The American Journal of Medicine
Volume 123, Issue 7 , Pages 646-651, July 2010

Influence of Obesity on Outcomes in Atrial Fibrillation: Yet Another Obesity Paradox

Part of the study results were presented as a poster at the 30th Annual Scientific Sessions of the Heart Rhythm Society held in Boston, MA, May 2009.

  • Apurva O. Badheka, MD

      Affiliations

    • Department of Internal Medicine, Wayne State University, Harper University Hospital, Detroit, Mich
    • ,
  • Ankit Rathod, MD

      Affiliations

    • Department of Internal Medicine, Wayne State University, Harper University Hospital, Detroit, Mich
    • ,
  • Mohammad A. Kizilbash, MD

      Affiliations

    • Division of Cardiology/Electrophysiology, Wayne State University, Harper University Hospital, Detroit, Mich
    • ,
  • Neha Garg, MD

      Affiliations

    • Department of Internal Medicine, Wayne State University, Harper University Hospital, Detroit, Mich
    • ,
  • Tamam Mohamad, MD

      Affiliations

    • Division of Cardiology/Electrophysiology, Wayne State University, Harper University Hospital, Detroit, Mich
    • ,
  • Luis Afonso, MD

      Affiliations

    • Department of Internal Medicine, Wayne State University, Harper University Hospital, Detroit, Mich
    • Division of Cardiology/Electrophysiology, Wayne State University, Harper University Hospital, Detroit, Mich
    • ,
  • Sony Jacob, MD

      Affiliations

    • Department of Internal Medicine, Wayne State University, Harper University Hospital, Detroit, Mich
    • Division of Cardiology/Electrophysiology, Wayne State University, Harper University Hospital, Detroit, Mich
    • Corresponding Author InformationRequests for reprints should be addressed to Sony Jacob, MD, 8 Webber South, Harper University Hospital, Division of Cardiology, Wayne State University, 3990 John R, Detroit, MI 48201

Article Outline

Abstract 

Background

Obese patients have favorable outcomes in congestive heart failure, hypertension, peripheral vascular disease, and coronary artery disease. Obesity also has been linked with increased incidence of atrial fibrillation, but its influence on outcomes in atrial fibrillation patients has not been investigated. The objective of this research is to investigate the effect of obesity on outcomes in atrial fibrillation.

Methods

The Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) study was one of the largest multicenter trials of atrial fibrillation, with 4060 patients. Subjects were randomized to rate versus rhythm-control strategy. We performed a post hoc analysis of the National Heart, Lung and Blood Institute limited access dataset of atrial fibrillation patients who had body mass index (BMI) data available in the AFFIRM study. BMI data were not available on 1542 patients. Patients with BMI ≥18.5 were split into normal (18.5-25), overweight (25-30), and obese (>30) categories as per BMI (kg/m2). Multivariate Cox proportional hazards regression was used on the eligible 2492 patients. End points were all-cause mortality and cardiovascular mortality.

Results

Over three fourths of all patients in our cohort were overweight or obese. There were 304 deaths (103 among normal weight, 108 among overweight, and 93 among obese) and 148 cardiovascular deaths (54 among normal weight, 41 among overweight, and 53 among obese) over a mean period of 3 years of patient follow-up. On multivariate analysis, overweight (hazard ratio [HR] 0.64; 95% confidence interval [CI], 0.48-0.84; P=.001) and obese (HR 0.80; 95% CI, 0.68-0.93; P=.005) categories were associated with lower all-cause mortality as compared with normal weight. Overweight (HR 0.40; 95% CI, 0.26-0.60; P <.001) and obese patients (HR 0.77; 95% CI, 0.62-0.95; P=.01) also had lower cardiovascular mortality as compared with the normal weight patients.

Conclusions

Although in prior studies, obesity has been associated with increased risk of atrial fibrillation, an obesity paradox exists for outcomes in atrial fibrillation. Obese patients with atrial fibrillation appear to have better long-term outcomes than nonobese patients.

