Spontaneous Ventricular Tachyarrhythmias Research Articles

Clinical findings and outcomes of Brugada syndrome in women

Abstract Introduction Brugada syndrome (BrS) is a genetic disorder characterized by typical ECG changes and association with spontaneous ventricular tachyarrhythmia (VTA) and sudden death in young patients. BrS has been widely established to be particularly prevalent in men, however less information exists regarding female patients and their long-term risk. Objectives The purpose of this study was to investigate the clinical characteristics and long-term prognosis of women with BrS. Methods This study includes a retrospective analysis of a single-center cohort of patients followed and observed for relevant clinical outcomes. The data collected included demographic data, severity of symptoms (e.g. syncope, VTA), cardioverter-defibrillator logs and occurrence of sudden cardiac death. Results 317 patients were diagnosed with BrS between 1998 and 2023. Among those, 112 (36%) were female. At presentation, 5 patients (4%) were symptomatic with history of survived cardiac arrest and/or documented VTA. 29 (26%) had history of unexplained syncope and 78 (70%) were asymptomatic. The average age at diagnosis was 42.1±15.1 yrs. as opposed to 40.1±14.2 yrs. in men. Females presented less frequently with a type 1 ECG pattern (5% vs 21%; p<0.01), had a trend to a higher rate of family history of sudden cardiac death (31% vs 25%; p=n.s.), and had less sustained VTA during programmed ventricular stimulation (4% vs 19%; p<0.01). Genetic testing was performed in 89 females (79% of the sample) and pathogenic variants were present in 36 (40%) women. An implantable cardioverter defibrillator was inserted in 24 (31%) females for primary prevention. During mean follow-up of 138±72 months, 11 women had cardiovascular events (syncope, VT/VF or death). Syncope was most common and occurred in 8 cases. No VTA were documented in any female patient. In the group of ICD patients, 8 shocks have occurred. None of these were deemed appropriate by medical controls. There were 3 deaths. Two were considered non-arrhythmic due to pulmonary embolism and breast carcinoma. One ICD patient died suddenly during sleep. Unfortunately, no device interrogation data was available. Conclusion Women typically present less symptomatic and demonstrate a reduced incidence of life-threatening arrhythmias during follow-up , often experiencing a frequent occurrence of inappropriate implantable defibrillator therapy. The less frequent prevalence of the BrS ECG pattern in women adds complexity to the diagnostic process. Further studies are still needed to elucidate gender differences for risk stratification of BrS.

Interpretable machine learning model using Extreme Gradient Boosting with Nonnegative Matrix Factorization improves the accuracy of arrhythmic risk prediction in Brugada Syndrome

Abstract Background Both depolarization and repolarization abnormalities contribute to ventricular arrhythmogenesis in Brugada syndrome (BrS). In this study, we tested the hypothesis that incorporating latent features extracted by various nonnegative matrix factorization (NML) techniques into an interpretable machine learning (IML) prediction model can outperform IML models without latent variables and logistic regression model. Methods This study was based on a published anonymised dataset of BrS patients from the Hong Kong, China. XGBoost was selected as the IML model, with and without incorporating latent features using 11 different NMF techniques: Bayesian nonnegative matrix factorization (BNMF), Iterated Conditional Modes nonnegative matrix factorization (ICM), Fisher Nonnegative Matrix Factorization for learning Local features (LFNMF), Alternating Nonnegative Least Squares Matrix Factorization Using Projected Gradient (bound constrained optimization) method for each subproblem (LSNMF), Non-smooth Nonnegative Matrix Factorization (NSNMF), Probabilistic Nonnegative Matrix Factorization (PMF), Probabilistic Sparse Matrix Factorization (PSMF), Sparse Nonnegative Matrix Factorization (SNMF) based on alternating nonnegativity constrained least squares, Sparse Network-Regularized Multiple Nonnegative Matrix Factorization (SNMNMF), Penalized Matrix Factorization for Constrained Clustering (PMFCC) and Separable Nonnegative Matrix Factorization (SepNMF). Results A total of 548 patients were included (7.3% females, age at diagnosis: 51.0 [38.0-61.0] years old. Of these, 66 suffered from spontaneous ventricular tachyarrhythmias over 84±55 months follow-up. The baseline model using multivariable logistic regression achieved an area under the curve (AUC) of 0.78 [0.72-0.85], which was improved to 0.88 [0.83-0.93] for the IML model without NMF. The AUC was further increased by incorporating additional latent variables extracted using NSNMF (0.95 [0.92-0.98]) and PMFCC (0.94 [0.88-1.00]). Conclusion Incorporation of latent variables by different NMF techniques into an IML prediction model significantly improved the accuracy of risk prediction in BrS.

