Circulation. 2002;105:85-92
doi: 10.1161/hc0102.101365
doi: 10.1161/hc0102.101365
(Circulation. 2002;105:85.)
© 2002 American Heart Association, Inc.
Basic Science Reports |
Genetic Alterations That Inhibit In Vivo Pressure-Overload Hypertrophy Prevent Cardiac Dysfunction Despite Increased Wall Stress
From the Departments of Medicine (G.E., A.R., S.V.N.P., H.T., H.A.R.) and Surgery (W.J.K.), Duke University Medical Center, Durham, NC, and the Department of Pharmacology, University of Pennsylvania, Philadelphia (S.A.T.).
Correspondence to Howard A. Rockman, MD, Department of Medicine, Duke University Medical Center, DUMC 3104, Durham, NC, 27710. E-mail h.rockman{at}duke.edu
Background— A long-standing hypothesis has been that hypertrophy is compensatory and by normalizing wall stress acts to maintain normal cardiac function. Epidemiological data, however, have shown that cardiac hypertrophy is associated with increased mortality, thus casting doubt on the validity of this hypothesis.
Methods and Results— To determine whether cardiac hypertrophy is necessary to preserve cardiac function, we used 2 genetically altered mouse models that have an attenuated hypertrophic response to 8 weeks of pressure overload. End-systolic wall stress (
es) obtained by sonomicrometry after 1 week of pressure overload showed complete normalization of es in pressure-overloaded wild-type mice (287±39 versus sham, 254±34 g/cm2), whereas the blunted hypertrophic response in the transgenic mice was inadequate to normalize es (415±81 g/cm2, P<0.05). Remarkably, despite inadequate normalization of es, cardiac function as measured by serial echocardiography showed little deterioration in either of the pressure-overloaded genetic models with blunted hypertrophy. In contrast, wild-type mice with similar pressure overload showed a significant increase in chamber dimensions and progressive deterioration in cardiac function. Analysis of downstream signaling pathways in the late stages of pressure overload suggests that phosphoinositide 3-kinase may play a pivotal role in the transition from hypertrophy to heart failure.
Conclusions— These data suggest that under conditions of pressure overload, the development of cardiac hypertrophy and normalization of wall stress may not be necessary to preserve cardiac function, as previously hypothesized.
Key Words: contractility • hypertrophy • heart failure • receptors, adrenergic, beta • signal transduction
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