Immune-regulating drug restores heart muscle regeneration in mouse model of coronary artery disease

A drug that promotes the stem-cell niche in heart muscle enables immediate regression of atrial fibrillation (AFib) a common form of heart rhythm disorder in a mouse model of atrial fibrillation. The study led by scientists at the Abramson Cancer Center at the University of Pennsylvania and published today in the journal Nature Communications could lead to therapies that could be used to treat patients with this common type of heart rhythm disorder. The research was led by Sharon Sue Solovey PhD and the study it name was co-led by Molly Johnson-Kirk PhD and senior authors Kevin J. Coggan PhD and Ninebo Shin PhD; and worked at the Abramson Family Heart Disease Research Institute.

AFib is a common but deadly condition that occurs when the heart loses its ability to pump oxygenated blood to meet the bodys demand. Interestingly enough AFib is not typically diagnosed in people younger than 60. When present at rest or during prolonged high-intensity exercise the heart may begin to lose muscle function and become unable to pump oxygenated blood as efficiently as when at rest. The primary causes of AFib are is a genetic mutation that occurs in patients with a protein mutation called APOE4.

Coggan and Shin have developed several drugs that target the stem-cell niche in heart muscle. In this previous clinical trial the two have demonstrated the safety of targeting the stem-cell niche of normal heart tissues in mice. This trial intensified over time as the animal population grew to more than 500 mice free of genetic mutations. The drug theory was that by increasing the activity of the stem-cell niche an increase in the amount of cells allowed for the regulation of the tunable repair of atrial fibrillation – a frequent mechanism of action of these therapies.

Thus reducing the amount of heart muscle stem cells in a foetal mouse model would not only increase the startle response rate (bradykinesia) which is a normal and useful (and potentially reversible) response prevented the abnormal switching (arrhythmias) and failure (arrhythmias) of heart muscle.

In the present study two of the two investigators studied the effect of adding a minute of lipids or compounds called fatty acid molecules to the inhibitor. The experimental drug used in the study was designed by the previous research group coordinating the phase 3 clinical trial. The trial involved two oral exogenous drug administrations in a 10-week period. The controls were a type 1 diabetic mouse and two controls were fed a regular mouse diet.

After 200 days both the experimental and control groups showed significant reduction in heart stenosis (the narrowing of the hearts 2th-floor duct a feature that can lead to blood clots heart attacks and stroke) which is the primary molecular predictor of death from heart rhythm disorders. Since the increase in heart muscle stem cells treated animals showed significantly greater improvement than the control group a significant 70 percent improvement in atrial fibrillation severity compared to the control group.

As the period progressed to 5- to 10-month the mice symptoms were much less severe than those that were seen in the control group. The mice saw improvement in their atrial fibrillation activity of nearly 60 percent after five weeks. In addition the rate of a completed cycle involving the atrial fibrillation module or ECG became 32 percent shorter compared to the control group. Thus moderate and mild episodes of atrial fibrillation in mice treated with the experimental drug has pretty much paralleled that of mice treated on the regular feeding diet.

The receptor from this drug has been identified in human heart tissue from patients and has assumed a predominant role in heart replacement said Solovey. Along with the firm evidence from clinical trials that it works or works well our data indicate it has far-reaching effects beyond its therapeutic use in patients.