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Updated: Jan 20, 2026
The Extracellular Matrix and Support Proteins in Tissues
Extracellular Matrix From Hypertrophic Myocardium Provokes Impaired Twitch Dynamics in Healthy Cardiomyocytes
Lorenzo R Sewanan1, Jonas Schwan1, Jonathan Kluger1
1Department of Biomedical Engineering, Yale University, New Haven, Connecticut.
Abstract:
Hypertrophic cardiomyopathy (HCM) is often caused by single sarcomeric gene mutations that affect muscle contraction. Pharmacological correction of mutation effects prevents but does not reverse disease in mouse models. Suspecting that diseased extracellular matrix is to blame, we obtained myocardium from a miniature swine model of HCM, decellularized thin slices of the tissue, and re-seeded them with healthy human induced pluripotent stem cell-derived cardiomyocytes. Compared with cardiomyocytes grown on healthy extracellular matrix, those grown on the diseased matrix exhibited prolonged contractions and poor relaxation. This outcome suggests that extracellular matrix abnormalities must be addressed in therapies targeting established HCM.
Insights
Hypertrophic cardiomyopathy (HCM) therapies may need to target the extracellular matrix. Diseased matrix, not just gene mutations, causes abnormal heart muscle cell contractions in HCM.
Area of Science:
- Cardiovascular Biology
- Extracellular Matrix Research
- Stem Cell Therapy
Background:
- Hypertrophic cardiomyopathy (HCM) is a genetic heart muscle disease.
- Current treatments for HCM focus on genetic mutations and prevent disease progression but do not reverse existing conditions.
- The role of the extracellular matrix (ECM) in established HCM is not fully understood.
Purpose of the Study:
- To investigate the impact of the diseased extracellular matrix in hypertrophic cardiomyopathy (HCM) on cardiomyocyte function.
- To determine if the ECM contributes to the contractile dysfunction observed in established HCM.
- To explore potential therapeutic strategies targeting the ECM in HCM.
Main Methods:
- Myocardium was obtained from a miniature swine model of HCM.
- Tissue slices were decellularized to isolate the extracellular matrix.
- Healthy human induced pluripotent stem cell-derived cardiomyocytes were re-seeded onto the decellularized matrices (diseased and healthy controls).
- Cardiomyocyte contraction and relaxation dynamics were analyzed on both matrix types.
Main Results:
- Cardiomyocytes cultured on the diseased HCM extracellular matrix exhibited significantly prolonged contractions.
- Impaired relaxation of cardiomyocytes was observed when grown on the diseased matrix.
- These functional deficits were not seen in cardiomyocytes cultured on healthy extracellular matrix.
Conclusions:
- Extracellular matrix abnormalities play a critical role in the pathophysiology of established hypertrophic cardiomyopathy (HCM).
- The diseased ECM contributes to impaired cardiomyocyte contractility and relaxation.
- Therapeutic strategies for established HCM should consider addressing extracellular matrix alterations in addition to genetic factors.
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