Association of ventricular tachycardia morphology induced on electrophysiology study after myocardial infarction: long-term survival and ventricular tachyarrhythmia recurrence

Abstract Background Electrophysiology study (EPS) presents a valuable risk stratification tool to facilitate the implantation of implantable cardioverter-defibrillators (ICDs) to prevent sudden cardiac death from ventricular tachyarrhythmia early after myocardial infarction. Purpose To investigate long-term survival of patients with inducible ventricular tachycardia (VT) at electrophysiology study (EPS) early after ST elevation myocardial infarction (MI) and possible association with site of origin of the induced VT. Methods Consecutive patients with LVEF ≤40% on day 3–5 after MI who underwent EPS were prospectively recruited. Positive EPS was defined as sustained monomorphic VT cycle length ≥200ms for >10 seconds, or shorter duration if hemodynamic compromise occurred. The primary outcome was time to death from any cause. The secondary outcome was time to the composite endpoint of first activation of ICD for ventricular tachyarrhythmia or death. Results A total of 126 patients with inducible VT on EPS early after MI were included with median follow up 6.7 years. 54% had LBBB and 46% had RBBB morphologies during induced VT. The distributions of age, sex, left ventricle ejection fraction, cardiovascular risk factors, infarct artery and EPS characteristics did not differ significantly by induced VT morphology. The estimated risk of death was independently associated with RBBB morphology of VT induced at EPS (adjusted HR 3.2, 95%CI 1.0-10.0, p=0.044). The estimated risk of the composite end-point of spontaneous ventricular tachyarrhythmia recurrence or death was also independently associated with RBBB morphology of VT induced at EPS (HR 1.8, 95%CI 1.0-3.2, p=0.043). Conclusion There is an increased risk of death and spontaneous ventricular tachyarrhythmia recurrence at median follow up of 6.7 years, associated with RBBB morphology of VT (likely origin from left ventricle) induced at EPS early after MI, in those with LVEF <40%. This study is the first to characterise the association between site of origin of VT induced at EPS after myocardial infarction, indicated by RBBB or LBBB morphology, and overall survival as well as activation free survival. The results could help to identify a group of patients that could benefit from closer monitoring post MI and more intense preventative management to improve long-term outcomes.

Alcohol and caffeine synergistically induce spontaneous ventricular tachyarrhythmias: ameliorated with dantrolene treatment.

Alcohol and caffeine are the 2 frequently consumed substances in the general population, and the 2 substances are frequently co-consumed. Both substances may increase cardiac arrhythmia risk. However, it is unknown whether alcohol and caffeine co-consumption can synergistically enhance cardiac arrhythmogenesis. The study sought to investigate whether caffeine and binge drinking synergistically affect cardiac arrhythmogenesis. A binge drinking rat model (alcohol 2 g/kg, intraperitoneal, every other day for 3 times) was used. Rats (4 months old, both sexes) were randomized into the following 4 groups: binge alcohol-only group (A) (n = 8), nonalcohol, caffeine-only (60 mg/kg, intraperitoneal) group (C) (n = 8), binge alcohol plus caffeine group (A+C) (n = 8), and binge alcohol + caffeine + dantrolene group (A+D) (n = 7, treated with dantrolene 10 mg/kg before each alcohol injection). We also investigated whether alcohol induces Ca2+ sparks and dantrolene treatment attenuates alcohol-induced Ca2+ leak in ventricular myocytes. No arrhythmia was induced with caffeine alone (group C, n = 0 of 8) or alcohol alone (group A, n = 0 of 8). However, alcohol + caffeine induced spontaneous ventricular tachyarrhythmias in all rats (group A+C, n = 8 of 8; P < .001 vs group C or A). Dantrolene prevented ventricular tachyarrhythmia induction in all 7 rats (group A+D, n = 0 of 7; P < .001 vs group A+C). In isolated ventricular myocytes, alcohol significantly increased Ca2+ sparks and dantrolene treatment reduced alcohol-induced Ca2+ sparks. Co-consumption of caffeine and binge drinking synergistically promote spontaneous ventricular tachyarrhythmias in rats. Dantrolene treatment can decrease alcohol-enhanced Ca2+ sparks invitro and prevented alcohol and caffeine induced ventricular tachyarrhythmias invivo.

Optimizing electrophysiology studies to prevent sudden cardiac death after myocardial infarction.

