Nora Eccles Harrison Cardiovascular Research and Training Institute, The University of Utah, Salt Lake City, Utah, United States.
Division of Cardiothoracic Surgery, Department of Surgery, The University of Utah, Salt Lake City, Utah, United States.
Am J Physiol Heart Circ Physiol. 2023 Jun 1;324(6):H751-H761. doi: 10.1152/ajpheart.00647.2022. Epub 2023 Mar 24.
Preclinical large animal models of chronic heart failure (HF) are crucial to both understanding pathological remodeling and translating fundamental discoveries into novel therapeutics for HF. Canine models of ischemic cardiomyopathy are historically limited by either high early mortality or failure to develop chronic heart failure. Twenty-nine healthy adult dogs (30 ± 4 kg, 15/29 male) underwent thoracotomy followed by one of three types of left anterior descending (LAD) coronary artery ligation procedures: ( = 4) (simple LAD: proximal and distal LAD ligation); ( = 14) (simple LAD plus lateral wall including ligation of the distal first diagonal and proximal first obtuse marginal); and ( = 11) (total LAD devascularization or TLD: simple LAD plus ligation of proximal LAD branches to both the right and left ventricles). Dogs were followed until chronic severe HF developed defined as left ventricular ejection fraction (LVEF) < 40% and NH-terminal-prohormone B-type natriuretic peptide (NT-proBNP) > 900 pmol/L. Overall early survival (48-h postligation) in 29 dogs was 83% and the survival rate at postligation 5 wk was 69%. and had 100% and 71% early survival, respectively, yet only a 50% success rate of developing chronic HF. had excellent survival at postligation 48 h (91%) and a 100% success in the development of chronic ischemic HF. The TLD approach, which limits full LAD and collateral flow to its perfusion bed, provides excellent early survival and reliable development of chronic ischemic HF in canine hearts. The novel total left anterior descending devascularization (TLD) approach in a canine ischemic heart failure model limits collateral flow in the ischemic zone and provides excellent early survival and repeatable development of chronic ischemic heart failure in the canine heart. This work provides a consistent large animal model for investigating heart failure mechanisms and testing novel therapeutics.
临床前大型动物慢性心力衰竭(HF)模型对于理解病理性重构以及将基础发现转化为 HF 的新疗法至关重要。犬缺血性心肌病模型历史上受到高早期死亡率或未能发展为慢性心力衰竭的限制。29 只健康成年犬(30±4kg,15/29 只雄性)接受开胸手术,然后进行三种左前降支(LAD)冠状动脉结扎术之一:(n=4)(单纯 LAD:近端和远端 LAD 结扎);(n=14)(单纯 LAD 加侧壁,包括远端第一对角支和近端第一钝缘支结扎);(n=11)(完全 LAD 血运重建或 TLD:单纯 LAD 加近端 LAD 分支至左右心室的结扎)。犬一直随访至慢性严重 HF 发展,定义为左心室射血分数(LVEF)<40%和 N 末端前脑钠肽 B 型(NT-proBNP)>900pmol/L。29 只犬的总体早期存活率(结扎后 48 小时)为 83%,结扎后 5 周的存活率为 69%。和分别有 100%和 71%的早期存活率,但只有 50%的犬成功发展为慢性 HF。结扎后 48 小时的 TLD 方法具有 91%的出色存活率,并且 100%的犬成功发展为慢性缺血性 HF。该 TLD 方法限制了 LAD 的完全和侧支血流至其灌注床,为犬心提供了出色的早期存活率和可靠的慢性缺血性 HF 发展。在犬缺血性心力衰竭模型中,新的完全左前降支血运重建(TLD)方法限制了缺血区的侧支血流,为犬心提供了出色的早期存活率和可重复的慢性缺血性心力衰竭发展。这项工作为研究心力衰竭机制和测试新疗法提供了一个一致的大动物模型。