Idiopathic ventricular fibrillation (IVF) affects 5–10

Amiodarone and dronedarone are commonly used antiarrhythmic drugs, affecting a wide range of ion channels. Emerging data suggest that both drugs have distinct acute and chronic effects, but the underlying mechanisms and their electrophysiological consequences remain incompletely understood. To address this, we employed an integrated experimental and computational approach to characterize their proarrhythmic potential over time. This abstract focuses on cellular action potential (AP) simulations.Simulations were conducted using a modified computer model of human ventricular cardiomyocyte electrophysiology [Tomek et al., 2019; 2020], in which the native peak and late Na+-current formulations were replaced with an established NaV1.5 Markov model that captures drug-channel interactions for charged and neutral drug fractions [Moreno et al., 2013]. The NaV1.5 Markov model was calibrated for acute and chronic drug effects using literature data [Maltsev et al., 2001; Ramon de Lime Conceicao et al., 2023; 2024] and whole-cell patch-clamp recordings in CHO cells, respectively. Additional effects of amiodarone and dronedarone on CaV1.2, KV4.3, KV11.1, KV7.1 [Crumb et al., 2016], and NCX1 [Watanabe and Kimura, 2000] were incorporated, with chronic effects on KV11.1 and KV7.1 informed by our recordings obtained after 48 h of incubation with 1 μM amiodarone or dronedarone.During acute exposure (0.3 and 1 μM), amiodarone and dronedarone induced a concentration-dependent prolongation of the AP duration at 50% (APD50) and 90% repolarization (APD90) and for both drugs, an increasing pacing rate (1–3 Hz) led to progressive shortening of APD50 and APD90. Chronic exposure to either drug (1 μM) induced an increase in late Na+ current and a reduction in KV11.1 current in CHO cells. Accordingly, simulations highlighted prolonged APD50 and APD90 with both drugs during chronic application, while still exhibiting rate-dependent shortening at higher pacing rates (1, 2, and 3 Hz).These results highlight distinct acute and chronic electrophysiological profiles for amiodarone and dronedarone. The exacerbation of APD prolongation during chronic exposure warrants attention in safety evaluations, as it may impact the Torsades de Pointes risk during sustained drug administration.

Small-conductance calcium-activated potassium (SK) channels are promising targets for atrial-specific antiarrhythmic therapies, with evidence suggesting tachycardia-dependent SK-channel upregulation. However, the dynamics of SK-channel gating and trafficking in human atrial electrophysiology remain unclear because of experimental limitations, including the availability of human cardiomyocytes and long patch clamp experiments. Although computational models help explore these mechanisms, none integrate SK-channel trafficking. In the present study, we expanded our Kv11.1 trafficking model to simulate rate-dependent SK-channel trafficking in a human atrial cardiomyocyte model. Calibrated against experimental data, our model replicates time- and rate-dependent SK-channel function, allowing simulations of SK-channel trafficking and its effects on action potentials. Tachypacing at 5 Hz increased SK-channel density, enhancing SK current and shortening action potential duration, with or without calcium buffering. Two-dimensional tissue simulations with physiological calcium handling showed that tachycardia increased re-entry duration and ectopic activity. SK-channel inhibition reduced re-entry duration but promoted ectopic activity, suggesting a reduction in atrial fibrillation burden rather than complete elimination. Our novel computational model highlights SK channels' role in re-entry-promoting effects of short atrial tachycardia episodes, offering insights into early atrial fibrillation progression and potential antiarrhythmic strategies. KEY POINTS: Small-conductance calcium-activated potassium (SK) channels have emerged as potential targets for atrial-specific antiarrhythmic therapies, especially in atrial fibrillation (AF). Emerging evidence suggests that tachycardia-induced SK-channel trafficking can regulate cardiac cellular electrophysiology over minutes, but investigating its impact on arrhythmogenesis in humans is experimentally challenging. We adapted our recent in silico Kv11.1 trafficking model to simulate SK-channel trafficking and incorporated it into a human atrial cardiomyocyte model, which was calibrated based on experimental results. Tachypacing at 5 Hz led to a substantial increase in SK channel-density at the membrane, resulting in enhanced SK current and a reduction in action potential duration. 2-D tissue simulations demonstrated that rapid pacing promoted both re-entry and ectopic (triggered) activity. Blocking SK channels reduced re-entry duration but increased ectopic activity, suggesting that SK channel inhibition could decrease AF burden, but may not eliminate AF per se.

