Cardiomyopathy induced by cardiac gs[alpha] overexpression.
Iwase, Mitsunori, Masami Uechi, Dorothy E. Vatner, Kuniya Asai,
Richard P. Shannon, Raymond K. Kudej, Thomas E. Wagner, David C.
Wight, Thomas A. Patrick, Yoshihiro Ishikawa, Charles J. Homcy, and
Stephen F. Vatner.
Department of Medicine, Harvard Medical School, Brigham &
Women's Hospital, Boston, MA 02115, the New England Regional Primate
Research Center, Southborough, MA 01772, West Roxbury VA Hospital,
Boston MA 02132, the Department of Molecular and Cellular Biology,
The Edison Institute, Ohio University, Athens, OH 45701, and COR
Therapeutics Inc., South San Francisco, CA 94080
APStracts 3:0450H, 1996.
The goal of this study was to determine if chronic endogenous
sympathetic stimulation resulting from overexpression of cardiac
Gs[alpha] in transgenic mice (15.3 +/- 0.1 months old) resulted in a
clinical picture of cardiomyopathy. Left ventricular (LV) ejection
fraction, measured by echocardiography, was reduced in older mice
with Gs[alpha] overexpression (50.4 +/- 5.4%) as compared with age
matched controls (70.9 +/- 1.6%, p<0.05). When ejection
fractions were compared at similar heart rates, the Gs[alpha] mice
exhibited a greater LV end-diastolic dimension than controls (4.3 +/-
0.2 mm vs. 3.7 +/- 0.1 mm, p< 0.05). Baseline heart rates were
elevated in conscious Gs[alpha] mice (722 +/- 27 beats/min, n=5) as
compared with controls (656 +/- 28 beats/min, n=5). Moreover,
electrocardiographic monitoring demonstrated a high incidence of
arrhythmias. Increased mortality, as compared with controls (31.6%,
vs. 3.0%, p<0.01), was also observed. Thus, older mice with
Gs[alpha] overexpression exhibit many of the features of dilated
cardiomyopathy. This study supports the concept that chronic
sympathetic stimulation over an extended period of time, i.e., over
the life of an animal, is deleterious and actually may result in
cardiomyopathy.
Received 23 July 1996; accepted in final form 1 October 1996.
APS Manuscript Number H657-6.
Article publication pending Am. J. Physiol. (Heart Circ. Physiology).
ISSN 1080-4757 Copyright 1996 The American Physiological Society.
Published in APStracts on 5 November 1996