Prediction of Cardiovascular Outcomes With Left Atrial Size Is Volume Superior to Area or Diameter?

Transcription

1 Journal of the American College of Cardiology Vol. 47, No. 5, by the American College of Cardiology Foundation ISSN /06/$32.00 Published by Elsevier Inc. doi: /j.jacc Prediction of Cardiovascular Outcomes With Left Atrial Size Is Volume Superior to Area or Diameter? Echocardiography Teresa S. M. Tsang, MD, FACC,* Walter P. Abhayaratna, MBBS, FRACP,* Marion E. Barnes, MS, Yoko Miyasaka, MD, PHD, FACC,* Bernard J. Gersh, MB, CHB, DPHIL, FACC,* Kent R. Bailey, PHD, Stephen S. Cha, MS, James B. Seward, MD, FACC* Rochester, Minnesota OBJECTIVES BACKGROUND METHODS RESULTS CONCLUSIONS We sought to compare left atrial (LA) volume to LA area and diameter for the prediction of adverse cardiovascular outcomes. The incremental value of LA volume compared with LA area or diameter as a cardiovascular risk marker has not been evaluated prospectively for patients with sinus rhythm or atrial fibrillation (AF). Left atrial size was assessed with biplane LA volume, four-chamber LA area, and M-mode dimension for 423 patients (mean age 71 8 years, 56% men) who were prospectively followed for development of first AF, congestive heart failure, stroke, transient ischemic attack, myocardial infarction, coronary revascularization, and cardiovascular death. Of the 317 subjects in sinus rhythm at baseline, 62 had 90 new events during a mean follow-up of years. All three LA size parameters were independently predictive of combined outcomes (all p ). The overall performance for the prediction of cardiovascular events was greatest for LA volume (area under the receiver operator characteristic curve: indexed LA volume 0.71; LA area 0.64; LA diameter 0.59). A graded association between the degree of LA enlargement and risk of cardiovascular events was only evident for indexed LA volume. For subjects with AF, there was no association between LA size and cardiovascular events. Left atrial volume is a more robust marker of cardiovascular events than LA area or diameter in subjects with sinus rhythm. The predictive utility of LA size for cardiovascular events in AF was poor, irrespective of the method of LA size quantitation. (J Am Coll Cardiol 2006; 47: ) 2006 by the American College of Cardiology Foundation Left atrial (LA) volume is a more accurate measure of LA size than LA diameter (1,2), although both LA size parameters have been shown to be markers of cardiovascular risk (3 12). We are unaware of any prospective studies that compare the utility of the two LA size parameters for the prediction of cardiovascular outcomes. Additionally, although LA volume has been demonstrated to be a robust predictor of cardiovascular outcomes among patients with sinus rhythm in a number of retrospective studies (5,6,13,14), its prognostic utility for patients with atrial fibrillation (AF) is unknown. In this prospective study, we assessed the clinical and echocardiographic correlations of biplane LA volume and M-mode LA dimension and compared the utility of LA volume, area, and dimension for the prediction of age-related cardiovascular outcomes in patients with sinus rhythm and those with AF. METHODS Study population. This study was approved by the Mayo Foundation Institutional Review Board. Patients age 50 From the *Division of Cardiovascular Diseases and Internal Medicine, Mayo Echocardiography Research Center, and the Section of Biostatistics, Mayo Clinic, Rochester, Minnesota. Dr. Tsang is supported by the National Institutes of Health (National Institute on Aging), the American Heart Association, and the American Society of Echocardiography. Manuscript received May 9, 2005; revised manuscript received August 3, 2005, accepted August 9, years referred for a general medical consultation were invited to participate if they had no history of congenital heart disease, treatment with pacemaker implantation, valvular surgery, or cardiac transplantation. Clinical data. Age, gender, height, weight, brachial blood pressure, cardiac rhythm, and history of comorbid conditions were recorded at enrollment. Definitions for all covariates have been previously published (15). Baseline cardiac rhythm was considered sinus if the patient was in sinus rhythm at the time of echocardiography and had no prior history of atrial arrhythmias. Paroxysmal AF was