 measurements by the same observer for LADI was r = 0.95 (95% CI 0.85-0.99), whereas for LAVI, it was 0.92 (95% CI 0.81-0.96). The percentage of patients with abnormal left atrial size was higher when categorized using LAVI than LADI criteria (53% vs 39%, P b .001). Clinical and echocardiographic features of the study group categorized by LAVI results are presented in Table II.
Dobutamine stress echocardiography results The mean maximal dose of dobutamine used during DSE was 32 ± 7 μg/kg per minute and atropine was 1.0 ± 0.6 mg. Heart rate increased from 71 ± 13 beats/min at baseline to 137 ± 23 beats/min at peak stress (P b .0001), and the rate-pressure product increased from 9,576 ± 2,389 mm Hg/min to 19,769 ± 5,107 mm Hg/min (P b .0001). Among the 225 patients with ejection fraction b55%, 139 (62%) patients had increased LAVI, whereas among the 756 patients with normal ejection fraction, 411 (54%) had increased LAVI. Dobutamine stress echocardiography was normal in 651 (66%) and abnormal in 330 (34%) patients. Among patients with abnormal DSE, 153 had fixed WMA, 152 with fixed plus inducible WMA, and 25 had inducible WMA. Among the 461 patients with normal LAVI, 327 (71%) had normal DSE and 134 (29%) had abnormal
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Table III. Predictors of death or nonfatal MI Univariate Variables Age (y) Male sex Hyperlipidemia Hypertension Diabetes mellitus Previous CABG Previous PCI Previous MI Antiischemic therapy LVEF (%) LADI (mm/m2) LAVI (mL/m2) Abnormal DSE
RR (95% CI)
Figure 2 Multivariate
P
RR (95% CI)
P
1.01 2.11 0.83 1.84 1.86 1.29 0.89 1.72 0.87
(0.99-1.04) (1.18-3.78) (0.49-1.41) (0.93-3.66) (1.09-3.18) (0.63-2.64) (0.42-1.87) (1.01-2.95) (0.49-1.51)
.2475 .0114 .4946 .0795 .0235 .4837 .7502 .0497 .6104
0.96 3.36 1.03 4.09
(0.94-0.97) (1.78-6.32) (1.02-1.05) (2.35-7.11)
.0001 0.98 (0.95-1.00) .0348 .0002 .0001 1.04 (1.02-1.05) .0001 .0001 2.70 (1.28-5.69) .0093
Data are presented as relative risk (RR) with corresponding 95% CIs.
Kaplan-Meier curves of patients with LAVI. The differences between LAVI ≤28 mL/m2 and 29 to 33 mL/m2 versus LAVI 34 to 39 mL/m2 and ≥40 mL/m2 curves are statistically significant (P = .001).
Table IV. Annual event rates Cumulative event rate at follow-up intervals
DSE Normal DSE Abnormal DSE Fixed WMA Inducible ischemia LAVI Normal LAVI Mildly increased LAVI Moderately increased LAVI Severely increased LAVI Normal DSE and LAVI ≤33 mL/m2 Abnormal DSE and LAVI ≤33 mL/m2 Normal DSE and LAVI N34 mL/m2 Abnormal DSE and LAVI N34 mL/m2
1 year
2 years
3 years
1.1% 4.6% 1.3% 6.0%
2.1% 11.2% 6.1% 10.4%
8.1% 21.0% 11.3% 39.6%
1.9% 0.6% 3.0% 7.9% 1.0% 2.2% 1.5% 9.8%
4.1% 2.0% 7.0% 16.0% 2.0% 5.9% 2.5% 23.1%
4.1% 6.9% 31.8% 27.5% 3.8% 9.2% 17.3% 48.8%
DSE. On the other hand, among the 520 patients with increased LAVI, 324 (62%) had normal DSE and 196 (38%) had abnormal DSE (P b .05 compared with patients with normal LAVI).
