- Email: [email protected]
Left Atrial Volume Index Is an Independent Predictor of Major Adverse Cardiovascular Events in Acute Coronary Syndrome
Canadian Journal of Cardiology 28 (2012) 561–566
Clinical Research
Left Atrial Volume Index Is an Independent Predictor of Major Adverse Cardiovascular Events in Acute Coronary Syndrome Ramsamy Gunasekaran, MMed,a Oteh Maskon, MRCPI,a Hamat H. Che Hassan, MRCPI,a Nazarudin Safian, MCommHealth,b and Rajalingham Sakthiswary, MRCP (UK)a a b
Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
Department of Public Health, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
ABSTRACT
RÉSUMÉ
Background: Left atrial volume index (LAVI) is well proven to be a reliable method of determining left atrial size, which has prognostic implications in cardiovascular diseases. Studies demonstrate that increased LAVI is a predictor of mortality in myocardial infarction, but its association with other major adverse cardiovascular events (MACEs) among patients post acute coronary syndrome (ACS) has not been adequately evaluated. Methods: We calculated the baseline LAVI for all patients who were admitted with ACS between December 2010 and August 2011. The patients were stratified into 2 arms: normal LAVI and increased LAVI, with a cutoff value of 28 mL/m2. All patients were prospectively followed up during 6 months for development of MACEs. Results: Of the 75 patients who completed the study, 32 had increased LAVI, and 43 had normal LAVI. More than half (55%) of the patients were diagnosed with unstable angina. During the follow-up period of 6 months, 30 patients (93.8%) in the increased-LAVI arm and 23 patients (53.5%) in the normal-LAVI arm developed at least a single MACE. Patients with increased LAVI had significantly more MACEs (P ⫽ 0.021). The occurrence of MACE remained significantly higher in the increased-LAVI group even when atrial fibrillation was excluded (P ⫽ 0.016). After adjusting for confounding variables by multivariate analysis, LAVI was found to have a significant association with MACEs (P ⫽ 0.030, odds ratio ⫽ 1.229 (95% confidence interval, 1.020-1.481).
Introduction : L’indice de volume auriculaire gauche (IVAG) est une méthode qui s’est révélée fiable pour déterminer la taille de l’oreillette gauche, qui a des implications pronostiques dans les maladies cardiovasculaires. Les études démontrent que l’augmentation de l’IVAG est un prédicteur de la mortalité dans l’infarctus du myocarde, mais son association à d’autres événements cardiaques indésirables majeurs (ÉCIM) après un syndrome coronarien aigu (SCA) n’a pas été évaluée de manière adéquate. Méthodes : Nous avons calculé l’IVAG initial chez tous les patients ayant un SCA qui ont été admis entre décembre 2010 et août 2011. Les patients ont été stratifiés en 2 bras : l’IVAG normal et l’IVAG augmenté, avec une valeur seuil de 28 ml/m2. Tous les patients ont été suivis prospectivement durant 6 mois en ce qui a trait au développement d’ÉCIM. Résultats : Parmi les 75 patients qui ont réalisé l’étude, 32 ont eu une augmentation de l’IVAG, et 43 ont eu un IVAG normal. Plus de la moitié (55 %) des patients ont eu un diagnostic d’angine instable. Durant le suivi de 6 mois, 30 patients (93,8 %) du bras de l’IVAG augmenté et 23 patients (53,5 %) du bras de l’IVAG normal ont manifesté au moins un ÉCIM. Les patients ayant une augmentation de l’IVAG ont eu significativement plus d’ÉCIM (P ⫽ 0,021). L’occurrence d’ÉCIM est demeurée significativement plus élevée dans le groupe de l’IVAG augmenté même lorsque la fibrillation auriculaire a été exclue
Cardiovascular disease is a leading cause of death across the globe. Malaysian data show that acute coronary syndrome (ACS) accounted for 20% to 25% of deaths in government hospitals between 2000 and 2005.1 ACS is an umbrella term that refers to a spectrum of clinical manifestations due to myo-
cardial ischemia and includes 3 disease entities, ie, ST-segment elevation myocardial infarction (STEMI), non–ST-segment elevation myocardial infarction (NSTEMI), and unstable angina (UA).2 ACS is associated with devastating sequelae often referred to as major adverse cardiovascular events (MACEs) in clinical research. MACEs are a composite of clinical events and end points that include death, revascularization, reinfarction, atrial fibrillation (AF), heart failure, and angina.3 Clinicians and researchers worldwide are constantly conducting studies to identify reliable markers and tools for prognostication post ACS. Echocardiographic parameters have been proven to prognosticate the long-term survival of this
Received for publication January 15, 2012. Accepted February 27, 2012. Corresponding author: Dr Rajalingham Sakthiswary, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Bandar Tun Razak, 56000, Cheras, Kuala Lumpur, Malaysia. E-mail: [email protected] See page 566 for disclosure information.
0828-282X/$ – see front matter © 2012 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2012.02.015
562
Canadian Journal of Cardiology Volume 28 2012
Conclusion: LAVI is a useful tool for prognostication and an independent predictor of MACEs post ACS.
(P ⫽ 0,016). Après l’ajustement des variables parasites par l’analyse multivariée, l’IVAG a montré une association significative aux ÉCIM (P ⫽ 0,030, ratio d’incidence approché ⫽ 1,229, intervalle de confiance de 95 %, 1,020-1,481). Conclusion : L’IVAG est un outil utile pour évaluer le pronostic et un prédicteur indépendant des ÉCIM après un SCA.
group of patients.4,5 In recent years, left atrial (LA) measurements have emerged as the focus of cardiovascular research. LA volume and size have close association with left ventricular (LV) systolic and diastolic function. Both systolic and diastolic dysfunction predict a poorer outcome after ACS.6,7 The reliable method of LA size measurement, according to the American Society of Echocardiography, is the LA volume index (LAVI), ie, LA volume divided by body surface area.8 Although studies have demonstrated that an increased LAVI is a predictor of mortality, there is still a paucity of data on its association with other MACEs. The main purpose of this study was to evaluate the association between LAVI and the various forms of MACEs among patients post ACS.
