Navigation Links
Studies point to novel target for treating arrhythmias
Date:1/21/2009

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 Bjrn 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.


'/>"/>

Contact: Leigh MacMillan
leigh.macmillan@vanderbilt.edu
615-322-4747
Vanderbilt University Medical Center
Source:Eurekalert

Related biology news :

1. Studies examine genetic determinants of ADHD
2. Studies offer guide as protein interaction mapping comes of age
3. Web-based case studies help students develop career skills
4. To improve forecasting earthquakes, NJIT mathematician studies grains
5. Studies on imaging and tracking transplanted cells
6. UI researchers help to improve carbon measurements in global climate studies
7. MSU researcher studies ties between cholesterol drugs, muscle problems
8. Studies of small water fleas help ecologists understand population dynamics
9. ASU researchers receive NIH awards for studies of malaria and emergent disease
10. Drug-embedded microparticles bolster heart function in animal studies
11. NIAID funds studies of how SARS and bird flu evade antiviral responses
Post Your Comments:
*Name:
*Comment:
*Email:
(Date:3/27/2021)... ... March 25, 2021 , ... Phlexglobal announced ... Planet Group, has selected Phlexglobal and its innovative regulatory SaaS software, PhlexSubmission, as ... a comprehensive review of five regulatory software companies, with the review team including ...
(Date:3/27/2021)... ... 25, 2021 , ... The 2021 Virtual Conference on Clinical Trial Supply-Europe ... More and more, clinical trial supply conferences are featuring speakers and forums that ... Asymmetrex’s founder and CEO, James L. Sherley, M.D., Ph.D., presented a talk ...
(Date:3/23/2021)... ... March 23, 2021 , ... G-CON Manufacturing (G-CON), the ... by Matica Biotechnology (Matica Bio), a contract development and manufacturing organization (CDMO) specializing ... the cleanroom build out for its new GMP production facility in College Station, ...
Breaking Biology News(10 mins):
(Date:3/27/2021)... ... March 24, 2021 , ... ... Life Sciences and Healthcare firms of all sizes, adds depth to its team ... specialist. Pardillo, who earned his doctorate in computational chemistry from Florida International University ...
(Date:3/27/2021)... ... March 24, 2021 , ... ABI Wellness, ... and reporting approach designed under CEO Mark Watson, today announced a webinar dedicated ... featuring guest speakers Dr. Cameron Clark, Neuropsychologist and Founder of Sharp Thinking, and ...
(Date:3/27/2021)... ... ... The Xtalks editorial team is pleased to announce the launch of the ... joined by editorial team members Ayesha Rashid, Sydney Perelmutter and Mira Nabulsi to discuss ... including insights from industry experts. , The Xtalks Life Science podcast will feature ...
(Date:3/23/2021)... Conn. (PRWEB) , ... March 23, 2021 , ... ... develops solutions for characterizing microbiome populations down to the strain level, recently unveiled ... applications. , Not all microbes are created equal: some are easy to ...
Breaking Biology Technology: