Optimizing ventricular tachycardia ablation through imaging-based assessment of arrhythmic substrate: A comprehensive review and roadmap for the future.

Ventricular tachycardia (VT) is a life-threatening heart rhythm and has long posed a complex challenge in the field of cardiology. Recent developments in advanced imaging modalities have aimed to improve comprehension of underlying arrhythmic substrate for VT. To this extent, high-resolution cardiac magnetic resonance (CMR) and cardiac computed tomography (CCT) have emerged as tools for accurately visualizing and characterizing scar tissue, fibrosis, and other critical structural abnormalities within the heart, providing novel insights into VT triggers and substrate. However, clinical implementation of knowledge derived from these advanced imaging techniques in improving VT treatment and guiding invasive therapeutic strategies continues to pose significant challenges. A pivotal concern lies in the absence of standardized imaging protocols and analysis methodologies, resulting in a large variance in data quality and consistency. Furthermore, the clinical significance and outcomes associated with VT substrate characterization through CMR and CCT remain dynamic and subject to ongoing evolution. This highlights the need for refinement of these techniques before their reliable integration into routine patient care can be realized. The primary objectives of this study are twofold: firstly, to provide a comprehensive overview of the studies conducted over the last 15 years, summarizing the current available literature on imaging-based assessment of VT substrate. Secondly, to critically analyze and evaluate the selected studies, with the aim of providing valuable insights that can inform current clinical practice and future research.

Validation of an algorithm to prioritize patients for comprehensive medication management in primary care settings.

BACKGROUND: Comprehensive medication management (CMM) programs optimize the effectiveness and safety of patients' medication regimens, but CMM may be underutilized. Whether healthcare claims data can identify patients appropriate for CMM is not well-studied. AIM: Determine the face validity of a claims-based algorithm to prioritize patients who likely need CMM. METHOD: We used claims data to construct patient-level markers of "regimen complexity" and "high-risk for adverse effects," which were combined to define four categories of claims-based CMM-need (very likely, likely, unlikely, very unlikely) among 180 patient records. Three clinicians independently reviewed each record to assess CMM need. We assessed concordance between the claims-based and clinician-review CMM need by calculating percent agreement as well as kappa statistic. RESULTS: Most records identified as 'very likely' (90%) by claims-based markers were identified by clinician-reviewers as needing CMM. Few records within the 'very unlikely' group (5%) were identified by clinician-reviewers as needing CMM. Interrater agreement between CMM-based algorithm and clinician review was moderate in strength (kappa = 0.6, p < 0.001). CONCLUSION: Claims-based pharmacy measures may offer a valid approach to prioritize patients into CMM-need groups. Further testing of this algorithm is needed prior to implementation in clinic settings.

Structural phenotyping in atrial fibrillation with combined cardiac CT and atrial MRI: Identifying and differentiating individual structural remodelling types in AF.