Torsades de pointes (TdP) is a potentially lethal ventricular tachyarrhythmia occuring in congenital long-QT syndrome or acquired QT prolongation. Trigger mechanisms of TdP in the beating heart are still poorly understood, but electromechanical reciprocity likely contributes. (1.) Determining the timing of left-ventricular (LV) mechanical events at TdP induction in a large animal model, particularly the impact of LV filling; (2.) Delaying the onset of LV filling with the myosin activator omecamtiv mecarbil with the aim of preventing TdP. In 9 anesthetized female Welsh mountain sheep, transthoracic echocardiography was performed, and LV pressure and surface ECG were measured. After baseline recordings, 1 mg/kg of omecamtiv mecarbil (OM) was given to delay the onset of diastolic LV filling. Following OM, long-QT syndrome type 2 (LQT2) was mimicked by the infusion of IKr blocker dofetilide (Dof) until TdP occurred or a maximum of 15 µg/kg was reached (Panel A). Data from seven additional sheep only treated with Dof before TdP induction were used as reference for TdP coupling intervals. Data are shown as mean±SD or median (25th to 75th percentile). Echocardiography-derived electromechanical window (EMW) was calculated by subtracting the QT time from the aortic-valve closure time. At baseline, the RR interval was 686±125 ms, QTc (Bazett) was 412±27 ms, and the EMW was -3 (-10 to 25) ms. After OM, RR and QTc remained unchanged, but the EMW was rendered more positive (88 (68 to 143) ms, p=0.004). The isovolumic relaxation time (IVRT, p=0.0002) and the mitral valve opening time (MVO, p=0.006) were also prolonged, indicating a delayed onset of passive LV filling upon OM. OM+Dof-treated animals that ultimately developed TdP (5/9, 9 µg/kg mean Dof dose at TdP induction) had a markedly different mechanical phenotype after OM with less positive EMW (74±11 vs. 135±34 ms, p=0.007), shorter IVRT (p=0.03), and shorter MVO (p=0.02), indicating a relatively earlier onset of passive LV filling in these animals. At the highest individual Dof dose per animal, no increase in RR intervals (p=0.71) was observed, but QTc was prolonged (p<0.0001, Panel B). The 5 animals that developed TdP upon OM+Dof did not differ from those resistant to TdP-induction in terms of RR (p=0.15) or QTc (p=0.72). However, tissue-doppler imaging of the LV revealed that TdP induction fell into the LV passive filling phase in all animals after OM+Dof, and TdP induction was separated from the T-wave unlike in classic R-on-T (Panel C). In OM+Dof vs. Dof-treated sheep, QTc before TdP onset did not differ between groups (p=0.80), but coupling intervals were significantly longer in OM+Dof-treated animals (656±43 vs. 549±54 ms, p=0.007). Passive LV filling is involved as a mechanoelectrical trigger of TdP in this experimental model, and can be modulated with omecamtiv mecarbil.Figure

Although SCN5A variants are an established cause of arrhythmia and conduction disease, their association with dilated cardiomyopathy (DCM) is less studied. This review summarizes recent insights into SCN5A-related cardiomyopathy, focusing on genotype-phenotype correlations, overlap with arrhythmia, and implications for management. Both gain- and loss-of-function SCN5A variants are associated with cardiomyopathy, found in 0.5–0.9

The apicobasal repolarization gradient (ABRG) plays an important role in determining the sequence of ventricular repolarization, but the effects of sex and age on ABRG are unknown. In this study, we investigate the age- and sex-related differences in ABRG and evaluate their possible role in vulnerability to arrhythmia. Electrocardiographic imaging was performed in 22 healthy subjects (16 females and 6 males) during sinus rhythm, and the average recovery time (RT) at the ventricular apex and base was determined. Fifty-six different ABRGs were simulated in a male and female model of human ventricular epicardium with sex-specific electrophysiology by simultaneously adjusting the apicobasal gradients of the slow and rapid delayed rectifier potassium currents. The models were burst paced from the ventricular apex and right ventricular outflow tract to assess the effect of ABRGs on arrhythmia vulnerability. Apicobasal differences in RT (human subjects) and repolarization time (simulation data) were calculated to quantify the ABRGs. In human subjects, ABRGs diminished and eventually inverted (longer RT at the apex than at the base) with increasing age (r = -0.7265, P = 0.0001). In both male and female models, apical pacing resulted in arrhythmia in 20/ 56 simulations, whereas right ventricular outflow tract pacing resulted in arrhythmia in 15/56 simulations. Arrhythmias were attributable to re-entry from unidirectional block and generally lasted longer in the models with shorter RT at the apex than at the base. Our findings demonstrate that the ABRG diminishes or inverts with ageing in both male and female human ventricles, which can reduce vulnerability to re-entrant ventricular arrhythmia. KEY POINTS: The apicobasal repolarization gradient (ABRG) determines the sequence of ventricular repolarization. Little is known about ABRG variability in humans and the effects of sex and age on the ABRG. Using electrocardiographic imaging data from healthy human subjects, we found that ABRG diminishes or inverts with ageing, in both males and females. Our simulations in computational models of human ventricular epicardium show that diminishing and inverting the ABRG is associated with a low vulnerability to arrhythmia. By linking together electrocardiographic imaging data and computer simulations, we demonstrate that vulnerability to ventricular arrhythmia might depend on age-related differences in ABRG.

