Reposted from U of U Health.
Heart failure remains the leading cause of illness and death worldwide, yet treatment options remain limited, with only a small number of therapies proven to significantly improve outcomes. One major challenge has been identifying actionable biological targets.
Now, researchers from University of Utah Health and the University of California San Diego have created the most detailed map to date of how gene regulation breaks down in human heart failure, revealing how genes are controlled in specific cell types as the disease develops and pointing to potential new therapeutic targets.
The study, published in Science, integrates multiple kinds of data to uncover the hidden rules underlying heart failure at single-cell resolution.
"This study provides a roadmap to the landscape of major cardiac cell types of all four chambers of the normal and failing human heart," said Stavros Drakos, professor of cardiovascular medicine at U of U Health. "These findings establish a mechanistic framework for biological pathways of heart failure development and present multiple targets for developing new therapies for heart failure."
"Our goal is to use this atlas to discover targets that we can act on therapeutically," added Neil Chi, professor of medicine at UC San Diego School of Medicine. "Right now, one of the biggest limitations in cardiology is not the lack of tools, but the lack of targets. This kind of data changes that."
A single-cell view of heart failure
Genetic studies have uncovered many genetic changes linked to heart disease, but more than 85% of these changes lie in noncoding regions of DNA-stretches that don't make proteins, but instead control when and how genes are turned on or off-making it difficult to determine how they contribute to disease.
To address this, the research team analyzed heart tissue from 36 individuals, including patients with and without heart failure. Using advanced single-cell techniques, they analyzed how genes are controlled and organized across more than 750,000 individual heart cells.
This comprehensive approach allowed the team to identify 12 major heart cell types and dozens of subpopulations, each with its own distinct patterns of gene control. They found that heart failure is associated with major shifts in cell composition. Failing hearts have fewer muscle cells and more immune cells and fibroblasts-cells responsible for structural support and scar tissue.
The research team also found that cells in failing hearts change the activity of more than 10,000 genes, and further alter how DNA is regulated at more than 50,000 locations. These changes were particularly pronounced in heart muscle cells and scar tissue cells.
Importantly, the team uncovered distinct disease-related cell states. For example, muscle cells progressed from healthy to diseased through several intermediate cell states.
"These intermediate states are where the disease is actively unfolding," Chi said. "If we can understand and target those transitions, we may be able to intervene earlier and more effectively."
Revealing risk and pinpointing new therapy targets
The study also sheds new light on how genetic risk contributes to heart failure. By integrating their atlas with genome-wide association data, the team showed that disease-associated genetic changes are concentrated in regulatory regions active in specific cell types-particularly heart muscle cells-and often act through long-range DNA interactions to influence gene expression. This suggests that genes in heart muscle cells may be more viable as treatment targets for heart disease than other cardiac cell types.
In addition to offering insights into heart disease, this work helps resolve a longstanding challenge in genetics: identifying which genetic changes are truly causal and which genes they affect. By mapping these connections, the researchers provide a framework for linking genetic risk to specific biological mechanisms in heart disease.
"This is a higher-order view of disease biology," Chi said. "Instead of just asking which genes are turned on or off, we're now understanding how their regulation is controlled across the genome-and that's where most disease risk actually resides."
Beyond its immediate findings, the study establishes a comprehensive resource for the scientific community. The dataset can be used to identify new drug targets, particularly in a field where therapeutic options remain limited.
Stavros adds that the new genetic map was made possible by donations of heart tissue by many heart failure patients over the years. He said, "It is incredibly exciting and rewarding to see that this research has led to discoveries that are now leading to new therapies for patients with heart failure-fulfilling the hopes and expectations of both the patients who so generously contributed to this research and all of us who have worked to turn their gift into better treatments for our patients."
This press release is modified from an original article published by the University of California San Diego.
This research is published in Science on July 23 as "Single cell multiomics and chromatin structure reveal gene regulatory dynamics in heart failure."
The study was funded, in part, by the National Institutes of Health, including the National Heart, Lung, and Blood Institute (grant numbers R01 HL135121, 1R01HL166513, T32HL007444, and 1K08HL168315-01), the National Human Genome Research Institute (HG012059), and others. Content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.
The following authors declare competing interests. Consultancy fees: Drakos (Abbott), Gaulton (Genentech). Gaulton has received honoraria from Pfizer, holds stock in Neurocrine Biosciences, and his spouse is employed at Altos Labs. Drakos acknowledges research support from Novartis. Elgamal is an employee and shareholder of Pfizer. Holman is an employee of Aspen Neuroscience and holds equity in the company. Ren is a shareholder and consultant of Arima Genomics Inc. and cofounder of Epigenome Technologies, Inc. Chi and the University of California San Diego are inventors of a filed patent. All other authors declare no competing interests.