INTRODUCTION: Atrial remodelling (AR) is the persistent change in atrial structure and/or function and contributes to the initiation, maintenance and progression of atrial fibrillation (AF) in a reciprocal self-perpetuating relationship. Left atrial (LA) size, geometry, fibrosis, wall thickness (LAWT) and ejection fraction (LAEF) have all been shown to vary with pathological atrial remodelling. The association of these global remodelling markers with each other for differentiating structural phenotypes in AF is not well investigated. METHOD: Patients referred for first-time AF ablation and controls without AF were prospectively recruited to undergo cardiac computed tomographic angiography (CCTA) and magnetic resonance imaging (MRI) with 3D atrial late-gadolinium enhanced (LGE) sequences. LAWT, atrial myocardial mass, LA volume and sphericity were calculated from CT. Biplane LA EF and LA fibrosis burden were derived from atrial MRI. Results were compared between patients with AF and controls. RESULTS: Forty two AF patients (64.3% male, age 64.6 ± 10.2 years, CHA2DS2-VASc 2.48 ± 1.5, 69.0% paroxysmal AF, 31% persistent AF, LVEF 57.9 ± 10.5%) and 37 controls (64.9% male, age 56.6 ± 7.2, CHA2DS2-VASc 1.54 ± 1.1, LVEF 60.4 ± 4.9%) were recruited. Patients with AF had a significantly higher LAWT (1.45 ± 0.52 mm vs 1.12 ± 0.42 mm, p = 0.003), tissue mass (15.81 ± 6.53 g vs. 12.18 ± 5.01 g, p = 0.011), fibrosis burden (9.33 ± 8.35% vs 2.41 ± 3.60%, p = 0.013), left atrial size/volume (95.68 ± 26.63 mL vs 81.22 ± 20.64 mL, p = 0.011) and lower LAEF (50.3 ± 15.3% vs 65.2 ± 8.6%, p < 0.001) compared to controls. There was no significant correlation between % fibrosis with LAWT (p = 0.29), mass (p = 0.89), volume (p = 0.49) or sphericity (p = 0.79). LAWT had a statistically significant weak positive correlation with LA volume (r = 0.25, p = .041), but not with sphericity (p = 0.86). LAEF had a statistically significant but weak negative correlation with fibrosis (r = -0.33, p = 0.008) and LAWT (r = -0.24, p = 0.07). CONCLUSION: AF is associated with significant quantifiable structural changes that are evident in LA size, tissue thickness, total LA tissue mass and fibrosis. These individual remodelling markers do not or only weakly correlate with each other suggesting different remodelling subtypes exist (e.g. fibrotic vs hypertrophic vs dilated). If confirmed, such a detailed understanding of the structural changes observed has the potential to inform clinical management strategies targeting individual mechanisms underlying the disease process.

Bariatric surgery partially reverses subclinical proarrhythmic structural, electrophysiological, and autonomic changes in obesity.

BACKGROUND: Obesity confers higher risks of cardiac arrhythmias. The extent to which weight loss reverses subclinical proarrhythmic adaptations in arrhythmia-free obese individuals is unknown. OBJECTIVE: The purpose of this study was to study structural, electrophysiological, and autonomic remodeling in arrhythmia-free obese patients and their reversibility with bariatric surgery using electrocardiographic imaging (ECGi). METHODS: Sixteen arrhythmia-free obese patients (mean age 43 ± 12 years; 13 (81%) female participants; BMI 46.7 ± 5.5 kg/m2) had ECGi pre-bariatric surgery, of whom 12 (75%) had ECGi postsurgery (BMI 36.8 ± 6.5 kg/m2). Sixteen age- and sex-matched lean healthy individuals (mean age 42 ± 11 years; BMI 22.8 ± 2.6 kg/m2) acted as controls and had ECGi only once. RESULTS: Obesity was associated with structural (increased epicardial fat volumes and left ventricular mass), autonomic (blunted heart rate variability), and electrophysiological (slower atrial conduction and steeper ventricular repolarization time gradients) remodeling. After bariatric surgery, there was partial structural reverse remodeling, with a reduction in epicardial fat volumes (68.7 cm3 vs 64.5 cm3; P = .0010) and left ventricular mass (33 g/m2.7 vs 25 g/m2.7; P < .0005). There was also partial electrophysiological reverse remodeling with a reduction in mean spatial ventricular repolarization gradients (26 mm/ms vs 19 mm/ms; P = .0009), although atrial activation remained prolonged. Heart rate variability, quantified by standard deviation of successive differences in R-R intervals, was also partially improved after bariatric surgery (18.7 ms vs 25.9 ms; P = .017). Computational modeling showed that presurgical obese hearts had a larger window of vulnerability to unidirectional block and had an earlier spiral-wave breakup with more complex reentry patterns than did postsurgery counterparts. CONCLUSION: Obesity is associated with adverse electrophysiological, structural, and autonomic remodeling that is partially reversed after bariatric surgery. These data have important implications for bariatric surgery weight thresholds and weight loss strategies.

ForCEPSS-A framework for cardiac electrophysiology simulations standardization.

