Complex Interaction Between Low-Frequency APD Oscillations and Beat-to-Beat APD Variability in Humans Is Governed by the Sympathetic Nervous System.

Stefan Van Duijvenboden,Baldeep Sidhu,Ben Hanson,Jesus Fernandez-Bes,Bradley Porter,Reza Razavi,Jaswinder S Gill,Justin Gould,David Adolfo Sampedro-Puente,Michele Orini,Peter Taggart,Esther Pueyo,Martin J Bishop,Christopher A Rinaldi,Pier Lambiase

doi:10.3389/fphys.2019.01582

Abstract

BackgroundRecent clinical, experimental and modeling studies link oscillations of ventricular repolarization in the low frequency (LF) (approx. 0.1 Hz) to arrhythmogenesis. Sympathetic provocation has been shown to enhance both LF oscillations of action potential duration (APD) and beat-to-beat variability (BVR) in humans. We hypothesized that beta-adrenergic blockade would reduce LF oscillations of APD and BVR of APD in humans and that the two processes might be linked.Methods and ResultsTwelve patients with normal ventricles were studied during routine electrophysiological procedures. Activation-recovery intervals (ARI) as a conventional surrogate for APD were recorded from 10 left and 10 right ventricular endocardial sites before and after acute beta-adrenergic adrenergic blockade. Cycle length was maintained constant with right ventricular pacing. Oscillatory behavior of ARI was quantified by spectral analysis and BVR as the short-term variability. Beta-adrenergic blockade reduced LF ARI oscillations (8.6 ± 4.5 ms2 vs. 5.5 ± 3.5 ms2, p = 0.027). A significant correlation was present between the initial control values and reduction seen following beta-adrenergic blockade in LF ARI (rs = 0.62, p = 0.037) such that when initial values are high the effect is greater. A similar relationship was also seen in the beat-to beat variability of ARI (rs = 0.74, p = 0.008). There was a significant correlation between the beta-adrenergic blockade induced reduction in LF power of ARI and the witnessed reduction of beat-to-beat variability of ARI (rs = 0.74, p = 0.01). These clinical results accord with recent computational modeling studies which provide mechanistic insight into the interactions of LF oscillations and beat-to-beat variability of APD at the cellular level.ConclusionBeta-adrenergic blockade reduces LF oscillatory behavior of APD (ARI) in humans in vivo. Our results support the importance of LF oscillations in modulating the response of BVR to beta-adrenergic blockers, suggesting that LF oscillations may play role in modulating beta-adrenergic mechanisms underlying BVR.

Highlights

MATERIALS AND METHODSFactors which influence the stability of ventricular repolarization are important in arrhythmogenesis
We have studied 12 patients during cardiac catheterization allowing us to measure activation-recovery intervals (ARI) as an approximation for action potential duration (APD) at 10 right ventricular (RV) and 10 left ventricular (LV) endocardial sites in order to investigate the effect of acute beta-adrenergic blockade on low frequency (LF) oscillations of ventricular APD and on beat variability (BVR) of APD, and the possible interaction between the two
Our main findings were: (1) we observed a wide variation of control values of LF power and beat-to-beat variability of ARI, systolic blood pressure (SBP) and dP/dtmax; (2) beta-adrenergic blockade was associated with a significant reduction of LF power of ARI and SBP, (3) individually no clear impact of beta-adrenergic blockade on the beat-to-beat variability of ARI, SBP and dP/dtmax was demonstrated, (4) there was a strong correlation between the reduction seen in the LF power of ARI, SBP, and dP/dtmax following betaadrenergic blockade, and the reduction in beat-to-beat variability

Summary

Introduction

MATERIALS AND METHODSFactors which influence the stability of ventricular repolarization are important in arrhythmogenesis. Enhanced oscillation of ventricular repolarization in the low frequency range and increased beat-to-beat variability (BVR) of ventricular repolarization are two of the strongest predictors of arrhythmia and sudden cardiac death (Atiga et al, 1998; Haigney et al, 2004; Thomsen et al, 2004; Gallacher et al, 2007; Tereshchenko et al, 2009; Abi-Gerges et al, 2010; Hinterseer et al, 2010; Jacobson et al, 2011; Sredniawa et al, 2012; Rizas et al, 2014, 2016, 2017; Baumert et al, 2016; Bauer et al, 2019) Both are enhanced by sympathetic stimulation and recent studies suggest a possible interactive mechanism (Porter et al, 2018). We hypothesized that beta-adrenergic blockade would reduce LF oscillations of APD and BVR of APD in humans and that the two processes might be linked

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