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Usefulness of Right Ventricular Dysfunction to Predict New-Onset Atrial Fibrillation Following Coronary Artery Bypass Grafting
Accepted Manuscript Usefulness of Right Ventricular Dysfunction to Predict New-Onset Atrial Fibrillation Following Coronary Artery Bypass Grafting Avi Shimony, MD Jonathan Afilalo, MD, MSc Aidan W. Flynn, MD, PhD David Langleben, MD Arvin K. Agnihotri, MD Jean-Francois Morin, MD David M. Shahian, MD Michael H. Picard, MD Lawrence G. Rudski, MD PII:
S0002-9149(13)02447-8
DOI:
10.1016/j.amjcard.2013.11.048
Reference:
AJC 20159
To appear in:
The American Journal of Cardiology
Received Date: 21 September 2013 Revised Date:
11 November 2013
Accepted Date: 18 November 2013
Please cite this article as: Shimony A, Afilalo J, Flynn AW, Langleben D, Agnihotri AK, Morin J-F, Shahian DM, Picard MH, Rudski LG, Usefulness of Right Ventricular Dysfunction to Predict New-Onset Atrial Fibrillation Following Coronary Artery Bypass Grafting, The American Journal of Cardiology (2014), doi: 10.1016/j.amjcard.2013.11.048. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Usefulness of Right Ventricular Dysfunction to Predict New-Onset Atrial Fibrillation Following Coronary Artery Bypass Grafting
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Running title: Post Coronary Artery Bypass Atrial Fibrillation Avi Shimony, M.D. a*, Jonathan Afilalo M.D. M.Sc. a,b*, Aidan W. Flynn M.D. Ph.D. b, David Langleben M.D. a, Arvin K. Agnihotri M.D. c, Jean-Francois Morin M.D. d, David M. Shahian M.D. c,e, Michael H. Picard M.D. b, Lawrence G. Rudski M.D. a a
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Division of Cardiology, Jewish General Hospital, Lady Davis Institute for Medical Research, McGill University, Montreal, QC, Canada; b Cardiac Ultrasound Laboratory, Division of Cardiology, Massachusetts General Hospital, Harvard University, Boston, Massachusetts, USA; c Division of Cardiac Surgery, Massachusetts General Hospital, Harvard University, Boston, Massachusetts, USA; d Division of Cardiac Surgery, Jewish General Hospital, Lady Davis Institute for Medical Research, McGill University, Montreal, QC, Canada; e Department of Surgery and Center for Quality and Safety, Massachusetts General Hospital, Harvard University, Boston, Massachusetts, USA
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Address for Correspondence Lawrence G. Rudski, M.D. Associate Professor of Medicine, McGill University Director, Noninvasive Cardiology Division of Cardiology, Jewish General Hospital 3755 Cote Ste Catherine Rd Montreal, QC H3T 1E2 Telephone: (514) 340-7531 / Fax: (514) 340-7534 Email: [email protected]
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The first two authors contributed equally to this paper (*). This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (NIH Award #UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic health care centers). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, the National Center for Research Resources, or the National Institutes of Health. Conflicts of interest for all authors: None
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ABSTRACT Post-operative atrial fibrillation (AF) is a serious yet common complication after
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coronary artery bypass grafting surgery (CABG). Risk factors for post-operative AF have been identified, including echocardiographic parameters, and these are relied upon to
implement preventative strategies that reduce the incidence of AF. There has yet to be a
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study examining the impact of echocardiographic right heart parameters for the
prediction of post-operative AF. Thus, a panel of right heart parameters was measured in
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a cohort of patients undergoing isolated CABG, excluding those who did not have echocardiographic assessment within 30 days before surgery and those with any prior history of AF. The primary outcome was post-operative AF defined as any episode of AF requiring treatment during the index hospitalization. Post-operative AF occurred in 197 of 768 patients (25.6%); these were older and more likely to have hypertension and
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chronic kidney disease. After adjustment for clinical and echocardiographic variables, left atrial volume index ≥34 mL/m2 (OR 1.98, 95% CI 1.36 to 2.87), abnormal right
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ventricular myocardial performance index (RV-MPI) (OR 1.50 95% CI 1.01 to 2.24), and advancing age (OR 1.05, 95% CI 1.03 to 1.07) were found to be independent predictors
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of post-operative AF. In conclusion, RV-MPI is a novel predictor of post-operative AF in patients undergoing isolated CABG and appears to be additive to established risk factors such as age and left atrial volume.
Key words: Post-operative atrial fibrillation; coronary artery bypass graft surgery; right ventricular myocardial performance index
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INTRODUCTION Post-operative atrial fibrillation (AF) is a serious yet common complication after
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coronary artery bypass grafting surgery (CABG). Risk factors for post-operative AF have been identified and are relied upon by clinicians to implement preventative strategies that have been shown to reduce the incidence of AF. To date, echocardiographic risk factors
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have been restricted to left heart parameters such as left atrial volume and left ventricular function. There has not yet been a study examining the impact of echocardiographic right
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heart parameters on the development of post-operative AF. Using the Pre-Operative Surgical Stratification by Echocardiography (POSSE) database (1), we hypothesized that echocardiographic right heart parameters would provide additive prognostic value to predict the occurrence of postoperative AF.
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METHODS
Consecutive patients undergoing isolated CABG without concomitant repair or
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replacement of the heart valves or great vessels were identified within the POSEE database. Data were obtained from two university-affiliated hospitals in the United States
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(Massachusetts General Hospital, Boston, MA, January 1 2007 to December 31 2009) and Canada (Jewish General Hospital, Montreal, QC, September 1 2010 to July 11 2011). From this cohort, subjects who had a digitally available preoperative echocardiogram within 30 days before surgery were eligible for inclusion (n=854). Subjects who had any prior history of AF were excluded (Figure 1). The study protocol was approved by the institutional review boards of both hospitals.