This study assessed associations of minimum final extrastimulus coupling interval utilized within electrophysiology study (EPS) after myocardial infarction (MI) and possible site of origin of induced ventricular tachycardia (VT) with long-term occurrence of spontaneous ventricular tachyarrhythmia and long-term survival. This prospective study recruited consecutive patients with left ventricular ejection fraction (LVEF) ≤ 40% who underwent EPS days 3-5 after MI between 2004 and 2017. Positive EPS was defined as sustained monomorphic VT cycle length ≥200 ms for ≥10 s or shorter duration if haemodynamic compromise occurred. Each of the four extrastimuli was shortened by 10 ms at a time, until it failed to capture the ventricle (ventricular refractoriness) or induced ventricular tachyarrhythmia. Outcomes included spontaneous ventricular tachyarrhythmia occurrence and all-cause mortality. Shorter coupling interval length of final extrastimulus that induced VT was associated with higher risk of spontaneous ventricular tachyarrhythmia (P < 0.001). Significantly higher rates of spontaneous ventricular tachyarrhythmia (65.2% vs. 23.2%; P < 0.001) were observed for final coupling interval at EPS <200 ms vs. >200 ms. Right bundle branch block (RBBB) morphology of induced VT, with possible site of origin from the left ventricle, was associated with all-cause mortality [hazard ratio (HR) 3.2, P = 0.044] and a composite of spontaneous ventricular tachyarrhythmia recurrence or mortality (HR 1.8, P = 0.043). Ventricular tachycardia induced with shorter coupling intervals was associated with higher risk of spontaneous ventricular tachyarrhythymia on follow-up, indicating that the final extrastimulus coupling interval at EPS early after MI should be determined by ventricular refractoriness. Induced VT with possible origin from left ventricle was associated with increased risk of spontaneous ventricular tachyarrhythmia recurrence or death.

Designing Very Fast and Accurate Convolutional Neural Networks With Application in ICD and Smart Electrocardiograph Devices

An implantable cardioverter-defibrillator (ICD) is a device that must detect VT and VF arrhythmias on time and treat them. In this project, three CNN networks are designed to introduce the practical methods of using deep learning in heart electrophysiology signals processing. This project presents two speedy intelligent detection methods of ventricular fibrillation and ventricular tachycardia arrhythmias for ICD devices. It also provides another quick, innovative diagnosis method for use in intelligent electrocardiograph devices to detect abnormal cardiac signals. The first network is 1D-CNN for smart electrocardiographic devices to detect abnormal ECG signals. Dataset MIT-BIH has been used to train this network. This network with the most optimal number of parameters due to high detection speed has a high accuracy of 91%. The second and third networks are 2D-CNNs for use in implantable defibrillators. For the second network, a data set of 20 patients with cardiac arrhythmia and 20 patients without cardiac arrhythmia in an 8-month period of ICD check-up has been prepared. The third network is trained using the Spontaneous Ventricular Tachyarrhythmia Database. The second and third networks are designed to detect EGM signals in VF and VT modes with the optimal number of parameters and 100% accuracy in the second network and 90% in the third network. All three designed networks are in an optimal condition regarding the number of parameters and layers, so they have optimal speed and energy consumption.

Abstract P1091: Granulocyte-Macrophage Colony-Stimulating Factor Signaling Pathway And Antiarrhythmic Effect Of Renal Denervation In Chronic Heart Failure

Renal denervation (RDN) is widely investigated in multiple studies of sympathetically driven cardiovascular diseases. While the therapeutic potential of RDN for ventricular arrhythmia has been reported, the mechanisms responsible for the antiarrhythmic effect of RDN are poorly understood. Our recent study showed that macrophage expansion-induced neuroinflammation in the stellate ganglion (SG) was a critical factor for cardiac sympathetic overactivation and ventricular arrhythmogenesis in chronic heart failure (CHF). This study aims to investigate if and how RDN decreases ventricular arrhythmias through attenuating neuroinflammation in cardiac sympathetic postganglionic (CSP) neurons in CHF. CHF was induced by acute surgical ligation of the left coronary artery in rats. Completed bilateral RDN was achieved by surgically cutting all the visible renal nerves around the renal artery and vein and followed by application of 70% ethanol around the vessels. Using immunofluorescence staining and Western blot analysis, we found that expression of granulocyte-macrophage colony-stimulating factor receptor-α subunit (GM-CSFRα), and Iba1 (an activated macrophage marker) in macrophages from the SG were increased in 16-week CHF rats, compared with age matched sham rats. In the ELISA experiment, we observed high levels of GM-CSF in kidney, serum, and SG in CHF rats, which were markedly reduced at 3 weeks after RDN. CHF-elevated macrophage activation and expression of GM-CSFRα in the SG were decreased by RDN. Flow cytometry data confirmed that CHF-increased percentage of macrophages in the SG was reduced at 3 weeks after RDN. Patch-clamp data found that RDN reduced the N-type Ca 2+ currents in CSP neurons from CHF rats (50.5+3.3 pA/pF in CHF rats vs. 28.6+2.2 pA/pF in CHF+RDN rats, P&lt;0.05). RDN attenuated CHF-enhanced cardiac sympathetic nerve activity. ECG data from 24-hour continuous telemetry recording in conscious rats revealed that RDN decreased the incidence and duration of spontaneous ventricular tachyarrhythmias in CHF rats. Based on these data, we confirm that RDN inhibits cardiac sympathetic overactivation and ventricular arrhythmogenesis through GM-CSF-macrophage activation-neuroinflammation-N-type Ca 2+ channel signaling axis in CHF.

