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(Stroke. 2009;40:1597.)
© 2009 American Heart Association, Inc.

Original Contributions

Inducible Nitric Oxide Synthase Promoter Polymorphism Affords Protection Against Cognitive Dysfunction After Carotid Endarterectomy

Gene T. Yocum, BS; John G. Gaudet, MD; Susie S. Lee, BM; Yaakov Stern, PhD; Lauren A. Teverbaugh, BA; Robert R. Sciacca, EngScD; Charles W. Emala, MD; Donald O. Quest, MD; Paul C. McCormick, MD, MPH; James F. McKinsey, MD; Nicholas J. Morrissey, MD; Robert A. Solomon, MD; E. Sander Connolly, Jr, MD Eric J. Heyer, MD, PhD

From the Departments of Anesthesiology (G.T.Y., J.G.G., S.S.L., L.A.T., C.W.E., E.J.H.), Medicine (R.R.S.), Neurological Surgery (D.O.Q., P.C.M., R.A.S., E.S.C.), Surgery (J.F.M., N.J.M.), and Neurology (E.S.C., E.J.H.), and the Cognitive Neuroscience Division, Taub Institute (Y.S.), Columbia University, New York, NY.

Correspondence to Eric J. Heyer, MD, PhD, Department of Anesthesiology, Columbia University, 630 W 168^th St, P&S Box 46, New York, NY 10032. E-mail ejh3{at}columbia.edu

Background and Purpose— Cognitive dysfunction occurs in 9% to 23% of patients during the first month after carotid endarterectomy (CEA). A 4-basepair (AAAT) tandem repeat polymorphism (either 3 or 4 repeats) has been described in the promoter region of inducible nitric oxide synthase (iNOS), a gene with complex roles in ischemic injury and preconditioning against ischemic injury. We investigated whether the 4-repeat variant (iNOS⁺) affects the incidence of cognitive dysfunction after CEA.

Methods— One-hundred eighty-five CEA and 60 spine surgery (control) subjects were included in this nested cohort analysis. Subjects underwent a battery of 7 neuropsychometric tests before and 1 day and 1 month after surgery. Multivariate logistic regression analyses were performed to determine if the iNOS promoter variant was independently associated with the incidence of cognitive dysfunction at 1 day and 1 month. Further, all right-hand-dominant CEA subjects were grouped by operative side and performance on each test was compared between iNOS⁺ and iNOS^– groups.

Results— Forty-four of 185 CEA subjects had at least 1 iNOS promoter allele containing 4 copies of the tandem repeat (iNOS⁺). iNOS⁺ status was significantly protective against moderate/severe cognitive dysfunction 1 month after CEA. Right-hand-dominant iNOS⁺ CEA subjects undergoing left-side CEA performed significantly better than iNOS^– subjects on a verbal learning test and those undergoing right-side CEA performed significantly better on a test of visuospatial function.

Conclusion— We demonstrate an iNOS promoter polymorphism variant provides protection against moderate/severe cognitive dysfunction 1 month after CEA. Further, this protection appears to involve cognitive domains localized ipsilateral to the operative carotid artery.

Key Words: carotid endarterectomy • carotid stenosis • cognitive impairment • nitric oxide