In Vivo Effects of Myocardial Creatine Depletion on Left Ventricular Function, Morphology, and Energy Metabolism—Consequences in Acute Myocardial Infarction

• Published in: Journal of cardiac failure Vol. 13; no. 3; pp. 230 - 237
• Main Authors: Lorentzon, Malin, BSc, Råmunddal, Truls, MD, Bollano, Entela, MD, PhD, Soussi, Bassam, PhD, Waagstein, Finn, MD, PhD, Omerovic, Elmir, PhD
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.04.2007
• Subjects: 31P magnetic resonance spectroscopy; Animal; Animals; Arrhythmia/diagnosis/etiology/metabolism; Arrhythmias, Cardiac - diagnosis; Arrhythmias, Cardiac - etiology; Arrhythmias, Cardiac - metabolism; Biological Markers/metabolism; Biomarkers - metabolism; Cardiac remodeling; Cardiovascular; Catecholamines - metabolism; Congestive heart failure; Creatine - metabolism; Disease Models; Disease Models, Animal; Electrocardiography; Energy Metabolism; Left/etiology/metabolism/ultrasonography; Magnetic Resonance Spectroscopy; Male; MEDICAL AND HEALTH SCIENCES; Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy); MEDICIN OCH HÄLSOVETENSKAP; Medicinsk bioteknologi (med inriktning mot cellbiologi (inklusive stamcellsbiologi), molekylärbiologi, mikrobiologi, biokemi eller biofarmaci); Myocardial Infarction - complications; Myocardial Infarction - diagnosis; Myocardial Infarction - metabolism; Myocardial Infarction/complications/diagnosis/metabolism; Myocardium - metabolism; Rats; Rats, Sprague-Dawley; Reference Values; Sprague-Dawley; Ultrasonography; Ventricular arrhythmias; Ventricular Dysfunction; Ventricular Dysfunction, Left - diagnostic imaging; Ventricular Dysfunction, Left - etiology; Ventricular Dysfunction, Left - metabolism; Ventricular arrhythmias; Energy metabolism; Congestive heart failure; Cardiac remodeling; 31P magnetic resonance spectroscopy
• ISSN: 1071-9164; 1532-8414; 1532-8414
• DOI: 10.1016/j.cardfail.2006.11.012

Abstract Background The failing heart is characterized by disturbed myocardial energy metabolism and creatine (Cr) depletion. The aims of this study were to in vivo evaluate the effects of Cr depletion on: a) left ventricular (LV) function and morphology during rest and stress, b) LV energy metabolism, c) catecholamine in LV and plasma content, and d) incidence of malignant ventricular arrhythmias (MVA) during acute myocardial infarction (MI). Methods and Results Male rats weighing approximately 200 g were used. Two groups were studied: the rats treated with Cr analogue beta-guanidinopropionic acid (BGP) (n = 25) and controls (n = 23). BGP (1 M) was administered by subcutaneously implanted osmotic minipumps over 4 weeks. The rats (BGP n = 9, control n = 12) were than examined with transthoracic echocardiography at basal and at stress conditions induced by transesophageal pacing. In vivo31 P magnetic resonance spectroscopy (MRS) was used for evaluation of myocardial energy status (BGP n = 7, control n = 12).31 P MRS, echocardiography and high-performance liquid chromatography analysis of myocardial Cr, total adenine nucleotides and catecholamines in myocardium and plasma were performed on noninfarcted hearts. Myocardial infarction was induced in a subgroup of animals (BGP n = 15, control n = 15) by ligation of the left coronary artery resulting in a large (∼50%) anterolateral MI and acute HF. A computerized electrocardiogram tracing was obtained continuously before induction of MI and up to 60 minutes postinfarction. Qualitative and quantitative variables of ventricular arrhythmias were analyzed using arrhythmia score. Body weight (BW) was lower ( P < .01), whereas LV/BW was higher ( P < .01) in the BGP group. Total myocardial Cr pool was decreased for at least 50% ( P < .01) compared with the controls. There was no difference in total nucleotide pool. Phosphocreatine/adenosine-3-phosphate ratio was lower in the BGP group ( P < .01). LV systolic function was disturbed during rest and stress ( P < .05). Similarly, LV dimensions were increased in the BGP group ( P < .05). Induction of acute MI resulted in markedly increased incidence of MVA and higher mortality in the BGP group ( P < .01). Conclusions Myocardial Cr depletion results in functional and structural LV alterations associated with lower myocardial energy reserve. Intact myocardial Cr metabolism is important for normal LV function during basal and stress conditions. Acute MI in the setting of myocardial Cr depletion leads to excessive mortality from ventricular arrhythmias and progressive heart failure.