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

B. Linz; S.M. Sattler; M. Flethoj; M.E.H. Hansen; E.M. Hesselkilde; A. Saljic; K. Wirth; D. Linz; J. Tfelt-Hansen; T. Jespersen

doi:10.1016/j.hrthm.2021.03.017

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

B. Linz^*, S.M. Sattler, M. Flethoj, M.E.H. Hansen, E.M. Hesselkilde, A. Saljic, K. Wirth, D. Linz^*, J. Tfelt-Hansen, T. Jespersen

^*Corresponding author for this work

Research output: Contribution to journal › Article › Academic › peer-review

Abstract

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.

Original language	English
Pages (from-to)	1384-1391
Number of pages	8
Journal	Heart Rhythm
Volume	18
Issue number	8
DOIs	https://doi.org/10.1016/j.hrthm.2021.03.017
Publication status	Published - 1 Aug 2021

Keywords

Arrhythmia
Electromechanical coupling
Long QT
Obstructive sleep apnea
Sudden cardiac death
POSITIVE AIRWAY PRESSURE
SLEEP-APNEA
ATRIAL-FIBRILLATION
ELECTROMECHANICAL WINDOW
CARDIAC REPOLARIZATION
MUELLER MANEUVER
CPAP ADHERENCE
RISK
INTERVAL
DEATH

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10.1016/j.hrthm.2021.03.017

Cite this

@article{5b45194ebbc149f09f2cf6a029f16051,

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

abstract = "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.",

keywords = "Arrhythmia, Electromechanical coupling, Long QT, Obstructive sleep apnea, Sudden cardiac death, POSITIVE AIRWAY PRESSURE, SLEEP-APNEA, ATRIAL-FIBRILLATION, ELECTROMECHANICAL WINDOW, CARDIAC REPOLARIZATION, MUELLER MANEUVER, CPAP ADHERENCE, RISK, INTERVAL, DEATH",

author = "B. Linz and S.M. Sattler and M. Flethoj and M.E.H. Hansen and E.M. Hesselkilde and A. Saljic and K. Wirth and D. Linz and J. Tfelt-Hansen and T. Jespersen",

year = "2021",

month = aug,

day = "1",

doi = "10.1016/j.hrthm.2021.03.017",

language = "English",

volume = "18",

pages = "1384--1391",

journal = "Heart Rhythm",

issn = "1547-5271",

publisher = "Elsevier Science",

number = "8",

}

TY - JOUR

T1 - Arrhythmogenic mechanisms of acute obstructive respiratory events in a porcine model of drug-induced long QT

AU - Linz, B.

AU - Sattler, S.M.

AU - Flethoj, M.

AU - Hansen, M.E.H.

AU - Hesselkilde, E.M.

AU - Saljic, A.

AU - Wirth, K.

AU - Linz, D.

AU - Tfelt-Hansen, J.

AU - Jespersen, T.

PY - 2021/8/1

Y1 - 2021/8/1

N2 - 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.

AB - 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.

KW - Arrhythmia

KW - Electromechanical coupling

KW - Long QT

KW - Obstructive sleep apnea

KW - Sudden cardiac death

KW - POSITIVE AIRWAY PRESSURE

KW - SLEEP-APNEA

KW - ATRIAL-FIBRILLATION

KW - ELECTROMECHANICAL WINDOW

KW - CARDIAC REPOLARIZATION

KW - MUELLER MANEUVER

KW - CPAP ADHERENCE

KW - RISK

KW - INTERVAL

KW - DEATH

U2 - 10.1016/j.hrthm.2021.03.017

DO - 10.1016/j.hrthm.2021.03.017

M3 - Article

C2 - 33722764

SN - 1547-5271

VL - 18

SP - 1384

EP - 1391

JO - Heart Rhythm

JF - Heart Rhythm

IS - 8

ER -