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Objective: To investigate the role of protein kinase C (PKC) in action potential duration (APD) restitution and ventricular tachyarrhythmias (VAs). Methods and results: Rabbits hearts were isolated and prepared for Langendorff perfusion technique. The stimuli–extra‐stimulus (S1–S2) method and dynamic S1 pacing protocol were performed to construct APD restitution and to induce APD alternans or VA, respectively, at 10 sites throughout the ventricular chamber. Administration of phorbol‐12‐myristate‐13‐acetate (PMA) (100 nM) (n = 15) greatly steepened the restitution curves (Smax > 1) (p <.01) at each site compared to the control group (n = 15). Furthermore, treatment with PMA also induced larger spatial dispersions of Smax (p <.05) and decreased the thresholds of the VA and APD alternans (p <.01). However, perfused with the PKC inhibitor, bisindolylmaleimide (BIM) (500 nM) (n = 10), reversibly flattened the APD restitution curves at each site (Smax < 1), decreased the spatial dispersions of Smax, and increased the thresholds of APD alternans and VA. According to the results of patch‐clamp, peak amplitude of L‐type Ca2+ current was significantly increased by addition of PMA compared with control (CTL) group (p <.05). Antagonize this current with verapamil (n = 10) can fully inhibited the PMA induced increasing of Smax and inducibility of VA and alternans. Conclusion: PKC activation increased the dispersion of APD restitution and thus led to occurrence of VA, which possibly related to the increased Ca2+ influx. [ABSTRACT FROM AUTHOR]

Background: Myotonic dystrophy type 1 (DM1) is a multiorgan disorder with significant cardiac involvement. ECG abnormalities, including arrhythmias, occur in 80 % of DM1 patients and are the second-most common cause of death after respiratory complications; however, the mechanisms underlying the arrhythmogenesis remain unclear. The objective of this study was to investigate the basis of the electrophysiological abnormalities in DM1 using the DMSXL mouse model. Methods: ECG parameters were evaluated at baseline and post flecainide challenge. Calcium transient and action potential parameters were evaluated in Langendorff-perfused hearts using fluorescence optical mapping. Calcium transient/sparks were evaluated in ventricular myocytes via confocal microscopy. Protein and mRNA levels for calcium handling proteins were evaluated using western blot and RT-qPCR, respectively. Results: DMSXL mice showed arrhythmic events on ECG including premature ventricular contractions and sinus block. DMSXL mice showed increased calcium transient time to peak without any change to voltage parameters. Calcium alternans and both sustained and non-sustained ventricular tachyarrhythmias were readily inducible in DMSXL mice. The confocal experiments also showed calcium transient alternans and increased frequency of calcium sparks in DMSXL cardiomyocytes. These calcium abnormalities were correlated with increased RyR2 phosphorylation without changes to the other calcium handling proteins. Conclusions: The DMSXL mouse model of DM1 exhibited enhanced arrhythmogenicity associated with abnormal intracellular calcium handling due to hyperphosphorylation of RyR2, pointing to RyR2 as a potential new therapeutic target in DM1 treatment.

Introduction: Takotsubo cardiomyopathy (TTC), also known as stress‐induced cardiomyopathy, resembles acute heart failure syndrome but lacks disease‐specific diagnosis and treatment strategies. TTC accounts for approximately 5–6% of all suspected cases of acute coronary syndrome in women. At present, animal models of TTC are often created by large amounts of exogenous catecholamines such as isoproterenol. However, isoproterenol injection cannot fully simulate the onset of stress‐induced cardiomyopathy in humans since stress is not an instantaneous event. Methods: Rats were immobilized for 6 h per day for 1–14 days. To examine whether the TTC model was successful, echocardiography was employed; Elisa detected serum sympathetic activation markers; and the Open‐Field test (OFT) was used to analyze behavioral changes in rats after stress. Western blot and histology were used to assess sympathetic remodeling, inflammation levels, and fibrosis; qRT‐PCR was used to explore the levels of fibrosis and myocardial hypertrophy. The electrical stability of ventricular was determined by electrophysiological testing. Results: The rats showed severe stress behavior and local sympathetic remodeling of the heart after only 1 day of stress. After 3 days of stress, the induction of ventricular tachyarrhythmia increased prominently. The highest incidence of TTC in rats was at 5 days of immobilization stress. The pathological left ventricular remodeling caused by immobilization (IMO) stress includes inflammatory infiltration, fibrosis, and myocardial hypertrophy. Conclusions: Our study confirms the hypothesis that IMO stress can mimic Takotsubo cardiomyopathy, and the various effects on the heart depending on the duration of IMO stress. We observed the highest incidence of TTC occurred after 5 days of stress. Furthermore, there is a gradual occurrence of electrical and structural remodeling as the stress duration prolongs. [ABSTRACT FROM AUTHOR]

Implantable cardioverter defibrillators (ICDs) reduce sudden cardiac death (SCD) when patients experience life-threatening ventricular arrhythmias (LTVA). However, current strategies determining ICD patient selection and risk stratification are inefficient. We used metabolomics to assess whether dysregulated metabolites are associated with LTVA and identify potential biomarkers. Baseline plasma samples were collected from 72 patients receiving ICDs. Over a median follow-up of 524.0 days (range 239.0–705.5), LTVA occurred in 23 (31.9%) patients (22 effective ICD treatments and 1 SCD). After confounding risk factors adjustment for age, smoking, secondary prevention, and creatine kinase MB, 23 metabolites were significantly associated with LTVA. Pathway analysis revealed LTVA associations with disrupted metabolism of glycine, serine, threonine, and branched chain amino acids. Pathway enrichment analysis identified a panel of 6 metabolites that potentially predicted LTVA, with an area under the receiver operating characteristic curve of 0.8. Future studies are necessary on biological mechanisms and potential clinical use. [ABSTRACT FROM AUTHOR]

