Researchers discovered that a chemical process called nitrosylation damages a protein in heart cells, causing the heart to become scarred and stiff. This scarring, called cardiac fibrosis, is a major problem in heart disease. The good news: scientists found that an existing drug called mitapivat, already approved for treating blood disorders, can stop this damaging process and may help prevent or even reverse heart scarring. This discovery could offer hope to millions of people with heart failure and other heart conditions.
The Quick Take
- What they studied: How a chemical modification of a protein called PKM2 causes heart scarring, and whether an existing drug could stop it
- Who participated: Laboratory mice with heart disease, rats with high blood pressure, human heart tissue samples from heart failure patients, and heart cells grown in the lab
- Key finding: A drug called mitapivat successfully reduced heart scarring in multiple test models by fixing the damaged PKM2 protein and preventing harmful changes inside heart cells
- What it means for you: This research suggests mitapivat could potentially become a new treatment for heart scarring, though human clinical trials are still needed to confirm safety and effectiveness
The Research Details
Scientists used multiple approaches to understand how heart scarring happens. First, they analyzed heart tissue from sick mice and rats to identify which proteins were damaged. They found that a protein called PKM2 was being chemically modified in a harmful way, specifically in the cells that create scar tissue (fibroblasts). To prove this was the problem, researchers created special mice without this protein and observed that their hearts got worse, confirming PKM2 is important. They then tested whether blocking the harmful modification could help by using a drug called mitapivat and another compound called TEPP-46, both of which activate PKM2 and restored normal heart function.
The researchers also studied human heart tissue from people with heart failure and found the same harmful protein modification present. They used advanced laboratory techniques to understand exactly how the damaged protein causes scarring—discovering it triggers excessive splitting of mitochondria (the energy factories inside cells), which damages the cells and leads to scarring.
This multi-layered approach, combining animal studies, human tissue analysis, and molecular investigation, provides strong evidence that the PKM2 modification is a real cause of heart scarring and that mitapivat could be a solution.
This research matters because current treatments for heart scarring are limited. By identifying the exact molecular problem (the PKM2 modification) and finding an existing drug that fixes it, scientists have discovered a potential new treatment path. Using an already-approved drug is particularly important because it could reach patients faster than developing a completely new medication.
This research was published in Circulation, one of the world’s most respected heart disease journals. The study used multiple complementary approaches (animal models, human tissue, cell studies, and molecular analysis) which strengthens the findings. The researchers tested their theory in different ways—creating mice without the protein, using drug treatments, and analyzing human tissue—all pointing to the same conclusion. However, the study was conducted in laboratory and animal settings, so human clinical trials are still needed to confirm these results work in real patients.
What the Results Show
The main discovery was that a harmful chemical modification of the PKM2 protein occurs specifically in scar-forming heart cells during heart disease. This modification was found in heart tissue from mice with induced heart damage, naturally hypertensive rats, and human patients with heart failure. When this modification occurred, it broke the PKM2 protein’s normal function, causing it to lose its ability to work properly and triggering excessive splitting of mitochondria inside the cells.
When researchers removed the PKM2 protein entirely from scar-forming cells, the heart scarring actually got worse, showing that the protein itself is protective. However, when they used a version of the protein that couldn’t be chemically modified, the heart function improved significantly. This proved that the harmful modification, not the protein itself, was the problem.
Most importantly, the drug mitapivat successfully reduced heart scarring in multiple test models. This drug works by reactivating the damaged PKM2 protein, restoring its normal function, and preventing the excessive mitochondrial splitting that leads to scarring. Another drug called TEPP-46 showed similar benefits, confirming that activating PKM2 is an effective strategy.
The research revealed the specific mechanism of how scarring happens: the harmful PKM2 modification causes it to lose interaction with a protein called gelsolin, which normally helps control the cell’s structural elements. Without this interaction, mitochondria split excessively, causing cellular energy problems and triggering the scarring process. The study also showed that the harmful modification occurs at two specific locations on the PKM2 protein (cysteine 49 and 326), providing precise targets for future treatments.
Previous research showed that excessive nitric oxide (a chemical messenger in the body) can damage the heart, but scientists didn’t know exactly how. This study identifies the specific protein and mechanism involved. The finding that mitapivat—a drug already approved for a rare blood disorder—can prevent heart scarring is novel and unexpected, suggesting existing medications might have additional benefits beyond their original purpose.
The study was primarily conducted in laboratory settings and animal models, so results may not directly translate to humans. The sample size of human tissue samples wasn’t specified in the research. The research doesn’t yet show whether mitapivat works in living human patients with heart disease—only in laboratory and animal models. Long-term effects and optimal dosing in humans remain unknown. Additionally, the study focused on one specific type of heart disease model, so it’s unclear whether these findings apply to all types of heart scarring.
The Bottom Line
Based on this research, mitapivat shows promise as a potential treatment for heart scarring and should be investigated further in human clinical trials (moderate confidence level). People with heart disease should not start taking mitapivat for this purpose outside of clinical trials, as human safety and effectiveness data are not yet available. Healthcare providers may want to monitor emerging clinical trial results on this application (low to moderate confidence for current clinical use).
This research is most relevant to people with heart failure, heart disease from high blood pressure, or other conditions causing heart scarring. Cardiologists and heart researchers should pay close attention to these findings. People with the rare blood disorder for which mitapivat is already approved might also benefit from knowing about this additional potential use. However, people with healthy hearts don’t need to take action based on this research yet.
In animal models, mitapivat showed effects relatively quickly, but human hearts may respond differently. If clinical trials proceed, it could take 3-5 years to determine whether the drug is safe and effective in heart disease patients. Even if approved, benefits might take weeks to months to become noticeable, similar to other heart medications.
Want to Apply This Research?
- Users should track heart-related symptoms weekly: shortness of breath during normal activities, ankle swelling, fatigue levels, and exercise tolerance. Rate each on a scale of 1-10 to monitor changes over time.
- Users can use the app to set reminders for heart-healthy habits while awaiting potential new treatments: taking current medications on schedule, monitoring sodium intake, tracking daily activity/exercise, and logging any new symptoms to discuss with their doctor.
- Create a long-term symptom diary within the app that tracks heart function indicators monthly. Users should also set reminders to check for clinical trial opportunities related to mitapivat and cardiac fibrosis, and maintain regular communication with their cardiologist about new treatment options.
This research is preliminary and based on laboratory and animal studies. Mitapivat is not currently approved by the FDA for treating heart scarring in humans. Do not start, stop, or change any heart medications without consulting your cardiologist. If you have heart disease or heart failure, discuss these findings with your healthcare provider to determine if participating in future clinical trials might be appropriate for you. This information is for educational purposes only and should not replace professional medical advice.