BACKGROUND AND OBJECTIVE: Simulation of cardiac electrophysiology (CEP) is an important research tool that is increasingly being adopted in industrial and clinical applications. Typical workflows for CEP simulation consist of a sequence of processing stages starting with building an anatomical model and then calibrating its electrophysiological properties to match observable data. While the calibration stages are common and generalizable, most CEP studies re-implement these steps in complex and highly variable workflows. This lack of standardization renders the execution of computational CEP studies in an efficient, robust, and reproducible manner a significant challenge. Here, we propose ForCEPSS as an efficient and robust, yet flexible, software framework for standardizing CEP simulation studies. METHODS AND RESULTS: Key processing stages of CEP simulation studies are identified and implemented in a standardized workflow that builds on openCARP1 Plank et al. (2021) and the Python-based carputils2 framework. Stages include (i) the definition and initialization of action potential phenotypes, (ii) the tissue scale calibration of conduction properties, (iii) the functional initialization to approximate a limit cycle corresponding to the dynamic reference state according to an experimental protocol, and, (iv) the execution of the CEP study where the electrophysiological response to a perturbation of the limit cycle is probed. As an exemplar application, we employ ForCEPSS to prepare a CEP study according to the Virtual Arrhythmia Risk Prediction protocol used for investigating the arrhythmogenic risk of developing infarct-related ventricular tachycardia (VT) in ischemic cardiomyopathy patients. We demonstrate that ForCEPSS enables a fully automated execution of all stages of this complex protocol. CONCLUSION: ForCEPSS offers a novel comprehensive, standardized, and automated CEP simulation workflow. The high degree of automation accelerates the execution of CEP simulation studies, reduces errors, improves robustness, and makes CEP studies reproducible. Verification of simulation studies within the CEP modeling community is thus possible. As such, ForCEPSS makes an important contribution towards increasing transparency, standardization, and reproducibility of in silico CEP experiments.

Predicting postinfarct ventricular tachycardia by integrating cardiac MRI and advanced computational reentrant pathway analysis.

BACKGROUND: Implantable cardiac defibrillator (ICD) implantation can protect against sudden cardiac death after myocardial infarction. However, improved risk stratification for device requirement is still needed. OBJECTIVE: The purpose of this study was to improve assessment of postinfarct ventricular electropathology and prediction of appropriate ICD therapy by combining late gadolinium enhancement (LGE) and advanced computational modeling. METHODS: ADAS 3D LV (ADAS LV Medical, Barcelona, Spain) and custom-made software were used to generate 3-dimensional patient-specific ventricular models in a prospective cohort of patients with a myocardial infarction (N = 40) having undergone LGE imaging before ICD implantation. Corridor metrics and 3-dimensional surface features were computed from LGE images. The Virtual Induction and Treatment of Arrhythmias (VITA) framework was applied to patient-specific models to comprehensively probe the vulnerability of the scar substrate to sustaining reentrant circuits. Imaging and VITA metrics, related to the numbers of induced ventricular tachycardias and their corresponding round trip times (RTTs), were compared with ICD therapy during follow-up. RESULTS: Patients with an event (n = 17) had a larger interface between healthy myocardium and scar and higher VITA metrics. Cox regression analysis demonstrated a significant independent association with an event: interface (hazard ratio [HR] 2.79; 95% confidence interval [CI] 1.44-5.44; P < .01), unique ventricular tachycardias (HR 1.67; 95% CI 1.04-2.68; P = .03), mean RTT (HR 2.14; 95% CI 1.11-4.12; P = .02), and maximum RTT (HR 2.13; 95% CI 1.19-3.81; P = .01). CONCLUSION: A detailed quantitative analysis of LGE-based scar maps, combined with advanced computational modeling, can accurately predict ICD therapy and could facilitate the early identification of high-risk patients in addition to left ventricular ejection fraction.

Developing Cardiac Digital Twins at Scale: Insights from Personalised Myocardial Conduction Velocity.

