Weighing the evidence for weight loss as a therapeutic strategy for atrial fibrillation

KEYWORDS:

• Obesity
• atrial fibrillation
• arrhythmia
• weight loss
• lifestyle
• exercise

Atrial fibrillation (AF) is increasing in prevalence with the aging population and its burden on the health-care system is substantial. Analyses of three federally funded databases in the US estimated that the total cost of treating AF was $6.7 billion in 2001 alone [1]. In parallel, obesity is considered an epidemic of the modern era and is associated with serious comorbidities and increased mortality. A US study found that, in 2011–2012, 35% of adults over age 20 were considered obese [2]. Obesity and AF often coexist. In recent years, it has become clearer that the two entities are not independent of one another, with obesity emerging as a modifiable risk factor for AF [3]. Despite what has been termed an ‘obesity paradox’, with higher body mass index (BMI) associated with decreased mortality in a few observational analyses [4], numerous studies have quantified the impact of healthy lifestyle modifications on obesity and cardiovascular outcomes. Herein, we critically review the evidence suggesting that weight loss can be an effective treatment strategy for secondary prevention of AF.

Obese individuals have a high prevalence of concomitant comorbidities such as sleep apnea, hypertension, diabetes, and dyslipidemia, all of which have been associated with AF. In addition to these shared comorbidities, obesity can itself predispose to AF. Adipocytes have well established proinflammatory and profibrotic properties [5]. Pericardial adipose tissue can have paracrine effects on adjacent myocardium, resulting in cardiac chamber remodeling, fibrosis, and altered electrical conduction [6]. Moreover, hemodynamic alterations associated with obesity, including increased blood volume, cardiac output, and filling pressures can further contribute to adverse cardiac remodeling that leads to diastolic dysfunction. Atrial enlargement and fibrosis may ensue, accompanied by electrical and structural remodeling. Upon reaching a critical mass, the remodeled left atrium becomes more susceptible to initiating and sustaining AF. This is evidenced by obese individuals having increased heterogeneity in atrial refractoriness [7] and enhanced sympathetic cardiac innervation, both of which render the atrial tissue more vulnerable to AF [8–10].

A few epidemiological studies, including The Danish Diet, Cancer and Health study, have suggested an association between obesity and AF [3]. More recently, an inverse correlation between fitness level and incident AF was described in a cohort of 2014 men followed for 35 years [11]. A superior age-adjusted fitness level was associated with a 23% lower risk of developing AF. Although causality cannot be inferred from such observational data, these findings fueled the hypothesis that weight loss could be exploited as an AF management strategy. Several authors have since studied the impact of weight loss on AF and have explored a potential dose–response relationship, sustainability of weight loss effects, and consequences of weight fluctuations.

In the LEGACY prospective cohort study, the long-term impact of weight loss and weight fluctuation was assessed in 355 obese individuals (BMI ≥ 27 kg/m²) with AF [12]. Multidisciplinary goal-directed weight loss tactics included face-to-face counseling, frequent follow-ups, a low-calorie diet, and behavior modification strategies. Participants were required to keep records of every meal and all physical activities. Arrhythmia recurrences were determined by 7-day Holter monitoring. A dose–response effect was established, with arrhythmia free survival rates of 40% with ≤3% weight loss, 66% with 3–10% weight loss, and 86% with ≥10% weight loss. Symptoms improved to a greater extent in patients with a weight loss ≥10%, as assessed by the AF Severity Scale. Echocardiographic parameters also significantly improved in the group that lost ≥10% of their body weight. However, beneficial effects of weight loss were partially offset by weight fluctuations >5%.

In the CARDIO-FIT study, the same group of investigators evaluated the effect of improved cardiorespiratory fitness on AF outcomes in 308 obese individuals [13]. Improved cardiorespiratory fitness was assessed by changes in peak metabolic equivalents (METs). Exercise testing was performed with a Bruce protocol at baseline and following risk factor management, including a tailored exercise program. Cardiorespiratory fitness had an additive effect on weight loss in reducing arrhythmia recurrences. An arrhythmia-free survival rate of 94% was observed in patients with weight loss ≥10% combined with a ≥2-MET improvement on exercise testing. Limited data also suggest that aggressive lifestyle modifications could be combined with catheter ablation in improving AF outcomes. In the ARREST-AF cohort study of 149 obese individuals with AF ablation, the 61 patients who followed a lifestyle modification program, including weight loss, glycemic control, and smoking cessation, had a significantly lower rate of recurrent AF compared to controls (10% vs. 33%) [14].