(power) 0.8. The type I error probability associated with this test was 0.05. In all, 103 patients were screened, and 75 were recruited. The remaining 28 patients were not included because they declined to participate in the study, did not meet the study criteria, or did not complete the study. The 75 participants were divided into 2 arms: normal LAVI and increased LAVI. The cutoff value used to define increased LAVI was more than 28 mL/m2 based on the American Society of Echocardiography criterion.8 After the initial admission for ACS, the patients were prospectively followed up during 6 months for development of clinical events. The following cardiac events were sought: death from cardiovascular causes; myocardial infarction; new-onset congestive heart failure; new-onset AF; and cardiac revascularization procedures, including percutaneous coronary intervention and coronary artery bypass graft. In addition, we obtained data by conducting telephone follow-up interviews with patients or their proxies in relation to emergency department visits, hospitalizations, or death. For all reported events, medical records or death certificates were retrieved. The outcome classification was determined by2 blinded adjudicators who reviewed each event in detail. Newonset heart failure was defined as the development of symptoms and signs consistent with cardiac failure and had been confirmed by the relevant investigations deemed necessary by the treating doctors. New-onset AF was defined as the development of AF based on a 12-lead electrocardiogram. Cardiac deaths were those secondary to ACS, arrhythmia, congestive heart failure, and death related to a cardiac event. Sudden death was counted as cardiac death if it was not better explained by noncardiac causes. Reinfarction refers to another episode or recurrent ACS. Each MACE was counted only once for each patient (eg, recurrent hospitalizations due to heart failure in the same participant were counted as 1 event). The study data were analyzed using Statistical Package for the Social Sciences version 19.0. Data were tested for normality with the Shapiro-Wilk test. All normally distributed data were reported as means, and comparison of the means was performed with the Student t test. The rest of the values were reported as median and were analyzed with the Mann-Whitney U statistic. The Fisher exact test was used to analyze associations between categorical variables. We used multivariate analysis to determine the independent predictor of MACEs, with confounding variables entered as covariates. A P value of ⬍ 0.05 was considered statistically significant.
Methods This was a prospective observational study conducted between December 2010 and August 2011 in Universiti Kebangsaan Malaysia Medical Centre, which is a tertiary hospital in Kuala Lumpur. Criteria for enrollment were a history of ACS, including STEMI, NSTEMI, and UA. STEMI, NSTEMI, and UA were defined according to standard criteria. Patients with the following underlying conditions were excluded: AF, restrictive cardiomyopathy, hypertrophic cardiomyopathy, constrictive pericarditis, and mitral valve disease. Patients with no known underlying AF but an electrocardiogram recording of AF within the first 72 hours of admission were excluded because of the possibility of baseline undiagnosed AF. Besides, patients with poor echocardiographic window, which may result in suboptimal and inaccurate measurements, were dropped from the study. All study participants provided informed consent for echocardiographic testing and review of medical records. The centre’s institutional review board approved the study protocol. All echocardiograms were performed by a single cardiac sonographer using a commercially available ultrasound system (Vivid I n GE Vingmed Ultrasound, N-3190; GE Medical Systems, Horten, Norway) on either day 2 or day 3 of admission. The cardiac sonographer was blinded to the clinical data of the patients. The echocardiographic studies were performed in the supine and left lateral recumbent positions. Following the protocol, LA volume was assessed by the biplane arealength method in both apical 4- and 2-chamber views. Measurements were taken at the end of systole. Sample size was determined with power and sample size calculation software. Data from a previous study by Moller stated that abnormal LA volume predicts 80% of adverse outcome.5 The proportion of patients with normal LA volume was estimated to be 50% as there was no previous data for reference. We had to study at least 38 patients with abnormal LA volume to be able to reject the null hypothesis with probability of
Results A total of 81 patients met all study criteria and consented to participate in this study. During the 6-month study period, 6 patients were lost to follow-up and were excluded. The study population was divided into 2 groups: increased LAVI, with 32
Gunasekaran et al. Left Atrial Volume Index in ACS
563
Table 1. Patients demographic data and baseline characteristics for both groups Characteristic Age ⬍ 65 ⬎ 65 Gender Male Female BMI (kg/m2) ⬍ 25 25-29.9 ⬎ 30 Hypertension Diabetes mellitus Hyperlipidemia Smoking
Increased LAVI n ⫽ 32 (%)
Normal LAVI n ⫽ 43 (%)
21 (66) 11 (34)
30 (70) 13 (30)
0.702
23 (72) 9 (28)
31 (72) 12 (28)
0.984
15 (47) 11 (34) 6 (19) 27 (84) 19 (59) 28 (88) 15 (47)
19 (44) 16 (37) 8 (19) 32 (74) 28 (65) 39 (91) 24 (56)
0.963
P value*
0.291 0.61 0.71 0.683
BMI, body mass index; LAVI, left atrial volume index. * P values are based on Fisher exact test.
patients, and normal LAVI, with 43 patients. Characteristics of the study population are outlined in Table 1. The groups’ baseline demographic features and comorbidities such as hypertension, smoking, diabetes mellitus, and hyperlipidemia were comparable. However, the increased-LAVI group had significantly higher median creatinine (P ⫽ 0.008), with lower glomerular filtration rate (GFR) (P ⫽ 0.001; Table 2). Besides, the E to E prime (E/E=) ratio, which is a quantitative estimate of LV filling pressure, was significantly higher in the increasedLAVI group, reflecting this group’s poorer diastolic function (P ⫽ 0.001; Table 3). Of the 75 patients, 18 (24%) had STEMI, 16 (21%) were diagnosed with NSTEMI, and 41 (55%) with UA. The incidence of STEMI, NSTEMI, and UA was similar in both groups (Fig. 1). Figure 1 compares the diagnosis, coronary angiogram findings, and management between the groups. During the 6-month follow-up period, 30 patients (93.8%) in the increased-LAVI arm experienced at least 1 MACE. The normal-LAVI arm, on the other hand, had 23 patients (53.5%) with a MACE. As the inclusion of AF as a MACE is highly debatable, data were analyzed with and without AF. As the proportion of patients with new-onset AF was relatively small across the groups, the occurrence of MACEs remained significantly higher in the increased-LAVI group, even if AF was not
Table 2. Comparison of baseline laboratory parameters between groups Parameter Total cholesterol Triglyceride LDL HDL Creatinine kinase Troponin T Creatinine GFR HbAIC
Increased LAVI
Normal LAVI
P value*
5.08 ⫾ 1.66 1.71 (1.02-1.82) 3.00 (1.83-3.96) 3.00 (1.83-3.96) 130.50 (94.00-394.00) 0.50 (0.00-1.00) 166.71 (85.00-173.50) 56.86 (30.50-87.00) 7.52 (5.70-7.25)
5.31 ⫾ 1.44 2.14 (1.20-2.62) 4.52 (2.52-4.20) 1.04 (0.86-1.27) 159.00 (76.00-345.00) 0.30 (0.00-1.00) 90.23 (72.00-101.00) 83.95 (62.50-104.00) 7.64 (6.16-9.00)
0.763† 0.052 0.211 0.693 0.642 0.763 0.008 0.001 0.320
All data presented as median (range). GFR, glomerular filtration rate; HbAIC, hemoglobin A1c; HDL, high-density lipoprotein; LAVI, left atrial volume index; LDL, low-density lipoprotein. * P values are based on Mann-Whitney U test. † Data presented as mean ⫾ standard deviation based on independent sample t test.
