Prediction of mortality benefit based on periodic repolarisation dynamics in patients undergoing prophylactic implantation of a defibrillator: a prospective, controlled, multicentre cohort study

Bauer, Axel; Klemm, Mathias; Rizas, Konstantinos D.; Hamm, Wolfgang; Stülpnagel, Lukas von; Dommasch, Michael; Steger, Alexander; Lubinski, Andrezej; Flevari, Panagiota; Harden, Markus; Friede, Tim; Kääb, Stefan; Merkely, Béla; Sticherling, Christian; Willems, Rik; Huikuri, Heikki V.; Malik, Marek; Schmidt, Georg; Zabel, Markus; Perge, Péter; Salló, Zoltán; Széplaki, Gábor; Lüthje, Lars; Schlögl, Simon; Haarmann, Helge; Bergau, Leonard; Seegers, Joachim; Hasenfuß, Gerd; Muñoz-Exposito, Pascal; Tichelbäcker, Tobias; Kirova, Aleksandra; Hnatkova, Katerina; Vos, Marc A.; Willich, Stefan N.; Reinhold, Thomas; Vandenberk, Bert; Klinika, Magdalena; Toplice, Krapinske; Flevari, Panayota; Κατσιμάρδος, Ανδρέας; Katsaras, Dimitrios; Hatala, Róbert; Svetlosak, Martin; Lubiński, Andrzej; Kuczejko, Tomasz; Hansen, Jim; Conen, David; Milosrdnice, Sestre; Pavlović, Nikola; Manola, Šime; Vinter, Ozren; Benko, Ivica; Tuinenburg, Anton E.; Meyer‐Zürn, Christine; Eick, Christian; Hastrup, Jesper; Brugada, Josép; Arbelo, Elena; Kaliská, Gabriela; Martinek, Jozef; Sinner, Moritz F.; Vdovin, Nikolay; Cygankiewicz, Iwona; Ptaszyński, Paweł; Kaczmarek, Krzysztof; Poddębska, Izabela; Iovev, Svetoslav; Novotný, Tomáš; Kozák, Milan; Kenttä, Tuomas; Pelli, Ari; Kasprzak, Jarosław D.; Qavoq, Dariusz; Brusich, Sandro; Avdović, Ervin; Klasan, Marina; Gałuszka, Jan; Táborský, Miloš; Velchev, Vasil; Dißmann, Rüdiger; Guzik, Przemysław; Bimmel, Dieter; Lieberz, Christiane; Stefanow, Stefan; Rüb, Norman; Wolpert, Christian; Maier, Lars S.; Behrens, Steffen; Jurišić, Zrinka; Braunschweig, Frieder; Blaschke, Florian; Pieske, Burkert; Bakotić, Zoran; Anić, Ante; Schwinger, Robert H. G.; Platonov, Pyotr G.

doi:10.1016/s0140-6736(19)31996-8

Cited by 51 publications

(53 citation statements)

References 27 publications

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“…A conceptually attractive aspect of the application of BVR is that experimental work in a canine complete AV block model indicates that the strong association with inducible TdP/VF reflects ventricular remodeling which is a characteristic feature of at-risk patients (Smoczynska et al, 2019). A recent multicenter prospective clinical trial involving 44 centers in 15 EU countries now provides convincing evidence for enhanced low frequency oscillations of ventricular repolarization, measured from the ECG T-wave vector referred to as Periodic Repolarization Dynamics (PRD), to be one of the strongest predictors of ventricular arrhythmia and sudden death in post MI patients (Bauer et al, 2019). Comparison of the potential clinical value of each of these various biomarkers is hindered by the fact that most studies have focused on just one or a small number of these parameters and the lack of any standardization of methodology and study population.…”

Section: Discussionmentioning

confidence: 99%

“…Understanding the mechanisms underlying the interaction between beta-adrenergic stimulation, the LF oscillatory behavior of APD and beat-to-beat APD variability is important for the development of therapeutic strategies for the prevention of arrhythmia and sudden cardiac death. Enhanced oscillations of ventricular repolarization in the LF range measured from the ECG T-wave vector and referred to as periodic repolarization dynamics (PRD) have emerged as one of the strongest predictors of arrhythmia and sudden cardiac death in cardiac patients and are the subject of ongoing clinical trials (Rizas et al, 2014(Rizas et al, , 2016(Rizas et al, , 2017(Rizas et al, , 2019Hamm et al, 2017;Bauer et al, 2019). The present work identifies several specific features of the interaction between beta-adrenergic stimulation, the LF oscillatory behavior of APD and beat-tobeat APD variability that are reproducible by computational modeling which enables mechanistic insight to be gained at the cellular level.…”

