Obesity mutes efficacy of sodium channel blockers for those with AFib

Atrial fibrillation patients who are obese are less likely to respond to sodium channel blockers than their normal-weight peers, according to a new study.

Obesity is a known risk factor for AFib, senior author Dawood Darbar, MBChB, MD, and colleagues at the University of Illinois at Chicago wrote in JAMA Cardiology, which is concerning given that two-thirds of the American population is either overweight or obese. The causal link between weight and AFib is something that cardiologists have been aware of for some time, but it took a 2017 mendelian randomization study to prove it on paper.

Antiarrhythmic drugs (AADs), including sodium channel blockers and potassium channel blockers, are still widely used to treat symptomatic AFib, even though patient response to such membrane-active drugs is unpredictable. Around half of patients on AADs will experience symptomatic recurrence of AFib within six months of initiating treatment.

“This variability is due to heterogeneity of the underlying substrate and failure to select mechanism-based therapies,” Darbar et al. wrote. “Although the underlying pathophysiologic factors by which obesity causes AFib are poorly understood, emerging evidence supports modulation of the cardiac sodium channel, Nav1.5, as one potential mechanism.”

The researchers studied the relationship between obesity and response to AADs in an observational cohort study of 311 AFib patients in a clinical-genetic registry. Symptomatic response was defined as continuation of the same AAD for at least three months; nonresponse was defined as discontinuation of the drugs within three months because of poor symptomatic control.

Patients were on average in their mid-sixties and a majority men. Darbar and colleagues found that more obese AFib patients taking sodium channel blockers experienced recurrence of AFib compared to their non-obese counterparts—30% vs. 6% of each group, respectively. Obesity wasn’t the only predictor of AAD efficacy, though; women were 2.3 times more likely than men to fail to respond to AADs, and people with hyperthyroidism were nearly 5 times more likely.

The authors reported that both obese and normal-weight patients had similar symptomatic responses to a potassium channel blocker AAD. The use of sodium channel blockers, however, was linked to a 4.5-fold increased risk of non-response in obese patients.

“Our findings may have clinical implications for the treatment of AFib in patients with obesity because class I AADs, which are frequently used to treat symptomatic AFib, block the cardiac sodium channel,” Darbar and co-authors wrote. “Emerging evidence supports obesity down-regulating Nav1.5 and the sodium current. Thus, prescribing class I AADs in patients with obesity and symptomatic AFib will further decrease the sodium current and may be pro-arrhythmic, paradoxically worsening AFib incidence and/or maintenance.”

The team furthered their findings in a separate study of mice, some of which they fed a high-fat diet for 10 weeks and all of which were treated with either flecainide acetate or sotalol hydrochloride. Two weeks after initiating treatment, 100% of obese rodents and 30% of healthy mice experienced pacing-induced AFib. Obese mice showed a greater reduction in AFib burden when treated with sotalol, a beta-blocker, compared to flecainide, a sodium channel blocker.

The authors said the mouse study can’t fully replicate the electrophysiological effects of drugs in human models, but the rodents’ results seemed to support their observations.