Heart failure is caused by mutations in certain genes, study results

Heart failure is caused by mutations in certain genes, study results

Heart failure is a common and devastating disease for which there is no cure. Many cardiomyopathies – diseases 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 patients with heart failure do not address these specific conditions.

Researchers at Brigham and Women's Hospital and Harvard Medical School (HMS) set out to identify molecules and signaling pathways that may contribute to heart failure, with the goal of providing more effective and personalized treatment. Using single nuclear RNA sequencing (snRNAseq) to gain insights into 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 common genetic signatures, others are different, providing new candidate therapeutic targets and predicting that personalized treatment could improve patient care. The results are published in Science.

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

This is basic research, but it identifies targets that can be pursued experimentally to advance future therapeutics. Our results also point to the importance of genotyping -; Genotyping not only strengthens research, but can also lead to better, personalized treatment for patients.”

Christine E. Seidman, co-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, worked with an international team. To conduct their study, Seidman and colleagues analyzed samples from 18 control hearts and 61 heart failure patients with DCM, ACM or an unknown cardiomyopathy. 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 scar formation), smooth muscle cells, and many more. Scientists use snRNAseq to examine the genetic readout of a single cell, allowing 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. Overall, the fibroblasts did not increase in size, but showed altered activity. Analyzes of multiple hearts with mutations in specific disease genes -; including TTN, PKP2 and LMNA revealed molecular and cellular differences as well as some common responses. 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, genotype differences promoted distinct signaling even in advanced disease.

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

“We could not 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 others can advance our understanding of disease, improve treatment and work on strategies to prevent heart failure.”

Source:

Brigham and Women's Hospital

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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