Abstract
Background: Idiopathic ventricular fibrillation (IVF) is a clinically challenging disease entity as phenotypic characteristics are lacking. We studied induced pluripotent stem cell-derived cardiomyocytes (iPS-CMs) from a patient with stress-induced IVF to define the cellular arrhythmic behavior and create a path to test therapeutics. Methods: iPS-CMs were generated from control (WT) and stress-induced IVF (si-IVF) patient-specific iPSC lines. Cells were characterized by single-cell optical mapping using calcium sensitive dye (Fluo-4) and electrical pacing (0.5Hz), with β-adrenergic stimulation (1x10 -6 mM isoproterenol (ISO)). Results: si-IVF cells had longer CaT rise time (ms) at baseline (BSL) (p<0.05) (86 +/- 5.45, n=54) and after ISO (83.88 +/- 5.12, n=41) than WT cells (BSL: 64.5 +/- 3.72, n=40) (ISO: 72 +/- 9.92, n=10). si-IVF cells had shorter CaT duration (ms) at BSL (1,069 +/- 36.00, n=54) than WT cells at BSL (1,280 +/- 37.59, n=40), with no significant difference after ISO (IVF: 1,073 +/- 44.51, n= 41 and WT: 1,230 +/- 32.79, n=10). Following ISO, 11.5% of si-IVF cells showed arrhythmic behavior with rapid continuous spontaneous Ca 2+ release (Fig. 1), compared to 0.0% of WT cells. Conclusion: We demonstrate feasibility of differentiating iPS-CMs from patients while investigating arrhythmogenicity of si-IVF cells compared to controls using optical mapping. Insights from CaT duration, rise time, and arrhythmogenic behavior helps establish the arrhythmogenic behavior, and begins to provide mechanistic insights into si-IVF. This methodology can be applied to test therapeutics for IVF patients with β-adrenergic triggers. Figure 1: Patient #1-specific si-IVF iPS-CM. A) Representative optical mapping recordings of iPS-CMs baseline paced at 1Hz (each trace is a separate cell) B) Application of ISO caused arrhythmic behavior and failure to capture paced beats in black, red, blue, and yellow traces but retention of paced response in green and grey traces.
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