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

心力衰竭伴保留射血分数(HFpEF)是心力衰竭患者发病率和死亡率的主要驱动因素 人口老龄化是一个快速增长的公共卫生问题。然而，目前还没有特效的治疗方法。 HFpEF和越来越多的临床试验的负面结果被认为在很大程度上是由于 HFpEF具有明显的临床异质性。这导致了一种更深入的表型分析的呼声，以更好地定位 治疗性临床试验。预后特别差的一种特殊的HFpEF表型是肺型 高血压(PH)，可由HFpEF中的肺血管慢性充血引起。更改后的 糖代谢也与HFpEF和PH有关，特别是PH-HFpEF 表型。我们近期II期PH-HFpEF心肺生理学的初步数据 临床试验表明，肺血管系统异常老化，其顺应性急剧下降。我们 发现PH-HFpEF患者典型的60岁以上的S有较高的代谢综合征患病率 特点。此外，观察性研究表明，二甲双胍可能与改善 导致心力衰竭的后果。此外，我们还研究了二甲双胍对肥胖动物模型的影响。 PH-HFpEF显示与5‘-腺苷升高相关的肺压力降低 单磷酸活化蛋白激酶(AMPK)的磷酸化。AMKP的增加与 在骨骼肌中发现上调的sirtuin-3(SIRT3)，但在肺或心脏中没有。AMPK调节 骨骼肌中的葡萄糖摄取，在代谢综合征、心力衰竭和PH中调节失调。我们有 在HFpEF患者和骨骼肌活检组织中发现SIRT3活性降低 SIRT3的激活促进了肌细胞因子成纤维细胞生长因子21(FGF21)的分泌。FGF21抑制 肺动脉平滑肌细胞的增殖和对胰岛素抵抗的全身性益处 AMPK依赖方式。这些证据共同表明二甲双胍有很大的前景 PH-HFpEF的特异性治疗。我们建议在PH-HFpEF中应用二甲双胍进行为期12周的盲法交叉试验 改善运动血流动力学、机能能力和葡萄糖代谢。这项第二阶段的临床试验将 提供PH-HFpEF的详细表型和生理数据(目标1)。主要结果将是 运动平均肺动脉压。次要终端将包括评估的功能容量 通过持续的运动负荷测试，用加速度计监测活动，6分钟步行距离， 以及心肺血流动力学(肺动脉压力、阻力和血管 合规性)。将评估葡萄糖耐量和胰岛素敏感性。将进行骨骼肌活组织检查 研究SIRT3-AMPK信号转导、肌纤维转换和FGF21-脂联素分泌(AIM 2)。结果来自 本研究将对PH-HFpEF的心肺和代谢生理学提供有价值的见解。 可能导致这种高危衰老疾病的新的和表型特异性的治疗。

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.