Mechanosensitivity of the failing myocardium: Role of mechanical unloading

Left ventricular assist devices (LVADs) were initially developed primarily to serve as a means of bridging heart failure patients to transplantation. However, reports show that significant myocardial functional recovery occurs in some LVAD patients to the extent that device explantation can be achieved without the need for transplantation. This phenomenon, described as reverse remodelling only occurs in about 4-10% of patients treated with LVADs and the basis for this is unknown. Myocardial fibrosis worsens with mechanical unloading but the mechanism remains poorly understood. Unloading is however associated with a reduction in microvascular luminal diameter suggesting a negative autoregulatory effect of unloading on the coronary collateral circulation. Coronary reperfusion after myocardial injury is associated with heightened regenerative responses in the zebrafish heart. However, the effect coronary reperfusion coupled with unloading has on cardiomyocyte proliferation is unknown. It is known that cardiomyocyte excitation-contraction coupling is improved by unloading but the effect of unloading on whole-heart contractility and on proteins that facilitate efficient excitation-contraction coupling such as; JPH2, BIN1, and Tcap, is unknown. In this thesis, we hypothesised that mechanical unloading of the reperfused ischaemic heart ameliorates unloading-induced increases in fibrosis and stimulates an upregulation of cardiomyocyte proliferation. We also hypothesised that these positive effects of mechanical unloading are associated with improvements in the expression and function of JPH2, BIN1, and Tcap, and in whole-heart contractility. Hearts of animal models of ischaemic cardiomyopathy, achieved following coronary artery ligation, were mechanically unloaded via heterotopic abdominal heart and lung transplantation after either being revascularised or left permanently ligated. We found that following acute myocardial infarction, ischaemia-reperfusion coupled with mechanical unloading was associated with a remarkable amelioration of the deleterious effect of unloading on myocardial fibrosis and a significant upregulation of cardiomyocyte proliferation. Two major findings that could have significant clinical implications for LVAD-induced myocardial recovery.Open Acces