Table 3. Echocardiographic measurements in both groups
E/A ratio DT E/E= PVs-PVd LVEDD LVESD LVPW FS EF
Increased LAVI n ⫽ 32
Normal LAVI n ⫽ 43
P value*
1.04 (0.72-1.41) 215.28 ⫾ 72.05 18.64 (11.40-21.34) 5.28 ⫾ 2.39 5.13 ⫾ 0.62 3.69 (3.30-4.27) 1.10 ⫾ 0.28 28.37 ⫾ 6.71 53.28 (42.25-64.00)
0.82 (0.65-1.15) 217.25 ⫾ 70.93 10.79 (8.65-12.43) 1.25 ⫾ 0.39 4.63 ⫾ 0.74 3.21 (2.60-3.50) 1.10 ⫾ 0.19 31.10 ⫾ 7.97 57.05 (50.00-64.00)
0.060 0.900† 0.001 0.240† 0.001† 0.001 0.920† 0.120† 0.170
All data presented as median (range). DT, deceleration time; E/A, early to late ventricular filling verlocity ratio; E/E=, E to E prime ratio; EF, ejection fraction; FS, fractional shortening; LAVI, left atrial volume index; LVEDD, left ventricular end diastolic diameter; LVESD, left ventricular end systolic diameter; LVPW, left ventricular posterior wall; PVs-PVd, pumonary vein systolic-pulmonary vein diastolic velocities. * P values are based on Mann-Whitney U test. † Data presented as mean ⫾ standard deviation based on independent sample t test.
counted. The P value was 0.021 with AF, whereas without AF it was 0.016 (Table 4). When the patients were further subdivided according to MACE, ie, angina, new-onset heart failure, reinfarction, new-onset AF, and death, there was no significant difference observed between the groups, with P values of 0.313, 0.380, 0.442, 0.103, and 0.390, respectively (Fig. 2). Confounding variables of MACEs were entered into multiple logistic regression analysis. These covariates were parameters with statistically significant differences by univariate analysis: GFR, creatinine, left ventricular end diastolic diameter, left ventricular end systolic diameter, and E-E=. Table 5 illustrates that only increased LAVI had significant association with MACEs, based on multivariate analysis (P ⫽ 0.030, odds ratio ⫽ 1.229 (95% confidence interval, 1.020-1.481). Discussion In recent decades, accumulating evidence has indicated LAVI as a robust predictor of cardiovascular events. LAVI has been proven to be a more accurate and objective method of assessment of LA dilatation compared with LA area or diameter.4 In this context, most researchers in the past focused on cohorts of patients after myocardial infarction (MI). Hence, the data on the prognostic significance of LAVI in patients with UA remains scarce. To the best of our knowledge, this is the first study that was powered to determine the significance of an increased LAVI in predicting MACEs post ACS. Unlike other past studies in this area, we included all categories of ACS, ie, STEMI, NSTEMI, and UA. The vast majority of our study participants fulfilled the diagnostic criteria for UA. The pathophysiology and clinical characteristics of UA are similar to but not the same as those of MI. UA represents a preinfarction state in which there is myocardial ischemia in the absence of release of enzymes or biomarkers of myocardial necrosis.9 Our findings support the hypothesis that LAVI is a reliable predictor of MACEs after ACS. Most previous studies reported cumulative MACEs during a mean follow-up period of 2 to 3 years.10,11 This study demonstrates that an increased LAVI leads to a significantly higher occurrence of cardiovascular
564
Canadian Journal of Cardiology Volume 28 2012
Figure 1. Distribution of diagnosis, coronary angiogram findings, and treatment approach in both groups. CABG, coronary artery bypass graft; LAVI, left atrial volume index; NSTEMI, non–ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; UA, unstable angina.
complications as early as within 6 months of ACS. The evaluated outcome events of the majority of similar studies focused on a single event type. The outcome measures in our study
Table 4. MACEs in both groups
MACEs (excluding AF) MACEs (including AF) AF
Increased LAVI n ⫽ 32 (%)
Normal LAVI n ⫽ 43 (%)
P value*
25 (78) 30 (94) 5 (16)
21 (49) 23 (54) 2 (5)
0.016 0.021 0.129
AF, atrial fibrillation; LAVI, left atrial volume index; MACE, major adverse cardiac event. * P values are based on Fisher exact test.
included various MACEs that are readily definable events, such as cardiovascular death, heart failure, and AF. Most researchers in the past excluded AF because of its well-documented association with increased LAVI. Our study design was quite different, with exclusion of patients with baseline AF, but the number of patients with new-onset AF in both arms was determined during the 6-month follow-up period from the time of ACS. Our study design allowed for the identification of newonset AF (a form of MACE) due to an increased LAVI, as other potential confounders were essentially insignificant. AF, however, did not contribute to the significant study findings of more MACEs in the increased-LAVI arm. Intriguingly, on the contrary, the exclusion of AF gave a lower P value (from 0.021 to 0.016), hence increasing the level of significance.