Background:In structurally normal hearts, premature ventricular complexes (PVCs) are primarily driven by enhanced automaticity or afterdepolarization-dependent triggered activity. Traditionally, re-entrant excitation has only been associated with cardiac conditions involving scar formation, such as post-myocardial infarction or cardiac sarcoidosis. Case summary:We present a case of an asymptomatic 28-year-old patient with a high burden of monomorphic PVCs originating near the posteromedial papillary muscle. Left ventricular (LV) dilatation with reduced systolic function (ejection fraction 45%) was diagnosed as PVC-induced cardiomyopathy, given the absence of fibrosis and coronary artery disease. During an electrophysiological study, a 2-cm2 region was identified where abnormal Purkinje potentials (P1), exhibiting markedly reduced conduction velocity (0.88 mm/ms), consistently followed the rapid conduction via the left posterior fascicle (LPF). Local activation time velocity vectors of P1 pinpointed the earliest abnormal Purkinje activation at the proximal LPF. The impulse excited the distal one-third of the interventricular septum before conducting retrogradely to the LPF. Radiofrequency ablation targeted at the Purkinje-myocardial pivot point successfully eliminated the PVCs, restoring LV systolic function at follow-up. Discussion:Even in the absence of structural heart disease, delayed anterograde Purkinje conduction can facilitate monomorphic PVCs via re-excitation. This highlights the potential for targeted ablation at the distal Purkinje network as an effective treatment strategy.

Electrically active cells like cardiomyocytes show variability in their size, shape, and electrical activity. But should we expect variability in the properties of their ionic currents? In this meta-analysis, we gather and visualize measurements of two important electrophysiological parameters: the midpoints of activation and inactivation of the cardiac fast sodium current, INa. We find a considerable variation in reported mean values between experiments, with a smaller cell-to-cell variation within experiments. We show how the between-experiment variability can be decomposed into a correlated component, affecting both midpoints almost equally, and an uncorrelated component, affecting the midpoints independently, and we find that the correlated component is much larger than the uncorrelated one. We then review biological and methodological issues that might explain the observed variability and attempt to classify each as a within-experiment or a correlated or uncorrelated between-experiment effect. Although the existence of some variability in measurements of ionic currents is well-known, we believe that this is the first work to systematically review it and that the scale of the observed variability is much larger than commonly appreciated, which has implications for modelling and machine-learning as well as experimental design, interpretation, and reporting.

Idiopathic ventricular fibrillation (VF) and polymorphic ventricular tachycardia (pVT) are often triggered by short-coupled premature ventricular complexes (SC-PVCs), with coupling intervals (CI) <350 ms. However, the timing, burden, and conditions of these PVCs remain largely unknown. To investigate the CIs and burden of (SC-)PVCs in idiopathic VF/pVT survivors, their relation to the time since the last event (i.e., VF/pVT episodes, appropriate ICD shocks, or antitachypacing), and to compare their characteristics between day and night. In 48 idiopathic VF/pVT survivors (26 male, 21 on β-blockers, no other antiarrhythmics), we analyzed extended ECG recordings (duration 42 [26-55] minutes, reported as median [Q1-Q3]), and extracted the shortest CI at rest. These were correlated to the time passed since the last event using a linear model, and tested for significance with an F-test. Differences between β-blocker users and non-users were assessed with a Mann-Whitney U test or chi-squared test. From 15 of these patients, 37 Holter recordings (24 hours each; 2 [1-4] recordings/patient; 13 [10-287] days post-event) were analyzed for day-night differences in CI, hourly PVC burden, and median RR intervals preceding PVCs, using a linear mixed-effects model, and tested for significance with a t-test. In the extended ECG recordings, a positive correlation was observed between the shortest PVC CI and the logarithmic time since the last event (p=0.03, Fig. 1A). PVC occurrence was more frequent in β-blocker users than in non-users (18/21 vs. 14/27, respectively, p=0.05), but SC-PVC occurrence (2/21 vs. 3/27, p=0.98), CI (410 [379-439] vs. 436 [411-482] ms, p=0.22), or time since the last event (483 [106-2022] vs. 446 [40-3262] days, p = 1.00) were not significantly different (Fig. 1B). Holter analysis revealed that the shortest CI was shorter during daytime than at night (341 [325-373] vs. 392 [353-458] ms, p=0.0001), and the same was true for median RR-intervals preceding PVCs (762 [709-802] vs. 864 [812-976] ms, p<0.0001) (Fig. 1C). No significant differences were found in the hourly PVC burden (63 [3-259] vs. 5 [1-163]/hour, p=0.78) or the hourly SC-PVC burden (0 [0.1-0.4] vs 0 [0-0]/hour, p=0.29) (Fig. 1D). In two patients with longitudinal Holter data, an arrhythmia recurred in between recordings, coinciding with a shorter CI, which later increased again in one patient (Fig. 2). In survivors of idiopathic VF/pVT, PVC CIs correlated positively with time since the last event, and were shorter during the day than at night. Occurrence of short-coupled PVCs was less frequent in patients further from the last event, and at night. In two patients, arrhythmia recurrence was linked to a shorter CI. These findings suggest that the potential triggers for idiopathic VF/pVT vary over time. In the presence of a (dynamic) substrate, this variability may help set the stage for arrhythmia initiation.Figure 1 Figure 2

