Can human stem cells lead to a new heart attack treatment?

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Heart attacks can kill many heart muscle cells, leading to death or heart failure. A new heart attack treatment drug that can save heart muscle cells is being developed.

Heart disease and the resulting heart failure is the most common cause of death worldwide. Heart attacks are one of the most devastating moments within heart disease. Heart attacks occur when blood flow to the heart is temporarily restricted. This causes heart muscle cells to die. The more heart muscle cells that die, the greater the risk to the patient. A new heart attack treatment would, therefore, have the potential to save many lives.

Many drugs have been developed in laboratories that seemed to prevent the death of heart muscle cells in a heart attack. Unfortunately, none of these drugs worked once they were tested in clinical trials. A large group of researchers in the US and the UK have been testing drugs using a new approach that they hope will be more successful. They recently published their results in the journal Cell Stem Cell.

Using human stem cells to grow heart muscle cells in the lab

Most of these drugs for heart attack treatment were initially tested in rodents or pigs. Many researchers argue that these animals aren’t good models for what happens in a heart attack in human beings. A better approach may be to directly test drugs on human heart muscle cells. These cells aren’t taken from human patients. Instead, they start with human stem cells, which can be transformed into heart muscle cells in a test tube. These lab-grown heart muscle cells can even contract, just like real heart muscle cells.

Blocking a protein that can kill heart muscle cells

The researchers started by investigating a protein called MAP4K4. They found that this protein is activated in a heart attack. When they used genetic engineering to turn MAP4K4 off, human heart muscle cells were less likely to die.

This genetic approach is not suitable for the treatment of heart attack patients. Instead, the researchers searched for drugs that could block the activity of MAP4K4. They tested almost 2,000 drugs, and found one that seemed to block MAP4K4. They then used computer modeling and chemical techniques to refine the molecular structure of the drug. This resulted in a drug called DMX-5804.

Testing on human heart muscle cells and mice

DMX-5804 helped to prevent human heart muscle cells from dying. It worked just as well as using genetic engineering to block MAP4K4.

The next step was to test the drug in an animal model of a heart attack. They opted to use mice. To mimic a heart attack, they anesthetized the mice and temporarily restricted blood flow to their heart.

They did two sets of heart attack experiments. In one set, they started giving the mice DMX-5804 20 minutes before the heart attack. In the second set of experiments, they started giving DMX-5804 one hour after the heart attack. This timing is much more relevant to the clinic, since most heart attack patients obviously won’t be given a heart attack treatment until after the heart attack.

Within an hour of the simulated heart attack, many heart muscle cells had already died in the mice. However, DMX-5804 treatment reduced the number of dead cells by almost a half. Giving DMX-5804 after the simulated heart attack seemed to work just as well as when it was given before.

Turning this into a new heart attack treatment

Although DMX-5804 worked in this study, it isn’t easily soluble in water or blood. This means that it had to be given orally. To treat human patients, heart attack drugs must be injected intravenously. This means that there need to be additional chemical modifications to the drug substance. The refined drug will need to be subjected to additional animal testing. It will then need to be tested on actual human patients in clinical trials.

Despite the amount of work remaining, the authors of this study consider this an important breakthrough. They determined that the protein MAP4K4 can cause the death of human heart muscle cells. They also demonstrated that drugs can be developed that will block the activity of this program. Finally, they hope that the use of heart muscle cells grown from human stem cells will be a more effective way of testing drugs before they are trialed on human patients.

Written by Bryan Hughes, PhD

References:

1. 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
2. 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

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