Large-cohort studies using cardiovascular imaging and diagnostic datasets have assessed cardiac anatomy, function, and outcomes, but typically do not reveal underlying biological mechanisms. Cardiac digital twins (CDTs) provide personalized physics- and physiology-constrained in-silico representations, enabling inference of multi-scale properties tied to these mechanisms. We constructed 3464 anatomically-accurate CDTs using cardiac magnetic resonance images from UK biobank and personalised their myocardial conduction velocities (CVs) from electrocardiograms (ECG), through an automated framework. We found well-known sex-specific differences in QRS duration were fully explained by myocardial anatomy, as CV remained consistent across sexes. Conversely, significant associations of CV with ageing and increased BMI suggest myocardial tissue remodelling. Novel associations were observed with left ventricular ejection fraction and mental-health phenotypes, through a phenome-wide association study, and CV was also linked with adverse clinical outcomes. Our study highlights the utility of population-based CDTs in assessing intersubject variability and uncovering strong links with mental health.

Managing arrhythmia in cardiac resynchronisation therapy.

Arrhythmia is an extremely common finding in patients receiving cardiac resynchronisation therapy (CRT). Despite this, in the majority of randomised trials testing CRT efficacy, patients with a recent history of arrhythmia were excluded. Most of our knowledge into the management of arrhythmia in CRT is therefore based on arrhythmia trials in the heart failure (HF) population, rather than from trials dedicated to the CRT population. However, unique to CRT patients is the aim to reach as close to 100% biventricular pacing (BVP) as possible, with HF outcomes greatly influenced by relatively small changes in pacing percentage. Thus, in comparison to the average HF patient, there is an even greater incentive for controlling arrhythmia, to achieve minimal interference with the effective delivery of BVP. In this review, we examine both atrial and ventricular arrhythmias, addressing their impact on CRT, and discuss the available evidence regarding optimal arrhythmia management in this patient group. We review pharmacological and procedural-based approaches, and lastly explore novel ways of harnessing device data to guide treatment of arrhythmia in CRT.

Associations between the use of a real-time benefit tool and measures related to prescription obtainment found in order type subgroups.

BACKGROUND: The use of real-time benefit tool (RTBT) may help increase transparency of patients' out-of-pocket (OOP) costs, thereby reducing patients' OOP spend and increasing prescription obtainment. OBJECTIVE: We have previously reported on the potential benefit of RTBT in electronic health records at a large health system. We explore the benefit of RTBT by subgroups of prescriptions (i.e., order types). METHODS: In a retrospective cohort, we reviewed orders generated with and without RTBT use. We compared the 2 groups on key metrics related to prescription obtainment (fill rate, modification rate, cancellation rate, time to ready, time to sold, abandonment rate, and cancellation and transfer rate). Subgroup analysis included orders without over-the-counter (OTC) medications, orders without specialty medications, and orders without OTC and specialty medications. RESULTS: Fill rate, cancellation rate, time to ready, time to sold, abandonment rate, and cancellation and transfer rate were statistically significantly different between the RTBT and non-RTBT groups, favoring the RTBT group (all, P < 0.01). Differences in modification rates were not statistically significant between the 2 groups. CONCLUSION: RTBTs have the potential to increase prescription obtainment. A consistent difference in key outcome measures between the RTBT and the non-RTBT groups was apparent among prescription orders regardless of whether OTC and specialty medications were included in the analysis.

Arrhythmogenic vulnerability of re-entrant pathways in post-infarct ventricular tachycardia assessed by advanced computational modelling.

AIMS: Substrate assessment of scar-mediated ventricular tachycardia (VT) is frequently performed using late gadolinium enhancement (LGE) images. Although this provides structural information about critical pathways through the scar, assessing the vulnerability of these pathways for sustaining VT is not possible with imaging alone.This study evaluated the performance of a novel automated re-entrant pathway finding algorithm to non-invasively predict VT circuit and inducibility. METHODS: Twenty post-infarct VT-ablation patients were included for retrospective analysis. Commercially available software (ADAS3D left ventricular) was used to generate scar maps from 2D-LGE images using the default 40-60 pixel-signal-intensity (PSI) threshold. In addition, algorithm sensitivity for altered thresholds was explored using PSI 45-55, 35-65, and 30-70. Simulations were performed on the Virtual Induction and Treatment of Arrhythmias (VITA) framework to identify potential sites of block and assess their vulnerability depending on the automatically computed round-trip-time (RTT). Metrics, indicative of substrate complexity, were correlated with VT-recurrence during follow-up. RESULTS: Total VTs (85 ± 43 vs. 42 ± 27) and unique VTs (9 ± 4 vs. 5 ± 4) were significantly higher in patients with- compared to patients without recurrence, and were predictive of recurrence with area under the curve of 0.820 and 0.770, respectively. VITA was robust to scar threshold variations with no significant impact on total and unique VTs, and mean RTT between the four models. Simulation metrics derived from PSI 45-55 model had the highest number of parameters predictive for post-ablation VT-recurrence. CONCLUSION: Advanced computational metrics can non-invasively and robustly assess VT substrate complexity, which may aid personalized clinical planning and decision-making in the treatment of post-infarction VT.