Gunasekaran et al. Left Atrial Volume Index in ACS
565
Figure 2. Distribution of major adverse coronary events (MACEs) in both groups. LAVI, left atrial volume index.
Although the total number of MACEs in the increasedLAVI group and the normal-LAVI group was significantly different statistically, the difference between the groups for each type of event when analyzed individually did not reach statistical significance. We believe that the relatively small sample size is a possible explanation. Most previous studies did not include patients with UA. In studies that included patients with only MI, the reported cardiovascular mortality rates were higher.10 The relatively low percentage of cardiovascular death in our study is best explained by our heterogeneous study population with predominance of UA, which is believed to carry a lower mortality risk than does MI. At baseline, the increased-LAVI group showed significantly higher median creatinine and lower median GFR. LV hypertrophy is a well-documented echocardiographic finding in patients with chronic kidney disease due to coexistence of hypertension and other hemodynamic alterations. Cioffi et al. reported that LV mass and LA volume were related to GFR, which was consistent with our findings.12 LAVI was found to be an independent predictor of MACEs after adjustment for GFR in multiple logistic regression analysis. The relationship between GFR and LAVI merits further investigation. From the
available evidence, we hypothesize that LV hypertrophy could be contributory to this finding. Several drawbacks of the study need to be considered in interpretation of the study findings. The presence of AF was detected during routine clinic follow-up in asymptomatic patients. Patients with paroxysmal AF would have been missed if they were in sinus rhythm at the time of the clinic visit. Interim monitoring for AF would probably yield a higher number of patients. In most studies aimed to identify predictors of a certain clinical event, Kaplan-Meier survival analysis and Cox regression analysis models have been used and the hazard ratio determined. Our study design, with a short study duration of 6 months, was thought to be unsuitable for such statistical analysis.
Conclusion LAVI is a useful tool for prognostication and an independent predictor of MACEs post ACS. The authors would like to recommend routine measurement of LAVI in all patients admitted with ACS. An increased LAVI warrants increased vigilance among clinicians for cardiovascular complications.
Table 5. Multivariate analysis with confounding variables 95% CI for EXP(B) Covariates
B
Wald
P value
Exp(B)
Lower
Upper
GFR Creatinine LVEDD LVESD E/E= LAVI
0.416 ⫺0.013 0.091 0.220 1.126 0.214
0.276 0.190 0.004 0.012 2.649 4.794
0.600 0.663 0.948 0.911 0.104 0.029*
1.515 0.987 1.096 1.246 3.083 1.238
0.321 0.931 0.069 0.026 0.795 1.023
7.146 1.047 17.328 58.797 11.966 1.499
B, slope coefficient; CI, confidence interval; E/E=, E to E prime ratio; EXP(B), odds ratio; GFR, glomerular filtration rate; LAVI, left atrial volume index; LVEDD, left ventricular end diastolic diameter; LVESD, left ventricular end systolic diameter. * Nagelkerke R2 ⫽ 0.452.
566
Canadian Journal of Cardiology Volume 28 2012
Funding Sources The study was funded by the Research Grant of Faculty of Medicine of Universiti Kebangsaan Malaysia Medical Centre.
6. Dini FL, Michelassi C, Micheli G, Rovai D. Prognostic value of pulmonary venous flow Doppler signal in left ventricular dysfunction: contribution of the difference in duration of pulmonary venous and mitral flow at atrial contraction. J Am Coll Cardiol 2000;36:1295-302.
Disclosures The authors have no conflicts of interest to disclose.
7. Moller JE, Sondergaard E, Poulsen SH, Egstrup K. Pseudonormal and restrictive filling patterns predict left ventricular dilation and cardiac death after a first myocardial infarction: a serial color M-mode Doppler echocardiographic study. J Am Coll Cardiol 2000;36:1841-6.
References 1. Association of Clinical Registries, Malaysia. National Cardiovascular Disease Database: Acute Coronary Syndrome (ACS) Registry 1st Annual Report 2006. Available at: http://www.acrm.org.my/ncvd/default.asp? page⫽/ncvd/reports_annualReports. Accessed March 5, 2012. 2. Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined—a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. J Am Coll Cardiol 2000;36:959-69. 3. Kip KE, Hollabaugh K, Marroquin OC, Williams DO. The problem with composite end points in cardiovascular studies: the story of major adverse cardiac events and percutaneous coronary intervention. J Am Coll Cardiol 2008;51:701-7.
8. Lang RM, Bierig M, Devereux RB, et al; Chamber Quantification Writing Group; American Society of Echocardiography’s Guidelines and Standards Committee; European Association of Echocardiography. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440-63. 9. Braunwald E. Unstable angina: a classification. Circulation 1989;80: 410-4. 10. Sakaguchi E, Yamada A, Sugimoto K, et al. Prognostic value of left atrial volume index in patients with first acute myocardial infarction. Eur J Echocardiogr 2011;12:440-4.
4. Tsang TS, Barnes ME, Gersh BJ, Bailey KR, Seward JB. Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to cardiovascular risk burden. Am J Cardiol 2002;90:1284-9.
11. Shah AM, Hung CL, Shin SH, et al. Cardiac structure and function, remodeling, and clinical outcomes among patients with diabetes after myocardial infarction complicated by left ventricular systolic dysfunction, heart failure, or both. Am Heart J 2011;162:685-91.
5. Moller JE, Hillis GS, Oh JK, et al. Left atrial volume: a powerful predictor of survival after acute myocardial infarction. Circulation 2003;107: 2207-12.
12. Cioffi G, Tarantini L, Frizzi R, et al. Chronic kidney disease elicits excessive increase in left ventricular mass growth in patients at increased risk for cardiovascular events. J Hypertens 2011;29:565-73.
