Impaired Binding to Junctophilin-2 and Nanostructural Alteration in CPVT Mutation.

[Figure: see text].

Role of Ca2+ in healthy and pathologic cardiac function: from normal excitation-contraction coupling to mutations that cause inherited arrhythmia.

Calcium (Ca2+) ions are a key second messenger involved in the rhythmic excitation and contraction of cardiomyocytes throughout the heart. Proper function of Ca2+-handling proteins is required for healthy cardiac function, whereas disruption in any of these can cause cardiac arrhythmias. This comprehensive review provides a broad overview of the roles of Ca2+-handling proteins and their regulators in healthy cardiac function and the mechanisms by which mutations in these proteins contribute to inherited arrhythmias. Major Ca2+ channels and Ca2+-sensitive regulatory proteins involved in cardiac excitation-contraction coupling are discussed, with special emphasis on the function of the RyR2 macromolecular complex. Inherited arrhythmia disorders including catecholaminergic polymorphic ventricular tachycardia, long QT syndrome, Brugada syndrome, short QT syndrome, and arrhythmogenic right-ventricular cardiomyopathy are discussed with particular emphasis on subtypes caused by mutations in Ca2+-handling proteins.

Left Ventricular Hypertrophy and Ventricular Tachyarrhythmia: The Role of Biomarkers.

Left ventricular hypertrophy (LVH) refers to a complex rebuilding of the left ventricle that can gradually lead to serious complications-heart failure and life-threatening ventricular arrhythmias. LVH is defined as an increase in the size of the left ventricle (i.e., anatomically), therefore the basic diagnosis detecting the increase in the LV size is the domain of imaging methods such as echocardiography and cardiac magnetic resonance. However, to evaluate the functional status indicating the gradual deterioration of the left ventricular myocardium, additional methods are available approaching the complex process of hypertrophic remodeling. The novel molecular and genetic biomarkers provide insights on the underlying processes, representing a potential basis for targeted therapy. This review summarizes the spectrum of the main biomarkers employed in the LVH valuation.

Intramural mapping of intramural septal ventricular arrhythmias.

BACKGROUND: Intramural ventricular arrhythmias (VAs) can originate in patients with or without structural heart disease. Electrogram (EGM) recordings from intramural sources of VA have not been described thoroughly. OBJECTIVE: We hypothesized that the presence of scar may be linked to the site of origin (SOO) of focal, intramural VAs. METHODS: In a series of 21 patients (age: 55 ± 11 years, 12 women, mean ejection fraction 43 ± 14%) in whom the SOO of intramural VAs was identified, we analyzed bipolar EGM characteristics at the SOO and compared the findings with the endocardial breakout site. The patients were from a pool of 86 patients with intramural VAs referred for ablation. RESULTS: In 16/21 patients intramural scarring was detected by cardiac magnetic resonance (CMR) imaging In patients in whom the intramural SOO was reached, intramural bipolar EGMs showed a lower voltage and had broader EGMs compared to the endocardial breakout sites (0.97 ± 0.56 vs. 2.28 ± 0.15 mV, p = .001; and 122.3 ± 31.6 vs. 96.5 ± 26.3 ms, p < .01). All intramural sampled sites at the SOO had either low voltage or broad abnormal EGMs. The activation time was significantly earlier at the intramural SOO than at breakout sites (-36.2 ± 11.8 vs. -23.2 ± 9.1 ms, p < .0001). CONCLUSIONS: Sites of origin of intramural VAs with scar by CMR display EGM characteristics of scarring, supporting that scar tissue localizes to the SOO of intramural outflow tract arrhythmias in some patients. Scarring identified by CMR may be helpful in planning ablation procedures in patients with suspected intramural VAs.

Effects of Cardiac Stem Cell on Postinfarction Arrhythmogenic Substrate.

