Arrhythmogenic mechanisms of acute obstructive respiratory events in a porcine model of drug-induced Long-QT
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Arrhythmogenic mechanisms of acute obstructive respiratory events in a porcine model of drug-induced Long-QT. / Linz, Benedikt; Sattler, Stefan Michael; Flethoj, Mette; Høtbjerg Hansen, Malthe Emil; Hesselkilde, Eva Melis; Saljic, Arnela; Wirth, Klaus; Linz, Dominik; Tfelt-Hansen, Jacob; Jespersen, Thomas.
In: Heart Rhythm, Vol. 18, No. 8, 2021, p. 1384-1391.Research output: Contribution to journal › Journal article › Research › peer-review
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TY - JOUR
T1 - Arrhythmogenic mechanisms of acute obstructive respiratory events in a porcine model of drug-induced Long-QT
AU - Linz, Benedikt
AU - Sattler, Stefan Michael
AU - Flethoj, Mette
AU - Høtbjerg Hansen, Malthe Emil
AU - Hesselkilde, Eva Melis
AU - Saljic, Arnela
AU - Wirth, Klaus
AU - Linz, Dominik
AU - Tfelt-Hansen, Jacob
AU - Jespersen, Thomas
N1 - Copyright © 2021. Published by Elsevier Inc.
PY - 2021
Y1 - 2021
N2 - 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.
AB - 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.
U2 - 10.1016/j.hrthm.2021.03.017
DO - 10.1016/j.hrthm.2021.03.017
M3 - Journal article
C2 - 33722764
VL - 18
SP - 1384
EP - 1391
JO - Heart Rhythm
JF - Heart Rhythm
SN - 1547-5271
IS - 8
ER -
ID: 258441624