Novel insight into the mechanisms and treatment of ventricular tachyarrhythmias

Progressive heart failure (HF) post myocardial infarction (MI) remains the leading cause of morbidity and mortality worldwide. Non-pharmacological interventions, including stem cell therapy and spinal cord stimulation (SCS), are emerging novel therapeutic approach to prevent or treat HF. Nevertheless, the potential impact of these interventions on the susceptibility for ventricular tachyarrhythmias (VT/VF), which are the most common cause of sudden death in HF patients remains unknown. For stem cell therapy, sympathetic hyperinnervation as reflected by nerve spouting, lack of gap junction and immature electrophysiological phenotypes of the transplanted cells are potentially trigger and/or substrate for VT/VF after transplantation. Previous studies suggested that stem cell transplantation post-MI may induce cardiac nerve sprouting but their effects on gap junction expression are unclear. Furthermore, the effects of stem cell transplantation on cardiac nerve spouting and gap junction expression in chronic myocardial ischemia have not been addressed. In Chapter 3, we investigated bone marrow (BM) derived mononuclear cells (MNCs) and endothelial progenitor cells (EPCs) via direct intramyocardial transplantation in a porcine model of chronic myocardial ischemia. Our results showed that BM-MNCs or BM-EPCs transplantation was not associated with increased cardiac nerve sprouting, which might account for their low risk of proarrhythmias observed in clinical and experimental studies. In Chapter 4, we investigated the susceptibility to develop VT/VF after embryonic stem cells (ESCs) and their derived cardiomyocytes (ESC-CMs) transplantation in a murine model of MI. Moreover, the potential application of bioengineered ESC-CMs with over-expression of Kir 2.1 to reduce their susceptibility to induce VT/VF was also studied. Our results showed that transplantation of ESC or ESC-CMs reduced cardiac nerve sprouting and increased gap junction expression in the infarcted regions when compared with MI alone. The inducibility of VT/VF after ESC-CM transplantation was significantly higher than ESC transplantation or MI alone. On the other hand, over-expression of Kir2.1 improved the electrical maturation of ESC-CMs which significantly attenuated their vulnerability for VT/VF. These results suggested that the immature electrical phenotypes of ESC-CMs, rather than cardiac nerve spouting and changes in gap junction expression, plays an important role for proarrhythmias after stem cells transplantation, which can be eliminated by bioengineering of ESC-CMs. Dysregulation of the autonomic nervous system with increased sympathetic tone and decreased parasympathetic tone has been well documented in HF progression, and is proposed to play an important role in arrhythmogenesis. In Chapter 5, we performed acute thoracic SCS at T1-T2 level in an animal model of ischemic HF (MI+HF) induced by MI and rapid ventricular pacing. Our results showed that acute SCS significantly increased left ventricular (LV) contractile function as determined by echocardiographic measurement of LV ejection fraction (LVEF) and invasive hemodynamic assessment of +dP/dt. Furthermore, myocardial oxygen consumption also significantly decreased during SCS without any change in serum norepinephrine level. Nevertheless, acute SCS failed to prevent spontaneous VT/VF provoked by prolonged (>2 minutes) acute myocardial ischemia. Taken together, our results provide important insights into the potential mechanisms of proarrhythmias after stem cell transplantation as well as the acute beneficial effects SCS in ischemic HF.published_or_final_versionMedicineDoctoralDoctor of Philosoph