Amiodarone is a widely used anti-arrhythmic drug (AAD), which is among the few treatment options available to patients with atrial fibrillation and/or ventricular tachycardia and structural heart disease. However, its use is limited by distinct cardiac and extracardiac toxicity. Dronedarone has been developed as a less-toxic amiodarone derivative, for which so far only one episode of Torsades de Pointes (TdP) arrhythmia has been reported in the literature, compared to 47 TdP cases with amiodarone. Differential electrophysiological effects between both AADs during long-term exposure remain largely unknown. Here, we aim to investigate PI3K/Akt signaling as a potential mechanism underlying distinct long-term effects of amiodarone and dronedarone. Long-term inhibition of PI3K/Akt has been shown to affect multiple ion currents, including the late sodium current (INaL). We recorded INaL in Chinese hamster ovary (CHO) cells transfected with wild-type NaV1.5 treated for 48 h, or in human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) treated for 5 h with 1 μM of amiodarone, dronedarone, Akt inhibitor (Akti), or dofetilide, which is recognized to augment INaL due to chronic PI3K inhibition. hiPSC-CMs were generated from blood from a healthy individual reprogrammed with episomal vectors carrying Yamanaka factors and subsequently differentiated into hiPSC-CMs by activating Wnt/β-catenin signaling. INaL was measured as the tetrodotoxin-sensitive current during 200-ms depolarizing pulses to −30 mV from a holding potential of −120 mV during whole-cell voltage-clamp experiments at 25 °C. INaL was increased following long-term treatment of CHO with dofetilide (−3.46 ± 1.48 pA/pF, n = 17), amiodarone (−3.83 ± 2.28 pA/pF, n = 14) or Akti (−4.44 ± 2.04 pA/pF, n = 15) compared to control (−1.60 ± 0.84 pA/pF, n = 16). This INaL increase was completely abolished by intrapipette phosphatidylinositol (3,4,5)-trisphosphate (PIP3). By contrast, dronedarone had no significant effect on INaL (−2.49 ± 1.63 pA/pF, n = 16), compared to control. We subsequently confirmed these results in hiPSC-CMs with an amiodarone-induced increase in INaL current (−2.26 ± 0.99 pA/pF, n = 8) vs control (−1.32 ± 0.64, n = 8). In conclusion, long-term treatment with amiodarone increases INaL in CHO and hiPSC-CMs, potentially via inhibition of PI3K/Akt signaling, as its effect is abolished by PIP3. Dronedarone does not augment INaL and hence might be considered a safer treatment option in proarrhythmia-susceptible patients. Although acute IKr block is common for amiodarone and dronedarone, elucidation of long-term drug effects on other ion currents, e.g., INaL, is required to characterize a compound's safety profile.This project is funded by the European Union's Horizon 2020 Research and Innovation Program under grant agreement No 858070.