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Demographic data, preoperative clinical variables, operative variables, and postoperative in-hospital outcomes were extracted from the Society of Thoracic Surgeons
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(STS) Adult Cardiac Surgery Database (2) at the Massachusetts General Hospital and from electronic medical records using identical data definitions at the Jewish General
Hospital. These covariates included but were not limited to: age, sex, body mass index,
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prior AF, supraventricular arrhythmia, ventricular arrhythmia, prior myocardial
infarction, diabetes, hypertension, dyslipidemia, chronic kidney disease, chronic lung
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disease, peripheral arterial disease, cerebrovascular disease, preoperative creatinine, preoperative medications, prior cardiac surgery and/or percutaneous coronary intervention, cardiac presentation, cardiogenic shock, intra-aortic balloon pump use, number of diseased coronary vessels, number of grafts, and whether the operation was elective or urgent/emergent.
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Echocardiographic parameters were re-measured offline from the digital echocardiograms by independent echocardiography-trained cardiologists who were
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blinded to the study outcomes. Disagreements were resolved by consensus and/or a third senior observer. These parameters encompassed left and right-sided chamber size,
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geometry, systolic function, diastolic function, as well as valvular regurgitation and stenosis. All were measured and classified according to the American Society of Echocardiography guidelines (3-7). Right and left atrial areas were traced at end-systole in the apical 4-chamber view.
RV endocardial borders were traced at end-diastole and end-systole in apical 4-chamber view. The RV fractional area change (FAC), a measure of RV systolic function, was calculated by the following formula: [(RV end-diastolic area – RV end-systolic area) /
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RV end-diastolic area] x 100. RV myocardial performance index (MPI), a measure of systolic and diastolic function, was measured by either the pulsed Doppler method or the
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tissue Doppler method and calculated using the following formula: [(tricuspid closure opening time – ejection time) / ejection time], using a cutoff of 0.40 for both methods (3). Pulmonary artery systolic pressure (PASP) was estimated using peak tricuspid
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regurgitation jet velocity with 10 mmHg added for right atrial pressure. LV mass was measured using the Devereux method and indexed to body surface area. LV ejection
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fraction (EF) was measured using the biplane Simpson’s method. Several parameters including pulsed Doppler of the mitral and pulmonary vein inflow and tissue Doppler septal and lateral mitral annulus early diastolic velocities were integrated to determine LV diastolic function. The degree of valvular regurgitation and stenosis were assessed using a multi-parametric approach according to ASE guidelines. Significant valvular
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regurgitation was defined as at least moderate in severity. Echocardiograms were performed with GE Vivid 7 or GE vivid E9 machines and
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interpreted on EchoPAC workstations (GE Healthcare, Milwaukee, WI) at the Jewish General Hospital and with the Philips IE33, Sonos 7500 and Xcelera workstations
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(Philips Healthcare, Andover, MA) or GE Vivid 7 machines and EchoPAC workstation (GE Healthcare, Milwaukee, WI) at the Massachusetts General Hospital. Patients were monitored by continuous telemetry for at least 72-96 hours after
surgery and by 12-lead electrocardiograms performed on a routine daily basis and when indicated due to clinical signs. AF was recognized universally as a supraventricualr arrhythmia with an irregularly irregular ventricular rhythm. The primary endpoint of this study was post-operative AF defined by the STS as an episode of AF of any duration
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diagnosed by the attending physician that occurred during the in-hospital postoperative period and required treatment (medical therapy and/or electrical cardioversion). The
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decision to treat a patient for atrial fibrillation was at the discretion of the attending physician. Postoperative in-hospital outcomes other than post-operative AF included death from any cause, stroke, acute renal failure, prolonged intubation, the need of
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reoperation, and postoperative length of stay.
Continuous variables were reported as mean ± standard deviation (SD) and
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compared using a two-tailed Student’s t-test. Categorical variables were reported as proportions and compared using a chi-square or Fisher’s exact test where appropriate. Demographic, clinical, and echocardiographic variables were entered in a multivariable logistic regression model. The Akaike’s Information Criterion (AIC) was used to select the optimal model (lowest AIC) to predict post-operative AF. STATA 12 (Stata-Corp,
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College Station TX, USA) was used to conduct analyses.
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RESULTS
The study population consisted of 768 patients (21.6% female), of which 197
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(25.6%) developed post-operative AF. No patient was lost to follow-up for the primary outcome measure. Patients who developed post-operative AF were older (mean age 71.3 vs. 64.9, p<0.001) and had a significantly higher rate of hypertension, chronic kidney disease, and congestive heart failure. They had slightly more diseased vessels and longer cardiopulmonary bypass times than patients without post-operative AF. There were no other notable differences between groups in baseline characteristics (Table 1).
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The composite outcome of in-hospital mortality and major morbidity was significantly higher in the post-operative AF group (23.9% vs. 10.9%, p<0.001). With
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respect to individual outcomes, mortality, renal failure, and prolonged intubation rates were significantly higher in the post-operative AF group; stroke and reoperation rates
tended to be higher in the post-operative AF group although these outcomes did not reach
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statistical significance. In addition, patients with post-operative AF remained in hospital 5.0 days longer on average.