Predictors of death or nonfatal MI During a median follow-up of 24 months (range 7 days to 77 months), 56 (6%) patients had events. Events occurred at a median of 17 months (range 7 days to 47 months) after the DSE and included death in 45 patients (cardiac in 28 patients and noncardiac in 17) and nonfatal MI in 11 patients. Coronary revascularization was performed in 74 patients (14 underwent coronary artery bypass grafting surgery, 54 percutaneous coronary intervention, and 6 both procedures), at an average time of 13 months after DSE stress test. These patients were censored at the time of the procedure.
Figure 3
Incremental value (expressed on y-axis as χ2 values with incremental degrees of freedom) of DSE results over clinical variables and LAVI, using a Cox model.
Table III presents the univariate and multivariate predictors of death and nonfatal MI. By univariate analysis, predictors of events were male sex, diabetes mellitus, previous MI, LVEF, LADI, LAVI, and abnormal DSE. By multivariate analysis, the independent predictors of events were LVEF (RR = 0.98, 95% CI 0.95-1.00), LAVI (RR = 1.04, 95% CI 1.02-1.05), and an abnormal DSE (RR = 2.70, 95% CI 1.28-5.69). The cumulative event rates for DSE and LAVI results are demonstrated in Table IV. The 3-year event-free survival was 92% in patients with normal DSE and 79% in those with abnormal DSE (P b .001 between groups). The category of WMA observed during DSE was determinant of prognosis with higher event rates occurring in patients with inducible ischemia.
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Figure 4
Kaplan-Meier curves of patients according to DSE and LAVI results. The differences between curves are statistically significant (P = .0001).
The Kaplan-Meier curves of event-free survival according to the categories of LAVI are illustrated in Figure 2. Patients with normal or mildly increased LAVI had significantly lower incidence of events than patients with moderately or severely increased LAVI (P = .001). No difference was observed between normal and mildly abnormal LAVI and between moderately and severely abnormal LAVI.
Incremental value of left atrial size parameters and stress echocardiography for predicting death and nonfatal infarction Sequential Cox regression models were fit to test the incremental value of LAVI analysis over clinical and DSE results (Figure 3). When considering the analysis of clinical variables (χ2 17.9), resting LAVI data increased the likelihood of death or nonfatal MI (χ236.8, P b .001). The presence of abnormal DSE added significant incremental value in predicting outcome over clinical and LAVI results (χ2 55.3, P b .001). Figure 4 illustrates the KaplanMeier curves of event-free survival according to DSE results and LAVI, categorized as normal or mildly increased LAVI (LAVI ≤33 mL/m2) and moderately or severely increased LAVI (LAVI N34 mL/m2). Patients with abnormal DSE and LAVI N34 mL/m2 had highest risk for death and MI (RR = 12.58, 95% CI 6.14-25.76, P = .0001).
Discussion Our study shows that LAVI is an independent predictor of death and nonfatal MI in patients who underwent DSE for known or suspected CAD. In these patients, LAVI had incremental prognostic value over clinical variables for predicting events, whereas DSE added significant prognostic information over clinical and resting LAVI data. Among patients with normal DSE, those with larger LAVI
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had worse outcome, and among patients with abnormal DSE, LAVI was still predictive. The left atrium serves as a contractile reservoir and conduit chamber that exert a profound effect on left ventricular filling and overall cardiovascular performance.18 Left atrial enlargement is considered a marker of both the severity and chronicity of systolic and diastolic dysfunction and magnitude of left atrial pressure elevation.10,19 In the setting of CAD, it has been shown that acute MI or infarction produces left atrial dilatation, enhances left atrial preload, and increases its emptying fraction by the Frank-Starling effect, which serves to maintain left ventricular stroke volume despite the reduction in systolic function.20 In patients with acute MI, augmented atrial booster pump function exerts a role for the maintenance of cardiovascular performance.21 Also, in patients with symptomatic CAD, there is an inverse correlation between left atrial stroke volume and left ventricular end-diastolic pressure, as demonstrated by Doppler echocardiography.19 Furthermore, other conditions commonly associated with coronary disease such as hypertension, diabetes mellitus, heart failure, and mitral regurgitation are also associated with elevated left ventricular filling pressures.22 All these factors combine to increase left atrial afterload and produce compensatory left atrial dilatation. Although the prognostic value of left atrial size has been recently investigated, no previous data exist regarding its relationship with prognosis after adjusting for DSE results.