Electrocardiographic imaging (ECGI) aims to noninvasively estimate heart surface potentials starting from body surface potentials. This is classically based on geometric information on the torso and the heart from imaging, which complicates clinical application. In this study, we aim to develop a deep learning framework to estimate heart surface potentials solely from body surface potentials, enabling wider clinical use. The framework introduces two main components: the transformation of 3D torso and heart geometries into standard 2D representations, and the development of a customized deep learning network model. The 2D torso and heart representations maintain a consistent layout across different subjects, making the proposed framework applicable to different torso-heart geometries. With spatial information incorporated in the 2D representations, the torso-heart physiological relationship can be learnt by the network. The deep learning model is based on a Pix2Pix network, adapted to work with 2.5D data in our task, i.e., 2D body surface potential maps (BSPMs) and 2D heart surface potential maps (HSPMs) with time sequential information. We propose a new loss function tailored to this specific task, which uses a cosine similarity and different weights for different inputs. BSPMs and HSPMs from 11 healthy subjects (8 females and 3 males) and 29 idiopathic ventricular fibrillation (IVF) patients (11 females and 18 males) were used in this study. Performance was assessed on a test set by measuring the similarity and error between the output of the proposed model and the solution provided by mainstream ECGI, by comparing HSPMs, the concatenated electrograms (EGMs), and the estimated activation time (AT) and recovery time (RT). The mean of the mean absolute error (MAE) for the HSPMs was 0.012 ± 0.011, and the mean of the corresponding structural similarity index measure (SSIM) was 0.984 ± 0.026. The mean of the MAE for the EGMs was 0.004 ± 0.004, and the mean of the corresponding Pearson correlation coefficient (PCC) was 0.643 ± 0.352. Results suggest that the model is able to precisely capture the structural and temporal characteristics of the HSPMs. The mean of the absolute time differences between estimated and reference activation times was 6.048 ± 5.188 ms, and the mean of the absolute differences for recovery times was 18.768 ± 17.299 ms. Overall, results show similar performance between the proposed model and standard ECGI, exhibiting low error and consistent clinical patterns, without the need for CT/MRI. The model shows to be effective across diverse torso-heart geometries, and it successfully integrates temporal information in the input. This in turn suggests the possible use of this model in cost effective clinical scenarios like patient screening or post-operative follow-up.

In healthy human hearts, the T-wave is concordant with the QRS-complex, which is often explained by the negative relationship between the activation (AT) and repolarization time (RT). Delayed ventricular conduction is typically accompanied by discordant T-waves, but the link to regional repolarization is unknown. The present study aimed to compare AT-RT relationships in patients with narrow QRS-complexes (nQRS) vs. patients with left bundle branch block (LBBB) or intraventricular conduction disturbances (IVCD) using electrocardiographic imaging to reconstruct epicardial unipolar electrograms. Evaluations included the slopes of AT-RT relationships, maximum (max) AT and RT, ventricular electrical uncoupling (VEU; the difference of mean AT or RT between the left and right ventricle), and the standard deviation of AT (SDAT) and RT (SDRT). In nQRS patients, the AT-RT slope was highly variable (-0.370 ± 1.125, P = 0.193 ± 0.212), whereas it was consistently positive in IVCD and LBBB patients (1.220 ± 0.907 and 0.968 ± 0.325, P = 0.0172 ± 0.0254 and P = 0.0219 ± 0.0657 respectively). Max AT, max RT, AT-VEU, RT-VEU, SDAT and SDRT were similar for IVCD and LBBB patients and significantly higher compared to nQRS patients. In patients with delayed ventricular activation, there was a positive association between AT-VEU and RT-VEU (r = 0.549, P = 0.0149). The present study demonstrates that, in nQRS rhythms with concordant T-waves, the physiological assumption that sites of late activation have shorter repolarization intervals might not be consistently present at the epicardium. Furthermore, delayed ventricular activation is associated with delayed completion of repolarization and a dyssynchronous activation is accompanied by a dyssynchronous repolarization. KEY POINTS: This study examines the relationships between activation and repolarization times in epicardial reconstructed unipolar electrograms derived from ECG-imaging in patients with normal and delayed ventricular activation. In patients with a narrow QRS-complex and concordant T-waves on a 12-lead ECG, ECG-imaging reveals significant variability in the activation-repolarization time relationship. The physiological assumption that late-activated regions have a shorter repolarization interval may thus not always be valid on the epicardium. Patients with delayed ventricular activation typically exhibit discordant T-wave polarity on a 12-lead ECG and consistently demonstrate a positive activation-repolarization time relationship on ECG-imaging: regions of early activation correspond to shorter repolarization intervals, whereas regions of late activation correspond to longer repolarization intervals.