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Echocardiographic variables for patients with and without post-operative AF are shown in Table 2. With respect to right-sided parameters, patients who developed postoperative AF had larger right atrial size, worse RV-MPI, worse tricuspid regurgitation severity, higher pulmonary artery systolic pressure, and no difference in RV-FAC. With Patients who developed post-operative AF had larger left atrial size, larger LV end-
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diastolic volume and mass, and lower LVEF. Furthermore, they were more likely to have LV diastolic dysfunction and moderate mitral regurgitation. There were no cases of
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severe mitral or tricuspid regurgitation (given the isolated CABG cohort that did not undergo any valve procedures).
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After adjustment for clinical and echocardiographic variables (Table 3), the optimal multivariable model to predict post-operative AF was found to include the following variables: left atrial volume index ≥34 mL/m2 (odd ratio [OR] 1.98, 95% confidence interval [CI] 1.36 to 2.87), abnormal RV-MPI (OR 1.50, 95% CI 1.01 to 2.24), and advancing age (OR 1.05 per year, 95% CI 1.03 to 1.07). Sensitivity analysis adjusting for preoperative medication use did not alter the results.
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DISCUSSION The present study has demonstrated that echocardiographic right ventricular
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performance is predictive of post-operative AF in patients undergoing isolated CABG. In particular, RV-MPI, a composite measure of RV systolic and diastolic function, was
additive to traditional risk factors for predicting post-operative AF (3). AF is one of the
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most commonly occurring arrhythmias after cardiac surgery and is associated with
significant morbidity and mortality (8). In the general population, the pathophysiology of
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AF has been extensively studied yet remains incompletely understood (9). Similarly, in the context of cardiac surgery, numerous risk factors for post-operative AF have been identified, but the pathophysiology of this entity is still to a large extent elusive (10-14). Right-sided cardiac dysfunction has been linked to AF and supraventricular tachycardia in other settings (15-17). Aziz et al. determined the incidence and predictors
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of AF in 904 patients who were admitted with decompensated heart failure (15). AF developed in 21% of these patients, with a higher incidence among those with RV
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dysfunction (39% vs. 12%). RV dysfunction was found to be the strongest independent predictor for the development of AF (OR 4.45, 95% CI 2.98 to 6.65). In a study of
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patients undergoing elective lung resection by Matyal et al., left atrial dilation, abnormal RV-MPI, and advanced age were identified as independent predictors of postoperative supraventricular tachycardia (17). Bouchardy et al. demonstrated that right atrial dilatation had a significant impact on the development of AF in adult patients with congenital heart disease patients who had right-sided cardiac pathologies (16). In their multivariable analysis, age (OR 1.07, 95% CI 1.04 to 1.1), left atrial area (OR 1.15, 95% CI 1.06 to 1.26), and right atrial area (OR 1.08, 95% CI 1.01 to 1.16) were significantly
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associated with AF. Interestingly, in a study of anesthetized lambs undergoing thoracic surgery, structural and functional changes that caused alterations in RV function were
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implicated in the genesis of postoperative supraventricular tachycardia (18). Our study is therefore consistent with the observation that RV function is relevant to the development of AF and extends this finding to the post-operative cardiac surgery patient.
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Most measures of right-sided cardiac function reflect systolic performance. AF is classically seen in the context of atrial dilation and may therefore be associated with
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abnormal diastolic function. In our study, RV FAC, a measure of RV systolic-only function, did not predict post-operative AF. Conversely, RV MPI, which is a measure of systolic and diastolic function, did predict post-operative AF; underscoring the importance of global right heart function as changes in both the atrium and ventricle may contribute to the pathogenesis of AF. It remains to be seen histologically whether
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abnormalities in RV-MPI are associated with pro-arrhythmic changes in the anatomic structure of the right atrium.
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A number of pathophysiological mechanisms may be postulated for AF emanating from the right heart in post-operative patients. Firstly, C-reactive protein, a
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marker of chronic inflammation, has been implicated as a risk factor for post-operative AF in both on-pump and off-pump bypass surgery (19). Similarly, C-reactive protein, IL6, and TNF-α have been implicated as risk factors for abnormal RV-MPI (20). This shared association may reflect an epiphenomenon rather than a causal link. Secondly, RV dysfunction may lead to circulatory failure, peri-operative fluid overload, myocardial ischemia, hypoxemia, and increased sympathetic activity after cardiac surgery (21-23). These in turn have been associated with AF (24-26). Thirdly, vasopressors are more often
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required postoperatively in patients with RV dysfunction (27). High dose inotropic support was reported as an independent predictor of post-operative AF following elective
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CABG (24). Finally, RV dysfunction may lead to right atrial dilation and remodeling which may alter atrial refractoriness and conduction and increase susceptibility to postoperative AF (9, 28).
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Our study has several potential limitations. First, since it is a retrospective study, general reservations pertaining to potential confounders and biases should be
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acknowledged. Second, we may have not have captured episodes of post-operative AF since systematic continuous telemetry was limited to the first 72-96 hours after surgery and not throughout the entire hospitalization. However, it is unlikely that this would have a major impact on our analysis since the vast majority of post-operative AF episodes are known to occur during the first 48-72 hours after surgery (11, 29-30). Third, we did not
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have access to postoperative medication usage within our data sources, and we could not ascertain the protective/negative effects of antiarrhythmic drugs. Finally, we have
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confined our analysis to patients undergoing isolated CABG which limits a wider
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generalizability of the findings to patients undergoing other types of cardiac surgery.
ACKNOWLEDGMENTS We would like to thank Marcia Leavitt, David Crowell, and Karen Lynch for their
invaluable help in obtaining clinical and echocardiographic data for this study. We would also like to thank all of the cardiac sonographers at the Massachusetts General Hospital and Jewish General Hospital for their excellence in acquiring the echocardiographic images that made this study possible.
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48:779-786.
