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Relation of Obesity to Recurrence Rate and Burden of Atrial Fibrillation

Published:January 03, 2011DOI:https://doi.org/10.1016/j.amjcard.2010.10.018
      Obesity is associated with new-onset atrial fibrillation (AF). However, the effect of obesity on AF recurrence or burden has not been studied. The aim of this study was to investigate the relation between AF recurrence, AF burden, and body mass index (BMI). A limited-access data set from the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial provided by the National Heart, Lung, and Blood Institute was used. Statistical analysis was done with a generalized linear mixed model. In 2,518 patients who had BMIs recorded, higher BMI was associated with a higher number of cardioversions (odds ratio [OR] 1.017, 95% confidence interval [CI] 1.005 to 1.029 for a BMI increase of 1 kg/m2; OR 1.088, 95% CI 1.024 to 1.155 for a BMI increase of 5 kg/m2; OR 1.183, 95% CI 1.049 to 1.334 for a BMI increase of 10 kg/m2; p = 0.006 for each). Increased BMI was also associated with a higher likelihood of being in AF on follow-up (OR 1.020, 95% CI 1.002 to 1.038 per 1 kg/m2 increased BMI, p = 0.0283; OR 1.104, 95% CI 1.011 to 1.205 per 5 kg/m2 increased BMI, p = 0.0283; OR 1.218, 95% CI 1.021 to 1.452 per 10 kg/m2 increased BMI, p = 0.0283). In a multivariate analysis, left atrial size but not BMI was an independent predictor of AF recurrence and AF burden. Because left atrial size was correlated with BMI, the effect of BMI on AF can be likely explained by greater left atrial size in subjects with higher BMIs. In conclusion, obesity is associated with a higher incidence of recurrence of AF and greater AF burden.
      Obesity is a risk factor for the development of new-onset atrial fibrillation (AF). Multiple studies have documented a strong and independent association between body mass index (BMI) and the incidence of AF.
      • Wang T.J.
      • Parise H.
      • Levy D.
      • D'Agostino Sr, R.B.
      • Wolf P.A.
      • Vasan R.S.
      • Benjamin E.J.
      Obesity and the risk of new-onset atrial fibrillation.
      • Frost L.
      • Hune L.J.
      • Vestergaard P.
      Overweight and obesity as risk factors for atrial fibrillation or flutter: the Danish Diet, Cancer, and Health Study.
      • Dublin S.
      • French B.
      • Glazer N.L.
      • Wiggins K.L.
      • Lumley T.
      • Psaty B.M.
      • Smith N.L.
      • Heckbert S.R.
      Risk of new-onset atrial fibrillation in relation to body mass index.
      • Tedrow U.B.
      • Conen D.
      • Ridker P.M.
      • Cook N.R.
      • Koplan B.A.
      • Manson J.E.
      • Buring J.E.
      • Albert C.M.
      The long- and short-term impact of elevated body mass index on the risk of new atrial fibrillation: the WHS (Women's Health Study).
      In the Framingham Heart Study, obese participants had a 45% to 50% increased risk for incident AF compared to participants with normal BMI, independent of other cardiovascular risk factors.
      • Wang T.J.
      • Parise H.
      • Levy D.
      • D'Agostino Sr, R.B.
      • Wolf P.A.
      • Vasan R.S.
      • Benjamin E.J.
      Obesity and the risk of new-onset atrial fibrillation.
      In a Danish study, overweight subjects were also at increased risk for incident AF.
      • Frost L.
      • Hune L.J.
      • Vestergaard P.
      Overweight and obesity as risk factors for atrial fibrillation or flutter: the Danish Diet, Cancer, and Health Study.
      In addition to increasing the susceptibility of developing AF, a recent longitudinal cohort study over 21 years
      • Tsang T.S.
      • Barnes M.E.
      • Miyasaka Y.
      • Cha S.S.
      • Bailey K.R.
      • Verzosa G.C.
      • Seward J.B.
      • Gersh B.J.
      Obesity as a risk factor for the progression of paroxysmal to permanent atrial fibrillation: a longitudinal cohort study of 21 years.
      suggested that obesity was an independent predictor of progression from paroxysmal to permanent AF. However, the association between obesity and total AF burden or recurrence rate has not been studied.

      Methods

      To evaluate the relation of obesity with recurrence of AF or burden of AF, we used a limited access data set from the Atrial Fibrillation Follow-Up Investigation of Rhythm Management (AFFIRM) trial, provided by the National Heart, Lung, and Blood Institute (Bethesda, Maryland). Detailed selection criteria for the study population, their baseline characteristics, and randomization into rate-control versus rhythm-control arms was previously explained.
      • Wyse D.G.
      • Waldo A.L.
      • DiMarco J.P.
      • Domanski M.J.
      • Rosenberg Y.
      • Schron E.B.
      • Kellen J.C.
      • Greene H.L.
      • Mickel M.C.
      • Dalquist J.E.
      • Corley S.D.
      A comparison of rate control and rhythm control in patients with atrial fibrillation.
      Our main independent variable was BMI. We used BMI (calculated as weight in kilograms divided by height in meters squared) entered in the data set by the AFFIRM investigators as a surrogate measure of obesity. It was analyzed as a continuous and a categorical variable.
      Two outcome measures were AF recurrence and AF burden. We used the number of cardioversions done throughout the follow-up period (electrical as well as pharmacological) as a surrogate marker of AF recurrence, and the number of follow-up visits when patients were in AF as a surrogate marker of AF burden. All the data were analyzed with a generalized linear mixed model using SAS (SAS Institute Inc., Cary, North Carolina). A univariate analysis was done first to identify variables linked to the recurrence rate and total burden of AF. The connection between BMI as our main variable of interest and the 2 outcomes was then examined in detail, for the whole AFFIRM population and for the rate- and rhythm-control arms separately.
      The following variables were also checked for association with AF recurrence rate or AF burden: age, use of angiotensinogen-converting enzyme inhibitors, use of β blockers, systolic blood pressure, history of hypertension, history of coronary artery disease, history of coronary artery bypass surgery, history of congestive heart failure, history of diabetes, history of cardiomyopathy, history of myocardial infarction, New York Heart Association class at baseline, the left ventricular ejection fraction, and left atrial size. Variables found to be significantly associated with the outcomes were then put in a multivariate model. Because left ventricular ejection fractions were missing in >50% of the cases, we calculated fractional shortening on the basis of left ventricular systolic and diastolic dimensions (fractional shortening = [left ventricular diastolic dimension − left ventricular systolic dimension]/left ventricular diastolic dimension) and used it for the final analysis. A p value of <0.05 was considered statistically significant.

      Results

      In the AFFIRM study, 4,060 patients were enrolled at baseline. We excluded 1,542 patients who did not have baseline BMI information. Of the remaining 2,518 patients, 1,255 were assigned to the rate-control arm and 1,263 to the rhythm-control arm; the mean BMIs were 29.0 and 28.8 kg/m2, respectively. These 2,518 patients had 22,753 follow-up visits and a total of 1,094 cardioversions, either pharmacologic or electrical: 888 in the rhythm-control arm and 206 in the rate-control arm.
      In a univariate analysis, BMI, left atrial size, age, and history of hypertension were independently associated with a higher AF recurrence rate (Table 1).
      Table 1Variables linked to number of cardioversions and burden of atrial fibrillation in a univariate analysis
      VariableNumber of CardioversionsNumber of Follow-Up Visits in AF
      OR95% CIp ValueOR95% CIp Value
      BMI1.0161.004–1.0290.00861.010.99–1.020.4233
      Age0.990.981–0.9990.02441.020.82–1.260.857
      Hypertension
      By history.
      1.2361.064–1.500.00750.990.98–1.000.1403
      Left atrial size1.3451.158–1.5610.00011.321.14–1.540.0003
      low asterisk By history.
      In the study population as a whole (n = 2,518), higher BMI was associated with a greater number of cardioversions. The odds ratios (OR) of receiving cardioversion were 1.017 (95% confidence interval [CI] 1.005 to 1.029, p = 0.006) for a BMI increase of 1 kg/m2, 1.088 (95% CI 1.024 to 1.155, p = 0.006) for a BMI increases of 5 kg/m2, and 1.183 (95% CI 1.049 to 1.334, p = 0.006) for a BMI increase of 10 kg/m2.
