Heart failure and atrial arrhythmias in CKD

 描述（申请人提供）：心力衰竭（HF）和心房颤动（AF）是慢性肾脏病中最常见的心血管疾病表现（CKD在美国超过4000万患者患有CKD，其中30%发展为HF，15 - 25%发展为AF。在患有HF的CKD患者中，射血分数保留（PEF）-HF的发生率超过射血分数降低（REF）-HF的发生率。即使没有临床HF或AF，75%的CKD患者有左心室疾病，30%有异常心电图，约50%有HF症状，所有这些都与HF和AF的发展有关。HF和AF通常同时发生，因此，它们可能通过共同的机制途径相互关联是合理的。更好地了解HF和AF的发病机制可能会发现可能的治疗靶点，以改善目前对CKD中这些疾病的治疗。心血管疾病的病理生理学在CKD中是独特的，部分原因是新的CKD特异性风险因素和清除率降低的代谢效应。在一般人群中，几种有前景的生物学途径与HF和AF的发病机制有关，可能适用于CKD，包括：心肌缺血、心肌牵张、心肌纤维化和炎症。循环心脏生物标志物提供了一个机会，以了解这些机制的途径在人类。NT-proBNP响应于压力或容量超负荷引起的心肌拉伸而从肌细胞分泌。肌钙蛋白T升高是对心肌损伤或重塑的反应。半乳糖凝集素-3是由巨噬细胞表达的β-半乳糖苷结合凝集素，其诱导心脏成纤维细胞，促进心肌纤维化和不良重塑。可溶性ST 2（sST 2）是IL-1受体家族的成员，其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TGF-β细胞因子，其响应于肌细胞缺血、机械拉伸和促炎细胞因子而增加。CKD特异性风险因素可能导致CKD中这些有希望的生物学途径的差异，因此需要在该人群中进行特异性评估。本提案的总体目标是测试这些生物标志物与临床HF和AF以及亚临床疾病的中间指标的相关性，以了解慢性肾病中HF和AF的生物学基础和发病机制。在拟定的研究中，我们旨在检验以下假设：在慢性肾功能不全队列研究的CKD受试者中，心肌缺血、心肌牵张、心肌纤维化和炎症的生物标志物与HF事件（特别是PEF-HF）、HF症状和HF的中间亚临床指标（目的1）相关。我们还将检验以下假设：这些生物标志物与CRIC参与者中的AF事件和AF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).