Complementing these observational studies, a clinical trial was conducted on 150 overweight or obese individuals with symptomatic AF randomized to weight management (intervention group) or general lifestyle advice (control group) [15]. The intervention arm consisted of a very low calorie diet with meal replacement and an intensive written exercise plan. After a median follow-up of 15 months, the intervention group experienced a greater reduction in weight (14 vs. 4 kg), with a BMI that decreased from 32 to 27 kg/m². Weight loss resulted in a significantly lower AF symptom burden score (12 vs. 3), symptom severity score (8 vs. 2), and number of AF episodes on 7-day Holter monitoring (2.5 vs. 0). In addition, interventricular septal thickness and left atrial volume decreased significantly. Further supporting biological plausibility, a cardiac magnetic resonance imaging substudy of 69 patients noted a reduction in pericardial adipose tissue and myocardial mass in the intervention group [6].

Specific studies have also addressed the association between obesity and AF in patients with diabetes. In an incident cohort of 7169 patients with type 2 diabetes, BMI > 30 kg/m² was associated with a threefold higher risk of developing AF over a median follow-up of 4.6 years [16]. Subjects who gained weight had a 1.5-fold increase in new-onset AF. The Look AHEAD trial randomized 5067 overweight or obese individuals with type 2 diabetes and no known AF to an intensive lifestyle intervention with caloric reduction and increased physical activity versus diabetes support and education [17]. A nonsignificant 30% reduction in incident AF between highest versus lowest quartiles for weight loss (hazard ratio 0.70, 95% confidence interval [0.41–1.18]) suggests that the trial may have been underpowered due to a relatively low event rate.

It is difficult, if not impossible, to isolate the effect of obesity on AF outcomes given the complex interactions between obesity, its associated comorbidities, and their cardiovascular effects. However, it can be argued that this is a moot point if obesity causes comorbidities that in turn beget AF. In such a causal chain, obesity-related comorbidities are so-called intermediate variables, not confounders, in the association linking obesity to AF. The totality of evidence, including support for pathophysiologically plausible mechanisms, reproducibility, dose–response effects, and impact of weight reduction interventions on outcomes, suggests that obesity is not merely an ‘innocent bystander’. Rather, it appears to be implicated in a causal web as a modifiable risk factor for AF. Importantly, proof of concept has been demonstrated by weight reduction interventions that decrease AF recurrence in a clinically relevant fashion. Moreover, these strategies are an integral component of a healthy lifestyle and impart numerous other benefits, including on diabetes, hypertension, lipids, and sleep apnea control.

There are, however, numerous challenges to translating these results to clinical practice. Rigorous multidisciplinary lifestyle intervention programs are resource intensive and may involve the expertise of nutritionists, physiotherapists or kinesiotherapists, nurses, physicians, and psychotherapists. This type of infrastructure may not be readily available to a large proportion of patients who stand to benefit. Cost-effectiveness analyses of weight loss programs have yielded variable results [18]. While lower cost strategies have been explored, such as social media or smart phone applications, in-person support appears essential to maximizing outcomes [19]. Cost-effectiveness is highly dependent on treatment efficacy, which in turn is dependent on patient motivation. By virtue of the Hawthorne effect, subjects under investigation, particularly those who voluntarily pursue demanding programs, are likely to outperform patients in the real-world setting.

Methodological limitations to the literature on weight loss and AF include relatively brief monitoring periods for arrhythmia detection, with potential underestimation of recurrence rates, especially considering the high prevalence of asymptomatic episodes. Recommendations for assessing outcomes in paroxysmal AF trials include a 12-lead electrocardiogram at each follow-up visit, 24-h Holter monitoring at the end of follow-up, and event monitors with regular recordings over several months, including during symptoms [20]. In addition, results of cohort studies based on a limited number of motivated individuals may be difficult to generalize to the wider population of overweight and obese individuals with AF. There is, therefore, the potential for larger cohort studies with more intense monitoring and real-world studies to further contribute to the growing pool of knowledge regarding the impact of weight loss on AF.

In our opinion, the literature is sufficiently solid to propose a Class IIA, Level B recommendation for weight loss in overweight and obese individuals with non-permanent AF as an essential component of a rhythm control strategy. This recommendation is based on moderate quality evidence from well-designed and well-executed observational studies and an adequately powered randomized clinical trial. The cardiology community is challenged to explore opportunities and overcome obstacles to the widespread implementation of multidisciplinary lifestyle modification programs in order to improve outcomes in the growing population with AF.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.