Section: Discussionmentioning

confidence: 99%

“…Factors 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;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).…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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Background: Recent 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 Results: Twelve 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. Betaadrenergic blockade reduced LF ARI oscillations (8.6 ± 4.5 ms 2 vs. 5.5 ± 3.5 ms 2 , p = 0.027). A significant correlation was present between the initial control values and reduction seen following beta-adrenergic blockade in LF ARI (r s = 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 (r s = 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 (r s = 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.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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“…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). Most notably, a very recent study has shown that those periodic repolarization dynamics are able to predict the efficacy of implanting a cardioverter defibrillator in patients undergoing primary prophylactic treatment (Bauer et al, 2019). In silico studies have provided insight into the cellular mechanisms underlying this oscillatory pattern of ventricular repolarization, which have been explained by the synergistic effect of phasic β-adrenergic stimulation (β-AS) and mechanical stretch, both accompanying enhanced sympathetic nerve activity.…”

Section: Introductionmentioning

confidence: 99%

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

et al. 2020

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Background and Objectives: Recent studies in humans and dogs have shown that ventricular repolarization exhibits a low-frequency (LF) oscillatory pattern following enhanced sympathetic activity, which has been related to arrhythmic risk. The appearance of LF oscillations in ventricular repolarization is, however, not immediate, but it may take up to some minutes. This study seeks to characterize the time course of the action potential (AP) duration (APD) oscillatory behavior in response to sympathetic provocations, unveil its underlying mechanisms and establish a potential link to arrhythmogenesis under disease conditions. Materials and Methods: A representative set of human ventricular computational models coupling cellular electrophysiology, calcium dynamics, β-adrenergic signaling, and mechanics was built. Sympathetic provocation was modeled via phasic changes in β-adrenergic stimulation (β-AS) and mechanical stretch at Mayer wave frequencies within the 0.03-0.15 Hz band.Results: Our results show that there are large inter-individual differences in the time lapse for the development of LF oscillations in APD following sympathetic provocation, with some cells requiring just a few seconds and other cells needing more than 3 min. Whereas, the oscillatory response to phasic mechanical stretch is almost immediate, the response to β-AS is much more prolonged, in line with experimentally reported evidences, thus being this component the one driving the slow development of APD oscillations following enhanced sympathetic activity. If β-adrenoceptors are priorly stimulated, the time for APD oscillations to become apparent is remarkably reduced, with the oscillation time lapse being an exponential function of the pre-stimulation level. The major mechanism underlying the delay in APD oscillations appearance is related to the slow I Ks phosphorylation kinetics, with its relevance being modulated by the I Ks conductance of each individual cell. Cells presenting short oscillation time lapses Sampedro-Puente et al. Time Course of Low-Frequency Oscillatory Behavior are commonly associated with large APD oscillation magnitudes, which facilitate the occurrence of pro-arrhythmic events under disease conditions involving calcium overload and reduced repolarization reserve. Conclusions:The time course of LF oscillatory behavior of APD in response to increased sympathetic activity presents high inter-individual variability, which is associated with different expression and PKA phosphorylation kinetics of the I Ks current. Short time lapses in the development of APD oscillations are associated with large oscillatory magnitudes and pro-arrhythmic risk under disease conditions.

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“…A recent 5-year prospective multicenter study (EUropean Comparative Effectiveness Research to Assess the Use of Primary ProphylacTic Implantable Cardioverter Defibrillators, EU-CERT-ICD) showed a strong correlation between the magnitude of the oscillations of ventricular repolarization with both arrhythmia and sudden death in patients with ischemic and non-ischemic cardiomyopathy. Thus, PRD has great potential as a clinical tool for risk stratification of patients who would benefit from implantation of implantable cardioverter defibrillators (Bauer et al, 2019).…”

Section: Low Frequency Oscillation T Wave Dynamics As a Marker Of Symmentioning

confidence: 99%

Low-Frequency Oscillations in Cardiac Sympathetic Neuronal Activity

Ang

Marina

2020

Front. Physiol.

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Sudden cardiac death caused by ventricular arrhythmias is among the leading causes of mortality, with approximately half of all deaths attributed to heart disease worldwide. Periodic repolarization dynamics (PRD) is a novel marker of repolarization instability and strong predictor of death in patients post-myocardial infarction that is believed to occur in association with low-frequency oscillations in sympathetic nerve activity. However, this hypothesis is based on associations of PRD with indices of sympathetic activity that are not directly linked to cardiac function, such as muscle vasoconstrictor activity and the variability of cardiovascular autospectra. In this review article, we critically evaluate existing scientific evidence obtained primarily in experimental animal models, with the aim of identifying the neuronal networks responsible for the generation of low-frequency sympathetic rhythms along the neurocardiac axis. We discuss the functional significance of rhythmic sympathetic activity on neurotransmission efficacy and explore its role in the pathogenesis of ventricular repolarization instability. Most importantly, we discuss important gaps in our knowledge that require further investigation in order to confirm the hypothesis that low frequency cardiac sympathetic oscillations play a causative role in the generation of PRD.

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Prediction of mortality benefit based on periodic repolarisation dynamics in patients undergoing prophylactic implantation of a defibrillator: a prospective, controlled, multicentre cohort study

Cited by 51 publications

References 27 publications

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

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

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

Low-Frequency Oscillations in Cardiac Sympathetic Neuronal Activity

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