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Third-party-funded project

Title:
Energy metabolism in heart failure

Project management at the University of Würzburg:

Participating scientists:

Abstract:
Inspite of intensive research efforts, it remains unclear whether changes in myocardial energy metabolism play a causal role in heart failure, and, if so, whether therapeutic manipulations are feasible. Previously, using experimental models and clinical studies, we found evidence for a causal role of energy metabolism in heart failure. The current project now follows several experimental strategies:
1. Using genetic ablation, transgenic mice with a null mutant of creatine cinase (CK)-M, mito-CK and double-knockout are available. Initially, methodological work is required: Establishment of chronic injury models in the mouse and phenotype analysis with in vivo catheterization, MR imaging and isolated heart perfusion (energy and calcium metabolism using 31P-MR spectroscopy and aequorin). Thereafter, we will examine the development of heart failure post-myocardial infarction and post-aortic banding in creatine kinase deficient mice.
2. Our previous work showed that feeding with creatine could not influence the derangement of energy metabolism in the chronic infarct model, since creatine did not accumulate intracellulary. Therefore, changes of the specific creatine transporter in heart failure will be examined using the rat infarct model. Furthermore, a mouse model of transgenic overexpression of the creatine transporter will be established. It is conceivable that this will lead to increased creatine and phosphocreatine levels in the heart. If so, the acute and chronic functional consequences of transgenic overexpression will be tested.
3. An alteration of glucose-utilization also might play a major role in altered energetics in hypertrophy and heart failure. Therefore, glucose utilization will be analyzed in normal and chronically failing hearts post-myocardial infarction: insuline dependent and –independent glucose uptake will be followed using 2, dioxyglucosephosphate perfusion and 31P-MR-spectroscopy, glycolysis flux rates will be measured with 5-3H-glucose perfusion and capacities of key enzymes of glycolysis will be measured with spectrophotometry. Clinical studies also are related to the role of energy metabolism in heart failure. The STEP-study examines the influence of chronic betareceptor blocker therapy on myocardial function and energy metabolism in dilated cardiomyopathy. Studies on energy metabolism in patients with aortic valve disease before and after valve replacement will be continued. Furthermore, 1H-MR spectroscopy will be developed for the use in patients with heart failure.

Key words:
    Energy metabolism
    heart failure
    creatine kinase knockout

Projekt period: from 01.1999 to 12.2001

Funding institution:
DFG ,Granting date: 02.12.1998

Publications:

Links:
University Hospital, Würzburg