International Journal of Cardiology 176 (2014) 1039–1041

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Letter to the Editor

Obesity and new-onset atrial fibrillation in acute myocardial infarction: a gender specific risk factor☆ Charles Guenancia a,b, Karim Stamboul a,b, Fabien Garnier a, Jean Claude Beer a, Claude Touzery a, Luc Lorgis a,b, Yves Cottin a,b, Marianne Zeller b,⁎ a b

Cardiology Department, University Hospital, Dijon, France Laboratory of Cardiometabolic Physiopathology and Pharmacology, UMR INSERM U866, University of Burgundy, Dijon, France

a r t i c l e

i n f o

Article history: Received 2 June 2014 Accepted 26 July 2014 Available online 12 August 2014 Keywords: Atrial fibrillation Acute myocardial infarction Obesity CRP Gender

In spite of the widespread use of contemporary therapies, new-onset atrial fibrillation (AF) in acute myocardial infarction (AMI) remains common, ranging from 2% to N20% [1] and is associated with considerable worse prognosis including all-cause mortality [1,2]. The identification of risk factors predisposing to AF in AMI is therefore an important goal. Several mechanisms can predispose to AF by creating either a substrate or a trigger for this arrhythmia. Older patients and those with heart failure, higher heart rates on admission, atrial enlargement and LV dysfunction are more prone to develop AF in AMI. Moreover, conditions associated with elevated levels of inflammation such as metabolic risk factors, may favor the development of such arrhythmias, In the community, obesity is an important, potentially modifiable risk factor for AF for both genders [3]. Obesity causes atrial structural remodeling as well as left ventricular diastolic dysfunction that induces acute left atrial dilation and stretch on volume loading [4]. Underlying mechanisms involve modulation of cardiac electrophysiology by epicardial adipocytes through increased inflammation, mechano-electrical regulation and direct adipocyte–myocytes interactions [5]. However,

☆ The authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: Laboratory of Cardiometabolic Physiopathology and Pharmacology, INSERM U866, UFR Sciences de Santé, 7 Bd Jeanne d'Arc, 21000 Dijon, France. Tel.: +33 380293536; fax: +33 3293879. E-mail address: [email protected] (M. Zeller).

http://dx.doi.org/10.1016/j.ijcard.2014.07.291 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.

in the setting of AMI, no study specifically addressed obesity as a predictor of new-onset AF. In patients with AMI, we aimed to examine the association between obesity and the risk of developing new-onset AF, with an echocardiographic assessment of LA dimensions. All the consecutive patients admitted for an AMI from 1st January 2012 to 31st December 2013 at the Coronary Care Unit (CCU) of Dijon University Hospital, were included, with the following criteria: 1) age ≥ 18 years, and 2) left atrial (LA) echocardiographic dimensions. Patients with a history of AF or atrial flutter were excluded. 178 patients were excluded from the analysis for missing data. AMI was defined according to current definition [6]. Obesity was defined according to WHO criteria as a BMI ≥30 kg/m2. AF was diagnosed on a 12-lead electrocardiogram or was seen for N 30 s on a rhythm strip [7]. AF was considered either at AMI presentation or any time during hospital stay. Left ventricular ejection fraction (LVEF) and LA dimensions were assessed by echocardiography on admission. Severe heart failure on admission was defined by Killip Class N 2. Blood samples were drawn on admission. Creatinine clearance was estimated on the Cockcroft formulae. The independent ethics committee of the University Hospital of Dijon approved the study protocol and written informed consent was obtained from the patient or his/her legal representative. Continuous data were expressed as medians (25th percentile–75th percentile) and dichotomous data as numbers (percentages). For continuous variables, normality was tested by the Shapiro–Wilk test. Mann–Whitney rank sum test or Student's t test was used for continuous parameters and χ2-analysis for categorical variables with Yates correction, when appropriate. Factors associated with the risk of developing AF were studied by backward logistic regression analysis. Variables entered into the multivariate model were chosen according to their univariate relationship (i.e. age, hypertension, obesity, CV history, LVEF b 40%, left atrial indexed volume, CRP N10 mg/l), with inclusion and exclusion cut-off at 5%. Given the major differences in the determinants of AF according to gender, we performed stratified analyses by gender. All the tests were two-sided, and a p value less than 0.05 was considered significant. All analyses were done using SPSS 20.0 (SPSS, Inc., Chicago, IL, USA). Among the 1123 patients included, 91 (8%) patients developed newonset AF during their hospital stay. Patients were dichotomized according to AF development. Baseline characteristics are shown in Table 1. When compared with patients without AF, patients with new-onset

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C. Guenancia et al. / International Journal of Cardiology 176 (2014) 1039–1041

Table 1 Baseline characteristics (n (%), or median (interquartile range)). AF (n = 91)

SR (n = 1032)

p

80 (70–86) 35 (39) 66 (73) 11 (12) 12 (13) 27 (23–30) 30 (33) 50 (55)

64 (53–77) 309 (30) 560 (54) 160 (16) 361 (35) 27 (24–29) 244 (24) 474 (46)

b0.001 0.091 b0.001 0.39 b0.001 0.93 0.047 0.098

CV history Stroke CAD Chronic renal failure

10 (11) 27 (30) 9 (10)

55 (5) 002 (20) 46 (5)

0.027 0.022 0.021

Chronic treatments Beta blocker Diuretic Statin ACE inhibitor

36 (40) 35 (39) 40 (44) 24 (26)

281 (27) 226 (22) 312 (30) 185 (18)

0.012 b0.001 0.007 0.047

Risk factors Age, years Female sex Hypertension Diabetes Smoking BMI, kg/m2 Obesity (BMI ≥30 kg/m2) Hypercholesterolemia

