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Researchers take important step toward new target to treat arrhythmia
A team of researchers led by Prof. Thomas Hund have identified a new target they hope will help make the next drug discovery for patients suffering from heart arrhythmias happen sooner.
The key may reside in voltage-gated sodium channels, nanoscopic pores that control the flow of sodium ions across the heart cell membrane. Normally, they open and close very quickly and in sync with other cell functions to make the heart work. In cells from sick hearts, these channels often don’t inactivate properly, allowing for excess sodium entry and a build-up of calcium, which ultimately promotes abnormal heart rate (arrhythmia) and symptoms of heart failure.
“We know dysregulation of a protein enzyme called multifunctional CaM kinase II plays a role in disrupting sodium channel function in cardiac disease, but it was a matter of determining how this occurred and whether we could we prevent it for therapeutic benefit,” said Hund, an associate professor of biomedical engineering.
Results of this research were recently published by the journal Circulation. Hund’s team identified a phosphorylation site (Serine 571) on the voltage-gated sodium channel targeted by CaM kinase II that serves as a switch for inappropriate “late” sodium influx. The team generated two genetically modified mouse models, one with the switch permanently turned off and another with it permanently turned on. The two models and a control group then underwent chronic cardiac stress.
While heart function dropped by almost 50 percent in the control group following chronic stress, the subjects with the switch turned off fared much better, showing less than a 10 percent reduction in heart function. In contrast, turning the switch permanently on led to increased late sodium channel current and arrhythmias even at baseline.
“This study identifies a specific site on the channel we can target to preserve normal sodium channel and heart function even under chronic stress,” Hund said. “Now, we need to better understand how this works at the molecular level so we can perhaps design therapeutics to prevent phosphorylation of that site.”
Cardiac arrhythmias are common and tend to increase with age. Some arrhythmias are brief and harmless, such as a flutter or a few skipped beats. Other forms can last long enough to affect how the heart works, or even cause a heart attack or sudden cardiac arrest.
Recent clinical trials have shown potential for treating arrhythmia with drugs that block late current. However, the drugs can also affect other sodium current functions. Hund believes strategies that specifically target Serine 571 hold greater promise.
Other members of the research team include Peter Mohler, Przemyslaw Radwanski and Sandor Gyorke. Hund's lab is located in The Dorothy M. Davis Heart & Lung Research Institute.
This research was supported by grants from the National Institutes of Health, as well as the James S. McDonnell Foundation, Saving Tiny Heart Society and the American Heart Association.
modified version of article by Marti Leitch, Wexner Medical Center Media Relations