      In the rhythm-control arm (n = 1,263), in which a higher rate of cardioversions was expected, the ORs for cardioversion were 1.015 (95% CI 1.003 to 1.028), 1.079 (95% CI 1.013 to 1.148), and 1.164 (95% CI 1.027 to 1.319) for BMI increases of 1, 5, and 10 kg/m2, respectively (p = 0.0178 for each). In the rate-control arm, in which there was a lower rate of cardioversions, the association between BMI and number of cardioversions was not significant (Table 2).
      Table 2Effect of body mass index as a continuous variable on number of cardioversions
      BMI Increase (kg/m2)Study ArmCardioversions
      OR95% CIp Value
      1Rate control1.0230.99–1.0580.1788
      Rhythm control1.0151.003–1.0280.0178
      5Rate control1.1210.949–1.3230.1788
      Rhythm control1.0791.013–1.1480.0178
      10Rate control1.2560.901–1.7510.1788
      Rhythm control1.1641.027–1.3190.0178
      When patients were classified into underweight (BMI <18.5 kg/m2), normal weight (BMI 18.5 to 24.9 kg/m2), overweight (BMI 25 to 29.9 kg/m2), and obese (BMI ≥30 kg/m2), obese patients were more likely to undergo cardioversion (OR 1.268, p = 0.0194; Table 3), with normal-weight patients used as a reference. We did not find a significant association between obesity and the number of cardioversions in the rate-control arm. However, in the rhythm-control arm, the OR of requiring cardioversion in obese subjects was 1.291 (p = 0.0173), with normal weight used as a reference.
      Table 3Effect of body mass index as a categorical variable on the number of cardioversions
      Study ArmBMI (kg/m2)Number of CardioversionsOR95% CIp Value
      Total<18.510 (6.2%)1.5180.68–3.3910.3086
      18.5–24.9231 (4.2%)Reference
      25–29.9401 (4.5%)1.0560.863–1.2910.5987
      ≥30452 (5.4%)1.2681.039–1.5480.0194
      Rate control<18.51 (2.1%)1.5110.138–16.5130.7353
      18.5–24.939 (1.5%)Reference
      25–29.987 (1.9%)1.1640.733–1.8490.5194
      ≥3079 (2.0%)1.2360.773–1.9770.3755
      Rhythm control<18.59 (7.8%)1.1760.533–2.5940.6875
      18.5–24.9192 (6.8%)Reference
      25–29.9314 (7.5%)1.1070.892–1.3720.3562
      ≥30373 (8.7%)1.2911.046–1.5930.0173
      During each follow-up visit, the current rhythm was recorded as AF versus no AF (presumed sinus rhythm). Of 22,374 follow-up visits, patients were found to be in AF or atrial flutter on 8,686 visits: 6,289 in the rate-control group and 2,397 in the rhythm-control arm. Using a linear mixed model, the ORs of a patient being in AF or atrial flutter were 1.020 (95% CI 1.002 to 1.038) per 1 kg/m2 BMI increase, 1.104 (95% CI 1.011 to 1.205) per 5 kg/m2 BMI increase, and 1.218 (95% CI 1.021 to 1.452) per 10 kg/m2 BMI increase (p = 0.0283 for each).
      In the rate-control arm, obese (BMI ≥30 kg/m2) patients had an OR of 1.55 (p = 0.0484) of being in AF on a follow-up visit, when normal weight (BMI 18.5 to 24.9 kg/m2) was used as a reference (Table 4). No significant association between BMI and the likelihood of being in AF was found in the rhythm-control arm.
      Table 4Body mass index effect on atrial fibrillation burden
      Study ArmBMI (kg/m2)Number of Visits in AFOR95% CIp Value
      Total<18.530 (19.7%)0.4260.123–1.4730.1776
      18.5–24.91,952 (36.3%)Reference
      25–29.93,451 (39.8%)1.2680.944–1.7040.115
      ≥303,253 (39.8%)1.3330.989–1.7970.0587
      Rate control<18.512 (31.6%)0.390.034–4.540.4521
      18.5–24.91,366 (52.5%)Reference
      25–29.92,594 (57.0%)1.370.896–2.0960.1461
      ≥302,317 (58.9%)1.551.003–2.3950.0484
      p <0.05.
