Vascular endothelial growth factor A is associated with the subsequent development of moderate or severe cardiac allograft vasculopathy in pediatric heart transplant recipients

Abstract

Background Cardiac allograft vasculopathy (CAV) is the leading cause of chronic allograft loss following pediatric heart transplantation. We hypothesize that biomarkers of endothelial injury and repair predict CAV development in pediatric heart transplant recipients. Methods Blood was collected from pediatric heart transplant recipients at the time of routine annual coronary angiography and the concentrations of 13 angiogenesis-related molecules were determined. The primary endpoint was the presence of moderate or severe CAV by angiography over a 5 y follow up period. Results Forty-eight children were enrolled. The cohort was 57% male with a median age of 15.5 y (range 2–22) and median time post-transplant of 5.8 y (range 2–15). Eight recipients developed moderate/severe CAV at a median follow-up of 4.7 y, of whom 3 died, 3 were re-transplanted, 1 had a myocardial infarction and 1 is listed for re-transplantation. Clinical characteristics associated with the development of moderate/severe CAV included prednisone use at enrollment (P=0.03) and positive recipient CMV IgG at time of transplant (P<0.01). In addition, multivariable Cox proportional hazards regression identified plasma VEGF-A concentration greater than 90 pg/mL at the time of blood draw as a significant predictor of time to moderate or severe CAV (hazard ratio of 14.3; 95% CI: 1.3–163). Receiver operating characteristic curve analysis demonstrated that VEGF-A shows moderate performance for association with the subsequent development of CAV (area under the curve of 0.77; CI: 0.61–0.92). Conclusions VEGF-A levels in pediatric heart transplant recipients are associated with clinically important CAV progression within the subsequent 5 years.

Elevated serum vascular endothelial growth factor and development of cardiac allograft vasculopathy in children

“…Although not directly comparable, our results demonstrating elevated serum VEGF concentrations in patients with IVUS-only disease contrast with previous work demonstrating similar plasma VEGF concentrations between patients with no CAV and mild CAV. 20 Importantly, serum VEGF concentrations are known to be higher than in plasma secondary to the release of platelet-derived VEGF during the process of clotting. 26,27 Therefore, similar cut-offs cannot be used for serum and plasma samples and serial VEGF measurements in the same patient over time (performed with the same methodology) will likely yield the highest predictive value.…”

“…Due to the small number of patients with moderate or severe CAV by angiography, no conclusions could be made with regard to VEGF concentrations and CAV grade by angiography. In addition, we are unable to comment on the effects of proliferation signal inhibitors, statin therapy, or maintenance prednisone therapy (determined to be an independent risk factor for the development of moderate or severe CAV 20 ) on VEGF levels, as none of our study subjects were on any of these medications at the time of blood sampling. Despite a non-significant statistical difference, a definitive association between donor-specific antibodies, indication for transplant, or elevated left ventricular end-diastolic pressure and elevated VEGF cannot be ruled out given the small number of subjects within each of these groups.…”

“…20 Conversely, plasma VEGF is elevated in pediatric heart transplant recipients with moderate to severe CAV, 20 as well as in adult heart transplant recipients with angiographically apparent CAV. 21,22 The purpose of this study was to evaluate circulating VEGF as a non-invasive predictive biomarker for the future development of CAV in the pediatric heart transplant population.…”

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

“…1 Identification of actionable risk markers of posttransplant adverse events may allow for a higher degree of individualization of current traditionally uniform posttransplant management, and it is hoped that it will increase survival and decrease the incidence of adverse events in patients who are undergoing heart transplantation. [6][7][8][9][10] The Clinical Trials in Organ Transplantation-05 (CTOT-05) study was designed to identify accurate and reproducible biomarkers capable of predicting outcomes following heart transplantation. However, although clinical predictors of mortality after heart transplantation have been identified using multiinstitutional and multinational data, 1,5 studies aimed at the identification of biomarkers in heart transplant recipients have been limited mostly to single-institution, cross-sectional investigations.…”

Angiogenesis on coronary angiography is a marker for accelerated cardiac allograft vasculopathy as assessed by intravascular ultrasound

“…Serum levels of VEGF‐A, VEGF‐C, and PF‐4 have been shown to be strongly associated with established CAV in adult patients . Similarly, elevated levels of VEGF‐A drawn early after pediatric heart transplant have been associated with increased moderate or severe CAV on subsequent surveillance angiogram . Moreover, proliferation of the vasa vasorum as detected by a novel but effort intensive intravascular ultrasound technique has been hypothesized to be a marker for increased arterial inflammation and angiogenesis, and further associated with greater increases in maximal intimal thickness, and a higher incidence of acute cellular rejection …”