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：
10181027
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 2023-06-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10181027
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) 是每年超过 100 万人住院治疗的主要诊断，“心力衰竭伴有射血分数保留”（HFpEF），占所有临床心力衰竭表现的 50%。考虑到这一点及其对医疗费用不断上升的影响，HFpEF 尚无循证疗法。部分原因是缺乏对 HFpEF 发病机制的了解，并且更多的研究 HFpEF 需要量身定制的个性化方法。大型结果试验和登记表明 HFpEF 是有效的。异质表型和超重/肥胖是主要风险因素 (70-84%)，同样，约 45% 的人。 HFpEF 患者肥胖，并且肥胖本身与 HF 的未来发展相关，尽管调整已确定的危险因素。肥胖症中肥胖的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方面发挥着关键作用。啮齿动物和人类有两种类型的产热脂肪细胞：经典棕色脂肪细胞和米色/“brite”脂肪细胞是响应后一种刺激而出现在白色脂肪组织中的 BAT。最近显示，“褐变”发生在代谢健康的瘦肉中。 HFpEF 小鼠，但自褐变以来，这些发现的相关性和转化意义尚不清楚可能会因应激源而被激活，例如与癌症相关的恶病质或严重烧伤。目前尚不清楚褐变是有害的还是适应性应激反应，以及它是否可以作为肥胖相关疾病的治疗靶点，例如 HFpEF 这一转化的广泛目标。因此，建议剖析 HFpEF 中白色脂肪组织褐变的调节，并探索我们将探讨这些发现的两个具体目标：目标 1：调查肥胖 HFpEF 患者脂肪组织褐变之间的关系和血管生成以及它们如何与急性临床失代偿和 HFpEF 相关进展。在一项针对患有 HFpEF 的肥胖患者的纵向前瞻性研究中，急性 HFpEF 失代偿（定义入院时）与：（i）皮下白色脂肪组织褐变增加，（ii）促血管生成因子（VEGF-A 和 ANG-1）的循环水平增加，抗血管生成因子降低因子（ANGPTL-4 和 ANG-2）和 (iii) 急性心衰入院期间血管生成因子的变化，与临床结果相关，定义为左室舒张功能障碍恶化、急性临床失代偿并预测重新入院时间。目的2：研究HFpEF在脂肪组织褐变和血管生成中的作用及效果肥胖 ZSF1 大鼠中褐变激活增加对 HFpEF 进展的影响。