UM Researchers Publish Findings on Sudden Cardiac Death

Sudden cardiac death is a leading cause of mortality in the United States and Western Europe, and it has recently been observed that an individual’s risk for sudden cardiac death is increased by having a family member with this condition, suggesting a genetic component. Now, Miller School researchers collaborating with a team in Amsterdam and others from the U.S. and Europe have conducted a genome-wide association study that uncovered a genetic locus not previously suspected to be involved in arrhythmia or sudden death. The findings were published today online in the journal Nature Genetics.

The majority of sudden cardiac deaths happen when someone is suffering a myocardial infarction or a heart attack. In about 25 percent of patients, heart attacks can cause a deadly arrhythmia known as ventricular fibrillation, the most common mechanism of cardiac arrest. The international research team performed the genetic study on a set of 972 patients from the Netherlands with a first acute myocardial infarction. Half developed ventricular fibrillation, and half did not. By comparing the two groups, the researchers hoped to identify genetic factors underlying susceptibility to ventricular fibrillation during a heart attack.

“The genome-wide association study turned up a susceptibility locus at chromosome21q21 that clustered very strongly among the patients who went into ventricular fibrillation,” said Robert J. Myerburg, M.D., professor of medicine at the Miller School and one of the study’s co-investigators. “The findings suggest we should look further in that area for identifying people who are at risk for cardiac arrest when they are suffering a heart attack.”

Of the eight single-nucleotide polymorphisms (SNPs) identified in the locus, the one most associated with the risk of ventricular fibrillation was rs2824292. More significantly, the closest gene to that SNP is CXADR, which encodes a protein called the Coxsackie-Adenovirus Receptor.

“The Coxsackie-Adenovirus Receptor imports the viruses, and while infection with adenovirus is almost universal, a few people get a cardiomyopathy that can be very dangerous,” explained Nanette Hahr Bishopric, M.D., professor of medicine, director of the Cardiovascular Genetics Laboratory at the Miller School, and another study co-investigator. “Infection with Coxsackie B virus is more rare but more commonly causes cardiomyopathy. Both Coxackie B and Adenovirus 2/5-associated cardiomyopathies are also linked to arrhythmias and sudden death. The same receptor is also linked to dilated cardiomyopathy. So this is a very interesting candidate gene.”

The study findings were replicated in an independent case-control set of patients with myocardial infarction and ventricular fibrillation and a group of patients who survived a myocardial infarction.

“Given that half of all sudden deaths occur as the first manifestation of underlying disease, it is imperative that we understand the genetic and molecular mechanisms that determine who is at risk for these common but deadly arrhythmias,” Bishopric said.

The study was supported by research grants from the Netherlands Heart Foundation, the Leducq Foundation in France, and the Interuniversity Cardiology Institute of the Netherlands.

Drs. Bishopric and Myerburg are part of the Transatlantic Networks of Excellence for Cardiovascular and Neurovascular Research, supported by the Leducq Foundation, headquartered in Paris. The foundation’s mission is to improve human health by promoting internationally collaborative research conducted by teams of scientists from North America and Europe in the area of cardiovascular disease.

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