Comparative Analysis of Methods to Induce Myocardial Infarction in a Closed-Chest Rabbit Model

Abstract

Objective. To develop a rabbit model of closed-chest catheter-induced myocardial infarction. Background. Limitations of rodent and large animal models justify the search for clinically relevant alternatives. Methods. Microcatheterization of the heart was performed in 47 anesthetized 3-4 kg New Zealand rabbits to test five techniques of myocardial ischemia: free coils (n = 4), interlocking coils (n = 4), thrombogenic gelatin sponge (n = 4), balloon occlusion (n = 4), and alcohol injection (n = 8). In order to limit ventricular fibrillation, an antiarrhythmic protocol was implemented, with beta-blockers/amiodarone before and xylocaine infusion during the procedure. Clinical, angiographic, and echographic data were gathered. End points included demonstration of vessel occlusion (TIMI flow grades 0 and 1 on the angiogram), impairment of left ventricular function at 2 weeks after procedure (by echocardiography), and pathologically confirmed myocardial infarction. Results. The best arterial access was determined to be through the right carotid artery. The internal mammary guiding catheter 4-Fr was selected as the optimal device for selective intracoronary injection. Free coils deployed prematurely and tended to prolapse into the aorta. Interlocking coils did not deploy completely and failed to provide reliable results. Gelatin sponge was difficult to handle, adhered to the catheter, and could not be clearly visualized by fluoroscopy. Balloon occlusion yielded inconsistent results. Alcohol injection was the most efficient and reproducible method for inducing myocardial infarction (4 out of 6 animals), the extent of which could be fine-tuned by using a coaxial balloon catheter as a microcatheter (0.52 mm) to achieve a superselective injection of 0.2 mL of alcohol. This approach resulted in a 20% decrease in LVEF and infarcted myocardium was confirmed histologically. Conclusions. By following a stepwise approach, a minimally invasive, effective, and reproducible rabbit model of catheter-induced myocardial infarction has been developed which addresses the limitations of rodent experiments while avoiding the logistical and cost issues associated with large animal models.

Guidelines for experimental models of myocardial ischemia and infarction

“…Extensive protocols providing technical details for performing permanent occlusion MI and reperfused MI in mice and rats are available ( 221 , 222 , 228 , 317 , 327 ). While MI is most commonly performed in rodent models, protocols in other animal models are also available ( 151 , 183 , 218 , 331 ). For mice, the quality of open-chest surgery to induce coronary occlusion directly impacts study outcomes ( 152 , 221 , 222 ).…”

Practical guidelines for rigor and reproducibility in preclinical and clinical studies on cardioprotection

“…So far, mostly New Zealand white rabbits have been used in myocardial infarction studies [ 15 , 17 , 18 , 128 , 218 , 223 , 244 ] although Japanese white rabbits have also been occasionally used [ 143 ]. New Zealand white rabbits are less aggressive in nature and have less health problems than other breeds [ 296 ].…”

“…For this reason, male rabbits are usually taken for initial studies. Mostly, young adult rabbits are used weighing 3.0–5.0 kg [ 223 , 244 ].…”

A novel method of standardized myocardial infarction in aged rabbits

“…Experience with coronary angiography reveals that these vessels vary greatly in length and diameter between hearts. As the literature suggests, targeting one specific vessel, whether it be LAD or LCX, leads to highly unpredictable infarctions (8). We have identified no ischemia or infarct studies to date that have accounted for the complexity of coronary anatomy, and no surgical solution has directly addressed this problem.…”

“…We have observed right coronary dominance in both young and aged rabbits as well as quadrifurcation of the LM in aged rabbits. Thus, coronary variability makes the one-size-fits-all infarct methodology susceptible to unpredictable outcomes (8).…”