Clinical data suggest that cardiosphere-derived cells (CDCs) could modify post-infarction scar and ventricular remodeling and reduce the incidence of ventricular tachycardia (VT). This paper assesses the effect of CDCs on VT substrate in a pig model of postinfarction monomorphic VT. We studied the effect of CDCs on the electrophysiological properties and histological structure of dense scar and heterogeneous tissue (HT). Optical mapping and histological evaluation were performed 16 weeks after the induction of a myocardial infarction by transient occlusion of the left anterior descending (LAD) artery in 21 pigs. Four weeks after LAD occlusion, pigs were randomized to receive intracoronary plus trans-myocardial CDCs (IC+TM group, n: 10) or to a control group. Optical mapping (OM) showed an action potential duration (APD) gradient between HT and normal tissue in both groups. CDCs increased conduction velocity (53 ± 5 vs. 45 ± 6 cm/s, p < 0.01), prolonged APD (280 ± 30 ms vs. 220 ± 40 ms, p < 0.01) and decreased APD dispersion in the HT. During OM, a VT was induced in one and seven of the IC+TM and control hearts (p = 0.03), respectively; five of these VTs had their critical isthmus located in intra-scar HT found adjacent to the coronary arteries. Histological evaluation of HT revealed less fibrosis (p < 0.01), lower density of myofibroblasts (p = 0.001), and higher density of connexin-43 in the IC+TM group. Scar and left ventricular volumes did not show differences between groups. Allogeneic CDCs early after myocardial infarction can modify the structure and electrophysiology of post-infarction scar. These findings pave the way for novel therapeutic properties of CDCs.

Metabolic heterogeneous zone assessed by 18 FDG-PET is predictive of postablation mortality in patients with ventricular tachycardia.

PURPOSE: We sought to study the predictive value of the metabolic heterogeneous zone (HZ) as determined by 18 Fluorodeoxyglucose (18 FDG) positron emission tomography (PET) viability studies in ventricular tachycardia (VT) patients. METHODS: PET studies utilizing 82 Rubidium (82 Rb) tracer for perfusion and 18 FDG tracer for viability were analyzed using PMOD (PMOD Technologies) and further analyzed using 684-segment plots. 18 FDG uptake was normalized to the area with maximal perfusion on the rest 82 Rb study. Metabolic scar, HZ, and healthy segments were defined with perfusion-normalized 18 FDG uptake between 0%-50%, 50%-70%, and >70%, respectively. RESULTS: Thirty-four VT patients (age, 63 ± 12 years) were evaluated with 18 FDG-PET viability study. Most (n = 31) patients underwent VT ablation. Patients were categorized to HZ < median versus HZ ≥ median based on a median HZ area size of 21.0 cm2 . HZ size was significantly larger in the deceased group than the alive group (35.2 cm2 vs. 18.1 cm2 , p = .01). Deaths were significantly higher in HZ ≥ 21 cm2 group than HZ < 21 cm2 group (58.8% vs. 11.8%, p = .005). Survival analysis showed significantly higher mortality in the HZ ≥ 21 cm2 group than the HZ < 21 cm2 group (HR = 4.1, 95% CI: 1.3-12.6, p = .016). In a multivariable analysis, HZ was found to be an independent predictor for all-cause mortality (HR = 1.07, 95% CI: 1.02-1.12, p = .01) CONCLUSIONS: Increased HZ size of myocardium was associated with increased mortality. Metabolic HZ quantification may be of value in risk stratification and management of ischemic and nonischemic patients with VT.

Novel cases of pediatric sudden cardiac death secondary to TRDN mutations presenting as long QT syndrome at rest and catecholaminergic polymorphic ventricular tachycardia during exercise: The TRDN arrhythmia syndrome.

