Researchers discovered that a protein called MTHFD2 helps protect the heart from damage caused by a virus called CVB3. When mice lacked this protein, their hearts became more inflamed and damaged. The study found that MTHFD2 works by controlling immune cells called macrophages, preventing them from becoming too aggressive and attacking heart tissue. Interestingly, mice that received extra MTHFD2 or ate a diet rich in folate (a B vitamin) had less heart inflammation and better heart function. This discovery suggests that boosting MTHFD2 levels might become a new way to treat viral heart infections in people.

The Quick Take

  • What they studied: Whether a protein called MTHFD2 can protect the heart from damage caused by a virus (CVB3) by controlling immune cell behavior
  • Who participated: Laboratory mice (C57BL/6J and BALB/c breeds) that were infected with CVB3 to mimic viral heart disease in humans. Some mice were genetically modified to lack the MTHFD2 protein
  • Key finding: Mice without MTHFD2 developed worse heart inflammation and damage when infected with CVB3. Mice given extra MTHFD2 or fed a high-folate diet had significantly less heart inflammation and better heart function
  • What it means for you: This research suggests that increasing MTHFD2 levels through diet or treatment might help protect people’s hearts from viral infections. However, this is early-stage research in mice, and human studies are needed before any treatments become available

The Research Details

Scientists used laboratory mice to study how a protein called MTHFD2 affects the immune response to a heart virus. They created two groups of mice: normal mice and mice genetically engineered to lack MTHFD2 in their immune cells. Both groups were infected with CVB3 virus to trigger viral myocarditis (heart inflammation). The researchers then examined blood samples, heart tissue, and immune cell behavior to understand what was happening.

The team also tested whether giving mice extra MTHFD2 or feeding them a diet high in folate (a B vitamin that MTHFD2 uses) would protect their hearts. They measured heart inflammation, tissue damage, and how well the hearts pumped blood to determine if these interventions helped.

Additionally, researchers studied immune cells grown in the laboratory to understand the exact mechanisms by which MTHFD2 works. They identified a protein called Rap1 as the key target through which MTHFD2 exerts its protective effects.

This research approach is important because it identifies a specific protein and mechanism that could be targeted with future treatments. By using genetically modified mice, scientists could prove that MTHFD2 is actually responsible for the protective effect, not just associated with it. Testing both genetic removal and dietary supplementation strengthens the evidence that MTHFD2 is a viable therapeutic target.

This study was published in Cardiovascular Research, a respected peer-reviewed journal. The research used multiple complementary approaches (genetic modification, dietary intervention, and laboratory cell studies) to confirm findings. The use of two different mouse breeds increases confidence that results aren’t specific to one genetic background. However, these are animal studies, so results may not directly translate to humans. The study would be strengthened by larger sample sizes and longer follow-up periods.

What the Results Show

When mice lacked the MTHFD2 protein, they developed significantly worse heart inflammation and damage after CVB3 infection compared to normal mice. Specifically, more immune cells infiltrated the heart tissue, and more of these immune cells were pro-inflammatory macrophages—cells that attack and damage tissue. The hearts of MTHFD2-deficient mice showed greater scarring and pumped blood less effectively.

Conversely, when researchers gave mice extra MTHFD2 or fed them a high-folate diet (folate is a B vitamin that MTHFD2 uses), their hearts were protected. These mice had less inflammation, less scarring, and better heart function compared to control mice.

The researchers identified the mechanism: MTHFD2 controls a protein called Rap1, which regulates how macrophages move and what type of immune response they mount. By controlling Rap1, MTHFD2 prevents macrophages from becoming overly aggressive and damaging the heart.

The study found that during viral heart infection, the body naturally increases MTHFD2 levels, suggesting this is a protective response. When MTHFD2 was removed, immune cells called macrophages migrated more readily to the heart and were more likely to become pro-inflammatory (tissue-damaging) rather than protective. The research also showed that MTHFD2 works through a specific signaling pathway involving Rap1 and p38 MAPK, providing a detailed molecular explanation for how this protein protects the heart.

This research builds on previous knowledge that macrophages play a central role in viral myocarditis damage. Earlier studies showed that controlling macrophage behavior could reduce heart damage, but the specific mechanisms weren’t well understood. This study identifies MTHFD2 and the Rap1 pathway as key regulators of macrophage function in this context. The finding that folate supplementation helps is novel and suggests a potential dietary approach to complement medical treatments.

This research was conducted entirely in laboratory mice, which have different immune systems than humans. The study doesn’t specify exact sample sizes for all experiments. The long-term effects of MTHFD2 supplementation or high-folate diets weren’t examined. The research focused on one specific virus (CVB3) and one type of heart disease, so results may not apply to other viral infections or heart conditions. Human clinical trials would be needed to determine if these findings translate to treating people with viral myocarditis.

The Bottom Line

Based on this research, there is moderate evidence that maintaining adequate folate intake may support heart health during viral infections, though this is not yet proven in humans. Current recommendations suggest eating folate-rich foods like leafy greens, legumes, and fortified grains as part of a healthy diet. However, do not take high-dose folate supplements specifically to prevent viral myocarditis without consulting a doctor, as this research is preliminary. If you have a viral heart infection, work with your cardiologist on proven treatments rather than relying on dietary changes alone.

This research is most relevant to people who have had or are at risk for viral myocarditis, cardiologists treating these patients, and researchers developing new heart disease treatments. People with recent viral infections affecting the heart should discuss these findings with their doctors. This is not yet applicable to the general population for prevention purposes. People with folate deficiency or certain genetic conditions affecting folate metabolism should consult their doctors before making dietary changes based on this research.

In the mouse studies, protective effects appeared within the timeframe of the infection (typically 1-2 weeks). If similar treatments were developed for humans, benefits would likely take weeks to months to become apparent. This is early-stage research, and it will likely take 5-10 years of additional studies before any new treatments based on MTHFD2 become available to patients.

Want to Apply This Research?

  • Track daily folate intake (in micrograms) from food sources and supplements, along with any cardiac symptoms like shortness of breath, chest discomfort, or unusual fatigue. Users can log folate-rich foods consumed and rate energy levels and exercise tolerance daily
  • Increase consumption of folate-rich foods such as spinach, kale, lentils, chickpeas, asparagus, and fortified cereals. Set a daily goal of 400 micrograms of folate from food sources. Users can log meals and receive reminders to include folate-rich options in their diet
  • Maintain a 30-day log of folate intake and any changes in energy, exercise tolerance, or cardiac symptoms. Share this data with healthcare providers during regular check-ups. For those with diagnosed viral myocarditis, track this alongside medical treatments and doctor-recommended monitoring

This research is preliminary and was conducted in laboratory mice, not humans. It should not be used as a basis for self-treatment or to replace medical advice from qualified healthcare providers. If you have been diagnosed with viral myocarditis or suspect you may have a viral heart infection, consult with a cardiologist immediately. Do not start high-dose folate supplementation without discussing it with your doctor, as excessive folate can interact with medications and may not be appropriate for all individuals. This article is for educational purposes only and does not constitute medical advice.