Clinical Research
Left Atrial Volume Index Is an Independent Predictor of Major Adverse Cardiovascular Events in Acute Coronary Syndrome Ramsamy Gunasekaran, MMed,a Oteh Maskon, MRCPI,a Hamat H. Che Hassan, MRCPI,a Nazarudin Safian, MCommHealth,b and Rajalingham Sakthiswary, MRCP (UK)a a b
Department of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
Department of Public Health, Universiti Kebangsaan Malaysia Medical Centre, Kuala Lumpur, Malaysia
ABSTRACT
RÉSUMÉ
Background: Left atrial volume index (LAVI) is well proven to be a reliable method of determining left atrial size, which has prognostic implications in cardiovascular diseases. Studies demonstrate that increased LAVI is a predictor of mortality in myocardial infarction, but its association with other major adverse cardiovascular events (MACEs) among patients post acute coronary syndrome (ACS) has not been adequately evaluated. Methods: We calculated the baseline LAVI for all patients who were admitted with ACS between December 2010 and August 2011. The patients were stratified into 2 arms: normal LAVI and increased LAVI, with a cutoff value of 28 mL/m2. All patients were prospectively followed up during 6 months for development of MACEs. Results: Of the 75 patients who completed the study, 32 had increased LAVI, and 43 had normal LAVI. More than half (55%) of the patients were diagnosed with unstable angina. During the follow-up period of 6 months, 30 patients (93.8%) in the increased-LAVI arm and 23 patients (53.5%) in the normal-LAVI arm developed at least a single MACE. Patients with increased LAVI had significantly more MACEs (P ⫽ 0.021). The occurrence of MACE remained significantly higher in the increased-LAVI group even when atrial fibrillation was excluded (P ⫽ 0.016). After adjusting for confounding variables by multivariate analysis, LAVI was found to have a significant association with MACEs (P ⫽ 0.030, odds ratio ⫽ 1.229 (95% confidence interval, 1.020-1.481).
Introduction : L’indice de volume auriculaire gauche (IVAG) est une méthode qui s’est révélée fiable pour déterminer la taille de l’oreillette gauche, qui a des implications pronostiques dans les maladies cardiovasculaires. Les études démontrent que l’augmentation de l’IVAG est un prédicteur de la mortalité dans l’infarctus du myocarde, mais son association à d’autres événements cardiaques indésirables majeurs (ÉCIM) après un syndrome coronarien aigu (SCA) n’a pas été évaluée de manière adéquate. Méthodes : Nous avons calculé l’IVAG initial chez tous les patients ayant un SCA qui ont été admis entre décembre 2010 et août 2011. Les patients ont été stratifiés en 2 bras : l’IVAG normal et l’IVAG augmenté, avec une valeur seuil de 28 ml/m2. Tous les patients ont été suivis prospectivement durant 6 mois en ce qui a trait au développement d’ÉCIM. Résultats : Parmi les 75 patients qui ont réalisé l’étude, 32 ont eu une augmentation de l’IVAG, et 43 ont eu un IVAG normal. Plus de la moitié (55 %) des patients ont eu un diagnostic d’angine instable. Durant le suivi de 6 mois, 30 patients (93,8 %) du bras de l’IVAG augmenté et 23 patients (53,5 %) du bras de l’IVAG normal ont manifesté au moins un ÉCIM. Les patients ayant une augmentation de l’IVAG ont eu significativement plus d’ÉCIM (P ⫽ 0,021). L’occurrence d’ÉCIM est demeurée significativement plus élevée dans le groupe de l’IVAG augmenté même lorsque la fibrillation auriculaire a été exclue
Cardiovascular disease is a leading cause of death across the globe. Malaysian data show that acute coronary syndrome (ACS) accounted for 20% to 25% of deaths in government hospitals between 2000 and 2005.1 ACS is an umbrella term that refers to a spectrum of clinical manifestations due to myo-
cardial ischemia and includes 3 disease entities, ie, ST-segment elevation myocardial infarction (STEMI), non–ST-segment elevation myocardial infarction (NSTEMI), and unstable angina (UA).2 ACS is associated with devastating sequelae often referred to as major adverse cardiovascular events (MACEs) in clinical research. MACEs are a composite of clinical events and end points that include death, revascularization, reinfarction, atrial fibrillation (AF), heart failure, and angina.3 Clinicians and researchers worldwide are constantly conducting studies to identify reliable markers and tools for prognostication post ACS. Echocardiographic parameters have been proven to prognosticate the long-term survival of this
Received for publication January 15, 2012. Accepted February 27, 2012. Corresponding author: Dr Rajalingham Sakthiswary, Department of Medicine, Faculty of Medicine, Universiti Kebangsaan Malaysia Medical Centre, Jalan Yaacob Latif, Bandar Tun Razak, 56000, Cheras, Kuala Lumpur, Malaysia. E-mail: [email protected] See page 566 for disclosure information.
0828-282X/$ – see front matter © 2012 Canadian Cardiovascular Society. Published by Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.cjca.2012.02.015
562
Canadian Journal of Cardiology Volume 28 2012
Conclusion: LAVI is a useful tool for prognostication and an independent predictor of MACEs post ACS.
(P ⫽ 0,016). Après l’ajustement des variables parasites par l’analyse multivariée, l’IVAG a montré une association significative aux ÉCIM (P ⫽ 0,030, ratio d’incidence approché ⫽ 1,229, intervalle de confiance de 95 %, 1,020-1,481). Conclusion : L’IVAG est un outil utile pour évaluer le pronostic et un prédicteur indépendant des ÉCIM après un SCA.
group of patients.4,5 In recent years, left atrial (LA) measurements have emerged as the focus of cardiovascular research. LA volume and size have close association with left ventricular (LV) systolic and diastolic function. Both systolic and diastolic dysfunction predict a poorer outcome after ACS.6,7 The reliable method of LA size measurement, according to the American Society of Echocardiography, is the LA volume index (LAVI), ie, LA volume divided by body surface area.8 Although studies have demonstrated that an increased LAVI is a predictor of mortality, there is still a paucity of data on its association with other MACEs. The main purpose of this study was to evaluate the association between LAVI and the various forms of MACEs among patients post ACS.
