The role of crosstalk and stress on hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy (HCM) is a disease where the walls of the heart become thicker than usual, squeezing the left ventricle and causing shortness of breath, chest pain, or even heart failure.

It is often caused by mutations that affect the sarcomere — a small unit of muscle tissue — and two genes, MYH7 and MYBPC3, that have been specifically linked to the disease.

Jiang et al. studied the effect of MYBPC3 on the disease phenotype using engineered human micro-heart tissue, recreating a holistic modeling environment.

“We knew from our prior studies that mechanical resistance and mechanical stress could bring out the HCM phenotype,” said author Nathaniel Huebsch. “By [using] something that’s structurally more like a real heart, we could push [the tissue] to be mature enough to see a disease phenotype.”

Specifically, the researchers saw that having connective tissue cells, called fibroblasts, present in the tissue helped to bring out the HCM phenotype in the tissue model with disease-causing MYBPC3 mutations.

Their micro-heart tissue, which allowed them to control the stiffness of the model, showed that the communication between the fibroblasts and cardiomyocytes was changed when the tissue stiffened.

The researchers also observed more breakdown of HCM cardiomyocytes’ sarcomere structures when fibroblasts were present. All the results implied that the team was modeling distinct disease stages of HCM.

“There’s always this question of how sophisticated you need these models to actually be,” Huebsch said. “And here, we’re seeing this crosstalk between the cardiomyocytes and the fibroblasts. That crosstalk is an argument that we really do need to think not just about how the cardiomyocytes with the mutation might secrete things that affect fibroblasts but how having them together — and having that paracrine crosstalk in real time — might be important.”

Source: “Biomechanical stress unmasks a fibroblast-dependent hypercontractile-disarray phenotype in MYBPC3 truncation HCM,” by Huanzhu Jiang, Ganesh Malayath, Nongmaithem Debeni Devi, Hsin-Yi Cindy Chou, Yasaman Kargar Gaz Kooh, Jingxuan Guo, Ghiska Ramahdita, Jenna Nguyen, Riya Bhakta, Lavanya Aryan, Sharon Cresci, and Nathaniel Huebsch, APL Bioengineering (2026). The article can be accessed at https://doi.org/10.1063/5.0336866 .