Phase II Trial of Metformin for Pulmonary Hypertension in Heart Failure with Preserved Ejection Fraction

射血分数保留性心力衰竭（HFpEF）是老年人发病率和死亡率的主要驱动因素， 人口老龄化是一个迅速增长的公共卫生问题。然而，没有具体的治疗方法 HFpEF和越来越多的临床试验的阴性结果被认为在很大程度上是由于 HFpEF的临床异质性。这导致了对更深入的表型分析的呼吁，以更好地靶向 治疗性临床试验一种具有特别差的结果的特定HFpEF表型是肺 高血压（PH），其可由HFpEF中肺血管的慢性充血引起。改变 葡萄糖代谢也与HFpEF和PH有关，特别是PH-HFpEF 表型。我们的初步数据，心肺生理的PH-HFpEF从最近的第二阶段， 临床试验提示肺血管的异常老化，其顺应性急剧下降。我们 发现PH-HFpEF患者通常在60多岁，代谢综合征患病率高 特色此外，观察性研究表明，二甲双胍可能与改善 心力衰竭的结果。此外，我们还研究了二甲双胍对肥胖动物模型的影响， PH-HFpEF，并显示与5'腺苷增加相关的肺动脉压降低 单磷酸活化蛋白激酶（AMPK）磷酸化。AMKP增加与 新发现的上调sirtuin-3（SIRT 3）在骨骼肌，但不是在肺或心脏。AMPK调节 葡萄糖在骨骼肌中的摄取，在代谢综合征、心力衰竭和PH中失调。 在HFpEF患者的骨骼肌活检中发现SIRT 3的活化减少， SIRT 3的激活驱动肌因子、成纤维细胞生长因子21（FGF 21）的分泌。FGF 21抑制 肺动脉平滑肌细胞增殖并对胰岛素抵抗产生全身性益处， AMPK依赖性方式。这些证据共同表明，二甲双胍具有显著的前景， PH-HFpEF的特异性治疗。我们建议在PH-HFpEF患者中进行一项为期12周的二甲双胍双盲交叉试验 改善运动血液动力学、功能能力和葡萄糖代谢。该II期临床试验将 提供了关于PH-HFpEF的详细表型和生理学数据（目的1）。主要结果将是 运动平均肺动脉压。次要终点将包括评估的功能能力 通过连续工作负荷运动测试，通过加速度计监测活动，6分钟内步行的距离， 以及心肺血液动力学（肺动脉压力、阻力和血管阻力）。 合规性）。将评估葡萄糖耐量和胰岛素敏感性。将进行骨骼肌活检 研究SIRT 3-AMPK信号传导、肌纤维转换和FGF 21-脂联素分泌（Aim 2）。结果 这项研究将为PH-HFpEF的心肺和代谢生理学提供有价值的见解， 可能导致新的和表型特异性治疗这种高风险的衰老疾病。

Heart failure with preserved ejection fraction (HFpEF) is a major driver of morbidity and mortality among the aging population and is a rapidly growing public health problem. However, there are no specific therapies for HFpEF and the negative results of a growing number of clinical trials are thought to be due, in large part, to substantial clinical heterogeneity of HFpEF. This has led to a call for deeper phenotyping to better target therapeutic clinical trials. One specific HFpEF phenotype with particularly poor outcomes is pulmonary hypertension (PH), which can result from chronic congestion of the pulmonary vasculature in HFpEF. Altered glucose metabolism has also been implicated in both HFpEF and PH, as well as specifically the PH-HFpEF phenotype. Our preliminary data on the cardiopulmonary physiology of PH-HFpEF from a recent phase II clinical trial suggests abnormal aging of the pulmonary vasculature with a steep decline in its compliance. We found that PH-HFpEF patients are typically in their 60's with a high prevalence of metabolic syndrome characteristics. Further, observational research suggests metformin may be associated with improved outcomes in heart failure. Additionally, we have studied the impact of metformin in an obese animal model of PH-HFpEF and shown a reduction in pulmonary pressures associated with increased 5' adenosine monophosphate-activated protein kinase (AMPK) phosphorylation. Increased AMKP was associated with a novel finding of upregulated sirtuin-3 (SIRT3) in skeletal muscle, but not in the lung or heart. AMPK regulates glucose uptake in skeletal muscle and is dysregulated in metabolic syndrome, heart failure, and PH. We have found decreased activation of SIRT3 in skeletal muscle biopsies from HFpEF patients and that skeletal muscle activation of SIRT3 drives secretion of the myokine, fibroblast growth factor 21 (FGF21). FGF21 inhibits pulmonary artery smooth muscle cell proliferation and confers systemic benefits on insulin resistance in an AMPK-dependent manner. These lines of evidence together suggest that metformin has significant promise for the specific treatment of PH-HFpEF. We propose a 12-week blinded cross over trial of metformin in PH-HFpEF to improve exercise hemodynamics, functional capacity, and glucose metabolism. This phase II clinical trial will provide detailed phenotyping and physiological data on PH-HFpEF (Aim 1). The primary outcome will be exercise mean pulmonary artery pressure. Secondary endpoints will include functional capacity as assessed by continuous work load exercise testing, activity monitoring by accelerometer, distance walked in 6 minutes, as well as cardiopulmonary hemodynamics (pulmonary artery pressures, resistance, and vascular compliance). Glucose tolerance and insulin sensitivity will be assessed. Skeletal muscle biopsies will be taken to study SIRT3-AMPK signaling, muscle fiber switch, and FGF21-adiponectin secretion (Aim 2). Results from this study will provide valuable insights into the cardiopulmonary and metabolic physiology of PH-HFpEF and may lead to novel and phenotypically specific therapy for this high-risk disease of aging.