Noninvasive detection of spatiotemporal activation-repolarization interactions that prime idiopathic ventricular fibrillation

Cluitmans, Matthijs; Bear, Laura; Nguyên, Uyên Châu; Rees, Bianca van; Stoks, Job; Bekke, Rachel M.A. ter; Mihl, Casper; Heijman, Jordi; Lau, K C; Vigmond, Edward J.; Bayer, Jason D.; Belterman, Charly; Abell, Emma; Labrousse, Louis; Rogier, Julien; Bernus, Olivier; Haı̈ssaguerre, Michel; Hassink, Rutger J.; Dubois, Rémi; Coronel, Ruben; Volders, Paul G.A.

doi:10.1126/scitranslmed.abi9317

Cited by 33 publications

(40 citation statements)

References 35 publications

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“…A typical S1–S2 protocol ( Sutanto et al, 2020 ; Cluitmans et al, 2021 ) was used to induce reentry arrhythmias in 2-D slice models. Specifically, under physiological conditions, the premature S2 stimulus was applied to a local region of the epicardium within the VW caused by transmural repolarization heterogeneity.…”

Section: Methodsmentioning

confidence: 99%

Mechanistic Insights Into Inflammation-Induced Arrhythmias: A Simulation Study

Zhang²,

Jiang³

et al. 2022

Front. Physiol.

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Cardiovascular diseases are the primary cause of death of humans, and among these, ventricular arrhythmias are the most common cause of death. There is plausible evidence implicating inflammation in the etiology of ventricular fibrillation (VF). In the case of systemic inflammation caused by an overactive immune response, the induced inflammatory cytokines directly affect the function of ion channels in cardiomyocytes, leading to a prolonged action potential duration (APD). However, the mechanistic links between inflammatory cytokine-induced molecular and cellular influences and inflammation-associated ventricular arrhythmias need to be elucidated. The present study aimed to determine the potential impact of systemic inflammation on ventricular electrophysiology by means of multiscale virtual heart models. The experimental data on the ionic current of three major cytokines [i.e., tumor necrosis factor-α (TNF-α), interleukin-1 (IL-1β), and interleukin-6 (IL-6)] were incorporated into the cell model, and the effects of each cytokine and their combined effect on the cell action potential (AP) were evaluated. Moreover, the integral effect of these cytokines on the conduction of excitation waves was also investigated in a tissue model. The simulation results suggested that inflammatory cytokines significantly prolonged APD, enhanced the transmural and regional repolarization heterogeneities that predispose to arrhythmias, and reduced the adaptability of ventricular tissue to fast heart rates. In addition, simulated pseudo-ECGs showed a prolonged QT interval—a manifestation consistent with clinical observations. In summary, the present study provides new insights into ventricular arrhythmias associated with inflammation.

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Section: Methodsmentioning

confidence: 99%

Mechanistic Insights Into Inflammation-Induced Arrhythmias: A Simulation Study

Zhang²,

Jiang³

et al. 2022

Front. Physiol.

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“…Dispersion of repolarization measured by TpTe has frequently been applied as a surrogate marker for heterogeneity in repolarization, although this has been controversial (Opthof et al, 2016 ). Arrhythmogenic gradients in repolarization may occur in the heart without changes in ECG‐measured TpTe (Cluitmans et al, 2021 ). However, our findings are consistent with previous experimental (Hsieh et al, 2014 ; Wisløff‐Aase et al, 2020 ) and clinical findings (Kim et al, 2014 ; Thomsen et al, 2021 ) at moderate hypothermia.…”

Section: Discussionmentioning

confidence: 99%

Myocardial electrophysiological and mechanical changes caused by moderate hypothermia—A clinical study