The role of left atrial size in predicting events Several studies have demonstrated that increased left atrial size is associated with adverse cardiovascular outcomes, including stroke, atrial fibrillation, heart failure, and death.10,23-25 In the Strong Heart Study involving 2,804 American Indians free of clinical cardiovascular disease, valvular disease, and atrial fibrillation, left atrial diameter independently predicted incident cardiovascular events after adjustment for established clinical, echocardiographic, and inflammatory risk factors.25 In another study, Tsang et al10 prospectively evaluated 140 patients without a history of atrial arrhythmias or valvular heart disease and demonstrated that LAVI expressed the severity of diastolic dysfunction and provided an index of cardiovascular risk and disease burden. Recently, the same group demonstrated that left atrial volume is a more robust risk marker of future cardiovascular events than diameter or area for patients in sinus rhythm, but the predictive use of left atrial size for cardiovascular events was poor in patients with atrial fibrillation, regardless of the method used for quantitating left atrial size.24 The present study was designed to address the prognostic value of LAVI in patients with known or suspected CAD. It was recently been shown that in patients referred for stress echocardiography, LADI provides independent
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value for predicting death and MI.25 Bangalore et al25 demonstrated in a large group of patients that LADI ≥24 mm/m2 was a significant predictor of events independent of left ventricular systolic dysfunction and ischemia. Anteroposterior diameter of the left atrium is easier to acquire and universally used in clinical practice and research, but its validity has recently been challenged.8 Because of the asymmetrical conformation of this cavity, left atrial size is more accurately reflected by measurement of volume rather than linear dimension.24 In our study, we observed a significant positive correlation between LADI and LAVI. However, a higher percentage of patients were classified as having increased left atrial size using LAVI parameter than LADI. Left atrial diameter indexed was predictor of hard events in univariate analysis but no longer had prognostic value when considering LAVI in multivariate model. Risk was mostly observed with moderate to severe as compared to mild enlargement or normal volume. Although the prognostic value of DSE considering only the wall motion analysis over clinical variables is established in different patient groups, normal wall motion responses to dobutamine were associated with annualized mortality rates up to 8%, and cardiac event rates up to 3.6%.2,5,26-29 Our results are in accordance with previous descriptions, in such a way that DSE results was a strong independent predictor of hard events. However, patients with normal DSE had a 3-year event rate of 8.1%. On the other hand, patients with normal DSE and normal LAVI had a 3-year event rate of 3.8%. Left atrial volume indexed was also an independent predictor as a continuous variable demonstrating that the bigger the left atrial volume is, the higher the probability of the patients to have a future event. The addition of LAVI information significantly increased the prognostic value of DSE for predicting death and MI. The LAVI volume index provided better stratification within each category of stress test results.
Limitations of the study Although the percentage of patients with atrial fibrillation at the time of DSE in our population was low (4%), we have to consider that this could be a possible cause of error in predicting prognosis. Because the history of intermittent atrial fibrillation was not included in the databank, it was not considered as a clinical variable because of the difficulties in determining this data retrospectively. With the relatively small number of events, the multivariable model may be unstable and thus validation of these findings in another dataset would add strength to the conclusions.
Conclusions Left atrial volume indexed provides independent prognostic information for predicting death and nonfatal
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MI in patients who underwent DSE for known or suspected CAD. Among patients with normal DSE, those with larger LAVI had worse outcome, and among patients with abnormal DSE, LAVI was still predictive.
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