Modulating the tension-time integral of the cardiac twitch prevents dilated cardiomyopathy in murine hearts.

Joseph D Powers,Kristina B Kooiker,Abigail E Teitgen,Jennifer Davis,Michael Regnier,Farid Moussavi-Harami,Steven D Schwartz,Galina V Flint,Jil C Tardiff,Allison B Mason,Andrew D Mcculloch

doi:10.1172/jci.insight.142446

Abstract

Dilated cardiomyopathy (DCM) is often associated with sarcomere protein mutations that confer reduced myofilament tension–generating capacity. We demonstrated that cardiac twitch tension-time integrals can be targeted and tuned to prevent DCM remodeling in hearts with contractile dysfunction. We employed a transgenic murine model of DCM caused by the D230N-tropomyosin (Tm) mutation and designed a sarcomere-based intervention specifically targeting the twitch tension-time integral of D230N-Tm hearts using multiscale computational models of intramolecular and intermolecular interactions in the thin filament and cell-level contractile simulations. Our models predicted that increasing the calcium sensitivity of thin filament activation using the cardiac troponin C (cTnC) variant L48Q can sufficiently augment twitch tension-time integrals of D230N-Tm hearts. Indeed, cardiac muscle isolated from double-transgenic hearts expressing D230N-Tm and L48Q cTnC had increased calcium sensitivity of tension development and increased twitch tension-time integrals compared with preparations from hearts with D230N-Tm alone. Longitudinal echocardiographic measurements revealed that DTG hearts retained normal cardiac morphology and function, whereas D230N-Tm hearts developed progressive DCM. We present a computational and experimental framework for targeting molecular mechanisms governing the twitch tension of cardiomyopathic hearts to counteract putative mechanical drivers of adverse remodeling and open possibilities for tension-based treatments of genetic cardiomyopathies.

Highlights

Dilated cardiomyopathy (DCM) is a common and deadly genetic cardiac disorder that affects approximately 1:250 individuals [1] and is typically characterized by enlarged chambers and a thinning of ventricular walls that leads to systolic heart failure [2, 3]
Fraction (EF) of D230N hearts progressively worsened from 2–5 months of age, whereas the fractional shortening (FS) and EF of DTG hearts were approximately constant with age and did not differ significantly from WT hearts at any age (Figure 5, C and D). (See Supplemental Table 3 for numerical values of all echocardiography measurements.) These results demonstrate that hearts containing D230N-Tm progressively developed DCM, whereas the expression of L48Q cardiac troponin C (cTnC) in these hearts prevented the development of the DCM phenotype
We used a combined experimental and computational approach to identify tunable molecular interactions in the sarcomere that would enable the modulation of the twitch T-time integral of hearts containing the DCM-causing D230N-Tm mutation

Summary

Introduction

Dilated cardiomyopathy (DCM) is a common and deadly genetic cardiac disorder that affects approximately 1:250 individuals [1] and is typically characterized by enlarged chambers and a thinning of ventricular walls that leads to systolic heart failure [2, 3]. DCM is often caused by loss-of-function mutations in genes encoding sarcomere proteins [4,5,6] that reduce the tension-generating capacity of the myofilaments, which leads to the adverse ventricular remodeling and heart failure. The authors systematically perturbed the contractile performance of the sarcomere using a wide variety of genetically engineered murine models and human-induced pluripotent stem cell–derived cardiomyocytes from patients with cardiomyopathies. They found that the twitch T-time integral of genetic variants relative to controls, termed the “T index” (TI), strongly correlates with the type and severity of cardiac growth in each model. Genetic modifications to the sarcomere that decrease the twitch T-time integral (i.e., have a TI < 0) strongly correlate with eccentric cardiac growth, whereas modifications that increase the twitch T-time integral (i.e., have a TI > 0) strongly correlate with concentric cardiac growth (Figure 1A)

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