defined by a history of AF episodes with intervening sinus rhythm. Because of the small number of paroxysmal AF patients, we did not try to differentiate whether conversion to sinus rhythm in these patients was spontaneous or not. Permanent AF was defined by AF at baseline and the persistence of the arrhythmia without intervening sinus episodes. Echocardiographic data. Data for all echocardiographic studies were collected prospectively, and the parameters of interest were specified a priori. Measurements were obtained at least two times for an average if the rhythm was sinus and at least three times if the rhythm was AF. M-mode LA dimension was measured as per the American Society of Echocardiography method (16). Single-plane area was evaluated from the four-chamber view of the left

2 JACC Vol. 47, No. 5, 2006 March 7, 2006: Tsang et al. LA Size and Cardiovascular Outcomes 1019 Abbreviations and Acronyms AF atrial fibrillation CHF congestive heart failure LA left atrial LV left ventricular MI myocardial infarction TIA transient ischemic attack atrium at end-ventricular systole, ensuring that there was no foreshortening of the atrium. The area was then planimetered with the inferior LA border defined as the plane of the mitral annulus, excluding the confluence of the pulmonary veins and the LA appendage. Maximal biplane LA volume was measured in all patients with a modified biplane area-length method (17). This method as well as the Simpson s method of disc had both been well-validated (18 20). Orthogonal apical views, most commonly apical four- and two-chamber views, were obtained for determination of LA area and length (from the middle of the plane of the mitral annulus to the posterior wall). The apical long-axis view was used instead of the two-chamber view if the left atrium in the latter view appeared foreshortened. Specifically, the maximal LA chamber area and length were measured at end ventricular systole, excluding the LA appendage and pulmonary veins. Left atrial volume was calculated on the basis of the algorithm ([0.85 A1 A2]/L); where A1 is the fourchamber LA area, A2 is the two-chamber or apical long axis LA area, and L is the average of the two lengths obtained from the orthogonal views) and indexed to body surface area. LA diameter, four-chamber LA area, and indexed LA volume were categorized according to current American Society of Echocardiography guidelines (21). Additionally, we also assessed non-indexed LA diameter with 40 mm as the cut-off for normal on the basis of common clinical practice. Other echocardiographic variables, specified a priori, included left ventricular (LV) dimension at end-systole and end-diastole; LV septal and posterior end-diastolic wall thickness; M-mode LV ejection fraction, mitral inflow filling velocities (peak E and A); mitral inflow deceleration time; mitral isovolumic relaxation time; pulmonary venous Table 1. Baseline Characteristics of the Study Population Sinus Rhythm (n 317) Atrial Fibrillation (n 106) No CV Events (n 255) CV Events (n 62) No CV Events (n 71) CV Events (n 35) Clinical Men, n (%) 132 (52) 38 (61) 40 (56) 26 (74) Age (yrs) Body mass index (kg/m 2 ) Heart rate (beats/min) Systolic blood pressure (mm Hg) Diastolic blood pressure (mm Hg) Pulse pressure (mm Hg) History of myocardial infarction, n (%) 34 (13) 18 (29) 7 (10) 9 (26) History of coronary artery disease, n (%) 71 (28) 33 (53) 18 (25) 16 (46) Diabetes mellitus, n (%) 40 (16) 15 (24) 11 (15) 9 (26) Current smoking, n (%) 20 (8) 7 (11) 2 (3) 2 (6) History of dyslipidemia, n (%) 136 (53) 42 (68) 40 (56) 18 (51) History of systemic hypertension, n (%) 151 (59) 43 (69) 42 (59) 26 (74) History of stroke, n (%) 16 (6) 5 (8) 7 (10) 4 (11) History of transient ischemic attack, n (%) 11 (4) 3 (5) 10 (14) 5 (14) History of congestive heart failure, n (%) 25 (10) 12 (19) 18 (25) 11 (31) History of valvular heart disease, n (%) 54 (21) 24 (39) 37 (52) 16 (46) Echocardiographic LV ejection fraction (%) LV end-diastolic septal wall thickness (mm) LV end-diastolic posterior wall thickness (mm) M-mode LA dimension (mm) LA diameter (mm/m 2 ) LA diameter 40 mm (%) chamber LA area (cm 2 ) LA volume (ml) LA volume (ml/m 2 ) LA volume 28 ml/m 2 (%) Mitral E (m/s) Mitral A (m/s) n/a n/a Mitral E/A n/a n/a Mitral deceleration time (ms) CV cardiovascular; EF ejection fraction; LA left atrial; LV left ventricular.

