When heart failure doesn't kill immediately, it kills slowly. The heart is said to “remodel” after injury but often can’t come back stronger. Injured sections lose their vital nerves, or gain back too many. Fibroblast cells thicken the pump’s walls with collagen. The adult heart scars, and this weakens its output.
The problem is that adult hearts aren’t programmed to bounce back to their prior abilities. Yet “everything you need to regenerate a heart should exist in the mammalian genome,” said Ahmed Mahmoud, who studies regenerative biology at the Sanford Burnham Prebys Medical Discovery Institute. “We know that early in life, the mammalian heart could actually do it by itself.” In 2011, Mahmoud and colleagues reported that mammals' hearts can regenerate at very young ages: One-day-old mice recovered from having small slivers of their hearts cut out; seven-day-old mice didn't.
New research suggests that adult mammals may be able to get their regenerative capability back with help from novel therapeutics. At an annual conference of the American Heart Association (AHA) last week, Mahmoud and other scientists shared progress toward helping the adult heart regenerate after a heart failure event by targeting the enzymes and genes responsible for stymying recovery.
Healing the heart
Since the earlier work with young mice, Mahmoud's team has investigated how the metabolism of heart cells can reprogram the muscle into a young, regenerative state. Their target: an enzyme called succinate dehydrogenase. Succinate dehydrogenase plays a dual role in the mitochondria of heart cells, transferring energy and producing energy. This means the enzyme can influence whether the cell devotes its energy toward regenerating or scarring after injury.
In 2021, Mahmoud’s team reported injecting mice with a compound that blocks succinate dehydrogenase daily for two weeks after a heart injury. Two weeks after treatment stopped, the mouse hearts had no scarring and meaningfully more muscle. “It had quite a profound effect,” Mahmoud said at the AHA conference. In preliminary work shared at the conference that has not yet been peer reviewed, the team explored targeting succinate dehydrogenase specifically in the heart.
Everything you need to regenerate a heart should exist in the mammalian genome.
– Ahmed Mahmoud, Sanford Burnham Prebys Medical Discovery Institute
Johannes Backs, an experimental cardiologist at Heidelberg University who also presented at the conference, has adopted a similar approach for treating so-called broken heart syndrome, also known as Takotsubo syndrome. The condition is an acute heart failure often triggered by stress. Though about 90 percent of cases occur in women, it's twice as deadly in men.
“For a long time, we thought of Takotsubo as benign [with] recovery within a few days, then no remaining cardiac dysfunction after a week,” Backs said at the AHA conference. But this type of heart failure also kills slowly. According to Backs, the long-term prognosis of Takotsubo survivors actually shows higher mortality than severe heart attacks called ST-segment elevation myocardial infarction (STEMI), yet no evidence-based therapies exist.
But why does broken heart syndrome spiral into this quiet pattern of long-term damage? To find out, Backs’ team developed a mouse model to study the syndrome in closer detail by mimicking Takotsubo with high doses of epinephrine. The mice recreated sex-dependent differences matching human observations, as well as the protein levels and electrical signals associated with Takotsubo.
This basic work hinted at a new way to treat the syndrome after Takotsubo attacks. Genes associated with inflammation in heart muscle appeared abnormally active — especially genes corresponding to an immune enzyme called calcineurin. When Backs' team analyzed blood samples from human patients, they noticed high levels of calcineurin as well. Backs’ team was pleased to know that a drug that regulates calcineurin levels already exists: an immunosuppressant called cyclosporine A given to transplant patients.
Backs’ recent research included preclinical studies in mice suggest blocking calcineurin may prevent long-term heart damage after Takotsubo attacks. When Backs’ team dosed mice two hours after the onset (simulating the time it would take a person to receive diagnosis and care), two calcineurin inhibitors "improved heart function and reduced myocardial injury." Phase II double-blind trials began this year to test cyclosporine A on humans. More than 20 patients have enrolled so far, and Backs expects to publish results about the repurposed drug in 2027.
Treating the heart at the molecular level
The molecular consequences of heart failure are also guiding researchers to entirely new types of treatments, such as microRNA therapy.
Unlike traditional RNA, microRNA don’t relay instructions to produce particular proteins. Yet based on discoveries from the 1990s that led to a 2024 Nobel prize, these small sections of genetic code somehow still control the protein output of our cells. “In human beings, the majority of all RNAs we detect are for noncoding RNAs,” said Thomas Thum, a cardiologist-scientist at the Hannover Medical School, founder of Cardior Pharmaceuticals, and advisor with Novo Nordisk, who presented at the conference. Yet of the nearly 5,000 modern pharmaceuticals, “basically all of them are based on the knowledge from coding RNAs.”
MicroRNAs standout because they don’t just target one single gene, they have the potential to regulate complex networks of disease pathways. In 2012, Thum's team reported that miRNA-132 contributed to dangerous thickening of heart tissue. When they designed an antisense oligonucleotide drug to block miRNA-132 in mice, the thickening stopped and the team prevented heart failure.
That discovery led Thum to launch Cardior, and the company then tested the treatment, CDR132L, in hundreds of pigs. Monthly doses improved heart function and reversed the problematic remodeling after heart failure. A Phase 1 study of 28 patients showed that CDR132L was safe and may improve cardiac function.
Last year, Novo Nordisk acquired Cardior and has invested further in Phase 2 trials for CDR132L. The company began a 12-month Phase II trial last year. Thum expects to publish results in 2026.
“The dogma was challenged 20 years ago,” he said. “These noncoding RNA networks are not only an unexplored territory, but also a great field to find novel therapeutic entry points for diseases where we currently have not seen much progress.”
In all three projects, such progress would be lifesaving. Roughly one million new cases of heart failure occur in the United States alone, and the cases are rising. Preventing emergencies is important but helping the heart prevent more damage may be the key to bouncing back to health.
