Vitamin B6, Vascular Dysfunction and Adhesion Molecules in Sickle Cell Disease

描述(申请人提供)：镰状细胞病(SCD)以急性临床症状为特征，包括疼痛危象、急性胸部综合征、异常勃起和中风，以及心、肺、肾、眼、脾和股骨头的慢性不可逆转损害。血管损伤和闭塞，主要影响微血管系统，是大多数这些并发症的基础。镰状细胞患者的另一个特征，无论是成人还是儿童，都是低维生素B6状态的高患病率(超过50%)，如低血浆吡哆醛-5‘-磷酸水平(&lt；20nmol/L)。在普通人群中，B6缺乏是心血管疾病、外周血管疾病和中风的危险因素，但尚不清楚低B6状态是否会影响SCD患者的血管发病率。我们实验室的初步数据表明，低B6状态与循环中介导红细胞和白细胞与血管内皮细胞黏附的黏附分子水平增加有关，这是SCD患者血管闭塞发病机制中的关键事件。因此，这项建议的长期目标是检验SCD患者补充B6将降低黏附分子水平和改善血管功能的假设。其具体目的是1)评估SCD患者B6状态、血管黏附分子和微血管形态和功能之间的横断面关系，以及2)评估B6补充剂对同一患者这些参数的影响。以标准血液学测量为特征的成人和儿童SCD患者将在基线时评估血液中吡哆醛-5‘-磷酸、已知与血管损伤有关的可溶性黏附分子的水平(通过实时多重分析)，以及血流速度和微血管形态测量(通过直接实时计算机辅助活体显微镜)。为了验证补充B6将改善微血管形态和血流与降低循环黏附分子水平相关的假设，这些患者将接受为期一年的维生素B6补充治疗，采用双盲、安慰剂对照研究设计。在干预期间，将每隔三个月重复测量B6状态、黏附分子水平和微血管特征。SCD的血管并发症对这些患者的发病率、死亡率和生活质量有很大的负面影响。维生素补充剂对健康的积极影响可以改善与这种疾病相关的高发病率和死亡率，具有以最小的成本和风险获得高收益的潜力。

DESCRIPTION (provided by applicant): Sickle cell disease (SCD) is characterized by acute clinical manifestations, including painful crisis, acute chest syndrome, priapism, and stroke, as well as chronic irreversible damage to the heart, lungs, kidneys, eyes, spleen and femoral heads. Vascular injury and occlusion, primarily affecting the microvasculature, underlie most of these complications. Another characteristic of sickle cell patients, both adult and pediatric, is a high prevalence of low vitamin B6 status (exceeding 50%), as indicated by low plasma pyridoxal-5'- phosphate levels (<20 nmol/L). B6 deficiency is a risk factor for cardiovascular disease, peripheral vascular disease, and stroke in the general population, but it is unknown if low B6 status affects vascular morbidity in SCD patients. Preliminary data from our laboratory indicate that low B6 status is associated with increased circulating levels of adhesion molecules that mediate erythrocyte and leukocyte adhesion to the vascular endothelium, key events in the pathogenesis of vascular occlusion in SCD patients. Accordingly, the long- term objective of this proposal is to test the hypothesis that B6 supplements in SCD patients will reduce levels of adhesion molecules and improve vascular function. The specific aims are 1) to assess the cross- sectional relationships between B6 status, vascular adhesion molecules, and microvascular morphology and function in SCD patients, and 2) to assess the effect of B6 supplements on these parameters in the same patients. Adult and pediatric SCD patients, characterized using standard hematological measurements, will be assessed at baseline for blood levels of pyridoxal-5'-phosphate, soluble adhesion molecules known to be related to vascular injury (by real-time multiplex assay), and blood flow velocity and microvessel morphometry (by direct real-time computer-assisted intravital microscopy). To test the hypothesis that B6 supplements will result in improved microvascular morphometry and blood flow associated with a decrease in levels of circulating adhesion molecules, these patients will be treated for one year with vitamin B6 supplements using a double-blind, placebo-controlled study design. Repeat measurements of B6 status, levels of adhesion molecules and microvascular characteristics will be carried out at three-month intervals during the period of intervention. The vascular complications of SCD have a major negative impact on morbidity, mortality, and quality of life for these patients. The positive health impact of vitamin supplementation that could ameliorate the high morbidity and mortality associated with this disorder has the potential for high benefit with minimal cost and risk.