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

Abstract

BACKGROUND: Cardiac allograft vasculopathy (CAV) is a leading cause of retransplantation and death in pediatric heart transplant recipients. Our aim was to evaluate the association between serum vascular endothelial growth factor-A (VEGF) and CAV development in the pediatric heart transplant population. METHODS: In this retrospective study performed at a university hospital, VEGF concentrations were measured by enzyme-linked immunosorbent assay in banked serum from pediatric heart transplant recipients undergoing routine cardiac catheterization. In subjects with CAV (n = 29), samples were obtained at 2 time-points: before CAV diagnosis (pre-CAV) and at the time of initial CAV diagnosis (CAV). In subjects without CAV (no-CAV, n = 16), only 1 time-point was used. VEGF concentrations (n = 74) were assayed in duplicate. RESULTS: Serum VEGF is elevated in pediatric heart transplant recipients before catheter-based diagnosis of CAV (no-CAV mean: 144.0 ± 89.05 pg/ml; pre-CAV mean: 316.2 ± 118.3 pg/ml; p = 0.0002). Receiver-operating characteristic curve analysis of pre-CAV VEGF levels demonstrated an area under the curve of 87.7% (p = 0.0002), with a VEGF level of 226.3 pg/ml predicting CAV development with 77.8% sensitivity and 91.7% specificity. VEGF is similarly elevated in subjects with angiographically diagnosed CAV and in those with normal angiography but intravascular ultrasound (IVUS) evidence of CAV. CONCLUSIONS: The increase in serum VEGF before onset of detectable CAV is fundamental to its utility as a predictive biomarker and suggests further investigations of VEGF in the pathogenesis of CAV are warranted in the pediatric heart transplant population.

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

“…Logistic regression exploring the association of plasma angiogenesisrelated protein levels measured before transplant with the composite endpoint reported on the association of higher plasma VEGF-A concentration and subsequent risk of CAV,8 and this finding was recently confirmed by Watanabe et al26 Our study extends these findings to the immediate posttransplant period, as elevation of VEGF-A at the time of transplantation was associated with a higher likelihood of reaching the study endpoints. A number of mechanisms could be implicated in the association of higher VEGF-A levels and CAV progression, including stimulation of the graft endothelial cells by VEGF-A, perhaps as soon as reperfusion takes place, and subsequent induced expression of adhesion molecules and chemokines by the endothelial cells, all these leading to vascular injury and CAV progression 27,28.…”

Cardiac allograft vasculopathy: A review

“…A study by Daly et al 7 looked at biomarkers of CAV in 33 adult heart transplant recipients and found that VEGF‐A and VEGF‐C, along with other angiogenesis factors were strongly associated with established CAV and could serve as a reliable, non‐invasive diagnostic tool in these patients. This has also been demonstrated more recently in pediatrics with studies revealing that an increase in serum VEGF‐A levels was associated with clinically important CAV and this increase in VEGF‐A occurred even before detectable CAV making it a very appealing predictive biomarker 8,9 …”

“…As previously discussed, the use of biomarkers of endothelial damage and repair such as VEGF and other angiogenesis factors have increasingly been studied over the last few years. Pediatric studies have demonstrated that VEGF and VEGF‐A in specific is pathophysiologic in the development of CAV and is present in the serum prior to detectable CAV making it a useful predictive biomarker 7‐9 . Other biomarkers, such as Troponin and CRP have been studied mainly in the adult population with mixed results.…”

“…This process of endothelial cell turnover leads to release of growth factors such as VEGF and angiogenic factors to stimulate the growth of new cells and repair of the surrounding tissue 4,6 . The understanding of this has led to recent studies by Daly et al and Watanabe et al in both adults and pediatrics, demonstrating that the angiogenic factors VEGF‐A and VEGF‐C are strongly associated with established CAV and that VEGF‐A specifically was found even before CAV was detectable, making it a very appealing predictive biomarker 7‐9 …”

Effects of mTOR inhibitor–related proteinuria on progression of cardiac allograft vasculopathy and outcomes among heart transplant recipients

“…As vascular endothelial growth factor (VEGF), a potent enhancer of vascular permeability, was found to be overexpressed in podocytes of patients with focal segmental glomerulosclerosis and SRL‐induced proteinuria, 24 it is possible that a connection exists between higher burden of CAV (as seen in our study) and presence of significant proteinuria. The presence of diffuse endothelial expression of VEGF was associated with a 2.5‐fold risk of developing CAV, 25 and the elevated serum VEGF levels precede the development of CAV and may be a predictive biomarker of CAV development in pediatric HT recipients 26,27 . VEGF‐A expression is induced in association with cell‐mediated immune responses, and its overexpression is associated with cellular and antibody‐mediated rejection in HT recipients 28,29 .…”