Pulmonary Hypertension and the Hypoxic Response in SCD (PUSH)

肺动脉高压和 SCD 中的缺氧反应 (PUSH)

基本信息

批准号：
8557979
负责人：
Gregory Kato
金额：
$ 5.57万
依托单位：
NATIONAL HEART, LUNG, AND BLOOD INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/8557979
关键词：
Adolescent Adult Age Alkaline Phosphatase Alleles Blood Urea Nitrogen Blood Vessels Blood Volume Caliber Candidate Disease Gene Cardiovascular Physiology Characteristics Child Childhood Clinical Clinical Markers Complex Data Data Analyses Echocardiography Enrollment Exercise Ferritin Fetal Hemoglobin Frequencies Genetic Genetic Polymorphism Genomics Healthcare Heart Atrium Hematological Disease Hemoglobin Hemoglobin SS Hemolysis Hemolytic Anemia Heritability Homozygote Hypoxia Hypoxia Inducible Factor Individual Inflammation Interleukin-8 Iron Iron Overload Laboratories Lactate Dehydrogenase Left Lung Manuscripts Mediating Meta-Analysis Microarray Analysis Mutation Nitric Oxide Osteoclasts Osteoporosis Pain Pathogenesis Pathologic Pathway Analysis Pathway interactions Patients Polycythemia Prevalence Prospective Studies Publications Pulmonary Hypertension Pulmonary artery structure RANTES Regulation Reporting Research Risk Risk Factors Role Sample Size Secondary to Serum Sickle Cell Anemia Specimen Systolic Pressure Thalassemia Tricuspid Valve Insufficiency Up-Regulation VHL gene Venous blood sampling Ventricular Walking aged bone cohort design follow-up genome wide association study genome-wide genotyping technology hypoxia inducible factor 1 iron deficiency mortality pressure prospective response tartrate-resistant acid phosphatase trait vaso-occlusive pain

项目摘要

The Pulmonary Hypertension and the Hypoxic Response in Sickle Cell Disease (PUSH) study has concluded enrollment and follow up. Data analysis on existing data and specimens continues to generate new information and new research manuscripts. The following information has been adapted from publications during 2011-2012. 1. Elevated tricuspid regurgitation velocity and decline in exercise capacity over 22 months of follow up in children and adolescents with sickle cell anemia While in adults with sickle cell disease an elevation of tricuspid regurgitation velocity is associated with increased mortality, the importance of this finding in children has not been established. We conducted a prospective, longitudinal, multi-center study of 160 individuals aged 3-20 years with hemoglobin SS, performing baseline and follow-up determinations of clinical markers, six-minute walk distance less than tricuspid regurgitation velocity and E/Etdi ratio by echocardiography. At baseline, 14.1% had tricuspid regurgitation velocity of 2.60 m/sec or over, which suggests elevated systolic pulmonary artery pressure, and 7.7% had increased E/Etdi, which suggests elevated left ventricular filling pressure. Over a median of 22 months, baseline elevation in tricuspid regurgitation velocity was associated with an estimated 4.4-fold increase in the odds of a 10% or more decline in age-standardized six-minute-walk distance (P = 0.015). During this interval, baseline values above the median for a hemolytic component derived from four markers of hemolysis were associated with a 9.0-fold increase in the odds of the new onset of elevated tricuspid regurgitation velocity (P = 0.008) and baseline E/Etdi elevation was associated with an estimated 6.1-fold increase in the odds (P = 0.039). In pathway analysis, higher baseline hemolytic component and E/Etdi predicted elevated tricuspid regurgitation velocity at both baseline and follow up, and these elevations in turn predicted decline in six-minute-walk distance. 2. Markers of severe vaso-occlusive painful episode frequency in children and adolescents with sickle cell anemia We sought to identify factors associated with frequent severe vaso-occlusive pain crises in a contemporary pediatric cohort of patients with sickle cell anemia (SCA) enrolled in a prospective study of pulmonary hypertension and the hypoxic response in sickle cell disease. We evaluated the clinical and laboratory characteristics of children with SCA who had 3 severe pain crises requiring health care in the preceding year were compared with those of subjects with <3 such episodes. We found that seventy-five children (20%) reported 3 severe pain episodes in the preceding year, and 232 (61%) had none. Frequent pain episodes were associated with older age (OR, 1.2; 95% CI, 1.1-1.3; P < .0001), -thalassemia trait (OR 3.5; 1.6-6.7; P = .002), higher median hemoglobin (OR 1.7; 95% CI: 1.2-2.4; P < .003), and lower lactate dehydrogenase concentration (OR 1.82; 95% CI: 1.07-3.11; P = .027). Children with high pain frequency also had an increased iron burden (serum ferritin, 480 vs 198 g/L; P = .006) and higher median tricuspid regurgitation jet velocity (2.41 vs 2.31 m/s; P = .001). In our cohort of children with SCA, increasing age was associated with higher frequency of severe pain episodes as were -thalassemia, iron overload, higher hemoglobin and lower lactate dehydrogenase concentration, and higher tricuspid regurgitation velocity. 