Heart failure arises from mutations in different genes, according to a study

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Heart failure is a common and devastating disorder for which there is no cure. Many cardiomyopathies – conditions that make it difficult for the heart to pump blood such as dilated cardiomyopathy (DCM) and arrhythmogenic cardiomyopathy (ACM) -; can lead to heart failure, but treatments for heart failure patients do not take these various conditions into account.

Researchers at Brigham and Women’s Hospital and Harvard Medical School (HMS) set out to identify molecules and pathways that may contribute to heart failure, with the goal of informing more effective and personalized treatment. Using single-nucleotide RNA sequencing (snRNAseq) to gain insight into the specific changes that occur in different cell types and cellular states, the team made several surprising discoveries. They found that while there are some shared genetic signatures, others are distinct, providing new candidate targets for therapy and predicting that personalized treatment could improve patient care. The results are published in Sciences.

“Our findings have enormous potential to rethink how we treat heart failure and point to the importance of understanding its root causes and the mutations that lead to changes that can alter heart function,” said corresponding co-author Christine E. Seidman. , MD. , director of the Center for Cardiovascular Genetics in Brigham’s Division of Cardiovascular Medicine, and the Thomas W. Smith Professor of Medicine at HMS.

This is fundamental research, but it identifies targets that can be pursued experimentally to drive future therapies. Our findings also point to the importance of genotyping -; Genotyping not only powers research, but may also lead to better personalized treatment for patients.”

Christine E. Seidman, Co-Corresponding Author and Director, Center for Cardiovascular Genetics, Division of Cardiovascular Medicine, Brigham and Women’s Hospital

Seidman and Jonathan Seidman, PhD, the Henrietta B. and Frederick H. Bugher Foundation Professor of Genetics at HMS, collaborated with an international team. To conduct their study, Seidman and colleagues analyzed samples from 18 controls and 61 defective human hearts from patients with DCM, ACM, or unknown cardiomyopathy disease. The human heart is made up of many different cell types, including cardiomyocytes (cells of the beating heart), fibroblasts (which help form connective tissue and contribute to scar formation), smooth muscle cells, and many more. Scientists use snRNAseq to look at the genetic readout of a single cell, allowing them to determine the cellular and molecular changes in each different cell type.

From these data, the team identified 10 major cell types and 71 distinct transcriptional states. They found that in tissue from DCM or ACM patients, cardiomyocytes were depleted while endothelial and immune cells increased. In general, the fibroblasts did not increase but showed altered activity. Analysis of multiple hearts with mutations in certain disease genes -; included TTN, PKP2, Y LMNA discovered molecular and cellular differences, as well as some shared responses. The team also leveraged machine learning approaches to identify cell patterns and genotypes in the data. This approach further confirmed that while some disease pathways converged, differences in genotype promoted distinct signals, even in advanced disease.

The authors note that future studies are needed to better define the molecular underpinnings of cardiomyopathies and heart failure based on gender, age, and other demographics, as well as in different areas of the heart. The team has made its datasets and platform freely available here.

“We couldn’t have done this work without patient sample donations,” Seidman said. “Our goal is to honor their contributions by accelerating research and making our work available so that others can continue to advance our understanding of the disease, improve treatment, and work on strategies to prevent heart failure.”


Brigham and Women’s Hospital

Magazine Reference:

Reichart, D. and others. (2022) Pathogenic variants damage cellular composition and single cell transcription in cardiomyopathies. Sciences. doi.org/10.1126/science.abo1984.

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