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J Thorac Cardiovasc Surg 2006;132:820-828
© 2006 The American Association for Thoracic Surgery

Surgery for Congenital Heart Disease

Proteomics of cerebral injury in a neonatal model of cardiopulmonary bypass with deep hypothermic circulatory arrest

Amir M. Sheikh, MBBS, MRCSa,1,*, Cindy Barrett, MDb, Nestor Villamizar, MDc, Oscar Alzate, PhDd, Sara Miller, PhDe, John Shelburne, MD, PhDf, Andrew Lodge, MDa, Jeffrey Lawson, MD, PhDc, James Jaggers, MDa

a Department of Pediatric Cardiac Surgery, the Neuroproteomics Center, Duke University Medical Center, Durham, NC
b Department of Pediatric Critical Care, the Neuroproteomics Center, Duke University Medical Center, Durham, NC
c Department of Surgery, the Neuroproteomics Center, Duke University Medical Center, Durham, NC
d Department of Neurobiology, Duke University Medical Center, Durham, NC
e Department of Pathology, Duke University Medical Center, Durham, NC
f Department of Pathology, Veterans Affairs Hospital, Durham, NC.

Received for publication April 27, 2006; revisions received July 11, 2006; accepted for publication July 13, 2006.

* Address for reprints: Amir M. Sheikh, MBBS, MRCS, 34 Thornhill Rd, Flat 4, Plymouth, PL3 5NE, United Kingdom. (Email: amsheikh10{at}hotmail.com).

Objective: Concern over neurologic injury limits safe duration of deep hypothermic circulatory arrest (DHCA) in surgery for congenital cardiac disease. Proteomics is a novel and powerful technique to study global protein changes in a given protein system. Using a neonatal model of cardiopulmonary bypass with DHCA, we sought to characterize the protein changes associated with DHCA brain injury.

Methods: Ten neonatal piglets were randomized to cardiopulmonary bypass with DHCA or sham operation. DHCA animals underwent induction of bypass (100 mL · kg–1 · min–1), cooling to 18°C, then DHCA for 60 minutes. Animals were rewarmed to normothermia, weaned from bypass, and harvested after 30 minutes off bypass. Sham animals underwent sternotomy without further instrumentation. Plasma samples were taken before bypass and before harvest. Proteins differentially expressed in the cerebral neocortex between the 2 groups were determined by 2-dimensional differential gel electrophoresis using fluorescent cyanine dyes and mass spectrometry. A second group of 4 piglets were similarly randomized and, after the experiment, tissues underwent perfusion-fixation for histologic examination.

Results: Cardiopulmonary bypass with DHCA caused extensive histologic and ultrastructural cerebral injury. Proteomic analysis of cerebral cortex found 10 protein spots to be differentially expressed; 9 were identified by mass spectrometry to represent 6 proteins, including apolipoprotein A-1, neurofilament-M protein, and enolase. Decreased expression of plasma apolipoprotein A-1 was found in DHCA.

Conclusions: The acute protein changes associated with cerebral injury in a neonatal model of cardiopulmonary bypass with DHCA have been characterized. These may direct further research aimed at attenuating injury seen from cardiopulmonary bypass with DHCA.

Abbreviations and Acronyms apoA1 = apolipoprotein A-1; CHMP4b = charged multivesicular body protein 4b; CPB = cardiopulmonary bypass; CSF = cerebrospinal fluid; DHCA = deep hypothermic circulatory arrest; IPG = immobilized pH gradient; MALDI = matrix-assisted laser desorption ionization; MS = mass spectrometry; MW = molecular weight; NFH = heavy-chain neurofilament protein; NFL = light-chain neurofilament protein; NFM = medium-chain neurofilament protein; NSE = neuron-specific enolase; TOF = time of flight




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A. M. Sheikh, C. Barrett, N. Villamizar, O. Alzate, A. M. Valente, J. R. Herlong, D. Craig, A. Lodge, J. Lawson, C. Milano, et al.
Right ventricular hypertrophy with early dysfunction: A proteomics study in a neonatal model.
J. Thorac. Cardiovasc. Surg., May 1, 2009; 137(5): 1146 - 1153.
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