© 1996 American Heart Association, Inc.
Articles |
Adverse Effects of Chronic Endogenous Sympathetic Drive Induced by Cardiac Gs
Overexpression
From the Department of Medicine, Harvard Medical School, Brigham & Women's Hospital, Boston, Mass; the New England Regional Primate Research Center, Southborough, Mass; the Department of Pathology, University of Alabama, Birmingham; the Department of Molecular and Cellular Biology, The Edison Institute, Ohio University, Athens; and COR Therapeutics Inc, San Francisco, Calif.
Correspondence to Stephen F. Vatner, MD, New England Regional Primate Research Center, One Pine Hill Drive, Post Office Box 9102, Southborough, MA 01772.
Abstract To study the physiological
effect of the overexpression of myocardial
Gs
(protein levels increased by
approximately threefold in transgenic mice), we examined the
responsiveness to sympathomimetic amines by
echocardiography (9 MHz) in five transgenic mice
and five control mice (both 10.3±0.2 months old). Myocardial
contractility in transgenic mice, as assessed by left
ventricular (LV) fractional shortening (LVFS) and LV
ejection fraction (LVEF), was not different from that of control mice
at baseline (LVFS, 40±3% versus 36±2%; LVEF, 78±3% versus
74±3%). LVFS and LVEF values in transgenic mice during isoproterenol
(ISO, 0.02 µg/kg per minute) infusion were higher than the values in
control mice (LVFS, 68±4% versus 48±3%; LVEF, 96±1%
versus
86±3%; P<.05). Norepinephrine (NE, 0.2
µg/kg per minute) infusion also increased LVFS and LVEF in transgenic
mice more than in control mice (LVFS, 59±4% versus 47±3%; LVEF,
93±2% versus 85±3%; P<.05). Heart rates of
transgenic
mice were higher than those of control mice during ISO and NE infusion.
In three transgenic mice with heart rates held constant, LV dP/dt rose
by 33±2% with ISO (0.02 µg/kg per minute) and by only 13±2%
in
three wild-type control mice (P<.01). NE (0.1 µg/kg
per minute) also induced a greater effect on LV dP/dt in the three
transgenic mice with heart rates held constant compared with three
wild-type control mice (65±8% versus 28±4%, P<.05).
Pathological and histological analyses of older
transgenic mouse hearts (16.0±0.8 months old) revealed
hypertrophy, degeneration, atrophy of cells, and
replacement fibrosis reflected by significant increases in collagen
volume in the subendocardium (5.2±1.4% versus 1.2±0.3%,
P<.05) and in the cross-sectional area of myocytes
(298±29 versus 187±12 µm2, P<.05)
compared with control mouse hearts. These results suggest that
Gs overexpression enhances the efficacy of
the ß-adrenergic receptor–Gs–adenylyl cyclase
signaling pathway. This in turn leads to augmented inotropic and
chronotropic responses to endogenous sympathetic
stimulation. This action over the life of the animal results in
myocardial damage characterized by cellular degeneration, necrosis, and
replacement fibrosis, with the remaining cells undergoing compensatory
hypertrophy. As a model, this transgenic mouse offers new
insights into the mechanisms of cardiomyopathy and
heart failure and provides a new tool for their study.
Key Words: transgenic mice • sympathetic drive • GTP stimulatory protein • echocardiography • heart failure
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