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FIGURE LEGEND
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Figure 1: Flow Diagram
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Table 1: Baseline Characteristics
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P-value
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Age (years) Female Body mass index (kg/m2) Obesity Hypertension Dyslipidemia Diabetes mellitus Chronic kidney disease Preoperative creatinine (mg/dL) Preoperative creatinine clearance Chronic lung disease Peripheral arterial disease Prior cerebrovascular disease Prior stroke Myocardial infarction Urgent/Emergent operative status Heart failure within 2 weeks Number of diseased vessels Cardiopulmonary bypass time Preoperative medication use ACE inhibitors Beta-blockers Statin Inotropes In-hospital outcomes Mortality or major morbidity Mortality Stroke Renal failure Prolonged intubation >24 hours Need for reoperation Postoperative length of stay (days)
Post Operative Atrial Fibrillation No Yes (N=571) (N=197) 64.9 ± 11.0 71.3 ± 9.9 125 (21.9%) 41 (20.8%) 28.5 ± 4.8 28.5 ± 5.1 185 (32.4%) 65 (33.0%) 443 (77.6%) 172 (87.3%) 281 (49.2%) 88 (44.7%) 215 (37.7%) 71 (36.0%) 169 (29.6%) 93 (47.2%) 1.22 ± 0.73 1.26 ± 0.44 80.0 ± 32.9 69.5 ± 34.7 55 (9.6%) 19 (9.6%) 83 (14.6%) 35 (17.8%) 86 (15.1%) 39 (19.9%) 48 (8.4%) 13 (6.6%) 236 (41.4%) 82 (41.6%) 485 (84.9%) 168 (85.3%) 129 (22.8%) 59 (30.6%) 3.5 ± 0.6 3.6 ± 0.6 121.1 ± 38.7 135.7 ± 52.4
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Variable
<0.001 0.75 1.0 0.88 <0.01 0.27 0.69 <0.001 0.47 <0.001 1.0 0.28 0.12 0.42 0.94 0.91 0.04 0.04 <0.001
156 (35.5%) 400 (91.1%) 334 (76.1%) 8 (1.4%)
46 (28.8%) 150 (93.4%) 128 (80.0%) 6 (3.0%)
0.23 0.49 0.58 0.32
62 (10.9%) 3 (0.5%) 4 (0.7%) 7 (1.2%) 39 (6.8%) 28 (4.9%) 7.5 ± 4.5
47 (23.9%) 5 (2.5%) 5 (2.5%) 17 (8.6%) 34 (17.3%) 17 (8.6%) 12.5 ± 10.4
<0.001 0.03 0.053 <0.001 <0.001 0.055 <0.001
Definitions: Obesity, body mass index >=30; Hypertension, diagnosis based on documented history of hypertension treated with medication or documented blood pressure >140 mmHg systolic or >90 mmHg diastolic on at least 2 occasions; Dyslipidemia, diagnosis based on total cholesterol >200 mg/dl, low-density lipoprotein >=130 mg/dl, or high-density lipoprotein <40 mg/dl in men or <50 mg/dl in women; Chronic kidney disease, estimated creatinine clearance <60 (ml/min).
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Table 2: Echocardiographic Parameters
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P-value
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234 (41.2%) 195 (34.3%) 77 (13.6%) 37 (6.5%) 25 (4.4%) 90.2 ± 24.2 31 (5.4%) 7.1 ± 1.9 7.9 ± 2.1 50.6 ± 8.7 0.32 ± 0.14 35.4 ± 10.2 12 (2.1%)
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Left atrium volume index (mL/m2) Left ventricular end-diastolic volume index (mL/m2) Left ventricular ejection fraction (%) Left ventricular diastolic function Normal Impaired Pseudonormal Restrictive N/A Left ventricular mass index (g/m2) Moderate/severe mitral regurgitation Right atrial area index (cm2/m2) Right ventricular end-diastolic area index (cm2/m2) Right ventricular fractional area change (%) Right ventricular myocardial performance index Pulmonary artery systolic pressure (mmHg) Moderate/severe tricuspid regurgitation
65 (33.0%) 66 (33.5%) 33 (16.8%) 27 (13.7%) 6 (3.1%) 94.8 ± 23.7 19 (9.6%) 7.6 ± 1.9 8.2 ± 2.3 49.5 ± 10.2 0.37 ± 0.16 39.4 ± 12.3 10 (5.1%)
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Variable
Post Operative Atrial Fibrillation No Yes (N=571) (N=197) 28.0 ± 11.4 32.0 ± 11.5 49.2 ± 18.2 55.7 ± 21.1 56.1 ± 12.9 53.7 ± 13.4
<0.001 <0.001 0.03
<0.05 0.87 0.26 <0.01 0.41 0.02 0.04 <0.01 0.09 0.14 <0.001 <0.001 0.03
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Table 3: Optimal Model to Predict Postoperative Atrial Fibrillation Adjusted
95% CI
1.98
Right ventricular myocardial performance index ≥0.4
1.50
Age, per year
1.05
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Left atrium volume index ≥34 mL/m2
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Odds Ratio 1.36 to 2.87
1.01 to 2.24
1.03 to 1.07
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The following variables were entered in the multivariable regression model: age, sex, body mass index, hypertension, chronic kidney disease, chronic lung disease, prior cardiac surgery, left atrial volume index, LV enddiastolic volume index, LV ejection fraction, LV hypertrophy, LV diastolic function, right atrial area, RV end-diastolic area, RV fractional area change, RV myocardial performance index, pulmonary arterial systolic pressure, mitral regurgitation, tricuspid regurgitation.
