Congestive heart failure due to idiopathic dilated cardiomyopathy (CHF) is a disease of epidemic proportions in the U.S. Nearly 4 million people in the U.S. have the diagnosis of CHF and in nearly half of these patients the etiology of their disease is unknown. Patients with heart failure have symptoms of fatigue, shortness of breath and edema and a 5 year mortality of 80%. Unfortunately, despite over two decades of both clinical and research investigations, our ability to improve symptoms and alter survival is disappointing. In 1991, it was first recognized that patients with CHF have elevated serum levels of the pro-inflammatory cytokine tumor necrosis factor alpha (TNFalpha). Subsequent studies have demonstrated: 1) that the failing but not the non-failing human heart expresses robust amounts of TNFalpha; 2) that TNFalpha is a potent negative inotrope; and 3) an inverse relationship between TNFalpha levels and cardiac hemodynamics. However, these studies did not define whether TNFalpha expression was an epiphenomenon associated with congestive failure or of pathophysiologic significance. Furthermore, clinical therapeutic strategies targeted at cytokine expression do not exist. Recently, the PI has developed a line of transgenic mice that over-express TNFalpha in a cardiac specific manner. Preliminary evaluations demonstrate that these transgenic mice develop a phenotype at 6 months of age that is consistent with that of dilated cardiomyopathy: 1) ventricular dilatation; 2) atrial dilatation: 3) interstitial fibrosis; 4) mild interstitial infiltrates; 5) a diminished ejection fraction; 6) attenuation of adrenergic responsiveness; and 7) sudden cardiac death. Thus, he hypothesizes that these mice will provide a novel model in which to evaluate the role of TNFalpha in the development of end-stage dilated cardiomyopathy. This proposal includes two specific aims:
Specific Aim 1 will test the hypothesis that TNFalpha over-expression in the mouse effects l) morphologic and histologic; 2) biochemical and molecular biological, 3) functional; and 4) electrophysiologic changes that are consistent with those seen in dilated cardiomyopathy. Using novel technology designed for or modified to the mouse, he will assess these various parameters during the development of dilatation and failure.
In Specific Aim 2 he will test the hypothesis that the development of end-stage failure can be attenuated by modulating signaling pathways upstream or downstream of TNFalpha receptor activation. Approaches will include: 1) therapy with monoclonal TNFalpha antibody, 2) adenoviral mediated gene transfer of soluble TNFalpha receptors, and 3) out-crossing TNFalpha overexpression mice with transgenic mice having enhanced adrenergic activity due to over- expression of BARK inhibitor or of the beta2 adrenergic receptor. These studies should enhance our understanding of the role of pro- inflammatory cytokines in CHF, validate the usefulness of this unique model, and provide invaluable information for designing mode therapeutic strategies in patients with CHF.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL060032-02
Application #
6017313
Study Section
Special Emphasis Panel (ZRG4-ECS (01))
Project Start
1998-06-01
Project End
2001-05-31
Budget Start
1999-06-01
Budget End
2000-05-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
053785812
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
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