BackgroundProtein phosphatase 2A (PP2A) is a serine/threonine-selective holoenzyme that controls Ca2+ homeostasis and contractility of the heart via dephosphorylation of regulatory proteins. In some genetically modified mouse models with increased arrhythmogenicity, a reduced expression of the regulatory subunit B56α of PP2A was found as a concomitant effect. Whether there is a general correlation between the abundance of B56α and the promotion of cardiac arrhythmogenesis remains unclear.MethodsThe aim of this study was therefore to investigate the role of PP2A-B56α in the propensity for arrhythmic activity in the heart. The experimental analysis of this question has been addressed by using a mouse model with deletion of the PP2A-B56α gene, PPP2R5A (KO), in comparison to wild-type animals (WT). Evidence for arrhythmogenicity was investigated in whole animal, isolated heart and cardiomyocytes by ECG, recording of monophasic action potential (MAP) induced by programmed electrical stimulation (PES), measurement of Ca2+ transients under increased pacing frequencies and determination of total K+ channel currents (IK).ResultsECG measurements showed a prolongation of QT time in KO vs. WT. KO mice exhibited a higher rate of premature ventricular contractions in the ECG. MAP measurements in Langendorff-perfused KO hearts showed increased episodes of ventricular tachyarrhythmia induced by PES. However, the KO hearts showed values for MAP duration that were similar to those in WT hearts. In contrast, KO showed more myocardial cells with spontaneous arrhythmogenic Ca2+ transient events compared to WT. The whole-cell patch-clamp technique applied to ventricular cardiomyocytes revealed comparable peak potassium channel current densities between KO and WT.ConclusionThese findings support the assumption that a decrease or even the loss of PP2A-B56α leads to an increased propensity of triggered arrhythmias. This could be based on the increased spontaneous Ca2+ tansients observed.

Background: Syncope is a significant prognostic factor in patients with Brugada syndrome (BrS). However, the risk of ventricular arrhythmia in patients with nonarrhythmic loss of consciousness (LOC) is similar to that in asymptomatic patients. LOC events after implantable cardioverter-defibrillator (ICD) implantation may provide insights into underlying causes of the initial LOC episode. Objective: The purpose of this study was to examine LOC characteristics following ICD implantation. Methods: We retrospectively analyzed 112 patients with BrS (mean age 47 years; 111 men) who were treated with an ICD. The patients were classified into 3 groups based on symptoms at implantation: asymptomatic (35 patients); LOC (46 patients); and ventricular tachyarrhythmia (VTA) (31 patients). We evaluated the incidence and cause of LOC during long-term follow-up after ICD implantation. Results: During mean follow-up of 12.2 years, 41 patients (37%) experienced LOC after ICD implantation. Arrhythmic LOC occurred in 5 asymptomatic patients, 14 LOC patients, and 16 patients with VTA. Nonarrhythmic LOC, similar to the initial episode, occurred after ICD implantation in 6 patients with prior LOC (2 with neurally mediated syncope and 4 with epilepsy). Most epileptic patients experienced LOC during rest or sleeping, and did not show an abnormal encephalogram during initial evaluation of the LOC episodes. Conclusion: After ICD implantation, 13% of patients had nonarrhythmic LOC similar to the initial episode. Accurate classification of LOC based on a detailed medical history is important for risk stratification, although distinguishing arrhythmic LOC from epilepsy-related LOC episodes can be challenging depending on the circumstances and characteristics of the LOC event.

Objective: Sudden cardiac death (SCD) and malignant ventricular arrhythmia (VA) are increasingly recognized as important issues for people living with a Fontan circulation, but data are lacking. We sought to characterize the cohort who had sudden cardiac death, most likely related to VA and/or documented VA in the Australia and New Zealand Fontan Registry including risk factors and clinical outcomes. Methods: A retrospective cohort study was performed. Inclusion criteria were documented non-sustained ventricular tachycardia, sustained ventricular tachycardia, ventricular fibrillation, resuscitated cardiac arrest or SCD > 30 days post-Fontan completion. Results: Of 1611 patients, 20 (1.2%) had VA; 14 (1.0%) had VA without SCD and 6 (<1%) had SCD (6% of all deaths recorded in Registry; 5 of those had documented VA at the time of arrest and 1 was presumed to be VA-associated). The median age at first VA was 20.5 (14–32) years, 10 (50%) were females, and the median age at Fontan operation was 8 (4–17) years. On univariable analysis, hypoplastic left heart syndrome (p = 0.03) and older age Fontan operation (p < 0.001) were associated with VA. Earlier Fontan era (p < 0.003), atriopulmonary Fontan (p < 0.001), pre-Fontan atrioventricular valve repair (p = 0.013) pre- or post-Fontan atrial arrhythmia (p = 0.010) were associated with SCD. Patients with VA had a 3 times higher risk of death or heart transplant (HR 3.27(1.19, 8.98), p = 0.02). Conclusions: A proportion of people living with a Fontan circulation have malignant VA. Routine VA screening in this cohort is essential. More data are needed to aid risk stratification. [ABSTRACT FROM AUTHOR]