Characterization of the PRAETORIAN score in Japanese patients undergoing subcutaneous implantable cardioverter-defibrillator implantation

BackgroundThe PRAETORIAN score was developed to evaluate the implant position and predict defibrillation success in patients implanted with a subcutaneous implantable cardioverter-defibrillator (S-ICD). However, usefulness of the PRAETORIAN score for Japanese patients is unknown. MethodsWe evaluated usefulness of this score, which was determined by width of sub-coil fat, sub-generator fat, and anterior positioning of the S-ICD generator by post-operative chest X-ray, in consecutive 100 Japanese S-ICD implanted patients [78 men, median age 59 (IQR 46.5–67.0) years, median body mass index (BMI) 24.2 (21.3–27.2) kg/m2]. ResultsThe median PRAETORIAN score was 30 (30–45) and 93 patients were classified as a low risk of conversion failure. The remaining seven were at an intermediate risk. Almost all patients were classified as an optimal pulse-generator position in the second and third steps of the PRAETORIAN score. The only difference observed was in the width of sub-coil fat in the first step. To further evaluate its significance, patients were divided into the Thicker group (sub-coil fat >1 coil width, n = 19) and the Thinner group (sub-coil fat ≤1 coil width, n = 81). BMI and post-shock impedance were both higher in the Thicker group than in the Thinner group [27.1 (25.6–31.6) versus 23.1 (20.9–25.7) kg/m2, p < 0.001, and 75 (68–88) versus 63 (55–74) Ω, p = 0.003, respectively]. During the median follow-up periods of 888 (523–1418) days, 7 patients experienced appropriate shock therapy for spontaneous ventricular tachyarrhythmias, who were all at a low risk. No conversion failure was observed. Inappropriate shock (IAS) occurred in 11 patients, and there was no difference in IAS rate between the Thicker group (n = 2) and the Thinner group (n = 9) (p = 0.747 by log-rank test). ConclusionsMost Japanese patients were classified as at low risk of conversion failure. The PRAETORIAN score may be useful for the evaluation of conversion failure in Japanese S-ICD implanted patients.

Gene therapy targeting protein trafficking regulator MOG1 in mouse models of Brugada syndrome, arrhythmias, and mild cardiomyopathy.

Brugada syndrome (BrS) is a fatal arrhythmia that causes an estimated 4% of all sudden death in high-incidence areas. SCN5A encodes cardiac sodium channel NaV1.5 and causes 25 to 30% of BrS cases. Here, we report generation of a knock-in (KI) mouse model of BrS (Scn5aG1746R/+). Heterozygous KI mice recapitulated some of the clinical features of BrS, including an ST segment abnormality (a prominent J wave) on electrocardiograms and development of spontaneous ventricular tachyarrhythmias (VTs), seizures, and sudden death. VTs were caused by shortened cardiac action potential duration and late phase 3 early afterdepolarizations associated with reduced sodium current density (INa) and increased Kcnd3 and Cacna1c expression. We developed a gene therapy using adeno-associated virus serotype 9 (AAV9) vector-mediated MOG1 delivery for up-regulation of MOG1, a chaperone that binds to NaV1.5 and traffics it to the cell surface. MOG1 was chosen for gene therapy because the large size of the SCN5A coding sequence (6048 base pairs) exceeds the packaging capacity of AAV vectors. AAV9-MOG1 gene therapy increased cell surface expression of NaV1.5 and ventricular INa, reversed up-regulation of Kcnd3 and Cacna1c expression, normalized cardiac action potential abnormalities, abolished J waves, and blocked VT in Scn5aG1746R/+ mice. Gene therapy also rescued the phenotypes of cardiac arrhythmias and contractile dysfunction in heterozygous humanized KI mice with SCN5A mutation p.D1275N. Using a small chaperone protein may have broad implications for targeting disease-causing genes exceeding the size capacity of AAV vectors.

Caffeine Induces Spontaneous Ventricular Tachyarrhythmias and Bidirectional Ventricular Tachycardia: Increased Vulnerability with Aging

