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Activity Of Calcium-handling Gene Appears To Prevent Cardiac Arrhythmias

Date:
March 25, 2004
Source:
Massachusetts General Hospital
Summary:
Activation of a gene already shown to correct heart failure by improving calcium metabolism in the heart muscle may also help prevent arrhythmias, sometimes-dangerous disturbances in heart rhythm, according to a study from the Massachusetts General Hospital (MGH) Cardiovascular Research Center (CVRC).

Activation of a gene already shown to correct heart failure by improving calcium metabolism in the heart muscle may also help prevent arrhythmias, sometimes-dangerous disturbances in heart rhythm, according to a study from the Massachusetts General Hospital (MGH) Cardiovascular Research Center (CVRC). The article, being released today in the early online edition of Proceedings of the National Academy of Sciences, describes how overexpression of the protein SERCA2a in the hearts of rats reduced the incidence of arrhythmia after heart muscle injury.

"If these results hold up in future studies, SERCA2a gene therapy could help protect patients at risk of arrhythmia because of existing heart disease or prevent rhythm disturbances that can occur after percutaneous coronary interventions," says Roger J. Hajjar, MD, of the CVRC and the MGH Heart Failure Center, the paper's senior author.

While arrhythmias are common, certain types may indicate serious heart disease. Significant rhythm disturbances of the ventricles - the lower chambers that pump blood out of the heart - can be dangerous. Ventricular fibrillation, in which the muscles contract in a rapid, uncoordinated fashion, is the leading cause of cardiac death occurring outside of a hospital. Such arrhythmias need to be stopped by application of electrical current through a defibrillator, and some patients with a history of fibrillation have permanent defibrillators implanted to correct their heart rhythm.

Contraction of any muscle cell requires the correct movement of calcium within the cell. It has been known for 20 years that heart failure - in which the heart muscle is weak and does not pump effectively - is associated with abnormal handling of calcium. Earlier research has shown that SERCA2a, which helps transport calcium between cellular structures, does not function well in heart failure. Cellular and animal studies by the same MGH CVRC team - led by Federica del Monte, MD, PhD - have confirmed that increasing the expression of SERCA2a could correct heart failure. Preclinical trials of a SERCA2a-based heart failure treatment are currently underway.

In anticipation of SERCA2a clinical trials in heart failure patients, a concern was raised that the gene's action of increasing calcium transport in heart cells could stimulate arrhythmias. In addition, recent research elsewhere has implicated calcium in the generation of ventricular fibrillation and the rapid rhythm called ventricular tachycardia. The current study was conducted to investigate the potential impact of SERCA2a expression on arrhythmia risk.

The researchers used standard gene therapy techniques to induce overproduction of SERCA2a in the hearts of normal rats. As controls, other groups of rats received gene therapy vectors that induce the production of two other genes, one of which codes for a muscle-fiber protein that counteracts excess calcium.

Two to six days later, each rat had one of its coronary arteries tied off for 30 minutes and then reopened, producing the kind of heart-muscle injury that can occur with a heart attack. EKG measurements of the rats' heart rhythm were taken throughout the experiment and for 24 hours afterwards. Two days after the cardiac injury, the hearts of all the rats were removed and examined.

Results showed that, contrary to the researchers' earlier concerns, the rats whose hearts overexpressed SERCA2a actually had a lower incidence of arrhythmia during cardiac injury and the following 24 hours than did the rats receiving the other two genes. In addition, the injured area of heart muscle - which would correspond to the amount of tissue destroyed in a heart attack - was smaller with expression of SERCA2a, which also improved heart muscle function.

"This finding increases our confidence that enhancing SERCA2a in cardiac cells of patients with severe heart failure will improve the function of the hearts without causing arrhythmias, a well known side effect of current intravenous treatments for advanced heart failure," says del Monte, the lead author and an assistant professor of Medicine at Harvard Medical School (HMS).

"If such results could be duplicated in humans, this kind of gene therapy could be an alternative to defibrillator implantation for some patients," say Hajjar, an HMS associate professor of Medicine. These types of experiments are currently being pursued in large animals that more closely mimic the human condition.

In addition to Hajjar and del Monte, the study's authors are Djamel Lebeche, PhD, Luis Guerrero, Tsuyoshi Tsuji of the MGH CVRC; Judith Gwathmey, PhD, VMD, of HMS, and Angelia Doye of Gwathmey, Inc. in Cambridge, Mass. The research was supported by grants from the National Institutes of Health and the American Federation of Aging Research.

Massachusetts General Hospital, established in 1811, is the original and largest teaching hospital of Harvard Medical School. The MGH conducts the largest hospital-based research program in the United States, with an annual research budget of more than $400 million and major research centers in AIDS, cardiovascular research, cancer, cutaneous biology, medical imaging, neurodegenerative disorders, transplantation biology and photomedicine. In 1994, MGH and Brigham and Women's Hospital joined to form Partners HealthCare System, an integrated health care delivery system comprising the two academic medical centers, specialty and community hospitals, a network of physician groups, and nonacute and home health services.


Story Source:

The above story is based on materials provided by Massachusetts General Hospital. Note: Materials may be edited for content and length.


Cite This Page:

Massachusetts General Hospital. "Activity Of Calcium-handling Gene Appears To Prevent Cardiac Arrhythmias." ScienceDaily. ScienceDaily, 25 March 2004. <www.sciencedaily.com/releases/2004/03/040323074107.htm>.
Massachusetts General Hospital. (2004, March 25). Activity Of Calcium-handling Gene Appears To Prevent Cardiac Arrhythmias. ScienceDaily. Retrieved October 23, 2014 from www.sciencedaily.com/releases/2004/03/040323074107.htm
Massachusetts General Hospital. "Activity Of Calcium-handling Gene Appears To Prevent Cardiac Arrhythmias." ScienceDaily. www.sciencedaily.com/releases/2004/03/040323074107.htm (accessed October 23, 2014).

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