Mechano-Energetics of Dynamically-Impeded Cardiac Trabeculae

Abstract

Cardiac muscle contraction results in coordinated stress-length changes that correspond to ventricular pressure-volume changes. Each contraction cycle occurs in four sequential phases: isovolumic contraction, ejection, relaxation, and refilling, the dynamics of which are dictated by both the mechanics of the muscles and the load imposed by the cardiovascular system. Compared with the complex geometry of the whole-heart, isolated tissues allow a simpler 1-dimensional assessment of cardiac function. When subjecting isolated muscles to work-loop contractions that mimic the four phases of the cardiac cycle (isometric contraction, shortening, relaxation and re-stretching), the length-change phases (shortening and re-stretching) are conventionally simplified to result in ‘flat-topped’ work-loops. Such simplification overlooks the dynamic nature of the cardiovascular load as the tissues experienced in vivo. In this project, I developed three model-based methods to improve the fidelity of mechanoenergetics experiments and measurements during work-loop contraction protocols designed for isolated cardiac tissues: i. a 3-element Windkessel model to represent the impedance of the arterial system, thereby allowing model-based, dynamic shortening trajectories, ii. a muscle-specific model to separate active from basal components of heat measurements, and, iii. a 6-compartment haemodynamic model of the cardiovascular system to achieve dynamic, load-dependent, muscle re-stretching. This study uncovers two major findings. Firstly, that the change of cardiac basal heat during muscle active contraction is muscle-specific and is not only length-dependent, but is also dependent on the rate of length-change. Secondly, the force-length work and mechanical energy efficiency of cardiac muscles in vitro have previously been restricted by simplified work-loop loading methods. Use of the methods in this thesis reveals that the boundaries of the ‘end-systolic zone’ were maintained, independent of load type, and confirmed the existence of shortening heat. The expansion of the real-time load to enable model-based dynamic re-stretching allows, for the first time, synchronous variation of preload and afterload for a better representation of ventricular dynamics when performing in vitro work-loops. The real-time impedance-loading methods developed in this project reveal the limitations imposed by conventional, simplified, loading methods, and enable potential avenues for exploring the cardiac force-length space, physiologically and pathophysiologically.