Torsade de pointes is a potentially lethal polymorphic ventricular tachyarrhythmia that can occur in the setting of long QT syndrome (LQTS). LQTS is multi-hit in nature and multiple factors combine their effects leading to increased arrhythmic risk. While hypokalemia and multiple medications are accounted for in LQTS, the arrhythmogenic role of systemic inflammation is increasingly recognized but often overlooked. We tested the hypothesis that the inflammatory cytokine interleukin(IL)-6 will significantly increase the incidence of arrhythmia when combined with other pro-arrhythmic conditions (hypokalemia and the psychotropic medication, quetiapine). Guinea pigs were injected intraperitoneally with IL-6/soluble IL-6 receptor and QT changes were measured in vivo. Subsequently, hearts were cannulated via Langendorff perfusion for ex vivo optical mapping measurements of action potential duration (APD 90) and arrhythmia inducibility. Computer simulations (MATLAB) were performed to investigate I Kr inhibition at varying IL-6 and quetiapine concentrations. IL-6 prolonged QTc in vivo guinea pigs from 306.74 ± 7.19 ms to 332.60 ± 8.75 ms (n = 8, p =.0021). Optical mapping on isolated hearts demonstrated APD prolongation in IL-6- vs saline groups (3Hz APD 90 :179.67 ± 2.47 ms vs 153.5 ± 7.86 ms, p =.0357). When hypokalemia was introduced, the APD 90 increased to 195.8 ± 5.02 ms[IL-6] and 174.57 ± 10.7 ms[saline] (p =.2797), and when quetiapine was added to hypokalemia to 207.67 ± 3.03 ms[IL-6] and 191.37 ± 9.49 ms[saline] (p =.2449). After the addition of hypokalemia ± quetiapine, arrhythmia was induced in 75% of IL-6-treated hearts (n = 8), while in none of the control hearts (n = 6). Computer simulations demonstrated spontaneous depolarizations at ∼83% aggregate I Kr inhibition. Our experimental observations strongly suggest that controlling inflammation, specifically IL-6, could be a viable and important route for reducing QT prolongation and arrhythmia incidence in the clinical setting. • Inflammation is often overlooked in treatment of Long QT Syndrome. • Patients taking psychotropic medication are at increased risk for arrhythmia. • Interleukin-6 can increase action potential duration and QT interval. • Our data shows IL-6 could be a novel therapeutic target for reducing arrhythmia risk. [ABSTRACT FROM AUTHOR]

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. 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. 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. 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. 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. [ABSTRACT FROM AUTHOR]

LMNA genotype-positive patients have high risk of experiencing life-threatening ventricular tachyarrhythmias (VTAs). The LMNA -risk VTA calculator published in 2019 has not been externally validated. The purpose of this study was to validate the LMNA -risk VTA calculator. We included LMNA genotype-positive patients without previous VTAs from 2 large Scandinavian centers. Patients underwent electrocardiography, 24-hour Holter monitoring, and echocardiographic examinations at baseline and repeatedly during follow-up. Validation of the LMNA -risk VTA calculator was performed using Harrell's C-statistic derived from multivariable Cox regression analysis. We included 118 patients (age 37 years [IQR 27–49 years]; 39 [33%] probands; 65 [55%] women; 100 [85%] with non-missense LMNA variants). Twenty-three patients (19%) experienced VTA during 6.1 years (interquartile range 3.0–9.1 years) follow-up, resulting in 3.0% (95% confidence interval 2.0%–4.5%) yearly incidence rate. Atrioventricular block and reduced left ventricular ejection fraction were independent predictors of VTAs, while nonsustained ventricular tachycardia, male sex, and non-missense LMNA variants were not. The LMNA -risk VTA calculator showed 83% sensitivity and 26% specificity for identifying patients with VTAs during the coming 5 years, and a Harrell's C-statistic of 0.85, when applying ≥7% predicted 5-year VTA risk as threshold. The sensitivity increased to 100% when reevaluating risk at the time of last consultation before VTA. The calculator overestimated arrhythmic risk in patients with mild and moderate phenotype, particularly in men. Validation of the LMNA -risk VTA calculator showed high sensitivity for subsequent VTAs, but overestimated arrhythmic risk when using ≥7% predicted 5-year risk as threshold. Frequent reevaluation of risk was necessary to maintain the sensitivity of the model. [Display omitted] [ABSTRACT FROM AUTHOR]

Aim. To perform a comparative analysis of indicators of transthoracic echocardiography (TE), to establish echocardiographic predictors and their predictive role in the occurrence of stable ventricular tachyarrhythmia (VT) paroxysms in patients with nonischemic chronic heart failure (HF) and cardioverter-defibrillator (ICD) implanted for primary prevention of sudden cardiac death.Material and Methods. A prospective study was carried out, which included 166 patients with nonischemic HF at the age of 54 (49; 59) years with the left ventricle ejection fraction (LV EF) ≤35% and an ICD implanted. The observation time was 24 months. The primary endpoint was the first-ever stable paroxysm of VT (lasting for ≥30 seconds), detected in the «monitor» zone of VT, or paroxysm of VT, which required ICD therapy. A total of 34 TE indicators were evaluated. Chi-square, Fischer, Manna-Whitney, single-factor logistic regression (LR), and multi-factor LR were used for data processing and analysis and for predictive modelling. Model accuracy was estimated using 4 metrics: ROC curve area (AUC), sensitivity, specificity and diagnostic efficiency.Results. During the two-year observation, 32 patients (19.3%) had a primary endpoint. The average time of occurrence of a stable VT episode was 21.6±0.6 months (95% confidence interval [CI] 20.5-22.8 months). The value of LV end-systolic dimension was the only parameter independently associated with VT (odds ratio 2.8 per unit increase, 95% CI 1.04-7.5; p=0.042). The complex analysis of echocardiographic indicators made it possible to identify 5 factors with the greatest predictive potential, which are linearly and nonlinearly related to occurrence of VT. These included the LV end-diastolic and end-systolic volumes, LV mass, index of relative LV wall thickness, upper-lower size of the right atrium. The metrics of the best predictive model were: AUC – 0.71 0.069 with 95% CI 0.574-0.843; specificity 50%, sensitivity 90.9%; diagnostic efficiency 57.1%.Conclusion. The study made it possible to evaluate the possibilities of the results of TE in predicting the probability of VT occurrence in patients with nonischemic HF and reduced LV EF. Predictive indicators have been identified that can be used to stratify the arrhythmic risk in the exposed cohort of patients.

