Single-cell map of heart failure suggests potential therapeutic targets

Scientists at the Precision Cardiology Lab (PCL) at the Broad Institute of MIT and Harvard and Bayer have created detailed maps of a variety of cell types in the heart that are involved in two major causes of heart failure: dilated and hypertrophic cardiomyopathy (DCM and HCM). , both of which affect the heart’s pumping ability.

The team’s findings, published today in Nature, suggest specific cell types and biological mechanisms that could be targets of new treatments. Heart failure is one of the most common causes of hospitalization in the United States. Existing drugs are limited and many patients eventually die from heart failure.

To create their cellular maps, the researchers used single-nuclei RNA sequencing (RNA-seq), which reveals which genes are active and at what level in individual cells. They studied heart tissue from patients with late-stage heart failure and found that DCM and HCM heart cells expressed different genes than non-failing hearts, but that gene expression profiles were similar for DCM and HCM patients. Some cardiomyopathy patients also had a unique array of fibroblasts, or connective tissue cells, that the researchers believe may contribute to tissue scarring in heart failure and be a target of future treatments.

This study builds on a previous effort to catalog individual cells in the healthy human heart, and is the result of a close collaboration with the team of Ken Margulies, a professor of medicine and heart failure physician at the University of Pennsylvania. By mapping cells involved in different forms of heart failure, researchers can identify markers that allow them to differentiate between disease types and predict clinical outcomes.

“Right now, almost all forms of heart failure are all treated the same, regardless of cause,” said Patrick Ellinor, who led the team and is an institute member at the Broad, director of the Demoulas Center for Cardiac Aritmias at Massachusetts General Hospital. . , and a professor at Harvard Medical School. “Our goal was to ask in people with disease whether there are cell populations or genes expressed that differ between health and disease? And yes, we found that genes indicative of highly active cardiac fibroblasts were found in some patients with disease.”

“Bayer and Broad scientists worked side by side to generate, analyze and validate the data in this study. This level of collaboration between academia and the pharmaceutical industry is extremely rare,” said Carla Klattenhoff, senior director and head of the joint Precision Cardiology Laboratory of Bayer and the Broad. “This map is a great resource for cardiology.”

“This is an important scientific contribution to deepening our understanding of diseases to deliver precision medicine for cardiology,” added Ulrich Nielsch, Bayer’s chief of Therapeutic Area 1 .

cell by cell

Previous studies have shown that failing hearts have unique gene expression profiles, or transcriptomes, compared to healthy hearts, but that work generated only a few genetic fingerprints for the whole heart. Using single-nucleus RNA-seq, in contrast, Ellinor’s team used computational methods to separate transcriptional signatures by cell type. This also allowed them to pick up signatures from rare cell types whose signals may have been drowned out in bulk analysis.

In their study, the scientists looked at DCM and HCM, which cause heart failure in different ways. In DCM, the left ventricle dilates and the 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 share the same transcriptional fingerprint. With further research, this finding could help doctors better identify which forms and stages of heart failure are similar and which are not, and tailor 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 failing hearts alone. “We noticed how specific the transcriptional profile of these cells really was,” said Mark Chaffin, a computational scientist at the Broad and lead author of the study. “There were thousands of these nuclei in cardiomyopathy hearts compared to virtually none in non-failing hearts.”

Using CRISPR screens, the team studied the function of the key genes that differentiate this population of fibroblasts from normal cardiac fibroblasts. They found that several genes were necessary for heart fibroblasts to transition from a dormant to an active state, in which cells form scar tissue that can hinder the heart’s pumping. Chaffin says these genes could be potential targets of future treatments for chronic scar tissue formation or fibrosis.

In the future, the researchers hope to find a way to detect heart failure in the earliest stages of patients, by looking for signs of certain types of fibroblasts or higher levels of scarring in the heart. To achieve this goal, the team has set out to investigate whether they can detect markers of activated fibroblasts in blood.