3. Genomic regulation of fetal hemoglobin expression Fetal hemoglobin (HbF) protects against many but not all of the hematologic and clinical complications of sickle cell anemia. Our aim was to perform a meta-analysis of genome-wide association studies (GWAS) to find genetic loci with modest effect sizes that were associated with HbF when a larger sample size was examined. In the CSSCD cohort, the most significant SNPs in BCL11A (rs766432) and the HMIP region (rs9494145) explained 11.1% and 3.2% of the phenotypic variability in HbF, respectively, and together explain only 14.7% of the variability. Twelve additional SNPs reached statistical significance of 10−5 or less, although none reached genome-wide significance. HbF is regulated as a complex trait and the missing heritability not detected by GWAS has various explanations. 4. Pulmonary artery pressure and iron deficiency in patients with upregulation of hypoxia sensing due to Chuvash polycythemia Patients with Chuvash polycythemia, (homozygosity for the R200W mutation in the von Hippel Lindau gene (VHL)), have elevated levels of hypoxia inducible factors HIF-1 and HIF-2, often become iron-deficient secondary to phlebotomy, and have elevated estimated pulmonary artery pressure by echocardiography. We performed a comprehensive assessment of cardiovascular physiology and to identify risk factors for elevation of tricuspid regurgitation velocity in children and adults with Chuvash polycythemia. The age-adjusted mean SE tricuspid regurgitation velocity was higher in VHL(R200W) homozygotes than controls with normal VHL alleles (2.50.03 vs. 2.30.05 m/sec, P=0.005). The age-adjusted left ventricular diastolic diameter (4.80.05 vs. 4.50.09 cm, P=0.005) and left atrial diameter (3.40.04 vs. 3.20.08 cm, P=0.011) were also greater in the VHL(R200W) homozygotes, consistent with increased blood volume, but the elevation in tricuspid regurgitation velocity persisted after adjustment for these variables. Among VHL(R200W) homozygotes, phlebotomy therapy was associated with lower serum ferritin concentration, and low ferritin independently predicted higher tricuspid regurgitation velocity (standardized beta=0.29; P=0.009). Children and adults with Chuvash polycythemia have higher estimated right ventricular systolic pressure, even after adjustment for echocardiography estimates of blood volume. Lower ferritin concentration, which is associated with phlebotomy, independently predicts higher tricuspid regurgitation velocity. 5. Predictors of osteoclast activity in patients with sickle cell disease Bone changes are common in sickle cell disease, but the pathogenesis is not fully understood. Tartrate-resistant acid phosphatase (TRACP) type 5b is produced by bone-resorbing osteoclasts. In other forms of hemolytic anemia, increased iron stores are associated with osteoporosis. We hypothesized that transfusional iron overload would be associated with increased osteoclast activity in patients with sickle cell disease. Tartrate-resistant acid phosphatase 5b concentrations were higher in 58 adults with sickle cell disease than in 22 controls (medians of 4.4 versus 2.4 U/L, respectively; P=0.0001). Among the patients with sickle cell disease, tartrate-resistant acid phosphatase 5b independently correlated with blood urea nitrogen (standardized beta=0.40, P=0.003), interleukin-8 (standardized beta=0.30, P=0.020), and chemokine C-C motif ligand 5 (standardized beta=−0.28, P=0.031) concentrations. There were strong correlations among tartrate-resistant acid phosphatase 5b, alkaline phosphatase and tricuspid regurgitation velocity (r>0.35, P<0.001). Patients with sickle cell disease have increased osteoclast activity as reflected by serum tartrate-resistant acid phosphatase 5b concentrations. Our results may support a potential role of inflammation rather than increased iron stores in stimulating osteoclast activity in sickle cell disease. The positive relationships among tartrate-resistant acid phosphatase 5b, alkaline phosphatase and tricuspid regurgitation velocity raise the possibility of a common pathway in the pulmonary and bone complications of sickle cell disease.