IntroductionCaffeine is generally suspected to trigger or exacerbate cardiac arrhythmias in patients, but so far clinical data have been conflicting. We have demonstrated previously that caffeine plus dobutamine challenge can induce ventricular tachyarrhythmias in normal rats (Heart Rhythm O2 2020;1:359‐367). However, whether caffeine alone can induce cardiac arrhythmias has not been investigated. We hypothesize that caffeine alone could trigger spontaneous cardiac arrhythmias, which may be affected by aging and sexes. In this study we have investigated the effect of caffeine on spontaneous cardiac arrhythmias in younger and older adult rats of both sexes.MethodsThis study used Sprague‐Dawley rats. Younger (5‐month‐old) and older (1‐year‐old) adult rats of both sexes were enrolled. The study consisted of the following groups: 5‐month‐old male rats (younger male, n=8) and 1‐year‐old male rats (older male, n=9), 5‐month‐old female rats (younger female, n=6) and 1‐year‐old female rats (older female, n=5). These rats received caffeine (80mg/kg, IP) injection. In addition, a group of 5‐month‐old rats (both sexes, n=8) receiving saline injection without caffeine served as the control group. Surface electrocardiogram (ECG, standard Lead II) was continuously monitored and recorded during the experiments.ResultsNo arrhythmia was induced in the control group with saline injection. Caffeine injection induced ventricular tachyarrhythmias in 8/9 older male rats, while only in 2/8 younger male rats (younger versus older male rats, p=0.0152, Fisher's exact test). Similarly, ventricular arrhythmias were induced in 5/5 older female rats, and only in 1/6 younger female rats (older versus younger female rats, p=0.0152). There were no significant differences in male versus female rats in both age groups. Induced ventricular arrhythmias include various premature ventricular contractions (PVC, Figure‐Panel A) in all rats, monomorphic ventricular tachycardia (VT, Panel B) in 3 rats and polymorphic VT and bidirectional VT (Panel C) in all rats. No atrial arrhythmia was observed.ConclusionCaffeine can induce spontaneous ventricular arrhythmias in normal rats, and the younger rats are more resistant to arrhythmia induction. Arrhythmia inducibility increases significantly in older rats. There is no sex difference in caffeine induced ventricular arrhythmias. Although different types of ventricular arrhythmias are induced, the characteristic bidirectional VT is highly prevalent among the caffeine induced arrhythmias and no atrial arrhythmia was observed.

PO-614-04 STABILIZING CARDIAC RYANODINE RECEPTOR WITH DANTROLENE PREVENTS BINGE ALCOHOL AND CAFFEINE INDUCED VENTRICULAR TACHYARRHYTHMIAS

Alcohol and caffeine are widely consumed worldwide. We have shown (Heart Rhythm 2021;18 [8 suppl]: S202) that binge alcohol and caffeine can synergistically induce spontaneous ventricular tachyarrhythmias in rats, yet the underlying mechanism is unclear.

Implantable cardioverter defibrillators in adult congenital heart disease: long-term follow up of therapies, complications and clinical events

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Adults with congenital heart disease (ACHD) at increased risk for sudden cardiac death (SCD) often undergo implantable cardioverter defibrillator (ICD) implantation at young ages. Data evaluating the long-term outcomes of ICD in this population remain scarce. We aimed to characterize the population with ACHD and an ICD. Methods Consecutive ACHD submitted to an ICD implantation in a single tertiary center were evaluated. Data on baseline clinical features, heart defect, indication for ICD, type of device, ICD-related complication and therapies and mortality during follow-up were collected. Results A total of 34 patients (P) were evaluated. Median age at implant was 39.3 years (interquartile range [IQR] 29-5-53.6) and median left ventricular ejection fraction (LVEF) was 43.5% (IQR 28.0-53.3). The most common heart defect was tetralogy of Fallot (11P;32,3%), followed by dextro-transposition of the great arteries, ostium secundum atrial septal defect (ASD) and ventricular septal defect (Figure 1). All P were submitted to surgical correction (median age at surgery 12.5 years [IQR 3.0-29.1]). Sixteen P underwent ICD implantation for primary prevention of SCD, owing to complex cardiopathy and ventricular dysfunction, and 18P due to spontaneous ventricular tachyarrhythmias. The implantable devices were a single-chamber ICD in 55.9%, a double-chamber ICD in 17.6%, a subcutaneous ICD in 20.6% and a CRT-D in 5.9%. During a median follow-up of 4.5 years (IQR 2.1-8.8), 52.9% of the P received appropriate ICD therapies, corresponding to 37.5% and 66.7% of primary and secondary prevention P, respectively. Median time to first arrhythmic event was 25.3 months (IQR 13.7-52.9). Six P (17.6%) suffered ICD-related complications and 20.6% received inappropriate therapies due to supraventricular tachyarrhythmias. During follow-up, 8.8% were submitted to heart transplant and 29.4% died (Table 1). ICD therapies were associated with a composite of death, cardiac transplantation and hospital admission (OR 5.0, 95% CI 1.0-24.3). Conclusion ACHD with ICD experience high rate of appropriate therapies, including those implanted for primary prevention. The long-term burden of ICD-related complications and inappropriate shocks underlines the need for careful risk stratification and close monitoring. The increased survival of this population justifies collecting data on long-term outcomes to improve its care. Abstract Figure.

Measures of repolarization variability predict ventricular arrhythmogenesis in heptanol-treated Langendorff-perfused mouse hearts.

