Researchers At Columbia Link Genetic Mutations To Exercise-Induced Cardiac Arrhythmias

Evidence Indicates Deficiency of Binding Protein Can Trigger Fatal Ventricular Arrhythmias in Structurally Normal Hearts New York, NY – June 26, 2003 – Researchers at Columbia University College of Physicians & Surgeons have completed research indicating that a genetic defect may make some people with otherwise structurally normal hearts more susceptible to exercise-induced cardiac arrhythmias. Their findings, which are reported in the June 27 issue of Cell, show that a deficiency of FKBP12.6, a protein that binds to the intracellular cardiac calcium channel (ryanodine receptor; “RyR2”) may result in abnormal calcium release and be linked to exercise-induced cardiac death. The researchers also have identified the biophysical properties of three distinct RyR2 mutations linked to these ventricular arrhythmias.

Headed by Dr. Andrew Marks, chairman of the Department of Physiology and Cellular Biophysics and director of the Center for Molecular Cardiology at Columbia University College of Physicians & Surgeons, the research team investigated the function of FKBP12.6, its effects on calcium channel function, and its association with exercise-induced ventricular arrhythmias (sudden cardiac death). Their focus was on a possible connection between a deficiency of FKBP12.6 and irregular calcium channel function. In normal cardiac muscle, the ryanodine receptor (RyR2) releases the calcium required for muscle contraction. The FKBP12.6 stabilizes the RyR2, preventing a release of too much calcium, which can trigger erratic heart activity during the resting phase of the cardiac cycle.

Dr. Marks’ team studied genetically modified mice, deficient in the FKBP12.6 gene, to observe heart function at rest and during exercise. “The research showed that the FKBP12.6-deficient mice consistently exhibited exercise-induced ventricular arrhythmias that cause sudden cardiac death--suggesting that ‘leaky’ RyR2 channels can trigger fatal cardiac arrhythmias,” says Dr. Xander H.T. Wehrens, postdoctoral research scientist at Columbia University, a member of the research team, and first author of the report in Cell.

Dr. Marks says these findings will significantly advance discovery of possible treatment. “Our findings show that if we can develop therapies that influence the binding of FKBP12.6 in the calcium channel, we can prevent one of the most common and baffling causes of cardiac death—exercise-induced arrhythmias in individuals with otherwise healthy hearts. Moreover, our findings may also provide clues for novel strategies to prevent cardiac arrhythmias in millions of patients with heart failure who have a similar leak in their calcium channels.”

Copies of the article may be obtained by contacting Rubab Kahn at Cell: (617) 397-2817;

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Columbia University College of Physicians & Surgeons Established in 1767, Columbia’s College of Physicians & Surgeons was the first institution in the country to grant the M.D. degree. Among the most selective medical schools in the country, the school is also home to the largest medical research enterprise in New York state and one of the largest in the country. New York-Presbyterian Hospital is the primary teaching hospital for the Columbia University College of Physicians & Surgeons, providing international leadership in biomedical research and patient care. Columbia’s Department of Physiology and Cellular Biophysics is one of the nation’s premier scientific groups focusing on cellular physiology, cardiovascular biology, and neurobiology research.


Andrew Marks, Columbia University, New York, Physicians Surgeons