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Figure 1: Study Flow Chart
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1386 patients underwent isolated CABG at the two sites
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532 did not have a preoperative echocardiogram available
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854 patients were eligible
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86 had preoperative atrial fibrillation
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768 patients were included
S0002-9149(13)02447-8
DOI:
10.1016/j.amjcard.2013.11.048
Reference:
AJC 20159
To appear in:
The American Journal of Cardiology
Received Date: 21 September 2013 Revised Date:
11 November 2013
Accepted Date: 18 November 2013
Please cite this article as: Shimony A, Afilalo J, Flynn AW, Langleben D, Agnihotri AK, Morin J-F, Shahian DM, Picard MH, Rudski LG, Usefulness of Right Ventricular Dysfunction to Predict New-Onset Atrial Fibrillation Following Coronary Artery Bypass Grafting, The American Journal of Cardiology (2014), doi: 10.1016/j.amjcard.2013.11.048. This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
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Usefulness of Right Ventricular Dysfunction to Predict New-Onset Atrial Fibrillation Following Coronary Artery Bypass Grafting
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Running title: Post Coronary Artery Bypass Atrial Fibrillation Avi Shimony, M.D. a*, Jonathan Afilalo M.D. M.Sc. a,b*, Aidan W. Flynn M.D. Ph.D. b, David Langleben M.D. a, Arvin K. Agnihotri M.D. c, Jean-Francois Morin M.D. d, David M. Shahian M.D. c,e, Michael H. Picard M.D. b, Lawrence G. Rudski M.D. a a
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Division of Cardiology, Jewish General Hospital, Lady Davis Institute for Medical Research, McGill University, Montreal, QC, Canada; b Cardiac Ultrasound Laboratory, Division of Cardiology, Massachusetts General Hospital, Harvard University, Boston, Massachusetts, USA; c Division of Cardiac Surgery, Massachusetts General Hospital, Harvard University, Boston, Massachusetts, USA; d Division of Cardiac Surgery, Jewish General Hospital, Lady Davis Institute for Medical Research, McGill University, Montreal, QC, Canada; e Department of Surgery and Center for Quality and Safety, Massachusetts General Hospital, Harvard University, Boston, Massachusetts, USA
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Address for Correspondence Lawrence G. Rudski, M.D. Associate Professor of Medicine, McGill University Director, Noninvasive Cardiology Division of Cardiology, Jewish General Hospital 3755 Cote Ste Catherine Rd Montreal, QC H3T 1E2 Telephone: (514) 340-7531 / Fax: (514) 340-7534 Email: [email protected]
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The first two authors contributed equally to this paper (*). This work was conducted with support from Harvard Catalyst | The Harvard Clinical and Translational Science Center (NIH Award #UL1 RR 025758 and financial contributions from Harvard University and its affiliated academic health care centers). The content is solely the responsibility of the authors and does not necessarily represent the official views of Harvard Catalyst, Harvard University and its affiliated academic health care centers, the National Center for Research Resources, or the National Institutes of Health. Conflicts of interest for all authors: None
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ABSTRACT Post-operative atrial fibrillation (AF) is a serious yet common complication after
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coronary artery bypass grafting surgery (CABG). Risk factors for post-operative AF have been identified, including echocardiographic parameters, and these are relied upon to
implement preventative strategies that reduce the incidence of AF. There has yet to be a
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study examining the impact of echocardiographic right heart parameters for the
prediction of post-operative AF. Thus, a panel of right heart parameters was measured in
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a cohort of patients undergoing isolated CABG, excluding those who did not have echocardiographic assessment within 30 days before surgery and those with any prior history of AF. The primary outcome was post-operative AF defined as any episode of AF requiring treatment during the index hospitalization. Post-operative AF occurred in 197 of 768 patients (25.6%); these were older and more likely to have hypertension and
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chronic kidney disease. After adjustment for clinical and echocardiographic variables, left atrial volume index ≥34 mL/m2 (OR 1.98, 95% CI 1.36 to 2.87), abnormal right
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ventricular myocardial performance index (RV-MPI) (OR 1.50 95% CI 1.01 to 2.24), and advancing age (OR 1.05, 95% CI 1.03 to 1.07) were found to be independent predictors
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of post-operative AF. In conclusion, RV-MPI is a novel predictor of post-operative AF in patients undergoing isolated CABG and appears to be additive to established risk factors such as age and left atrial volume.
Key words: Post-operative atrial fibrillation; coronary artery bypass graft surgery; right ventricular myocardial performance index
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INTRODUCTION Post-operative atrial fibrillation (AF) is a serious yet common complication after
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coronary artery bypass grafting surgery (CABG). Risk factors for post-operative AF have been identified and are relied upon by clinicians to implement preventative strategies that have been shown to reduce the incidence of AF. To date, echocardiographic risk factors
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have been restricted to left heart parameters such as left atrial volume and left ventricular function. There has not yet been a study examining the impact of echocardiographic right
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heart parameters on the development of post-operative AF. Using the Pre-Operative Surgical Stratification by Echocardiography (POSSE) database (1), we hypothesized that echocardiographic right heart parameters would provide additive prognostic value to predict the occurrence of postoperative AF.
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METHODS
Consecutive patients undergoing isolated CABG without concomitant repair or
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replacement of the heart valves or great vessels were identified within the POSEE database. Data were obtained from two university-affiliated hospitals in the United States
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(Massachusetts General Hospital, Boston, MA, January 1 2007 to December 31 2009) and Canada (Jewish General Hospital, Montreal, QC, September 1 2010 to July 11 2011). From this cohort, subjects who had a digitally available preoperative echocardiogram within 30 days before surgery were eligible for inclusion (n=854). Subjects who had any prior history of AF were excluded (Figure 1). The study protocol was approved by the institutional review boards of both hospitals.