TRDN mutations cause catecholaminergic polymorphic ventricular tachycardia (CPVT) but may present with abnormal electrocardiogram (ECG) findings provoking a diagnosis of long QT syndrome (LQTS). We report two novel cases of sudden cardiac death in children due to mutations of TRDN, providing further insight into this rare and aggressive inherited arrhythmia syndrome. Whole exome sequencing (WES) was performed in two unrelated children who experienced cardiac arrest during exercise and were negative for targeted testing of LQTS. WES identified a novel homozygous splice-site mutation in both patients, denoted c.22+1G>T, absent from gnomAD and suggesting a founder variant in the Iranian population. We now summarize the genetic architecture of all reported TRDN-related patients, including 27 patients from 21 families. The average age-onset was 30 months (range 1-10) for all cases. Adrenergic-mediated cardiac events were common, occurring in 23 of 27 cases (85%). LQTS was diagnosed in 10 cases (37%), CPVT in 10 (37%) cases, and in 7 cases. No phenotypic diagnosis was provided. Five cases (15%) had evidence for associated skeletal myopathy. Four missense TRDN variants (24%) were observed in diseased cases, while the remaining variants reflect putative loss-of-function (LOF) mutations. No disease phenotype was reported in 26 heterozygous carriers. In conclusion, TRDN mutations cause a rare autosomal recessive arrhythmia syndrome presenting with adrenergic-mediated arrhythmic events, but with ECG abnormalities leading to a diagnosis of LQTS in a proportion of cases. Heterozygous carriers are free of disease manifestations.

Interplay between Triadin and Calsequestrin in the Pathogenesis of CPVT in the Mouse.

Recessive forms of catecholaminergic polymorphic ventricular tachycardia (CPVT) are induced by mutations in genes encoding triadin or calsequestrin, two proteins that belong to the Ca2+ release complex, responsible for intracellular Ca2+ release triggering cardiac contractions. To better understand the mechanisms of triadin-induced CPVT and to assay multiple therapeutic interventions, we used a triadin knockout mouse model presenting a CPVT-like phenotype associated with a decrease in calsequestrin protein level. We assessed different approaches to rescue protein expression and to correct intracellular Ca2+ release and cardiac function: pharmacological treatment with kifunensine or a viral gene transfer-based approach, using adeno-associated virus serotype 2/9 (AAV2/9) encoding the triadin or calsequestrin. We observed that the levels of triadin and calsequestrin are intimately linked, and that reduction of both proteins contributes to the CPVT phenotype. Different combinations of triadin and calsequestrin expression level were obtained using these therapeutic approaches. A full expression of each is not necessary to correct the phenotype; a fine-tuning of the relative re-expression of both triadin and calsequestrin is required to correct the CPVT phenotype and rescue the cardiac function. AAV-mediated gene delivery of calsequestrin or triadin and treatment with kifunensine are potential treatments for recessive forms of CPVT due to triadin mutations.

Pediatric Catecholaminergic Polymorphic Ventricular Tachycardia: A Translational Perspective for the Clinician-Scientist.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a rare and potentially lethal inherited arrhythmia disease characterized by exercise or emotion-induced bidirectional or polymorphic ventricular tachyarrhythmias. The median age of disease onset is reported to be approximately 10 years of age. The majority of CPVT patients have pathogenic variants in the gene encoding the cardiac ryanodine receptor, or calsequestrin 2. These lead to mishandling of calcium in cardiomyocytes resulting in after-depolarizations, and ventricular arrhythmias. Disease severity is particularly pronounced in younger individuals who usually present with cardiac arrest and arrhythmic syncope. Risk stratification is imprecise and long-term prognosis on therapy is unknown despite decades of research focused on pediatric CPVT populations. The purpose of this review is to summarize contemporary data on pediatric CPVT, highlight knowledge gaps and present future research directions for the clinician-scientist to address.

Effect of icosapent ethyl on susceptibility to ventricular arrhythmias in postinfarcted rat hearts: Role of GPR120-mediated connexin43 phosphorylation.

