Lost in translation: Interpreting cardiac muscle mechanics data in clinical practice

Abstract

Current inotropic therapies improve systolic function in heart failure patients but also elicit undesirable side effects such as arrhythmias and increased intracellular Ca²⁺ transients. In order to maintain myocyte Ca²⁺ homeostasis, the increased cytosolic Ca²⁺ needs to be actively transported back to sarcoplasmic reticulum leading to depleted ATP reserves. Thus, an emerging approach is to design sarcomere-based treatments to correct impaired contractility via a direct and allosteric modulation of myosin's intrinsic force-generating behavior -a concept that potentially avoids the "off-target" effects. To achieve this goal, various biophysical approaches are utilized to investigate the mechanistic impact of sarcomeric modulators but information derived from diverse approaches is not fully integrated into therapeutic applications. This is in part due to the lack of information that provides a coherent connecting link between biophysical data to in vivo function. Hence, our ability to clearly discern the drug-mediated impact on whole-heart function is diminished. Reducing this translational barrier can significantly accelerate clinical progress related to sarcomere-based therapies by optimizing drug-dosing and treatment duration protocols based on information obtained from biophysical studies. Therefore, we attempt to link biophysical mechanical measurements obtained in isolated cardiac muscle and in vivo contractile function.

Keywords: Biophysical measurements; Cross-bridge behavior; Failing myocardium; In vivo function; Myosin modulators; Sarcomere-based therapies.