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. 2020 Oct 19;6(11):e616.
doi: 10.1097/TXD.0000000000001065. eCollection 2020 Nov.

Rejection-associated Mitochondrial Impairment After Heart Transplantation

Erick Romero  1 , Eleanor Chang  2 , Esteban Tabak  3 , Diego Pinheiro  1 , Jose Tallaj  4 , Silvio Litovsky  4 , Brendan Keating  5 , Mario Deng  2 , Martin Cadeiras  1
Affiliations

Rejection-associated Mitochondrial Impairment After Heart Transplantation

Erick Romero et al. Transplant Direct. .

Abstract

Background: Mitochondrial dysfunction is associated with poor allograft prognosis. Mitochondrial-related gene expression (GE) in endomyocardial biopsies (EMBs) could be useful as a nonimmune functional marker of rejection. We hypothesize that acute cardiac allograft rejection is associated with decreased mitochondrial-related GE in EMBs.

Methods: We collected 64 routines or clinically indicated EMB from 47 patients after heart transplant. The EMBs were subjected to mRNA sequencing. We conducted weighted gene coexpression network analysis to construct module-derived eigengenes. The modules were assessed by gene ontology enrichment and hub gene analysis. Modules were correlated with the EMBs following the International Society of Heart and Lung Transplantation histology-based criteria and a classification based on GE alone; we also correlated with clinical parameters.

Results: The modules enriched with mitochondria-related and immune-response genes showed the strongest correlation to the clinical traits. Compared with the no-rejection samples, rejection samples had a decreased activity of mitochondrial-related genes and an increased activity of immune-response genes. Biologic processes and hub genes in the mitochondria-related modules were primarily involved with energy generation, substrate metabolism, and regulation of oxidative stress. Compared with International Society of Heart and Lung Transplantation criteria, GE-based classification had stronger correlation to the weighted gene coexpression network analysis-derived functional modules. The brain natriuretic peptide level, ImmuKnow, and Allomap scores had negative relationships with the expression of mitochondria-related modules and positive relationships with immune-response modules.

Conclusions: During acute cardiac allograft rejection, there was a decreased activity of mitochondrial-related genes, related to an increased activity of immune-response genes, and depressed allograft function manifested by brain natriuretic peptide elevation. This suggests a rejection-associated mitochondrial impairment.

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Conflict of interest statement

The authors declare no conflicts of interest.

Figures

FIGURE 1.
FIGURE 1.
Gene module-clinical trait association. Each row corresponds to a module eigengene. The columns represent clinical traits of the 3 unsupervised classes: ISHLT rejection trait, RA pressure, PAP mean, PA systolic, PA diastolic, PCPW, CO, CI, WBC, BNP, ImmuKnow, Allomap, and LVEF. Within each cell, the correlation value (top) and P value (bottom) are depicted. BNP, brain natriuretic peptide; CI, cardiac index; CO, cardiac output; LVEF, left ventricular ejection fraction; PA, pulmonary artery; PAP, pulmonary artery pressure; PCPW, Pulmonary-Capillary Wedge Pressure; RA, right atrium; WBC, white blood cells.
FIGURE 2.
FIGURE 2.
Hub mitochondria-related genes. The figure represents the hub genes identified in the mitochondria modules and their possible contribution to an inflammatory response. FAO, fatty acid β-oxidation; mtDNA, mitochondrial DNA; ROS, reactive oxygen species; TCA, tricarboxylic acid cycle.
See this image and copyright information in PMC

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