      Rhythm control<18.518 (15.8%)0.8950.267–3.0040.858
      18.5–24.9586 (21.1%)Reference
      25–29.9857 (20.8%)1.0010.705–1.4210.9965
      ≥30936 (22.1%)1.1560.816–1.6370.4155
      low asterisk p <0.05.
      Of the possible confounding variables that could influence AF recurrence rate and AF burden, a history of hypertension, left ventricular fractional shortening, and left atrial size were found to be significantly associated with AF recurrence rate (p = 0.025, p = 0.004, and p <0.001, respectively).
      After adjusting for age, history of hypertension, fractional shortening, and left atrial size, the latter appeared to be the only determinant of both outcomes in a multivariate analysis. At the same time, BMI was correlated significantly with left atrial size (Spearman's correlation coefficient 0.22, p <0.0001).

      Discussion

      In this analysis of a limited-access data set from the AFFIRM trial, we have demonstrated for the first time that obesity is associated with a higher recurrence rate and greater burden of AF compared to nonobese patients. Because in the rate-control arm, the strategy was not to restore sinus rhythm, patients spent more time in AF than patients in the rhythm-control arm. The difference between AF burden in obese versus nonobese patients was significant in the rate-control arm as well as in the whole data set, but not in the rhythm-control arm. In contrast, more cardioversions, pharmacologic or electrical, were performed in the rhythm-control arm. More cardioversions in obese versus nonobese patients were demonstrated in this arm and in the whole data set, but not in the rate-control arm.
      Obesity was first reported as an important, potentially modifiable risk factor for new-onset AF by the Framingham investigators. A 4% increase in AF risk per 1 kg/m2 increase in BMI was observed, with adjusted hazard ratios for AF associated with obesity of 1.52 (95% CI 1.09 to 2.13, p = 0.02) and 1.46 (95% CI 1.03 to 2.07, p = 0.03) for men and women, respectively, compared to subjects with normal BMIs.
      • Wang T.J.
      • Parise H.
      • Levy D.
      • D'Agostino Sr, R.B.
      • Wolf P.A.
      • Vasan R.S.
      • Benjamin E.J.
      Obesity and the risk of new-onset atrial fibrillation.
      Subsequently, it was shown that the association of obesity with sustained AF is stronger than for transitory or intermittent AF. On average, AF risk is 3% higher per unit increase in BMI. The risk is higher by 7% per BMI unit increase for sustained AF, by 4% for intermittent AF, and by 1% for transitory AF. The obesity-AF association appears to be partially mediated by diabetes mellitus but minimally through other cardiovascular risk factors.
      • Dublin S.
      • French B.
      • Glazer N.L.
      • Wiggins K.L.
      • Lumley T.
      • Psaty B.M.
      • Smith N.L.
      • Heckbert S.R.
      Risk of new-onset atrial fibrillation in relation to body mass index.
      In the longitudinal cohort study from Olmsted County, Minnesota, BMI independently predicted progression to permanent AF. Compared to normal BMI, obesity (BMI 30 to 34.9 kg/m2) and severe obesity (BMI ≥35 kg/m2) were associated with increased risk for progression to permanent AF. This relation was not weakened by left atrial volume, which was independent of and incremental to BMI for the prediction of progression to permanent AF.
      • Tsang T.S.
      • Barnes M.E.
      • Miyasaka Y.
      • Cha S.S.
      • Bailey K.R.
      • Verzosa G.C.
      • Seward J.B.
      • Gersh B.J.
      Obesity as a risk factor for the progression of paroxysmal to permanent atrial fibrillation: a longitudinal cohort study of 21 years.
      Similarly, in the Swedish Primary Prevention Study, body surface area at age 20 years (calculated from recalled weight and measured height) was strongly related to subsequent AF (p <0.0001), as were midlife BMI and weight gain from age 20 years to midlife (p <0.0001).
      • Rosengren A.
      • Hauptman P.J.
      • Lappas G.
      • Olsson L.
      • Wilhelmsen L.
      • Swedberg K.
      Big men and atrial fibrillation: effects of body size and weight gain on risk of atrial fibrillation in men.
