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

Abstract

Current inotropic therapies improve systolic function in heart failure patients but they also elicit undesirable side effects such as arrhythmias and increased intracellular Ca 2+ transients. In order to maintain myocyte Ca 2+ homeostasis, the increased cytosolic Ca 2+ 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.

Analysis of Contractile Function of Permeabilized Human Hypertrophic Cardiomyopathy Multicellular Heart Tissue

“…Patients with double mutations generally show an earlier disease presentation, more severe LV hypertrophy, higher prevalence of advanced heart failure, and an increased risk of sudden cardiac death than patients with single heterozygous mutations (Maron et al., 2012; Biagini et al., 2014; Fazeli Dehkordy et al., 2018). A differential Ca 2+ sensitivity has also been observed in other studies with different HCM disease genes (Ren et al., 2018; Mamidi et al., 2019). It therefore seems that the direction and magnitude of the change not only depends on the affected gene ( MYBPC3 vs. MYH7 ) but also on the genetic status (single vs. double heterozygous), but not on the mutation type (missense vs. truncating).…”

AAV9 gene transfer of cMyBPC N-terminal domains ameliorates cardiomyopathy in cMyBPC-deficient mice

“…Once the myocardial preparations attained a steady-state force, they were subjected to a sudden 2% stretch of their initial muscle length (ML), held at the new ML for 8 seconds, and returned back to their initial ML. The characteristic features of the cardiac muscle stretch activation responses have been described earlier (68,70). Briefly, a sudden 2% stretch in ML elicits an instantaneous spike in the force (P1) due to a sudden strain of elastic elements within the strongly bound XBs (Phase 1).…”

The HCM-causing Y235S cMyBPC mutation accelerates contractile function by altering C1 domain structure

“…The impact of the Y235S mutation on the rate of XB detachment was assessed by measuring k rel [88]. Our results show that the KO Y235S myocardium displays accelerated k rel (~31%; P<0.05) and a greater magnitude of XB detachment (0.031±0.012 for KO WT vs. −0.008±0.015 for KO Y235S ; P<0.05) compared to the KO WT myocardium (Table 2).…”

“…The impact of the Y235S mutation on the rate and magnitude of XB recruitment was assessed by measuring k df and P df , respectively [88]. The rate of XB recruitment (k df ) of the KO WT myocardium was 6.36±0.41 s −1 , whereas k df in the KO Y235S myocardium was 8.11±0.43 s −1 (~28% increase, Table 2).…”