title: Cyclosporine A reduces microvascular obstruction and preserves left ventricular function deterioration following myocardial ischemia and reperfusion.
abstract: Postconditioning and cyclosporine A prevent mitochondrial permeability transition pore opening providing cardioprotection during ischemia/reperfusion. Whether microvascular obstruction is affected by these interventions is largely unknown. Pigs subjected to coronary occlusion for 1 h followed by 3 h of reperfusion were assigned to control (n = 8), postconditioning (n = 9) or cyclosporine A intravenous infusion 10-15 min before the end of ischemia (n = 8). Postconditioning was induced by 8 cycles of repeated 30-s balloon inflation and deflation. After 3 h of reperfusion magnetic resonance imaging, triphenyltetrazolium chloride/Evans blue staining and histopathology were performed. Microvascular obstruction (MVO, percentage of gadolinium-hyperenhanced area) was measured early (3 min) and late (12 min) after contrast injection. Infarct size with double staining was smaller in cyclosporine (46.2 ± 3.1%, P = 0.016) and postconditioning pigs (47.6 ± 3.9%, P = 0.008) versus controls (53.8 ± 4.1%). Late MVO was significantly reduced by cyclosporine (13.9 ± 9.6%, P = 0.047) but not postconditioning (23.6 ± 11.7%, P = 0.66) when compared with controls (32.0 ± 16.9%). Myocardial blood flow in the late MVO was improved with cyclosporine versus controls (0.30 ± 0.06 vs 0.21 ± 0.03 ml/g/min, P = 0.002) and was inversely correlated with late-MVO extent (R(2) = 0.93, P < 0.0001). Deterioration of left ventricular ejection fraction (LVEF) between baseline and 3 h of reperfusion was smaller with cyclosporine (-7.9 ± 2.4%, P = 0.008) but not postconditioning (-12.0 ± 5.5%, P = 0.22) when compared with controls (-16.4 ± 5.5%). In the three groups, infarct size (β = -0.69, P < 0.001) and late MVO (β = -0.33, P = 0.02) were independent predictors of LVEF deterioration following ischemia/reperfusion (R(2) = 0.73, P < 0.001). Despite both cyclosporine A and postconditioning reduce infarct size, only cyclosporine A infusion had a beneficial effect on microvascular damage and was associated with better preserved LV function when compared with controls.
authors.affiliation: Cardiology, Department of Cardiovascular Sciences, KU Leuven, Herestraat 49, 3000, Leuven, Belgium, jzalews@szpitaljp2.krakow.pl.
authors.forename: Jaroslaw
authors.initials: J
authors.lastname: Zalewski
authors.forename: Piet
authors.initials: P
authors.lastname: Claus
authors.forename: Jan
authors.initials: J
authors.lastname: Bogaert
authors.forename: Nina Vanden
authors.initials: NV
authors.lastname: Driessche
authors.forename: Ronald B
authors.initials: RB
authors.lastname: Driesen
authors.forename: Diogo T
authors.initials: DT
authors.lastname: Galan
authors.forename: Karin R
authors.initials: KR
authors.lastname: Sipido
authors.forename: Piotr
authors.initials: P
authors.lastname: Buszman
authors.forename: Krzysztof
authors.initials: K
authors.lastname: Milewski
authors.forename: Frans
authors.initials: F
authors.lastname: Van de Werf
mesh_terms: D000818:Animals; D016572:Cyclosporine / Q000494:pharmacology*; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005260:Female; D057775:Ischemic Postconditioning / Q000379:methods*; D008297:Male; D009203:Myocardial Infarction / Q000473:pathology* / Q000503:physiopathology; D015428:Myocardial Reperfusion Injury / Q000473:pathology* / Q000503:physiopathology / Q000517:prevention & control; D013552:Swine
chemical_list: D004791:Enzyme Inhibitors; D016572:Cyclosporine