Ventricular Arrhythmias in First Acute Myocardial Infarction: Epidemiology, Mechanisms, and Interventions in Large Animal Models

Abstract

Ventricular arrhythmia and subsequent sudden cardiac death (SCD) due to acute myocardial infarction (AMI) is one of the most frequent causes of death in humans. Lethal ventricular arrhythmias like ventricular fibrillation (VF) prior to hospitalization have been reported to occur in more than 10% of all AMI cases and survival in these patients is poor. Identification of risk factors and mechanisms for VF following AMI as well as implementing new risk stratification models and therapeutic approaches is therefore an important step to reduce mortality in people with high cardiovascular risk. Studying spontaneous VF following AMI in humans is challenging as it often occurs unexpectedly in a low risk subgroup. Large animal models of AMI can help to bridge this knowledge gap and are utilized to investigate occurrence of arrhythmias, involved mechanisms and therapeutic options. Comparable anatomy and physiology allow for this translational approach. Through experimental focus, using state-of-the-art technologies, including refined electrical mapping equipment and novel pharmacological investigations, valuable insights into arrhythmia mechanisms and possible interventions for arrhythmia-induced SCD during the early phase of AMI are now beginning to emerge. This review describes large experimental animal models of AMI with focus on first AMI-associated ventricular arrhythmias. In this context, epidemiology of first AMI, arrhythmogenic mechanisms and various potential therapeutic pharmacological targets will be discussed.

Development and Long-Term Follow-Up of an Experimental Model of Myocardial Infarction in Rabbits

“…The inducibility of ventricular arrhythmias has been studied in the chronic phase of infarction [ 50 , 51 , 52 ], a phase in which dead cardiomyocytes are replaced by collagen, leading to scar formation. This scar acts as an inexcitable anatomic obstacle that can impair the normal progression of the excitation process and increase electrophysiological heterogeneity, thus favoring the appearance of arrhythmias [ 8 , 53 ]. The increase in electrophysiological heterogeneity with the appearance of conduction blocks and the spatial dispersion of repolarization promotes the appearance of reentry processes and arrhythmias caused by this mechanism [ 54 ].…”

“…The acute phase of myocardial infarction is characterized by great instability that results in episodes of VF and sudden death in patients. Factors, such as the extent of the ischemic area, the characteristics of collateral flow, the speed of the establishment of the coronary irrigation deficit, the activity of the autonomic nervous system, and the presence of the reperfusion phenomenon, play a role [8,18]. In chronic models of myocardial damage due to ischemia/reperfusion, there are other factors, including the structural alterations inherent to the healing process, that determine the characteristics of the substrate that facilitates the appearance of certain arrhythmias, such as VT and/or VF.…”

“…Cardiovascular disease, especially ischemic heart disease, is the leading cause of death nowadays [ 1 , 2 , 3 , 4 , 5 ], and global medium-term projections still consider ischemic heart disease as the most frequent [ 6 ]. Basic research and its transfer to the clinic are necessary to deepen the knowledge on the causes and mechanisms involved, as well as in the development and improvement of preventive, diagnostic, and therapeutic procedures to detect the disease in the preclinical stages, prevent its manifestations, and/or reduce the adverse effects [ 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 ].…”

“…The use of animal models to study ischemic heart disease and, more specifically, the phenomena that characterize the processes of myocardial ischemia and reperfusion has provided a wide range of information. This information covers the molecular mechanisms and signaling pathways involved in the development of myocardial damage to the local and general regulatory mechanisms that can be modified to protect and limit the adverse consequences of the disease, including remodeling, ventricular dysfunction, cardiac arrhythmias, and sudden death [ 7 , 8 , 10 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 ]. Sudden cardiac death is a major public health problem.…”

“…Therefore, it is of interest to investigate the mechanisms implicated in its occurrence, which, in most cases, are related to the induction of malignant ventricular arrhythmias, such as ventricular tachycardia (VT) or fibrillation (VF). With respect to the analysis of the arrhythmogenic mechanisms occurring in ischemic heart disease, experimental studies can closely mimic the main characteristics of the human pathology [ 8 ]. Experimental models have also provided valid information on the meaning, usefulness, and applications of various diagnostic and therapeutic techniques, including those based on cardiac imaging, recording of electrophysiological activity, and coronary intervention [ 13 , 15 , 26 ], which are all techniques that can improve patient care when used in clinical practice.…”