Wisløff-Aase

Skulstad

Haugaa

et al. 2022

Physiological Reports

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Moderate hypothermia has been used to improve outcomes in comatose out‐of‐hospital cardiac arrest survivors during the past two decades, although the effects remain controversial. We have recently shown in an experimental study that myocardial electrophysiological and mechanical relationships were altered during moderate hypothermia. Electromechanical window positivity increased, and electrical dispersion of repolarization decreased, both of which are changes associated with decreased arrhythmogenicity in clinical conditions. Mechanical dispersion, a parameter also linked to arrhythmic risk, remained unaltered. Whether corresponding electrophysiological and mechanical changes occur in humans during moderate hypothermia, has not been previously explored. Twenty patients with normal left ventricular function were included. Measurements were obtained at 36 and 32°C prior to ascending aortic repair while on partial cardiopulmonary bypass and at 36°C after repair. Registrations were performed in the presence of both spontaneous and comparable paced heart rate during standardized loading conditions. The following electrical and mechanical parameters were explored: (1) Electromechanical window, measured as time difference between mechanical and electrical systole, (2) dispersion of repolarization from ECG T‐wave, and (3) mechanical dispersion, measured as segmental variation in time to peak echocardiographic strain. At moderate hypothermia, mechanical systolic prolongation (425 ± 43–588 ± 67 ms, p < 0.001) exceeded electrical systolic prolongation (397 ± 49–497 ± 79 ms, p < 0.001), whereby, electromechanical window positivity increased (29 ± 30–86 ± 50 ms, p < 0.001). Dispersion of repolarization and mechanical dispersion remained unchanged. Corresponding electrophysiological and mechanical relationships were present at comparable paced heart rates. After rewarming, the increased electromechanical window was reversed in the presence of both spontaneous and paced heart rates. Moderate hypothermia increased electromechanical window positivity, while dispersion of repolarization and mechanical dispersion remained unchanged. This impact of hypothermia may be clinically relevant for selected groups of patients after cardiac arrest.

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“…Langendorff isolated heart experiments have previously been described in Bear et al (2019Bear et al ( , 2021; drug infusion and RT gradient determination have previously been described in Cluitmans et al (2021). A brief summary is given here, and a more thorough description is given in the Appendix.…”

Section: Experimental Protocolmentioning

confidence: 99%

Steep repolarization time gradients in pig hearts cause distinct changes in composite electrocardiographic T‐wave parameters

Waal

Bear

Meijborg

et al. 2022

Noninvasive Electrocardiol

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Background The T wave of the electrocardiogram (ECG) reflects ventricular repolarization. Repolarization heterogeneity is associated with reentrant arrhythmias. Several T‐wave markers (including QT interval) have been associated with ventricular arrhythmias, but studies linking such markers to underlying local repolarization time (RT) inhomogeneities are lacking. We aimed to investigate the relation of several T‐wave markers to controlled drug‐induced regional RT gradients in intact pig hearts. Methods Repolarization time gradients were created by regional infusion of dofetilide and pinacidil in four atrially paced porcine Langendorff‐perfused hearts placed inside a torso tank. From the 12‐lead ECG on the torso tank, the mean, maximum, and dispersion (max–min) of QTtime, JTtime, Tpeak–end, Twidth, TQratio, dV/dtmax, Tarea, Tamp, and T‐upslope duration were determined, as well as upslope end difference between leads V1 and V6. Results Temporal T‐wave parameters Tpeak–end, Twidth, and TQratio show a significant and high correlation with RT gradient, best reflected by mean value. Tarea (mean, max and dispersion) and dV/dtmax dispersion show only a moderate significant correlation. T‐upslope duration shows a significant correlation in particular for mean values. Mean, maximum, or dispersion of QTtime and V1–V6 upslope end difference were not significantly correlated with RT gradient. Conclusion Composite 12‐lead ECG T‐wave parameters Tpeak–end, Twidth, TQratio, upslope duration, and Tarea show a good correlation with underlying RT heterogeneity, whereas standard clinical metrics such as QTtime do not reflect local RT heterogeneity. The composite T‐wave metrics may thus provide better insights in arrhythmia susceptibility than traditional QTtime metrics.

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Noninvasive detection of spatiotemporal activation-repolarization interactions that prime idiopathic ventricular fibrillation

Abstract: Premature beats originating in clinically concealed areas of local early repolarization promote ventricular arrhythmias and sudden cardiac arrest.

Cited by 33 publications

References 35 publications

Mechanistic Insights Into Inflammation-Induced Arrhythmias: A Simulation Study

Mechanistic Insights Into Inflammation-Induced Arrhythmias: A Simulation Study

Myocardial electrophysiological and mechanical changes caused by moderate hypothermia—A clinical study

Steep repolarization time gradients in pig hearts cause distinct changes in composite electrocardiographic T‐wave parameters

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