title: Dobutamine responsiveness, PET mismatch, and lack of necrosis in low-flow ischemia: is this hibernation in the isolated rat heart?
abstract: The clinical hallmarks of hibernating myocardium include hypocontractility while retaining an inotropic reserve (using dobutamine echocardiography), having normal or increased [18F]fluoro-2-deoxyglucose-6-phosphate (18FDG6P) accumulation associated with decreased coronary flow [flow-metabolism mismatch by positron emission tomography (PET)], and recovering completely postrevascularization. In this study, we investigated an isolated rat heart model of hibernation using experimental equivalents of these clinical techniques. Rat hearts (n = 5 hearts/group) were perfused with Krebs-Henseleit buffer for 40 min at 100% flow and 3 h at 10% flow and reperfused at 100% flow for 30 min (paced at 300 beats/min throughout). Left ventricular developed pressure fell to 30 +/- 8% during 10% flow and recovered to 90 +/- 7% after reperfusion. In an additional group, this recovery of function was found to be preserved over 2 h of reperfusion. Electron microscopic examination of hearts fixed at the end of the hibernation period demonstrated a lack of ischemic injury and an accumulation of glycogen granules, a phenomenon observed clinically. In a further group, hearts were challenged with dobutamine during the low-flow period. Hearts demonstrated an inotropic reserve at the expense of increased lactate leakage, with no appreciable creatine kinase release. PET studies used the same basic protocol in both dual- and globally perfused hearts (with 250MBq 18FDG in Krebs buffer +/- 0.4 mmol/l oleate). PET data showed flow-metabolism "mismatch;" whether regional or global, 18FDG6P accumulation in ischemic tissue was the same as (glucose only) or significantly higher than (glucose + oleate) control tissue (0.023 +/- 0.002 vs. 0.011 +/- 0.002 normalized counts. s-1x g-1x min-1, P < 0.05) despite receiving 10% of the flow. This isolated rat heart model of acute hibernation exhibits many of the same characteristics demonstrated clinically in hibernating myocardium.
authors.affiliation: Department of Radiological Sciences, Guy's Hospital, London SE1 9RT, UK.
authors.forename: Richard
authors.initials: R
authors.lastname: Southworth
authors.forename: Pamela B
authors.initials: PB
authors.lastname: Garlick
mesh_terms: D000318:Adrenergic beta-Agonists / Q000494:pharmacology*; D000818:Animals; D001794:Blood Pressure / Q000502:physiology; D003402:Creatine Kinase / Q000097:blood; D004280:Dobutamine / Q000494:pharmacology*; D019788:Fluorodeoxyglucose F18; D006321:Heart / Q000000981:diagnostic imaging* / Q000503:physiopathology*; D066298:In Vitro Techniques; D019344:Lactic Acid / Q000097:blood; D008297:Male; D008854:Microscopy, Electron; D017202:Myocardial Ischemia / Q000473:pathology / Q000503:physiopathology*; D015425:Myocardial Reperfusion; D017682:Myocardial Stunning / Q000473:pathology / Q000503:physiopathology*; D009206:Myocardium / Q000473:pathology; D009336:Necrosis; D019275:Radiopharmaceuticals; D051381:Rats; D017208:Rats, Wistar; D013318:Stroke Volume / Q000502:physiology; D014055:Tomography, Emission-Computed; D016277:Ventricular Function, Left / Q000187:drug effects / Q000502:physiology
chemical_list: D000318:Adrenergic beta-Agonists; D019275:Radiopharmaceuticals; D019788:Fluorodeoxyglucose F18; D019344:Lactic Acid; D004280:Dobutamine; D003402:Creatine Kinase