What is the clinical evidence from this study?

Study design: Other. Population: Hypertrophic cardiomyopathy. Intervention: Substrate stiffness (stiff hydrogels mimicking HCM myocardium) vs. Soft hydrogels mimicking healthy myocardium. Primary outcome: Mitochondrial metabolic activity and membrane potential.

What does this research mean for the field?

Increased extracellular matrix stiffness mimicking hypertrophic cardiomyopathy is sufficient to induce a hypermetabolic mitochondrial state in cardiac myocytes via a maladaptive mechanosensing feedback mechanism with the cytoskeleton. Novelty: ClaimNovelty.NOVEL_FINDING. Consensus alignment: ConsensusAlignment.NEUTRAL.

January 3, 2023Open Access

A maladaptive feedback mechanism between the extracellular matrix and cytoskeleton contributes to hypertrophic cardiomyopathy pathophysiology

HVHelena M. ViolaVictor Chang Cardiac Research Institute CRCaitlyn RichworthThe University of Western Australia TSTanya SolomonUniversity of British Columbia

Key Result

Culturing wild-type cardiac myocytes on hydrogels with stiffness mimicking hypertrophic cardiomyopathy myocardium induced a hypermetabolic mitochondrial state.

Structured PICO

Population

H9C2 myoblast cell line isolated from rat ventricular tissue, cardiac myocytes isolated from 10 to 15-week-old wild-type mice, and 30-50-week-old cTnI-G203S mice (murine model of human hypertrophic cardiomyopathy).

Intervention

Culturing on stiff polyacrylamide hydrogels (Young's Modulus 34.1 ± 0.9 kPa) mimicking hypertrophic cardiomyopathy myocardium.

Comparator

Culturing on soft polyacrylamide hydrogels (Young's Modulus 12.5 ± 0.4 kPa) mimicking healthy myocardium.

Outcome

Mitochondrial metabolic activity (flavoprotein oxidation) and mitochondrial membrane potential (Ψm).surrogate

Increased extracellular matrix stiffness contributes to hypertrophic cardiomyopathy pathophysiology by inducing a hypermetabolic mitochondrial state via a mechanosensing feedback mechanism between the cytoskeleton and the L-type calcium channel.

Limitations

Studies were performed in quiescent cardiac myocytes, so measurements of contractility are required to further elucidate the role of ECM stiffness.
Further investigation is required to confirm the involvement of the proposed mechanism in the development of specific HCM causing sarcomeric gene mutations.
Further functional studies utilizing the platforms described would be required to confirm a causal role of mTOR in disease progression.

Abstract

Hypertrophic cardiomyopathy is an inherited disorder due to mutations in contractile proteins that results in a stiff, hypercontractile myocardium. To understand the role of cardiac stiffness in disease progression, here we create an in vitro model of hypertrophic cardiomyopathy utilizing hydrogel technology. Culturing wild-type cardiac myocytes on hydrogels with a Young's Moduli (stiffness) mimicking hypertrophic cardiomyopathy myocardium is sufficient to induce a hypermetabolic mitochondrial state versus myocytes plated on hydrogels simulating healthy myocardium. Significantly, these data mirror that of myocytes isolated from a murine model of human hypertrophic cardiomyopathy (cTnI-G203S). Conversely, cTnI-G203S myocyte mitochondrial function is completely restored when plated on hydrogels mimicking healthy myocardium. We identify a mechanosensing feedback mechanism between the extracellular matrix and cytoskeletal network that regulates mitochondrial function under healthy conditions, but participates in the progression of hypertrophic cardiomyopathy pathophysiology resulting from sarcomeric gene mutations. Importantly, we pinpoint key 'linker' sites in this schema that may represent potential therapeutic targets.

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