Variant patterns of electrical activation and recovery in normal human hearts revealed by noninvasive electrocardiographic imaging.

AIMS: Although electrical activity of the normal human heart is well characterized by the electrocardiogram, detailed insights into within-subject and between-subject variations of ventricular activation and recovery by noninvasive electroanatomic mapping are lacking. We characterized human epicardial activation and recovery within and between normal subjects using non-invasive electrocardiographic imaging (ECGI) as a basis to better understand pathology. METHODS AND RESULTS: Epicardial activation and recovery were assessed by ECGI in 22 normal subjects, 4 subjects with bundle branch block (BBB) and 4 with long-QT syndrome (LQTS). We compared characteristics between the ventricles [left ventricle (LV) and right ventricle (RV)], sexes, and age groups (<50/≥50years). Pearson's correlation coefficient (CC) was used for within-subject and between-subject comparisons. Age of normal subjects averaged 49 ± 14 years, 6/22 were male, and no structural/electrical heart disease was present. The average activation time was longer in LV than in RV, but not different by sex or age. Electrical recovery was similar for the ventricles, but started earlier and was on average shorter in males. Median CCs of between-subject comparisons of the ECG signals, activation, and recovery patterns were 0.61, 0.32, and 0.19, respectively. Within-subject beat-to-beat comparisons yielded higher CCs (0.98, 0.89, and 0.82, respectively). Activation and/or recovery patterns of patients with BBB or LQTS contrasted significantly with those found in the normal population. CONCLUSION: Activation and recovery patterns vary profoundly between normal subjects, but are stable individually beat to beat, with a male preponderance to shorter recovery. Individual characterization by ECGI at baseline serves as reference to better understand the emergence, progression, and treatment of electrical heart disease.

Impact of repeat ablation of ventricular tachycardia in patients with structural heart disease.

AIMS: Recurrences of ventricular tachycardia (VT) after initial catheter ablation is a significant clinical problem. In this study, we report the efficacy and risks of repeat VT ablation in patients with structural heart disease (SHD) in a tertiary single centre over a 7-year period. METHODS AND RESULTS: Two hundred ten consecutive patients referred for repeat VT ablation after previous ablation in our institution were included in the analysis (53% ischaemic cardiomyopathy, 91% males, median age 65 years, mean left ventricular ejection fraction 35%). After performing repeat ablation, the clinical VTs were acutely eliminated in 82% of the patients, but 46% of the cohort presented with VT recurrence during the 25-month follow-up. Repeat ablation led to a 73% reduction of shock burden in the first year and 61% reduction until the end of follow-up. Similarly, VT burden was reduced 55% in the first year and 36% until the end of the study. Fifty-two patients (25%) reached the combined endpoint of ventricular assist device implantation, heart transplantation, or death. Advanced New York Heart Association functional class, anteroseptal substrate, and periprocedural complication after repeat ablation were associated with worse prognosis independently of the type of cardiomyopathy. CONCLUSION: While complete freedom from VT after repeat ablation in SHD was difficult to achieve, ablation led to a significant reduction in VT and shock burden. Besides advanced heart failure characteristics, anteroseptal substrate and periprocedural complications predicted a worse outcome.

The genetic basis of apparently idiopathic ventricular fibrillation: a retrospective overview.

