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Zebrafish Yield Insights into Treating Heart Disease

Thu, 06/12/2014 - 1:53pm
Examples of a normal young adult zebrafish (A) and a fish with arrhythmogenic cardiomyopathy (B) showing a greatly enlarged heart (ventral bulge) and reduced body size. (Source: HMS/Calum MacRae)Using a zebrafish model, investigators have identified a drug compound that appears to reverse arrhythmogenic cardiomyopathy (ACM), a hereditary disease and leading cause of sudden death in young people. The study, led by investigators at Harvard Medical School, Beth Israel Deaconess Medical Center and Brigham and Women’s Hospital, provides a key first step in developing new therapies for this dangerous condition, for which there is currently no preventive treatment.
 
The study appears in Science Translational Medicine.
 
“For some individuals, ACM has no symptoms or warning signs, meaning that the first and only manifestation of disease is sudden death,” said corresponding author Jeffrey Saffitz, the HMS Mallinckrodt Professor of Pathology and chair of the Department of Pathology at Beth Israel Deaconess. The condition affects approximately 1 in 5,000 individuals worldwide, often striking people under age 35.
 
ACM damages the muscle of the heart’s ventricles (the pumping chambers) so that over time, muscle cells, or myocytes, are replaced by fatty deposits and fibrosis, leaving patients especially susceptible to arrhythmias. Once an arrhythmia develops, the heartbeat becomes rapid and erratic, causing the victim to grow dizzy or collapse—and, in the most serious cases, to suffer sudden cardiac death.
 
“There are currently no drugs available that can reliably prevent arrhythmias and sudden death in ACM,” explained Saffitz. Patients who exhibit frequent arrhythmias or experience repeated fainting spells are considered to be at risk for sudden death, and often undergo implantation of an automatic cardiac defibrillator (ICD), which continuously monitors heart rhythm and delivers a shock to the heart if it detects a potentially lethal rhythm abnormality.
 
“While ICDs can be lifesaving, they are expensive and can create a serious psychological burden for the patient,” added Saffitz. “Waiting for a life-threatening arrhythmia to develop and then relying on a device to stop it by delivering a painful shock is not the ideal way to manage this condition. We have to find drugs that can prevent the arrhythmia from occurring in the first place.”
 
To identify the mechanisms underlying this dangerous disease and to find potential drugs to prevent its onset, co-senior author Calum MacRae, HMS associate professor of medicine and a geneticist in the Division of Cardiovascular Medicine at Brigham and Women’s Hospital, 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. By working with zebrafish, which develop rapidly and can be produced in large quantities, the investigators could see clear evidence of heart disease after only 48 hours of embryonic development. 
 
They then conducted a high-throughput screen to test 4,800 chemicals to identify a suppressor of the disease phenotype. One chemical in particular, SB216763, showed a remarkable ability to prevent or reverse the disease in the fish. Armed with this new information, the investigators confirmed their findings through studies of both mammalian models of ACM and human heart muscle cells derived from adult stem cells from ACM patients.
 
“We found that a single small molecule [SB216763] could reverse both the muscle cell injury and the arrhythmia components of ACM,” said Saffitz. These new findings provide strong evidence that these complex disease processes are linked to a common mechanism, which appears to involve a defect in forward trafficking of key proteins to the intercalated discs, sites of cell-cell adhesion.
 
“It also appears that we have discovered a new mechanism-based anti-arrhythmic drug that can prevent or reverse major abnormalities of cellular electrophysiology in the heart in cases of ACM,” said Saffitz.
 
“This work shows that it is possible to model a complex human disease in fish and use high-throughput screens of large chemical libraries for the discovery of effective new drugs and could help provide the foundation for future chemical biology efforts to bring such drugs to clinical use.”
 
Source: HMS
 
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