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Mechanistic underpinnings of increased adipose tissue in HFpEF

HFpEF 中脂肪组织增加的机制基础

基本信息

批准号：
10444973
负责人：
Flora Sam
金额：
$ 66.31万
依托单位：
BOSTON UNIVERSITY MEDICAL CAMPUS
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-01 至 2024-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10444973
关键词：
Accounting Acute Adipocytes Adipose tissue Admission activity Adult Anatomy Angiogenic Factor Angiopoietin-2 Biopsy Brown Fat Buffers Burn injury Cardiac Cell Culture Techniques Clinical Cues Data Development Diagnosis EFRAC Environment Functional disorder Funding Future Glare Health Care Costs Healthcare Heart Diseases Heart failure Hospitalization Human Hypertension In Vitro Infant Inflammation Knowledge Longitudinal prospective study Malignant Neoplasms Metabolic Modeling Morbidity - disease rate Mus Obesity Obesity associated disease Outcome Overweight Pathogenesis Patients Phenotype Play Prevalence Process Rattus Registries Regulation Reporting Risk Factors Rodent Role Serum Stimulus Stress Structure Syndrome Therapeutic Thinness Time Vascular Endothelial Growth Factors Work angiogenesis base biological adaptation to stress cancer cachexia cardiogenesis clinically relevant energy balance evidence base experimental study hospital readmission improved insight mortality novel novel therapeutic intervention obese patients personalized approach preservation response stem stressor subcutaneous therapeutic target

项目摘要

Heart failure (HF) is the major diagnosis in >1 million hospitalizations annually, with “HF with preserved ejection fraction” (HFpEF), accounting for up to 50% of all clinical HF presentations. Yet, despite this and its impact on escalating health care costs, there are no evidence-based therapies for HFpEF. This stems, in part, from a lack of mechanistic understanding about the pathogenesis of HFpEF and that a more tailored, personalized approach is needed for HFpEF. Large outcome trials and registries reveal that HFpEF is a heterogeneous phenotype and being overweight/obese is a major risk factor (70-84%). Likewise, ~45% of patients with HFpEF are obese and obesity, in itself, is associated with the future development of HF despite adjusting for established risk factors. Increased adiposity in obesity promotes inflammation and hypertension which may contribute to HFpEF pathophysiology. Brown adipose tissue (BAT) plays a pivotal role in regulating whole-body energy balance. In both rodents and humans, there are two types of thermogenic adipocytes: classical brown adipocytes and beige/“brite” adipocytes. The latter are BAT that appears among white adipose tissue in response to a stimulus through a process termed “browning”. “Browning” was recently shown to occur in lean, metabolically healthy HFpEF mice but the relevance and translational implications of these findings are unknown since browning may be activated in response to stressors, such as cancer-associated cachexia or massive burns. Therefore it is unknown whether browning is deleterious or an adaptive stress response and whether it may serve as a therapeutic target for obesity-associated diseases, such as HFpEF. The broad objective of this translational proposal is therefore to dissect the regulation of browning in white adipose tissue in HFpEF and to explore the clinical relevance of these findings. We will explore 2 specific aims: Aim 1: To investigate in patients with obese HFpEF, the relationship between adipose tissue browning and angiogenesis and how these correlate with acute clinical decompensation and HFpEF progression. In a longitudinal, prospective study in obese patients with HFpEF, acute HFpEF decompensation (defined as a hospital admission) is associated with: (i) increased browning in subcutaneous white adipose tissue, (ii) increased circulating levels of pro-angiogenic factors (VEGF-A and ANG-1) and decreased anti-angiogenic factors (ANGPTL-4 and ANG-2) and (iii) changes in angiogenic factors during the acute HF admission, associates with clinical outcomes defined as worsened LV diastolic dysfunction, acute clinical decompensation and predicts time-to-readmission. Aim 2: To investigate the role of HFpEF in browning and angiogenesis in adipose tissue and the effect of increased browning activation on HFpEF progression in obese ZSF1 rats.

心力衰竭（HF）是每年> 100万次住院治疗的主要诊断，其中“HF伴射血分数保留”（HFpEF），占所有临床HF表现的50%。但尽管这一点及其对不断上升的医疗保健成本的影响，目前还没有针对HFpEF的循证疗法。这部分原因是对HFpEF的发病机制缺乏了解， HFpEF需要量身定制的个性化方法。大型结局试验和登记研究表明，HFpEF是异质表型和超重/肥胖是主要的风险因素（70-84%）。同样，约45%的 HFpEF患者肥胖，肥胖本身与HF的未来发展相关，调整已确定的风险因素。肥胖症中的肥胖增加会促进炎症和高血压这可能有助于HFpEF的病理生理学。棕色脂肪组织（BAT）在调节全身能量平衡中起着关键作用。无论是啮齿动物和人类，有两种类型的产热脂肪细胞：经典的棕色脂肪细胞和米色/“brite”脂肪细胞。后者是BAT，出现在白色脂肪组织中以响应刺激经过一个称为“布朗宁”的过程。“布朗宁”最近被证明发生在精瘦的，代谢健康的 HFpEF小鼠，但这些发现的相关性和翻译意义是未知的，因为布朗宁可能在应激源如癌症相关的恶病质或大面积烧伤时被激活。因此布朗宁是有害的还是一种适应性应激反应，以及它是否可以作为一种肥胖相关疾病的治疗靶点，如HFpEF。本翻译的主要目的因此，建议剖析HFpEF中白色脂肪组织中布朗宁的调节，并探索这些发现的临床意义。我们将探讨两个具体目标：目的1：探讨肥胖HFpEF患者脂肪组织布朗宁与HFpEF的关系以及这些与急性临床失代偿和HFpEF的关系进展在一项针对肥胖HFpEF患者的纵向、前瞻性研究中，急性HFpEF失代偿（定义为（i）皮下白色脂肪组织中增加的布朗宁，（ii）增加促血管生成因子（VEGF-A和ANG-1）的循环水平，降低抗血管生成因子（VEGF-A和ANG-1）的循环水平。因子（ANGPTL-4和ANG-2）和（iii）急性HF入院期间血管生成因子的变化，与定义为LV舒张功能障碍恶化、急性临床失代偿的临床结局相关并预测再入院时间。目的2：探讨HFpEF在脂肪组织布朗宁褐变和血管生成中的作用及其效果增加的布朗宁激活对HFpEF的进展，在肥胖的HFRF 1大鼠。