AIMS: During the diagnostic work-up of patients with idiopathic ventricular fibrillation (VF), next-generation sequencing panels can be considered to identify genotypes associated with arrhythmias. However, consensus for gene panel testing is still lacking, and variants of uncertain significance (VUS) are often identified. The aim of this study was to evaluate genetic testing and its results in idiopathic VF patients. METHODS AND RESULTS: We investigated 419 patients with available medical records from the Dutch Idiopathic VF Registry. Genetic testing was performed in 379 (91%) patients [median age at event 39 years (27-51), 60% male]. Single-gene testing was performed in 87 patients (23%) and was initiated more often in patients with idiopathic VF before 2010. Panel testing was performed in 292 patients (77%). The majority of causal (likely) pathogenic variants (LP/P, n = 56, 15%) entailed the DPP6 risk haplotype (n = 39, 70%). Moreover, 10 LP/P variants were found in cardiomyopathy genes (FLNC, MYL2, MYH7, PLN (two), TTN (four), RBM20), and 7 LP/P variants were identified in genes associated with cardiac arrhythmias (KCNQ1, SCN5A (2), RYR2 (four)). For eight patients (2%), identification of an LP/P variant resulted in a change of diagnosis. In 113 patients (30%), a VUS was identified. Broad panel testing resulted in a higher incidence of VUS in comparison to single-gene testing (38% vs. 3%, P < 0.001). CONCLUSION: Almost all patients from the registry underwent, albeit not broad, genetic testing. The genetic yield of causal LP/P variants in idiopathic VF patients is 5%, increasing to 15% when including DPP6. In specific cases, the LP/P variant is the underlying diagnosis. A gene panel specifically for idiopathic VF patients is proposed.

STereotactic Arrhythmia Radioablation (STAR): the Standardized Treatment and Outcome Platform for Stereotactic Therapy Of Re-entrant tachycardia by a Multidisciplinary consortium (STOPSTORM.eu) and review of current patterns of STAR practice in Europe.

The EU Horizon 2020 Framework-funded Standardized Treatment and Outcome Platform for Stereotactic Therapy Of Re-entrant tachycardia by a Multidisciplinary (STOPSTORM) consortium has been established as a large research network for investigating STereotactic Arrhythmia Radioablation (STAR) for ventricular tachycardia (VT). The aim is to provide a pooled treatment database to evaluate patterns of practice and outcomes of STAR and finally to harmonize STAR within Europe. The consortium comprises 31 clinical and research institutions. The project is divided into nine work packages (WPs): (i) observational cohort; (ii) standardization and harmonization of target delineation; (iii) harmonized prospective cohort; (iv) quality assurance (QA); (v) analysis and evaluation; (vi, ix) ethics and regulations; and (vii, viii) project coordination and dissemination. To provide a review of current clinical STAR practice in Europe, a comprehensive questionnaire was performed at project start. The STOPSTORM Institutions' experience in VT catheter ablation (83% ≥ 20 ann.) and stereotactic body radiotherapy (59% > 200 ann.) was adequate, and 84 STAR treatments were performed until project launch, while 8/22 centres already recruited VT patients in national clinical trials. The majority currently base their target definition on mapping during VT (96%) and/or pace mapping (75%), reduced voltage areas (63%), or late ventricular potentials (75%) during sinus rhythm. The majority currently apply a single-fraction dose of 25 Gy while planning techniques and dose prescription methods vary greatly. The current clinical STAR practice in the STOPSTORM consortium highlights potential areas of optimization and harmonization for substrate mapping, target delineation, motion management, dosimetry, and QA, which will be addressed in the various WPs.

Electromechanical reciprocity and arrhythmogenesis in long-QT syndrome and beyond.

An abundance of literature describes physiological and pathological determinants of cardiac performance, building on the principles of excitation-contraction coupling. However, the mutual influencing of excitation-contraction and mechano-electrical feedback in the beating heart, here designated 'electromechanical reciprocity', remains poorly recognized clinically, despite the awareness that external and cardiac-internal mechanical stimuli can trigger electrical responses and arrhythmia. This review focuses on electromechanical reciprocity in the long-QT syndrome (LQTS), historically considered a purely electrical disease, but now appreciated as paradigmatic for the understanding of mechano-electrical contributions to arrhythmogenesis in this and other cardiac conditions. Electromechanical dispersion in LQTS is characterized by heterogeneously prolonged ventricular repolarization, besides altered contraction duration and relaxation. Mechanical alterations may deviate from what would be expected from global and regional repolarization abnormalities. Pathological repolarization prolongation outlasts mechanical systole in patients with LQTS, yielding a negative electromechanical window (EMW), which is most pronounced in symptomatic patients. The electromechanical window is a superior and independent arrhythmia-risk predictor compared with the heart rate-corrected QT. A negative EMW implies that the ventricle is deformed-by volume loading during the rapid filling phase-when repolarization is still ongoing. This creates a 'sensitized' electromechanical substrate, in which inadvertent electrical or mechanical stimuli such as local after-depolarizations, after-contractions, or dyssynchrony can trigger abnormal impulses. Increased sympathetic-nerve activity and pause-dependent potentiation further exaggerate electromechanical heterogeneities, promoting arrhythmogenesis. Unraveling electromechanical reciprocity advances the understanding of arrhythmia formation in various conditions. Real-time image integration of cardiac electrophysiology and mechanics offers new opportunities to address challenges in arrhythmia management.

