A Minimally-Invasive Method for the Induction of Permanent Myocardial Infarction in Mice: A Novel Approach

Abstract

Approximately 25% of patients suffering from acute myocardial infarction (MI) develop heart failure, with a survival rate of only 50% beyond five years, primarily due to adverse remodeling of the left ventricle. The mechanisms driving the progression to heart failure remain poorly understood. To address this, preclinical models of MI have been developed globally to better comprehend the disease’s prognosis and to explore potential therapeutic interventions. However, these models rely on the open-chest thoracotomy technique, which exposes the heart for 25 to 30 minutes, increasing the risks of bleeding, infection, larger wound size, pericardial rupture, and aggressive ligation of the left anterior descending (LAD) coronary artery using a 7-0 curved needle, damaging surrounding tissues. Despite various strategies to minimize thoracotomy size, reduce bleeding, and improve outcomes, variability across animal models remains significant. Advances in biomedical technology, enable the induction of MI in a more minimally invasive manner. The aim of this study is to establish a minimally-invasive technique able to induce MI, to validate its efficacy by conducting a comparative analysis against the standard invasive MI model, and to demonstrate that the minimally-invasive technique is able to induce MI with varying sizes. Our study used echocardiography and Doppler imaging, capable of visualizing and precisely locking onto the LAD artery at more than 250 frames per second (fps) for real-time observation in a stable position coupled to an electrocauterization needle that is able to occlude the LAD in seconds (in plane needle guidance to the LAD). Cardiac parameter analysis demonstrated a significant reduction in Ejection Fraction (EF), and echocardiographic assessment of the left ventricle (LV) revealed akinesia of the anterior wall, confirming successful occlusion of the left anterior descending artery (LAD). Additionally, hemodynamic parameters, including left ventricular end-systolic volume (LVESV) and left ventricular end-systolic diameter (LVESD), exhibited marked increase following MI. These findings were consistent with some of results observed in the invasive MI model. Histological analysis further indicated an increase in infarct size and collagen deposition in both the novel and invasive MI models. Notably, the pericardium remained intact in the minimally-invasive technique, whereas it was disrupted in the invasive model. The minimally-invasive model demonstrated its capability to induce varying MI sizes by using pulse wave (PW) Doppler velocity to LAD artery occlusion. Our findings indicate that occlusion of the LAD at regions with higher blood flow results in larger MI, as evidenced by a significant reduction EF, with similar correlations observed for other MI sizes. In conclusion, our minimally-invasive myocardial infarction model offers a superior alternative to the invasive MI model for adoption in research laboratories globally. This approach provides higher translational relevance to clinical settings, demonstrating improved efficiency, reproducibility, and the ability to induce well-controlled MI sizes. Adopting this novel minimally invasive model may therefore enhance the accuracy and applicability of preclinical research, bridging the gap between experimental outcomes and clinical translation