Antipsychotics (AP) induced prolongation of the QT interval in patients with schizophrenia (Sch) is an actual interdisciplinary problem as it increases the risk of sudden death syndrome. Long QT syndrome (LQTS) as a cardiac adverse drug reaction is a multifactorial symptomatic disorder, the development of which is influenced by modifying factors (APs' dose, duration of APs therapy, APs polytherapy, and monotherapy, etc.) and non-modifying factors (genetic predisposition, gender, age, etc.). The genetic predisposition to AP-induced LQTS may be due to several causes, including causal mutations in the genes responsible for monoheme forms of LQTS, single nucleotide variants (SNVs) of the candidate genes encoding voltage-dependent ion channels expressed both in the brain and in the heart, and SNVs of candidate genes encoding key enzymes of APs metabolism. This narrative review summarizes the results of genetic studies on AP-induced LQTS and proposes a new personalized approach to assessing the risk of its development (low, moderate, high). We recommend implementation in protocols of primary diagnosis of AP-induced LQTS and medication dispensary additional observations of the risk category of patients receiving APs, deoxyribonucleic acid profiling, regular electrocardiogram monitoring, and regular therapeutic drug monitoring of the blood APs levels. [ABSTRACT FROM AUTHOR]

Limited data regarding the outcome of patients with different types of ventricular tachyarrhythmias is available. This study sought to assess the prognostic impact of different types of ventricular tachyarrhythmias stratified by underlying cardiac disease. A large retrospective registry was used including all consecutive patients presenting with ventricular tachycardia (VT) and fibrillation (VF) on admission from 2002 to 2016. Patients with non-sustained VT (ns-VT), sustained VT (s-VT) and VF were compared using uni- and multivariable Cox regression models. Risk stratification was performed after stratification by underlying cardiac disease (i.e., acute myocardial infarction (AMI), ischemic heart disease (IHD), non-ischemic cardiomyopathy (NICM) and patients considered as lower-risk for ventricular tachyarrhythmias). The primary endpoint was defined as all-cause mortality at 2.5 years. Secondary endpoints were cardiac death at 24 h, all-cause mortality at 5 years, cardiac rehospitalization and a composite arrhythmic endpoint at 2.5 years. In 2422 consecutive patients with ventricular tachyarrhythmias, most patients were admitted with VF (44%), followed by ns-VT (30%) and s-VT (26%). Patients with VF suffered most commonly from AMI (42%), whereas heart failure was more common in s-VT patients (32%). In patients with AMI (HR = 1.146; 95% CI 0.751–1.750; p = 0.527) and in the lower-risk group (HR = 1.357; 95% CI 0.702–2.625; p = 0.364), the risk of all-cause mortality did not differ in VF and s-VT patients. In IHD patients, VF was associated with impaired prognosis compared to s-VT (HR = 2.502; 95% CI 1.936–3.235; p = 0.001). In conclusion, VF was associated with worse long-term prognosis compared to s-VT in IHD patients, whereas the risk of all-cause mortality among VF and s-VT patients did not differ in patients with AMI, NICM and in patients considered at lower risk for ventricular tachyarrhythmias. [ABSTRACT FROM AUTHOR]

Implantable cardioverter-defibrillators (ICDs) serve to reduce the risk of sudden death; however, ICD shocks worsen patient prognosis. Therefore, attempts have been made to terminate life-threatening arrhythmias without ICD shocks. A 71-year-old man with non-ischemic cardiomyopathy, who previously underwent cardiac resynchronization therapy-defibrillator (CRT-D) placement, was hospitalized for ventricular tachyarrhythmia (VT) that was refractory to traditional anti-tachycardia pacing (ATP). Endocardial and epicardial ablation failed to prevent VT recurrence. Since the CRT-D battery was exhausted, it was replaced with a Cobalt™ XT HF CRT-D (Medtronic, Minneapolis, MN, USA), and the intrinsic ATP (iATP) algorithm was employed. Although VT recurred frequently, recurrent VTs were terminated by the iATP, which created a conduction block in the circuit without VT acceleration or shock. This is the first reported case wherein an iATP algorithm was effective against VT resistant to traditional anti-tachycardia pacing. This novel ATP algorithm has the potential to terminate refractory VT without ICD shocks and provide a better prognosis.

Abstract Background This study evaluates cardiac diseases and prognosis in young adults and adults presenting with ventricular tachyarrhythmias (VTA). Methods The present longitudinal, observational, registry-based, monocentric cohort study includes all consecutive patients 45 years old or younger presenting with VTA at admission from 2002 to 2016. Rates of coronary angiography, coronary artery disease (CAD) and need for percutaneous coronary intervention (PCI), cardiac diseases associated with VTA, and differences in long-term prognostic endpoints for young adults (20–34 years old) were analyzed and compared to those of adults (35–45 years old), for whom multivariable risk prediction models were developed. Kaplan–Meier analyses were performed according to age and type of VTA. Results A total of 259 consecutive patients were included in the study (36% young adults and 64% adults). At admission, 38% of young adults had VTA due to CAD that required PCI. Furthermore, VTA in young adults was commonly idiopathic (27%), or had underlying channelopathies (18%), primary cardiomyopathies (13%) or acute myocardial infarction (AMI, 11%). In adults, VTA was mostly associated with AMI (28%), though the rate of idiopathy was still high (20%). A total 41% of all patients received cardiopulmonary resuscitation (CPR), for whom AMI (STEMI 17%, NSTEMI 24%) was most frequently observed. Irrespective of the type of VTA, all-cause mortality was similar for young adults and adults. In young adults, left ventricular ejection fraction (LVEF)

