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J Thorac Cardiovasc Surg 2008;136:335-342
© 2008 The American Association for Thoracic Surgery

Surgery for Congenital Heart Disease

Remote ischemic preconditioning elaborates a transferable blood-borne effector that protects mitochondrial structure and function and preserves myocardial performance after neonatal cardioplegic arrest

Lixing Wang, MD, PhDa, Norihiko Oka, MDa, Michael Tropak, PhDb, John Callahan, PhDb,c, John Lee, MDa, Greg Wilson, MDd, Andrew Redington, MDa, Christopher A. Caldaronea,c,*

a Division of Cardiovascular Research, Hospital for Sick Children, Toronto, Ontario, Canada
b Division of Genetics and Genome Biology, Hospital for Sick Children, Toronto, Ontario, Canada
c Division of Cardiovascular Surgery, Hospital for Sick Children, Toronto, Ontario, Canada
d Division of Pathology, Hospital for Sick Children, Toronto, Ontario, Canada

Received for publication September 25, 2007; revisions received October 24, 2007; accepted for publication December 18, 2007.

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

Objective: Remote ischemic preconditioning is known to elicit production of a blood-borne cardioprotective factor that is infarct sparing in models of ischemia–reperfusion injury and myocardial damage reducing after cardiopulmonary bypass in human subjects. The mechanism of protection remains incompletely understood. In this study, we examined effects on mitochondrial structure and function in a noninfarct model of cardioplegic arrest.

Methods: Explanted neonatal rabbit hearts were mounted in a Langendorff preparation and perfused with dialysate of blood taken from sham-treated or remotely preconditioned rabbits. Each heart was subsequently subjected to 1-hour cardioplegic arrest and 30-minute reperfusion periods, during which hemodynamic responses were measured. Mitochondria were isolated for structural and functional measurements.

Results: Relative to hearts with sham-treated dialysate, myocardial performance (systolic pressure, maximum positive and negative first derivatives of left ventricular pressure, and left ventricular end-diastolic pressure) was better preserved with dialysate from preconditioned rabbits. Similarly, mitochondria isolated from hearts with dialysate from preconditioned rabbits showed preserved respiration at complex I and IV in the electron transport chain (P < .01 and P < .05, respectively). Mitochondrial outer membrane integrity was also preserved, with diminished sensitivity of mitochondrial respiration to exogenous cytochrome c (P < .01) and less cytosolic diffusion of cytochrome c (P < .01). Mitochondrial resistance to calcium-mediated mitochondrial permeability transition pore opening was not affected.

Conclusion: The cardioprotective factor in plasma dialysate after remote preconditioning preserves mitochondrial structure and function in a noninfarct cardioplegic arrest model. This protection is associated with preservation of global myocardial performance.

Abbreviations and Acronyms KHB = Krebs–Henseleit; KATP = adenosine triphosphate–dependent potassium; LV = left ventricle; MPT = mitochondrial permeability transition; rIPC = remote ischemic preconditioning






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