镰状细胞疾病（PUSH）研究中的肺动脉高压和低氧反应已得出结论和随访。现有数据和标本的数据分析继续生成新的信息和新的研究手稿。以下信息已从2011 - 2012年期间的出版物中进行了调整。 1。在儿童和青少年患有镰状细胞贫血的儿童和青少年的随访中，升高三尖端反流速度和运动能力下降尽管在患有镰状细胞疾病的成年人中，三尖瓣反流速度的升高与死亡率的增加有关，但该发现在儿童中的重要性尚未确定。我们对160个年龄3-20岁的血红蛋白SS，进行基线和临床标记的随访确定，对临床标志物的后续测定，步行距离六分钟，比三尖端的距离距离三尖端反流速度和E/ETDI的比率小于临床标记的距离，对临床标记的距离远低6分钟。在基线时，14.1％的三尖体反流速度为2.60 m/sec或以上，这表明收缩期肺动脉压力升高，而7.7％的E/ETDI增加了E/ETDI，这表明左心室填充压力升高。在22个月的中位数中，三尖瓣反流速度的基线升高与年龄标准化的六分钟步行距离下降10％或以上的几率估计增加了4.4倍（p = 0.015）。在此时间间隔内，源自四个标记的溶血成分中位数高于中位数的基线值与三尖升高升高的反流速度的新发作的几率增加了9.0倍（p = 0.008）和基线E/ETDI的增加和估计的6.1-FOLTIA升高与估计的6.1-FOLT升高相关。在途径分析中，较高的基线溶血成分和E/ETDI预测基线和随访时的三尖瓣反流速度升高，而这些升高反过来又预测了六分钟步行距离的下降。 2。患有镰状细胞贫血的儿童和青少年严重的血管合作疼痛发作频率我们试图确定与镰状细胞贫血患者（SCA）的频繁严重的血管闭塞性疼痛危机有关的因素，该因素是对肺部高血压的前瞻性研究和镰状细胞病的低氧反应的前瞻性研究。我们评估了SCA儿童的临床和实验室特征，他们患有3种严重的疼痛危机，需要在上一年进行医疗保健，将其与<3个此类事件的受试者的临床危机进行了比较。我们发现上一年有75名儿童（20％）报告了3个严重的疼痛发作，而232名（61％）没有。频繁的疼痛发作与年龄相关（OR，1.2; 95％CI，1.1-1.3; p <.0001）， - 核阿无血性特征（OR 3.5; 1.6-6.7; P = .002），较高的中位血红蛋白，1.7; 95％CI：95％CI：1.2-2.4; p <.003; p <.003）and latctasate and lactasate deh and lactasate; 1.8; CI：1.07-3.11; p = .027）。疼痛频率高的儿童也具有增加的铁负担（血清铁蛋白，480 vs 198 g/L; p = .006）和较高的中位三尖瓣反流射流速度（2.41 vs 2.31 m/s; p = .001）。在我们的SCA儿童队列中，年龄的增长与 - tharassymia，铁超载，较高的血红蛋白和较低乳酸脱氢酶浓度以及较高的三尖端刺激性反流速度有关。 3。胎儿血红蛋白表达的基因组调节胎儿血红蛋白（HBF）可预防镰状细胞贫血的许多但并非所有的血液学和临床并发症。我们的目的是对全基因组关联研究（GWAS）进行荟萃分析，以找到具有适度效应大小的遗传基因座，当检查了较大的样本量时，它们与HBF相关。在CSSCD队列中，BCL11A（rs766432）和HMIP区域（rs9494145）中最重要的SNP分别解释了HBF中表型变异性的11.1％和3.2％，仅解释了可变性性的14.7％。