(power) 0.8. The type I error probability associated with this test was 0.05. In all, 103 patients were screened, and 75 were recruited. The remaining 28 patients were not included because they declined to participate in the study, did not meet the study criteria, or did not complete the study. The 75 participants were divided into 2 arms: normal LAVI and increased LAVI. The cutoff value used to define increased LAVI was more than 28 mL/m2 based on the American Society of Echocardiography criterion.8 After the initial admission for ACS, the patients were prospectively followed up during 6 months for development of clinical events. The following cardiac events were sought: death from cardiovascular causes; myocardial infarction; new-onset congestive heart failure; new-onset AF; and cardiac revascularization procedures, including percutaneous coronary intervention and coronary artery bypass graft. In addition, we obtained data by conducting telephone follow-up interviews with patients or their proxies in relation to emergency department visits, hospitalizations, or death. For all reported events, medical records or death certificates were retrieved. The outcome classification was determined by2 blinded adjudicators who reviewed each event in detail. Newonset heart failure was defined as the development of symptoms and signs consistent with cardiac failure and had been confirmed by the relevant investigations deemed necessary by the treating doctors. New-onset AF was defined as the development of AF based on a 12-lead electrocardiogram. Cardiac deaths were those secondary to ACS, arrhythmia, congestive heart failure, and death related to a cardiac event. Sudden death was counted as cardiac death if it was not better explained by noncardiac causes. Reinfarction refers to another episode or recurrent ACS. Each MACE was counted only once for each patient (eg, recurrent hospitalizations due to heart failure in the same participant were counted as 1 event). The study data were analyzed using Statistical Package for the Social Sciences version 19.0. Data were tested for normality with the Shapiro-Wilk test. All normally distributed data were reported as means, and comparison of the means was performed with the Student t test. The rest of the values were reported as median and were analyzed with the Mann-Whitney U statistic. The Fisher exact test was used to analyze associations between categorical variables. We used multivariate analysis to determine the independent predictor of MACEs, with confounding variables entered as covariates. A P value of ⬍ 0.05 was considered statistically significant.
Methods This was a prospective observational study conducted between December 2010 and August 2011 in Universiti Kebangsaan Malaysia Medical Centre, which is a tertiary hospital in Kuala Lumpur. Criteria for enrollment were a history of ACS, including STEMI, NSTEMI, and UA. STEMI, NSTEMI, and UA were defined according to standard criteria. Patients with the following underlying conditions were excluded: AF, restrictive cardiomyopathy, hypertrophic cardiomyopathy, constrictive pericarditis, and mitral valve disease. Patients with no known underlying AF but an electrocardiogram recording of AF within the first 72 hours of admission were excluded because of the possibility of baseline undiagnosed AF. Besides, patients with poor echocardiographic window, which may result in suboptimal and inaccurate measurements, were dropped from the study. All study participants provided informed consent for echocardiographic testing and review of medical records. The centre’s institutional review board approved the study protocol. All echocardiograms were performed by a single cardiac sonographer using a commercially available ultrasound system (Vivid I n GE Vingmed Ultrasound, N-3190; GE Medical Systems, Horten, Norway) on either day 2 or day 3 of admission. The cardiac sonographer was blinded to the clinical data of the patients. The echocardiographic studies were performed in the supine and left lateral recumbent positions. Following the protocol, LA volume was assessed by the biplane arealength method in both apical 4- and 2-chamber views. Measurements were taken at the end of systole. Sample size was determined with power and sample size calculation software. Data from a previous study by Moller stated that abnormal LA volume predicts 80% of adverse outcome.5 The proportion of patients with normal LA volume was estimated to be 50% as there was no previous data for reference. We had to study at least 38 patients with abnormal LA volume to be able to reject the null hypothesis with probability of
Results A total of 81 patients met all study criteria and consented to participate in this study. During the 6-month study period, 6 patients were lost to follow-up and were excluded. The study population was divided into 2 groups: increased LAVI, with 32
Gunasekaran et al. Left Atrial Volume Index in ACS
563
Table 1. Patients demographic data and baseline characteristics for both groups Characteristic Age ⬍ 65 ⬎ 65 Gender Male Female BMI (kg/m2) ⬍ 25 25-29.9 ⬎ 30 Hypertension Diabetes mellitus Hyperlipidemia Smoking
Increased LAVI n ⫽ 32 (%)
Normal LAVI n ⫽ 43 (%)
21 (66) 11 (34)
30 (70) 13 (30)
0.702
23 (72) 9 (28)
31 (72) 12 (28)
0.984
15 (47) 11 (34) 6 (19) 27 (84) 19 (59) 28 (88) 15 (47)
19 (44) 16 (37) 8 (19) 32 (74) 28 (65) 39 (91) 24 (56)
0.963
P value*
0.291 0.61 0.71 0.683
BMI, body mass index; LAVI, left atrial volume index. * P values are based on Fisher exact test.
patients, and normal LAVI, with 43 patients. Characteristics of the study population are outlined in Table 1. The groups’ baseline demographic features and comorbidities such as hypertension, smoking, diabetes mellitus, and hyperlipidemia were comparable. However, the increased-LAVI group had significantly higher median creatinine (P ⫽ 0.008), with lower glomerular filtration rate (GFR) (P ⫽ 0.001; Table 2). Besides, the E to E prime (E/E=) ratio, which is a quantitative estimate of LV filling pressure, was significantly higher in the increasedLAVI group, reflecting this group’s poorer diastolic function (P ⫽ 0.001; Table 3). Of the 75 patients, 18 (24%) had STEMI, 16 (21%) were diagnosed with NSTEMI, and 41 (55%) with UA. The incidence of STEMI, NSTEMI, and UA was similar in both groups (Fig. 1). Figure 1 compares the diagnosis, coronary angiogram findings, and management between the groups. During the 6-month follow-up period, 30 patients (93.8%) in the increased-LAVI arm experienced at least 1 MACE. The normal-LAVI arm, on the other hand, had 23 patients (53.5%) with a MACE. As the inclusion of AF as a MACE is highly debatable, data were analyzed with and without AF. As the proportion of patients with new-onset AF was relatively small across the groups, the occurrence of MACEs remained significantly higher in the increased-LAVI group, even if AF was not
Table 2. Comparison of baseline laboratory parameters between groups Parameter Total cholesterol Triglyceride LDL HDL Creatinine kinase Troponin T Creatinine GFR HbAIC
Increased LAVI
Normal LAVI
P value*
5.08 ⫾ 1.66 1.71 (1.02-1.82) 3.00 (1.83-3.96) 3.00 (1.83-3.96) 130.50 (94.00-394.00) 0.50 (0.00-1.00) 166.71 (85.00-173.50) 56.86 (30.50-87.00) 7.52 (5.70-7.25)
5.31 ⫾ 1.44 2.14 (1.20-2.62) 4.52 (2.52-4.20) 1.04 (0.86-1.27) 159.00 (76.00-345.00) 0.30 (0.00-1.00) 90.23 (72.00-101.00) 83.95 (62.50-104.00) 7.64 (6.16-9.00)
0.763† 0.052 0.211 0.693 0.642 0.763 0.008 0.001 0.320
All data presented as median (range). GFR, glomerular filtration rate; HbAIC, hemoglobin A1c; HDL, high-density lipoprotein; LAVI, left atrial volume index; LDL, low-density lipoprotein. * P values are based on Mann-Whitney U test. † Data presented as mean ⫾ standard deviation based on independent sample t test.