Myotonic dystrophy type 1 (DM1) is a multiorgan disorder with significant cardiac involvement. ECG abnormalities, including arrhythmias, occur in 80 % of DM1 patients and are the second-most common cause of death after respiratory complications; however, the mechanisms underlying the arrhythmogenesis remain unclear. The objective of this study was to investigate the basis of the electrophysiological abnormalities in DM1 using the DMSXL mouse model. ECG parameters were evaluated at baseline and post flecainide challenge. Calcium transient and action potential parameters were evaluated in Langendorff-perfused hearts using fluorescence optical mapping. Calcium transient/sparks were evaluated in ventricular myocytes via confocal microscopy. Protein and mRNA levels for calcium handling proteins were evaluated using western blot and RT-qPCR, respectively. DMSXL mice showed arrhythmic events on ECG including premature ventricular contractions and sinus block. DMSXL mice showed increased calcium transient time to peak without any change to voltage parameters. Calcium alternans and both sustained and non-sustained ventricular tachyarrhythmias were readily inducible in DMSXL mice. The confocal experiments also showed calcium transient alternans and increased frequency of calcium sparks in DMSXL cardiomyocytes. These calcium abnormalities were correlated with increased RyR2 phosphorylation without changes to the other calcium handling proteins. The DMSXL mouse model of DM1 exhibited enhanced arrhythmogenicity associated with abnormal intracellular calcium handling due to hyperphosphorylation of RyR2, pointing to RyR2 as a potential new therapeutic target in DM1 treatment. [Display omitted] • DM1 patients have reduced life expectancy due to cardiac causes; however, the underlying mechanisms are unclear. • The DMSXL mouse model of DM1 was more prone to VTs and exhibited arrhythmic events including PVCs and sinus block. • These arrhythmic events were associated with abnormal intracellular calcium transients/sparks in DMSXL mice. • Our findings suggest a significant arrhythmogenic role for RyR2/phospho-RyR2, which provide novel therapeutic targets. [ABSTRACT FROM AUTHOR]

Background: Current implantable cardioverter-defibrillator (ICD) devices are equipped with a device-embedded accelerometer capable of capturing physical activity (PA). In contrast, wearable accelerometer-based methods enable the measurement of physical behavior (PB) that encompasses not only PA but also sleep behavior, sedentary time, and rest-activity patterns. Objective: This systematic review evaluates accelerometer-based methods used in patients carrying an ICD or at high risk of sudden cardiac death. Methods: Papers were identified via the OVID MEDLINE and OVID EMBASE databases. PB could be assessed using a wearable accelerometer or an embedded accelerometer in the ICD. Results: A total of 52 papers were deemed appropriate for this review. Out of these studies, 30 examined device-embedded accelerometry (189,811 patients), 19 examined wearable accelerometry (1601 patients), and 3 validated wearable accelerometry against device-embedded accelerometry (106 patients). The main findings were that a low level of PA after implantation of the ICD and a decline in PA were both associated with an increased risk of mortality, heart failure hospitalization, and appropriate ICD shock. Second, PA was affected by cardiac factors (eg, onset of atrial fibrillation, ICD shocks) and noncardiac factors (eg, seasonal differences, societal factors). Conclusion: This review demonstrated the potential of accelerometer-measured PA as a marker of clinical deterioration and ventricular arrhythmias. Notwithstanding that the evidence of PB assessed using wearable accelerometry was limited, there seems to be potential for accelerometers to improve early warning systems and facilitate preventative and proactive strategies.

Background: Pulmonary valve replacement (PVR) is recommended for severe pulmonary regurgitation in repaired tetralogy of Fallot (rTOF).Objective: The purpose of this study was to investigate the event rate and effectiveness of PVR.Methods: A retrospective study of tetralogy of Fallot patients who survived total repair from 1970 to 2020 was conducted.Results: We identified 1744 rTOF patients; 86.6% with classic rTOF, 11.5% with pulmonary atresia, 0.8% with endocardial cushion defect, and 1.1% with absent pulmonary valve. Annual risks of tachyarrhythmia/sudden cardiac arrest (SCA) increased to 0.295% and 1.338% in patients aged 10-30 and 30-60 years, respectively, without sex predominance. PVR (223 surgical and 39 percutaneous) event rate was 34.7% ± 2.1% by 30 years after repair (annual risk: 1.57% between 10 and 30 years after repair). The second PVR rate was 9.9% ± 4.1% by 20 years after the first PVR. Tachyarrhythmia/SCA risk was higher in PVR patients than in No PVR patients and was reduced in PVR patients without tachyarrhythmia/SCA before PVR. However, survival in patients with ventricular tachyarrhythmia/SCA still was better after PVR. At PVR, 13% of patients had tachyarrhythmia/SCA, which was the major predictor of events after PVR. Before PVR, although the ventricular tachyarrhythmia/SCA risks included QRS duration >160 ms and New York Heart Association functional class III or IV, supraventricular tachyarrhythmia was associated with PVR age ≥28 years and N-terminal pro-brain natriuretic peptide >450 pg/mL.Conclusion: Tachyarrhythmia/SCA occurrence and the need for PVR increased with age during young adulthood. PVR reduced subsequent arrhythmias only in those patients without arrhythmias before PVR. [ABSTRACT FROM AUTHOR]

Background Arrhythmogenic right-ventricular cardiomyopathy (ARVC) is a hereditary cardiomyopathy characterized by fibro-fat replacement of the right-ventricular myocardium. There are many factors associated with poor prognosis in patients with ARVC. Among these factors, intensive physical exertion is considered an important risk factor for sudden cardiac death. Case summary Herein, we report a case series of siblings with ARVC and an early manifestation of ventricular tachyarrhythmia. Plakophilin-2 (PKP2) genetic variant, which is one of the causative genetic variants of ARVC, was detected by genetic testing in all three siblings. They were young athletes with lethal/symptomatic ventricular tachycardias. The eldest sibling was implanted with a transvenous implantable cardioverter defibrillator (ICD) due to resuscitated cardiopulmonary arrest at 18 years of age; the next oldest patient was treated with successful catheter ablation at 17 years; the youngest patient was treated with catheter ablation and subcutaneous ICD implantation at 17 years. Discussion A recent experimental model revealed that physical exertion in PKP2 knockout mice diminished cardiac muscle mass and increased cardiac myocyte apoptosis, despite enhanced arrhythmogenicity such as increased fractional shortening and calcium transient amplitude. The three siblings were heterozygous for the previously reported pathologic splice site variant c.2489 + 1G > A in Intron 12 of the PKP2. The variant might play an important role in facilitating the vulnerability to arrhythmia under intensive endurance training. Most ARVC patients with PKP2 variant, especially pathologic splice site variant c.2489 + 1G > A in Intron 12 of the PKP2, might have to be managed strictly regarding daily exercise. [ABSTRACT FROM AUTHOR]

