Studies point to novel target for treating arrhythmias

Jan 21, 2009

Abnormal heart rhythms - arrhythmias - are killers. They strike without warning, causing sudden cardiac death, which accounts for about 10 percent of all deaths in the United States.

Vanderbilt investigators have discovered a new molecular mechanism associated with arrhythmias. Their findings, reported in The Journal of Clinical Investigation, could lead to novel arrhythmia treatments.

"The current antiarrhythmic drugs do not prolong life," said Björn Knollmann, M.D., Ph.D., associate professor of Medicine and Pharmacology and the senior author of the current report. "There's a large need for new approaches to antiarrhythmic therapy."

In their quest to understand how irregular heart rhythms arise - as a way to find new molecular targets for treatment - Knollmann and his colleagues have focused on the role of calcium inside heart muscle cells.

Calcium is central to the contractile cycle. After it is released from its storage sites in heart muscle cells, it interacts with proteins called troponins, part of the cell's myofilament contractile apparatus. The interaction of calcium with troponins regulates myofilament activation and contraction.

Mutations in troponin genes had been linked to inherited forms of hypertrophic cardiomyopathy (HCM), which carries a high risk of sudden cardiac death. HCM is perhaps most famous as a cause of sudden cardiac death in young athletes, but it can affect individuals of any age.

In previous studies, Knollmann's team demonstrated that troponin mutations associated with HCM increase the sensitivity of the troponins to calcium - they bind calcium more readily, which activates the myofilaments more easily and results in stronger contractions.

Increased myofilament calcium sensitivity has also been found in acquired heart diseases, such as heart failure, that have a high incidence of sudden cardiac death, Knollmann said. He and his colleagues proposed that increased myofilament calcium sensitivity contributes to arrhythmia susceptibility.

The researchers examined the heart rhythms of mice expressing various troponin mutants that cause HCM and showed that the mice develop ventricular tachycardia (a particular arrhythmia). The risk for this arrhythmia was directly related to the degree of calcium sensitization caused by the troponin mutation: the higher the calcium sensitivity, the greater the arrhythmia risk.

The investigators then tested whether or not a calcium-sensitizing drug - infused into the mouse heart - would cause arrhythmias. It did.

"We could make a normal heart prone to arrhythmias simply by changing the sensitivity of the myofilaments to calcium," Knollmann said.

Calcium-sensitizing drugs are used clinically in Europe and Japan to treat heart failure (because they increase the strength of contraction), but they have not been approved for use in the United States. The current studies suggest that these agents would increase the risk of arrhythmias.

In addition to demonstrating that a calcium-sensitizing drug could cause arrhythmias, Knollmann and colleagues showed that an agent that desensitizes the myofilaments - makes them less "willing" to bind calcium - prevented arrhythmias. The drug they used is limited to in vitro testing, but the studies validate the concept of calcium desensitization as a way to prevent or block arrhythmias.

"The next step is to look for agents that have a desensitizing effect and then try them therapeutically, first in our mouse models, and then potentially further along to patients," Knollmann said.

"We're excited about these studies because we believe that we have identified a novel mechanism that renders the heart susceptible to arrhythmias and a new therapeutic target for familial hypertrophic cardiomyopathy and other arrhythmia syndromes."

The first author of the current report, Franz Baudenbacher, Ph.D., assistant professor of Biomedical Engineering and Physics, played a key role in studying the electrical changes that caused the arrhythmias. Using optical imaging, he and colleagues in the Vanderbilt Institute for Integrative Biosystems Research and Education (VIIBRE) measured how electrical excitation traveled across the hearts expressing troponin mutants or treated with calcium-sensitizing agents. These experiments defined the electrical underpinnings of the arrhythmias.

Source: Vanderbilt University

Explore further: Ebola expert calls for European anti-virus 'corps'

add to favorites email to friend print save as pdf

Related Stories

Targeted drug therapy prevents exercise-induced arrhythmias

Mar 29, 2009

A 12-year-old Dutch boy - bedridden for three years because of an inherited cardiac arrhythmia syndrome - can now join his friends on the soccer field thanks to a discovery made by Vanderbilt University Medical Center researchers.

Keeping a beating heart in rhythm

Mar 31, 2011

Screening for a group of genetic mutations in people with a special heart condition could help doctors determine who is at risk for cardiac arrest or sudden death, reports a new study in Science Translational Medicine today. ...

Recommended for you

Ebola expert calls for European anti-virus 'corps'

Dec 26, 2014

Europe will be "vulnerable" if it does not regard viruses as a "national security issue" like the United States, the microbiologist who discovered Ebola said in an interview published Friday.

In Liberia, Ebola steals Christmas

Dec 26, 2014

The Ebola epidemic has cast a dark shadow over Christmas this year in Liberia, where small businesses are especially feeling the pinch.

Firm recalls caramel apples amid listeria fears

Dec 25, 2014

A Missouri firm is recalling its Happy Apple brand caramel apples because of the potential that they could be contaminated with listeria. The recall comes after at least three deaths and at least 29 illnesses in 10 states ...

User comments : 0

Please sign in to add a comment. Registration is free, and takes less than a minute. Read more

Click here to reset your password.
Sign in to get notified via email when new comments are made.