Section on Geriatrics and Gerontology, Department of Cardiovascular Medicine, Wake Forest University School of Medicine, Winston-Salem, NC, USA.
Department of Medicine, Massachusetts General Brigham, Boston, MA, USA.
Eur J Heart Fail. 2024 Sep;26(9):2013-2024. doi: 10.1002/ejhf.3305. Epub 2024 Jun 26.
Compared with those without obesity, patients with obesity-related heart failure with preserved ejection fraction (HFpEF) have worse symptoms, haemodynamics, and outcomes. Current weight loss strategies (diet, drug, and surgical) work through decreased energy intake rather than increased expenditure and cause significant loss of skeletal muscle mass in addition to adipose tissue. This may have adverse implications for patients with HFpEF, who already have reduced skeletal muscle mass and function and high rates of physical frailty. Mitochondrial uncoupling agents may have unique beneficial effects by producing weight loss via increased catabolism rather than reduced caloric intake, thereby causing loss of adipose tissue while sparing skeletal muscle. HU6 is a controlled metabolic accelerator that is metabolized to the mitochondrial uncoupling agent 2,4-dinotrophenol. HU6 selectively increases carbon oxidation from fat and glucose while also decreasing toxic reactive oxygen species (ROS) production. In addition to sparing skeletal muscle loss, HU6 may have other benefits relevant to obesity-related HFpEF, including reduced specific tissue depots contributing to HFpEF; improved glucose utilization; and reduction in systemic inflammation via both decreased ROS production from mitochondria and decreased cytokine elaboration from excess, dysfunctional adipose.
We describe the rationale and design of HuMAIN-HFpEF, a Phase 2a randomized, double-blind, placebo-controlled, dose-titration, parallel-group trial in patients with obesity-related HFpEF to evaluate the effects of HU6 on weight loss, body composition, exercise capacity, cardiac structure and function, metabolism, and inflammation, and identify optimal dosage for future Phase 3 trials.
HuMAIN will test a promising novel agent for obesity-related HFpEF.
与非肥胖相关的射血分数保留心力衰竭（HFpEF）患者相比，肥胖相关 HFpEF 患者的症状、血液动力学和结局更差。目前的减肥策略（饮食、药物和手术）通过减少能量摄入起作用，而不是通过增加支出，除了脂肪组织外，还会导致骨骼肌大量流失。这可能对已经存在骨骼肌质量和功能减少以及高比例身体虚弱的 HFpEF 患者产生不利影响。解偶联剂可能具有独特的有益效果，通过增加分解代谢而不是减少热量摄入来减轻体重，从而导致脂肪组织丢失，同时保留骨骼肌。HU6 是一种受控的代谢加速剂，可代谢为解偶联剂 2,4-二硝基苯酚。HU6 选择性地增加来自脂肪和葡萄糖的碳氧化，同时减少毒性活性氧物质（ROS）的产生。除了避免骨骼肌丢失外，HU6 可能对肥胖相关 HFpEF 具有其他益处，包括减少导致 HFpEF 的特定组织蓄积；改善葡萄糖利用；通过减少线粒体产生的 ROS 和减少来自过多、功能失调脂肪的细胞因子产生，减轻全身炎症。
我们描述了 HuMAIN-HFpEF 的原理和设计，这是一项在肥胖相关 HFpEF 患者中进行的 2a 期随机、双盲、安慰剂对照、剂量滴定、平行组试验，以评估 HU6 对体重减轻、身体成分、运动能力、心脏结构和功能、代谢和炎症的影响，并确定未来 3 期试验的最佳剂量。
HuMAIN 将测试一种治疗肥胖相关 HFpEF 的有前途的新型药物。