Stereotactic arrhythmia radioablation (STAR) for ventricular tachycardia (VT) is a non-invasive treatment modality to reduce the VT burden by delivering a single high radiation dose to the arrhythmogenic substrate. Identification and delineation of the arrhythmogenic substrate, definition of the radiation target, and transfer of this target across different imaging modalities from the invasive electroanatomic map (EAM) to the planning computed tomography (CT) scan are key to the success of therapeutic radiation. The VT substrate is identified using EAM data and co-localized with radiological correlates of the ventricular scar. Precise transfer to the non-ECG-gated treatment planning CT is essential for safe and effective STAR delivery. Current challenges include translating the endocardial or epicardial EAM surface target into a 3D cardiac target volume (CTV), reconciling different acquisition methods (e.g., (exhale-gated) EAM, contrast-enhanced ECG-gated CT angiography, and non-gated non-contrast planning CT), and achieving accurate CTV transfer using multi-modal image integration. Early approaches relied on manual delineation using side-by-side EAM and CT rendering, leading to poor reproducibility and potential treatment failure. Emerging (semi)auto-segmentation software based on the American Heart Association (AHA) 17-segment left ventricular model offers promise but lacks standardized weighing of identified segments and methods for handling partially involved segments. More recently, 2D-to-3D and 3D-to-3D target transfer methods, including commercial and in-house computer-aided tools, have been developed to address these difficulties. Currently, a standardized workflow has not been established. This review addresses the need to standardize CTV definitions and transfer workflows, assessing available tools and proposing quality assurance measures based on recommendations of the STOPSTORM.eu consortium.

The short-QT syndrome (SQTS) is a rare cardiac disorder associated with abnormally short repolarization duration and increased risk of ventricular tachyarrhythmia (VT). In-vivo depolarization and repolarization patterns in patients with SQTS are unknown. First characterization of epicardial depolarization and repolarization in SQTS using noninvasive ECG imaging (ECGi). ECGi was performed in a 54-year-old male SQTS patient (QTc 318 ms, inferolateral J-wave elevation, SQTS score 4, no causal mutation identified) with a history of syncope and long-coupled apical non-sustained VT, treated with metoprolol (Figure 1). Ten consecutive sinus beats were recorded at rest, directly after air cycling, and five minutes after exercise. Results were compared to a control group of n=11 healthy controls (27% male, 59±6 years, QTc 415±18 ms). ECGi consisted of a 224-electrode body-surface potential map and a contrast-enhanced CT scan to determine torso and heart geometry. Local activation (AT) and recovery times (RT) were derived from reconstructed epicardial unipolar electrograms. Data are shown as mean±SD. RR intervals of the SQTS patient and controls were comparable (1019±9 vs. 955±157 ms, p=0.68). The initial phase of AT (minimum AT=5th percentile of AT) was significantly longer in SQTS than in controls (10.7±1.7 vs. 4.5±2.1 ms, p=0.004). Mean AT (25.5±1.6 vs. 18.0±3.4 ms, p=0.056) tended to be longer in the SQTS patient. Especially the inferior ventricular regions showed a prolonged mean AT (35.7±1.7 vs. 20.5±5.2 ms, p=0.016), colocalizing to the area of J-wave elevation on the simultaneously recorded 12-lead ECG (Figure 2A/B). Repolarization intervals were shorter in the SQTS patient, with shorter activation-recovery intervals (ARI; 170±2 vs. 257±24 ms, p=0.008) and RTs (202±2 vs. 276±3 ms, p=0.02; Figure 2C). No differences in RT gradients (mean: 23±1 vs. 29±10 ms/cm, p=0.58) were observed between SQTS and controls. During exercise, the RR interval decreased to 732±58 ms (p<0.0001) in the SQTS patient, partly recovering to 928±18 ms (p<0.0001) five minutes thereafter. QT, ARI and RT further shortened in response to increased sympathetic drive, indicating the presence of an at least partially intact repolarization reserve (Figure 2D): RT decreased to 179±3 ms (p<0.0001), and returned to baseline levels five minutes in recovery (199±3 ms). Mean and maximum RT gradients decreased in response to exercise. In this case of SQTS, the areas of J-wave elevation on the 12-lead ECG colocalized with regions of prolonged AT in the inferior ventricular epicardium based on ECGi, not with local repolarization abnormalities. Homogeneously shortened repolarization with normal RT gradients and partially intact repolarization reserve characterized the SQTS substrate. ECG imaging surrounding VT induction is needed to correlate these findings with underlying mechanisms of arrhythmia induction.Figure 1 Figure 2

