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

Eric S. Weiss; Kevin K.W. Wang; Jeremiah G. Allen; Mary E. Blue; Lois U. Nwakanma; Ming Cheng Liu; Mary S. Lange; Jennifer Berrong; Mary Ann Wilson; Vincent L. Gott; Juan C. Troncoso; Ronald L. Hayes; Michael V. Johnston; William A. Baumgartner

doi:10.1016/j.athoracsur.2009.04.016

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

Eric S. Weiss, Kevin K.W. Wang, Jeremiah G. Allen, Mary E. Blue, Lois U. Nwakanma, Ming Cheng Liu, Mary S. Lange, Jennifer Berrong, Mary Ann Wilson, Vincent L. Gott, Juan C. Troncoso, Ronald L. Hayes, Michael V. Johnston, William A. Baumgartner

School of Medicine

Research output: Contribution to journal › Article › peer-review

26 Scopus citations

Abstract

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 (αII-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 αII-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 αII-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 αII-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 αII-SBDPs as markers of neurologic injury after cardiac surgery. Our analysis demonstrates that calpain- and caspase-produced αII-SBDPs may be an important and novel marker of neurologic injury after HCA.

Original language	English (US)
Pages (from-to)	543-550
Number of pages	8
Journal	Annals of Thoracic Surgery
Volume	88
Issue number	2
DOIs	https://doi.org/10.1016/j.athoracsur.2009.04.016
State	Published - Aug 2009

ASJC Scopus subject areas

Surgery
Pulmonary and Respiratory Medicine
Cardiology and Cardiovascular Medicine

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Weiss, E. S., Wang, K. K. W., Allen, J. G., Blue, M. E., Nwakanma, L. U., Liu, M. C., Lange, M. S., Berrong, J., Wilson, M. A., Gott, V. L., Troncoso, J. C., Hayes, R. L., Johnston, M. V., & Baumgartner, W. A. (2009). Alpha II-Spectrin Breakdown Products Serve as Novel Markers of Brain Injury Severity in a Canine Model of Hypothermic Circulatory Arrest. Annals of Thoracic Surgery, 88(2), 543-550. https://doi.org/10.1016/j.athoracsur.2009.04.016

Weiss, ES, Wang, KKW, Allen, JG, Blue, ME, Nwakanma, LU, Liu, MC, Lange, MS, Berrong, J, Wilson, MA, Gott, VL, Troncoso, JC, Hayes, RL, Johnston, MV & Baumgartner, WA 2009, 'Alpha II-Spectrin Breakdown Products Serve as Novel Markers of Brain Injury Severity in a Canine Model of Hypothermic Circulatory Arrest', Annals of Thoracic Surgery, vol. 88, no. 2, pp. 543-550. https://doi.org/10.1016/j.athoracsur.2009.04.016

@article{3127425a02b94a0693e8e34d097a37c8,

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

abstract = "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 (αII-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 αII-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 αII-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 αII-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 αII-SBDPs as markers of neurologic injury after cardiac surgery. Our analysis demonstrates that calpain- and caspase-produced αII-SBDPs may be an important and novel marker of neurologic injury after HCA.",

author = "Weiss, {Eric S.} and Wang, {Kevin K.W.} and Allen, {Jeremiah G.} and Blue, {Mary E.} and Nwakanma, {Lois U.} and Liu, {Ming Cheng} and Lange, {Mary S.} and Jennifer Berrong and Wilson, {Mary Ann} and Gott, {Vincent L.} and Troncoso, {Juan C.} and Hayes, {Ronald L.} and Johnston, {Michael V.} and Baumgartner, {William A.}",

note = "Funding Information: This study was supported by the Dana and Albert Broccoli Center for Aortic Diseases, the Mildred and Carmont Blitz Cardiac Research Fund, and the National Institutes of Health (NIH R37NS31238-10 [W.A.B.] and NIH 2T32DK007713-12 [E.S.W.]). Doctor Weiss is the Irene Piccinini Investigator in Cardiac Surgery and Drs Allen and Nwakanma are Hugh R. Sharp Cardiac Surgery Research Fellows. The authors wish to thank Mr Jeffrey Brawn, Mrs Melissa Jones, and Ms Tamara Treat for their outstanding technical assistance. This project could not have been completed without their participation. The authors would also like to acknowledge the support of Department of Defense grants DAMMED-03-1-0066 and NIH grant R01 NS049175-01-A1. Doctors Kevin Wang and Ronald Hayes own stock, receive royalties from, and are executive officers of Banyan Biomarkers, Inc, and as such may benefit financially as a result of the outcomes of this research or the work reported in this publication.",

year = "2009",

month = aug,

doi = "10.1016/j.athoracsur.2009.04.016",

language = "English (US)",

volume = "88",

pages = "543--550",

journal = "Annals of Thoracic Surgery",

issn = "0003-4975",

publisher = "Elsevier USA",

number = "2",

}

TY - JOUR

T1 - Alpha II-Spectrin Breakdown Products Serve as Novel Markers of Brain Injury Severity in a Canine Model of Hypothermic Circulatory Arrest

AU - Weiss, Eric S.

AU - Wang, Kevin K.W.

AU - Allen, Jeremiah G.

AU - Blue, Mary E.

AU - Nwakanma, Lois U.

AU - Liu, Ming Cheng

AU - Lange, Mary S.

AU - Berrong, Jennifer

AU - Wilson, Mary Ann

AU - Gott, Vincent L.

AU - Troncoso, Juan C.

AU - Hayes, Ronald L.

AU - Johnston, Michael V.

AU - Baumgartner, William A.

N1 - Funding Information: This study was supported by the Dana and Albert Broccoli Center for Aortic Diseases, the Mildred and Carmont Blitz Cardiac Research Fund, and the National Institutes of Health (NIH R37NS31238-10 [W.A.B.] and NIH 2T32DK007713-12 [E.S.W.]). Doctor Weiss is the Irene Piccinini Investigator in Cardiac Surgery and Drs Allen and Nwakanma are Hugh R. Sharp Cardiac Surgery Research Fellows. The authors wish to thank Mr Jeffrey Brawn, Mrs Melissa Jones, and Ms Tamara Treat for their outstanding technical assistance. This project could not have been completed without their participation. The authors would also like to acknowledge the support of Department of Defense grants DAMMED-03-1-0066 and NIH grant R01 NS049175-01-A1. Doctors Kevin Wang and Ronald Hayes own stock, receive royalties from, and are executive officers of Banyan Biomarkers, Inc, and as such may benefit financially as a result of the outcomes of this research or the work reported in this publication.

PY - 2009/8

Y1 - 2009/8

N2 - 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 (αII-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 αII-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 αII-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 αII-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 αII-SBDPs as markers of neurologic injury after cardiac surgery. Our analysis demonstrates that calpain- and caspase-produced αII-SBDPs may be an important and novel marker of neurologic injury after HCA.

AB - 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 (αII-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 αII-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 αII-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 αII-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 αII-SBDPs as markers of neurologic injury after cardiac surgery. Our analysis demonstrates that calpain- and caspase-produced αII-SBDPs may be an important and novel marker of neurologic injury after HCA.

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

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