Keywords: Atrial fibrillation, Obesity, Reverse epidemiology

 

Atrial fibrillation is the most common sustained arrhythmia in the US,1 and it is expected to affect more than 12.1 million people by 2050.2 Atrial fibrillation has been associated with increased morbidity and mortality.3, 4 Likewise, obesity, too, has become a major health problem in the US, with more than 70% of adults classified as overweight or obese.5 Obesity has been associated with increased cardiovascular risk6 and could be responsible for almost 60% of the increase in atrial fibrillation incidence.2 These data indicate that both obesity and atrial fibrillation are contemporary interlinked epidemics and pose a large public health burden in the future.

Clinical Significance

 


•Obese patients may be more prone to develop atrial fibrillation but may have more favorable long-term outcomes.

•Pathophysiologic changes in obese patients with atrial fibrillation may be different from lean patients.

•Utility of weight loss in atrial fibrillation patients is unknown.

Prior studies have examined the relationship between obesity and atrial fibrillation in both population-based and post-cardiac-surgery cohorts.7, 8, 9, 10 Obese patients have a 1.5-times higher risk of developing atrial fibrillation as compared with normal weight individuals when body mass index (BMI) is considered as a categorical variable. Also, when BMI is investigated as a continuous variable, each unit increase in BMI has been associated with 4% increase in new-onset atrial fibrillation.7, 10 Although the precise mechanism for this association is not well understood, changes in atrial and ventricular structure, diastolic function, autonomic function, and increased total blood volume might play a role.11, 12, 13, 14, 15 Furthermore, obesity is associated with left atrial enlargement, which is considered an “intermediate phenotype” for atrial fibrillation.10

Obesity also is implicated as a risk factor for progression of paroxysmal atrial fibrillation to permanent atrial fibrillation,16 and is associated with increased defibrillation thresholds on internal cardioversion.17 Although catheter ablation of atrial fibrillation is successful in obese patients,18 they often require more than twice the effective radiation dose as compared with normal-weight patients.19 Finally, obstructive sleep apnea (and its association with obesity) also has been correlated with increased incidence, prevalence, and recurrence of atrial fibrillation.20, 21, 22, 23

Despite overwhelming data linking obesity and atrial fibrillation, the effect of obesity on outcomes in atrial fibrillation has not been investigated before. We attempted to explore this relationship further in our study. An “obesity paradox” exists in heart failure, coronary artery disease, coronary interventions, peripheral vascular disease, and hypertension.24, 25, 26, 27, 28, 29 Because atrial fibrillation has been linked with both congestive heart failure and hypertension,30 we hypothesized that a similar paradox might exist in atrial fibrillation.

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Methods 

We performed a post hoc analysis of the Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Trial. A public-use limited-access dataset that was devoid of all patient identifiers was obtained from the National Heart, Lung and Blood Institute (NHLBI). None of the authors are affiliated with the NHLBI or were part of the AFFIRM trial. Appropriate Institutional Review Board approval was obtained from Wayne State University.

Details of the AFFIRM study have been described previously.31, 32, 33 The AFFIRM study was one of the largest studies of atrial fibrillation, involving 4060 patients at risk for stroke or death. Patients were randomized to rate control (n=2027) versus rhythm control (n=2033) groups. BMI data were not available on 1542 patients who were excluded. Patients with BMI >18.5 (n=2492) were considered for this study. BMI was analyzed as a continuous, as well as categorical, variable (in terms of normal, overweight, and obese categories). The patients were split into normal (BMI <25), overweight (BMI 25-30), and obese (BMI >30) categories as per World Health Organization criteria (kg/m2).34 Patients with BMI <18.5 (n=26) were not grouped separately due to the small number and were excluded from the primary analyses. End points of the analyses were all-cause mortality and cardiovascular mortality. A composite end point of death, ventricular tachycardia, ventricular fibrillation, cardiac arrest, ischemic stroke, major bleeding, systemic embolism, pulmonary embolism, and myocardial infarction, called “combined end point,” also was analyzed. The combined end point was defined by the NHLBI and the AFFIRM investigators and made available in the public-access dataset. For those who had more than one event in the combined end-point category, only the first recorded event on follow-up was used as the combined end-point event in analyses. Thus, the combined end point was analyzed as a categorical variable, with patients either having a qualifying event or not. Further breakdown into the individual arrhythmic, embolic, and cardiovascular end points was not possible due to the limitations of the dataset.