Spatiotemporal approximation of cardiac activation and recovery isochrones.

BACKGROUND: The sequence of myocardial activation and recovery can be studied in detail by invasive catheter recordings of cardiac electrograms (EGMs), or noninvasive inverse reconstructions thereof with electrocardiographic imaging (ECGI). Local activation and recovery times are obtained from a unipolar EGM by the moment of maximum downslope of the QRS complex or maximum upslope of the T wave, respectively. However, both invasive and noninvasive recordings of intracardiac EGMs may suffer from noise and fractionation, making reliable detection of these deflections nontrivial. METHODS: Here, we introduce a novel method that benefits from the spatial coupling of these processes, and incorporate not only the temporal EGM deflection, but also the spatial gradients. We validated this approach in computer simulations, in animal data with ECGI and invasive electrode recordings, and illustrated its use in a clinical case. RESULTS: In the simulated data, the spatiotemporal approach was able to incorporate spatial information to better select the correct deflection in artificially fractionated EGMs and outperformed the traditional temporal-only method. In experimental data, the accuracy of time estimation from ECGI compared to invasive recordings significantly increased from R = 0.73 (activation) and R = 0.58 (recovery) with the temporal-only method to R = 0.79 (activation) and R = 0.72 (recovery) with the novel approach. Localization of the pacing origin of paced beats improved significantly from 36 mm mean error with the temporal-only approach to 23 mm with the spatiotemporal approach. CONCLUSION: The spatiotemporal method to compute activation and recovery times from EGMs outperformed the traditional temporal-only approach in which spatial information was not taken into account.

Elimination of Benign Ventricular Premature Beats or Ventricular Tachycardia with Catheter Ablation versus Two Different Optimal Antiarrhythmic Drug Treatment Regimens (Sotalol or Verapamil/Flecainide).

BACKGROUND: Symptomatic idiopathic ventricular arrhythmias (VA), including premature beats (VPB) and nonsustained ventricular tachycardia (VT) are commonly encountered arrhythmias. Although these VA are usually benign, their treatment can be a challenge to primary and secondary health care providers. Mainstay treatment is comprised of antiarrhythmic drugs (AAD) and, in case of drug intolerance or failure, patients are referred for catheter ablation to tertiary health care centers. These patients require extensive medical attention and drug regimens usually have disappointing results. A direct comparison between the efficacy of the most potent AAD and primary catheter ablation in these patients is lacking. The ECTOPIA trial will evaluate the efficacy of 2 pharmacological strategies and 1 interventional approach to: suppress the VA burden, improve the quality of life (QoL), and safety. HYPOTHESIS: We hypothesize that flecainide/verapamil combination and catheter ablation are both superior to sotalol in suppressing VA in patients with symptomatic idiopathic VA. STUDY DESIGN: The Elimination of Ventricular Premature Beats with Catheter Ablation versus Optimal Antiarrhythmic Drug Treatment (ECTOPIA) trial is a randomized, multicenter, prospective clinical trial to compare the efficacy of catheter ablation versus optimal AAD treatment with sotalol or flecainide/verapamil. One hundred eighty patients with frequent symptomatic VA in the absence of structural heart disease or underlying cardiac ischemia who are eligible for catheter ablation with an identifiable monomorphic VA origin with a burden ≥5% on 24-h ambulatory rhythm monitoring will be included. Patients will be randomized in a 1:1:1 fashion. The primary endpoint is defined as >80% reduction of the VA burden on 24-h ambulatory Holter monitoring. After reaching the primary endpoint, patients randomized to one of the 2 AAD arms will undergo a cross-over to the other AAD treatment arm to explore differences in drug efficacy and QoL in individual patients. Due to the use of different AAD (with and without ß-blocking characteristics) we will be able to explore the influence of alterations in sympathetic tone on VA burden reduction in different subgroups. Finally, this study will assess the safety of treatment with 2 different AAD and ablation of VA.