Left bundle branch area pacing reduces epicardial dispersion of repolarization compared with biventricular cardiac resynchronization therapy.

BACKGROUND: Biventricular endocardial pacing (BiV-endo) and left bundle branch area pacing (LBBAP) are novel methods of delivering cardiac resynchronization therapy. These techniques are associated with improved activation times and acute hemodynamic response compared with conventional biventricular epicardial pacing (BiV-epi); however, the effects on repolarization and arrhythmic risk are unknown. OBJECTIVE: The purpose of this study was to compare the effects of temporary BiV-epi, BiV-endo, and LBBAP on epicardial left ventricular (LV) repolarization using electrocardiographic imaging (ECGi). METHODS: Eleven patients indicated for cardiac resynchronization therapy underwent a temporary pacing protocol with ECGi. BiV-endo was delivered via endocardial stimulation of the LV lateral wall. LBBAP was delivered by pacing the LV septum. Epicardial LV repolarization time (LVRT-95; time taken for 95% of the LV to repolarize), LV RT dispersion, mean LV activation recovery interval (ARI), LV ARI dispersion, and RT gradients were calculated. RESULTS: The protocol was completed in 10 patients. During LBBAP, there were significant reductions in LVRT-95 (94.9 ± 17.4 ms vs 125.0 ± 29.4 ms; P = .03) and LV RT dispersion (29.4 ± 6.3 ms vs 40.8 ± 11.4 ms; P = .015) compared with BiV-epi. In contrast, there were no significant differences between baseline, BiV-epi, or BiV-endo. There was a nonsignificant reduction in mean RT gradients between LBBAP and baseline rhythm (0.74 ± 0.22 ms/mm vs 1.01 ± 0.31 ms/mm; P = .07). There were no significant differences in mean LV ARI or LV ARI dispersion between groups. CONCLUSION: Temporary LBBAP reduces epicardial dispersion of repolarization compared with conventional BiV-epi. Further study is required to determine whether these repolarization changes on ECGi translate into a reduced risk of ventricular arrhythmia in clinical practice.

Additional coils mitigate elevated defibrillation threshold in right-sided implantable cardioverter defibrillator generator placement: a simulation study.

AIMS: The standard implantable cardioverter defibrillator (ICD) generator (can) is placed in the left pectoral area; however, in certain circumstances, right-sided cans may be required which may increase defibrillation threshold (DFT) due to suboptimal shock vectors. We aim to quantitatively assess whether the potential increase in DFT of right-sided can configurations may be mitigated by alternate positioning of the right ventricular (RV) shocking coil or adding coils in the superior vena cava (SVC) and coronary sinus (CS). METHODS AND RESULTS: A cohort of CT-derived torso models was used to assess DFT of ICD configurations with right-sided cans and alternate positioning of RV shock coils. Efficacy changes with additional coils in the SVC and CS were evaluated. A right-sided can with an apical RV shock coil significantly increased DFT compared to a left-sided can [19.5 (16.4, 27.1) J vs. 13.3 (11.7, 19.9) J, P < 0.001]. Septal positioning of the RV coil led to a further DFT increase when using a right-sided can [26.7 (18.1, 36.1) J vs. 19.5 (16.4, 27.1) J, P < 0.001], but not a left-sided can [12.1 (8.1, 17.6) J vs. 13.3 (11.7, 19.9) J, P = 0.099). Defibrillation threshold of a right-sided can with apical or septal coil was reduced the most by adding both SVC and CS coils [19.5 (16.4, 27.1) J vs. 6.6 (3.9, 9.9) J, P < 0.001, and 26.7 (18.1, 36.1) J vs. 12.1 (5.7, 13.5) J, P < 0.001]. CONCLUSION: Right-sided, compared to left-sided, can positioning results in a 50% increase in DFT. For right-sided cans, apical shock coil positioning produces a lower DFT than septal positions. Elevated right-sided can DFTs may be mitigated by utilizing additional coils in SVC and CS.