Mean follow-up period was 3±0.9 years/patient. Each follow-up visit was scheduled every 4 months, and all pertinent clinical data were collected at each visit.

Statistical Analysis 

Continuous variables and categorical variables were compared using analysis of variance and chi-squared tests, respectively. Categorical variables are presented as numbers and percentages, and continuous variables are presented as means±SD (Table 1). Univariate analysis and multivariate regression using Cox proportional hazard model was carried out for all-cause mortality, cardiovascular mortality, and the combined end point. Age, sex, history of congestive heart failure, hypertension, diabetes, coronary artery disease, beta-blocker therapy, and lipid-lowering therapy use at baseline were included in the model along with obesity. Further variable selection in the model was conducted using stepwise selection. P-values <.05 were considered to be statistically significant and used for further stepwise selection. Cox curves adjusted for baseline differences were prepared for combined end point to estimate the cumulative hazard. SAS 9.1 statistical software (SAS Institute Inc., Cary, NC) and SPSS-17 software (SPSS Inc., Chicago, Ill) were used to perform statistical analysis and to plot graphs.

Table 1. Baseline Characteristics Based on BMI
CharacteristicBMI <25 (n = 637)BMI 25-30 (n = 965)BMI ≥30 (n = 890)
Age72.4±770.7±7.5⁎66.4±8.4†,‡
Duration of atrial fibrillation (in years)2.9±1.32.9±1.32.9±1.3
Left atrial diameter (cm)4.1±0.64.3±0.6⁎4.5±0.6†,‡
Treatment arm (rate control)51.3351.7149.44
Sex - male49.6168.39⁎60.34†,‡
Coronary artery disease31.2241.87⁎35.84†
Angina21.0429.43⁎23.71†
Myocardial infarction13.6619.17⁎15.84†
Congestive heart failure19.4719.6924.38‡
Hypertension61.5468.19⁎81.35†,‡
Cardiomyopathy8.796.427.87
PVD6.757.154.94
Diabetes11.4616.89⁎29.66†,‡
Hepatic or renal disease5.735.495.96
Pulmonary disease15.5412.7515.28
Smoker13.5010.2611.69†
Stroke15.3812.75⁎10.45‡
CABG12.0915.13⁎11.01
PCI4.879.53⁎8.99†,‡
Pacemaker7.856.11⁎4.04‡
First episode of atrial fibrillation33.5937.10⁎41.69‡
Antiarrhythmic drug failure14.9312.1214.04
Sinus rhythm at randomization54.0753.7055.15
ACE inhibitor32.6538.45⁎46.18†,‡
Beta-blocker41.7646.7445.39†
Digoxin54.0047.25⁎48.65†,‡
Diuretic36.4238.13⁎51.24‡
Diltiazem43.8947.98⁎53.48‡
Lipid-lowering therapy20.4128.39⁎26.74†,‡
Aspirin28.7331.6128.65
Warfarin87.1387.4686.63
Heparin20.8818.5519.21
INR at baseline2.3±0.72.3±0.72.3±0.7

ACE=angiotensin-converting enzyme; BMI=body mass index; CABG=coronary artery bypass graft; INR=international normalized ratio; PCI=percutaneous coronary intervention; PVD=peripheral vascular disease.

(All values are in n or % except for continuous variables representing mean±SD).

⁎P <.05 for Column II vs Column I.

†P <.05 for Column III vs Column I.

‡P <.05 for Column III vs Column II.

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Results 

There were 637 patients with normal BMI, 965 in the overweight category, and 890 in the obese group. Baseline characteristics of patients in each group are shown in Table 1. Mean age for the entire study population was 69.5±8 years, and 60.71% of the population were males; 16.57% had history of myocardial infarction and 21.31% had history of congestive heart failure. Mean BMI was 29.02±5.9 kg/m2. A total of 304 deaths and 148 cardiovascular deaths occurred over the approximately 3-year/patient follow-up. One hundred three (16.2%) died in the normal BMI group, 108 (11.2%) died in the overweight group, and 93 (10.5%) died in the obese group. Fifty-four (8.5%), 41 (4.3%), and 53 (5.9%) had a cardiac cause of death in the normal BMI, overweight, and obese groups, respectively. Four hundred ninety-four events occurred as combined end point in the study population: 152 (23.8%) events occurred in the normal BMI group, 192 (19.9%) in the overweight group, and 150 (16.8%) in the obese group.

