No abstract

The in vivo rat model of CHF combined with EP analysis could be used to determine the arrhythmogenic potential of new treatments for CHF.

Introduction: We have developed a computer user interface able to provide prescribed programmed electrical stimulation (PES) to induce sustained-ventricular tachycardia (VT) in rats with chronic heart failure (CHF). We propose this program to examine the cardiac electrophysiology (EP) properties and arrhythmogenic potential in varying disease models and as a method of evaluating drug safety in an intact animal. Methods: Using custom MATLAB software developed in our laboratory, we performed monophasic action potential (MAP) recordings and initiated protocols to induce sustained-VT through right ventricular epicardium PES outputs. Studies were performed in adult male Sprague-Dawley rats (N=22) six weeks after left coronary artery ligation under anesthesia and open chest. Results: CHF was verified by standard hemodynamic and echocardiographic parameters as is standard in our laboratory. In the CHF group, 71% (10/14) of the rats exhibited sustained-VT in response to PES versus 0% (0/8) of Sham rats. MAP recordings taken prior-to and during VT induction provided examples of localized activity for arrhythmia mechanisms such as delayed afterdepolarizations. Mechanical alternans, electrical alternans, intermittent pulse generations, and pulseless electrical activity were all observed in this model. EP data analysis showed a decreased (p<0.05) electrogram amplitude in border and infarct zones (Healthy (H): 8.7 ±2.1 mV, Border: 5.3±1.6 mV, Infarct (I): 2.3±1.2 mV), a similar trend for MAP amplitudes, and an increased (p<0.05) repolarization heterogeneity in the border zone (H: 8.1±1.5 ms, B: 20.2±3.1 ms). Conclusions: We have developed a custom computer user interface capable of performing clinically relevant in-vivo EP studies in rats with CHF. This rat model reproduces common clinical prognosis factors such as mechanical alternans, electrical alternans, and pulseless electrical activity. These EP studies demonstrate this program’s ability to test the arrhythmogenic potential of pharmaceutic agents, biologics, and implantables in an intact animal model before clinical advancement. We introduce this program to study an animal model’s EP characteristics before, during, and after treatments for CHF, and potentially other disease states.

Background: Chronic Heart Failure (CHF) is the leading cause of hospital readmissions and mortality in the US. Here we report the effects of surgically delivering a human bioengineered patch of human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs) and fibroblasts on left ventricular (LV) function in rats with CHF. We evaluate improvements in LV systolic and diastolic function, electromechanical coupling and gene expression after patch implantation. Methods: Adult male Sprague-Dawley rats underwent left coronary artery ligation and were randomized to Sham (N=8), CHF (N=8-21), and CHF+hiPSC-CM patch (N=20-24). Heterogeneous hiPSC-CMs were seeded and co-cultured onto a vicryl matrix embedded with human dermal fibroblasts. Echocardiography was performed at 3 and 6 weeks post-randomization. Hemodynamic pressure measurements were performed at 6 weeks post-ligation with Millar solid state micromanometer pressure catheters. Open chest Electrophysiologic (EP) mapping was performed at 6 weeks post ligation. Gene expression was evaluated through qRT-PCR. Results: 48 hours into culture hiPSC-CMs patches displayed synchronized and spontaneous contractions which developed in robustness over time. At maximal robustness, contractions were visualized across the full thickness of the construct. Contractions were recorded at 36 + 5 beats BPM. Three weeks after patch implantation (6 weeks post ligation) the hiPSC-CM patch decreased (P<0.05) LV EDP (45%), Tau (29%), E/e’ (23%) and increased (P<0.05), e’/a’ (36%) with trending improvements in EF (14%) and e’ (20%). EP studies show electro-mechanical coupling between the patch and the native myocardium with normal activation through the patch and increases (P<0.05) voltage amplitude in CHF versus hiPSC-CM patch treated rats (1±0.5 mV vs 6±1.5mV). Rats treated with the hiPSC-CM patch showed significant (P<0.05) fold expression of Cx43 (3.3), ANG-1 (13.63), VEGF (3.8), βMYH7 (6.4) and IGF-1 (22.9) versus control. Conclusion: Cardiac patch implantation with hiPSC derived cardiomyocytes is an effective and feasible method of treating CHF with improvements in systolic function, diastolic function, and electro-mechanical coupling in rats with CHF.