The ω-3 fatty acids exert as an antioxidant via the G protein-coupled receptor 120 (GPR120). Icosapent ethyl, a purified eicosapentaenoic acid, showed a marked reduction in sudden cardiac death. Connexin43 is sensitive to redox status. We assessed whether icosapent ethyl attenuates fatal arrhythmias after myocardial infarction, a status of high oxidative stress, through increased connexin43 expression and whether the GPR120 signalling is involved in the protection. Male Wistar rats after ligating coronary artery were assigned to either vehicle or icosapent ethyl for 4 weeks. The postinfarction period was associated with increased oxidative-nitrosative stress. In concert, myocardial connexin43 levels revealed a significant decrease in vehicle-treated infarcted rats compared with sham. These changes of oxidative-nitrosative stress and connexin43 levels were blunted after icosapent ethyl administration. Provocative arrhythmias in the infarcted rats treated with icosapent ethyl were significantly improved than vehicle. Icosapent ethyl significantly increased GPR120 compared to vehicle after infarction. The effects of icosapent ethyl on superoxide and connexin43 were similar to GPR120 agonist GW9508. Besides, the effects of icosapent ethyl on oxidative-nitrosative stress and connexin43 phosphorylation were abolished by administering AH-7614, an inhibitor of GPR120. SIN-1 abolished the Cx43 phosphorylation of icosapent ethyl without affecting GPR120 levels. Taken together, chronic use of icosapent ethyl after infarction is associated with up-regulation of connexin43 phosphorylation through a GPR120-dependent antioxidant pathway and thus plays a beneficial effect on arrhythmogenic response to programmed electrical stimulation.

Development and Validation of a New Risk Prediction Score for Life-Threatening Ventricular Tachyarrhythmias in Laminopathies.

BACKGROUND: An accurate estimation of the risk of life-threatening (LT) ventricular tachyarrhythmia (VTA) in patients with LMNA mutations is crucial to select candidates for implantable cardioverter-defibrillator implantation. METHODS: We included 839 adult patients with LMNA mutations, including 660 from a French nationwide registry in the development sample, and 179 from other countries, referred to 5 tertiary centers for cardiomyopathies, in the validation sample. LTVTA was defined as (1) sudden cardiac death or (2) implantable cardioverter defibrillator-treated or hemodynamically unstable VTA. The prognostic model was derived using the Fine-Gray regression model. The net reclassification was compared with current clinical practice guidelines. The results are presented as means (SD) or medians [interquartile range]. RESULTS: We included 444 patients, 40.6 (14.1) years of age, in the derivation sample and 145 patients, 38.2 (15.0) years, in the validation sample, of whom 86 (19.3%) and 34 (23.4%) experienced LTVTA over 3.6 [1.0-7.2] and 5.1 [2.0-9.3] years of follow-up, respectively. Predictors of LTVTA in the derivation sample were: male sex, nonmissense LMNA mutation, first degree and higher atrioventricular block, nonsustained ventricular tachycardia, and left ventricular ejection fraction (https://lmna-risk-vta.fr). In the derivation sample, C-index (95% CI) of the model was 0.776 (0.711-0.842), and the calibration slope 0.827. In the external validation sample, the C-index was 0.800 (0.642-0.959), and the calibration slope was 1.082 (95% CI, 0.643-1.522). A 5-year estimated risk threshold ≥7% predicted 96.2% of LTVTA and net reclassified 28.8% of patients with LTVTA in comparison with the guidelines-based approach. CONCLUSIONS: In comparison with the current standard of care, this risk prediction model for LTVTA in laminopathies significantly facilitated the choice of candidates for implantable cardioverter defibrillators. CLINICAL TRIAL REGISTRATION: URL: https://www.clinicaltrials.gov. Unique identifier: NCT03058185.

Insights Into the Pathogenesis of Catecholaminergic Polymorphic Ventricular Tachycardia From Engineered Human Heart Tissue.

