Hearts may grow concentrically to balance ATP supply and demand and eccentrically to stabilize titin-based stress

Abstract

Hearts change their wall thickness (concentric growth) and chamber size (eccentric growth) as they adapt to circulatory demands and the intrinsic function of their contractile cells. Factors associated with wall thickening include variants of sarcomeric proteins that enhance contractility, mitochondrial dysfunction, and hypertension. Chambers can dilate due to many factors including sarcomeric variants that depress contractility and aortic and / or mitral valve insufficiency. Despite intensive study, the mechanisms that regulate cardiac growth remain unclear. It is also uncertain whether inherited variants induce growth via the same mechanisms as more common clinical pathologies, such as hypertension. Here we show that computer simulations of a beating left ventricle reproduce both variant and non-variant-related growth patterns when myocytes grow concentrically to regulate intracellular ATP concentration and eccentrically to maintain titin-based intracellular stress. The simulations support the hypothesis that cardiac growth reflects homeostatic feedback through three interacting systems whereby myocytes add or remove mitochondria and sarcomeres (1) in parallel to match ATP generation to myocardial energy demand, and (2) in series to regulate passive tension, while (3) the autonomic nervous system regulates cardiac power, and thus myocardial ATPase, via baroreflex control. The new framework provides a mechanistic basis for the patterns of eccentric and concentric growth induced by a wide range of clinically-relevant conditions and could facilitate in silico testing of potential therapies for cardiac disease. Significance statementHearts grow in response to both physiological and pathological stimuli. The patterns of concentric (wall thickening / thinning) and eccentric (chamber dilation / constriction) induced by different challenges are well recognized but the underlying mechanisms remain unclear. This work presents simulations of a beating left ventricle where (1) concentric growth is regulated by myocytes attempting to stabilize the intracellular ATP concentration and (2) eccentric growth is regulated by titin-mediated stress. The calculations reproduce the growth associated with inherited variants of sarcomeric proteins, mitochondrial dysfunction, hypertension, and both mitral and aortic valve insufficiency. The new ability to predict cardiac growth and its potential modification by treatments, including myotropes, brings the field closer to in silico optimization of therapy for cardiovascular disease.