Arrhythmogenic mechanisms of acute obstructive respiratory events in a porcine model of drug-induced Long-QT
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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.
|Publication status||E-pub ahead of print - 13 Mar 2021|