Hypothermia Modulates Arrhythmia Substrates During Different Phases of Resuscitation From Ischemic Cardiac Arrest

Abstract

BackgroundWe designed an innovative porcine model of ischemia‐induced arrest to determine dynamic arrhythmia substrates during focal infarct, global ischemia from ventricular tachycardia or fibrillation (VT/VF) and then reperfusion to determine the effect of therapeutic hypothermia (TH) on dynamic arrhythmia substrates and resuscitation outcomes.Methods and ResultsAnesthetized adult pigs underwent thoracotomy and regional plunge electrode placement in the left ventricle. Subjects were then maintained at either control (CT; 37°C, n=9) or TH (33°C, n=8). The left anterior descending artery (LAD) was occluded and ventricular fibrillation occurred spontaneously or was induced after 30 minutes. Advanced cardiac life support was started after 8 minutes, and LAD reperfusion occurred 60 minutes after occlusion. Incidences of VF/VT and survival were compared with ventricular ectopy, cardiac alternans, global dispersion of repolarization during LAD occlusion, and LAD reperfusion. There was no difference in incidence of VT/VF between groups during LAD occlusion (44% in CT versus 50% in TH; P=1s). During LAD occlusion, ectopy was increased in CT and suppressed in TH (33±11 ventricular ectopic beats/min versus 4±6 ventricular ectopic beats/min; P=0.009). Global dispersion of repolarization and cardiac alternans were similar between groups. During LAD reperfusion, TH doubled the incidence of cardiac alternans compared with CT, with a marked increase in VF/VT (100% in TH versus 17% in CT; P=0.004). Ectopy and global dispersion of repolarization were similar between groups during LAD reperfusion.Conclusions TH alters arrhythmia substrates in a porcine translational model of resuscitation from ischemic cardiac arrest during the complex phases of resuscitation. TH worsens cardiac alternans, which was associated with an increase in spontaneous VT/VF during reperfusion.

New Concepts in Sudden Cardiac Arrest to Address an Intractable Epidemic

“…Targeted temperature management (TTM; therapeutic hypothermia) may reduce damage to the central nervous system as tracked by biomarkers(34), and also reduce metabolic demands or arrhythmias(35). Nevertheless, the role of TTM is under discussion(36) as it has been linked to events such as coronary (stent) thrombosis(37).…”

Translational Models of Arrhythmia Mechanisms and Susceptibility: Success and Challenges of Modeling Human Disease

“…These phases have distinct electrophysiological properties that are not accounted for by current ACLS protocols, and the interplay of arrhythmia substrates and susceptibilities during each phase is unknown. All these phases can be incorporated into a large animal porcine model (22). In vivo porcine models have provided important results on resuscitation approaches and outcomes, although mechanistic information on arrhythmia formation and maintenance is less well-understood (49, 50, 53, 54).…”

“…We recently reported that in a porcine translational model of ischemia-induced SCA that arrhythmia substrates were in fact dynamic during different phases of resuscitation that they were modified by therapeutic hypothermia. In addition, cardiac alternans was an important mechanism of recurrent VF during resuscitation (22). Regarding species specific models of cardiopulmonary resuscitation, the advantages of transmural and regional ion currents, more human like conduction system and lower susceptibility to VF in dog vs. pig is a consideration when evaluating outcomes or therapies (11, 14).…”

“…Models of acute ischemia/reperfusion and MI (3) have been adapted to more chronic models of ischemic cardiomyopathy, with and without acute ischemia (18, 19). Important arrhythmogenic conditions closely related to MI include models of resuscitation from SCD secondary to ischemia and exercise induced VT/VF (20–22). As many as 50% of patients with HF die of arrhythmogenic SCD, so significant effort has been made to model human HF and determine arrhythmia mechanisms in other structural heart diseases, such as isolated hypertrophy (23).…”

Development and Evaluation of a Novel Mouse Model of Asphyxial Cardiac Arrest Revealed Severely Impaired Lymphopoiesis After Resuscitation

“…For example, such studies have shed considerable light on how therapeutic hypothermia affects various aspects of the organ response to CA, including the heart, brain, and immune system. 3 , 4 , 5 , 6 , 7 However, pig and rat models have critical limitations, which include difficulties in genetically modulating specific genes or pathways to perform detailed mechanistic studies. Consequently, mouse models have been increasingly used in experimental CA research.…”