Beat-to-Beat Variability of Ventricular Action Potential Duration Oscillates at Low Frequency During Sympathetic Provocation in Humans

Abstract

Background: The temporal pattern of ventricular repolarization is of critical importance in arrhythmogenesis. Enhanced beat-to-beat variability (BBV) of ventricular action potential duration (APD) is pro-arrhythmic and is increased during sympathetic provocation. Since sympathetic nerve activity characteristically exhibits burst patterning in the low frequency range, we hypothesized that physiologically enhanced sympathetic activity may not only increase BBV of left ventricular APD but also impose a low frequency oscillation which further increases repolarization instability in humans.Methods and Results: Heart failure patients with cardiac resynchronization therapy defibrillator devices (n = 11) had activation recovery intervals (ARI, surrogate for APD) recorded from left ventricular epicardial electrodes alongside simultaneous non-invasive blood pressure and respiratory recordings. Fixed cycle length was achieved by right ventricular pacing. Recordings took place during resting conditions and following an autonomic stimulus (Valsalva). The variability of ARI and the normalized variability of ARI showed significant increases post Valsalva when compared to control (p = 0.019 and p = 0.032, respectively). The oscillatory behavior was quantified by spectral analysis. Significant increases in low frequency (LF) power (p = 0.002) and normalized LF power (p = 0.019) of ARI were seen following Valsalva. The Valsalva did not induce changes in conduction variability nor the LF oscillatory behavior of conduction. However, increases in the LF power of ARI were accompanied by increases in the LF power of systolic blood pressure (SBP) and the rate of systolic pressure increase (dP/dtmax). Positive correlations were found between LF-SBP and LF-dP/dtmax (rs = 0.933, p < 0.001), LF-ARI and LF-SBP (rs = 0.681, p = 0.001) and between LF-ARI and LF-dP/dtmax (rs = 0.623, p = 0.004). There was a strong positive correlation between the variability of ARI and LF power of ARI (rs = 0.679, p < 0.001).Conclusions: In heart failure patients, physiological sympathetic provocation induced low frequency oscillation (~0.1 Hz) of left ventricular APD with a strong positive correlation between the LF power of APD and the BBV of APD. These findings may be of importance in mechanisms underlying stability/instability of repolarization and arrhythmogenesis in humans.

Long-Term Microgravity Exposure Increases ECG Repolarization Instability Manifested by Low-Frequency Oscillations of T-Wave Vector

“…In our study, those changes are shown not to be explained by HRV changes but to reflect direct autonomic modulation of the ventricular myocardium, in accordance with the findings reported in Rizas et al (2014Rizas et al ( , 2016. In vivo studies in patients have demonstrated that the same low-frequency oscillatory behavior of ventricular repolarization occurs locally, as measured from activation recovery intervals (ARIs) obtained from unipolar epicardial electrograms during ventricular pacing (Hanson et al, 2014;Porter et al, 2018). In those studies, heightened arousal of the sympathetic nervous system was elicited and maintained by mental stress or by Valsalva maneuver, which allowed characterization of low-frequency oscillations in ARI, a surrogate of action potential duration (APD), showing that those oscillations are coupled to oscillations in systolic and diastolic blood pressure (Hanson et al, 2014;Porter et al, 2018).…”

“…In vivo studies in patients have demonstrated that the same low-frequency oscillatory behavior of ventricular repolarization occurs locally, as measured from activation recovery intervals (ARIs) obtained from unipolar epicardial electrograms during ventricular pacing (Hanson et al, 2014;Porter et al, 2018). In those studies, heightened arousal of the sympathetic nervous system was elicited and maintained by mental stress or by Valsalva maneuver, which allowed characterization of low-frequency oscillations in ARI, a surrogate of action potential duration (APD), showing that those oscillations are coupled to oscillations in systolic and diastolic blood pressure (Hanson et al, 2014;Porter et al, 2018). Computational studies have provided insight into the mechanisms underlying sympathetically-mediated lowfrequency oscillations of APD and the observed inter-individual differences (Pueyo et al, 2016;Sampedro-Puente et al, 2019).…”

Time Course of Low-Frequency Oscillatory Behavior in Human Ventricular Repolarization Following Enhanced Sympathetic Activity and Relation to Arrhythmogenesis

“…In those studies ventricular repolarization was modulated both by direct sympathetic action on the ventricular myocardium as well as indirectly by heart raterelated effects. In the present study, CL was kept constant and the ventricular response was thus only assessed as due to sympathetic effects on the ventricle, as in in vivo electrogram recordings from patients where LF oscillations of ARI have been characterized while controlling CL with right ventricular pacing (Hanson et al, 2014;Porter et al, 2018).…”

“…Ventricular repolarization has been shown to exhibit a low-frequency (LF) oscillatory pattern following enhanced sympathetic activity. In humans, this has been demonstrated by quantification of so-called periodic repolarization dynamics in the T-wave vector of the electrocardiogram (ECG) (Rizas et al, 2014(Rizas et al, , 2016 as well as by in vivo evaluation of LF components in activation recovery intervals (ARI) of ventricular electrograms (Hanson et al, 2014;Porter et al, 2018). In post-infarction patients, an increased magnitude of LF oscillations in ECG repolarization has been proved to be a significant predictor of total mortality and sudden cardiac death (Rizas et al, 2017).…”

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

“…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;Średniawa et al, 2012;Rizas et al, 2014Rizas et al, , 2016Rizas et al, , 2017Baumert 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). However, the mechanisms underlying the effect of beta-adrenergic stimulation on LF oscillations of repolarization and beat-to-beat variability of repolarization remain unclear.…”