Innovative Treatment for Heart Attacks: A New Drug on the Horizon

The Impact of Heart Attacks on Heart Muscle Cells

Heart attacks can result in the death of numerous heart muscle cells, potentially leading to fatal outcomes or heart failure. Heart disease remains the leading cause of death globally, with heart attacks being particularly devastating. These events occur when blood flow to the heart is temporarily blocked, causing heart muscle cells to perish. The loss of these cells increases the risk to the patient’s health. Therefore, a new treatment targeting heart attacks has the potential to save many lives.

Challenges in Previous Drug Development

Numerous drugs have been created in laboratories aimed at preventing the death of heart muscle cells during a heart attack. However, none of these candidates have shown effectiveness in clinical trials. A collaborative research team from the US and the UK has employed a novel approach in their investigations, recently sharing their findings in the journal *Cell Stem Cell*.

Utilizing Human Stem Cells for Drug Testing

Traditionally, heart attack treatments were tested in animal models, such as rodents or pigs. Many researchers argue that these animals do not adequately reflect human heart attack conditions. A more effective strategy may involve direct testing on human heart muscle cells. These cells are derived from human stem cells, which can be converted into heart muscle cells in a laboratory setting. Remarkably, these lab-grown cells can contract similarly to natural heart muscle cells.

Targeting MAP4K4 Protein to Protect Heart Muscle Cells

The researchers began by examining a protein known as MAP4K4, which becomes activated during a heart attack. By using genetic engineering techniques to deactivate MAP4K4, they observed a significant decrease in the death rate of human heart muscle cells. However, this genetic method is not feasible for treating patients. Consequently, the researchers sought drugs that could inhibit MAP4K4’s activity. After screening nearly 2,000 drugs, they identified one that effectively blocked MAP4K4 and subsequently refined its molecular structure, resulting in the drug DMX-5804.

Evaluating DMX-5804 in Animal Models

DMX-5804 showed promise in preventing the death of human heart muscle cells, performing comparably to the genetic engineering approach. The researchers next tested DMX-5804 in a mouse model simulating a heart attack. They anesthetized the mice and temporarily restricted blood flow to their hearts. Two sets of experiments were conducted: one where DMX-5804 was administered 20 minutes before the heart attack and another where treatment began one hour after the event. The latter timing is clinically relevant, as most patients receive treatment post-heart attack.

Within an hour, many heart muscle cells had perished in the mice, but DMX-5804 treatment nearly halved the number of dead cells. The drug proved effective regardless of whether it was administered before or after the simulated heart attack.

Future Directions for Heart Attack Treatment

Although DMX-5804 exhibited effectiveness in this study, its poor solubility in water and blood necessitates oral administration. For human patients, heart attack medications must be administered intravenously, which will require further chemical modifications to the drug. Additional animal testing and subsequent clinical trials on human patients will be necessary.

Despite the challenges ahead, the study’s authors view their findings as a significant breakthrough. They identified MAP4K4 as a contributor to the death of human heart muscle cells and demonstrated the potential to develop drugs that inhibit its activity. Furthermore, they believe that utilizing heart muscle cells derived from human stem cells may enhance the efficacy of drug testing prior to human trials.

References

Fiedler, L. R., Chapman, K., Xie, M., Maifoshie, E., Jenkins, M., Golforoush, P. A., Bellahcene, M., Noseda, M., Faust, D., Jarvis, A., Newton, G., Paiva, M. A., Harada, M., Stuckey, D. J., Song, W., Habib, J., Narasimham, P., Aqil, R., Sanmugalingam, D., Yan, R., Pavanello, L., Sano, M., Wang, S. C., Sampson, R. D., Kanayaganam, S., Taffet, G. E., Michael, L. H., Entman, M. L., Tan, T.-H., Harding, S. E., Low, C. M. R., Tralau-Stewart, C., Perrior, T. & Schneider, M. D. MAP4K4 Inhibition Promotes Survival of Human Stem Cell-Derived Cardiomyocytes and Reduces Infarct Size In Vivo. *Cell Stem Cell* (2019). https://doi.org/10.1016/j.stem.2019.01.013

Tedaldi, L. Potential new heart attack treatment. British Heart Foundation. Accessed at https://www.bhf.org.uk/what-we-do/news-from-the-bhf/news-archive/2019/march/new-heart-attack-treatment