      A meta-analysis of 16 studies enrolling a total of 123,249 subjects found that obese subjects have an associated 49% increased risk for developing AF compared to nonobese subjects. In postoperative AF, however, BMI did not appear to play an important role
      • Wanahita N.
      • Messerli F.H.
      • Bangalore S.
      • Gami A.S.
      • Somers V.K.
      • Steinberg J.S.
      Atrial fibrillation and obesity—results of a meta-analysis.
      and was even associated with a lower incidence of AF.
      • Banach M.
      • Goch A.
      • Misztal M.
      • Rysz J.
      • Jaszewski R.
      • Goch J.H.
      Predictors of paroxysmal atrial fibrillation in patients undergoing aortic valve replacement.
      In a recently published study by Tedrow et al,
      • Tedrow U.B.
      • Conen D.
      • Ridker P.M.
      • Cook N.R.
      • Koplan B.A.
      • Manson J.E.
      • Buring J.E.
      • Albert C.M.
      The long- and short-term impact of elevated body mass index on the risk of new atrial fibrillation: the WHS (Women's Health Study).
      it was demonstrated for the first time that the risk for incident AF is especially high in subjects who gained weight rapidly. Even more important, they proved that this risk decreases after normalization of BMI. Obesity therefore appears to be a reversible risk factor for AF.
      The association between obesity, left atrial size, and AF is well established.
      • Stritzke J.
      • Markus M.R.
      • Duderstadt S.
      • Lieb W.
      • Luchner A.
      • Doring A.
      • Keil U.
      • Hense H.W.
      • Schunkert H.
      • Investigators M.K.
      The aging process of the heart: obesity is the main risk factor for left atrial enlargement during aging the MONICA/KORA (Monitoring of Trends and Determinations in Cardiovascular Disease/Cooperative Research in the Region of Augsburg) study.
      Obesity is identified as the most important determinant of left atrial enlargement. In our study, left atrial size was independently correlated with BMI. Therefore, obesity may increase the rate of new-onset AF, the recurrence rate, the transition from paroxysmal to permanent AF, and total AF burden, not directly but through increased left atrial size. It is noteworthy that in the study from the Framingham cohort establishing the link between obesity and new-onset AF, after adjustment for left atrial diameter, BMI was no longer associated with AF risk.
      • Wang T.J.
      • Parise H.
      • Levy D.
      • D'Agostino Sr, R.B.
      • Wolf P.A.
      • Vasan R.S.
      • Benjamin E.J.
      Obesity and the risk of new-onset atrial fibrillation.
      The investigators concluded that effect of obesity was mediated by left atrial dilatation.
      In contrast, left atrial remodeling and enlargement is a well-known effect of AF itself, and obesity contributing to AF recurrence and burden and therefore promoting left atrial dilatation is another possible course of the events.
      Two other studies used the same data set to analyze effects of obesity in AF, and both concluded that extra weight is associated with lower cardiovascular mortality.
      • Ardestani A.
      • Hoffman H.J.
      • Cooper H.A.
      Obesity and outcomes among patients with established atrial fibrillation.
      • Badheka A.O.
      • Rathod A.
      • Kizilbash M.A.
      • Garg N.
      • Mohamad T.
      • Afonso L.
      • Jacob S.
      Influence of obesity on outcomes in atrial fibrillation: yet another obesity paradox.
      Neither study, however, addressed the issues of recurrence and burden of AF in obese versus nonobese patients.
      Our findings are in concurrence with other studies investigating the connection between BMI and AF. Although the mechanism of obesity-related increased risk for AF is unclear, a consistent pattern of increased AF incidence, prevalence, recurrence, and overall burden suggests that lifestyle modifications directed toward a healthier weight may reduce AF and all the risks and complications associated with it.
      We analyzed only the data available from the limited-access data set of the AFFIRM trial and did not have access to the complete study data. In addition, this was a retrospective analysis of the main trial; therefore, the results should be interpreted with caution. The number of clinic visits at which patients appeared to be in AF was used as a surrogate of AF burden, and the number of cardioversions as a surrogate of AF recurrence rate. Data for left atrial size were missing in 24% of patients with known BMIs.

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