3 1020 Tsang et al. JACC Vol. 47, No. 5, 2006 LA Size and Cardiovascular Outcomes March 7, 2006: systolic and diastolic forward flow, and atrial reversal flow velocities; and mitral annular motion septal velocity by tissue Doppler imaging (E ). Outcome ascertainment. All patients were prospectively followed for development of new outcome events, which included AF, stroke, transient ischemic attack (TIA), myocardial infarction (MI), coronary revascularization, congestive heart failure (CHF), and cardiovascular death. Statistical analysis. Continuous variables are presented as means standard deviation. Categorical variables are displayed as percentages. Differences between group means were evaluated with t tests (continuous variables) or chisquare analyses (categorical variables), as appropriate. Spearman correlations were used to assess the relation between LA size and other clinical and echocardiographic variables. Receiver-operator characteristic curves were generated to assess the overall performance of the various LA size parameters for the prediction of cardiovascular events. Differences in rates of cardiovascular events by LA size categories were examined with log-rank tests. Cox proportional hazards modeling was used to determine the association between LA dimension, LA area, and LA volume with future cardiovascular events, after adjusting for age, gender, and other significant covariates. RESULTS Baseline characteristics. A total of 423 patients (mean age 71 8 years, 56% men) met all study criteria and consented to participate. Clinical indications for medical consultation included: dyspnea (24%); chest discomfort (23%); palpitations, presyncope, and syncope (16%); and other reasons (11%). Of these, 317 (74%) were in sinus rhythm and had no prior history of AF, 49 (12%) had a history of paroxysmal AF, and 57 (13%) had permanent AF. Characteristics of the study population are outlined in Table 1, stratified by the baseline cardiac rhythm. Table 2. Correlates of Left Atrial Dimension and Left Atrial Volume LA Dimension LA Volume r p Value r p Value Clinical Age Men Body mass index Body surface area n/a Heart rate Systolic blood pressure Diastolic blood pressure Permanent AF Paroxysmal AF History of myocardial infarction History of coronary artery disease Diabetes mellitus History of systemic hypertension History of stroke History of transient ischemic attack History of CHF History of valvular heart disease Echocardiographic LV ejection fraction LV septal wall thickness LV posterior wall thickness LV end-diastolic dimension LV end-systolic dimension LV mass indexed by height Mitral E Mitral A Mitral E/A Mitral deceleration time Mitral A duration PV systolic forward flow PV diastolic forward flow PV atrial reversal flow Tricuspid regurgitation velocity RV systolic pressure Not significantly associated with LA dimension or indexed LA volume: smoking history, dyslipidemia, pulmonary venous atrial reversal duration. AF atrial fibrillation; CHF congestive heart failure; PV pulmonary venous; RV right ventricular; other abbreviations as in Table 1.

