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Background Although atrial fibrillation ablation is increasingly used for rhythm control therapy, antiarrhythmic drugs (AADs) are commonly used, either alone or in combination with ablation. The effectiveness of AADs is highly variable. Previous work from our group suggests that alterations in atrial resting membrane potential (RMP) induced by low Pitx2 expression could explain the variable effect of flecainide. Objective The purpose of this study was to assess whether alterations in atrial/cardiac RMP modify the effectiveness of multiple clinically used AADs. Methods The sodium channel blocking effects of propafenone (300 nM, 1 μM), flecainide (1 μM), and dronedarone (5 μM, 10 μM) were measured in human stem cell–derived cardiac myocytes, HEK293 expressing human NaV1.5, primary murine atrial cardiac myocytes, and murine hearts with reduced Pitx2c. Results A more positive atrial RMP delayed INa recovery, slowed channel inactivation, and decreased peak action potential (AP) upstroke velocity. All 3 AADs displayed enhanced sodium channel block at more positive atrial RMPs. Dronedarone was the most sensitive to changes in atrial RMP. Dronedarone caused greater reductions in AP amplitude and peak AP upstroke velocity at more positive RMPs. Dronedarone evoked greater prolongation of the atrial effective refractory period and postrepolarization refractoriness in murine Langendorff-perfused Pitx2c+/– hearts, which have a more positive RMP compared to wild type. Conclusion Atrial RMP modifies the effectiveness of several clinically used AADs. Dronedarone is more sensitive to changes in atrial RMP than flecainide or propafenone. Identifying and modifying atrial RMP may offer a novel approach to enhancing the effectiveness of AADs or personalizing AAD selection.

Background The recreational abuse of anabolic steroids is an emerging global health concern and may disrupt cardiac electrophysiology. Every fifth man joining a gym in the UK uses anabolic steroids for performance enhancement. Based on molecular signaling analyses and considering the volume-loading effects of testosterone, individuals with vulnerable desmosomal (cell-cell contact) proteins may be at increased risk of anabolic steroid induced cardiac electrical remodeling. We therefore studied the impact of chronic anabolic steroid exposure on left atrial (LA) electrophysiology in wildtype (WT) and plakoglobin (Plako; or gamma-catenin, a key desmosomal protein) deficient mice using dihydro-testosterone (DHT-a stable derivative of testosterone). Methods Young adult WT and Plako +/- male mice, bred on 129/sv background were fitted with subcutaneous osmotic mini-pumps containing either DHT (62.5mg/ml) in ethanol, or ethanol alone (Placebo), for 6 weeks. Following treatment, we examined transmembrane action potentials, and generated high spatial resolution activation maps in the Di-4-Anepps loaded LA using the Hamamatsu ORCA flash 4. Significance was taken as P Results DHT minipump exposure lead to supraphysiological DHT plasma levels and increased the ventricular mass:tibial length ratio of both genotypes (WT Placebo 79 ± 2 Plako +/- Placebo 78 ± 2 WT DHT 86 ± 3 Plako +/- DHT 92 ± 3 mg/cm, P +/- LA mass:tibial length ratio (WT Placebo 2.4 ± 0.1 Plako +/- Placebo 2.3 ± 0.1 WT DHT 2.6 ± 0.2 Plako +/- DHT 3.2 ± 0.2mg/cm, P +/- Placebo 0.14 ± 0.006 WT DHT 0.16 ± 0.004, Plako +/- DHT 0.24 ± 0.04 mm 2 , P DHT reduced action potential amplitude in Plako +/- LA, but not WT LA (WT Placebo 82 ± 2 Plako+/- Placebo 80 ± 2 WT DHT 80 ± 2 Plako+/- DHT 71 ± 2mV, P +/- DHT 82 ± 5 V/s, P +/- LA following DHT exposure (WT Placebo 40 ± 0.3 Plako +/- Placebo 40 ± 0.9 WT DHT 37 ± 1.3 Plako +/- DHT 36 ± 1.4 cm/s, P Conclusion Reduced cardiac plakoglobin expression increased susceptibility to steroid-induced left atrial hypertrophy, reduced action potential amplitude and lead to significant conduction slowing. These differences are likely to provide an enhanced substrate for atrial arrhythmogenesis. Our results suggest a potentially important interaction between reduced mechanical cell-cell contacts and anabolic steroid use.