BackgroundTime-domain and non-linear methods can be used to quantify beat-to-beat repolarization variability but whether measures of repolarization variability can predict ventricular arrhythmogenesis in mice have never been explored.MethodsLeft ventricular monophasic action potentials (MAPs) were recorded during constant right ventricular 8 ​Hz pacing in Langendorff-perfused mouse hearts, in the presence or absence of the gap junction and sodium channel inhibitor heptanol (0.1, 0.5, 1 or 2 ​mM).ResultsUnder control conditions, mean action potential duration (APD) was 39.4 ​± ​8.1 ​ms. Standard deviation (SD) of APDs was 0.3 ​± ​0.2 ​ms, coefficient of variation was 0.9 ​± ​0.8% and the root mean square (RMS) of successive differences in APDs was 0.15 ​± ​0.14 ​ms. Poincaré plots of APDn+1 against APDn revealed ellipsoid morphologies with a SD along the line-of-identity (SD2) to SD perpendicular to the line-of-identity (SD1) ratio of 4.6 ​± ​2.1. Approximate and sample entropy were 0.61 ​± ​0.12 and 0.76 ​± ​0.26, respectively. Detrended fluctuation analysis revealed short- and long-term fluctuation slopes of 1.49 ​± ​0.27 and 0.81 ​± ​0.36, respectively. Heptanol at 2 ​mM induced ventricular tachycardia in five out of six hearts. None of the above parameters were altered by heptanol during which reproducible electrical activity was observed (KW-ANOVA, P ​> ​0.05). Contrastingly, SD2/SD1 decreased to 2.03 ​± ​0.41, approximate and sample entropy increased to 0.82 ​± ​0.12 and 1.45 ​± ​0.34, and short-term fluctuation slope decreased to 0.82 ​± ​0.19 during the 20-s period preceding spontaneous ventricular tachy-arrhythmias (n ​= ​6, KW-ANOVA, P ​< ​0.05).ConclusionMeasures of repolarization variability, such as SD2/SD1, entropy, and fluctuation slope are altered preceding the occurrence of ventricular arrhythmogenesis in mouse hearts. Changes in these variables may allow detection of impending arrhythmias for early intervention.

Anticipation of ventricular tachyarrhythmias by a novel mathematical method: Further insights towards an early warning system in implantable cardioverter defibrillators.

Implantable cardioverter defibrillators (ICD) are the most effective therapy to terminate malignant ventricular arrhythmias (VA) and therefore to prevent sudden cardiac death. Until today, there is no way to predict the onset of such VA. Our aim was to develop a mathematical model that could predict VA in a timely fashion. We analyzed the time series of R-R intervals from 3 groups. Two groups from the Spontaneous Ventricular Tachyarrhythmia Database (v 1.0) were analyzed from a set of 81 pairs of R-R interval time series records from patients, each pair containing one record before the VT episode (Dataset 1A) and one control record which was obtained during the follow up visit (Dataset 1B). A third data set was composed of the R-R interval time series of 54 subjects without a significant arrhythmia heart disease (Dataset 2). We developed a new method to transform a time series into a network for its analysis, the ε-regular graphs. This novel approach transforms a time series into a network which is sensitive to the quantitative properties of the time series, it has a single parameter (ε) to be adjusted, and it can trace long-range correlations. This procedure allows to use graph theory to extract the dynamics of any time series. The average of the difference between the VT and the control record graph degree of each patient, at each time window, reached a global minimum value of -2.12 followed by a drastic increase of the average graph until reaching a local maximum of 5.59. The global minimum and the following local maxima occur at the windows 276 and 393, respectively. This change in the connectivity of the graphs distinguishes two distinct dynamics occurring during the VA, while the states in between the 276 and 393, determine a transitional state. We propose this change in the dynamic of the R-R intervals as a measurable and detectable "early warning" of the VT event, occurring an average of 514.625 seconds (8:30 minutes) before the onset of the VT episode. It is feasible to detect retrospectively early warnings of the VA episode using their corresponding ε-regular graphs, with an average of 8:30 minutes before the ICD terminates the VA event.

Association between heart rate variability indices and features of spontaneous ventricular tachyarrhythmias in mice.

Direct evidence is limited for the association between heart rate variability (HRV) indices and ventricular tachyarrhythmias (VTAs). While galectin-3 (Gal-3) is regarded as a causal factor for cardiac remodelling and a biomarker for arrhythmias, its regulation on VTAs and HVR is unknown. Using aged transgenic (TG) mice with cardiac overexpression of β2 -adrenoceptors and spontaneous VTAs, we studied whether changes in HRV indices correlated with the severity of VTAs, and whether Gal-3 gene knockout (KO) in TG mice might limit VTA. Body-surface ECG was recorded (10-minute period) in 9- to 10-month-old mice of non-transgenic (nTG), TG and TG×Gal-3 knockout (TG/KO). Time-domain, frequency-domain and nonlinear-domain HRV indices were calculated using the R-R intervals extracted from ECG signals and compared with frequency of VTAs. TG and TG/KO mice developed frequent VTAs and showed significant changes in certain time-domain and nonlinear-domain HRV indices relative to nTG mice. The severity of VTAs in TG and TG/KO mice in combination, estimated by VTA counts and arrhythmia score, was significantly correlated with certain time-domain and nonlinear-domain HRV indices. In conclusion, significant changes in HRV indices were evident and correlated with the severity of spontaneous VTAs in TG mice. The frequency of VTA and HRV indices were largely comparable between TG and TG/KO mice. Deletion of Gal-3 in TG mice altered certain HRV indices implying influence by neuronally localized Gal-3 on autonomic nervous activity.

