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 in a nearly linear fashion with the amount of fibrosis as heart failure progresses.
Objective: Although death can be mitigated by the prophylactic insertion of intracardiac defibrillators, the clinical metrics currently in use remain of low sensitivity and specificity in predicting future arrhythmic events. Henceforth investigating the role of structural heterogeneity, such as fibrosis, as a potential driver in arrhythmia initiation is crucial.
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/WT hearts (age/weight matched pigs, weight ca. 35-40Kg) were simultaneously mapped in steady state pacing and arrhythmic conditions.
Results: As expected, baseline electrophysiological metrics showed significant alterations in conduction velocities (DMD: 1.15±0.65m.s-1, WT: 1.86±0.25m.s-1, p < 0.05), action potential duration (APD75, DMD: 224±22ms, WT: 208±10ms, p = 0.07) and repolarization abnormalities (DMD: 37±10ms, WT:15±5ms, p < 0.05). Activation maps revealed fixed lines of block at directly preceding the onset of fibrillation in DMD. Furthermore, DMD hearts showed a decreased fibrillation threshold compared to the control group (DMD: 4.5±0.5Hz, WT: 5.3±0.2Hz). 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, that could coincide with the areas of extensive coupling between fibrosis and cardiomyocytes. This suggests a potential correlation between organization of fibrillatory activity in the excitable tissue and diffuse fibrosis. These findings are congruent with the extensive molecular and genetic work already published by our group on this model.
Conclusion: Tailored analysis of wave patterns and spirals allows us to determine the stability properties and characterize the influence of heterogeneity-induced alterations in arrhythmogenic substrates.
