| Heart failure (HF) is a syndrome characterized by the depression of cardiac pump function such that the output of the heart is unable to provide the body with sufficient blood supply. The mechanisms underlying this syndrome are incompletely understood. To enable us to study the cross bridge cycling kinetics and post-translational modifications in HF, we developed two Beta-Myosin Heavy Chain (MHC) models of HF. We established a 3-stage, clinically relevant, chronic pressure overload Beta-MHC model of systolic HF by surgically implanting AngiotensinII (AngII) pumps (400ng/kg/min)/saline pumps (0.9%) and a mechanically stressed aortic banding (AOB) model of diastolic HF in female Dunkin Hartley Guinea pigs weighing 400g, for 12-20 wks. We characterized the AngII model at three different clinical stages, early hypertrophy (4wks), compensatory responses (8wks) and decompensatory responses (12wks). Echocardiography and cardiovascular hemodynamic based indices of contractility and relaxation in the whole heart were derived from both the models. We employed the single myofibril technique to study cross-bridge cycling kinetics and 2-D Differential In Gel Electrophoresis (2-D DIGE) technique to study post-translational modifications in the contractile proteins in myofilaments. Our major findings from the study are that i) sarcomeric dysfunction translates directly to global cardiac pump dysfunction and is a key end-stage development in the progression of heart failure regardless of etiology, ii) myofilament sensitivity to calcium is increased at compensatory stage and decreased at the decompensatory stage of heart failure, iii) kinetics of cross-bridge cycling are depressed in heart failure, and slower and prolonged relaxation kinetics play a leading role in heart failure, iv) energetics of cross-bridge cycling are depressed in heart failure, v) decreased phosphorylation of cMyBP-C, MLC-2 and TnI at various stages during the pathophysiology of heart failure are the most likely underlying cause of altered cross-bridge cycling kinetics, v) a switch from compensatory stage to the decompensatory stage in heart failure is potentially dictated by phosphorylation of MLC-2 and vi) decreased phosphorylation of TnI and MyBP-C could distinguish between underlying defining cause of diastolic heart failure vs. systolic heart failure. To conclude, depressed cross-bridge cycling kinetics and altered phospho-proteome of the regulatory contractile proteins of the thin and the thick myofilaments might be the key end event in the pathophysiology of the syndrome. |
