Studying heart samples from patients with cardiomyopathies, as well as from controls without heart disease, researchers have provided new insights into the cellular and molecular biology of human heart failure – a highly fatal condition that affects 23 million people worldwide. These results – which leveraged a technique called single-nucleus RNA-sequencing (snRNAseq) analysis – "upend a prevalent dogma that heart failure results from a common final pathway," say the study's authors, "and can guide the future development of therapies with selective targets to enhance personalized medicine."
Cardiomyopathy is a group of diseases that affect the heart muscle in ways that interfere with the organ's ability to pump blood effectively. These serious disorders are major 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 diverse functions in cardiac biology.
However, how the pathogenic variants in genes associated with DCM and ACM convey such high risks for the development of heart failure is unknown. While the notion that diverse stimuli converge on a common final pathway to lead to heart failure has been propelled, new technologies provide direct opportunities to evaluate whether, instead, genotype 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 those without structural heart disease.
Using machine learning to probe the 880,000 transcriptomes the analysis generated, Reichart et al. were able to identify distinct cell types involved in the path towards heart failure and their locations in the heart, as well as genotype-associated pathways, intercellular interactions, and differential gene expression for these disorders at the single-cell resolution.
"This network showed remarkably high prediction of the genotypes for each cardiac sample, thereby reinforcing our conclusion that genotypes activate very specific heart failure pathways," said the authors. "Although interrogation of these datasets provides ongoing opportunities for discovery, our findings provided substantial evidence that genotype influenced pathological remodeling of the heart."
Reichart, D., et al. (2022) Pathogenic variants damage cell composition and single cell transcription in cardiomyopathies. Science. doi.org/10.1126/science.abo1984.