Study provides new insights into the cellular and molecular biology of human heart failure

Study provides new insights into the cellular and molecular biology of human heart failure

By studying heart samples from patients with cardiomyopathies as well as controls without heart disease, researchers have gained new insights into the cellular and molecular biology of human heart failure - a highly fatal disease that affects 23 million people worldwide. These results — which used a technique called single-nucleus RNA sequencing (snRNAseq) analysis — “upend a prevailing dogma that heart failure results from a common terminal pathway,” say the study authors, “and may guide future development of therapies targeting selective targets to improve personalized medicine.”

Cardiomyopathy is a group of diseases that affect the heart muscle in ways that impair the organ's ability to pump blood effectively. These serious diseases are leading causes of heart failure and leading indications for heart transplantation. Some cardiomyopathies, including dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM), can arise from mutations in genes that encode proteins with different functions in cardiac biology.

However, how the pathogenic variants in genes associated with DCM and ACM confer such a high risk of developing heart failure is unknown. While the idea has been popularized that various stimuli converge on a common final pathway to lead to heart failure, new technologies provide direct opportunities to evaluate whether genotype instead influences disease pathways. Daniel Reichart and colleagues performed snRNAseq in heart tissue samples from patients with genetic and idiopathic (mutation-negative) DCM and ACM and in patients without structural heart disease.

Reichart et al. used machine learning to examine the 880,000 transcriptomes the analysis generated. were able to identify distinct cell types involved in the pathway to heart failure and identify their locations in the heart as well as genotype-associated pathways, intercellular interactions, and differential gene expression for these diseases at single-cell resolution.

“This network showed remarkably high prediction of genotypes for each heart sample, confirming our conclusion that genotypes activate very specific heart failure pathways,” the authors said. “Although interrogation of these datasets provides ongoing discovery opportunities, our results provided substantial evidence that genotype influenced pathological remodeling of the heart.”

Source:

American Association for the Advancement of Science

Reference:

Reichart, D., et al. (2022) Pathogenic variants damage cell composition and single-cell transcription in cardiomyopathies. Science. doi.org/10.1126/science.abo1984.

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