Sleep-disordered breathing (SDB) is associated with an increased risk of adverse events in patients with heart failure (HF); however, its impact in patients implanted with a left ventricular assist device (LVAD) remains unclear. We aimed to investigate the prevalence of SDB in patients with LVAD and its impact on their clinical outcomes. Fifty consecutive patients with LVAD who underwent portable sleep monitoring between September 2017 and April 2018 were prospectively enrolled, and they were followed up for 170 ± 36 days. According to their respiratory disturbance indexes (RDIs), they were categorized into the SDB group (RDI ≥ 15, n = 12) and the non-SDB group (RDI < 15, n = 38). The incidence of adverse events during the follow-up period was investigated after enrollment. Multivariate logistic regression analysis revealed significant differences in SDB in LVAD-implanted patients in terms of the logarithmic transformation brain natriuretic peptide (BNP) values (p = 0.005). The optimal BNP cut-off value for SDB prediction in LVAD-implanted patients was 300 pg/mL (sensitivity: 58.3%, specificity: 94.7%). During follow-up, ventricular tachyarrhythmias (VTas) occurred significantly more frequently in the SDB group (4 [33%] vs. 2 [5%] patients, p = 0.02); Atrial tachyarrhythmia (ATa) also tended to occur more frequently in the SDB group (2 [25%] vs. 2 [2%] patients, p = 0.07). SBD was prevalent in 24% of the LVAD-implanted patients with advanced HF. Furthermore, SDB was significantly associated with high BNP levels and was also potentially associated with subsequent incidence of VTa in patients with LVAD. [ABSTRACT FROM AUTHOR]

Introduction: The implantable cardioverter defibrillator reduces mortality among patients with heart failure (HF) due to ischemic heart disease. Clinical trial data have called into question the benefit of an ICD in patients with HF due to nonischemic cardiomyopathy (NICM). We developed a risk stratification score for ventricular tachyarrhythmia (VTA) among patients with NICM receiving a primary prevention ICD., Methods: The study population comprised 1515 patients with NICM who were enrolled in the landmark MADIT trials. Fine and Gray analysis was used to develop a model to predict the occurrence of VTAs and ICD therapies while accounting for the competing risk of non-arrhythmic mortality. External validation was carried out in the RAID Trial population., Results: Four risk factors associated with increased risk for VTA were identified: male sex, left ventricular ejection fraction ≤25%, no indication for cardiac resynchronization therapy with a defibrillator (CRT-D), and Black race. A score was generated based on this model, and patients were stratified into low (N = 390), intermediate (N = 728), and high-risk (N = 387) groups. The 5-year cumulative incidences of VTA were 15%, 24%, and 42%, respectively. Application of score groups for the secondary endpoints of Fast VT or VF and Appropriate ICD Shock revealed similar findings. Recurrent event analysis yielded consistent results. The AUC in the validation cohort for the endpoint of Appropriate ICD Shock was 69.3., Conclusions: Our study shows that patients with NICM can be risk stratified using demographic and clinical variables and may be used when evaluating such patients for a primary prevention ICD., (© 2024 Wiley Periodicals LLC.)

Objective: To investigate the role of protein kinase C (PKC) in action potential duration (APD) restitution and ventricular tachyarrhythmias (VAs)., Methods and Results: Rabbits hearts were isolated and prepared for Langendorff perfusion technique. The stimuli-extra-stimulus (S 1 -S 2 ) method and dynamic S 1 pacing protocol were performed to construct APD restitution and to induce APD alternans or VA, respectively, at 10 sites throughout the ventricular chamber. Administration of phorbol-12-myristate-13-acetate (PMA) (100 nM) (n = 15) greatly steepened the restitution curves (S max  > 1) (p < .01) at each site compared to the control group (n = 15). Furthermore, treatment with PMA also induced larger spatial dispersions of S max (p < .05) and decreased the thresholds of the VA and APD alternans (p < .01). However, perfused with the PKC inhibitor, bisindolylmaleimide (BIM) (500 nM) (n = 10), reversibly flattened the APD restitution curves at each site (S max  < 1), decreased the spatial dispersions of S max , and increased the thresholds of APD alternans and VA. According to the results of patch-clamp, peak amplitude of L-type Ca 2+ current was significantly increased by addition of PMA compared with control (CTL) group (p < .05). Antagonize this current with verapamil (n = 10) can fully inhibited the PMA induced increasing of S max and inducibility of VA and alternans., Conclusion: PKC activation increased the dispersion of APD restitution and thus led to occurrence of VA, which possibly related to the increased Ca 2+ influx., (© 2024 Wiley Periodicals LLC.)

The article discusses the challenges of mapping scar-mediated ventricular tachycardia (VT) in ischemic cardiomyopathy and proposes a new technique based on spatially identifying electrodes activating during specific phases of VT. It states that this method, presented by Ciaccio et al. in JCE, offers a promising approach relying solely on electroanatomic mapping, potentially improving the efficiency of VT ablation procedures.

