Pitt Cardiologists Identify New Gene Responsible for Sudden Cardiac Arrest

Researchers in Pitt’s School of Medicine have identified a new gene responsible for a rare, inherited form of sudden cardiac arrest known as Brugada syndrome.

The team hopes identification of this new gene will shed light on more common causes of heart attacks and heart failure, and will help the development of new, effective therapeutic treatments that will prevent all types of fatal arrhythmias.

The team was led by Barry London, the Harry S. Tack professor of medicine, chief of the division of cardiology in Pitt’s School of Medicine, and director of the University of Pittsburgh Medical Center (UPMC) Cardiovascular Institute.

Their findings were reported in the Nov. 12 issue of Circulation: Journal of the American Heart Association. The paper is online and available by going to circ.ahajournals.org.

Brugada syndrome is a rare inherited arrhythmia, more commonly found in men. It can be discovered when the patient has an electrocardiogram (ECG) after reporting unexplained fainting spells.

In about 20 percent of Brugada syndrome patients, mutations in the heart’s sodium channels lead to less current flow and shorter heartbeats in part of the heart. That puts patients at risk for rapid, abnormal heart rhythms. Without warning, a seemingly healthy patient can pass out or suffer a sudden cardiac arrest from an arrhythmia.

Arrhythmias remain a major public health problem leading to more than 250,000 sudden cardiac deaths each year. Brugada syndrome was only identified approximately 15 years ago and much is still not understood about the condition, London said. It is found all over the world and presently there is no cure.

The best therapy to date is to implant a defibrillator into the chests of patients who are clinically found to be at high risk.

Using positional cloning and gene sequencing on a family affected with Brugada syndrome, London and colleagues identified a mutation in a previously unstudied gene, GPD1-L, on chromosome 3p24. This mutation impairs the heart’s natural electrical ability to beat in a coordinated manner and maintain a stable rhythm, he said.

Patients with Brugada syndrome rarely have symptoms, London said, though they carry the genetic mutation all the time. “So, the question now is, why do arrhythmias or sudden death happen on any one particular day?” he said. “Something else is happening concurrently with this mutation to trigger the potentially lethal rhythm problems.”

With the identification of the GPD1-L gene, London’s team hopes to discover additional genes that control the heart’s rhythms and increase their understanding of the mechanisms that lead to arrhythmias in Brugada syndrome patients and others.

London’s collaborators include Michael Michalec, Haider Mehdi, Xiadong Zhu, Laurie Kerchner, Prakash C. Viswanathan, Mohan Madhusudanan, Catherine Baty, Stephen Lagana, Ryan Aleong, Rebecca Gutmann, and Dennis McNamara, all from the University of Pittsburgh Cardiovascular Institute; along with researchers from the Mayo Clinic College of Medicine, Ohio State University, Emory University, and the Atlanta VA Medical Center.

His study was funded in part by the National Heart, Lung, and Blood Institute, a U.S. Department of Veterans Affairs grant and the American Heart Association Established Investigator Awards.