Clinical data STEMI Anterior wall location Severe heart failure GRACE score PCI

41 (45) 33 (36) 36 (40) 190 (157–210) 48 (53)

484 (47) 355 (34) 92 (9) 136 (116–163) 725 (70)

0.74 0.72 b0.001 b0.001 0.001

Echocardiographical data LVEF (%) LA diameter (indexed) mm/m2 LA surface (indexed) cm2/m2 LA volume (indexed) ml/m2

45 (39–60) 2.4 (2.1–2.8) 10.9 (9.4–12.9) 32.2 (24.9–44.7)

55 (45–60) 2.1 (1.8–2.5) 9.4 (7.8–11.2) 25.1 (18.8–34.1)

b0.001 b0.001 b0.001 b0.001

450 (124–2117) 83 (57–110) 6.8 (5.7–8.8) 291 (28)

b0.001 b0.001 b0.001 b0.001

Biological data NT-pro BNP, pg/ml Creatinine clearance, ml/min Glucose, mmol/l CRP N10 mg/l

3484 (1400–21,154) 52 (37–75) 8.2 (6.5–10.6) 47 (52)

ACE: angiotensin conversion enzyme; AF: atrial fibrillation; BMI: body mass index; CAD: coronary artery disease; CRP: C reactive protein; CV: cardiovascular; GRACE: global registry of acute coronary events; LA: left atrial; LVEF: left ventricular ejection fraction; NT Pro-BNP: N terminal pro-brain natriuretic peptide; PCI = percutaneous coronary intervention; SR: sinus rhythm; and STEMI: ST elevation myocardial infarction.

AF were markedly older, more often hypertensive, or with cardiovascular history (stroke, coronary artery disease, renal failure). Patients who developed AF were more often obese (33% vs 24, p = 0.047). Also, they had lower LVEF, more often severe heart failure on admission and increased left atrial dimensions (indexed diameters, surfaces and volumes) than patients without AF. In obese patients, LA indexed

volumes were higher than in patients with lower BMI (27.5 (20.5– 34.5) vs 24.3 (18.4–33.8), ml/m2, p = 0.008). AF patients had markedly higher CRP, NT-pro BNP, and glucose levels and lower creatinine clearance. As expected, AF patients had dramatically more hospital cardiovascular events, with a respectively 4 and 6 fold increase in death or cardiogenic shock (Fig. 1.). After multivariate analysis, clinical, echocardiographic and biological factors were independently associated with the occurrence of newonset AF: age (OR (95% CI): 1.06 (1.04–1.09); p b 0.001), obesity (OR (95% CI): 2.28 (1.33–3.91); p = 0.003), LA indexed volume (OR (95% CI): 1.02 (1.01–1.04); p = 0.014), LVEF b 40% (OR (95% CI): 2.03 (1.14–3.62); p = 0.017) and CRP N 10 mg/l (OR (95% CI): 1.67 (1.01– 2.75); p = 0.046). In stratified analysis we found marked differences in risk factors of AF by gender. In women, only age (OR (95% CI): 1.06 (1.02–1.10); p = 0.003) and LVEF b 40% on admission (OR (95% CI): 2.69 (1.11– 6.50); p = 0.03) were independently associated with AF. In contrast, in men, age (OR (95% CI): 1.07 (1.04–1.10); p b 0.001), CRP N10 mg/l (OR (95% CI): 2.80 (1.49–5.26); p = 0.001), LA indexed volume (OR (95% CI): 1.03 (1.01–1.05); p = 0.011) and obesity (OR (95% CI): 2.51 (1.26–4.99); p = 0.009) were independent predictors of AF. There was a strong interaction of obesity with CRP to predict AF in men, suggesting that part of the excess risk of AF in obese patients is mediated through increased inflammation, The present study describes for the first time that except for age, the determinants of new onset AF were markedly gender-specific and we showed a strong men-specific association between obesity- and obesity-related substrate- and AF risk in AMI. Obese men have higher sympathetic neural activity than obese women [8]. Moreover, there is consistent data to suggest males have higher sympathetic cardiac autonomic activity (SAA). Since SAA dysfunction plays a key role in the onset of AF during AMI [9], our findings may be at least partly explained by stronger autonomic system dysfunction in men, probably through different pattern of fat distribution between the genders [9]. In obesity-induced AF, the involvement of adipokines on LA electrophysiological and morphological remodeling has been suggested [5]. Therefore, in our findings, systemic inflammation, as reflected by increased CRP levels, may be considered as a substrate for the development of AF in men through LA fibrosis and enlargement. Congestive heart failure produces major atrial structural remodeling and was the context in which the important contribution of structural remodeling to AF pathophysiology was first identified [10]. In women, an acute increase in cardiac filling pressure, as assessed by Killip Class N2 and LVEF impairment, is the main trigger for onset of AF after AMI. Further experimental studies are warranted to elucidate the sex-specific underlying mechanisms leading to the development of AF in AMI. Funding This work was supported by the University Hospital of Dijon, Association de Cardiologie de Bourgogne, and by grants from the Agence Régionale de Santé (ARS) de Bourgogne, Conseil Régional de Bourgogne, Fédération Française de Cardiologie (FFC) and Société Française de Cardiologie (SFC). Conflict of interest No financial relationship to disclose. Acknowledgments

Fig. 1. Major hospital events. ***p b 0.001.

We wish to thank Florence Bichat and Aline Chagnon for the research assistance and Philip Bastable for the English assistance.

C. Guenancia et al. / International Journal of Cardiology 176 (2014) 1039–1041

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Obesity and new-onset atrial fibrillation in acute myocardial infarction: a gender specific risk factor.

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