Aims: Low blood pressure (BP) has been shown to be associated with increased mortality in patients with chronic heart failure. This study was designed to evaluate the relationships between diagnosed hypertension and the risk of ventricular arrhythmia (VA) and all-cause death in chronic heart failure (CHF) patients with implantable cardioverter-defibrillators (ICD), including those with preserved left ventricular ejection fraction (HFpEF) and indication for ICD secondary prevention. We hypothesized that a stable hypertension status, along with an increasing BP level, is associated with a reduction in the risk of VA in this population, thereby limiting ICD efficacy. Methods: We retrospectively enrolled 964 CHF patients, with hypertension diagnosis and hospitalized BP measurements obtained before ICD implantation. The primary outcome measure was defined as the composite of SCD, appropriate ICD therapy, and sustained VT. The secondary endpoint was time to death or heart transplantation (HTx). We performed multivariable Cox proportional hazard regression and entropy balancing to calculate weights to control for baseline imbalances with or without hypertension. The Fine–Gray subdistribution hazard model was used to confirm the results. The effect of random BP measurements on the primary outcome was illustrated in the Cox model with inverse probability weighting. Results: The 964 patients had a mean (SD) age of 58.9 (13.1) years; 762 (79.0%) were men. During the interrogation follow-up [median 2.81 years (interquartile range: 1.32–5.27 years)], 380 patients (39.4%) reached the primary outcome. A total of 244 (45.2%) VA events in non-hypertension patients and 136 (32.1%) in hypertension patients were observed. A total of 202 (21.0%) patients died, and 31 (3.2%) patients underwent heart transplantation (incidence 5.89 per 100 person-years; 95% CI: 5.16–6.70 per 100 person-years) during a median survival follow-up of 4.5 (IQR 2.8–6.8) years. A lower cumulative incidence of VA events was observed in hypertension patients in the initial unadjusted Kaplan–Meier time-to-event analysis [hazard ratio (HR): 0.65, 95% confidence interval (CI): 0.53–0.80]. The protective effect was robust after entropy balancing (HR: 0.71, 95% CI: 0.56–0.89) and counting death as a competing risk (HR: 0.71, 95% CI: 0.51–1.00). Hypertension diagnosis did not associate with all-cause mortality in this population. Random systolic blood pressure was negatively associated with VA outcomes (p = 0.065). Conclusions: In hospitalized chronic heart failure patients with implantable cardioverter-defibrillators, the hypertension status and higher systolic blood pressure measurements are independently associated with a lower risk of combined endpoints of ventricular arrhythmia and sudden cardiac death but not with all-cause mortality. Randomized controlled trials are needed to confirm the protective effect of hypertension on ventricular arrhythmia in chronic heart failure patients. [ABSTRACT FROM AUTHOR]

Background: This study evaluates cardiac diseases and prognosis in young adults and adults presenting with ventricular tachyarrhythmias (VTA).Methods: The present longitudinal, observational, registry-based, monocentric cohort study includes all consecutive patients 45 years old or younger presenting with VTA at admission from 2002 to 2016. Rates of coronary angiography, coronary artery disease (CAD) and need for percutaneous coronary intervention (PCI), cardiac diseases associated with VTA, and differences in long-term prognostic endpoints for young adults (20-34 years old) were analyzed and compared to those of adults (35-45 years old), for whom multivariable risk prediction models were developed. Kaplan-Meier analyses were performed according to age and type of VTA.Results: A total of 259 consecutive patients were included in the study (36% young adults and 64% adults). At admission, 38% of young adults had VTA due to CAD that required PCI. Furthermore, VTA in young adults was commonly idiopathic (27%), or had underlying channelopathies (18%), primary cardiomyopathies (13%) or acute myocardial infarction (AMI, 11%). In adults, VTA was mostly associated with AMI (28%), though the rate of idiopathy was still high (20%). A total 41% of all patients received cardiopulmonary resuscitation (CPR), for whom AMI (STEMI 17%, NSTEMI 24%) was most frequently observed. Irrespective of the type of VTA, all-cause mortality was similar for young adults and adults. In young adults, left ventricular ejection fraction (LVEF) < 35% (HR = 33.590) was associated with increased long-term all-cause mortality.Conclusion: Despite high rates of idiopathic ventricular tachyarrhythmias, CAD and AMI are common causes of VTA and CPR in adults 45 years old and younger. Young adults and adults had comparable survival at index hospitalization and after 2.5 years irrespective of the type of VTA. Clinical trial registration clinicaltrials.gov identifier: NCT02982473. [ABSTRACT FROM AUTHOR]

Aims: Sudden death is a leading cause of mortality in heart failure with reduced ejection fraction (HFrEF). In PARADIGM‐HF, sacubitril/valsartan reduced the incidence of sudden death. The purpose of this post hoc study was to analyse the effect of sacubitril/valsartan, compared to enalapril, on the incidence of ventricular arrhythmias. Methods and results: Adverse event reports related to ventricular arrhythmias were examined in PARADIGM‐HF. The effect of randomized treatment on two arrhythmia outcomes was analysed: ventricular arrhythmias and the composite of a ventricular arrhythmia, implantable cardioverter defibrillator (ICD) shock or resuscitated cardiac arrest. The risk of death related to a ventricular arrhythmia was examined in time‐updated models. The interaction between heart failure aetiology, or baseline ICD/cardiac resynchronization therapy‐defibrillator (CRT‐D) use, and the effect of sacubitril/valsartan was analysed. Of the 8399 participants, 333 (4.0%) reported a ventricular arrhythmia and 372 (4.4%) the composite arrhythmia outcome. Ventricular arrhythmias were associated with higher mortality. Compared with enalapril, sacubitril/valsartan reduced the risk of a ventricular arrhythmia (hazard ratio [HR] 0.76, 95% confidence interval [CI] 0.62–0.95; p = 0.015) and the composite arrhythmia outcome (HR 0.79, 95% CI 0.65–0.97; p = 0.025). The treatment effect was maintained after adjustment and accounting for the competing risk of death. Baseline ICD/CRT‐D use did not modify the effect of sacubitril/valsartan, but aetiology did: HR in patients with an ischaemic aetiology 0.93 (95% CI 0.71–1.21) versus 0.53 (95% CI 0.37–0.78) in those without an ischaemic aetiology (p for interaction = 0.020). Conclusions: Sacubitril/valsartan reduced the incidence of investigator‐reported ventricular arrhythmias in patients with HFrEF. This effect may have been greater in patients with a non‐ischaemic aetiology. [ABSTRACT FROM AUTHOR]

