Arrhythmogenic Delayed Afterdepolarizations Are Promoted by Severe Hypothermia But Not Therapeutic Hypothermia

Abstract

ryanodine receptor (RyR) dysfunction. 16-18 Given clinical observations of increased ventricular ectopy and irritability during SH, frequent triggered arrhythmias would be predicted. 10,19,20 Moreover, although repolarization abnormalities induced by hypothermia are known to promote substrates for re-entrant VF, 21 the effect of hypothermia on VF triggers is poorly understood.Despite the contrast in arrhythmia susceptibility associated with TH vs. SH, there have been very few systematic studies that have investigated the underlying arrhythmia mechanisms. Existing data on the effect of hypothermia on Ca dysregulation and triggered activity is difficult to interpret because many studies have been performed at temperatures even colder than those observed during SH (e.g., room temperature) and in varied species. 22,23 Moreover, the effect of hypothermia on cellular Ca regulation is complex, such that the net impact on susceptibility to arrhythmias is difficult to predict. Therefore, we aimed to investigate the effects of clinically relevant temperatures on Ca dysregulation and triggered arrhythmias in a single animal model at the tissue, cellular and subcellular level. We hypothesized T herapeutic hypothermia (TH) improves neurologic outcomes and survival in patients with return of spontaneous circulation (ROSC) after cardiac arrest. 1,2 Current cardiopulmonary resuscitation guidelines recommend that all comatose patients with ROSC should be cooled to have temperature maintained between 32 and 36°C for 24 h. 3-6 In addition to improving neurological outcomes, several recent experimental and clinical studies 7-9 suggest that TH decreases infarct size in acute myocardial infarction. Importantly, the incidence of lethal arrhythmias in post-resuscitated patients treated with TH is relatively low, 1,4,10 suggesting that temperatures used in clinical TH may be antiarrhythmic, although this is controversial. 11- 13 Unlike TH, severe hypothermia (SH, less than 30°C), is well known to be pro-arrhythmic. Arrhythmias in patients with accidental SH are common and include ventricular fibrillation (VF), which can be refractory to standard therapy. 14,15 Experimental studies have shown that hypothermia causes dysregulation of cellular calcium (Ca), which has been associated with intracellular Ca overload and Background: Severe hypothermia (SH) is known to be arrhythmogenic, but the effect of therapeutic hypothermia (TH) on arrhythmias is unclear. It is hypothesized that susceptibility to Ca-mediated arrhythmia triggers would be increased only by SH.

Therapy-Resistant Ventricular Arrhythmias Developed More Often in Advanced Than in Therapeutic Mild Hypothermic Condition

“…Fukaya, et al reported in their canine experimental model that calcium-mediated premature beats which triggered VF increased in advanced hypothermic conditions. 25) The mechanisms of triggered premature beats and maintenance of hypothermic VA could not be studied in this study. Third, using a small number of electrodes placed in the wedge preparation may underestimate the change in the myocardial depolarization and repolarization during the hypothermic condition.…”

Beneficial Electrophysiological Effects of Rotigaptide Are Unable to Suppress Therapeutic Hypothermia-Provoked Ventricular Fibrillation in Failing Rabbit Hearts With Acute Ischemia–Reperfusion Injury

“…Hypothermia retards the activation and/or inactivation process, leading to ion channel dysfunction. For example, Fukaya et al showed that hypothermia caused Ca i overload and slowing of SR Ca 2+ release kinetics through RyR2 dysfunction in a temperature-dependent manner ( Fukaya et al, 2017 ). Millet et al (2021) reported that hypothermia retarded SERCA2a-mediated Ca 2+ uptake into the SR to facilitate Ca i alternans during tachycardia.…”

Temperature alters the inotropic, chronotropic and proarrhythmic effects of histamine in atrial muscle preparations from humans and H2-receptor overexpressing mice

“…In both cold and hot environments, humans may experience atrial or ventricular arrhythmias such as ventricular fibrillation (Fig. 1 A) (Fukaya et al 2017 ; Mackiewicz and Lewartowski 2006 ; review: Antzelevitch and Yan 2010 ). Histamine may cause atrial and ventricular cardiac arrhythmias, even under normothermia (review: Neumann et al 2021b ).…”