Heart failure and atrial arrhythmias in CKD

CKD 中的心力衰竭和房性心律失常

• 批准号: 9335354
• 负责人: Nisha Bansal
• 金额: $ 27.16万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-08-25 至 2019-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9335354
• 关键词: Arrhythmia; Atrial Fibrillation; Autonomic Dysfunction; Biological; Biological Markers; Caliber; Cardiac; Cardiac Myocytes; Cardiomyopathies; Cardiovascular Diseases; Cardiovascular Manifestation; Cardiovascular system; Chronic Kidney Failure; Chronic Kidney Insufficiency; Clinical; Cohort Studies; Complication; Data; Disease; EFRAC; Echocardiography; Electrocardiogram; Evaluation; Event; Family; Fibroblasts; Fibrosis; Functional disorder; Future; GDF15 gene; Galactose Binding Lectin; Galectin 3; General Population; Goals; Heart Atrium; Heart Rate; Heart failure; Human; Hypertrophy; Incidence; Inferior vena cava structure; Inflammation; Inflammatory; Injury; Interleukin-1 Receptors; Ischemia; Kansas; Kidney Diseases; Lead; Left; Left Ventricular Ejection Fraction; Left Ventricular Mass; Link; Lung; Measures; Mechanics; Metabolic; Monitor; Morbidity - disease rate; Muscle Cells; Myocardial; Myocardial Ischemia; Outcome; PLAB Protein; Participant; Pathogenesis; Pathway interactions; Patients; Pattern; Population; Risk; Risk Factors; Stretching; Symptoms; Testing; Transforming Growth Factor alpha; Transforming Growth Factor beta; Troponin T; Ventricular; cardiogenesis; cardiovascular disorder risk; cohort; coronary fibrosis; cytokine; heart rate variability; high risk; improved; macrophage; member; mortality; new therapeutic target; novel; pressure; pro-brain natriuretic peptide (1-76); public health relevance; response; therapeutic target

 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).

 描述（申请人提供）：心力衰竭（HF）和心房颤动（AF）是慢性肾病（CKD）中心血管疾病最常见的表现。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。在合并 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。 即使没有临床心力衰竭或房颤，75% 的 CKD 患者患有左心室疾病，30% 的心电图异常，约 50% 的心力衰竭症状，所有这些都与心力衰竭和房颤的发生有关。心力衰竭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，这似乎是合理的。更好地了解 HF 和 AF 的发病机制可能会确定可能的治疗靶点 改善目前对这些 CKD 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 特异性危险因素和清除率降低的代谢效应。一些有前景的生物学途径与一般人群中 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为了解人类的这些机制途径提供了机会。 NT-proBNP 是由心肌细胞分泌的，以响应压力或容量超负荷引起的心肌拉伸。肌钙蛋白 T 因心肌损伤或重塑而升高。 Galectin-3 是一种由巨噬细胞表达的 β-半乳糖苷结合凝集素，可诱导心脏成纤维细胞， 促进心肌纤维化和不良重塑。可溶性 ST2 (sST2) 是 IL-1 受体家族的成员，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 TGF-β 细胞因子，它会因心肌细胞缺血、机械拉伸和促炎细胞因子而增加。 CKD 特异性 危险因素可能导致 CKD 中这些有前景的生物学途径存在差异，因此需要对该人群进行具体评估。该提案的总体目标是测试这些生物标志物与临床 HF 和 AF 以及与亚临床疾病的中间指标的关联，以了解 CKD 中 HF 和 AF 的生物学基础和发病机制。在拟议的研究中，我们旨在检验心肌生物标志物的假设 在慢性肾功能不全队列研究中，缺血、心肌牵张、心肌纤维化和炎症与 HF 事件（特别是 PEF-HF）、HF 症状和 HF 的中间亚临床测量（目标 1）相关。我们还将检验以下假设：这些生物标志物与 CRIC 参与者中发生的 AF 和 AF 的中间亚临床测量相关（Aim 2）。