Complexity in genetic cardiomyopathies and new approaches for mechanism-based precision medicine

Abstract

Genetic cardiomyopathies have been studied for decades, and it has become increasingly clear that these progressive diseases are more complex than originally thought. These complexities can be seen both in the molecular etiologies of these disorders and in the clinical phenotypes observed in patients. While these disorders can be caused by mutations in cardiac genes, including ones encoding sarcomeric proteins, the disease presentation varies depending on the patient mutation, where mutations even within the same gene can cause divergent phenotypes. Moreover, it is challenging to connect the mutation-induced molecular insult that drives the disease pathogenesis with the various compensatory and maladaptive pathways that are activated during the course of the subsequent progressive, pathogenic cardiac remodeling. These inherent complexities have frustrated our ability to understand and develop broadly effective treatments for these disorders. It has been proposed that it might be possible to improve patient outcomes by adopting a precision medicine approach. Here, we lay out a practical framework for such an approach, where patient subpopulations are binned based on common underlying biophysical mechanisms that drive the molecular disease pathogenesis, and we propose that this function-based approach will enable the development of targeted therapeutics that ameliorate these effects. We highlight several mutations to illustrate the need for mechanistic molecular experiments that span organizational and temporal scales, and we describe recent advances in the development of novel therapeutics based on functional targets. Finally, we describe many of the outstanding questions for the field and how fundamental mechanistic studies, informed by our more nuanced understanding of the clinical disorders, will play a central role in realizing the potential of precision medicine for genetic cardiomyopathies.

Mechanical dysfunction of the sarcomere induced by a pathogenic mutation in troponin T drives cellular adaptation

“…We believe that cardiomyopathies are excellent candidates for a precision medicine approach ( McNally and Mestroni, 2017 ; Fatkin et al, 2019 ; Lavine and Greenberg, 2020 ; Greenberg and Tardiff, 2021 ). Recently, there was a report of a HCM mutation in α-actinin linked to action potential prolongation attributed to increased calcium current density ( Prondzynski et al, 2019 ), and the patient harboring this mutation was successfully treated with the L-type calcium channel blocker diltiazem.…”

“…The disease presentation in HCM is quite complex, with functional differences seen at scales ranging from molecules to tissues; however, the molecular triggers that drive the disease pathogenesis are alterations in the abundance, stability, and/or functionality of mutant protein ( Greenberg and Tardiff, 2021 ). This initial trigger activates downstream adaptive and maladaptive processes, some of which can take years to decades to manifest, including ventricular remodeling, and eventually symptomatic disease.…”

A troponin T variant linked with pediatric dilated cardiomyopathy reduces the coupling of thin filament activation to myosin and calcium binding

“…However, the mechanisms by which mutation-induced changes in protein interactions at the molecular level affect cardiac contraction and drive the disease pathogenesis at the cellular level are not wellunderstood. Furthermore, these disease-driving defects can vary between mutations, even within the same molecule (Lynn et al, 2018;Greenberg and Tardiff, 2021;Lavine and Greenberg, 2021). Understanding these mechanisms is a critical step in developing precision medicine therapeutics that target mutation-specific defects.…”

Toward an understanding of myofibrillar function in health and disease

“…To an increasing degree, it has become evident that both spontaneous and heritable mutations in cardiac MyBP-C can cause cardiac myopathies which in their most virulent forms can cause sudden cardiac death ( Greenberg and Tardiff, 2021 ). Also, in end-stage heart disease, such as congestive heart failure, the myocardium exhibits diminished or absent responsiveness to physiological processes such as increased β-adrenergic tone or the Frank–Frank–Starling mechanism (increased stroke volume due to increased end-diastolic volume) that are normally activated when cardiac output and systolic blood pressure are reduced.…”

“…Two additional articles in this issue focus on mutations that cause myopathies. Greenberg and Tardiff (2021) review the biophysical basis of cardiomyopathies that are due to mutations in myofilament proteins. Based on their analyses, they propose that developing effective treatments for these disorders will greatly benefit from binning patient subpopulations based on common underlying biophysical mechanisms that drive the molecular disease pathogenesis.…”