BACKGROUND: Modeling of human arrhythmias with induced pluripotent stem cell-derived cardiomyocytes has focused on single-cell phenotypes. However, arrhythmias are the emergent properties of cells assembled into tissues, and the impact of inherited arrhythmia mutations on tissue-level properties of human heart tissue has not been reported. METHODS: Here, we report an optogenetically based, human engineered tissue model of catecholaminergic polymorphic ventricular tachycardia (CPVT), an inherited arrhythmia caused by mutation of the cardiac ryanodine channel and triggered by exercise. We developed a human induced pluripotent stem cell-derived cardiomyocyte-based platform to study the tissue-level properties of engineered human myocardium. We investigated pathogenic mechanisms in CPVT by combining this novel platform with genome editing. RESULTS: In our model, CPVT tissues were vulnerable to developing reentrant rhythms when stimulated by rapid pacing and catecholamine, recapitulating hallmark features of the disease. These conditions elevated diastolic Ca2+ levels and increased temporal and spatial dispersion of Ca2+ wave speed, creating a vulnerable arrhythmia substrate. Using Cas9 genome editing, we pinpointed a single catecholamine-driven phosphorylation event, ryanodine receptor-serine 2814 phosphorylation by Ca2+/calmodulin-dependent protein kinase II, that is required to unmask the arrhythmic potential of CPVT tissues. CONCLUSIONS: Our study illuminates the molecular and cellular pathogenesis of CPVT and reveals a critical role of calmodulin-dependent protein kinase II-dependent reentry in the tissue-scale mechanism of this disease. We anticipate that this approach will be useful for modeling other inherited and acquired cardiac arrhythmias.

Dantrolene prevents ventricular tachycardia by stabilizing the ryanodine receptor in pressure- overload induced failing hearts.

Aberrant Ca2+ release from cardiac ryanodine receptors (RyR2) has been shown to be one of the most important causes of lethal arrhythmia in various types of failing hearts. We previously showed that dantrolene, a specific agent for the treatment of malignant hyperthermia, inhibits Ca2+ leakage from the RyR2 by correcting the defective inter-domain interaction between the N-terminal (1-619 amino acids) and central (2000-2500 amino acids) domains of the RyR2 and allosterically enhancing the binding affinity of calmodulin to the RyR2 in diseased hearts. In this study, we examined whether dantrolene inhibits this Ca2+ leakage, thereby preventing the pharmacologically inducible ventricular tachycardia in ventricular pressure-overloaded failing hearts. Ventricular tachycardia (VT) was easily induced after an injection of epinephrine in mice after 8 weeks of transverse aortic constriction-induced pressure-overload. Pretreatment with dantrolene almost completely inhibited the pharmacologically inducible VT. In the presence of dantrolene, the occurrence of both Ca2+ sparks and spontaneous Ca2+ transients was inhibited, which was associated with enhanced calmodulin binding affinity to the RyR2. These results suggest that dantrolene could be a new potent agent in the treatment of lethal arrhythmia in cases of acquired heart failure.

Classification and correlation of RYR2 missense variants in individuals with catecholaminergic polymorphic ventricular tachycardia reveals phenotypic relationships.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is predominantly caused by heterozygous missense variants in the cardiac ryanodine receptor, RYR2. However, many RYR2 missense variants are classified as variants of uncertain significance (VUS). We systematically re-evaluated all RYR2 variants in healthy individuals and those with CPVT or arrhythmia using the 2015 American College of Medical Genomics guidelines. RYR2 variants were identified by the NW Genomic Laboratory Hub, from the published literature and databases of sequence variants. Each variant was assessed based on minor allele frequencies, in silico prediction tools and appraisal of functional studies and classified according to the ACMG-AMP guidelines. Phenotype data was collated where available. Of the 326 identified RYR2 missense variants, 55 (16.9%), previously disease-associated variants were reclassified as benign. Application of the gnomAD database of >140,000 controls allowed reclassification of 11 variants more than the ExAC database. CPVT-associated RYR2 variants clustered predominantly between amino acid positions 3949-4332 and 4867-4967 as well as the RyR and IP3R homology-associated and ion transport domains (p < 0.005). CPVT-associated RYR2 variants occurred at more conserved amino acid positions compared with controls, and variants associated with sudden death had higher conservation scores (p < 0.005). There were five potentially pathogenic RYR2 variants associated with sudden death during sleep which were located almost exclusively in the C-terminus of the protein. In conclusion, control sequence databases facilitate reclassification of RYR2 variants but the majority remain as VUS. Notably, pathogenic variants in RYR2 are associated with death in sleep.

