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. 2024 Feb 13;25(4):2262.
doi: 10.3390/ijms25042262.

HTK vs. HTK-N for Coronary Endothelial Protection during Hypothermic, Oxygenated Perfusion of Hearts Donated after Circulatory Death

Lars Saemann  1   2 , Kristin Wächter  1 , Nitin Gharpure  1 , Sabine Pohl  1 , Fabio Hoorn  2 , Sevil Korkmaz-Icöz  1   2 , Matthias Karck  2 , Gábor Veres  1   2 , Andreas Simm  1 , Gábor Szabó  1   2
Affiliations

HTK vs. HTK-N for Coronary Endothelial Protection during Hypothermic, Oxygenated Perfusion of Hearts Donated after Circulatory Death

Lars Saemann et al. Int J Mol Sci. .

Abstract

Protection of the coronary arteries during donor heart maintenance is pivotal to improve results and prevent the development of coronary allograft vasculopathy. The effect of hypothermic, oxygenated perfusion (HOP) with the traditional HTK and the novel HTK-N solution on the coronary microvasculature of donation-after-circulatory-death (DCD) hearts is known. However, the effect on the coronary macrovasculature is unknown. Thus, we maintained porcine DCD hearts by HOP with HTK or HTK-N for 4 h, followed by transplantation-equivalent reperfusion with blood for 2 h. Then, we removed the left anterior descending coronary artery (LAD) and compared the endothelial-dependent and -independent vasomotor function of both groups using bradykinin and sodium-nitroprusside (SNP). We also determined the transcriptome of LAD samples using microarrays. The endothelial-dependent relaxation was significantly better after HOP with HTK-N. The endothelial-independent relaxation was comparable between both groups. In total, 257 genes were expressed higher, and 668 genes were expressed lower in the HTK-N group. Upregulated genes/pathways were involved in endothelial and vascular smooth muscle cell preservation and heart development. Downregulated genes were related to ischemia/reperfusion injury, oxidative stress, mitochondrion organization, and immune reaction. The novel HTK-N solution preserves the endothelial function of DCD heart coronary arteries more effectively than traditional HTK.

Keywords: Bretschneider; Custodiol; Custodiol-N; coronary endothelium; donation after circulatory death; endothelium; heart transplantation; machine perfusion; organ preservation.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

Figure 1
Figure 1
Dose-response curves. (A) Dose-response curve for endothelial-dependent vasorelaxation to bradykinin. (B) Dose-response curve for endothelial-independent vasorelaxation to sodium-nitroprusside. BK: bradykinin. HTK: histidine-tryptophane-ketoglutarate. HTK-N: histidine-tryptophane-ketoglutarate-N. SNP: sodium nitroprusside. N = 8 per group. * p < 0.05 vs. HTK. ** p < 0.001 vs. HTK.
Figure 2
Figure 2
Characteristic functional parameters. BK: bradykinin. EC: effective concentration. HTK: histidine-tryptophane-ketoglutarate. HTK-N: histidine-tryptophane-ketoglutarate-N. KCL: potassium chloride. pD2: logEC50. SNP: sodium nitroprusside. N = 8 per group. * p < 0.05 vs HTK.
Figure 3
Figure 3
Regulated genes in HTK-N vs. HTK.
Figure 4
Figure 4
Gene regulation. (A) Scatter plot. (B) Heat map. HTK: histidine-tryptophane-ketoglutarate. HTK-N: histidine-tryptophane-ketoglutarate-N. KCL: potassium chloride. N = 8 per group. Blue: downregulated transcripts. Red: upregulated transcripts.
Figure 5
Figure 5
Network analysis of the top 20 downregulated genes of HTK-N vs. HTK. The network was built utilizing the Gene String online tool (STRING: functional protein association networks (string-db.org; assessed date: 18 January 2024). HTK: histidine-tryptophane-ketoglutarate. HTK-N: histidine-tryptophane-ketoglutarate-N.
Figure 6
Figure 6
Pathway analysis. BP: biological process. DE: differentially expressed. CC: cellular component. GO: gene ontology. HTK: histidine-tryptophane-ketoglutarate. HTK-N: histidine-tryptophane-ketoglutarate-N. HPO: human phenotype ontology. MF: molecular function. The dashed black line represents the normalized enrichment score. All plotted pathways are p < 0.05. N = 8 per group.
Figure 7
Figure 7
Machine perfusion system.
See this image and copyright information in PMC

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