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- W2807899726 abstract "BACKGROUND: Neuroprotection studies are generally unable to demonstrate efficacy in humans. Our specific hypothesis is that multiple pathophysiologic pathways, of variable importance, contribute to ischemic brain damage. As a corollary to this, we discuss the broad hypothesis that a multifaceted approach will improve the probability of efficacious neuroprotection. But to properly test this hypothesis the nature and importance of the multiple contributing pathways needs elucidation. Our aim is to demonstrate, using functional genomics, in human cardiac surgery procedures associated with cerebral ischemia, that the pathogenesis of perioperative human ischemic brain damage involves the function of multiple variably weighted proteins involving several pathways. We then use these data and literature to develop a proposal for rational design of human neuroprotection protocols. METHODS: Ninety-four patients undergoing deep hypothermic circulatory arrest(DHCA) and/or aortic valve replacement surgery had brain damage biomarkers, S100β and neurofilament H (NFH), assessed at baseline, 1, & 24 hours’ post-cardiopulmonary bypass(CPB) with analysis for association with 92 single nucleotide polymorphisms (SNPs) (selected by co-author WAK) related to important proteins involved in pathogenesis of cerebral ischemia. RESULTS: At the nominal significance level of 0.05, changes in S100β and in NFH at 1 & 24 hours post-CPB were associated with multiple SNPs involving several prospectively determined pathophysiologic pathways, but were not individually significant after multiple comparison adjustments. Variable weights for the several evaluated SNPs are apparent on regression analysis and, notably, are dissimilar related to the two biomarkers and over time post CPB. Based on our step-wise regression model, at 1 hour post-CPB, SOD2, SUMO4 and GP6 are related to relative change of NFH while TNF, CAPN10, NPPB and SERPINE1 are related to the relative change of S100B. At 24 hour post-CPB, ADRA2A, SELE and BAX are related to the relative change of NFH while SLC4A7, HSPA1B and FGA are related to S100B. CONCLUSIONS: In support of the proposed hypothesis, association SNP data suggest function of specific disparate proteins, as reflected by genetic variation, may be more important than others with variation at different post-insult times after human brain ischemia. Such information may support rational design of post-insult time-sensitive multifaceted neuroprotective therapies" @default.
- W2807899726 created "2018-06-21" @default.
- W2807899726 creator A5000624898 @default.
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- W2807899726 date "2018-06-26" @default.
- W2807899726 modified "2023-10-11" @default.
- W2807899726 title "Reframing the Biological Basis of Neuroprotection Using Functional Genomics: Differentially Weighted, Time-Dependent Multifactor Pathogenesis of Human Ischemic Brain Damage" @default.
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