Table 3. Echocardiographic measurements in both groups
E/A ratio DT E/E= PVs-PVd LVEDD LVESD LVPW FS EF
Increased LAVI n ⫽ 32
Normal LAVI n ⫽ 43
P value*
1.04 (0.72-1.41) 215.28 ⫾ 72.05 18.64 (11.40-21.34) 5.28 ⫾ 2.39 5.13 ⫾ 0.62 3.69 (3.30-4.27) 1.10 ⫾ 0.28 28.37 ⫾ 6.71 53.28 (42.25-64.00)
0.82 (0.65-1.15) 217.25 ⫾ 70.93 10.79 (8.65-12.43) 1.25 ⫾ 0.39 4.63 ⫾ 0.74 3.21 (2.60-3.50) 1.10 ⫾ 0.19 31.10 ⫾ 7.97 57.05 (50.00-64.00)
0.060 0.900† 0.001 0.240† 0.001† 0.001 0.920† 0.120† 0.170
All data presented as median (range). DT, deceleration time; E/A, early to late ventricular filling verlocity ratio; E/E=, E to E prime ratio; EF, ejection fraction; FS, fractional shortening; LAVI, left atrial volume index; LVEDD, left ventricular end diastolic diameter; LVESD, left ventricular end systolic diameter; LVPW, left ventricular posterior wall; PVs-PVd, pumonary vein systolic-pulmonary vein diastolic velocities. * P values are based on Mann-Whitney U test. † Data presented as mean ⫾ standard deviation based on independent sample t test.
counted. The P value was 0.021 with AF, whereas without AF it was 0.016 (Table 4). When the patients were further subdivided according to MACE, ie, angina, new-onset heart failure, reinfarction, new-onset AF, and death, there was no significant difference observed between the groups, with P values of 0.313, 0.380, 0.442, 0.103, and 0.390, respectively (Fig. 2). Confounding variables of MACEs were entered into multiple logistic regression analysis. These covariates were parameters with statistically significant differences by univariate analysis: GFR, creatinine, left ventricular end diastolic diameter, left ventricular end systolic diameter, and E-E=. Table 5 illustrates that only increased LAVI had significant association with MACEs, based on multivariate analysis (P ⫽ 0.030, odds ratio ⫽ 1.229 (95% confidence interval, 1.020-1.481). Discussion In recent decades, accumulating evidence has indicated LAVI as a robust predictor of cardiovascular events. LAVI has been proven to be a more accurate and objective method of assessment of LA dilatation compared with LA area or diameter.4 In this context, most researchers in the past focused on cohorts of patients after myocardial infarction (MI). Hence, the data on the prognostic significance of LAVI in patients with UA remains scarce. To the best of our knowledge, this is the first study that was powered to determine the significance of an increased LAVI in predicting MACEs post ACS. Unlike other past studies in this area, we included all categories of ACS, ie, STEMI, NSTEMI, and UA. The vast majority of our study participants fulfilled the diagnostic criteria for UA. The pathophysiology and clinical characteristics of UA are similar to but not the same as those of MI. UA represents a preinfarction state in which there is myocardial ischemia in the absence of release of enzymes or biomarkers of myocardial necrosis.9 Our findings support the hypothesis that LAVI is a reliable predictor of MACEs after ACS. Most previous studies reported cumulative MACEs during a mean follow-up period of 2 to 3 years.10,11 This study demonstrates that an increased LAVI leads to a significantly higher occurrence of cardiovascular
564
Canadian Journal of Cardiology Volume 28 2012
Figure 1. Distribution of diagnosis, coronary angiogram findings, and treatment approach in both groups. CABG, coronary artery bypass graft; LAVI, left atrial volume index; NSTEMI, non–ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; STEMI, ST-segment elevation myocardial infarction; UA, unstable angina.
complications as early as within 6 months of ACS. The evaluated outcome events of the majority of similar studies focused on a single event type. The outcome measures in our study
Table 4. MACEs in both groups
MACEs (excluding AF) MACEs (including AF) AF
Increased LAVI n ⫽ 32 (%)
Normal LAVI n ⫽ 43 (%)
P value*
25 (78) 30 (94) 5 (16)
21 (49) 23 (54) 2 (5)
0.016 0.021 0.129
AF, atrial fibrillation; LAVI, left atrial volume index; MACE, major adverse cardiac event. * P values are based on Fisher exact test.
included various MACEs that are readily definable events, such as cardiovascular death, heart failure, and AF. Most researchers in the past excluded AF because of its well-documented association with increased LAVI. Our study design was quite different, with exclusion of patients with baseline AF, but the number of patients with new-onset AF in both arms was determined during the 6-month follow-up period from the time of ACS. Our study design allowed for the identification of newonset AF (a form of MACE) due to an increased LAVI, as other potential confounders were essentially insignificant. AF, however, did not contribute to the significant study findings of more MACEs in the increased-LAVI arm. Intriguingly, on the contrary, the exclusion of AF gave a lower P value (from 0.021 to 0.016), hence increasing the level of significance.
Gunasekaran et al. Left Atrial Volume Index in ACS
565
Figure 2. Distribution of major adverse coronary events (MACEs) in both groups. LAVI, left atrial volume index.
