Heart failure stems from mutations in several genes, study finds

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

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, aiming to provide information about more effective and personalized treatment. Using single nucleus RNA sequencing (snRNAseq) to understand the specific changes that occur in different cell types and cell states, the team made several surprising discoveries. They found that while there are some shared genetic signatures, others are different, offer new candidate targets for therapy and predict that personalized treatment could improve patient care. Results will be published in Science.

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

This is basic research, but it identifies targets that can be pursued experimentally to propel future therapies. Our findings also point to the importance of genotyping -; genotyping not only enables research, but can also lead to better, personalized treatment of patients.”

Christine E. Seidman, co-corresponding author and director, Cardiovascular Genetics Center, Division of Cardiovascular Medicine, Brigham and Women’s Hospital

Seidman and Jonathan Seidman, PhD, 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 control and 61 failing human hearts from patients with DCM, ACM or an unknown cardiomyopathy disease. The human heart is made up of many different cell types, including cardiomyocytes (beating heart cells), fibroblasts (which help form connective tissue and contribute to scarring), smooth muscle cells, and many more. Scientists use snRNAseq to look at the genetic readout of a single cell, allowing the researchers to determine cellular and molecular changes in each individual cell type.

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

The authors note that future studies are needed to further define the molecular underpinnings of cardiomyopathies and heart failure for gender, age and other demographics, as well as for different parts of the heart. The team has made its datasets and platform available for free here.

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


Brigham and the Women’s Hospital

Reference magazine:

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

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