Abstract:
Context: Since myocardial wall stress is known to be one of the primary determinants of myocardial oxygen consumption, many studies have attempted to understand alteration in wall stress as a feedback mechanism governing the progress of heart disease. Approaches to improving cardiac performance in heart disease are equally applicable to the left ventricle (LV) and right ventricle (RV). However, appropriate therapy for LV dysfunction has been shown to be not necessarily ideal for treating RV dysfunction. Therefore, understanding ventricular wall stress is thought to provide important insights into the underlying ventricular mechanics and energetics in compromised hearts. Different stresses acting in the ventricular walls lead to different contraction properties between LV and RV in a normal heart. Quantification of ventricular wall stress is necessary for an understanding of both normal and pathological ventricular mechanics. Aims: The aim of my study was to determine whether the wall stress in cardiac muscle differs between LV and RV, and to examine the underlying mechanism of that difference at the cellular level through both experimental and mathematical modelling studies. Methods: To obtain a realistic quantitative assessment of ventricular wall stress, quasi-isometric contractions were measured using isolated cardiac muscles. Underlying mechanisms were investigated by measuring Ca²⁺ imaging with a confocal microscope. Simulation of a biophysical whole cell model was performed using the CellML standard and OpenCOR software. Results: the main findings of this study are: 1. Assessing the stress of isolated trabeculae muscles showed: (1) stress between LV and RV trabeculae was not significant different but the twitch time constants were significantly smaller in RV trabeculae than in LV trabeculae and the stress-frequency relationship (SFR) in both groups was flattened in the range of physiological frequencies at 37°C; (2) β-adrenergic stimulation with isoproterenol (ISO) resulted in a positive SFR with significant reduction in the twitch time constants and an increased maximum rate of stress development in both groups in the range of physiological frequencies at 37°C; and (3) non-specific adrenergic stimulation with norepinephrine (NE) produced an increase in stress, but unchanged, flattened SFRs and twitch time constants in both groups in the range of physiological frequencies at 37°C. 2. Measuring Ca²⁺ transients in isolated single myocytes showed: (1) the average peak ratio of Ca²⁺ transients between LV and RV myocytes was not significantly different; however, the decay of Ca²⁺ transients was much faster in RV than in LV myocytes at 25°C; and (2) the effect of β-adrenergic stimulation on Ca²⁺ transients was greater, with delayed decay in RV myocytes compared to LV myocytes at 25°C. 3. Simulating action potentials (APs), Ca²⁺ dynamics, and isometric tension for a single myocyte showed: (1) there was close agreement between the experimentally recorded and the simulated AP and Ca²⁺ transient waveforms; (2) the simulated LV AP showed prolonged AP duration and a more prominent plateau phase compared with the simulated RV AP; (3) the simulated Ca²⁺ transient showed prolonged duration and higher diastolic value in LV compared to RV myocytes; (4) the peak value and relaxation of the simulated isometric tension were larger and slower, respectively, in the LV compared to the RV myocyte. Conclusions: To my knowledge, this is the first comprehensive study of multi-scale electromechanics of the rat heart to examine ventricular wall stress using both experiments and simulations. The results from the current study indicate that there are significant differences in some electromechanical parameters between left and right ventricles.