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Predictors and Modifiable Risk Factors for Atrial Fibrillation
© 2023 HMP Global. All Rights Reserved.
Any views and opinions expressed are those of the author(s) and/or participants and do not necessarily reflect the views, policy, or position of EP Lab Digest or HMP Global, their employees, and affiliates.
EP LAB DIGEST. 2023;23(6):1,8-13.
Atrial fibrillation (AF) is the most common arrhythmia, with approximately more than 33 million cases worldwide.1 The lifetime risks of developing AF are 1 in 4 for women and men aged 40 years and older. This risk substantially increases between the sixth and eighth decade of life.2 With an aging society, enormous morbidity and mortality threats are imposed. Patients with AF have an increased risk of stroke, dementia, heart failure (HF), myocardial infarction, and overall mortality.3 While many studies and recommendations are concentrated on effective pharmacological and procedural therapies for AF, there are suboptimal efforts for AF prevention.4 In fact, more than half of AF burden is potentially preventable through modification of lifestyle risk factors and cardiovascular predictors.5 In this article, we review the modifiable risk factors for AF.
Lifestyle Risk Factors
Obesity
Obesity is defined as a body mass index (BMI) ≥30 kg/m2 and the overweight range is defined as a BMI of 25-30 kg/m2. Obese individuals with no preexisting cardiovascular or endocrine diseases have more than a 2.5-fold increased risk of AF, while overweight individuals are at an 1.4-1.7–fold increased risk.6 One prospective observational study showed a 4% increased risk of AF per one unit increase in BMI greater than 25 kg/m2.7
Genetic variants related to high BMI are associated with AF incidence, suggesting a causal relationship.8 Phenotypically, an increase in body size predisposes an increase in left atrial (LA) size. It also promotes diastolic dysfunction as well as structural remodeling within the aria.9 Furthermore, epicardial and pericardial fat, seen with higher BMI, potentially worsens atrial irritability and inflammation by partially infiltrating the atrial walls.10
This strong correlation inspired many observational studies and randomized control trials (RCT) to test the impact of weight loss on AF incidence and burden, summarized in Table 1. More than 300 patients with AF and BMI >27 kg/m2 underwent weight loss management and were followed for 4 years in the LEGACY prospective observational study.11 Patients with more than 10% weight loss had a 6-fold greater probability of AF-free survival compared to those with moderate (3%-9%) or minimal (<3%) weight loss.11 A further subanalysis of these patients in the REVERSE-AF study showed that 88% of patients with the greatest weight loss reversed from persistent to paroxysmal or no AF.12 Three other RCTs investigated the role of weight management in AF (Table 1). Both the RACE 3 trial13 and the study by Abed et al14 showed significant AF reduction in patients with AF. However, the Look AHEAD trial failed to show a decreased risk of new AF in obese patients receiving intensive lifestyle intervention vs usual care.15 Conversely, in the SOS prospective study, bariatric surgery and resultant 20% weight loss reduced new AF development by almost 30% over a 19-year follow-up period.16
Obesity is an important modifiable risk factor for AF. Weight reduction by at least 10% should be promoted for both obese and overweight patients with AF. Bariatric surgery might also be considered for patients with severe obesity with or without AF.
Exercise
A sedentary lifestyle can also increase AF risk.17 One cohort study of greater than 500,000 participants from the Korean National Health Insurance Service (NHIS) sample showed a 12% risk reduction in AF with moderate activity (500-1000 metabolic equivalent task minutes/week).18 Additionally, moderate-intensity training can improve quality of life and AF-related symptoms in patients with established AF.19,20
Conversely, the role of high-intensity training (HIT) in AF prevention remains uncertain. One RCT of 51 subjects suggested AF reduction after 12 weeks of aerobic interval training.21 However, in the Korean NHIS study, participants in HIT had only a modest and nonsignificant AF risk reduction.18 Similarly, another RCT of 76 patients with AF failed to show the superiority of high-intensity exercise in reducing AF burden over low-intensity exercise.22 Another RCT of 50 patients with hypertension (HTN) and chronic kidney disease showed higher rates of new AF with high-intensity interval training (HIIT) compared to moderate training,23 depicted in Table 1. Likewise, in one meta-analysis of 6 case-control studies, patients with AF were 6 times more likely to be athletes than age-matched nonathletes.24
The relation between physical activity and AF risk appears best represented in a U-shaped curve where subjects with regular moderate-intensity exercise are at lowest risk of AF, and those at both ends of the spectrum (minimal and excessive activity lifestyle) are at increased risk of AF.
