Early immune biomarkers and intermediate-term outcomes after heart transplantation: Results of Clinical Trials in Organ Transplantation-18

Abstract

Clinical Trials in Organ Transplantation-18 (CTOT-18) is a follow-up analysis of the 200-subject multicenter heart transplant CTOT-05 cohort. CTOT-18 aimed to identify clinical, epidemiologic, and biologic markers associated with adverse clinical events past 1 year posttransplantation. We examined various candidate biomarkers including serum antibodies, angiogenic proteins, blood gene expression profiles, and T cell alloreactivity. The composite endpoint (CE) included death, retransplantation, coronary stent, myocardial infarction, and cardiac allograft vasculopathy. The mean follow-up was 4.5 ± SD 1.1 years. Subjects with serum anti-cardiac myosin (CM) antibody detected at transplantation and at 12 months had a higher risk of meeting the CE compared to those without anti-CM antibody (hazard ratio [HR] = 2.9, P = .046). Plasma VEGF-A and VEGF-C levels pretransplant were associated with CE (odds ratio [OR] = 13.24, P = .029; and OR = 0.13, P = .037, respectively). Early intravascular ultrasound findings or other candidate biomarkers were not associated with the study outcomes. In conclusion, anti-CM antibody and plasma levels of VEGF-A and VEGF-C were associated with an increased risk of adverse events. Although this multicenter report supports further evaluation of the mechanisms through which anti-CM antibody and plasma angiogenesis proteins lead to allograft injury, we could not identify additional markers of adverse events or potential novel therapeutic targets.

Keywords: alloantibody; clinical research/practice; heart (allograft) function/dysfunction; heart transplantation/cardiology; vasculopathy.

Figure 1.

Overview of study outcomes. Consort diagram illustrating the outcomes of subjects throughout the course of the study. Of 200 transplanted subjects, 16 met composite end-point within 12 months after transplant. Of the 178 subjects enrolled in the study past 12 months after transplant, 26 subjects reached the composite endpoint between month 12 and last follow-up.

Figure 2.

A. Freedom from composite endpoint and B. freedom from death or retransplant, stratified by the presence or absence of anti-CM antibody pre-transplant. C. Freedom from composite endpoint and D. freedom from death or retransplant, stratified by persistence or absence of anti-CM antibody at both transplant and 12 month time-points. CM – cardiac myosin

Figure 3.

Expression profiles of FasL, CXCL10, Foxp3, PRF1, HPRT and GZMB genes and composite outcome past 12 months after transplant. Blood samples were pooled based on whether the patients reached the composite outcome. Black crosses indicate copy numbers for respective genes in patients not reaching composite endpoint after 12 months. Red circles indicate gene copy numbers for respective genes in patients reaching composite endpoint after 12 months. No significant differences were seen between the two groups in the absolute copy numbers for each of the listed genes normalized to the copy number of 18SrRNA.

Figure 4.

Change in percent atheroma volume between baseline and month 12 in patients who did not and who did meet the composite endpoint, the endpoint of death and retransplant and the endpoint of stent, myocardial infarction or CAV diagnosis after 12 months.