Congestive heart failure (CHF) is associated with abnormal myocardial energy metabolism. The mechanisms for this abnormality and the contribution to the evolution from compensated hypertrophy to CHF are not known. The myocardial ATP concentration is significantly decreased in failing hearts or hearts with severe hypertrophy; this ATP depletion could result from increased production of reactive oxygen species (ROS), progressive loss of the myocardial total adenine nucleotide pool (TAN), or insufficient enhancement of glucose metabolic pathways. The central hypothesis of this proposal is that alterations of myocardial energy metabolism contribute to contractile dysfunction of the failing heart and that interventions which improve myocardial energetics will improve LV function and consequently prevent the evolution to heart failure. Using swine models of postinfarction LV remodeling (eccentric hypertrophy) or pressure overload (concentric hypertrophy), the main aims are: (1) to examine whether the myocardial bioenergetic inefficiency contributes to LV dysfunction in failing hearts, and (2) whether interventions that enhance glucose metabolism and/or the TCA cycle intermediate pool size will improve myocardial energetics and attenuate the structural and functional changes that occur in infarcted or overloaded hearts. The effects of the interventions on LV contractile function will be followed longitudinally using MR imaging; myocardial oxygenation will be measured by 1H-MR spectroscopy, and HEP content and kinetics will be measured with 31P-MR spectroscopy. Potentially beneficial effects of anaplerotic interventions on myocardial energetics and function will be examined. We will examine whether the OXPHOS abnormalities in the hypertrophied hearts are caused by increased ROS production that causes mitochondrial electron transport chain inefficiency and/or are secondary to chronic loss of the TAN pool. We will test whether ribose administration can prevent loss of the TAN to preserve ATP, and whether this can prevent the development of CHF. Additional studies will determine whether interventions that enhance glucose metabolism and/or the TCA cycle intermediate pool size to enhance oxidative ATP production will ameliorate the abnormal myocardial OXPHOS and attenuate structural and functional changes in the post-infarct or overloaded hearts. The results of these experiments may lead to better preventive and therapeutic modalities for heart failure. ? ?

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
2R01HL050470-09A2
Application #
6863028
Study Section
Special Emphasis Panel (ZRG1-MIM (01))
Program Officer
Buxton, Denis B
Project Start
1993-07-05
Project End
2009-12-31
Budget Start
2005-01-01
Budget End
2005-12-31
Support Year
9
Fiscal Year
2005
Total Cost
$336,375
Indirect Cost
Name
University of Minnesota Twin Cities
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
555917996
City
Minneapolis
State
MN
Country
United States
Zip Code
55455
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