Mechanics and Energetics of Diabetic Human Cardiac Tissues

Abstract

Diabetic cardiomyopathy is a multifactorial disease associated with both mechanical and energetic dysfunction. At the cellular level, the interplay between myofilament force production and changes in metabolic state arising from diabetes is not well understood. Thus, the primary aim of this research was to explore the effects of diabetes on cross-bridge kinetics and metabolite sensitivity through the development of a human cardiac cross-bridge model that is responsive to cellular metabolic state. In achieving this aim, I established an experimental-modelling pipeline centred around the measurement of cardiac active complex modulus: cross-bridge stiffness as a function of frequency. I used a purpose-built experimental apparatus to measure this in permeabilised isolated muscles across a range of metabolite conditions, first from rat hearts and then from human atria. Using linearisation techniques to uncover underlying physiological mechanisms, I constructed a mean-field cross-bridge model that was sensitive to ATP and Pi concentration, based on rat experimental data. Using the same framework, I then parameterised a human cross-bridge model to the data that I had collected from cardiac tissues of non-diabetic and diabetic patients. The human cross-bridge model was incorporated into a muscle model to explore the mechanical and energetic performance of diabetic muscle under isometric and work-loop contractions. My development of this experimental-modelling pipeline produced insights into the complex modulus measurement and cross-bridge model properties, including those associated with metabolite sensitivity. From the experimental measurements and model simulations, I found several key differences in the cellular and tissue function of diabetic human atrial trabeculae. Diabetic muscles produced lower active stress and stiffness, with structural imaging linking this to lower myocyte density. They also exhibited a leftward shift in the complex modulus, identified in model fitting to be driven by slower cross-bridge cycling rates. Reflecting these parameter differences, muscle model simulations of isometric contractions revealed a prolonged relaxation phase in diabetes, which was exacerbated under reduced ATP concentration. Work-loop simulations showed that diabetes reduced work and shortening power but increased cross-bridge efficiency. A lower sensitivity to Pi in diabetic muscles diminished the extent to which muscle power was decreased under conditions of raised Pi. This reduced sensitivity and the increase in efficiency suggest the presence of compensatory mechanisms that mitigate the effects of metabolic dysfunction in the diabetic heart. As well as identifying several mechanisms that underlie myofilament dysfunction in diabetic cardiomyopathy, in this project I have developed a suite of robust experimental and modelling methods that are suitable and will be broadly applicable for future studies of cross-bridge dysfunction in cardiac and metabolic disorders.