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Original Articles: Adult Cardiac

Alpha II-Spectrin Breakdown Products Serve as Novel Markers of Brain Injury Severity in a Canine Model of Hypothermic Circulatory Arrest

^a Division of Cardiac Surgery, The Johns Hopkins Medical Institutions, Baltimore, Maryland
^b Department of Neurology, The Johns Hopkins Medical Institutions, Baltimore, Maryland
^c Division of Neuropathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland
^d Kennedy-Krieger Institute, Baltimore, Maryland
^e Departments of Neuroscience and Psychiatry, Center for Traumatic Brain Injury Studies, University of Florida, Gainesville, and Banyan Biomarkers Inc, Alachua, Florida

Accepted for publication April 3, 2009.

^_* Address correspondence to Dr Baumgartner, Division of Cardiac Surgery, Department of Surgery, The Johns Hopkins University School of Medicine, Blalock 618, The Johns Hopkins Hospital, 600 N Wolfe St, Baltimore, MD 21287 (Email: wbaumgar{at}jhmi.edu).

Presented at the Basic Science Forum of the Fifty-fifth Annual Meeting of the Southern Thoracic Surgical Association, Austin, TX, Nov 5–8, 2008.

Background: The development of specific biomarkers to aid in the diagnosis and prognosis of neuronal injury is of paramount importance in cardiac surgery. Alpha II-spectrin is a structural protein abundant in neurons of the central nervous system and cleaved into signature fragments by proteases involved in necrotic and apoptotic cell death. We measured cerebrospinal fluid alpha II-spectrin breakdown products (II-SBDPs) in a canine model of hypothermic circulatory arrest (HCA) and cardiopulmonary bypass.

Methods: Canine subjects were exposed to either 1 hour of HCA (n = 8; mean lowest tympanic temperature 18.0 ± 1.2°C) or standard cardiopulmonary bypass (n = 7). Cerebrospinal fluid samples were collected before treatment and 8 and 24 hours after treatment. Using polyacrylamide gel electrophoresis and immunoblotting, SBDPs were isolated and compared between groups using computer-assisted densitometric scanning. Necrotic versus apoptotic cell death was indexed by measuring calpain and caspase-3 cleaved II-SBDPs (SBDP 145+150 and SBDP 120, respectively).

Results: Animals undergoing HCA demonstrated mild patterns of histologic cellular injury and clinically detectable neurologic dysfunction. Calpain-produced II-SBDPs (150 kDa+145 kDa bands–necrosis) 8 hours after HCA were significantly increased (p = 0.02) as compared with levels before HCA, and remained elevated at 24 hours after HCA. In contrast, caspase-3 II-SBDP (120 kDa band–apoptosis) was not significantly increased. Animals receiving cardiopulmonary bypass did not demonstrate clinical or histologic evidence of injury, with no increases in necrotic or apoptotic cellular markers.

Conclusions: We report the use of II-SBDPs as markers of neurologic injury after cardiac surgery. Our analysis demonstrates that calpain- and caspase-produced II-SBDPs may be an important and novel marker of neurologic injury after HCA.