Shorter RSPV cryoapplications result in less phrenic nerve injury and similar 1-year freedom from atrial fibrillation.

BACKGROUND: In the 123-study, we prospectively assessed, in a randomized fashion, the minimal cryoballoon application time necessary to achieve pulmonary vein (PV) isolation (PVI) in patients with paroxysmal atrial fibrillation (AF) with the aim to reduce complications by shortening the application duration. The first results of this study demonstrated that shortened cryoballoon applications (<2 minutes) resulted in less phrenic nerve injury (PNI) without compromising acute isolation efficacy for the right PVs. We now report the 1-year follow-up results regarding safety and efficacy of shorter cryoballoon applications. METHODS: A total of 222 patients with AF were randomized to two applications of 1 min "short," 2 min "medium," or 3 min "long" duration, 74 per group. Recurrence of AF and PV reconduction at 1-year follow-up were assessed. RESULTS: The overall 1-year freedom from AF was 79% and did not differ significantly between the short, medium, and long application groups (77%, 74%, and 85% for short, medium, and long application groups, respectively; P = 0.07). In 30 patients, a redo PVI procedure was performed. For all four PVs, there was no significant difference in reconduction between the three groups. Reconduction was most common in the left superior PV (57%). The right superior PV (RSPV) showed significantly less reconduction (17%) compared to the other PVs. CONCLUSIONS: Shortening cryoballoon applications of the RSPV to <2 minutes results in less PNI, while acute success and 1-year freedom from AF are not compromised. Therefore, shorter cryoballoon applications (especially) in the RSPV could be used to reduce PNI.

Shorter cryoballoon applications times do effect efficacy but result in less phrenic nerve injury: Results of the randomized 123 study.

BACKGROUND: The second-generation cryoballoon significantly improves outcome of pulmonary vein isolation (PVI) but may cause more complications than the first generation. Currently, no consensus regarding optimal cryoballoon application time exists. The 123-study aimed to assess the minimal cryoballoon application duration necessary to achieve PVI (primary endpoint) and the effect of application duration on prevention of phrenic nerve injury (PNI). METHODS: Patients <75 years of age with paroxysmal atrial fibrillation, normal PV anatomy, and left atrial size <40 cc/m² or <50 mm were randomized to two applications of different duration: "short," "medium," or "long." A total of 222 patients were enrolled, 74 per group. RESULTS: Duration per application was 105 (101-108), 164 (160-168), and 224 (219-226) s and isolation was achieved in 79, 89, and 90% (P < 0.001) of the PVs after two applications in groups short, medium, and long, respectively. Only for the left PVs, the success rate of the short group was significantly less compared to the medium- and long-duration groups (P < 0.001). PNI during the procedure occurred in 19 PVs (6.5%) in the medium and in 20 PVs (6.8%) in the long duration groups compared to only five PVs (1.7%) in the short duration group (P < 0.001). CONCLUSIONS: Short cryoballoon ablation application times, less than 2 min, did affect the success for the left PVs but not for the right PVs and resulted in less PNI. A PV tailored approach with shorter application times for the right PVs might be advocated.

Electromechanical window negativity in genotyped long-QT syndrome patients: relation to arrhythmia risk.

