Stone Christopher, Harris Dwight D, Broadwin Mark, Kanuparthy Meghamsh, Nho Ju-Woo, Yalamanchili Keertana, Hamze Jad, Abid M Ruhul, Sellke Frank W
Department of Cardiothoracic Surgery, Brown University, Providence, RI.
Arterioscler Thromb Vasc Biol. 2025 Feb;45(2):285-297. doi: 10.1161/ATVBAHA.124.321850. Epub 2024 Dec 12.
Coronary artery disease is the leading cause of death worldwide. It imposes an enormous symptomatic burden on patients, leaving many with residual disease despite optimal procedural therapy and up to one-thirds with debilitating angina amenable neither to procedures, nor to current pharmacological options. Semaglutide (SEM), a GLP-1 (glucagon-like peptide 1) agonist originally approved for management of diabetes, has garnered substantial attention for its capacity to attenuate cardiovascular risk. Although subgroup analyses in patients indicate promise, studies explicitly designed to isolate the impact of SEM on the sequelae of coronary artery disease, independently of comorbid diabetes or obesity, are lacking.
Yorkshire swine (n=17) underwent placement of an ameroid constrictor around the left circumflex coronary artery to induce coronary artery disease. Oral SEM was initiated postoperatively at 1.5 mg and scaled up in 2 weeks to 3 mg in treatment animals (n=8) for a total of 5 weeks, while control animals (n=9) received no drug. All then underwent myocardial harvest with acquisition of perfusion and functional data using microsphere injection and pressure-volume loop catheterization. Immunoblotting, immunohistochemistry, and immunofluorescence were performed on the most ischemic myocardial segments for mechanistic elucidation.
SEM animals exhibited improved left ventricular ejection fraction, both at rest and during rapid myocardial pacing (both <0.03), accompanied by increased perfusion to the most ischemic myocardial region at rest and during rapid pacing (both <0.03); reduced perivascular and interstitial fibrosis (both <0.03); and apoptosis (=0.008). These changes were associated with increased activation of the endothelial-protective AMPK (AMP-activated protein kinase) pathway (=0.005), coupled with downstream increases in eNOS (endothelial NO synthase; =0.014).
This study reveals the capacity of oral SEM to augment cardiac function in the chronically ischemic heart in a highly translational large animal model, likely through AMPK-mediated improvement in endothelial function and perfusion to the ischemic myocardium.
冠状动脉疾病是全球主要的死亡原因。它给患者带来了巨大的症状负担，尽管采用了最佳的手术治疗，仍有许多患者存在残余疾病，高达三分之一的患者患有使人衰弱的心绞痛，既无法通过手术治疗，也无法通过目前的药物治疗方案缓解。司美格鲁肽（SEM）是一种最初被批准用于治疗糖尿病的胰高血糖素样肽1（GLP-1）激动剂，因其降低心血管风险的能力而备受关注。尽管对患者的亚组分析显示出前景，但缺乏专门设计用于分离司美格鲁肽对冠状动脉疾病后遗症的影响（独立于合并糖尿病或肥胖）的研究。
17只约克夏猪在左旋冠状动脉周围放置阿梅洛氏缩窄环以诱导冠状动脉疾病。治疗组动物（n = 8）术后开始口服司美格鲁肽，初始剂量为1.5毫克，2周内增至3毫克，共治疗5周，而对照组动物（n = 9）不接受药物治疗。然后所有动物均进行心肌采集，通过微球注射和压力-容积环导管插入术获取灌注和功能数据。对最缺血的心肌节段进行免疫印迹、免疫组织化学和免疫荧光分析以阐明机制。
司美格鲁肽治疗组动物在静息和快速心肌起搏时左心室射血分数均有所改善（均P<0.03），同时在静息和快速起搏时最缺血心肌区域的灌注增加（均P<0.03）；血管周围和间质纤维化减少（均P<0.03）；细胞凋亡减少（P = 0.008）。这些变化与内皮保护的AMPK（AMP激活蛋白激酶）途径的激活增加有关（P = 0.005），同时eNOS（内皮型一氧化氮合酶）下游表达增加（P = 0.014）。
本研究揭示了在高度转化的大型动物模型中，口服司美格鲁肽能够增强慢性缺血心脏的心脏功能，可能是通过AMPK介导的内皮功能改善和缺血心肌灌注增加实现的。
