The role of the L-type calcium channel and extracellular matrix stiffness in the regulation of cardiac metabolic activity in hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a primary myocardial disorder that affects 1 in 200 of the general population. Gene mutations encoding proteins involved in the cardiac contractile apparatus account for 60% of HCM aetiology. The pathological hallmark of HCM is unexplained left ventricular hypertrophy, and asymmetric septal hypertrophy, although almost any pattern of left ventricular hypertrophy can be associated with the disease. It is characterised by myocyte remodeling, disorganisation of sarcomeric proteins, impaired energy metabolism and altered cardiac contractility. Using murine models of human HCM, we have shown that mutations in sarcomeric proteins are associated with altered L-type calcium channel kinetics, impaired structural-functional communication between the L-type calcium channel and mitochondria, and increased metabolic activity (consistent with the human phenotype). However the mechanisms by which mutations in sarcomeric proteins lead to alterations in metabolic activity remain unknown.

Cardiomyocytes can ‘sense’ extracellular matrix (ECM) mechanics via a process called mechanotransduction. This involves conversion of mechanical stimuli into biochemical events that can alter myocardial structure and function. Since human HCM is characterised by a stiff myocardium, we developed an in vitro model to determine the role of increased ECM stiffness on metabolic activity. We are using this model to characterise the signalling mechanisms associated with the development of the pathology.

Speaker Biography:

Livia Hool completed her PhD as a Gaston Bauer Cardiovascular Fellow in the Cellular Electrophysiology Laboratory at the Royal North Shore Hospital, Sydney in 1995. She was then awarded an American Heart Association Postdoctoral Fellowship to work in the Department of Physiology and Biophysics, Case Western Reserve University, Cleveland. Subsequently, with an NHMRC Peter Doherty Fellowship she returned to Australia and relocated to The University of Western Australia. She is Head of the Cardiovascular Electrophysiology Laboratory in the School of Human Sciences and has received continuous competitive funding from national and international granting bodies including the American Heart Association, Australian Research Council and National Health and Medical Research Council of Australia (NHMRC) since obtaining her PhD. Her research focuses on the role of calcium in the excitability of the heart and in the regulation of mitochondrial energetics, with an emphasis on designing therapy to prevent the development of cardiomyopathy and heart failure

Professor Hool is an elected member of the World Council of International Society for Heart Research (ISHR) and Immediate Past President of ISHR Australasian Section (2013-16; 2016-19). She is a Fellow of the American Heart Association, a Fellow of the Cardiac Society of Australia and New Zealand and a Fellow of the International Society for Heart Research. She develops cardiovascular health policy internationally (ISHR World Council) and nationally with Cardiac Society of Australia and New Zealand as a member of Scientific Committee. She is a member of the Heart Foundation Research Committee. She has held numerous positions on university committees, society councils including World Congress scientific programming committees, grant review panels for WA Department of Health, ARC, Heart Foundation of Australia, NHMRC and Canadian Institutes for Health Research. She serves on the Editorial Boards of Journal of Physiology (London), Current Opinion in Physiology and Heart, Lung Circulation.