Molecular Genetics of Lidocaine-Containing Cardioplegia in the Human Heart During Cardiac Surgery

Abstract

Background: During cardiac surgery with cardiopulmonary bypass, delivery of cardioplegia solution to achieve electromechanical cardiac quiescence is obligatory. The addition of lidocaine to cardioplegia has advantages, although its consequences at a molecular level remain unclear. We performed whole-genome RNA sequencing of the human left ventricular (LV) myocardium to elucidate the differences between whole-blood (WB) cardioplegia with and without addition of lidocaine (LC) on gene expression.

Methods: We prospectively enrolled 130 patients undergoing aortic valve replacement surgery. Patients received high-potassium blood cardioplegia either with (n = 37) or without (n = 93) lidocaine. The LV apex was biopsied at baseline, and after an average of 74 minutes of cold cardioplegic arrest. We performed differential gene expression analysis for 18,258 genes between these 2 groups. Clinical and demographic variables were adjusted in the model. Gene ontology (GO) and network enrichment analysis of the retained genes were performed using g:Profiler and Cytoscape.

Results: A total of 1,298 genes were differentially expressed between cardioplegic treatments. Compared with the WB group, genes upregulated in the LC group were identified by network enrichment to play a protective role in ischemic injury by inhibiting apoptosis, increasing transferrin endocytosis, and increasing cell viability. Downregulated genes in the LC group were identified to play a role in inflammatory diseases, oxygen transport, and neutrophil aggregation.

Conclusions: The addition of lidocaine to cardioplegia had pronounced effects on a molecular level with genes responsible for decreased inflammation, reduced intracellular calcium binding, enhanced antiapoptotic protection, augmented oxygen accessibility through transferrins, and increased cell viability showing measurable differences.

Copyright © 2018 The Society of Thoracic Surgeons. Published by Elsevier Inc. All rights reserved.

Figures

Figure 1.

Volcano plot of top up & down differentially expressed genes for whole-blood cardioplegia (WB) versus lidocaine cardioplegia (LC); each dot represents a gene; Red-dots represent genes with an adjusted p-value 2 fold change > 0.5; Green-dots represent genes for both an adjusted p-value < 0.05 and a log2 fold change > 0.5.

Figure 2.

(a) Comparison of mean gene-expression between whole-blood cardioplegia (WB) versus whole-blood with lidocaine cardioplegia (LC) for top ten up-regulated genes. Genes expression are expressed as means, with 25th and 75th percentiles (shown by vertical dimension of the box), and the 10th and 90th percentiles indicated by the whiskers. (b) Comparison of mean gene-expression between whole-blood cardioplegia (WB) versus whole-blood with lidocaine cardioplegia (LC) for top ten down-regulated genes. Genes expression are expressed as means, with 25th and 75th percentiles (shown by vertical dimension of the box), and the 10th and 90th percentiles indicated by the whiskers.

Figure 3.

Gene-set enrichment analysis. This figure shows enrichment of specific functions (GO terms) by interactions between functions. Nodes represent gene-sets and edges represent mutual overlap. Each circle (red) represents a biological function of a specific gene-set containing at least one gene. Each node (green-line) represents connectivity between these gene-sets. The yellow circle (RAGE) represents the highest significant gene-set enrichment (P=2.11E-08).