Although the total number of MACEs in the increasedLAVI group and the normal-LAVI group was significantly different statistically, the difference between the groups for each type of event when analyzed individually did not reach statistical significance. We believe that the relatively small sample size is a possible explanation. Most previous studies did not include patients with UA. In studies that included patients with only MI, the reported cardiovascular mortality rates were higher.10 The relatively low percentage of cardiovascular death in our study is best explained by our heterogeneous study population with predominance of UA, which is believed to carry a lower mortality risk than does MI. At baseline, the increased-LAVI group showed significantly higher median creatinine and lower median GFR. LV hypertrophy is a well-documented echocardiographic finding in patients with chronic kidney disease due to coexistence of hypertension and other hemodynamic alterations. Cioffi et al. reported that LV mass and LA volume were related to GFR, which was consistent with our findings.12 LAVI was found to be an independent predictor of MACEs after adjustment for GFR in multiple logistic regression analysis. The relationship between GFR and LAVI merits further investigation. From the
available evidence, we hypothesize that LV hypertrophy could be contributory to this finding. Several drawbacks of the study need to be considered in interpretation of the study findings. The presence of AF was detected during routine clinic follow-up in asymptomatic patients. Patients with paroxysmal AF would have been missed if they were in sinus rhythm at the time of the clinic visit. Interim monitoring for AF would probably yield a higher number of patients. In most studies aimed to identify predictors of a certain clinical event, Kaplan-Meier survival analysis and Cox regression analysis models have been used and the hazard ratio determined. Our study design, with a short study duration of 6 months, was thought to be unsuitable for such statistical analysis.
Conclusion LAVI is a useful tool for prognostication and an independent predictor of MACEs post ACS. The authors would like to recommend routine measurement of LAVI in all patients admitted with ACS. An increased LAVI warrants increased vigilance among clinicians for cardiovascular complications.
Table 5. Multivariate analysis with confounding variables 95% CI for EXP(B) Covariates
B
Wald
P value
Exp(B)
Lower
Upper
GFR Creatinine LVEDD LVESD E/E= LAVI
0.416 ⫺0.013 0.091 0.220 1.126 0.214
0.276 0.190 0.004 0.012 2.649 4.794
0.600 0.663 0.948 0.911 0.104 0.029*
1.515 0.987 1.096 1.246 3.083 1.238
0.321 0.931 0.069 0.026 0.795 1.023
7.146 1.047 17.328 58.797 11.966 1.499
B, slope coefficient; CI, confidence interval; E/E=, E to E prime ratio; EXP(B), odds ratio; GFR, glomerular filtration rate; LAVI, left atrial volume index; LVEDD, left ventricular end diastolic diameter; LVESD, left ventricular end systolic diameter. * Nagelkerke R2 ⫽ 0.452.
566
Canadian Journal of Cardiology Volume 28 2012
Funding Sources The study was funded by the Research Grant of Faculty of Medicine of Universiti Kebangsaan Malaysia Medical Centre.
6. Dini FL, Michelassi C, Micheli G, Rovai D. Prognostic value of pulmonary venous flow Doppler signal in left ventricular dysfunction: contribution of the difference in duration of pulmonary venous and mitral flow at atrial contraction. J Am Coll Cardiol 2000;36:1295-302.
Disclosures The authors have no conflicts of interest to disclose.
7. Moller JE, Sondergaard E, Poulsen SH, Egstrup K. Pseudonormal and restrictive filling patterns predict left ventricular dilation and cardiac death after a first myocardial infarction: a serial color M-mode Doppler echocardiographic study. J Am Coll Cardiol 2000;36:1841-6.
References 1. Association of Clinical Registries, Malaysia. National Cardiovascular Disease Database: Acute Coronary Syndrome (ACS) Registry 1st Annual Report 2006. Available at: http://www.acrm.org.my/ncvd/default.asp? page⫽/ncvd/reports_annualReports. Accessed March 5, 2012. 2. Alpert JS, Thygesen K, Antman E, Bassand JP. Myocardial infarction redefined—a consensus document of the Joint European Society of Cardiology/American College of Cardiology Committee for the Redefinition of Myocardial Infarction. J Am Coll Cardiol 2000;36:959-69. 3. Kip KE, Hollabaugh K, Marroquin OC, Williams DO. The problem with composite end points in cardiovascular studies: the story of major adverse cardiac events and percutaneous coronary intervention. J Am Coll Cardiol 2008;51:701-7.
8. Lang RM, Bierig M, Devereux RB, et al; Chamber Quantification Writing Group; American Society of Echocardiography’s Guidelines and Standards Committee; European Association of Echocardiography. Recommendations for chamber quantification: a report from the American Society of Echocardiography’s Guidelines and Standards Committee and the Chamber Quantification Writing Group, developed in conjunction with the European Association of Echocardiography, a branch of the European Society of Cardiology. J Am Soc Echocardiogr 2005;18:1440-63. 9. Braunwald E. Unstable angina: a classification. Circulation 1989;80: 410-4. 10. Sakaguchi E, Yamada A, Sugimoto K, et al. Prognostic value of left atrial volume index in patients with first acute myocardial infarction. Eur J Echocardiogr 2011;12:440-4.
4. Tsang TS, Barnes ME, Gersh BJ, Bailey KR, Seward JB. Left atrial volume as a morphophysiologic expression of left ventricular diastolic dysfunction and relation to cardiovascular risk burden. Am J Cardiol 2002;90:1284-9.
11. Shah AM, Hung CL, Shin SH, et al. Cardiac structure and function, remodeling, and clinical outcomes among patients with diabetes after myocardial infarction complicated by left ventricular systolic dysfunction, heart failure, or both. Am Heart J 2011;162:685-91.
5. Moller JE, Hillis GS, Oh JK, et al. Left atrial volume: a powerful predictor of survival after acute myocardial infarction. Circulation 2003;107: 2207-12.
12. Cioffi G, Tarantini L, Frizzi R, et al. Chronic kidney disease elicits excessive increase in left ventricular mass growth in patients at increased risk for cardiovascular events. J Hypertens 2011;29:565-73.