title: Genetic alterations that inhibit in vivo pressure-overload hypertrophy prevent cardiac dysfunction despite increased wall stress.
abstract: 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.
  
  
  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 (sigma(es)) obtained by sonomicrometry after 1 week of pressure overload showed complete normalization of sigma(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 sigma(es) (415+/-81 g/cm2, P<0.05). Remarkably, despite inadequate normalization of sigma(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.
authors.affiliation: Department of Medicine, Duke University Medical Center, Durham, NC 27710, USA.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Esposito
authors.forename: Antonio
authors.initials: A
authors.lastname: Rapacciuolo
authors.forename: Sathyamangla V
authors.initials: SV
authors.lastname: Naga Prasad
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Takaoka
authors.forename: Steven A
authors.initials: SA
authors.lastname: Thomas
authors.forename: Walter J
authors.initials: WJ
authors.lastname: Koch
authors.forename: Howard A
authors.initials: HA
authors.lastname: Rockman
mesh_terms: D000262:Adenylyl Cyclases / Q000378:metabolism; D000818:Animals; D006332:Cardiomegaly / Q000235:genetics / Q000378:metabolism / Q000503:physiopathology*; D003250:Constriction; D017868:Cyclic AMP-Dependent Protein Kinases / Q000378:metabolism; D004299:Dopamine beta-Hydroxylase / Q000235:genetics; D004452:Echocardiography; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D006321:Heart / Q000503:physiopathology*; D020962:Heterotrimeric GTP-Binding Proteins / Q000235:genetics; D051379:Mice; D018345:Mice, Knockout; D008822:Mice, Transgenic; D020928:Mitogen-Activated Protein Kinases / Q000378:metabolism; D009206:Myocardium / Q000378:metabolism / Q000473:pathology; D051058:Oncogene Protein v-akt; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011943:Receptors, Adrenergic, beta / Q000378:metabolism; D015682:Retroviridae Proteins, Oncogenic / Q000378:metabolism; D015398:Signal Transduction; D051552:beta-Adrenergic Receptor Kinases
chemical_list: D011943:Receptors, Adrenergic, beta; D015682:Retroviridae Proteins, Oncogenic; D004299:Dopamine beta-Hydroxylase; D019869:Phosphatidylinositol 3-Kinases; D051058:Oncogene Protein v-akt; D017868:Cyclic AMP-Dependent Protein Kinases; D051552:beta-Adrenergic Receptor Kinases; D020928:Mitogen-Activated Protein Kinases; D043802:GTP-Binding Protein alpha Subunits, Gq-G11; D020962:Heterotrimeric GTP-Binding Proteins; D000262:Adenylyl Cyclases