Stereotactic body radiotherapy for ventricular tachycardia (cardiac radiosurgery) : First-in-patient treatment in Germany.

PURPOSE: Single-session cardiac stereotactic body radiotherapy, called cardiac radiosurgery (CRS) or radioablation (RA), may offer a potential treatment option for patients with refractory ventricular tachycardia (VT) and electrical storm who are otherwise ineligible for catheter ablation. However, there is only limited clinical experience. We now present the first-in-patient treatment using (CRS/RA) for VT in Germany. METHODS: A 78-year-old male patient with dilated cardiomyopathy and significantly reduced ejection fraction (15%) presented with monomorphic VT refractory to poly-anti-arrhythmic medication and causing multiple implantable cardioverter-defibrillator (ICD) interventions over the course of several weeks, necessitating prolonged treatment on an intensive care unit. Ultra-high-resolution electroanatomical voltage mapping (EVM) revealed a re-entry circuit in the cardiac septum inaccessible for catheter ablation. Based on the EVM, CRS/RA with a single session dose of 25 Gy (83% isodose) was delivered to the VT substrate (8.1 cc) using a c-arm-based high-precision linear accelerator on November 30, 2018. RESULTS: CRS/RA was performed without incident and dysfunction of the ICD was not observed. Following the procedure, a significant reduction in monomorphic VT from 5.0 to 1.6 episodes per week and of ICD shock interventions by 81.2% was observed. Besides periprocedural nausea with a single episode of vomiting, no treatment-associated side effects were noted. Unfortunately, the patient died 57 days after CRS/RA due to sepsis-associated cardiac circulatory failure after Clostridium difficile-associated colitis developed during rehabilitation. Histopathologic examination of the heart as part of a clinical autopsy revealed diffuse fibrosis on most sections of the heart without apparent differences between the target area and the posterior cardiac wall serving as a control. CONCLUSION: CRS/RA appears to be a possible treatment option for otherwise untreatable patients suffering from refractory VT and electrical storm. A relevant reduction in VT incidence and ICD interventions was observed, although long-term outcome and consequences of CRS/RA remain unclear. Clinical trials are strongly warranted and have been initiated.

Deletion in mice of X-linked, Brugada syndrome- and atrial fibrillation-associated Kcne5 augments ventricular KV currents and predisposes to ventricular arrhythmia.

