Arrhythmogenic mechanisms of acute obstructive respiratory events in a porcine model of drug-induced long QT.

Abstract Background Obstructive sleep apnea (OSA) is associated with increased risk of sudden cardiac death. Objective In pigs, we aimed to elucidate changes in ventricular repolarization and electromechanical interaction during obstructive respiratory events simulated by intermittent negative upper airway pressure (INAP). Moreover, we investigated the effect of a reduced repolarization reserve in drug-induced Long-QT (LQT) following INAP induced changes in ventricular repolarization. Methods In sedated spontaneously breathing pigs, 75 seconds of INAP were applied by a negative pressure device connected to the endotracheal tube. Ventricular electromechanical coupling was determined by the electromechanical window (EMW) before (Pre-INAP), during (INAP) and after INAP (Post-INAP). Incidence rates of premature ventricular contractions (PVC) were measured respectively. Moreover, a drug-induced LQT was modelled by treating the pigs with the hERG1 blocker dofetilide (DOF). Results While QT-interval increased during and decreased after INAP (Pre-INAP: 273±5ms; INAP: 281±6ms; Post-INAP: 254±9ms), EMW shortened progressively throughout INAP and Post-INAP periods (Pre-INAP: 81±4ms; Post-INAP: 44±7ms). DOF shortened EMW at baseline. Throughout INAP, EMW decreased in a comparable fashion as prior to DOF (Pre-INAP/+DOF: 61±7ms; Post-INAP/+DOF: 14±9ms), yet resulting in shorter absolute EMW-levels. Short EMW-levels were associated with increased occurrence of PVCs (Pre-INAP 7±2ms vs. Post-INAP 26±6ms; p=0.02), which were potentiated in DOF-pigs (Pre-INAP/+DOF 5±2ms vs. Post-INAP/+DOF 40±8ms; p=0.006). Administration of atenolol prevented Post-INAP EMW-shortening and decreased occurrence of PVCs. Conclusion Transient dissociation of ventricular electromechanical coupling during simulated obstructive respiratory events creates a dynamic ventricular arrhythmogenic substrate, which is sympathetically mediated and aggravated by drug-induced LQT.