BACKGROUND Allograft failure in African-Americans remains higher than in Caucasians. Single nucleotide polymorphisms (SNPs) have been associated with altered allograft outcomes. METHODS In this multi-center study we compared SNP frequencies in 364 pediatric heart recipients from three ethnic/racial groups: Caucasian (n = 243), African-American (n = 39), and Hispanic (n = 82). The target genes were: tumor necrosis factor-alpha, interleukin (IL)-10, IL-6, interferon (IFN)-gamma, vascular endothelial growth factor (VEGF), transforming growth factor-beta1, Fas, FasL, granzyme B, ABCB1, CYP3A5. RESULTS Compared to Caucasians, African-Americans exhibited a higher prevalence of genotypes associated with low expression of IFN-gamma (24% vs. 45.7%, P < 0.001) and IL-10 (33% vs. 57.1%, P = 0.052). African-Americans also exhibited an increased prevalence of high IL-6 (82.9% vs. 38.1%; P < 0.001). VEGF -2578 C/C and -460 C/C genotypes were found more frequently in African-Americans and Hispanics as compared to Caucasians (P < 0.001). G/G genotype of Fas and T/T genotype of FasL were expressed more often by African-American recipients. The prevalence of Granzyme B (-295A/G) genotype was differentially distributed in the three groups. Compared with Caucasians, African-Americans were twice as likely to carry the ABCB1 2677 G/G genotype (78.6% vs. 33.7%, P < 0.0025), and they were more frequent carriers of the CYP3A5 *1/*1 genotype (35.7% vs. 0.6% in Caucasians and 7.2% in Hispanics; P < 0.001). CONCLUSION African-Americans have a genetic background that may predispose to proinflammatory/lower regulatory environment, reduced drug exposure and immunosuppressive efficacy. In this ongoing multicenter study, these gene polymorphisms differences among ethnic/racial groups are being documented so that therapeutic strategies can be devised to optimize outcomes for pediatric transplant recipients.

Disparate distribution of 16 candidate single nucleotide polymorphisms among racial and ethnic groups of pediatric heart transplant patients.

Background-Vascular endothelial growth factor (VEGF) is a heparin-binding glycoprotein that plays a critical role in angiogenesis, vascular remodeling, and regulation of vascular tone and permeability. Because myocardial and peripheral edema and systemic hypotension occur frequently after cardiac operations, we examined the effects of cardiopulmonary bypass (CPB) and cardioplegia on gene expressions of VEGF protein and the VEGF tyrosine kinase receptor flk-1 and coronary vascular responses to VEGF. Methods and Results-Pigs (n=6) were placed on normothermic CPB and hearts were arrested for I hour with a hyperkalemic, cold blood cardioplegic solution. Pigs were then separated from CPB and perfused off CPB for an additional 2 hours. Myocardial and skeletal muscle specimens were obtained for Northern analysis of VEGF protein, flk-1 receptor, and basic fibroblast growth factor (bFGF) mRNA before CPB and after 2 hours of reperfusion. Isolated, precontracted coronary arterioles in pre-CPB dilated potently to exogenous VEGF (dilation=26±4% of precontraction at 10 -12 mol/L VEGF). Cardioplegia-reperfusion was associated with a 4±2-fold (P<0.05 vs pre-CPB) increase in myocardial VEGF protein mRNA, whereas no similar increase was observed in the skeletal muscle. Flk-1 mRNA was increased 6±3-fold (P<0.05 vs pre-CPB) after reperfusion, whereas it was unchanged in the skeletal muscle. Relaxations of precontracted coronary arterioles to VEGF were significantly increased (40±6% at 10 - 12 mol/L, P<0.05 vs pre-CPB) after 2 hours of reperfusion, but those to the endothelium-dependent vasodilator ADP and the endothelium-independent vasodilator nitroprusside were not changed, suggesting that the VEGF receptors remain intact and function is selectively upregulated. In contrast, relaxation responses of microvessels to bFGF were not altered after cardioplegia-reperfusion, and there was no increase in bFGF mRNA in either myocardium or skeletal muscle. Conclusions-This study shows that VEGF protein and its flk-1 receptor gene expressions are selectively increased and the potent VEGF-induced vascular responses are enhanced in the coronary microcirculation after blood cardioplegia. The respective parameters are unchanged in the skeletal muscle after normothermic CPB. These findings may have important implications regarding postoperative coronary blood flow regulation, increases in myocardial edema, and vascular remodeling after cardioplegia-reperfusion.

Myocardial VEGF expression after cardiopulmonary bypass and cardioplegia. Commentary

Endothelial nitric oxide synthase (eNOS) phosphorylation increases nitric oxide formation, for example, after VEGF stimulation. We investigated whether nitric oxide formed after overexpression of VEGF or of phosphomimetic eNOS (S1177D) affects PMN-induced myocardial detriment after ischemia and reperfusion. Pigs (n=8 per group) were subjected to percutaneous liposome-based gene transfer by retroinfusion of the anterior interventricular vein 48 h before LAD occlusion (60 min) and reperfusion (24 h). Thereafter, regional myocardial function was assessed as subendocardial segment shortening (SES), and infarct size was determined. Tissue from the infarct region, the noninfarcted area at risk, and a control region was analyzed for NF-kappaB activation (EMSA), tumor necrosis factor (TNF)-alpha, and E-selectin mRNA and infiltration of polymorphonuclear neutrophils (PMN). L-NAME was applied in one group of VEGF-transfected animals. NF-kappaB activition, PMN infiltration in the infarct region, and AAR were reduced after transfection of VEGF or eNOS S1177D, but not after VEGF+L-NAME coapplication. Infarct size decreased, whereas SES improved after either VEGF or eNOS S1177D transfection, an effect inhibited by L-NAME coapplication. Retroinfusion of liposomal VEGF cDNA reduces NF-kappaB-dependent postischemic inflammation and subsequent myocardial reperfusion injury, an effect mediated at least in part by enhanced eNOS phosphorylation.

VEGF165 transfection decreases postischemic NF-kappa B-dependent myocardial reperfusion injury in vivo: role of eNOS phosphorylation.

Transplant-associated coronary artery disease (CAD) is the principal limiting factor for the long-term survival of heart transplant patients. This review discusses early risk factors for the subsequent development of transplant-associated CAD. Early risk factors associated with a prothrombogenic mic

Pathologic markers of allograft arteriopathy: insight into the pathophysiology of cardiac allograft chronic rejection.

Clinical Impact of Cytokine and Growth Factor Genetic Polymorphisms in Thoracic Organ Transplantation

Increased Vascular Endothelial Growth Factor Expression in Human Hearts with Microvascular Fibrin

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Increased Vascular Endothelial Growth Factor Expression in Human Hearts with Microvascular Fibrin