Reperfusion-induced sustained ventricular tachycardia, leading to ventricular fibrillation, in chronically instrumented, intact, conscious mice

Abstract

Reperfusion-induced lethal ventricular arrhythmias are observed during relief of coronary artery spasm, with unstable angina, exercise-induced ischemia, and silent ischemia. Accordingly, significant efforts are underway to understand the mechanisms responsible for reperfusion-induced lethal arrhythmias and mice have become increasingly important in these efforts. However, although reperfusion-induced sustained ventricular tachycardia leading to ventricular fibrillation (VF) has been recorded in many models, reports in mice are sparse and of limited success. Importantly, none of these studies were conducted in intact, conscious mice. Accordingly, a chronically instrumented, intact, conscious murine model of reperfusion-induced lethal arrhythmias has the potential to be of major importance for advancing the concepts and methods that drive cardiovascular therapies. Therefore, we describe, for the first time, the use of an intact, conscious, murine model of reperfusion-induced lethal arrhythmias. Male mice (n = 9) were instrumented to record cardiac output and the electrocardiogram. In addition, a snare was placed around the left main coronary artery. Following recovery, the susceptibility to sustained ventricular tachycardia produced by 3 min of occlusion and reperfusion of the left main coronary artery was determined in conscious mice by pulling on the snare. Reperfusion culminated in sustained ventricular tachycardia, leading to VF, in all nine conscious mice. The procedures conducted in conscious C57BL/6J mice, a strain commonly used in transgenic studies, can be utilized in genetically modified models to enhance our understanding of single gene defects on reperfusion-induced lethal ventricular arrhythmias in intact, conscious, and complex animals.

Keywords: arrhythmia; murine model; reperfusion injury.

Figure 1.

One second original recordings of cardiac output (A) and the electrocardiogram (ECG; B) before occlusion of the left main coronary artery (control), at 3 min of occlusion, and during reperfusion in an intact conscious mouse. In this mouse, reperfusion elicited sustained ventricular tachycardia (VT) within 15.35 sec.

Figure 2.

Five seconds original recordings of cardiac output (A) and the electrocardiogram (ECG; B) during the reperfusion period in an intact, conscious, male mouse. The dotted line indicates the onset of sustained ventricular tachycardia. In this mouse, reperfusion elicited sustained ventricular tachycardia within 14.65 sec.

Figure 3.

Cardiac output (A) and heart rate (B) during weeks 1, 2, and 3 before occlusion (control) of the left main coronary artery, during minutes 1, 2, and 3 of occlusion and following 30 min of reperfusion in intact conscious mice. P < 0.05, control versus during occlusion.

Figure 4.

Photomicrographs of ventricular sections from one chronically instrumented mouse heart. The only collagen (i.e., blue stain, documenting tissue injury) shows placement of the coronary artery occluder. Thus, little tissue damage occurs during the ischemia; however, life threatening arrhythmias occurred during reperfusion.