Effect of Amiodarone and Hypothermia on Arrhythmia Substrates During Resuscitation.

Background Amiodarone is administered during resuscitation, but its antiarrhythmic effects during targeted temperature management are unknown. The purpose of this study was to determine the effect of both therapeutic hypothermia and amiodarone on arrhythmia substrates during resuscitation from cardiac arrest. Methods and Results We utilized 2 complementary models: (1) In vitro no-flow global ischemia canine left ventricular transmural wedge preparation. Wedges at different temperatures (36°C or 32°C) were given 5 µmol/L amiodarone (36-Amio or 32-Amio, each n=8) and subsequently underwent ischemia and reperfusion. Results were compared with previous controls. Optical mapping was used to measure action potential duration, dispersion of repolarization (DOR), and conduction velocity (CV). (2) In vivo pig model of resuscitation. Pigs (control or targeted temperature management, 32-34°C) underwent ischemic cardiac arrest and were administered amiodarone (or not) after 8 minutes of ventricular fibrillation. In vitro: therapeutic hypothermia but not amiodarone prolonged action potential duration. During ischemia, DOR increased in the 32-Amio group versus 32-Alone (84±7 ms versus 40±7 ms, P<0.05) while CV slowed in the 32-Amio group. Amiodarone did not affect CV, DOR, or action potential duration during ischemia at 36°C. Conduction block was only observed at 36°C (5/8 36-Amio versus 6/7 36-Alone, 0/8 32-Amio, versus 0/7 32-Alone). In vivo: QTc decreased upon reperfusion from ischemia that was ameliorated by targeted temperature management. Amiodarone did not worsen DOR or CV. Amiodarone suppressed rearrest caused by ventricular fibrillation (7/8 without amiodarone, 2/7 with amiodarone, P=0.041), but not pulseless electrical activity (2/8 without amiodarone, 5/7 with amiodarone, P=0.13). Conclusions Although amiodarone abolishes a beneficial effect of therapeutic hypothermia on ischemia-induced DOR and CV, it did not worsen susceptibility to ventricular tachycardia/ventricular fibrillation during resuscitation.

S-phase Synchronization Facilitates the Early Progression of Induced-Cardiomyocyte Reprogramming through Enhanced Cell-Cycle Exit.

Direct reprogramming of fibroblasts into induced cardiomyocytes (iCMs) holds a great promise for regenerative medicine and has been studied in several major directions. However, cell-cycle regulation, a fundamental biological process, has not been investigated during iCM-reprogramming. Here, our time-lapse imaging on iCMs, reprogrammed by Gata4, Mef2c, and Tbx5 (GMT) monocistronic retroviruses, revealed that iCM-reprogramming was majorly initiated at late-G1- or S-phase and nearly half of GMT-reprogrammed iCMs divided soon after reprogramming. iCMs exited cell cycle along the process of reprogramming with decreased percentage of 5-ethynyl-20-deoxyuridine (EdU)⁺/α-myosin heavy chain (αMHC)-GFP⁺ cells. S-phase synchronization post-GMT-infection could enhance cell-cycle exit of reprogrammed iCMs and yield more GFPhigh iCMs, which achieved an advanced reprogramming with more expression of cardiac genes than GFPlow cells. However, S-phase synchronization did not enhance the reprogramming with a polycistronic-viral vector, in which cell-cycle exit had been accelerated. In conclusion, post-infection synchronization of S-phase facilitated the early progression of GMT-reprogramming through a mechanism of enhanced cell-cycle exit.

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

BACKGROUND: We 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 RESULTS: Anesthetized 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.

KChIP2 is a core transcriptional regulator of cardiac excitability.

Arrhythmogenesis from aberrant electrical remodeling is a primary cause of death among patients with heart disease. Amongst a multitude of remodeling events, reduced expression of the ion channel subunit KChIP2 is consistently observed in numerous cardiac pathologies. However, it remains unknown if KChIP2 loss is merely a symptom or involved in disease development. Using rat and human derived cardiomyocytes, we identify a previously unobserved transcriptional capacity for cardiac KChIP2 critical in maintaining electrical stability. Through interaction with genetic elements, KChIP2 transcriptionally repressed the miRNAs miR-34b and miR-34c, which subsequently targeted key depolarizing (INa) and repolarizing (Ito) currents altered in cardiac disease. Genetically maintaining KChIP2 expression or inhibiting miR-34 under pathologic conditions restored channel function and moreover, prevented the incidence of reentrant arrhythmias. This identifies the KChIP2/miR-34 axis as a central regulator in developing electrical dysfunction and reveals miR-34 as a therapeutic target for treating arrhythmogenesis in heart disease.