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Demographic data, preoperative clinical variables, operative variables, and postoperative in-hospital outcomes were extracted from the Society of Thoracic Surgeons
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(STS) Adult Cardiac Surgery Database (2) at the Massachusetts General Hospital and from electronic medical records using identical data definitions at the Jewish General
Hospital. These covariates included but were not limited to: age, sex, body mass index,
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prior AF, supraventricular arrhythmia, ventricular arrhythmia, prior myocardial
infarction, diabetes, hypertension, dyslipidemia, chronic kidney disease, chronic lung
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disease, peripheral arterial disease, cerebrovascular disease, preoperative creatinine, preoperative medications, prior cardiac surgery and/or percutaneous coronary intervention, cardiac presentation, cardiogenic shock, intra-aortic balloon pump use, number of diseased coronary vessels, number of grafts, and whether the operation was elective or urgent/emergent.
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Echocardiographic parameters were re-measured offline from the digital echocardiograms by independent echocardiography-trained cardiologists who were
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blinded to the study outcomes. Disagreements were resolved by consensus and/or a third senior observer. These parameters encompassed left and right-sided chamber size,
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geometry, systolic function, diastolic function, as well as valvular regurgitation and stenosis. All were measured and classified according to the American Society of Echocardiography guidelines (3-7). Right and left atrial areas were traced at end-systole in the apical 4-chamber view.
RV endocardial borders were traced at end-diastole and end-systole in apical 4-chamber view. The RV fractional area change (FAC), a measure of RV systolic function, was calculated by the following formula: [(RV end-diastolic area – RV end-systolic area) /
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RV end-diastolic area] x 100. RV myocardial performance index (MPI), a measure of systolic and diastolic function, was measured by either the pulsed Doppler method or the
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tissue Doppler method and calculated using the following formula: [(tricuspid closure opening time – ejection time) / ejection time], using a cutoff of 0.40 for both methods (3). Pulmonary artery systolic pressure (PASP) was estimated using peak tricuspid
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regurgitation jet velocity with 10 mmHg added for right atrial pressure. LV mass was measured using the Devereux method and indexed to body surface area. LV ejection
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fraction (EF) was measured using the biplane Simpson’s method. Several parameters including pulsed Doppler of the mitral and pulmonary vein inflow and tissue Doppler septal and lateral mitral annulus early diastolic velocities were integrated to determine LV diastolic function. The degree of valvular regurgitation and stenosis were assessed using a multi-parametric approach according to ASE guidelines. Significant valvular
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regurgitation was defined as at least moderate in severity. Echocardiograms were performed with GE Vivid 7 or GE vivid E9 machines and
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interpreted on EchoPAC workstations (GE Healthcare, Milwaukee, WI) at the Jewish General Hospital and with the Philips IE33, Sonos 7500 and Xcelera workstations
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(Philips Healthcare, Andover, MA) or GE Vivid 7 machines and EchoPAC workstation (GE Healthcare, Milwaukee, WI) at the Massachusetts General Hospital. Patients were monitored by continuous telemetry for at least 72-96 hours after
surgery and by 12-lead electrocardiograms performed on a routine daily basis and when indicated due to clinical signs. AF was recognized universally as a supraventricualr arrhythmia with an irregularly irregular ventricular rhythm. The primary endpoint of this study was post-operative AF defined by the STS as an episode of AF of any duration
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diagnosed by the attending physician that occurred during the in-hospital postoperative period and required treatment (medical therapy and/or electrical cardioversion). The
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decision to treat a patient for atrial fibrillation was at the discretion of the attending physician. Postoperative in-hospital outcomes other than post-operative AF included death from any cause, stroke, acute renal failure, prolonged intubation, the need of
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reoperation, and postoperative length of stay.
Continuous variables were reported as mean ± standard deviation (SD) and
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compared using a two-tailed Student’s t-test. Categorical variables were reported as proportions and compared using a chi-square or Fisher’s exact test where appropriate. Demographic, clinical, and echocardiographic variables were entered in a multivariable logistic regression model. The Akaike’s Information Criterion (AIC) was used to select the optimal model (lowest AIC) to predict post-operative AF. STATA 12 (Stata-Corp,
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College Station TX, USA) was used to conduct analyses.
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RESULTS
The study population consisted of 768 patients (21.6% female), of which 197
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(25.6%) developed post-operative AF. No patient was lost to follow-up for the primary outcome measure. Patients who developed post-operative AF were older (mean age 71.3 vs. 64.9, p<0.001) and had a significantly higher rate of hypertension, chronic kidney disease, and congestive heart failure. They had slightly more diseased vessels and longer cardiopulmonary bypass times than patients without post-operative AF. There were no other notable differences between groups in baseline characteristics (Table 1).
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The composite outcome of in-hospital mortality and major morbidity was significantly higher in the post-operative AF group (23.9% vs. 10.9%, p<0.001). With
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respect to individual outcomes, mortality, renal failure, and prolonged intubation rates were significantly higher in the post-operative AF group; stroke and reoperation rates
tended to be higher in the post-operative AF group although these outcomes did not reach
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statistical significance. In addition, patients with post-operative AF remained in hospital 5.0 days longer on average.
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Echocardiographic variables for patients with and without post-operative AF are shown in Table 2. With respect to right-sided parameters, patients who developed postoperative AF had larger right atrial size, worse RV-MPI, worse tricuspid regurgitation severity, higher pulmonary artery systolic pressure, and no difference in RV-FAC. With Patients who developed post-operative AF had larger left atrial size, larger LV end-
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diastolic volume and mass, and lower LVEF. Furthermore, they were more likely to have LV diastolic dysfunction and moderate mitral regurgitation. There were no cases of
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severe mitral or tricuspid regurgitation (given the isolated CABG cohort that did not undergo any valve procedures).
