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:4/5/2017)... Allen Institute for Cell Science today announces the launch ... dynamic digital window into the human cell. The website ... deep learning to create predictive models of cell organization, ... suite of powerful tools. The Allen Cell Explorer will ... resources created and shared by the Allen Institute for ...
(Date:4/3/2017)... 3, 2017  Data captured by IsoCode, ... detected a statistically significant association between the ... treatment and objective response of cancer patients ... predict whether cancer patients will respond to ... well as to improve both pre-infusion potency testing ...
(Date:3/29/2017)... , March 29, 2017  higi, the health IT ... North America , today announced a ... the acquisition of EveryMove. The new investment and acquisition ... of tools to transform population health activities through the ... data. higi collects and secures data today ...
Breaking Biology News(10 mins):
(Date:9/25/2017)... , Sept. 25, 2017  Renova™ Therapeutics, a biotechnology ... metabolic diseases, announced that the company,s CEO and Co-founder, ... a panel at the Cell & Gene Therapy ... and its Vice President of Preclinical Research and Pharmacology, ... Boulder Peptide Symposium in Boulder, ...
(Date:9/25/2017)... ... September 25, 2017 , ... ... be presenting multiple case studies, presentations and demonstrations at SCDM 2017, held ... data managers, medical review teams and CRO partners for more automated capabilities ...
(Date:9/22/2017)... ... September 22, 2017 , ... Precision Periodontics and Implant Dentistry's ... LAPIP™ laser treatments. Drs. Hoge and Zalewsky are members of an elite class ... less painful option that produces real results. , "Like many of my colleagues, ...
(Date:9/21/2017)... ... 21, 2017 , ... Vixiar Medical announced today that it ... to The LaunchPort™ Accelerator at the City Garage in Port Covington. The LaunchPort™, ... business services to its Residents. , Vixiar Medical recently closed a $1.5 ...
Breaking Biology Technology: