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

Mamidi, Ranganath, Li, Jiayang, Doh, Chang Yoon, Holmes, Joshua B., Stelzer, Julian E.
Archives of biochemistry and biophysics 2019 v.662 pp. 213-218
adenosine triphosphate, adverse effects, arrhythmia, calcium, heart failure, homeostasis, mechanics, myocardium, myosin, patients, protocols, sarcoplasmic reticulum, therapeutics
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.