AIM: Prolonged and dispersed left-ventricular (LV) contraction is present in patients with long-QT syndrome (LQTS). Electrical and mechanical abnormalities appear most pronounced in symptomatic individuals. We focus on the 'electromechanical window' (EMW; duration of LV-mechanical systole minus QT interval) in patients with genotyped LQTS. Profound EMW negativity heralds torsades de pointes in animal models of drug-induced LQTS. METHODS AND RESULTS: We included 244 LQTS patients from three centres, of whom 97 had experienced arrhythmic events. Seventy-six matched healthy individuals served as controls. QT interval was subtracted from the duration of Q-onset to aortic-valve closure (QAoC) midline assessed non-invasively by continuous-wave echocardiography, measured in the same beat. Electromechanical window was positive in controls but negative in LQTS patients (22 ± 19 vs. -43 ± 46 ms; P < 0.0001), being even more negative in symptomatic than event-free patients (-67 ± 42 vs. -27 ± 41 ms; P < 0.0001). QT, QTc, and QAoC were longer in LQTS subjects (451 ± 57, 465 ± 50, and 408 ± 37 ms, P < 0.0001). Electromechanical window was a better discriminator of patients with previous arrhythmic events than resting QTc (AUC 0.77 (95% CI, 0.71-0.83) and 0.71 (95% CI, 0.65-0.78); P = 0.03). In multivariate analysis, EMW predicted arrhythmic events independently of QTc (odds ratio 1.25; 95% CI, 1.11-1.40; P = 0.001). Adding EMW to QTc for risk assessment led to a net reclassification improvement of 13.3% (P = 0.03). No EMW differences were found between the three major LQTS genotypes. CONCLUSIONS: Patients with genotype-positive LQTS express EMW negativity, which is most pronounced in patients with documented arrhythmic events.

The Electromechanical Window for Arrhythmia-Risk Assessment.

The electromechanical window (EMW) is calculated by subtracting the repolarization duration from a mechanical reference representing contraction duration in the same heartbeat (e.g., aortic-valve closure during echocardiography with simultaneous ECG). 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 cut-off values for both abnormal EMW negativity and positivity, (3) discuss pathophysiologic underpinnings of EMW negativity, and (4) outline the potential future role of cardiac electromechanical relations in patients with proarrhythmic conditions.

A Framework for Assessing the Effect of Cardiac and Respiratory Motion for Stereotactic Arrhythmia Radioablation Using a Digital Phantom With a 17-Segment Model: A STOPSTORM.eu Consortium Study.

PURPOSE: The optimal motion management strategy for patients receiving stereotactic arrhythmia radioablation (STAR) for the treatment of ventricular tachycardia (VT) is not fully known. We developed a framework using a digital phantom to simulate cardiorespiratory motion in combination with different motion management strategies to gain insight into the effect of cardiorespiratory motion on STAR. METHODS AND MATERIALS: The 4-dimensional (4D) extended cardiac-torso (XCAT) phantom was expanded with the 17-segment left ventricular (LV) model, which allowed placement of STAR targets in standardized ventricular regions. Cardiac- and respiratory-binned 4D computed tomography (CT) scans were simulated for free-breathing, reduced free-breathing, respiratory-gating, and breath-hold scenarios. Respiratory motion of the heart was set to population-averaged values of patients with VT: 6, 2, and 1 mm in the superior-inferior, posterior-anterior, and left-right direction, respectively. Cardiac contraction was adjusted by reducing LV ejection fraction to 35%. Target displacement was evaluated for all segments using envelopes encompassing the cardiorespiratory motion. Envelopes incorporating only the diastole plus respiratory motion were created to simulate the scenario where cardiac motion is not fully captured on 4D respiratory CT scans used for radiation therapy planning. RESULTS: The average volume of the 17 segments was 6 cm3 (1-9 cm3). Cardiac contraction-relaxation resulted in maximum segment (centroid) motion of 4, 6, and 3.5 mm in the superior-inferior, posterior-anterior, and left-right direction, respectively. Cardiac contraction-relaxation resulted in a motion envelope increase of 49% (24%-79%) compared with individual segment volumes, whereas envelopes increased by 126% (79%-167%) if respiratory motion also was considered. Envelopes incorporating only the diastole and respiration motion covered on average 68% to 75% of the motion envelope. CONCLUSIONS: The developed LV-segmental XCAT framework showed that free-wall regions display the most cardiorespiratory displacement. Our framework supports the optimization of STAR by evaluating the effect of (cardio)respiratory motion and motion management strategies for patients with VT.