KCNE5 is an X-linked gene encoding KCNE5, an ancillary subunit to voltage-gated potassium (KV) channels. Human KCNE5 mutations are associated with atrial fibrillation (AF)- and Brugada syndrome (BrS)-induced cardiac arrhythmias that can arise from increased potassium current in cardiomyocytes. Seeking to establish underlying molecular mechanisms, we created and studied Kcne5 knockout ( Kcne5-/0) mice. Intracardiac ECG revealed that Kcne5 deletion caused ventricular premature beats, increased susceptibility to induction of polymorphic ventricular tachycardia (60 vs. 24% in Kcne5+/0 mice), and 10% shorter ventricular refractory period. Kcne5 deletion increased mean ventricular myocyte KV current density in the apex and also in the subpopulation of septal myocytes that lack fast transient outward current ( Ito,f). The current increases arose from an apex-specific increase in slow transient outward current-1 ( IKslow,1) (conducted by KV1.5) and Ito,f (conducted by KV4) and an increase in IKslow,2 (conducted by KV2.1) in both apex and septum. Kcne5 protein localized to the intercalated discs in ventricular myocytes, where KV2.1 was also detected in both Kcne5-/0 and Kcne5+/0 mice. In HL-1 cardiac cells and human embryonic kidney cells, KCNE5 and KV2.1 colocalized at the cell surface, but predominantly in intracellular vesicles, suggesting that Kcne5 deletion increases IK,slow2 by reducing KV2.1 intracellular sequestration. The human AF-associated mutation KCNE5-L65F negative shifted the voltage dependence of KV2.1-KCNE5 channels, increasing their maximum current density >2-fold, whereas BrS-associated KCNE5 mutations produced more subtle negative shifts in KV2.1 voltage dependence. The findings represent the first reported native role for Kcne5 and the first demonstrated Kcne regulation of KV2.1 in mouse heart. Increased KV current is a manifestation of KCNE5 disruption that is most likely common to both mouse and human hearts, providing a plausible mechanistic basis for human KCNE5-linked AF and BrS.-David, J.-P., Lisewski, U., Crump, S. M., Jepps, T. A., Bocksteins, E., Wilck, N., Lossie, J., Roepke, T. K., Schmitt, N., Abbott, G. W. Deletion in mice of X-linked, Brugada syndrome- and atrial fibrillation-associated Kcne5 augments ventricular KV currents and predisposes to ventricular arrhythmia.

A novel multielectrode catheter for high-density ventricular mapping: electrogram characterization and utility for scar mapping.

AIMS: Multielectrode mapping catheters can be advantageous for identifying surviving myocardial bundles in scar. This study aimed to evaluate the utility of a new multielectrode catheter with increased number of small and closely spaced electrodes for mapping ventricles with healed infarction. METHODS AND RESULTS: In 12 swine (four healthy and eight with infarction), the left ventricle was mapped with investigational (OctarayTM) and standard (PentarayTM) multielectrode mapping catheters. The investigational catheter has more electrodes (48 vs. 20), each with a smaller surface area (0.9 vs. 2.0 mm2) and spacing is fixed at 2 mm (vs. 2-6-2 mm). Electrogram (EGM) characteristics, mapping efficiency and scar description were compared between the catheters and late gadolinium enhancement (LGE). Electrogram acquisition rate was faster with the investigational catheter (814 ± 126 vs. 148 ± 58 EGM/min, P = 0.02) resulting in higher density maps (38 ± 10.3 vs. 10.1 ± 10.4 EGM/cm2, P = 0.02). Bipolar voltage amplitude was similar between the catheters in normal and infarcted myocardium (P = 0.265 and P = 0.44) and the infarct surface area was similar between the catheters (P = 0.12) and corresponded to subendocardial LGE. The investigational catheter identified a higher proportion of near-field local abnormal ventricular activities within the low-voltage area (53 ± 16% vs. 34 ± 16%, P = 0.03) that were considered far-field EGMs by the standard catheter. The investigational catheter was also advantageous for mapping haemodymically non-tolerated ventricular tachycardias due to its higher acquisition rate (P < 0.001). CONCLUSION: A novel multielectrode mapping catheter with higher number of small, and closely spaced electrodes increases the mapping speed, EGM density and the ability to recognize low amplitude near-field EGMs in ventricles with healed infarction.

Ventricular scar channel entrances identified by new wideband cardiac magnetic resonance sequence to guide ventricular tachycardia ablation in patients with cardiac defibrillators.