十二个额外的SNP达到10-5或以下的统计显着性，尽管没有任何人达到全基因组的显着性。 HBF被视为一种复杂的特征，GWAS未检测到的缺失的遗传力有各种解释。 4。由于Chuvash多性炎症引起的缺氧感应上调的患者的肺动脉压力和铁缺乏症 CHUVASH多性高血症患者（von Hippel Lindau基因（VHL）R200W突变的纯合性患者，缺氧诱导型HIF-1和HIF-2的水平升高，通常成为屈光度术的铁缺陷型，并且通过肺炎估计的肺部压力升高。我们对心血管生理学进行了全面的评估，并确定了Chuvash多性心血症的儿童和成年人的三尖替刺流速度升高的危险因素。在VHL（R200W）纯合子中，年龄调整后的平均SE三尖瓣反流速度高于正常VHL等位基因（2.50.03 vs. 2.30.05 m/sec，p = 0.005）的对照。年龄调整后的左心室舒张直径（4.80.05 vs. 4.50.09 cm，p = 0.005）和左心房直径（3.40.04 vs. 3.20.04 vs. 3.20.08 cm，p = 0.011）的VHL（R200W）固有剂量也更大，但具有较高的血液，但一致，但一致，但一致，但均一致，但均一致，但均一致。调整这些变量后持续存在。在VHL（R200W）纯合子中，静脉切开术疗法与较低的血清铁蛋白浓度相关，而低铁蛋白独立预测了较高的三尖瓣反流质量（标准化β= 0.29； P = 0.009）。 Chuvash多性性高血压的儿童和成人的右心收缩压估计更高，即使在调整了血容量的超声心动图估计后。较低的铁蛋白浓度与静脉切开术有关，独立地预测了较高的三尖瓣反流速度。 5。镰状细胞病患者破骨细胞活性的预测因子骨变化在镰状细胞病中很常见，但发病机理尚未完全了解。耐锈酸磷酸酶（TRACP）5B是通过骨变形的破骨细胞产生的。在其他形式的溶血性贫血中，铁储存量增加与骨质疏松症有关。我们假设输血铁超负荷与镰状细胞疾病患者的破骨细胞活性增加有关。在58名患有镰状细胞疾病的成年人中，耐锈酸酸性磷酸酶5b的浓度高于22个对照组（分别为4.4 v和2.4 u/L； p = 0.0001）。 Among the patients with sickle cell disease, tartrate-resistant acid phosphatase 5b independently correlated with blood urea nitrogen (standardized beta=0.40, P=0.003), interleukin-8 (standardized beta=0.30, P=0.020), and chemokine C-C motif ligand 5 (standardized beta=−0.28, P=0.031) concentrations.耐锈酸磷酸酶5b，碱性磷酸酶和三尖替刺流速度之间存在很强的相关性（r> 0.35，p <0.001）。镰状细胞疾病患者的破骨细胞活性增加了，如血清抗性抑制酸磷酸酶5b浓度所反映的那样。我们的结果可能支持炎症的潜在作用，而不是增加铁储存在刺激镰状细胞病中的破骨细胞活性中。耐锈酸磷酸酶5b，碱性磷酸酶和三尖速流速度之间的正相关关系增加了镰状细胞病的肺和骨并发症中常见途径的可能性。