Machine learning analysis of complex late gadolinium enhancement patterns to improve risk prediction of major arrhythmic events.

Background: Machine learning analysis of complex myocardial scar patterns affords the potential to enhance risk prediction of life-threatening arrhythmia in stable coronary artery disease (CAD). Objective: To assess the utility of computational image analysis, alongside a machine learning (ML) approach, to identify scar microstructure features on late gadolinium enhancement cardiovascular magnetic resonance (LGE-CMR) that predict major arrhythmic events in patients with CAD. Methods: Patients with stable CAD were prospectively recruited into a CMR registry. Shape-based scar microstructure features characterizing heterogeneous ('peri-infarct') and homogeneous ('core') fibrosis were extracted. An ensemble of machine learning approaches were used for risk stratification, in addition to conventional analysis using Cox modeling. Results: Of 397 patients (mean LVEF 45.4 ± 16.0) followed for a median of 6 years, 55 patients (14%) experienced a major arrhythmic event. When applied within an ML model for binary classification, peri-infarct zone (PIZ) entropy, peri-infarct components and core interface area outperformed a model representative of the current standard of care (LVEF<35% and NYHA>Class I): AUROC (95%CI) 0.81 (0.81-0.82) vs. 0.64 (0.63-0.65), p = 0.002. In multivariate cox regression analysis, these features again remained significant after adjusting for LVEF<35% and NYHA>Class I: PIZ entropy hazard ratio (HR) 1.88, 95% confidence interval (CI) 1.38-2.56, p < 0.001; number of PIZ components HR 1.34, 95% CI 1.08-1.67, p = 0.009; core interface area HR 1.6, 95% CI 1.29-1.99, p = <0.001. Conclusion: Machine learning models using LGE-CMR scar microstructure improved arrhythmic risk stratification as compared to guideline-based clinical parameters; highlighting a potential novel approach to identifying candidates for implantable cardioverter defibrillators in stable CAD.

Comprehensive Phenotypic Characterization of Late Gadolinium Enhancement Predicts Sudden Cardiac Death in Coronary Artery Disease.

BACKGROUND: Late gadolinium enhancement (LGE) cardiac magnetic resonance (CMR) offers the potential to noninvasively characterize the phenotypic substrate for sudden cardiac death (SCD). OBJECTIVES: The authors assessed the utility of infarct characterization by CMR, including scar microstructure analysis, to predict SCD in patients with coronary artery disease (CAD). METHODS: Patients with stable CAD were prospectively recruited into a CMR registry. LGE quantification of core infarction and the peri-infarct zone (PIZ) was performed alongside computational image analysis to extract morphologic and texture scar microstructure features. The primary outcome was SCD or aborted SCD. RESULTS: Of 437 patients (mean age: 64 years; mean left ventricular ejection fraction [LVEF]: 47%) followed for a median of 6.3 years, 49 patients (11.2%) experienced the primary outcome. On multivariable analysis, PIZ mass and core infarct mass were independently associated with the primary outcome (per gram: HR: 1.07 [95% CI: 1.02-1.12]; P = 0.002 and HR: 1.03 [95% CI: 1.01-1.05]; P = 0.01, respectively), and the addition of both parameters improved discrimination of the model (Harrell's C-statistic: 0.64-0.79). PIZ mass, however, did not provide incremental prognostic value over core infarct mass based on Harrell's C-statistic or risk reclassification analysis. Severely reduced LVEF did not predict the primary endpoint after adjustment for scar mass. On scar microstructure analysis, the number of LGE islands in addition to scar transmurality, radiality, interface area, and entropy were all associated with the primary outcome after adjustment for severely reduced LVEF and New York Heart Association functional class of >1. No scar microstructure feature remained associated with the primary endpoint when PIZ mass and core infarct mass were added to the regression models. CONCLUSIONS: Comprehensive LGE characterization independently predicted SCD risk beyond conventional predictors used in implantable cardioverter-defibrillator (ICD) insertion guidelines. These results signify the potential for a more personalized approach to determining ICD candidacy in CAD.