Over 35.7% of all atrial fibrillation patients in our sample were obese, and 74.4% of all atrial fibrillation patients were either overweight or obese. Obese patients were younger and had significantly increased prevalence of comorbidities like hypertension, myocardial infarction, congestive heart failure, diabetes, and coronary artery disease as compared with patients with normal BMI. Percentage of males also was higher in the obese subgroup compared with the normal BMI group. Overweight and obese patients also had enlarged left atrial diameters as compared with normal weight patients. Patients with normal BMI were more likely to be smokers and have suffered a stroke compared with patients in the overweight and obese subgroups. Patients in the overweight and obese groups were more likely to be on lipid-lowering therapy, beta-blocker, and angiotensin-converting enzyme inhibitor drug therapy compared with patients with normal BMI. No significant difference was observed for anticoagulation and aspirin use among the 3 groups (Table 1).

Multivariate analyses for the end points showed that the overweight and obese patients were at significantly less risk of suffering death, cardiovascular death, or the combined end points of the original AFFIRM trial when using normal BMI as the reference (Figure 1). Table 2 shows the final multivariate model of predictors for all-cause mortality based on stepwise selection. On multivariate analysis, overweight (hazard ratio [HR] 0.64; 95% confidence interval [CI], 0.48-0.84; P=.001) and obese (HR 0.80; 95% CI, 0.68-0.93; P=.005) categories were associated with lower all-cause mortality as compared with normal weight. Overweight (HR 0.40; 95% CI, 0.26-0.60; P <.001) and obese patients (HR 0.77; 95% CI, 0.62-0.95; P=.01) also had lower cardiovascular mortality as compared with the normal weight (Figure 2). On including the BMI <18.5 patients in the normal BMI group, the same trend of results was obtained in the categorical analysis. Analysis of BMI as a continuous variable also did not change after including the underweight patients. Figure 3 shows the survival estimates from all-cause mortality for the entire cohort (including BMI <18.5, n=2518) based on their BMI.

Table 2. Final Multivariate Model for All-cause Mortality
VariableHazard Ratio95% CIP Value
BMI (continous distribution)0.950.93-0.98.003
Age1.051.03-1.06.02
Congestive heart failure2.161.71-2.72<.01
Coronary artery disease1.811.44-2.28<.01
Diabetes1.961.53-2.51<.01
Smoking1.721.26-2.37.007
Rhythm control arm1.301.04-1.61.02

BMI=body mass index; CI=confidence interval.

Male sex (P=.73), beta-blocker therapy (P=.08), and hypertension (P=.12) were removed on running stepwise selection.

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Discussion 

In our study, almost three fourths of all atrial fibrillation patients were obese or overweight. We report for the first time a beneficial effect of increasing BMI on outcomes in atrial fibrillation. Because the AFFIRM trial population is considered to be a reasonable representation of the general atrial fibrillation population, our study has significant implications. Similar “obesity paradoxes” have been observed among the elderly and for disorders such as acquired immune deficiency syndrome, chronic obstructive pulmonary disease, advanced cancers, rheumatoid arthritis, and maintenance hemodialysis.35, 36

Obesity predisposes to atrial fibrillation; however, paradoxically, in our study obese patients were found to have better outcomes with atrial fibrillation. This relationship remained unchanged after controlling for heart failure and coronary artery disease status (2 conditions known to be associated with obesity paradox). Because the reasons for the “obesity paradoxes” in cardiovascular outcomes are not entirely clear,27 we can only offer possible (and not conclusive) explanations for our observations.

Possible Explanations for the Obesity Paradox in Atrial Fibrillation 

Inflammation and increased inflammatory markers are believed to be at the core of atrial fibrillation initiation and maintenance.37 Tumor necrosis factor-α has been associated with increased atrial arrhythmogenesis.38, 39 Because adipose tissue produces soluble tumor necrosis factor-α type I and II receptors, this could result in a more favorable anti-arrythmogenic milieu in obese patients with atrial fibrillation.40

Similarly, the renin-angiotensin system has been associated with atrial fibrosis and electrical remodeling in atrial fibrillation.41 Weber et al42 showed that obese patients had lower increases in plasma renin and norepinephrine as compared with similar lean patients during treadmill testing. Hence, obese patients with atrial fibrillation may have diminished stress responses as compared with lean patients, which may improve long-term cardiovascular outcomes.

