Abstract 15690: Fibroblasts From Failing Human Heart Exhibit Increased Sensitivity to Dronedarone-Induced Oxidative Stress and Cell Death

Abstract

Introduction: Dronedarone (DR), a structural analog of amiodarone designed to reduce its extracardiac toxicity, recently was shown in clinical trials to increase heart failure (HF) and cardiovascular death in patients with severe myocardial dysfunction, but the mechanisms for these adverse cardiac effects are not known. Hypothesis: We hypothesized that DR increases oxidative stress and cell death in failing hearts with compromised energetic reserves compared to nonfailing hearts. Methods: Ventricular fibroblasts (VFB) from patients without HF (trauma victims) and with HF (left ventricular assist device implants) were cultured under similar conditions to passage 3 and treated with DR (0-10 μM) for 24h. Reactive oxygen species (ROS) production was assessed in cells loaded with general oxidative stress indicator CM-H2DCFDA (2μM), mitochondrial superoxide indicator MitoSOX Red (5 μM), and Hoechst 33342 (1μg/ml) for nuclear staining using confocal microscopy. Cell viability was assessed by counting the number of viable cells and lactate dehydrogenase assay. Results: VFB from HF patients exhibited a higher baseline level of total ROS (CM-H2DCFDA green fluorescence) when compared with non-HF patients (Fig. A). DR dose-dependently increased ROS production in VFB from HF patients (Fig. B) exhibiting a higher sensitivity to oxidative stress and cell death (Fig. C). Conclusions: The sensitivity of DR-induced oxidative stress and cytotoxicity is significantly increased in VFB from patients with HF and provides an explanation for adverse effects of DR reported in HF patients in clinical trials.