Frequency Domain Analysis of Endocardial Electrograms for Detection of Nontransmural Myocardial Fibrosis in Nonischemic Cardiomyopathy.

BACKGROUND: Voltage mapping in nonischemic cardiomyopathy can fail to identify midmyocardial substrate for ventricular arrhythmias, an important cause of ablation failure. OBJECTIVES: The aim of this study was to assess whether frequency domain analysis of endocardial left ventricular electrograms (EGMs) can better predict the presence of midmyocardial fibrosis (MMF) compared with voltage amplitude. METHODS: Nonischemic cardiomyopathy patients undergoing ventricular tachycardia ablation with registered preprocedural cardiac computed tomography and late iodine enhancement were included. Presence of fibrosis at each EGM site was assessed. Bipolar and unipolar EGMs were transformed to the frequency domain using multitaper spectral analysis. Singular value decomposition of the EGM frequency spectrum was used within a supervised machine learning process to select features to predict the presence of MMF and compare against predictions using voltage amplitude. RESULTS: Thirteen patients were included (median age 57 years [IQR: 28-73 years], median ejection fraction 40% [IQR: 15%-57%]). A total of 6,015 EGM pairs were processed: 2,459 EGM pairs in MMF areas and 3,556 EGM pairs in non-MMF areas. Supervised classifiers were trained with stratified k-fold cross-validation within patients. The distribution of mean area under the curve metrics using frequency features, f, was significantly greater than voltage feature area under the curve metrics, v, (mean f = 0.841 [95% CI: 0.789-0.884] vs mean v = 0.591 [95% CI: 0.530-0.658]; P < 0.001), indicating that frequency-trained classifiers better predicted the presence of MMF. CONCLUSIONS: These data indicate the promising discriminatory value of endocardial EGM frequency content in the assessment of concealed myocardial substrate. Further studies are needed to investigate the importance of the specific frequency features identified.

Assessing the arrhythmogenic risk of engineered heart tissue patches through in silico application on infarcted ventricle models.

BACKGROUND: Post myocardial infarction (MI) ventricles contain fibrotic tissue and may have disrupted electrical properties, both of which predispose to an increased risk of life-threatening arrhythmias. Application of epicardial patches obtained from human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) are a potential long-term therapy to treat heart failure resulting from post MI remodelling. However, whether the introduction of these patches is anti- or pro-arrhythmic has not been studied. METHODS: We studied arrhythmic risk using in silico engineered heart tissue (EHT) patch engraftment on human post-MI ventricular models. Two patient models were studied, including one with a large dense scar and one with an apparent channel of preserved viability bordered on both sides by scar. In each heart model a virtual EHT patch was introduced as a layer of viable tissue overlying the scarred area, with hiPSC-CMs electrophysiological properties. The incidence of re-entrant and sustained activation in simulations with and without EHT patches was assessed and the arrhythmia inducibility compared in the context of different EHT patch properties (conduction velocity (CV) and action potential duration (APD)). The impact of the EHT patch on the likelihood of focal ectopic impulse propagation was estimated by assessing the minimum stimulus strength and duration required to generate a propagating impulse in the scar border zone (BZ) with and without patch. RESULTS: We uncovered two main mechanisms by which ventricular tachycardia (VT) risk could be either augmented or attenuated by the interaction of the patch with the tissue. In the case of isthmus-related VT, our simulations predict that EHT patches can prevent the induction of VT when the, generally longer, hiPSC-CMs APD is reduced towards more physiological values. In the case of large dense scar, we found that, an EHT patch with CV similar to the host myocardium does not promote VT, while EHT patches with lower CV increase the risk of VT, by promoting both non-sustained and sustained re-entry. Finally, our simulations indicate that electrically coupled EHT patches reduce the likelihood of propagation of focal ectopic impulses. CONCLUSIONS: The introduction of EHT patches as a treatment for heart failure has the potential to augment or attenuate the risk of ventricular arrhythmias, and variations in the anatomic configuration of the substrate, the functional properties of the BZ and the electrophysiologic properties of the patch itself will determine the overall impact. Planning for delivery of this therapy will need to consider the possible impact on arrhythmia.

