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Heart failure is caused by changes in different genes, a study shows


Heart failure is a devastating condition that affects many people and for which there is no cure.

Heart failure can be caused by a variety of cardiomyopathies, including dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM), but treatments for heart failure patients do not take these distinct conditions into consideration.

In order to develop more effective and individualized treatments, researchers from Brigham and Women’s Hospital and Harvard Medical School (HMS) set out to identify molecules and pathways that may contribute to heart failure.

The team made several unexpected discoveries using single nucleus RNA sequencing (snRNAseq) to gain understanding of the precise changes that take place in various cell types and cell states.

While some genetic signatures were discovered to be shared, others were found to be unique, offering new potential therapeutic targets and suggesting that patient care might be enhanced by personalized medicine. Science publishes the findings.

Gene mutations cause heart failure, study finds
Gene mutations cause heart failure, study finds

The Thomas W. Smith Professor of Medicine at Harvard Medical School and co-corresponding author Christine E. Seidman, MD.

Pointed out that “our findings hold enormous potential for rethinking how we treat heart failure and point to the importance of understanding its root causes and the mutations that lead to changes that may alter how the heart functions.”

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Seidman worked alongside an international group of researchers as did Jonathan Seidman, PhD, the Henrietta B. and Frederick H. Bugher Foundation Professor of Genetics at HMS. Seidman and colleagues examined samples from 61 failing human hearts from patients with DCM, ACM, or an unidentified cardiomyopathy disease, as well as 18 failing human hearts from controls for their study.

The beating heart cells, or cardiomyocytes, the connective tissue-forming and scarring cells, the smooth muscle cells, and a variety of other cell types make up the human heart.

Researchers can identify cellular and molecular changes in each different cell type by using snRNAseq to examine the genetic readout from a single cell.

The team determined 71 different transcriptional states and 10 main cell types from these data. They discovered that endothelial and immune cells increased while cardiomyocytes were decreased in tissue from patients with DCM or ACM.

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Fibroblast activity was altered but did not increase overall. Analysis of numerous hearts that had the disease genes TTN, PKP2, and LMNA mutated revealed molecular and cellular variations as well as some common responses.

The group used machine learning techniques to find patterns in the data related to cells and genotypes. This strategy reinforced the finding that, despite some disease pathways converging, genotype variations promoted distinct signals even in advanced disease.

Future research is required, according to the authors, to better understand the molecular causes of cardiomyopathies and heart failure across gender, age, and other demographics as well as in various heart regions.

Here, the team has made its platform and datasets available without charge.

Without the sample donations from patients, Seidman claimed, “We could not have completed this work.”

“Our mission is to accelerate research and make our work accessible so that others can continue to advance our understanding of disease, improve treatment, and develop strategies to prevent heart failure,” the statement reads. “We want to honor their contributions.”

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