Background: Recently, obesity has been established as a causal factor for the development of atrial fibrillation (AF). One possible mechanism reported is reduced cardiac sodium channel current (I_Na) and expression. Current standard of care for AF treatment are antiarrhythmic drugs (AADs) that either block sodium channels (e.g. flecainide) or potassium channels (e.g. sotalol) among others. Consequently, it is of utmost interest to determine if obesity alters response to flecainide or sotalol.

Objective: To determine whether response to AAD therapy in patients with AF is modulated by obesity and elucidate the underlying mechanisms.  

 
Methods: We investigated 302 patients (170 men, 132 women; ages 59.6±12.3 years) prospectively enrolled in a clinical-DNA biorepository. AAD therapy outcome was defined as failure if there was less than 75% increase in the AFEQT score and/or cessation of the AAD within 3 months. To study if obesity increases susceptibility to AF by regulating cardiac sodium channels, we used a genetic (melanocortin-4 receptor knockout, Mc4r-KO) and an acquired (diet-induced obesity, DIO) mouse model. Both Mc4r-KO and DIO mice were compared with wild-type (control) mice. The expression of cardiac sodium channel (Nav1.5) was evaluated with Western blots. Left atrial cells were isolated from the three mouse groups and patch-clamping was used to assess I_Na. Invasive electrophysiological testing was performed to study the AF burden all three groups and response to pharmacologic treatment with either flecainide or sotalol in DIO mice.

 
Results: Obesity (BMI ≥30 kg/m²) was present in 150 (49.7%) patients treated with AADs for symptomatic AF. After controlling for AAD class, obese patients were 2.5 times more likely to be switched to an alternate AAD or therapy versus non-obese patients (odds ratio [OR] 2.5, 95% confidence interval [CI] 1.02-5.97; P=0.04). Obese patients were more likely to not respond to Class I AADs than non-obese patients (33% vs 7%, P < 0.02; Figure 1A). Protein expression of Nav1.5 was significantly reduced in both and Mc4r-KO mice versus control (P < 0.01; Figure 1B).  Patch-clamping revealed significantly diminished I_Na density (Figure 1C) and relative cell conductance in DIO and Mc4r-KO mice. Electrophysiologic testing showed increased AF burden in both DIO and Mc4r-KO mice (Figure 1D). In DIO mice, flecainide significantly diminished AF burden compared to sotalol (Figure 1E).

Conclusions: Our findings reveal that obesity differentially modulates response to sodium channel blockers and potassium channel blockers. This is supported by the observation that obesity increases the AF burden and simultaneously downregulates the cardiac sodium channel.

Figure 1: A: Obese patients have a significantly higher failure rate with sodium channel blocker (Class I) vs. potassium channel blocker (Class III) antiarrhythic drugs (AADs) for atrial fibrillation (AF); B: Both diet-induced obese (DIO) and Mc4r-KO mice have reduced Nav1.5 expression vs. control; C: Sodium current (I_Na) density is decreased in DIO and Mc4r-KO vs. Control; *P<0.05; **P<0.01; ***P<0.0001; D: Burden (duration) of  pacing-induced AF among the 3 groups; n = 24, 19, and 10 respectively for control, DIO, and Mc4r-KO mice; E: AF reduction (%) in DIO mice after treatment with flecainide and sotalol. *P < 0.05, **P < 0.01; ***P < 0.001, ****P < 0.0001.