Metformin Preconditioning Augments Cardiac Perfusion and Performance in a Large Animal Model of Chronic Coronary Artery Disease.

IF 7.5 1区 医学 Q1 SURGERY
Annals of surgery Pub Date : 2024-10-01 Epub Date: 2024-07-23 DOI:10.1097/SLA.0000000000006437
Christopher Stone, Sharif A Sabe, Dwight D Harris, Mark Broadwin, Rajeev J Kant, Meghamsh Kanuparthy, M Ruhul Abid, Frank W Sellke
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Abstract

Objective: To test the efficacy of metformin (MET) during the induction of coronary ischemia on myocardial performance in a large animal model of coronary artery disease (CAD) and metabolic syndrome (MS), with or without concomitant extracellular vesicular (EV) therapy.

Background: Although surgical and endovascular revascularization are durably efficacious for many patients with CAD, up to one-third are poor candidates for standard therapies. For these patients, many of whom have comorbid MS, adjunctive strategies are needed. EV therapy has shown promise in this context, but its efficacy is attenuated by MS. We investigated whether MET pretreatment could ameliorate therapeutic decrements associated with MS.

Methods: Yorkshire swine (n = 29) were provided a high-fat diet to induce MS, whereupon an ameroid constrictor was placed to induce CAD. Animals were initiated on 1000 mg oral MET or placebo; all then underwent repeat thoracotomy for intramyocardial injection of EVs or saline. Swine were maintained for 5 weeks before the acquisition of functional and perfusion data immediately before terminal myocardial harvest. Immunoblotting and immunofluorescence were performed on the most ischemic tissue from all groups.

Results: Regardless of EV administration, animals that received MET exhibited significantly improved ejection fraction, cardiac index, and contractility at rest and during rapid myocardial pacing, improved perfusion to the most ischemic myocardial region at rest and during pacing, and markedly reduced apoptosis.

Conclusions: MET administration reduced apoptotic cell death, improved perfusion, and augmented both intrinsic and load-dependent myocardial performance in a highly translatable large animal model of chronic myocardial ischemia and MS.

二甲双胍预处理可增强慢性冠状动脉疾病大型动物模型的心脏灌注和功能。
目的在冠状动脉疾病(CAD)和代谢综合征(MS)的大型动物模型中,测试二甲双胍在诱导冠状动脉缺血期间对心肌表现的疗效,无论是否同时进行细胞外囊泡疗法:背景:尽管外科手术和血管内再通术对许多 CAD 患者具有持久疗效,但仍有多达三分之一的患者不适合标准疗法。对于这些患者(其中许多人合并多发性硬化症),需要采取辅助治疗策略。在这种情况下,EV疗法大有可为,但其疗效会因多发性硬化症而减弱。我们研究了二甲双胍预处理是否能改善与多发性硬化症相关的治疗效果下降:约克夏猪(n=29)以高脂肪饮食诱发 MS,然后放置气门收缩器诱发 CAD。动物开始服用 1000 毫克二甲双胍或安慰剂;然后所有动物都接受了重复开胸手术,以在心肌内注射 EVs 或生理盐水。在采集终末心肌前获得功能和灌注数据之前,猪被饲养五周。对各组缺血最严重的组织进行免疫印迹和免疫荧光检测:结果:无论给予哪种 EV,接受二甲双胍治疗的动物在静息状态和快速心肌起搏时的射血分数、心脏指数和收缩力都有显著改善;静息状态和起搏时最缺血心肌区域的灌注改善;细胞凋亡明显减少:二甲双胍可减少细胞凋亡,改善灌注,并提高慢性心肌缺血和代谢综合征大型动物模型的内在和负荷依赖性心肌性能。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
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来源期刊
Annals of surgery
Annals of surgery 医学-外科
CiteScore
14.40
自引率
4.40%
发文量
687
审稿时长
4 months
期刊介绍: The Annals of Surgery is a renowned surgery journal, recognized globally for its extensive scholarly references. It serves as a valuable resource for the international medical community by disseminating knowledge regarding important developments in surgical science and practice. Surgeons regularly turn to the Annals of Surgery to stay updated on innovative practices and techniques. The journal also offers special editorial features such as "Advances in Surgical Technique," offering timely coverage of ongoing clinical issues. Additionally, the journal publishes monthly review articles that address the latest concerns in surgical practice.
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