Heart failure and atrial arrhythmias in CKD

 描述(申请人提供)：心力衰竭(HF)和房颤(AF)是慢性肾脏疾病(CKD)中最常见的心血管疾病表现(CKD在美国超过4000万患者，其中30%发展为心衰，15%-25%发展为房颤)。在CKD合并心力衰竭患者中，保留射血分数(PEF)-HF的发生率高于降低射血分数(REF)-HF的发生率。即使临床上无心衰或房颤，75%的CKD患者有左心室病变，30%的患者有异常的心电图，约50%的患者有心力衰竭症状，这些都与心力衰竭和房颤的发生有关。心衰和房颤经常同时发生，因此，它们可能通过共同的机制途径相互关联。更好地了解心力衰竭和房颤的发病机制可能会确定可能的治疗靶点，以改进目前对CKD这些疾病的治疗。心血管疾病的病理生理学在慢性肾脏病中是独一无二的，部分原因是由于新的慢性肾脏病特有的危险因素和清除率降低的代谢效应。在普通人群中，有几种可能的生物学途径参与了心力衰竭和房颤的发病机制，并可能适用于慢性肾脏病，包括：心肌缺血、心肌牵张、心肌纤维化和炎症。循环中的心脏生物标记物提供了一个了解人类这些机制途径的机会。NT-proBNP是心肌细胞对压力或容量超负荷引起的心肌拉伸的反应而分泌的。肌钙蛋白T升高是对心肌损伤或重构的反应。Galectin-3是一种β-半乳糖苷结合凝集素，由巨噬细胞表达，可诱导心脏成纤维细胞，促进心肌纤维化和不良重构。可溶性ST2(Sst2)是IL-1受体家族的一员，可促进心肌细胞肥大和心肌纤维化。生长分化因子(GDF)-15是一种转化生长因子-β(TGF-β)，可在心肌细胞缺血、机械牵张和促炎细胞因子作用下增加。CKD特有的危险因素可能会导致CKD中这些有希望的生物学途径的差异，因此需要在这一人群中进行特定的评估。这项建议的总体目标是测试这些生物标记物与临床心衰和房颤以及亚临床疾病的中间措施的相关性，以了解CKD中心力衰竭和房颤的生物学基础和发病机制。在这项拟议的研究中，我们旨在检验这一假说，即在慢性肾功能不全队列研究中，心肌缺血、心肌拉伸、心肌纤维化和炎症的生物标志物与慢性肾功能不全队列研究中慢性肾功能不全患者中发生的心衰(特别是PEF-心衰)、心衰症状和心力衰竭的中间亚临床措施(目标1)相关。我们还将检验这一假设，即这些生物标记物与CRIC参与者中的房颤事件和房颤的中间亚临床指标相关(目标2)。

 DESCRIPTION (provided by applicant): Heart failure (HF) and atrial fibrillation (AF) are the most common manifestations of cardiovascular disease in chronic kidney disease (CKD Over 40 million patients have CKD in the U.S. of which 30% develop HF and 15- 25% develop AF. Among CKD patients with HF, the incidence of preserved ejection fraction (PEF)-HF exceeds that of reduced ejection fraction (REF)-HF. Even the absence of clinical HF or AF, 75% of patients with CKD have left ventricular disease, 30% have abnormal electrocardiograms and ~50% have HF symptoms, all of which are associated with development of HF and AF. HF and AF often occur simultaneously, thus it is plausible that they may be interrelated through shared mechanistic pathways. Better understanding of the pathogenesis of HF and AF may identify possible therapeutic targets to improve current treatment for these diseases in CKD. The pathophysiology of cardiovascular disease is unique in CKD in part due to novel CKD-specific risk factors and metabolic effects of decreased clearance. Several promising biological pathways have been implicated in the pathogenesis of HF and AF in the general population and may be applicable to CKD including: myocardial ischemia, myocardial stretch, myocardial fibrosis and inflammation. Circulating cardiac biomarkers present an opportunity to understand these mechanistic pathways in humans. NT-proBNP is secreted from myocytes in response to myocardial stretch from pressure or volume overload. Troponin T rises in response to myocardial injury or remodeling. Galectin-3 is a beta-galactoside-binding lectin expressed by macrophages that induces cardiac fibroblasts, promoting myocardial fibrosis and adverse remodeling. Soluble ST2 (sST2) is a member of the IL-1 receptor family that promotes cardiomyocyte hypertrophy and myocardial fibrosis. Growth differentiation factor (GDF)-15 is a TGF-beta cytokine that increases in response to myocyte ischemia, mechanical stretch and proinflammatory cytokines. CKD-specific risk factors may lead to differences in these promising biological pathways in CKD, thus warranting specific evaluation in this population. The overall goal of this proposal is to test the association of these biomarkers with clinical HF and AF and with intermediate measures of subclinical disease to understand the biological underpinnings and pathogenesis of HF and AF in CKD. In the proposed study, we aim to test the hypothesis that biomarkers of myocardial ischemia, myocardial stretch, myocardial fibrosis and inflammation are associated with incident HF (particularly PEF-HF), HF symptoms and intermediate subclinical measures of HF (Aim 1) among participants with CKD in the Chronic Renal Insufficiency Cohort study. We will also test the hypothesis that these biomarkers are associated with incident AF and intermediate subclinical measures of AF among CRIC participants (Aim 2).