4 JACC Vol. 47, No. 5, 2006 March 7, 2006: Tsang et al. LA Size and Cardiovascular Outcomes 1021 Table 3. Classification of Left Atrial Size Abnormality by the American Society of Echocardiography Guidelines for Both Sinus and AF Subgroups Diameter Sinus (n 317) AF (n 106) Area Volume Diameter Area Volume Normal (%) Mildly abnormal (%) Moderately abnormal (%) Severely abnormal (%) See Tsang et al. (22). AF atrial fibrillation. Correlates of LA dimension and indexed LA volume. Clinical and echocardiographic correlates of LA dimension or indexed LA volume are listed in Table 2. Some parameters were significantly associated with one LA size parameter but not the other. Many baseline characteristics correlated significantly but not closely with LA size. For both LA dimension and indexed LA volume, LV mass indexed to height and permanent AF were the two strongest correlates. Prediction of cardiovascular events. PATIENTS IN SINUS RHYTHM. Over a mean follow-up period of years, 62 patients had 90 new events (23 new AF, 8 strokes, 6 TIAs, 12 MIs, 14 developed CHF, 26 coronary revascularizations, and 1 cardiovascular death). Of 317 subjects in sinus rhythm at baseline, 26% had a LA diameter 40 mm and therefore considered normal. According to the American Society of Echocardiography guidelines (22), there were significant differences in the categorization of the LA size abnormality, depending on which LA size parameter was used (Table 3). Patients who developed cardiovascular events had larger LA size at baseline, irrespective of the method of quantitation (Table 1). When the overall sensitivity and specificity of different methods of LA size quantitation using receiver operator characteristic curves were compared, the area under the curve for indexed LA volume was greater than that of the other two methods, and its sensitivity was superior throughout the range of LA size (Fig. 1), even if coronary revascularization was excluded as an end point (area under curve for LA volume 0.73 versus 0.70 and 0.66 for LA area and diameter, respectively). There was a stepwise increase in risk of cardiovascular events with each increment of LA volume category (p ) (Fig. 2). Although there was an overall association between indexed LA dimension and LA area and future cardiovascular events (both p ), a graded association between increasing indexed LA diameter or LA area and risk of events was not present. After adjustment for age, gender, and other covariates, larger indexed LA volume and LA dimension predicted higher risks of cardiovascular events (Table 4). PATIENTS WITH ATRIAL FIBRILLATION. Among the 106 patients with paroxysmal or permanent AF at baseline, 35 had 43 new events (10 strokes, 4 TIA, 5 MI, 16 CHF, and 8 coronary revascularization procedures) after a mean follow-up period of years. Subjects with AF at baseline were more likely than those with sinus rhythm to develop new events (36.8% vs. 19.6%, p ). Specifically, AF patients had a higher incidence of stroke (9.4% vs. 2.5%, p 0.002), TIA (3.8% vs. 1.9%, p 0.27), and CHF (15.1% vs. 4.4%, p ), but there was no difference between subgroups in the incidence of MI (4.7% vs. 3.8%, p 0.67) or coronary revascularization (7.6% vs. 8.3%, p 0.83). The difference in LA diameter, area, or indexed volume between individuals with and without a cardiovascular event during follow-up did not reach significance. For those with and without events, baseline median (interquartile range) LA dimension was 51 mm (47 to 57 mm) versus Figure 1. Receiver-operator characteristic curves for the overall performance of left atrial (LA) diameter, LA area, and indexed LA volume for the prediction of cardiovascular events in patients with sinus rhythm. Figure 2. Graded relationship between Kaplan-Meier cumulative eventfree survival and categorical increment of indexed left atrial (LA) volume.

