Introduction: Sudden cardiac death from arrhythmias is the most common direct cause of mortality in patients with Duchenne muscular dystrophy (DMD). The inducibility of arrhythmias increases as heart failure (HF) progresses.
Objective: With rising mortality and limited therapy options, we address calcium (Ca) homeostasis impairment in DMD by targeting the SarcoEndoplasmic Reticulum Ca-ATPase (SERCA) as a potential treatment for advanced HF and arrhythmogenicity. The direct role of SERCA dysfunction in DMD remains undetermined, highlighting the need for well-designed pre-clinical studies.
Methods: Using high resolution optical mapping designed for porcine hearts (spatial-temporal resolution: 100µm, 0.5kHz), the anterior and posterior walls of ex-vivo retrograde perfused DMD and SERCA-treated DMD hearts (age/weight matched pigs, weight ca. 40-45Kg) were simultaneously mapped in steady state pacing and arrhythmic conditions.
Results: As expected, baseline electrophysiological metrics showed significant alterations in conduction velocities and repolarization abnormalities in DMD compared to WT. Overexpression of SERCA in DMD hearts lead to a decrease in activation time at 3Hz pacing (20±5ms at BCL 330ms, p = 0.07), and 30% increase in conduction velocity across the anterior and posterior walls (DMD: 1.0±0.3m.s-1 , SERCA: 1.4±0.35m.s-1 , p < 0.05). Activation maps revealed fixed lines of block in DMD, whereas SERCA treated hearts showed a continuously planar propagation from the pacing site in the RV to the boundaries. A reversal in the action potential duration (APD) was observed in SERCA-treated hearts with a significant leftward shift of the APD-histogram (APD75, DMD: 216±33ms, SERCA: 185±20ms, p < 0.05). The latter was also associated with a decline in the dispersion index (DI, DMD: 0.75±0.10ms, SERCA: 0.20±0.13ms, p < 0.01). Furthermore, SERCA hearts showed an increased fibrillation threshold compared to the untreated group (DMD: 4.5±0.7Hz, SERCA: 5.5±0.5Hz). Cardiac activity during fibrillation is converted to a phase representation where spiral waves and phase singularities (PS) are identified. Using PS tracking methods, density maps showed preferred patterns of initiation and annihilation during fibrillation with a predilection to avoid areas of prolonged APD. This suggests a potential correlation between organization of fibrillatory activity in the excitable tissue and diffuse fibrosis that could potentially be reversed with SERCA. These findings are congruent with the extensive molecular and genetic work already published by our group on this model.
Conclusion: A better understanding of the potential role that SERCA upregulation could play in DMD presents a novel angle that could open new avenues for modulating arrhythmogenicity in HF.
