Profiling the Biomechanical Responses to Workload on the Human Myocyte to Explore the Concept of Myocardial Fatigue and Reversibility: Rationale and Design of the POWER Heart Failure Study

Abstract

It remains unclear why some patients develop heart failure without evidence of structural damage. One theory relates to impaired myocardial energetics and ventricular-arterial decoupling as the heart works against adverse mechanical load. In this original study, we propose the novel concept of myocardial fatigue to capture this phenomenon and aim to investigate this using human cardiomyocytes subjected to a modern work-loop contractility model that closely mimics in vivo cardiac cycles. This proof-of-concept study (NCT04899635 ) will use human myocardial tissue samples from patients undergoing cardiac surgery to develop a reproducible protocol to isolate robust calcium-tolerant cardiomyocytes. Thereafter, work-loop contractility experiments will be performed over a range of preload, afterload and cycle frequency as a function of time to elicit any reversible reduction in contractile performance (i.e. fatigue). This will provide novel insight into mechanisms behind heart failure and myocardial recovery and serve as a valuable research platform in translational cardiovascular research.

The Stiffness of the Ascending Aorta Has a Direct Impact on Left Ventricular Function: An In Silico Model

“…Such muscle fatigue provokes a release of myokines, e.g., interleukin-6, which trigger a downstream cascade of endothelial inflammation, mitochondrial dysfunction and oxidative stress. The consequent impairment of contractility and relaxation of a stressed but otherwise intact muscle fits well with the theory of myocardial inflammation in HfpEF [ 45 , 46 ]. If such a fatigued myocardium is left without the opportunity for recovery, a vicious cycle of increased myocardial stress, reactive myocardial hypertrophy and subsequent myocardial fatigue, rising ventricular end-diastolic/left atrial pressure and increasing wall stress eventually leads to HFpEF symptoms [ 12 , 40 , 41 , 45 ] ( Figure 7 ).…”

“…The consequent impairment of contractility and relaxation of a stressed but otherwise intact muscle fits well with the theory of myocardial inflammation in HfpEF [ 45 , 46 ]. If such a fatigued myocardium is left without the opportunity for recovery, a vicious cycle of increased myocardial stress, reactive myocardial hypertrophy and subsequent myocardial fatigue, rising ventricular end-diastolic/left atrial pressure and increasing wall stress eventually leads to HFpEF symptoms [ 12 , 40 , 41 , 45 ] ( Figure 7 ).…”