Alcohol
Alcohol consumption is estimated to cause 5%-10% of all AF diagnoses. Chronic alcohol use triggers atrial fibrosis, LA dilation, and autonomic dysfunction.25
Alcohol has a dose-dependent relationship with AF risk and burden. One large cohort study in Norway showed no AF risk with <2 drinks/day, a minimal risk with <7 drinks/week, and substantial risk with >14 drinks/week.26 In patients with AF who drank >10 drinks/week, one RCT showed significant improvement in rhythm control with abstinence from alcohol.25 Consequently, regular counseling to reduce moderate and high alcohol consumption is warranted in AF prevention.
Tobacco
Tobacco use is also associated with an elevated risk of AF. Like alcohol, tobacco has a dose-dependent relationship with AF. One meta-analysis of 9 prospective studies showed a 33% increased risk of new AF in smokers when compared to nonsmokers.27 In patients with well-known AF, concomitant smoking further intensifies the risk of stroke and death.28 Additionally, smoking negatively impacts success rates for AF ablation.29 Thus, smoking cessation counseling and adequate support are imperative to any AF prevention strategy.
Comorbid Medical Conditions
Hypertension
Outside of lifestyle behaviors, HTN is the most prevalent modifiable risk factor for AF, with a population-attributable fraction of 21.6%.5 It is well-recognized that long-standing HTN results in left ventricular (LV) dysfunction, LA dilatation, and fibrosis. Particularly, circulating levels of angiotensin II and aldosterone promote inflammation, impaired calcium handling, ion channel remodeling, and gap junction uncoupling in atria.30 Elevated blood pressure (BP) also increases pulmonary vein diameter, prolongs conduction time, and shortens event-related potentials. These electroanatomic changes encourage AF susceptibility.31 Hence, effective antihypertensive therapy ought to support AF reduction. In one meta-analysis of pooled data from 9 RCTs, renin-angiotensin system (RAS) inhibition medications were associated with an 18% risk reduction of new AF.32 The LIFE trial detected a significant new AF reduction rate in LV hypertrophy patients with losartan use when compared to atenolol therapy.33 The VALUE trial also detected a reduction in new-onset AF with valsartan use compared to amlodipine,34 shown in Table 2. However, in another meta-analysis of 6 RCTs, RAS inhibition did not show a significant reduction in the overall odds ratio for new AF; it is worth noting there was significant heterogeneity among included trials.35 Mineralocorticoid receptor antagonist therapy is shown to significantly reduce development of new-onset AF.36 Finally, in patients with AF diagnosis, there has been modest evidence favoring sympathetic denervation. In a small, randomized study of patients with established AF and resistant HTN, those who received renal artery denervation in addition to AF ablation had a significant reduction in AF recurrence compared to those who underwent AF ablation alone.37
Guideline-directed HTN management remains recommended in all patients, especially with an AF prevention approach.
