The mitochondrial permeability transition pore as a target for cardioprotection in hypertrophic cardiomyopathy.

Abstract

Hypertrophic cardiomyopathy (HCM) is the most common inherited cardiomyopathy, and is the leading cause of sudden cardiac death in the young and a major cause of heart failure [1]. Numerous studies have shown that myocardial ischemia caused by an inability to increase myocardial blood flow (MBF) during stress contribute to the pathophysiology of HCM and are associated with adverse left ventricular (LV) remodelling and systolic dysfunction [1]. Numerous studies have shown that myocardial ischemia, which is caused by an inability to increase myocardial blood flow (MBF) during stress, contributes to the pathophysiology of HCM and is associated with adverse left ventricular (LV) remodelling and systolic dysfunction. In this regard the opening of the mitochondrial permeability transition pore (MPTP) at the onset of reperfusion is a critical determinant of cardiomyocyte death following myocardial ischaemiareperfusion injury (IRI) [2, 3]. Pharmacological inhibition of MPTP opening at the onset of reperfusion, using agents such as ciclosporin-A (CsA), has been reported to reduce myocardial infarct (MI) size in animal models of IRI [4]. Importantly, MPTP inhibition at the time of myocardial reperfusion has been demonstrated to protect human atrial cardiomyocytes and trabeculae, harvested from patients undergoing coronary artery bypass graft (CABG) surgery, against simulated IRI [5]. Furthermore, CsA has been reported to be reduce MI size in patients when administered at the time of myocardial reperfusion [6, 7]. MPTP inhibition can also be achieved by pharmacologically activating pro-survival kinases such as Akt and Erk1/2 using the HMG Co-A reductase inhibitor, atorvastatin [8]. Experimental animal studies have demonstrated a reduction in MI size with the administration of atorvastatin at reperfusion in both animal and human heart tissue models of simulated IRI [8, 9]. Whilst these cardioprotective mechanisms are known to operate in the setting of “normal” myocardium, little is understood about potential cardioprotective signaling pathways in HCM. The ability of pharmacological agents to inhibit MPTP opening as a strategy for limiting myocardial IRI, may provide a novel therapeutic intervention for patients with HCM. Therefore, in the current study, the overall objective was to demonstrate the MPTP to be a viable target for cardioprotection in patients with HCM.