Mechanistic underpinnings of increased adipose tissue in HFpEF

心力衰竭(HF)是每年100万例住院患者的主要诊断，“心力衰竭伴 射血分数“(HFpEF)，占所有临床心衰患者的50%。然而，尽管 这一点及其对不断上升的医疗成本的影响，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，而且更多的 HFpEF需要量身定做、个性化的方法。大型结果试验和登记显示，HFpEF是 表型异质性和超重/肥胖是主要风险因素(70%-84%)。同样，约45%的 HFpEF患者是肥胖的，肥胖本身与HF的未来发展有关，尽管 对既定的风险因素进行调整。肥胖者肥胖增加会促进炎症和高血压 这可能与HFpEF的病理生理机制有关。 棕色脂肪组织(BAT)在调节全身能量平衡中起着关键作用。在这两个地方 在啮齿动物和人类中，有两种类型的生热脂肪细胞：经典的棕色脂肪细胞和 米色/“浅褐色”脂肪细胞。后者是出现在白色脂肪组织中的蝙蝠，对刺激做出反应 通过一种被称为“褐变”的过程。“褐变”最近被证明发生在新陈代谢健康的精瘦人群中。 HFpEF小鼠，但由于褐化，这些发现的相关性和翻译含义尚不清楚 可能会在应激源(如癌症相关性恶病质或大面积烧伤)时被激活。因此，它 目前尚不清楚褐化是有害的还是适应性的应激反应，以及它是否可能作为一种 肥胖相关疾病的治疗目标，如HFpEF。此翻译的广泛目标是 因此，建议对HFpEF中白色脂肪组织的褐变规律进行剖析，并探讨 这些发现的临床相关性。我们将探讨两个具体目标： 目的1：探讨肥胖性高脂血症患者脂肪组织褐变的关系 和血管生成及其与急性临床失代偿和HFpEF的关系 进步。 在一项对患有HFpEF的肥胖患者进行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)循环水平升高，抗血管生成作用减弱 因子(ANGPTL-4和Ang-2)和(Iii)急性心力衰竭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不全恶化，急性临床失代偿 并预测重新入院的时间。 目的：探讨HFpEF在脂肪组织褐变和血管生成中的作用及其作用。 在肥胖的ZSF1大鼠的HFpEF进展中，褐变激活增加。

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.