Secrets of Hypertrophic Cardiomyopathy

Researchers have for the first time documented altered ligand receptor gene expression at the single cell level in samples from human patients with clinically documented obstructive hypertrophic cardiomyopathy (HCM) and mostly without sarcomere gene mutations. These results suggest alterations in intercellular communication and extracellular matrix signaling in these patients.

What you should know about hypertrophic cardiomyopathy

Hypertrophic cardiomyopathy is a relatively common genetic disorder of the heart muscle that causes an abnormal thickening of the left ventricle. The disease affects about 1 in 500 people and leads to various complications such as heart failure and cardiac arrhythmias. The symptoms of HCM can include chest pain or discomfort, shortness of breath, especially during physical activity, palpitations or irregular heartbeats, dizziness or fainting, and also swelling in the legs, ankles, or feet. It is often caused by mutations in genes involved in the structure and function of the heart muscle cells (called sarcomeres), with the most common being MYBPC3 and MYH7.

However, genetic testing is only able to explain HCM in about 30% of cases, and environmental and other genetic factors may also play a role. Researchers are studying the pathways that lead to HCM complications, particularly left ventricular outflow tract obstruction, in order to identify potential targets for new treatments. Using single cell RNA-sequencing, they have examined gene expression in heart tissue from patients with HCM and unused donor hearts to identify cell-specific pathological pathways that may contribute to the development of left ventricular outflow tract obstruction in HCM.

Investigating the Link between Altered Communication and Matrix Signaling

In a new study, researchers used single cell RNA-sequencing to examine gene expression in heart tissue samples from patients with hypertrophic cardiomyopathy and unused donor hearts. They used a technique called nuclei isolation to prepare the samples for sequencing, and processed the sequencing data using the Cell Ranger and Seurat software. After that, they used clustering and dimensionality reduction techniques to identify patterns of gene expression and to assign cell type identities to the cells in the samples. They also used differential gene expression analysis to identify genes that were differentially expressed between the HCM and control samples.

The researchers found that there were 34 distinct cell populations in the samples, which could be classified into 10 different cell types based on marker gene expression. There were differences in sarcomere and extracellular matrix gene expression between the HCM and control samples. Analysis of expressed ligand-receptor pairs across multiple cell types also showed significant changes in intercellular communication in HCM, particularly between cardiomyocytes and fibroblasts, fibroblasts and lymphocytes, and involving integrin β1 and its extracellular matrix cognate ligands. These findings suggest that sarcomere dysfunction in HCM may be associated with reduced cardiomyocyte secretion of extracellular matrix ligands, altered fibroblast ligand-receptor interactions with other cell types, and increased fibroblast to lymphocyte signaling. This can alter the composition of the extracellular matrix and contribute to nonmyocyte phenotypes in HCM.

The clinical implications of this work are that another paradigm for HCM pathogenesis beyond sarcomere dysfunction needs to be considered, involving intercellular communication between cardiomyocytes, the extracellular matrix, fibroblasts and components of the immune system. Understanding the roles of cells other than myocytes will identify other potential therapeutic targets for disease-specific and personalized therapies. The discovery of a potential role for integrin-β1 and its ECM ligands in human HCM-associated LVOT obstruction provides an opportunity for further mechanistic studies in experimental models and also for potential clinical trials with FDA-approved anti-integrin therapies.