Right-ventricular enlargement in arrhythmogenic right-ventricular cardiomyopathy is associated with decreased QRS amplitudes and T-wave negativity.

BACKGROUND: Arrhythmogenic right-ventricular cardiomyopathy (ARVC) can lead to RV dilatation. We hypothesized that electrocardiographic characteristics including QRS amplitudes in the extremity- and precordial leads, the S amplitude in lead V1 , and extent of T-wave negativity over the precordial leads are related to RV dilatation in this condition. METHODS: In 42 ARVC patients and 42 controls, we correlated total QRS amplitude in the extremity leads (∑QRSext ), precordial leads (∑QRSprec ) and in all leads (∑QRStot : summation of ∑QRSext and ∑QRSprec ), S amplitude in lead V1 and the extent of T-wave inversion in the precordial leads (V1 vs. beyond V1 ) with RV end diastolic diameter (RVEDD) by echocardiography. RESULTS: In the ARVC group, the mean age was 46 ± 14 years, 31 patients were male, 28 had an implantable cardioverter defibrillator (ICD), and 7 had a LV ejection fraction (EF) < 55%. The control group was age- and gender matched to the ARVC cohort. In contrast to controls, the ∑QRSext (regression coefficient (RC), -0.29; P = 0.020), ∑QRSprec (RC, -0.20; P = 0.015), and ∑QRStot (RC, -0.14; P = 0.009) were lower with RV dilatation in ARVC. S amplitude in lead V1 was not related to RV diameter (RC, -0.98; P = 0.088). Precordial T-wave inversion beyond lead V1 (V2 -V6 ) was associated with a larger RV diameter (RC, 8.58; P = 0.012). CONCLUSIONS: Summed QRS amplitudes in the extremity and precordial leads, and T-wave inversion beyond lead V1 are associated with RV dilatation in patients with ARVC.

The great deceiver: a case series of 'double fire' atrioventricular nodal response.

Background: The 'double fire' (DF) atrioventricular (AV) nodal response is a rare mechanism of two ventricular electrical activations following a single atrial beat due to dual AV node physiology. DF AV nodal response is often misdiagnosed and may lead to unnecessary invasive procedures. Case summary: We describe a series of three cases with distinct clinical manifestations of DF AV nodal response: Patient 1 remained symptomatic after slow pathway modification for common AV nodal re-entry tachycardia. Patient 2 was misdiagnosed as having junctional bigeminy and developed heart failure with reduced left ventricle ejection fraction. Patient 3 was misdiagnosed as having atrial fibrillation (AF) and underwent two pulmonary vein isolation (PVI) procedures, without clinical improvement. All patients underwent an electrophysiological study (EPS) during which DF AV nodal response was confirmed and treated with radiofrequency ablation of the slow pathway. All patients were afterwards relieved from their symptoms. Discussion and conclusion: DF AV nodal response is a rare electrophysiological phenomenon which can be clinically misinterpreted as other common arrhythmias, such as premature junctional bigeminy or AF and can contribute to tachycardia induced cardiomyopathy. Typical electrocardiogram- and EPS-derived findings can be indicative for DF AV nodal response. DF AV nodal response can be easily and effectively treated by slow pathway ablation.

The circle of reentry: Characteristics of trigger-substrate interaction leading to sudden cardiac arrest.

Sudden cardiac death is often caused by ventricular arrhythmias driven by reentry. Comprehensive characterization of the potential triggers and substrate in survivors of sudden cardiac arrest has provided insights into the trigger-substrate interaction leading to reentry. Previously, a "Triangle of Arrhythmogenesis", reflecting interactions between substrate, trigger and modulating factors, has been proposed to reason about arrhythmia initiation. Here, we expand upon this concept by separating the trigger and substrate characteristics in their spatial and temporal components. This yields four key elements that are required for the initiation of reentry: local dispersion of excitability (e.g., the presence of steep repolarization time gradients), a critical relative size of the region of excitability and the region of inexcitability (e.g., a sufficiently large region with early repolarization), a trigger that originates at a time when some tissue is excitable and other tissue is inexcitable (e.g., an early premature complex), and which occurs from an excitable region (e.g., from a region with early repolarization). We discuss how these findings yield a new mechanistic framework for reasoning about reentry initiation, the "Circle of Reentry." In a patient case of unexplained ventricular fibrillation, we then illustrate how a comprehensive clinical investigation of these trigger-substrate characteristics may help to understand the associated arrhythmia mechanism. We will also discuss how this reentry initiation concept may help to identify patients at risk, and how similar reasoning may apply to other reentrant arrhythmias.

