Atrial Fibrillation, Neurocognitive Decline, and Gene Expression after Cardiopulmonary Bypass

Abstract

OBJECTIVE Atrial fibrillation and neurocognitive decline are common complications after cardiopulmonary bypass. By utilizing genomic microarrays we investigate whether gene expression is associated with postoperative atrial fibrillation and neurocognitive decline.METHODS Twenty one cardiac surgery patients were prospectively matched and underwent neurocognitive assessments pre-operatively and four days postoperatively. The whole blood collected in the pre-cardiopulmonary bypass, 6 hours after-cardiopulmonary bypass, and on the 4th postoperative day was hybridized to Affymetrix Gene Chip U133 Plus 2.0 Microarrays. Gene expression in patients who developed postoperative atrial fibrillation and neurocognitive decline (n=6; POAF+NCD) was compared with gene expression in patients with postoperative atrial fibrillation and normal cognitive function (n=5; POAF+NORM) and patients with sinus rhythm and normal cognitive function (n=10; SR+NORM). Regulated genes were identified using JMP Genomics 4.0 with a false discovery rate of 0.05 and fold change of >1.5 or <-1.5.RESULTS Eleven patients developed postoperative atrial fibrillation. Six of these also developed neurocognitive decline. Of the 12 patients with sinus rhythm, only 2 developed neurocognitive decline. POAF+NCD patients had unique regulation of 17 named genes preoperatively, 60 named genes six hours after cardiopulmonary bypass, and 34 named genes four days postoperatively (P<0.05) compared with normal patients. Pathway analysis demonstrated that these genes are involved in cell death, inflammation, cardiac remodeling and nervous system function.CONCLUSION Patients who developed postoperative atrial fibrillation and neurocognitive decline after cardiopulmonary bypass may have differential genomic responses compared to normal patients and patients with only postoperative atrial fibrillation, suggesting common pathophysiology for these conditions. Further exploration of these genes may provide insight into the etiology and improvements of these morbid outcomes.

Tissue-specific multi-omics analysis of atrial fibrillation

“…As expected, also the putative core genes identified by trans-eQTLs and trans-pQTLs were involved in those mechanisms. In addition, all identified transcripts and some of the proteins have been described in the context of arrhythmias or cardiovascular disease [29][30][31][32][33][34][44][45][46][47][48][49][50] (Supplementary Table 12, differential expression results in Supplementary Tables 13-14). As observed for the cis-QTL analysis, the trans-analysis revealed similar differences between transcriptomics and proteomics level.…”

Novel insights into potential therapeutic targets and biomarkers using integrated multi-omicsapproaches for dilated and ischemic cardiomyopathies

“…Another candidate gene and potential biomarker of note, TMEM259, has some associations with ischemic conditions as well as ER protein degradation pathways 65 . A number of other genes: FOC, REC8, FHOD1 as well as TAOK1 and MINDY2, are involved in the modulation of cell proliferation, immune signalling and protein turnover 69,117 . These findings provided the first hints of potential exacerbation of the ER stress as well as inflammation induced fibrotic tissue damage propagating the ischemia cycle.…”

“…Protein 259 (TMEM259), REC8 Meiotic Recombination Protein (REC8) and Formin Homology 2 Domain Containing 1 (FHOD1), that were significantly expressed and some of the genes, such as CX3CL1 and TMEM259, are candidate genes for novel biomarkers and/or therapeutic targets for the ischemic heart disease 17, [62][63][64] . The group of downregulated genes in ischemia, for example, TAO Kinase 1 (TAOK1) and MINDY2 (Lysine 48 Deubiquitinase 2), are categorised as involved in some inflammatory processes [65][66][67][68][69][70][71][72][73] .…”