Diabetes Mellitus (DM)
Metabolic syndrome is strongly associated with AF. Explicitly, diabetic patients are at a 35% increased risk of AF compared to their nondiabetic matched cohorts.38 The risk further increases in patients with diabetes and resultant kidney dysfunction.39
It is hypothesized that long-standing DM increases LV wall thickness, arterial stiffness, and leads to atrial remodeling, fibrosis, and dilation.40 Similar to elevated BP, high serum glucose is suspected to affect electromechanical and electric remodeling within the atria. In diabetic rat models, atrial arrhythmogenicity and intra-atrial conduction disturbances were much higher than in nondiabetic rat controls.41
AF development reasonably decreases with DM management. Two large retrospective studies demonstrated a decreased risk of AF with firm glycemic control, 30% reduced risk with thiazolidinedione use,42 and 19% reduced risk with metformin use after adjustment for comorbidities.43
Comparable to other major cardiovascular diseases, mainly HF with reduced ejection fraction, sodium-glucose cotransporter-2 (SGLT2) inhibitors appear to play a beneficial role in AF primary prevention. In a meta-analysis of 16 RCTs, SGLT2 inhibitors significantly reduced AF risk when controlling for age, body weight, hemoglobin (HbA1c), and systolic BP (RR: .76).44 Moreover, in patients with established AF, higher HbA1c is shown to be associated with increased recurrence after ablation,45 while adequate serum glucose control is shown to diminish the risk of repeat ablation.46 Therefore, optimal blood sugar control is a central strategy in reducing risk of AF and burden of AF recurrence.
Obstructive Sleep Apnea (OSA)
OSA appears to be strongly associated with AF, with an estimated prevalence ranging from 21%-74%.47 One meta-analysis of 9 studies with more than 19,000 patients demonstrated a doubled risk of AF in patients with OSA or sleep-disordered breathing.48 The risk of AF and its recurrence seems directly proportional to the severity of OSA. In a longitudinal cohort from a sleep clinic, OSA diagnosis and severity were associated with increased incidence of AF independent of obesity and other risk factors.49
In theory, apnea-related deoxygenation-reoxygenation episodes, obstruction-related intrathoracic pressure changes with resultant atrial stretch, and sympathovagal stimulation create an optimal medium for atrial arrhythmogenesis.47 Despite the lack of RCTs, several observational studies do support better outcomes of AF with OSA treatment. In one meta-analysis of 7 prospective cohort studies, continuous positive airway pressure (CPAP) therapy was associated with a 42% relative risk reduction in recurrence of AF in patients with OSA.50 Additionally, in the ORBIT-AF cohort, patients with OSA and CPAP therapy were less likely to progress to permanent AF.51
It is also important to note that AF patients do not necessarily experience typical snoring and daytime sleepiness, with new evidence of reduced predictive value of standard questionnaires such as the STOP-BANG questionnaire to a specificity of 45%.52 Therefore, it is imperative to ensure adherence to therapy in OSA patients in an attempt to prevent AF development. It is also rational to recommend routine screening of AF patients for OSA.
Comprehensive RFM
Comprehensive risk factor modification (RFM) reduces AF burden, as demonstrated in multiple RCTs including ARREST-AF,53 CARDIO-FIT,54 and REVERSE-AF,12 detailed in Table 3. However, AF risk factors are dynamic and ever-evolving, which often makes modification challenging. Within current health care systems, RFM is limited by fragmentation of AF care, potential duplication of services, and imbalanced allocation of resources to tertiary prevention. Almost two-thirds of AF costs are related and allocated to disease progression and complications. Conversely, when implementing RFM, projected 10-year cost-savings in the RFM group was $12,094.55
Integrated care models (ICM)56 have been proposed as a solution. ICMs entail efficient and coordinated care delivery to minimize gaps and optimize patient care. This involves several stakeholders including health care workers, health systems, policy makers, regulators, and patients. The creation of an AF clinic would potentially ensure partnership between different stakeholders within primary, auxiliary, and tertiary care settings. In this scenario, AF clinic dedication is not only for effective pharmacotherapy but ongoing risk factor screening, assessment, and formulated interventions with adherence monitoring. Another suggested setup with increasing popularity is the creation of post-AF ablation rehab programs in which patients are followed up with for periods of time to ensure weight control, appropriate dietary and exercise habits, blood pressure control, and sleep apnea screening.
Conclusion
AF is a complex disease with multiple, highly interconnected risk factors. As a result, cardiovascular and medical communities should recognize the comprehensive role of RFM. An ideal approach would consist of an integrated AF clinic focusing on the different predictors at the individual level, while coordinating between health services and communities.
Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. They report no conflicts of interest regarding the content herein.
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