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(Circulation. 2001;104:1844.)
© 2001 American Heart Association, Inc.

Basic Science Reports

Chronic Phosphocreatine Depletion by the Creatine Analogue ß-Guanidinopropionate Is Associated With Increased Mortality and Loss of ATP in Rats After Myocardial Infarction

Michael Horn, PhD; Helga Remkes, MSc; Hinrik Strömer, MD; Charlotte Dienesch; Stefan Neubauer, MD

From the Medizinische Universitätsklinik, Würzburg University, Germany (M.H., H.R., H.S., C.D., S.N.); Wallenberg Laboratory, Sahlgrenska Hospital, Gothenburg University, Sweden (M.H.); and the Department of Cardiovascular Medicine, John Radcliffe Hospital, University of Oxford, UK (S.N.).

Correspondence to Michael Horn, PhD, Sahlgrenska Sjukhuset, Wallenberg Laboratoriet, 41345 Göteborg, Sweden. E-mail m.horn{at}wlab.gu.se

Background— The failing myocardium is characterized by reductions of phosphocreatine (PCr) and free creatine content and by decreases of energy reserve via creatine kinase (CK), ie, CK reaction velocity (Flux_CK). It has remained unclear whether these changes contribute directly to contractile dysfunction. In the present study, myocardial PCr stores in a heart failure model were further depleted by feeding of the PCr analogue ß-guanidinopropionate (GP). Functional and metabolic consequences were studied.

Methods and Results— Rats were subjected to sham operation or left coronary artery ligation (MI). Surviving rats were assigned to 4 groups and fed with 0% (n=7, Sham; n=5, MI) or 1% (n=7 Sham+GP, n=8 MI+GP) GP. Two additional groups were fed GP for 2 or 4 weeks before MI. After 8 weeks, hearts were isolated and perfused, and left ventricular pressure-volume curves were obtained. High-energy phosphate metabolism was determined with ³¹P NMR spectroscopy. After GP feeding or MI, left ventricular pressure-volume curves were depressed by 33% and 32%, respectively, but GP feeding in MI hearts did not further impair mechanical function. Both MI and GP feeding reduced PCr content and Flux_CK, but here, effects were additive. In MI+GP rats, PCr levels and Flux_CK were reduced by 87% and 94%, respectively. Although ATP levels were maintained in the GP and MI groups, ATP content was reduced by 18% in MI+GP hearts. Furthermore, 24-hour mortality in GP-prefed rats was 100%.

Conclusions— Rats with an 87% predepletion of myocardial PCr content cannot survive an acute MI. Chronically infarcted hearts subjected to additional PCr depletion cannot maintain ATP homeostasis.

Key Words: magnetic resonance imaging • spectroscopy • heart failure • myocardial infarction • creatine kinase

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