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Bjorn Knollman, M.D., Ph.D., is studying the role calcium handling may play in arrhythmias. Photo by Susan Urmy

Calcium handling key to heart rhythm: study

BY: LEIGH MACMILLAN

9/08/2006 - “Drink your milk,” we say to our children, knowing that milk is a good source of the calcium their growing bones require.

Heart muscle cells need calcium too — the right amount at the right time to power the heartbeat and maintain its rhythm.

A team of Vanderbilt University Medical Center investigators is studying how heart cells handle calcium and what role calcium handling plays in cardiac arrhythmias, or irregular heartbeats. The group reported this month in the Journal of Clinical Investigation that deletion of a calcium-binding protein called calsequestrin makes mice susceptible to arrhythmias.

Mutations in the human calsequestrin gene were first reported in 2001 in patients suffering cardiac arrhythmias. The new paper describes a mouse model for this human disease.

“Having the mouse model gives us the opportunity to study the chain of events that lead from a genetic defect to a cardiac arrhythmia, and we can use these mice to study medications and interventions that target steps in this chain of events,” said Björn Knollmann, M.D., Ph.D., associate professor of Medicine and Pharmacology.

It was surprising, Knollmann said, that humans and mice can live without calsequestrin.

“There's a 30-year-old scientific literature showing that calsequestrin's responsible for storing a large portion of the calcium in the cell that's being released with each heartbeat. If you remove that calcium storage protein, you would expect heart failure,” Knollmann said.

But humans and mice without calsequestrin don't suffer heart failure. Instead, they have apparently normal hearts, in terms of structure and rhythm, until they are stressed. With exercise, activity or emotions that cause adrenaline surges (the “fight or flight” response), humans and mice without calsequestrin develop a special form of cardiac arrhythmia called polymorphic ventricular tachycardia, leading to sudden death in some cases.

The calcium storage “container” inside heart cells is called the sarcoplasmic reticulum. Calsequestrin hangs out inside the sarcoplasmic reticulum, binding calcium and holding it at the ready for release into the heart cell at the appropriate time. When calsequestrin is missing, the researchers showed, calcium spontaneously seeps out of the sarcoplasmic reticulum and triggers cardiac arrhythmias.

“Our studies suggest that calsequestrin is not so important as a calcium storage protein, but that its more important role is as a sort of 'safety switch' that regulates the proper timing of calcium release in order to maintain a regular heart rhythm,” Knollmann said. “There's nothing worse than having spontaneous premature calcium releases from the sarcoplasmic reticulum.”

Such spontaneous calcium releases have been proposed as the most prominent mechanism for triggering cardiac arrhythmias in patients with heart failure, he said. In addition, several clinically-used drugs, including anti-depressant and anti-psychotic medications, inhibit calsequestrin. The new findings could explain why patients taking high doses of such drugs have a higher risk of arrhythmias and sudden death, Knollmann said.

“Now having a model where we can study these phenomena will let us examine how calcium release is maintained and regulated. I think that's a fundamental step forward.”

But Knollmann is even more excited about what he calls the group's “really novel and unprecedented finding.”

The investigators had observed that heart cells in mice lacking calsequestrin could still release the same amount of calcium as normal mice, even without expressing other calcium-storage proteins.

“I thought, well one crazy idea is that maybe the structure of the sarcoplasmic reticulum has changed,” Knollmann recalled.

The investigators turned to collaborator Clara Franzini-Armstrong, Ph.D., who used electron microscopy to evaluate the internal structures of heart muscle cells. The sarcoplasmic reticulum had indeed changed: it was 50 percent larger than normal in heart cells from the mice lacking calsequestrin.

“The remodeling of the storage organelle appears to be how the heart adapts to maintain calcium storage so that it's on par with what calcium storage is normally,” Knollmann said, noting that his group is now performing functional measurements to confirm this idea.

“This kind of change in the sarcoplasmic reticulum has never been reported in other forms of heart disease, but then no one has really looked,” he added. “It's a completely new area to pursue — what regulates organelle size in heart cells, and is it involved in disease.”

Knollmann is a new faculty member in the Division of Clinical Pharmacology and the John A. Oates Institute for Experimental Therapeutics. He came to Vanderbilt from Georgetown University, where he was chief of Clinical Pharmacology.

He decided to move to Vanderbilt, he said, because it has “the best Clinical Pharmacology division in the country, with an emphasis on the biology of cardiac arrhythmias” that nicely complemented his own research program. He also cited the lure of “powerful core facilities.”

“The environment here enables me to branch out a little bit and test some wild ideas while we push forward with our regular studies.”

The research was supported by the National Institutes of Health.

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