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After adjustment for clinical and echocardiographic variables (Table 3), the optimal multivariable model to predict post-operative AF was found to include the following variables: left atrial volume index ≥34 mL/m2 (odd ratio [OR] 1.98, 95% confidence interval [CI] 1.36 to 2.87), abnormal RV-MPI (OR 1.50, 95% CI 1.01 to 2.24), and advancing age (OR 1.05 per year, 95% CI 1.03 to 1.07). Sensitivity analysis adjusting for preoperative medication use did not alter the results.
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DISCUSSION The present study has demonstrated that echocardiographic right ventricular
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performance is predictive of post-operative AF in patients undergoing isolated CABG. In particular, RV-MPI, a composite measure of RV systolic and diastolic function, was
additive to traditional risk factors for predicting post-operative AF (3). AF is one of the
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most commonly occurring arrhythmias after cardiac surgery and is associated with
significant morbidity and mortality (8). In the general population, the pathophysiology of
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AF has been extensively studied yet remains incompletely understood (9). Similarly, in the context of cardiac surgery, numerous risk factors for post-operative AF have been identified, but the pathophysiology of this entity is still to a large extent elusive (10-14). Right-sided cardiac dysfunction has been linked to AF and supraventricular tachycardia in other settings (15-17). Aziz et al. determined the incidence and predictors
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of AF in 904 patients who were admitted with decompensated heart failure (15). AF developed in 21% of these patients, with a higher incidence among those with RV
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dysfunction (39% vs. 12%). RV dysfunction was found to be the strongest independent predictor for the development of AF (OR 4.45, 95% CI 2.98 to 6.65). In a study of
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patients undergoing elective lung resection by Matyal et al., left atrial dilation, abnormal RV-MPI, and advanced age were identified as independent predictors of postoperative supraventricular tachycardia (17). Bouchardy et al. demonstrated that right atrial dilatation had a significant impact on the development of AF in adult patients with congenital heart disease patients who had right-sided cardiac pathologies (16). In their multivariable analysis, age (OR 1.07, 95% CI 1.04 to 1.1), left atrial area (OR 1.15, 95% CI 1.06 to 1.26), and right atrial area (OR 1.08, 95% CI 1.01 to 1.16) were significantly
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associated with AF. Interestingly, in a study of anesthetized lambs undergoing thoracic surgery, structural and functional changes that caused alterations in RV function were
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implicated in the genesis of postoperative supraventricular tachycardia (18). Our study is therefore consistent with the observation that RV function is relevant to the development of AF and extends this finding to the post-operative cardiac surgery patient.
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Most measures of right-sided cardiac function reflect systolic performance. AF is classically seen in the context of atrial dilation and may therefore be associated with
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abnormal diastolic function. In our study, RV FAC, a measure of RV systolic-only function, did not predict post-operative AF. Conversely, RV MPI, which is a measure of systolic and diastolic function, did predict post-operative AF; underscoring the importance of global right heart function as changes in both the atrium and ventricle may contribute to the pathogenesis of AF. It remains to be seen histologically whether
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abnormalities in RV-MPI are associated with pro-arrhythmic changes in the anatomic structure of the right atrium.
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A number of pathophysiological mechanisms may be postulated for AF emanating from the right heart in post-operative patients. Firstly, C-reactive protein, a
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marker of chronic inflammation, has been implicated as a risk factor for post-operative AF in both on-pump and off-pump bypass surgery (19). Similarly, C-reactive protein, IL6, and TNF-α have been implicated as risk factors for abnormal RV-MPI (20). This shared association may reflect an epiphenomenon rather than a causal link. Secondly, RV dysfunction may lead to circulatory failure, peri-operative fluid overload, myocardial ischemia, hypoxemia, and increased sympathetic activity after cardiac surgery (21-23). These in turn have been associated with AF (24-26). Thirdly, vasopressors are more often
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required postoperatively in patients with RV dysfunction (27). High dose inotropic support was reported as an independent predictor of post-operative AF following elective
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CABG (24). Finally, RV dysfunction may lead to right atrial dilation and remodeling which may alter atrial refractoriness and conduction and increase susceptibility to postoperative AF (9, 28).
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Our study has several potential limitations. First, since it is a retrospective study, general reservations pertaining to potential confounders and biases should be
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acknowledged. Second, we may have not have captured episodes of post-operative AF since systematic continuous telemetry was limited to the first 72-96 hours after surgery and not throughout the entire hospitalization. However, it is unlikely that this would have a major impact on our analysis since the vast majority of post-operative AF episodes are known to occur during the first 48-72 hours after surgery (11, 29-30). Third, we did not
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have access to postoperative medication usage within our data sources, and we could not ascertain the protective/negative effects of antiarrhythmic drugs. Finally, we have
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confined our analysis to patients undergoing isolated CABG which limits a wider
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generalizability of the findings to patients undergoing other types of cardiac surgery.
ACKNOWLEDGMENTS We would like to thank Marcia Leavitt, David Crowell, and Karen Lynch for their
invaluable help in obtaining clinical and echocardiographic data for this study. We would also like to thank all of the cardiac sonographers at the Massachusetts General Hospital and Jewish General Hospital for their excellence in acquiring the echocardiographic images that made this study possible.
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48:779-786.