Atrial natriuretic peptide levels are significantly increased in atrial fibrillation and predict mortality in atrial fibrillation patients with advanced heart failure.43, 44 Obesity is associated with lower atrial natriuretic peptide levels,45 which could serve as a possible protective mechanism in atrial fibrillation patients with elevated BMI.

Another hypothesis, called the “Endotoxin-Lipoprotein hypothesis,” states that obese patients have higher cholesterol and lipoprotein concentrations, which can bind and remove circulating endotoxins, resulting in decreased inflammation.46 The applicability of this hypothesis to atrial fibrillation patients is unclear. A recent paper showed no relation between endotoxins and atrial fibrillation, however, this study was hampered by a healthy cohort (<1% yearly incidence of atrial fibrillation) and lack of follow-up.47

An alternative rationale for the obesity paradox is that, because obese patients have more hypertension than lean patients, they may be candidates for aggressive use of “beneficial medications” such as angiotensin-converting enzyme inhibitors and beta-blockers.48 Increasing prevalence of hypercholesterolemia may lead to atrial fibrillation patients with obesity to be on more lipid-lowering therapy. Both of these relationships are observed in our analysis. It also might be possible that obese patients have other cardiovascular risk factors that cause them to present at a younger age to medical care, which also is supported by our results. All these could possibly result in a selection bias.49

A phenomenon of “cardiac cachexia” has been described leading to a state of under-nutrition, inflammation, and susceptibility to infection.36, 50, 51 Conventional cardiovascular risk factors of obesity and hypercholesterolemia due to supra optimal nutrition are long-term killers, whereas under-nutrition is a short-term killer. Hence, there is a possible temporal discordance bias, with cachectic patients dying earlier and obese patients being affected only in the future.36, 50, 51

Our study is limited by the drawbacks of a retrospective analysis. We did not have BMI information on all patients enrolled in the AFFIRM trial. Data about nutritional intake and caloric intake also were unavailable. Measures of inflammation were not available. Additionally, our analysis was based on the BMI of the patients at time of enrollment and lacks information about follow-up BMI. Our study did not address the influence of weight change on the outcomes.52 Obese patients could have developed atrial fibrillation secondary to their obesity, whereas the leaner patients could have developed atrial fibrillation due to a different pathophysiologic substrate, which made their prognosis worse. Another hypothesis is that high BMI cannot make the distinction between high muscle mass or high fat. It has been suggested that measuring percent body fat rather than BMI may be more appropriate because high BMI from elevated muscle mass may be associated with better outcomes. However, this explanation has been refuted by Lavie et al,52, 53 who found a similar obesity paradox when percent body fat (rather than BMI) was investigated.

In conclusion, our study is the first study to show improved outcomes in atrial fibrillation with increasing BMI. These findings are important, as the AFFIRM study population is a large heterogeneous atrial fibrillation cohort similar to those in the general population.33 However, our study needs to be interpreted as hypothesis-generating in nature. Further studies exploring the possible underlying etiopathogenic mechanisms are warranted.

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Acknowledgment 

The authors would like to thank the National Heart, Lung and Blood Institute (NHLBI), Mr. Sean Coady (NHLBI), and Mr. Kevin Purkiser (NHLBI) for all their help and input.

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 Funding: None.

 Conflict of Interest: None of the authors have any financial disclosure or conflict of interest to report. None of the study authors are associated with the National Heart, Lung and Blood Institute or the Atrial Fibrillation Follow-up Investigation of Rhythm Management trial.

 Authorship: All authors had access to the data and were involved in the conception, data analysis, and writing of the manuscript.

PII: S0002-9343(10)00255-X

doi:10.1016/j.amjmed.2009.11.026

The American Journal of Medicine
Volume 123, Issue 7 , Pages 646-651, July 2010

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