Cellular Mechanism Underlying Hypothermia-Induced Ventricular Tachycardia/Ventricular Fibrillation in the Setting of Early Repolarization and the Protective Effect of Quinidine, Cilostazol, and Milrinone

Abstract

Background Hypothermia has been reported to induce ventricular tachycardia and fibrillation (VT/VF) in patients with early repolarization (ER) pattern. This study examines the cellular mechanisms underlying VT/VF associated with hypothermia in an experimental model of ER syndrome (ERS) and examines the effectiveness of quinidine, cilostazol and milrinone to prevent hypothermia-induced arrhythmias. Method and Results Transmembrane action potentials (AP) were simultaneously recorded from 2 epicardial and 1 endocardial site of coronary-perfused canine left-ventricular wedge preparations, together with a pseudo-ECG. A combination of NS5806 (3–10 µM) and verapamil (1µM) was used to pharmacologically model the genetic mutations responsible for ERS. Acetylcholine (3µM) was used to simulate increased parasympathetic tone, which is known to promote ER. In control, lowering the temperature of the coronary perfusate to induce mild hypothermia (32°C-34°C) resulted in increased J wave area on the ECG and accentuated epicardial AP notch but no arrhythmic activity. In the setting of ER, hypothermia caused further accentuation of the epicardial AP notch, leading to loss of the AP dome at some sites but not others, thus creating the substrate for development of phase-2-reentry and VT/VF. Addition of the Ito antagonist quinidine (5 µM) or the phosphodiesterase III inhibitors cilostazol (10 µM) or milrinone (5 µM), diminished the ER manifestations and prevented the hypothermia-induced phase 2 reentry and VT/VF. Conclusions Hypothermia leads to VT/VF in the setting of ER by exaggerating repolarization abnormalities, leading to development of phase-2-reentry. Quinidine, cilostazol and milrinone suppress the hypothermia-induced VT/VF by reversing the repolarization abnormalities.

Brugada Syndrome: Clinical, Genetic, Molecular, Cellular, and Ionic Aspects

“…161, 168, 215, 216 Interestingly, a recent experimental study suggests that quinidine exerts a protective effect against hypothermia-induced VT/VF in a J wave syndrome model. 217 …”

A Randomized Comparison Study Assessing the Impact of Cilostazol on the Heart Rate and Arrhythmias by 24-Hour Ambulatory Holter Electrocardiographic Monitoring after Drug-Eluting Stent Implantation for Coronary Artery Disease

“…It remains unclear whether the risk of the positive chronotropic effects of cilostazol may outisoform of the enzyme, which is selectively localized in the microsomal fraction 39) . Moreover, some studies have shown that cilostazol had anti-arrhythmogenic 40,41) or therapeutic neutrality in arrythmias 42) . Additionally, cilostazol was reported to prevent episodes of VF 43) or failed to prevent them in Brugada patients 44) .…”

Accidental hypothermia-induced electrical storm successfully treated with isoproterenol

“…6 In the patient with hypothermia, the prominent J wave is induced as the result of a marked accentuation of epicardial AP, probably due to the effect of cold temperatures, which slow the activation kinetic of I to to less than that of the I Ca current. 6,7 Loss of the AP duration usually is heterogeneous, resulting in marked abbreviation of the AP at some sites but not others. The AP dome of cells with relatively intact morphologies propagates to adjacent, rapidly repolarized cells to produce phase 2 reentry.…”