Semi-quantitative versus quantitative assessments of late gadolinium enhancement extent for predicting spontaneous ventricular tachyarrhythmia events in patients with hypertrophic cardiomyopathy

Extent of late gadolinium enhancement (LGE) quantified by cardiac magnetic resonance was reportedly helpful for predicting the risk of ventricular tachyarrhythmias (VTA) in hypertrophic cardiomyopathy (HCM) patients. However, only a few data exist on the clinical implication of semi-quantitative assessment LGE extent in this patient population. The extent of left ventricular (LV) LGE was measured in 310 consecutive HCM patients using semi-quantitative (summing the LV segments with LGE, spatial extent) and quantitative (calculating the LGE volume percentage [vol% of LGE] against the total LV myocardial volume) methods, respectively. LV LGE was detected in 255 (82%) patients, most frequently in the mid-LV septum (n = 160, 52%). During the 49 ± 45 month follow-up, spontaneous VTA events were observed in 48 patients (16%) including aborted sudden cardiac death (SCD), appropriate defibrillator shock, and non-sustained VTA. The extent of LGE assessed by the two different methods showed a strong positive correlation (Spearman’s r = 0.63, P < 0.001). Moreover, there was a graded increase in the rates of VTA with the LGE extent evaluated semi-quantitatively and quantitatively. The extent of LGE was identified as an independent predictor of VTA events and more extensive LGE (positive ≥ 4 segments) significantly raised the risk of VTA, irrespective of the presence of conventional risk factors for SCD including family history, unexplained syncope, LV wall thickness ≥30 mm. The extent of LGE, whether assessed by semi-quantitative or quantitative methods, was closely associated with an increased risk of spontaneous VTA events in HCM patients.

P5029Inducibility of ventricular tachyarrhythmias by up to two extrastimuli does not predict future cardiac events in asymptomatic Brugada patients: results from long-term follow-up

Abstract Background Most recent consensus conference report recommends Implantable Cardioverter Defibrillator (ICD) implantation for asymptomatic Brugada patients with spontaneous or fever-induced type-1 ECG (A-BrS) and inducible ventricular tachyarrhythmias (VTs) by up to two extrastimuli as class IIb indication. However, the validity of the inducible VTs by up to two extrastimuli in A-BrS is still unknown. Purpose To evaluate the validity of the inducibility by up to two extrastimuli in A-BrS in a large Japanese cohort of BrS (The Japan Idiopathic Ventricular Fibrillation Study [J-IVFS]). Methods A total of 193 consecutive A-BrS patients performed programmed electrical stimulation (PES) with non-aggressive uniform protocol (mean age 50±13 years, 180 males) were enrolled. PES protocol was using 2 basic pacing cycles and the order of introduction of up to 2 ventricular extra-stimuli from right ventricular apex [RVA] first, then right ventricular outflow tract [RVOT], 3 ventricular extra-stimuli from RVA then RVOT down to the minimum of 200ms. Clinical outcomes during the follow-up period were compared between A-BrS patients with and without inducible VTs by up to two extrastimuli. Results Thirty-five A-BrS (18%) had inducible VTs by up to two extrastimuli. During a mean follow-up period of 101±48 months, 7 A-BrS experienced cardiac events (sudden cardiac death [SCD] or VTs, 0.4%/yr). None of the 7 A-BrS had inducible VTs by up to two extrastimuli. The incidences of cardiac events tended to be higher in A-BrS without inducible VTs by up to two extrastimuli than in those with inducible VTs (p=0.10), as determined by the Kaplan-Meier method. In the A-BrS, the annual incidences of cardiac events in A-BrS with family history of SCD, inferolateral J wave, wide QRS duration &gt;90msec in lead V2, or inducible VT/VF by 3 extrastimuli were 0.7, 0.7, 0.6, and 0.3%/yr, respectively. Conclusions Our large-scaled multicentre study with long-term follow-up revealed the inducibility of ventricular tachyarrhythmias by up to two extrastimuli does not predict future cardiac events in A-BrS, even using non-aggressive uniform protocol. Rather, other parameters such as family history of SCD or inferolateral J wave might be helpful for risk assessment in A-BrS.

Is programmed electrical stimulation mandatory for recognition of ventricular arrhythmogenicity in heart failure?

