Current Status and Limitations of Myocardial Infarction Large Animal Models in Cardiovascular Translational Research

Abstract

Establishing an appropriate disease model that mimics the complexities of human cardiovascular disease is critical for evaluating the clinical efficacy and translation success. The multifaceted and complex nature of human ischemic heart disease is difficult to recapitulate in animal models. This difficulty is often compounded by the methodological biases introduced in animal studies. Considerable variations across animal species, modifications made in surgical procedures, and inadequate randomization, sample size calculation, blinding, and heterogeneity of animal models used often produce preclinical cardiovascular research that looks promising but is irreproducible and not translatable. Moreover, many published papers are not transparent enough for other investigators to verify the feasibility of the studies and the therapeutics’ efficacy. Unfortunately, successful translation of these innovative therapies in such a closed and biased research is difficult. This review discusses some challenges in current preclinical myocardial infarction research, focusing on the following three major inhibitors for its successful translation: Inappropriate disease model, frequent modifications to surgical procedures, and insufficient reporting transparency.

Comparison of Swine and Human Computational Hemodynamics Models for the Study of Coronary Atherosclerosis

“…Swine models have contributed to a deeper understanding of the natural history of coronary atherosclerosis, with a valuable application to multiple research fields, such as the study of novel clinical treatment procedures efficacy (Getz and Reardon, 2012;Daugherty et al, 2017;Shin et al, 2021). The translation of results obtained in swine models to the patient situation is mainly based on intra-species comparisons of the coronary anatomy (Weaver et al, 1986;Lelovas et al, 2014), pathophysiology (Lelovas et al, 2014;Shim et al, 2016), cholesterol levels (Mahley et al, 1975) and sites of lesion formation (Shim et al, 2016).…”

“…For this reason, several large animal models based on the use of rabbits, pigs, or non-human primates, have been adopted to e.g. : 1) study coronary atherosclerosis natural history (Getz and Reardon, 2012;Daugherty et al, 2017); 2) evaluate the efficacy of clinical treatment procedures (Shin et al, 2021); 3) identify predictive tools for the evolution of the disease, which most of the time is asymptomatic (De Nisco et al, 2020;Hoogendoorn et al, 2020;Mazzi et al, 2021). Most of the animal model-based studies on atherosclerosis onset and progression imply that their findings reliably inform human studies, sometimes suggesting a direct translation to humans.…”

“…In relation to coronary atherosclerotic disease, the capability of an animal model to mimic the complexity of the human coronary pathophysiology plays a critical role (Daugherty et al, 2017;Shin et al, 2021). In this regard, due to their similarities to humans in terms of anatomy (i.e., size and distribution) (Weaver et al, 1986;Lelovas et al, 2014), pathophysiology (Lelovas et al, 2014;Shim et al, 2016), lipoprotein profile (Mahley et al, 1975), and site of lesion formation (Shim et al, 2016), swine models are massively applied to study coronary atherosclerosis (Xiangdong et al, 2011;Daugherty et al, 2017).…”

Therapeutic hypothermia for acute myocardial infarction: a narrative review of evidence from animal and clinical studies

“…There are several animal models of MI that include small animals such as rodents, or large animals such as swine and sheep. The pig model is an attractive choice given its similarity to humans in terms of cardiac circulatory anatomy and cardiac contraction relaxation kinetics, and cardiac output [ 41 ]. In pigs, the left coronary artery is larger and longer than the right coronary artery, as in humans.…”

GSDMD contributes to myocardial reperfusion injury by regulating pyroptosis

“…Multiple studies have demonstrated that the inflammatory response, calcium overload and oxidative stress are involved in this complex and dynamic process and induce various modes of cardiomyocyte death ( 2 , 4 , 5 ). However, due to various reasons, such as the significant differences between animal models and AMI patients, many effective therapeutic strategies in the laboratory have been proved limited in clinical efficacy ( 5 – 10 ). Therefore, the underlying mechanisms and new effective therapeutic strategies are urgent to be explored.…”