Heart failure arises from mutations in distinct genes, study finds

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 patients with heart failure do not take these distinct conditions into account.

Investigators from 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 aim of informing more effective and personalized treatment. Using single nucleus RNA sequencing (snRNAseq) to gain insight 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 shared genetic signatures, others are distinct, providing new candidate targets for therapy and predicting that personalized treatment could improve patient care. Results are published in Science.

"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," said co-corresponding author Christine E. Seidman, MD, director of the Cardiovascular Genetics Center in the Division of Cardiovascular Medicine at the Brigham, and the Thomas W. Smith Professor of Medicine at HMS.

This is fundamental research, but it identifies targets that can be experimentally pursued to propel future therapeutics. Our findings also point to the importance of genotyping -; not only does genotyping empower research but it can also lead to better, personalized treatment for 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 composed 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 from a single cell, allowing the researchers to determine cellular and molecular changes in each distinct cell type.

From these data, the team identified 10 major cell types and 71 distinct transcriptional states. They found that in the tissue from patients with DCM or ACM, cardiomyocytes were depleted while endothelial and immune cells were increased. Overall, fibroblasts did not increase but showed altered activity. Analyses of multiple hearts with mutations in certain disease genes -; including TTN, PKP2, and LMNA uncovered molecular, and cellular differences as well as some shared responses. The team also leveraged 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 distinct signals, even in advanced disease.

The authors note that future studies are needed to further define the molecular underpinnings of cardiomyopathies and heart failure across sex, 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," said Seidman. "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."