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J Thorac Cardiovasc Surg 2008;135:585-593
© 2008 The American Association for Thoracic Surgery

Cardiopulmonary Support and Physiology

Inhibition of mitochondrial remodeling by cyclosporine A preserves myocardial performance in a neonatal rabbit model of cardioplegic arrest

Norihiko Oka, MD, Lixing Wang, MD, PhD, Wenyu Mi, MD, Christopher A. Caldarone, MD*

The Division of Cardiovascular Surgery at the Hospital for Sick Children, University of Toronto, Toronto, Ontario, Canada

Received for publication August 21, 2007; revisions received September 12, 2007; accepted for publication September 24, 2007.

* Address for reprints: Christopher A. Caldarone, MD, Division of Cardiovascular Surgery, The Hospital for Sick Children, 555 University Ave, Toronto, Ontario, Canada M5G 1X8. (Email: christopher.caldarone{at}sickkids.ca).

Objective: Mitochondrial permeability transition pore opening is associated with apoptotic signaling and alterations in mitochondrial structure and function. We tested whether inhibition of mitochondrial permeability transition pore opening with cyclosporine A preserved mitochondrial structure and function after cardioplegic arrest and whether this preservation is associated with improved myocardial performance.

Methods: Langendorff-perfused neonatal rabbit hearts were perfused for 30 minutes with Krebs–Henseleit buffer (CCP; n = 6) or Krebs–Henseleit buffer containing 2 µmol/L of cyclosporine A (CCP+CsA; n = 6) followed by 60 minutes of normothermic crystalloid cardioplegia (CCP) and 60 minutes of reperfusion. Control hearts (non-CCP; n = 6) were constantly perfused for 150 minutes without cardioplegic arrest.

Results: In comparison with non-CCP, CCP was associated with Bax translocation to the mitochondria, cytochrome c release, and greater frequency of terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling–positive myocytes These changes were also associated with deficits in isolated mitochondrial oxygen consumption at complex I. CsA pretreatment minimized or prevented all these findings. Myocardial performance (systolic pressure, maximum positive and negative dP/dt, and elevated left ventricular end-diastolic pressure) at 5, 15, 30, and 60 minutes after reperfusion was diminished in CCP hearts when compared with non-CPB, and these deficits could be minimized with cyclosporine A pretreatment. (P < .05 all comparisons)

Conclusions: Cyclosporine A prevents apoptosis-related mitochondrial permeabilization and dysfunction after cardioplegic arrest. This protection is associated with improved myocardial performance. Prevention of mitochondrial permeability transition pore opening is a valuable target for mitochondrial (and myocardial) preservation after neonatal cardioplegic arrest.

Abbreviations and Acronyms ARMD = apoptosis-related mitochondrial dysfunction; BSA = bovine serum albumin; CCP = crystalloid cardioplegia; COX IV = cytochrome c oxidase IV; CsA = cyclosporine A; ±dP/dtmax = maximum first derivative of left ventricular pressure; IgG = immunoglobulin G; KH = Krebs–Henseleit buffer; LV = left ventricular; MIB = mitochondrial isolation buffer; MPTP = mitochondrial permeability transition pore; TMPD = N,N,N'N'-tetramethyl-p-phenylenediamine; TUNEL = terminal deoxynucleotidyl transferase–mediated dUTP nick end labeling






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