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FIGURE LEGEND
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Figure 1: Flow Diagram
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Table 1: Baseline Characteristics
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P-value
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Age (years) Female Body mass index (kg/m2) Obesity Hypertension Dyslipidemia Diabetes mellitus Chronic kidney disease Preoperative creatinine (mg/dL) Preoperative creatinine clearance Chronic lung disease Peripheral arterial disease Prior cerebrovascular disease Prior stroke Myocardial infarction Urgent/Emergent operative status Heart failure within 2 weeks Number of diseased vessels Cardiopulmonary bypass time Preoperative medication use ACE inhibitors Beta-blockers Statin Inotropes In-hospital outcomes Mortality or major morbidity Mortality Stroke Renal failure Prolonged intubation >24 hours Need for reoperation Postoperative length of stay (days)
Post Operative Atrial Fibrillation No Yes (N=571) (N=197) 64.9 ± 11.0 71.3 ± 9.9 125 (21.9%) 41 (20.8%) 28.5 ± 4.8 28.5 ± 5.1 185 (32.4%) 65 (33.0%) 443 (77.6%) 172 (87.3%) 281 (49.2%) 88 (44.7%) 215 (37.7%) 71 (36.0%) 169 (29.6%) 93 (47.2%) 1.22 ± 0.73 1.26 ± 0.44 80.0 ± 32.9 69.5 ± 34.7 55 (9.6%) 19 (9.6%) 83 (14.6%) 35 (17.8%) 86 (15.1%) 39 (19.9%) 48 (8.4%) 13 (6.6%) 236 (41.4%) 82 (41.6%) 485 (84.9%) 168 (85.3%) 129 (22.8%) 59 (30.6%) 3.5 ± 0.6 3.6 ± 0.6 121.1 ± 38.7 135.7 ± 52.4
M AN U
Variable
<0.001 0.75 1.0 0.88 <0.01 0.27 0.69 <0.001 0.47 <0.001 1.0 0.28 0.12 0.42 0.94 0.91 0.04 0.04 <0.001
156 (35.5%) 400 (91.1%) 334 (76.1%) 8 (1.4%)
46 (28.8%) 150 (93.4%) 128 (80.0%) 6 (3.0%)
0.23 0.49 0.58 0.32
62 (10.9%) 3 (0.5%) 4 (0.7%) 7 (1.2%) 39 (6.8%) 28 (4.9%) 7.5 ± 4.5
47 (23.9%) 5 (2.5%) 5 (2.5%) 17 (8.6%) 34 (17.3%) 17 (8.6%) 12.5 ± 10.4
<0.001 0.03 0.053 <0.001 <0.001 0.055 <0.001
Definitions: Obesity, body mass index >=30; Hypertension, diagnosis based on documented history of hypertension treated with medication or documented blood pressure >140 mmHg systolic or >90 mmHg diastolic on at least 2 occasions; Dyslipidemia, diagnosis based on total cholesterol >200 mg/dl, low-density lipoprotein >=130 mg/dl, or high-density lipoprotein <40 mg/dl in men or <50 mg/dl in women; Chronic kidney disease, estimated creatinine clearance <60 (ml/min).
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Table 2: Echocardiographic Parameters
TE D
EP AC C
P-value
RI PT
234 (41.2%) 195 (34.3%) 77 (13.6%) 37 (6.5%) 25 (4.4%) 90.2 ± 24.2 31 (5.4%) 7.1 ± 1.9 7.9 ± 2.1 50.6 ± 8.7 0.32 ± 0.14 35.4 ± 10.2 12 (2.1%)
M AN U
Left atrium volume index (mL/m2) Left ventricular end-diastolic volume index (mL/m2) Left ventricular ejection fraction (%) Left ventricular diastolic function Normal Impaired Pseudonormal Restrictive N/A Left ventricular mass index (g/m2) Moderate/severe mitral regurgitation Right atrial area index (cm2/m2) Right ventricular end-diastolic area index (cm2/m2) Right ventricular fractional area change (%) Right ventricular myocardial performance index Pulmonary artery systolic pressure (mmHg) Moderate/severe tricuspid regurgitation
65 (33.0%) 66 (33.5%) 33 (16.8%) 27 (13.7%) 6 (3.1%) 94.8 ± 23.7 19 (9.6%) 7.6 ± 1.9 8.2 ± 2.3 49.5 ± 10.2 0.37 ± 0.16 39.4 ± 12.3 10 (5.1%)
SC
Variable
Post Operative Atrial Fibrillation No Yes (N=571) (N=197) 28.0 ± 11.4 32.0 ± 11.5 49.2 ± 18.2 55.7 ± 21.1 56.1 ± 12.9 53.7 ± 13.4
<0.001 <0.001 0.03
<0.05 0.87 0.26 <0.01 0.41 0.02 0.04 <0.01 0.09 0.14 <0.001 <0.001 0.03
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Table 3: Optimal Model to Predict Postoperative Atrial Fibrillation Adjusted
95% CI
1.98
Right ventricular myocardial performance index ≥0.4
1.50
Age, per year
1.05
SC
Left atrium volume index ≥34 mL/m2
RI PT
Odds Ratio 1.36 to 2.87
1.01 to 2.24
1.03 to 1.07
AC C
EP
TE D
M AN U
The following variables were entered in the multivariable regression model: age, sex, body mass index, hypertension, chronic kidney disease, chronic lung disease, prior cardiac surgery, left atrial volume index, LV enddiastolic volume index, LV ejection fraction, LV hypertrophy, LV diastolic function, right atrial area, RV end-diastolic area, RV fractional area change, RV myocardial performance index, pulmonary arterial systolic pressure, mitral regurgitation, tricuspid regurgitation.
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Figure 1: Study Flow Chart
RI PT
1386 patients underwent isolated CABG at the two sites
SC
532 did not have a preoperative echocardiogram available
M AN U
854 patients were eligible
TE D
86 had preoperative atrial fibrillation
AC C
EP
768 patients were included