5 1022 Tsang et al. JACC Vol. 47, No. 5, 2006 LA Size and Cardiovascular Outcomes March 7, 2006: Table 4. Left Atrial Dimension and Left Atrial Volume in Unadjusted, and Multivariable Models Adjusting for Age, Gender, and Other Covariates for the Prediction of Cardiovascular Events in Patients With Sinus Rhythm at Baseline Unadjusted Adjusted* % Hazards Ratio p Value Hazards Ratio p Value Left atrial dimension 40 mm left atrial diameter Mildly increased Moderately increased Severely increased Left atrial area Mildly increased Moderately increased Severely increased left atrial volume Mildly increased Moderately increased Severely increased *Multivariate model: adjusted for age, gender, left ventricular ejection fraction, history of systemic hypertension, diabetes mellitus, myocardial infarction, and valvular heart disease; p value refers to the significance of the variable treated as a continuous variable. 51 mm (45 to 57 mm) (p 0.84); four-chamber LA area 30 cm 2 (26 to 35 cm 2 ) versus 28 cm 2 (24 tot 36 cm 2 )(p 0.49); and indexed LA volume 57 ml/m 2 (46 to 78 ml/m 2 ) versus 53 ml/m 2 (37 to 68 ml/m 2 )(p 0.34). The overall performance of LA diameter or indexed volume to distinguish AF patients who did or did not have subsequent cardiovascular events was poor, irrespective of whether coronary revascularization was included as an end point. In the AF subgroup, none of the LA size parameters was independently predictive of the combined outcome when adjusted for age, gender, hypertension, diabetes, heart failure, and myocardial infarction. Even when warfarin therapy at baseline was considered, a relationship between LA size and future events was not detected. Of the 106 patients with AF, 52 (49%) were receiving warfarin at baseline (compared with 18 of 317 [6%] of patients with sinus rhythm, p ). In multivariable models for the prediction of events in the AF group, warfarin therapy was not independently related to the combined end point. For instance, in the multivariate model with clinical parameters (hypertension, diabetes, congestive heart failure, coronary artery disease, and ejection fraction), there seemed to be a trend toward higher risk of events associated with warfarin use (hazard ratio 1.89, p 0.063). DISCUSSION LA volume was a more sensitive risk marker of future cardiovascular events than LA diameter or area for patients in sinus rhythm. The predictive utility of LA size for future cardiovascular events was poor in AF patients, regardless of the method used for quantitating LA size. Dilatation of the left atrium, in the absence of organic mitral valve disease or history of AF, has been shown to reflect the burden of cardiovascular disease (22 24). During ventricular diastole, the left atrium is exposed to the pressures of the left ventricle. With increased stiffness of the left ventricle, LA pressure rises to maintain adequate LV filling, and the increased atrial wall tension leads to chamber dilatation and stretch of the atrial myocardium. Although M-mode LA dimension is easy to acquire, its validity has recently been challenged (1). Because the left atrium is an asymmetrical cavity, LA size is more accurately reflected by a measurement of volume rather than area or a linear dimension. Furthermore, LA dilatation might not be evenly distributed in all planes, and measurement of anteroposterior dimension is likely to be insensitive to changes in LA size. In the presence of AF, however, our findings suggest that LA enlargement needs to be interpreted with caution. The mechanism responsible for the lack of an association between LA size and cardiovascular events in the presence of AF cannot be fully determined in this study. In addition to the various mechanisms that lead to increased LV filling pressures and thus LA enlargement in sinus patients, AF patients might also develop progressive and refractory LA dilation from tachycardia-induced atrial myopathy (20) with advanced remodeling of the atrium with replacement fibrosis, independent of increased LV filling pressures. The more prevalent use of warfarin in the AF group could not explain the lack of association between LA size and risk for development of cardiovascular events. Rather than exerting a protective effect with lowering the risk of combined events, warfarin use seemed to be associated with a nonsignificant trend toward a higher risk for such events. This was most likely secondary to a selection process; that is, patients receiving warfarin at baseline were at higher risk for cardiovascular events. Admittedly, the relatively small sample of AF patients in this study might not have provided sufficient power to detect an association between LA size and out-

6 JACC Vol. 47, No. 5, 2006 March 7, 2006: Tsang et al. LA Size and Cardiovascular Outcomes 1023 comes in this subgroup. Nonetheless, LA enlargement in AF patients does not seem to have the same robustness for prediction of cardiovascular outcomes as it does in sinus rhythm. Study limitations. The study population is referral-based, and the extent to which the data can be generalized to other population groups is not known. The contribution of medical therapy to change in LA size was not considered in this study, given the relatively small sample size, the diverse range of reasons for which the patients were seen, and the differences in dosage and duration of various therapies. Conclusions. LA volume is a more robust cardiovascular risk marker than LA area or diameter in patients who are in sinus rhythm; however, in patients with AF, the predictive utility of LA size for future cardiovascular events seemed unsatisfactory, regardless of the method of LA quantitation. 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