Exercise-induced sudden cardiac death is a particularly disturbing form of heart failure. While most heart failure is preceded by coronary artery disease, and most coronary artery disease is preceded and abetted by a sedentary lifestyle, it's the opposite with exercise-induced cardiac death. It is epitomized by healthy young athletes who literally drop dead without warning while doing what is supposed to be good for their hearts - working out.

In the May 16, 2006, issue of the Proceedings of the National Academy of Sciences, researchers from Columbia University in New York City, the Maryland Biotechnology Institute and the University of Maryland, both in Baltimore, demonstrated that exercise-induced cardiac death shares molecular mechanisms with other forms of heart failure. They also reported on a molecule, JVT-519, that can stabilize calcium channels and prevent the arrhythmias that lead to exercise-induced cardiac death.

The paper's conflict of interest disclosure notes that senior author Andrew Marks, professor and chair of physiology at Columbia University, is "on the scientific advisory board and owns shares in ARMGO Pharma, Inc., a start-up company that is developing JTV519 derivatives for clinical use in the treatment of heart failure and sudden cardiac death." Two of the paper's co-authors are also consultants to ARMGO.

ARMGO received its Series A funding May 1. Marks told BioWorld Today the company is located in Columbia University's biotechnology incubator and has about 10 employees and "excellent" funding, though he declined to specify sources.

ARMGO is focused on the ryanodine receptor technology, which also can be applied to striated muscle, rather than heart failure per se. While the exercised-induced sudden cardiac death that is the focus of the current PNAS paper is comparatively rare, sudden cardiac death is not limited to athletes. And heart failure is certainly not. According to American Heart Association statistics, 5 million Americans are afflicted.

A regular heartbeat needs a finely choreographed series of ion movements, and one of those ions is calcium. Calcium is sequestered in heart cells in the endoplasmic reticulum. Marks and his colleagues have demonstrated that a leaky internal calcium channel can be a cause of heart failure. ARMGO President and Chief Operating Officer Carolyn Paradise stressed that it is "totally separate" from voltage-gated L-type calcium channels. This particular calcium channel - the ryanodine receptor channel - has four subunits. Each of those subunits binds to a stabilizing subunit, and if something interferes with the binding of the stabilizer, named calstabin 2, to the receptor subunits, the channel will spend more time in an open state, causing calcium to leak.

In the PNAS paper, the scientists used calstabin-deficient mice to test whether JVT-519 could prevent arrhythmias, comparing animals with normal amounts of calstabin, heterozygous knockouts with half the normal calstabin, and homozygous knockouts with no calstabin.

Neither the calstabin mutation nor JVT-519 affected resting heart rate, but electrical stimulation of the heart induced irregular heartbeats that could be prevented by JVT-519 in animals with low levels of calstabin. Animals with no calstabin at all were impervious to JVT-519s effects, suggesting JVT-519 can strengthen the binding of calstabin to the ryanodine receptor but is powerless if there is no calstabin around to bind.

"Heart failure" is something of a catch-all phrase; it occurs whenever the heart can't pump enough blood to supply the body's needs. But calstabin-ryanodine receptor binding snafus are a molecular feature that are common to different forms of heart failure. Sudden cardiac death due to exercise occurs in people with mutations in the ryanodine receptor channel, which then can't bind calstabin. In heart failure due to coronary artery disease, calstabin can't bind because the ryanodine receptor channel complex is overly phosphorylated. Using cultured cells, Marks and his colleagues showed that JVT-519 improved the functioning of such overly phosphorylated ryanodine receptor complexes.

Currently, the most common treatments for heart failure are indirect; they work by reducing blood pressure, which lowers the heart's workload. Paradise said that ARMGO is optimistic that targeting the ryanodine receptor complex is a promising strategy because it restores normal function of a channel.

"We are not blocking anything," she said.

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