Optimization of anti-tachycardia pacing efficacy through scar-specific delivery and minimization of re-initiation: a virtual study on a cohort of infarcted porcine hearts.

AIMS: Anti-tachycardia pacing (ATP) is a reliable electrotherapy to painlessly terminate ventricular tachycardia (VT). However, ATP is often ineffective, particularly for fast VTs. The efficacy may be enhanced by optimized delivery closer to the re-entrant circuit driving the VT. This study aims to compare ATP efficacy for different delivery locations with respect to the re-entrant circuit, and further optimize ATP by minimizing failure through re-initiation. METHODS AND RESULTS: Seventy-three sustained VTs were induced in a cohort of seven infarcted porcine ventricular computational models, largely dominated by a single re-entrant pathway. The efficacy of burst ATP delivered from three locations proximal to the re-entrant circuit (septum) and three distal locations (lateral/posterior left ventricle) was compared. Re-initiation episodes were used to develop an algorithm utilizing correlations between successive sensed electrogram morphologies to automatically truncate ATP pulse delivery. Anti-tachycardia pacing was more efficacious at terminating slow compared with fast VTs (65 vs. 46%, P = 0.000039). A separate analysis of slow VTs showed that the efficacy was significantly higher when delivered from distal compared with proximal locations (distal 72%, proximal 59%), being reversed for fast VTs (distal 41%, proximal 51%). Application of our early termination detection algorithm (ETDA) accurately detected VT termination in 79% of re-initiated cases, improving the overall efficacy for proximal delivery with delivery inside the critical isthmus (CI) itself being overall most effective. CONCLUSION: Anti-tachycardia pacing delivery proximal to the re-entrant circuit is more effective at terminating fast VTs, but less so slow VTs, due to frequent re-initiation. Attenuating re-initiation, through ETDA, increases the efficacy of delivery within the CI for all VTs.

Initiation of ventricular arrhythmia in the acquired long QT syndrome.

AIMS: Long QT syndrome (LQTS) carries a risk of life-threatening polymorphic ventricular tachycardia (Torsades de Pointes, TdP) and is a major cause of premature sudden cardiac death. TdP is induced by R-on-T premature ventricular complexes (PVCs), thought to be generated by cellular early-afterdepolarisations (EADs). However, EADs in tissue require cellular synchronisation, and their role in TdP induction remains unclear. We aimed to determine the mechanism of TdP induction in rabbit hearts with acquired LQTS (aLQTS). METHODS AND RESULTS: Optical mapping of action potentials (APs) and intracellular Ca2+ was performed in Langendorff-perfused rabbit hearts (n = 17). TdP induced by R-on-T PVCs was observed during aLQTS (50% K+/Mg++ & E4031) conditions in all hearts (P < 0.0001 vs. control). Islands of AP prolongation bounded by steep voltage gradients (VGs) were consistently observed before arrhythmia and peak VGs were more closely related to the PVC upstroke than EADs, both temporally (7 ± 5 ms vs. 44 ± 27 ms, P < 0.0001) and spatially (1.0 ± 0.7 vs. 3.6 ± 0.9 mm, P < 0.0001). PVCs were initiated at estimated voltages of ∼ -40 mV and had upstroke dF/dtmax and Vm-Ca2+ dynamics compatible with ICaL activation. Computational simulations demonstrated that PVCs could arise directly from VGs, through electrotonic triggering of ICaL. In experiments and the model, sub-maximal L-type Ca2+ channel (LTCC) block (200 nM nifedipine and 90% gCaL, respectively) abolished both PVCs and TdP in the continued presence of aLQTS. CONCLUSION: These data demonstrate that ICaL activation at sites displaying steep VGs generates the PVCs which induce TdP, providing a mechanism and rationale for LTCC blockers as a novel therapeutic approach in LQTS.