A new drug compound isolated from zebrafish may reverse arrhythmogenic cardiomyopathy, say HMS researchers at Beth Israel Deaconess Medical Center and Brigham and Women’s Hospital. Their finding, reported in the June 11 issue of Science Translational Medicine, may one day lead to new therapies for this condition.
Arrhythmogenic cardiomyopathy, or ACM, is a hereditary disease. The condition affects approximately 1 in 5,000 individuals worldwide, and is the leading cause of sudden death in young people under age 35.
Over time, the disease damages the muscle of the heart’s ventricles, causing the muscles’ cells, or myocytes, to be replaced by fatty deposits and fibrosis. These changes leave patients especially susceptible to arrhythmias, the rapid and erratic heartbeats that cause dizziness, collapse, and, in the most serious cases, sudden cardiac death.
“There are currently no drugs available that can reliably prevent arrhythmias and sudden death in ACM,” says team leader Jeffrey Saffitz, the HMS Mallinckrodt Professor of Pathology and chair of the Department of Pathology at Beth Israel Deaconess. Patients who exhibit frequent arrhythmias or experience repeated fainting spells are considered to be at risk for sudden death, and often undergo implantation of a cardiac defibrillator, which continuously monitors heart rhythm and delivers a shock to the heart if it detects a potentially lethal rhythm abnormality.
To identify the mechanisms underlying this dangerous condition and to find potential drugs to prevent its onset, the research group created a screenable zebrafish model of ACM with cardiac myocyte-specific expression of a human mutation in the gene encoding plakoglobin, which is known to cause ACM in humans. (Zebrafish develop rapidly so the investigators could see clear evidence of heart disease after only 48 hours of embryonic development.) The scientists then screened thousands of chemicals to find any that could suppress the disease. One chemical, SB216763, showed a remarkable ability to prevent or reverse the disease in the fish.