Methods with suboptimal efficiency for detecting cardiovascular side-effects burden the pharmaceutical industry. As scalable, human-based alternatives to traditional models, hiPSC-CMs show great promise in the field. However, for widespread industrial application, high quality validation studies are critical. Our goal was to establish a highly predictive in vitro hiPSC-CM drug screening protocol leveraging the power of morphological profiling multiplexed with established electrophysiological readouts (multi-electrode array; MEA). Three healthy control hiPSC-CM lines were cultured in serum-free conditions and then treated with a library of seventeen compounds at ranges comparable to maximal clinical plasma concentrations. High content imaging assays for sarcomeres, mitochondria, DNA damage, Golgi, endoplasmic reticulum, gap junctions, peroxisomes and lysosomes were validated in a 384 well plate format. Morphological data was analyzed in combination with MEA recordings. For deeper mechanistic insight, RNA sequencing was also performed. As expected, positive control, doxorubicin reduced viability up to 70 %. Investigating its effect on each readout served as a key step in establishing proof of concept. In accordance with its mechanism of action, dose-dependent increase in γH2AX (marker of DNA damage) was present with minor differences in sensitivity between cell lines. Lysosomal, nucleolar, and gap junction morphology was affected as well. Electrophysiological activity was altered even at low concentrations, while arrhythmia/quiescence was detected >1 μM. With 0.1 μM Doxorubicin, 125 genes were differentially expressed compared to vehicle, several of which were involved in cellular responses to DNA damage and the p53 pathway. Notably, TOP2A, a marker of DNA stress and a target of doxorubicin, was significantly downregulated. For all 17 drugs tested, each parameter was examined. All parameters were collated for bioinformatic analysis. Collecting such an elaborate set of features is fundamental for profiling assays. First, principal component analysis revealed compound effects that otherwise remained hidden. Second, to build a predictive cardiac safety score, partial least squares-discriminant analysis revealed specific spatial clustering of compounds with potential toxicity. Hence, morphological analysis in combination with traditional readouts and bioinformatics enables deeper understanding and in vitro prediction of compound activity and toxicity. Drug-induced deregulation in pathways provides mechanistic explanations for the structural and functional changes in hiPSC-CMs.

In structurally normal hearts, premature ventricular complexes (PVCs) are primarily driven by enhanced automaticity or afterdepolarization-dependent triggered activity. Traditionally, re-entrant excitation has only been associated with cardiac conditions involving scar formation, such as post-myocardial infarction or cardiac sarcoidosis. We present a case of an asymptomatic 28-year-old patient with a high burden of monomorphic PVCs originating near the posteromedial papillary muscle. Left ventricular (LV) dilatation with reduced systolic function (ejection fraction 45%) was diagnosed as PVC-induced cardiomyopathy, given the absence of fibrosis and coronary artery disease. During an electrophysiological study, a 2-cm2 region was identified where abnormal Purkinje potentials (P1), exhibiting markedly reduced conduction velocity (0.88 mm/ms), consistently followed the rapid conduction via the left posterior fascicle (LPF). Local activation time velocity vectors of P1 pinpointed the earliest abnormal Purkinje activation at the proximal LPF. The impulse excited the distal one-third of the interventricular septum before conducting retrogradely to the LPF. Radiofrequency ablation targeted at the Purkinje-myocardial pivot point successfully eliminated the PVCs, restoring LV systolic function at follow-up. Even in the absence of structural heart disease, delayed anterograde Purkinje conduction can facilitate monomorphic PVCs via re-excitation. This highlights the potential for targeted ablation at the distal Purkinje network as an effective treatment strategy.

Abstract Background/introduction Noninvasive stereotactic radiotherapy (STAR) is an emerging transmural ablative therapy for refractory ventricular tachycardia (VT). Delineation of the arrhythmogenic gross target volume (GTV) relies on electrical (exit and isthmus) VT characteristics and anatomical scar detailing. 17-AHA segmental approaches or eyeballing techniques are adopted to transfer the GTV to the treatment planning CT. An individualized 3D GTV delineated with ADAS3D based on the areas of interest of each modality could lead to a smaller GTV compared to 17-AHA segmental approaches. Purpose We investigated whether our workflow using ADAS3D for the delineating of the GTV renders smaller GTV compared to 17-AHA segmental approaches whilst remaining effective for VT treatment during follow-up. Methods We targeted 3D-personalized GTV with STAR in patients with refractory VT in structural heart disease. Electroanatomical detailing was achieved by combining high-resolution invasive and noninvasive (ECG imaging during noninvasive programmed stimulation) mapping, combined with wall thickness analyses by cardiac CT. After coregistration in ADAS3D, a 3D DICOM-radiation therapy file including the delineated target volume was generated and transferred into the free-breathing and respiration-corrected 4D CT scan. Standard STAR using a single-fraction of 20-25 Gy was applied. We compared conventional (17-AHA segmental approaches) versus 3D-based GTV demarcation, and assessed VT burden and procedural safety. Results From January 2023 to February 2024 STAR was successfully performed in three patients (all male, mean age 73±1 years, two ischemic cardiomyopathy, one laminopathy) with persistent VT despite ≥2 catheter-based (endocardial/epicardial) ablation procedures. The 3D-derived GTVs showed a statistical trend towards smaller volumes compared to conventional segmental delineation (11±4 versus 21±3 cm3, p=0.07). VT burden and ICD therapy was reduced by 100% over 9 patients-months (8-week blanking period). No acute or subacute adverse events occurred. One patient died of progressive heart failure. Conclusion 3D-individualized target volume annotation may hold promise for effective and safe STAR employment.ELSTAR workflow