High-resolution structural-functional substrate-trigger characterization: Future roadmap for catheter ablation of ventricular tachycardia.

Introduction: Patients with ventricular tachyarrhythmias (VT) are at high risk of sudden cardiac death. When appropriate, catheter ablation is modestly effective, with relatively high VT recurrence and complication rates. Personalized models that incorporate imaging and computational approaches have advanced VT management. However, 3D patient-specific functional electrical information is typically not considered. We hypothesize that incorporating non-invasive 3D electrical and structural characterization in a patient-specific model improves VT-substrate recognition and ablation targeting. Materials and methods: In a 53-year-old male with ischemic cardiomyopathy and recurrent monomorphic VT, we built a structural-functional model based on high-resolution 3D late-gadolinium enhancement (LGE) cardiac magnetic resonance imaging (3D-LGE CMR), multi-detector computed tomography (CT), and electrocardiographic imaging (ECGI). Invasive data from high-density contact and pace mapping obtained during endocardial VT-substrate modification were also incorporated. The integrated 3D electro-anatomic model was analyzed off-line. Results: Merging the invasive voltage maps and 3D-LGE CMR endocardial geometry led to a mean Euclidean node-to-node distance of 5 ± 2 mm. Inferolateral and apical areas of low bipolar voltage (<1.5 mV) were associated with high 3D-LGE CMR signal intensity (>0.4) and with higher transmurality of fibrosis. Areas of functional conduction delay or block (evoked delayed potentials, EDPs) were in close proximity to 3D-LGE CMR-derived heterogeneous tissue corridors. ECGI pinpointed the epicardial VT exit at ∼10 mm from the endocardial site of origin, both juxtaposed to the distal ends of two heterogeneous tissue corridors in the inferobasal left ventricle. Radiofrequency ablation at the entrances of these corridors, eliminating all EDPs, and at the VT site of origin rendered the patient non-inducible and arrhythmia-free until the present day (20 months follow-up). Off-line analysis in our model uncovered dynamic electrical instability of the LV inferolateral heterogeneous scar region which set the stage for an evolving VT circuit. Discussion and conclusion: We developed a personalized 3D model that integrates high-resolution structural and electrical information and allows the investigation of their dynamic interaction during arrhythmia formation. This model enhances our mechanistic understanding of scar-related VT and provides an advanced, non-invasive roadmap for catheter ablation.

Juvenile-onset multifocal atrial arrhythmias, atrial standstill and compound heterozygosity of genetic variants in TAF1A: sentinel event for evolving dilated cardiomyopathy-a case report.

Background: Juvenile onset of extensive atrial electromechanical failure, including atrial standstill, is a rare disease entity that may precede ventricular cardiomyopathy. Genetic variants associated with early-onset atrioventricular (AV) cardiomyopathy are increasingly recognized. Case summary: A 16-year-old patient presented with atrial brady- and tachyarrhythmias and concomitant impaired atrial electromechanical function (atrial standstill). The atrial phenotype preceded the development of a predominantly right-sided AV dilated cardiomyopathy with pronounced myocardial fibrosis. A His-bundle pacemaker was installed for high-degree AV conduction block and sinus arrest. Using familial-based whole-exome sequencing, a missense mutation and a copy number variant deletion (compound heterozygosity) of the TAF1A gene (involved in ribosomal RNA synthesis) were identified. Discussion: Juvenile onset of severe atrial electromechanical failure with atrial arrhythmias should prompt deep pheno- and genotyping and calls for vigilance for downstream cardiomyopathic deterioration.

Standing genetic variation affects phenotypic heterogeneity in an SCN5A-mutation founder population with excess sudden cardiac death.

