Activity of calcium-handling gene appears
to prevent cardiac arrhythmias
Calcium pump could help prevent
or treat dangerous rhythm disturbances
BOSTON - March 22, 2004 - 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
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.
Media Contact: Michelle
Marcella, MGH Public Affairs
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