title: Targeting myocardial reperfusion injuries with cyclosporine in the CIRCUS Trial - pharmacological reasons for failure.
abstract: The mitochondrial permeability transition (mPTP) is a key feature of cardiac cell death in ischaemia-reperfusion injury (I/R). The mPTP blocker, cyclosporine A (CsA), has been shown to give protection against reperfusion-induced myocardial necrosis and troubles generated by acute coronary artery repermeabilization. Nevertheless, the results of the CIRCUS trial (Does Cyclosporine Improve Clinical Outcome in ST-Elevation Myocardial Infarction Patients) seem to go against this hypothesis. Pharmacological reasons linked to CsA pharmacokinetics and pharmacodynamics could be suggested. First, it could be explained by a limited diffusion of the drug in the area at risk, due to the only inclusion of patients with a TIMI 0 or 1 coronary blood flow in the anterior territory and the absence of collateral perfusion. Second, to explain a low tissue diffusion of the compound, blood cell capture and high metabolism could be suggested. Moreover, CsA is highly metabolized by cytochrome P450 3A4 (CYP3A4), a polymorphic enzyme leading to variations of Cmax and AUC between 10-20% in patients using CsA. Finally, CsA blocks calcineurin, a protein implied in I/R damage but calcineurin inhibition could contribute to protection towards I/R damage only when Rcan1, a calcineurin natural inhibitor, expression is low. The results of the CIRCUS trial are disappointing and could contribute to the withdrawal of the mPTP blockade pharmacological strategy as a way to protect the myocardium from I/R lesions. Nevertheless, many pharmacological insights could have contributed to an increased variability and, as a consequence, an important reduction of the pharmacological power of the study.
authors.affiliation: Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire (EA7296), CHU de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, Faculté de Médecine, 11 rue Humann, Strasbourg, France.
authors.forename: Laurent
authors.initials: L
authors.lastname: Monassier
authors.affiliation: Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire (EA7296), CHU de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, Faculté de Médecine, 11 rue Humann, Strasbourg, France.
authors.forename: Estelle
authors.initials: E
authors.lastname: Ayme-Dietrich
authors.affiliation: Laboratoire de Neurobiologie et Pharmacologie Cardiovasculaire (EA7296), CHU de Strasbourg, Fédération de Médecine Translationnelle de Strasbourg, Faculté de Médecine, 11 rue Humann, Strasbourg, France.
authors.forename: Gaëlle
authors.initials: G
authors.lastname: Aubertin-Kirch
authors.affiliation: Clinique Pasteur, Centre de Recherche Clinique Cardiovasculaire Pasteur, 45 avenue de Lombez, 31000 Toulouse, Toulouse, France.
authors.forename: Atul
authors.initials: A
authors.lastname: Pathak
mesh_terms: D000818:Animals; D019703:Calcineurin / Q000378:metabolism; D065095:Calcineurin Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D016572:Cyclosporine / Q000494:pharmacology* / Q000627:therapeutic use*; D006801:Humans; D008929:Mitochondria, Heart / Q000187:drug effects / Q000378:metabolism; D033681:Mitochondrial Membrane Transport Proteins / Q000378:metabolism; D000083162:Mitochondrial Permeability Transition Pore; D015428:Myocardial Reperfusion Injury / Q000188:drug therapy*; D009206:Myocardium / Q000378:metabolism
chemical_list: D065095:Calcineurin Inhibitors; D033681:Mitochondrial Membrane Transport Proteins; D000083162:Mitochondrial Permeability Transition Pore; D016572:Cyclosporine; D019703:Calcineurin
keywords: CIRCUS; cyclosporine; ischaemia; myocardial; reperfusion