Inducible nitric oxide synthase promoter polymorphism affords protection against cognitive dysfunction after carotid endarterectomy.
OBJECTIVE
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.


CONCLUSIONS
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.
Yocum
Gene T
GT
Department of Anesthesiology, Columbia University, New York, NY 10032, USA.
Gaudet
John G
JG
Lee
Susie S
SS
Stern
Yaakov
Y
Teverbaugh
Lauren A
LA
Sciacca
Robert R
RR
Emala
Charles W
CW
Quest
Donald O
DO
McCormick
Paul C
PC
McKinsey
James F
JF
Morrissey
Nicholas J
NJ
Solomon
Robert A
RA
Connolly
E Sander
ES
Heyer
Eric J
EJ
D000368:Aged; D000483:Alleles; D001057:Apolipoproteins E / Q000235:genetics; D003072:Cognition Disorders / Q000209:etiology* / Q000235:genetics* / Q000523:psychology; D016894:Endarterectomy, Carotid / Q000009:adverse effects*; D005260:Female; D005838:Genotype; D006801:Humans; D016015:Logistic Models; D008297:Male; D009483:Neuropsychological Tests; D009569:Nitric Oxide / Q000096:biosynthesis / Q000502:physiology; D052247:Nitric Oxide Synthase Type II / Q000235:genetics*; D011110:Polymorphism, Genetic / Q000235:genetics; D011183:Postoperative Complications / Q000523:psychology*; D011401:Promoter Regions, Genetic / Q000235:genetics*
D001057:Apolipoproteins E; D009569:Nitric Oxide; D052247:Nitric Oxide Synthase Type II