A Novel Large Animal Model of Thrombogenic Coronary Microembolization

Abstract

Coronary microembolization is one of the main causes of the “no-reflow” phenomenon, which commonly occurs after reperfusion of an occluded coronary artery. Given its high incidence and the fact that it has been proven to be an independent predictor of cardiac morbidity and mortality, there is an imperative need to study its underlying mechanisms and pathophysiology. Large animal models are essential to perform translational studies. Currently there is no animal model that recapitulates a clinical scenario of thrombogenic microembolism with preceding myocardial ischemia. Therefore, the goal of this study was to develop and characterize a novel pig model of coronary microembolization using autologous thrombus injection (CMET). Twenty-three pigs underwent myocardial infarction through percutaneous balloon occlusion of the left anterior descending artery (LAD). Each animal was enrolled in one of two groups: (1) the CMET group, in which the LAD occlusion was followed by delivery of autologous clotted blood in the LAD (distal to the balloon occlusion) and reperfusion; (2) the ischemic reperfusion (I/R) group, in which the LAD ischemia was followed by reperfusion. Surviving animals underwent functional and morphological characterization at 1-week post-procedure. Three sham operated animals were used as a control. CMET resulted in impaired left ventricular function compared to I/R pigs at 1 week. Three-dimensional echocardiography demonstrated reduced ejection fraction in the CMET group (CMET vs. I/R: 35.6 ± 4.2% vs. 47.6 ± 2.4%, p = 0.028). Invasive hemodynamic measurements by Swan-Ganz and left ventricular pressure-volume catheters revealed that CMET impaired left ventricular contractility and diastolic function. This was confirmed by both load-dependent indices including cardiac output (CMET vs. I/R: 2.7 ± 0.2 l/min, vs. 4.0 ± 0.1 l/min, p = 0.002) and load independent indices including preload-recruitable stroke work (CMET vs. I/R: 25.8 ± 4.0 vs. 47.5 ± 6.5 mmHg, p = 0.05) and end-diastolic pressure-volume relationship (slope, 0.68 ± 0.07 vs. 0.40 ± 0.11 mmHg/ml, p = 0.01). Our unique closed-chest model of coronary microembolization using autologous thrombus injection resembles the clinical condition of thrombogenic coronary microembolization in I/R injury. This model offers opportunities to conduct translational studies for understanding and treating coronary microembolization in myocardial infarction.

Human Urinary Kallidinogenase (HUK) Alleviates Myocardial Injury in Rats with Coronary Microembolism Through PI3K/Akt/FoxO1 Signaling Pathway.

“…CME may cause postoperative "no ow" or "slow ow" and microcirculation dysfunction, which in turn may lead to myocardial ischemia, arrhythmia, heart failure, and other consequences [13]. Given its high incidence, it has been viewed as an independent predictor of heart disease incidence and mortality [14].…”

A fresh look at coronary microembolization

“…An alternative but somewhat less standardized approach is the intracoronary infusion of exogenously (ex vivo) generated homologous or autologous thrombotic material that, although not inert, still does not include atherosclerotic debris and soluble factors released from an atherosclerotic culprit lesion. This method has been used in rats 44 and pigs 45 .…”

“…Limitations Non-human species Young age No underlying atherosclerosis Inert embolic material, except for autologous thrombi 44 , 45 …”

Preclinical models of myocardial infarction: from mechanism to translation

“…Ventricular fibrillation is more common in pigs and other large animals after MI than in rodents, and the use of antiarrhythmic therapy and/or cardioversion is recommended to reduce perioperative mortality. Closed‐chest ischaemia can also be induced by creation of a microembolism in the coronary artery, taking the model even closer to the human condition (Bikou et al, 2019), particularly when combined with hypercholesterolaemia (Andreadou et al, 2020). In older humans, myocardial ischaemia is frequently the result of gradual narrowing of coronary arteries, rather than all or nothing sudden occlusion.…”