BACKGROUND: The Worm Study, ascertained from a multigeneration pedigree segregating a single amino acid deletion in SCN5A (c.4850_4852delTCT, p.(Phe1617del), rs749697698), is characterized by substantial phenotypic heterogeneity and overlap of sudden cardiac death, long-QT syndrome, cardiac conduction disease, Brugada syndrome, and isorhythmic atrioventricular dissociation. Linkage analysis for a synthetic trait derived from these phenotypes identified a single peak (logarithm of the odds [LOD] = 4.52) at the SCN5A/SCN10A/SCN11A locus on chromosome 3. OBJECTIVE: This study explored the role of additional genetic variation in the chromosome 3 locus as a source of phenotypic heterogeneity in the Worm Study population. METHODS: Genotypes underlying the linkage peak (n = 70) were characterized using microarrays. Haplotypes were determined using family-aware phasing and a population-specific reference panel. Variants with minor allele frequencies >0.10 were tested for association with cardiac conduction disease and isorhythmic dissociation using LAMP and logistic regression. RESULTS: Only 1 haplotype carried the p.Phe1617del/rs749697698 deletion, suggesting relatively recent development (∼18 generations); this haplotype contained 5 other missense variants spanning SCN5A/SCN10A/SCN11A. Noncarrier haplotypes (n = 74) ranged in frequency from 0.5% to 5%. Although no variants were associated with cardiac conduction disease, a homozygous missense variant in SCN10A was associated with isorhythmic dissociation after correction for multiple comparisons (odds ratio 11.23; 95% confidence interval 2.76-23.39; P = 1.2 × 10-4). This variant (rs12632942) was previously associated with PR interval. CONCLUSION: Our data suggest that other variants, alongside a pathogenic mutation, are associated with phenotypic heterogeneity. Single-mutation screening may be insufficient to predict electrical heart disease in patients and family members. In the Worm Study population, segregating a pathogenic SCN5A mutation, compound variation in the SCN5A/SCN10A/SCN11A locus determines arrhythmic outcome.

Myocardial Scar Detection Using High-Resolution Free-Breathing 3D Dark-Blood and Standard Breath-Holding 2D Bright-Blood Late Gadolinium Enhancement MRI: A Comparison of Observer Confidence.

OBJECTIVE: To compare observer confidence for myocardial scar detection using 3 different late gadolinium enhancement (LGE) data sets by 2 observers with different levels of experience. MATERIALS AND METHODS: Forty-one consecutive patients, who were referred for 3D dark-blood LGE MRI before implantable cardioverter-defibrillator implantation or ablation therapy and who underwent 2D bright-blood LGE MRI within a time frame of 3 months, were prospectively included. From all 3D dark-blood LGE data sets, a stack of 2D short-axis slices was reconstructed. All acquired LGE data sets were anonymized and randomized and evaluated by 2 independent observers with different levels of experience in cardiovascular imaging (beginner and expert). Confidence in detection of ischemic scar, nonischemic scar, papillary muscle scar, and right ventricular scar for each LGE data set was scored using a using a 3-point Likert scale (1 = low, 2 = medium, or 3 = high). Observer confidence scores were compared using the Friedman omnibus test and Wilcoxon signed-rank post hoc test. RESULTS: For the beginner observer, a significant difference in confidence regarding ischemic scar detection was observed in favor of reconstructed 2D dark-blood LGE compared with standard 2D bright-blood LGE (p = 0.030) while for the expert observer, no significant difference was found (p = 0.166). Similarly, for right ventricular scar detection, a significant difference in confidence was observed in favor of reconstructed 2D dark-blood LGE compared with standard 2D bright-blood LGE (p = 0.006) while for the expert observer, no significant difference was found (p = 0.662). Although not significantly different for other areas of interest, 3D dark-blood LGE and its derived 2D dark-blood LGE data set showed a tendency to score higher for all areas of interest at both experience levels. CONCLUSIONS: The combination of dark-blood LGE contrast and high isotropic voxels may contribute to increased observer confidence in myocardial scar detection, independent of observer's experience level but in particular for beginner observers.