Animal models of lethal arrhythmias

Abstract

Sudden cardiac death resulting from ventricular tachyarrhythmias remains the leading cause of death in industrially developed countries, accounting for between 300,000 and 500,000 deaths each year in the United States. Yet, despite the enormity of this problem, the development of safe and effective antiarrhythmic agents remains elusive. Indeed, several class I (encainide and flecainide) and class III (dsotalol) drugs have actually been shown to increase, rather than decrease, the risk of arrhythmic death in patients recovering from myocardial infarction. The identification of effective antiarrhythmic agents is critically dependent on the use of appropriate animal models of human disease. In particular, myocardial ischemia may be an important determinant for the development of the life-threatening ventricular arrhythmias. For example, preclinical studies demonstrate that many drugs that prevent arrhythmias induced by programmed electrical stimulation fail to prevent ventricular fibrillation provoked by ischemia in the same animals. Thus, one would predict that animal models in which lethal arrhythmias are induced by myocardial ischemia would be the most effective tools for the identification of potential antiarrhythmic medications. This review first evaluates several animal models of lethal ventricular arrhythmias with particular emphasis placed on canine models. Then it closes with a brief discussion of ATP-sensitive potassium-channel antagonists as an example of antiarrhythmic drugs that may act selectively on the ischemic myocardium. Drug Dev. Res. 55:59-72, 2002.

Effects of a Novel Cardioselective ATP-Sensitive Potassium Channel Antagonist, 1-[[5-[2-(5-Chloro-o-anisamido)ethyl]-β-methoxyethoxyphenyl]sulfonyl]-3-methylthiourea, Sodium Salt (HMR 1402), on Susceptibility to Ventricular Fibrillation Induced by Myocardial Ischemia: In Vitro and in Vivo Studies

“…In the present study, HMR 1402 significantly reduced the incidence of ventricular fibrillation, protecting seven of eight animals tested. In agreement with these findings, both the nonselective K ATP antagonist glibenclamide and the cardioselective K ATP HMR 1883 protected against ischemically induced malignant arrhythmias (Billman, 2002). However, it is important to emphasize that, in contrast to the actions of either HMR 1402 or HMR 1883, glibenclamide significantly reduced both exercise and reactive hyperemia-induced increases in coronary blood flow, as well …”

Tyrosine Phosphorylation linked to Cardiac Arrhythmias via HCN Pacemaker Channel

“…Previous animal models for studying arrhythmias frequently used (Hynes et al, 2002) aorta bandage to create ischemic condition (Billman, 2002;, (2) fast pacing to induce heart failure (Shinbane et al, 1997;Moe et al, 1998;Kashem et al, 2003;Timek et al, 2003), (3) genetic ablation (Benkusky et al, 2007). Significant progress has been made regarding the underlying mechanisms of a variety of cardiac arrhythmias.…”