Ischemic cardiomyopathy often presents with advanced heart failure necessitating an intensive multidisciplinary approach to management. These patients constitute a very difficult population presenting with angina and ventricular tachyarrhythmias sometimes presenting as sudden cardiac death. In those patients presenting with spontaneous ventricular tachyarrhythmias, treatment with automated intracardiac defibrillator implantation has a significant mortality benefit. In patients with significant left ventricular (LV) dilatation and a left ventricular ejection fraction ≤ 30%, guidelines state that device implantation should be preceded by programmed electrical stimulation, which demonstrates inducible ventricular tachyarrhythmia. The treatment options for patients with moderate LV dilatation and ejection fraction ≥ 30% is individualized. Devices have their associated problems. Radiofrequency ablation has mixed results. Surgical cryoablation when performed concomitantly with surgical ventricular restoration has shown promising results. But, this option remains isolated to patients eligible for surgical ventricular restoration. Programmed electrical stimulation for inducibility of ventricular tachyarrhythmias in these patients also has a questionable role. The need for programmed electrical stimulation prior to cryoablation also seems highly individualized. In this review, we discuss the mechanisms of ischemic ventricular tachyarrhythmias and treatment options in heart failure. The mechanisms of ventricular arrhythmogenesis in ischemic cardiomyopathy help in formulating novel technical modifications for cryoablation when performed concomitantly with surgical ventricular restoration.

Potent immunomodulation and angiogenic effects of mesenchymal stem cells versus cardiomyocytes derived from pluripotent stem cells for treatment of heart failure

BackgroundOptimal cell type as cell-based therapies for heart failure (HF) remains unclear. We sought to compare the safety and efficacy of direct intramyocardial transplantation of human embryonic stem cell-derived cardiomyocytes (hESC-CMs) and human induced pluripotent stem cell-derived mesenchymal stem cells (hiPSC-MSCs) in a porcine model of HF.MethodsEight weeks after induction of HF with myocardial infarction (MI) and rapid pacing, animals with impaired left ventricular ejection fraction (LVEF) were randomly assigned to receive direct intramyocardial injection of saline (MI group), 2 × 108 hESC-CMs (hESC-CM group), or 2 × 108 hiPSC-MSCs (hiPSC-MSC group). The hearts were harvested for immunohistochemical evaluation after serial echocardiography and hemodynamic evaluation and ventricular tachyarrhythmia (VT) induction by in vivo programmed electrical stimulation.ResultsAt 8 weeks post-transplantation, LVEF, left ventricular maximal positive pressure derivative, and end systolic pressure-volume relationship were significantly higher in the hiPSC-MSC group but not in the hESC-CM group compared with the MI group. The incidence of early spontaneous ventricular tachyarrhythmia (VT) episodes was higher in the hESC-CM group but the incidence of inducible VT was similar among the different groups. Histological examination showed no tumor formation but hiPSC-MSCs exhibited a stronger survival capacity by activating regulatory T cells and reducing the inflammatory cells. In vitro study showed that hiPSC-MSCs were insensitive to pro-inflammatory interferon-gamma-induced human leukocyte antigen class II expression compared with hESC-CMs. Moreover, hiPSC-MSCs also significantly enhanced angiogenesis compared with other groups via increasing expression of distinct angiogenic factors.ConclusionsOur results demonstrate that transplantation of hiPSC-MSCs is safe and does not increase proarrhythmia or tumor formation and superior to hESC-CMs for the improvement of cardiac function in HF. This is due to their immunomodulation that improves in vivo survival and enhanced angiogenesis via paracrine effects.

Subcutaneous implantable cardioverter defibrillator in patients with arrhythmogenic right ventricular cardiomyopathy: Results from an Italian multicenter registry

BackgroundDespite expanding indication of the subcutaneous implantable cardioverter defibrillator (S-ICD) in clinical practice, limited data exists on safety and efficacy of S-ICD in arrhythmogenic right ventricular cardiomyopathy (ARVC) patients. The aim of this multicenter study was to evaluate the safety and efficacy of S-ICD in ARVC patients. MethodsThe study population included 44 consecutive patients with definite ARVC diagnosis according to the 2010 ITF criteria (57% male, mean age 37 ± 17 years [range 10–75 years]) who received an S-ICD. Eighteen (41%) patients were implanted for secondary prevention. ResultsAt implant, all inducible patients (34/44) had conversion of ventricular fibrillation at 65 J. No early complications occurred. During a median follow-up of 12 months (7–19), 3 (6.8%) patients experienced complications requiring surgical revision. No local or systemic device-related infections were observed. Six patients (14%) received a total of 61 appropriate and successful shocks on ventricular arrhythmias. Six (14%) patients experienced 8 inappropriate shocks for oversensing of cardiac signal (4 cases) and non-cardiac signal (4 cases) with one patient requiring device explantation. No patients had the device explanted due to the need for antitachycardia pacing. ConclusionsThe study shows that S-ICD provides safe and effective therapy for termination of both induced and spontaneous malignant ventricular tachyarrhythmias with high energy shocks in ARVC patients, but the risk of inappropriate shocks and complications needing surgical revision should be considered.