Scientists at the Precision Cardiology Laboratory (PCL) at MIT’s Broad Institute and Harvard and Bayer have generated detailed maps of various heart cell types implicated in two major causes of heart failure: dilated and hypertrophic cardiomyopathy (DCM and HCM), both of which impair the pumping ability of the heart.
The team’s findings, published today in Nature, suggest specific cell types and biological mechanisms that could be targeted by novel treatments. Heart failure is one of the most common causes of hospitalization in the United States. Existing drugs are limited and many patients end up dying heart failure.
To create their cellular maps, the researchers used single-nucleus RNA sequencing (RNA-seq), which reveals which genes are active and at what levels in individual cells. They studied heart tissues from patients with advanced heart failure and found that DCM and HCM cardiac cells expressed different genes than non-failing hearts, but gene expression profiles were similar for DCM and HCM patients. Some cardiomyopathy patients also had a unique set of fibroblasts, or connective tissue cells, which the researchers believe may contribute to tissue scarring in heart failure and could be targets for future treatments.
This study builds on an earlier effort to catalog individual cells from the healthy human heart and is the result of close collaboration with the team of Ken Margulies, Professor of Medicine and Heart Failure Physician at the University of Pennsylvania. Mapping the cells involved in distinct forms of heart failure could help researchers identify markers that would allow them to differentiate disease types and predict clinical outcomes.
“At present, almost all forms of heart failure are all treated equally, regardless of their cause,” said Patrick Ellinor, who led the team and is a fellow at the Broad Institute. , director of the Demoulas Center for Cardiac Arrhythmias at Massachusetts General Hospital. , and professor at Harvard Medical School. “Our goal was to ask, in people with disease, are there cell populations or expressed genes that are different between health and disease? And yes, we have found that genes indicating highly active cardiac fibroblasts have been found in some disease patients.
“Bayer and Broad scientists worked side-by-side to generate, analyze and validate the data for this study. This level of collaboration between academia and the pharmaceutical industry is extremely rare,” said Carla Klattenhoff, senior director and head of Bayer and Broad’s joint Precision Cardiology Laboratory. “This map is an incredible resource for the field of cardiology.
“This is an important scientific contribution to deepening our understanding of diseases in order to provide precision medicines for cardiology,” added Ulrich Nielsch, Head of Therapeutic Area 1 at Bayer.
Cell by cell
Previous studies have shown that failing hearts have unique properties gene expression profiles, or transcriptomes, compared to healthy hearts, but this work only generated single genetic fingerprints for the entire heart. Using a single RNA-seq core, in contrast, the Ellinor team used calculation methods to separate transcriptional signatures by cell type. It also allowed them to detect signatures of rare cell types whose signals might have been drowned out in a bulk scan.
In their study, the scientists looked at DCM and HCM, which cause heart failure in different ways. In DCM, the left ventricle of the heart expands and its walls become thinner, and in HCM, the walls of the heart become stiffer and thicker. To their surprise, the researchers found that despite these differences, the conditions have the same transcriptional footprint. With further research, this finding could help doctors better identify which forms and stages of heart failure are similar and which are not, and refine treatments accordingly.
Ellinor’s team also found that the abundance of certain heart cell types differed between cardiomyopathy and healthy patients. Failing hearts had fewer muscle cells but more fibroblasts than non-failing hearts, which could indicate the presence of scar tissue. Among these fibroblasts, the researchers also discovered a unique population in the only failing hearts. “We were struck by the specificity of the transcriptional profile of these cells,” said Mark Chaffin, a computer scientist at Broad and first author of the study. “There were thousands of these nuclei in the cardiomyopathy hearts, compared to virtually none in the non-failing hearts.”
Using CRISPR screens, the team studied the function of key genes that differentiated this population of fibroblasts from normal cardiac fibroblasts. They found that several genes were required for cardiac fibroblasts to switch from a dormant state to an active state, in which the cells form scar tissue that can impede heart pumping. Chaffin says these genes could be possible targets for future treatments for chronic scar tissue formation, or fibrosis.
In the future, researchers hope to find a way to detect heart failure in its early stages in patients, by looking for signs of certain types of fibroblasts or higher levels of scarring in the heart. To achieve this goal, the team began researching whether they could detect markers of activated fibroblasts in the blood.
Mark Chaffin et al, Single-nucleus profiling of human dilated and hypertrophic cardiomyopathy, Nature (2022). DOI: 10.1038/s41586-022-04817-8
Broad Institute of MIT and Harvard
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