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

BACKGROUND Obstructive sleep apnea is associated with increased risk of sudden cardiac death. OBJECTIVE The purpose of this study was to elucidate changes in ventricular repolarization and electromechanical interaction during obstructive respiratory events simulated by intermittent negative upper airway pressure (INAP) in pigs. We also 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 was applied by a negative pressure device connected to the endotracheal tube. Ventricular electromechanical coupling was determined by the electromechanical window (EMW) before (preINAP), during (INAP), and after INAP (post-INAP). Incidence rates of premature ventricular contractions (PVCs) were measured respectively. A drug-induced LQT was modeled by treating the pigs with the hERG1 Mocker dofetilide (DOE). RESULTS Whereas QT interval increased during and decreased after INAP (pre-INAP: 273 +/- 5 ms; INAP 281 +/- 6 ms; post-INAP 254 +/- 9 ms), EMW shortened progressively throughout INAP and post-INAP periods (pre-INAP 81 +/- 4 ms; post-INAP 44 +/- 7 ms). DOF shortened EMW at baseline. Throughout INAP, EMW decreased in a comparable fashion as before DOF (pre-INAP/+DOF 61 +/- 7 ms; post-INAP/+DOF 14 +/- 9 ms) but resulted in shorter absolute EMW levels. Short EMW levels were associated with increased occurrence of PVCs (pre-INAP 7 +/- 2 ms vs post-INAP 26 +/- 6 ms; P = .02), which were potentiated in DOF pigs (pre-INAP/+DOF 5 +/- 2 ms vs post-INAP/+DOF 40 +/- 8 ms; P = .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.

Automated summary

This study investigated changes in ventricular repolarization and electromechanical coupling during obstructive respiratory events, as well as the impact of drug-induced long QT on these changes. It was found that drug-induced LQT increased the occurrence of premature ventricular contractions during simulated obstructive respiratory events.