When Neil Chi operates on a failing heart, he sees an organ that has lost its rhythm. But the real problem, he knows, runs deeper than muscle — it begins in the instruction manual that tells each heart cell what to do.
Chi, a heart specialist and researcher at the University of California San Diego, has spent years searching for new ways to treat heart failure, a condition that affects 26 million people worldwide and kills hundreds of thousands each year. The challenge, he explains, is not a lack of tools. It's a lack of targets — specific genes or molecules that doctors can actually aim treatments at.
Now, Chi and his team have built something that could change that. In research published in the journal Science, they created the most detailed map ever made of what goes wrong at the genetic level when a heart fails.
The work is remarkable for its scale. The researchers examined more than 750,000 individual heart cells from 36 people — some with healthy hearts, some with failing ones. Using powerful new laboratory techniques, they read the "control instructions" for each cell, showing not just which genes were active, but how those genes were being turned on and off.
"These technologies allow us to look beyond which genes are active to understand how the genome is organized and controlled," said Bing Ren, a UC San Diego researcher who co-led the study. The team identified 12 major types of heart cells, plus dozens of smaller subgroups, each with its own distinct patterns of gene control.
The differences between healthy and failing hearts were stark. In diseased hearts, the researchers found more than 10,000 genes with abnormal activity and over 50,000 regions of DNA that had changed how easily proteins could access them. Certain cell types — particularly the muscle cells that make the heart beat and the connective tissue cells called fibroblasts — showed extensive rewiring of their genetic programs.
Perhaps most exciting, the team discovered that heart cells don't simply flip from healthy to sick. Instead, they pass through intermediate states — stages where the disease is actively developing.
"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."
The research also explains why earlier genetic studies of heart disease were hard to use. More than 85 percent of genetic changes linked to heart failure occur in parts of DNA that don't make proteins — they only act as on-off switches. By mapping these switches in specific cell types, the team identified which genes are most likely to be safe and effective targets for new medicines.
For patients and families facing heart failure, this work offers more than scientific insight. It offers a new set of directions to explore. As Chi put it: "This kind of data changes that."