AIMS: Ventricular tachycardia (VT) substrate-based ablation has become a standard procedure. Electroanatomical mapping (EAM) detects scar tissue heterogeneity and define conduction channels (CCs) that are the ablation target. Late gadolinium enhancement cardiac magnetic resonance (LGE-CMR) is able to depict CCs and increase ablation success. Most patients undergoing VT ablation have an implantable cardioverter-defibrillator (ICD) that can cause image artefacts in LGE-CMR. Recently wideband (WB) LGE-CMR sequence has demonstrated to decrease these artefacts. The aim of this study is to analyse accuracy of WB-LGE-CMR in identifying the CC entrances. METHODS AND RESULTS: Thirteen consecutive ICD-patients who underwent VT ablation after WB-LGE-CMR were included. Number and location of CC entrances in three-dimensional EAM and in WB-LGE-CMR reconstruction were compared. Concordance was compared with a historical cohort matched by cardiomyopathy, scar location, and age (26 patients) with LGE-CMR prior to ICD and VT ablation. In WB-CMR group, 101 and 93 CC entrances were identified in EAM and WB-LGE-CMR, respectively. In historical cohort, 179 CC entrances were identified in both EAM and LGE-CMR. The EAM/CMR concordance was 85.1% and 92.2% in the WB and historical group, respectively (P = 0.66). There were no differences in false-positive rate (CC entrances detected in CMR and absent in EAM: 7.5% vs 7.8% in WB vs. conventional CMR, P = 0.92) nor in false-negative rate (CC entrances present in EAM not detected in CMR: 14.9% vs.7.8% in WB vs. conventional CMR, P = 0.23). Epicardial CCs was predictor of poor CMR/EAM concordance (OR 2.15, P = 0.031). CONCLUSION: Use of WB-LGE-CMR sequence in ICD-patients allows adequate VT substrate characterization to guide VT ablation with similar accuracy than conventional LGE-CMR in patients without an ICD.

Hybrid Ventricular Tachycardia Ablation after Failed Percutaneous Endocardial and Epicardial Ablation.

INTRODUCTION: Recurrent ventricular tachycardia (VT) after percutaneous ablation is associated with a high morbidity and mortality. We assessed the feasibility of open chest extracorporeal circulation (ECC)-supported 3D multielectrode mapping and targeted VT substrate ablation in patients with previously failed percutaneous endocardial and epicardial VT ablations. METHODS: In patients with previously failed percutaneous endocardial and epicardial VT ablations and a high risk of hemodynamic collapse during the procedure, open chest ECC-supported mapping and ablation were performed in a hybrid EP lab setting. Electro-anatomic maps (3D) were acquired during sinus rhythm and VT using a multielectrode mapping catheter (HD grid; Abbott or Pentaray, Biosense Webster). Irrigated radiofrequency ablations of all inducible VT were performed with a contact force ablation catheter. RESULTS: Hybrid VT ablation was performed in 5 patients with structural heart disease (i.e., 3 with previous old myocardial infarction and 2 with nonischemic cardiomy-opathy) and recurrent VT. Acute procedural success was achieved in all patients. Four patients were successfully weaned off the ECC. In 1 patient with a severely reduced LVEF (16%), damage to the venous graft occurred after sternotomy and that patient died after 1 month. Four patients (80%) remained VT free after a median follow-up of 6 (IQR 4-10) months. CONCLUSION: In high-risk patients with previously failed percutaneous endocardial and epicardial VT ablations, open chest ECC-supported multielectrode epicardial mapping revealed a VT substrate in all of the patients, and targeted epicardial ablation abolished VT substrate in these patients.

The Brain-Heart Connection in Sympathetically Triggered Inherited Arrhythmia Syndromes.

Sympathetically triggered inherited arrhythmia syndromes, including the long QT syndrome (LQTS) and catecholaminergic polymorphic ventricular tachycardia (CPVT), can cause sudden cardiac death in young individuals with structurally normal hearts. With cardiac events typically triggered by physical or emotional stress, not surprisingly, two of the most common treatments are neuromodulators, including mainstay beta blocker pharmacotherapy, and surgical sympathetic cardiac denervation. This review updates the clinician on the relevant anatomy and physiology of the cardiac autonomic nervous system, outlines neurocardiac arrhythmia mechanisms, and discusses the latest rationale for a neurocardiac therapeutic approach to manage sympathetic-induced arrhythmia in patients with inherited cardiac disease.