Abstract Background Electromechanical window (EMW) negativity is a novel parameter that identifies long-QT syndrome (LQTS) patients at increased arrhythmia risk. Whether the EMW remains stable or alters, especially close to arrhythmic events, is unknown. Purpose To study temporal variability of the EMW in controls and in patients with LQTS or drug-induced QT prolongation (di-QTprol), in relation to the timing of torsades de pointes (TdP) or ventricular fibrillation (VF). Methods In a retrospective cohort study with 5 participating centers, we assessed the EMW (ms) at 2 or 3 timepoints (if applicable, one of them close to TdP/VF) from cw-Doppler echocardiography in the apical long-axis view and concomitant ECG. EMW was calculated by subtracting the QT time from the aortic-valve closure time measured from QRS onset (surrogate of mechanical systole). Data are shown as mean±SD or median (25th to 75th percentile). Results Forty patients (75% female, 43±18 years old) were included: 8 controls, 27 LQTS (10 symptomatic: 9 TdP, 1 VF), and 5 di-QTprol (all TdP). LQTS genotypes were LQT1 (n=11), LQT2 (n=6), LQT3 (n=7), LQT7 (n=2), and genotype-negative (n=1). Overall, 67% of LQTS patients and 20% of di-QTprol were treated with β-blockers. Baseline QTc was 409±32 ms in controls, 444±32 ms in asymptomatic LQTS, 491±41 ms in symptomatic LQTS, and 498±49 ms in di-QTprol. Baseline EMW was 6±14 ms in controls, -12±29 ms in asymptomatic LQTS, -52±16 ms in symptomatic LQTS, and -5±69 ms in di-QTprol. Over years of follow-up, EMW remained stable in controls (8±10 ms; Fig. 1A) and the asymptomatic LQTS group (-17±20 ms; Fig. 1B). In LQTS patients with TdP/VF, EMW (baseline measured at -534 (-962 to -143) days before arrhythmia) had become profoundly more negative, -127±42 ms, (p=0.01 vs. baseline) at 1 (0 to 5) days after the arrhythmia and returned to basal values, -52±18 ms, (p=0.005) after 722 (155 to 3100) days (Fig. 1C). There was a significant correlation between time-to-event and EMW negativity (r=0.72, p<0.0001), indicating stronger EMW negativity when measured closer to TdP/VF. For the di-QTprol patients (n=2 amiodarone; n=2 escitalopram; n=1 sotalol) a trend towards more exaggerated EMW negativity was observed: from baseline (at -19 (-785 to -13) days before the event) to -125±33 ms (p=0.08 vs. baseline) at 1 (1 to 5) days after TdP (Fig. 1D). Again, significant correlation was found between time-to-event and EMW negativity (r=0.6, p=0.03). Conclusion Episodes of electrical instability in patients with LQTS or di-QTprol are associated with profound but reversible exaggeration of EMW negativity. If also present just prior to TdP/VF (as in experimental models of torsadogenic di-QTprol and anecdotal LQTS cases), imminent ventricular arrhythmias may be anticipated as electromechanical reciprocity may contribute to arrhythmogenesis.Figure 1Graphical Abstract

The electromechanical window (EMW) is calculated by subtracting the repolarization duration from a mechanical reference representing contraction duration in the same heartbeat (eg, aortic valve closure during echocardiography with simultaneous electrocardiography). Here, we review the current knowledge on the role of the EMW as an independent parameter for ventricular arrhythmia-risk stratification. We (1) provide a standardized approach to echocardiographic EMW assessment, (2) define relevant cutoff values for both abnormal EMW negativity and positivity, (3) discuss pathophysiological underpinnings of EMW negativity, and (4) outline the potential future role of cardiac electromechanical relations in patients with proarrhythmic conditions.