Background: The Brugada pattern manifests as a spontaneous variability of the electrocardiographic marker, suggesting a variability of the underlying electrical substrate.Objective: The purpose of this study was to investigate the response of the epicardial substrate of Brugada syndrome (BrS) to programmed ventricular stimulation and to Na blocker infusion.Methods: We investigated 6 patients (all male; mean age 54 ± 14 years) with BrS and recurrent ventricular fibrillation. Five had no type 1 BrS electrocardiogram pattern at admission. They underwent combined epicardial-endocardial mapping using multielectrode catheters. Changes in epicardial electrograms were evaluated during single endocardial extrastimulation and after low-dose ajmaline infusion (0.5 mg/kg in 5 minutes).Results: All patients had a region in the anterior epicardial right ventricle with prolonged multicomponent electrograms. Single extrastimulation prolonged late epicardial components by 59 ± 31 ms and in 4 patients abolished epicardial components at some sites, without reactivation by surrounding activated sites. These localized blocks occurred at an initial coupling interval of 335 ± 58 ms and then expanded to other sites, being observed in up to 40% of epicardial sites. Ajmaline infusion prolonged electrogram duration in all and produced localized blocks in 62% of sites in the same patients as during extrastimulation. Epicardial conduction recovery after ajmaline occurred intermittently and at discontinuous sites and produced beat-to-beat changes in local repolarization, resulting in an area of marked electrical disparity. These changes were consistent with models based on microstructural alterations under critical propagation conditions.Conclusion: In BrS, localized functional conduction blocks occur at multiple epicardial sites and with variable patterns, without being reactivated from the surrounding sites. [ABSTRACT FROM AUTHOR]

Background This case reviews the cardiac involvement of myotonic dystrophy type 2 in terms of ventricular arrhythmias (VAs) and individual myocardial scar formation as target for catheter ablation. Case summary A 62-year-old woman with myotonic dystrophy type 2 and a severely reduced left ventricular ejection fraction (25%) presented with recurrent episodes of VAs and consecutive implantable cardioverter-defibrillator therapies. The patient already underwent two VA ablation attempts focusing on an ischaemia-related arrhythmia substrate in the left ventricle. The patient was scheduled for repeat ablation after the progression of coronary artery disease was ruled out. Interestingly bipolar voltage as well as activation mapping revealed an arrhythmia substrate along with the basal and inferior aspects of the right ventricle (RV). Catheter ablation of this scarred area in the RV resulted in specific termination of the VAs. Due to end-stage heart failure, key heart transplant criteria were met. The patient was evaluated for heart transplantation and added to the waiting list. Hitherto, no further VAs were documented during follow-up. Discussion As these patients present with specific dystrophia-related arrhythmia substrates, we propose pre-procedural visualization of dystrophy-associated arrhythmia substrates using cardiac magnetic resonance imaging allowing for personalized ablation approaches in these patients. [ABSTRACT FROM AUTHOR]

Background: The clinical implications of chronic kidney disease (CKD) and cardiac sympathetic nervous activity (CSNA) regarding lethal arrhythmic events have not yet been fully elucidated in patients with chronic heart failure (CHF). We hypothesized that the combination of CKD and abnormal CSNA, assessed by 123I‐metaiodobenzylguanidine (123I‐MIBG) scintigraphy, may provide useful prognostic information for lethal arrhythmic events. Methods: We studied 165 consecutive hospitalized CHF patients without dialysis. Cardiac 123I‐MIBG scintigraphy was performed in a clinically stable condition, and abnormal CSNA was defined as a late heart‐to‐mediastinum ratio of <1.6. CKD was defined as an estimated glomerular filtration rate of <60 ml/min/1.73 m2. We then investigated the incidence of lethal arrhythmic events (sustained ventricular tachyarrhythmia, appropriate implantable cardioverter‐defibrillator therapy, or sudden cardiac death). Results: During a median follow‐up of 5.3 years, lethal arrhythmic events were observed in 40 patients (24.2%). The patients were divided into four groups according to the presence of CKD and CSNA abnormality: non‐CKD/normal CSNA (n = 52), CKD/normal CSNA (n = 39), non‐CKD/abnormal CSNA (n = 33), and CKD/abnormal CSNA (n = 41). Kaplan–Meier analysis showed that CKD/abnormal CSNA had the highest event rate (log‐rank p =.004). Additionally, the Cox proportional hazard analysis revealed that CKD/abnormal CSNA was a predictor for lethal arrhythmic events compared with non‐CKD/normal CSNA (hazard ratio, 5.368, p =.001). However, the other two groups did not show significant differences compared with the non‐CKD/normal CSNA group. Conclusions: The combination of CKD and abnormal CSNA, assessed by 123I‐MIBG scintigraphy, had a high predictive value for lethal arrhythmic events in patients with CHF. [ABSTRACT FROM AUTHOR]

Wearable cardioverter-defibrillator (WCD) is a novel tool that may be of interest in situations with atransient risk of sudden cardiac death. It offers a temporary and easy to remove protection against malignant ventricular arrhythmias. In this review, the authors describe evidence in literature and different international guidelines and consensus. The authors searched PubMed, Cochrane Central Register of controlled trials, and Google Scholar for relevant studies and comments. If a WCD is indicated, the observance must be as perfect as possible. Thus, patients need proper education in wearing the WCD. The temporary use of a WCD is reasonable in patients with a high risk for SCD, even with a low level of evidence with only one randomized clinical trial (VEST), as its disadvantages are limited to a transitory impairment in quality of life and a low risk of inappropriate shock. Indications are now well accepted: ischemic cardiomyopathy with LVEF below 35% before reassessment, recent onset of NICM or presumed myocarditis with LVEF ≤35% before reassessment, after ICD explant until reimplantation (e.g. infection), and bridge to transplant. Future guidelines on WCD in the prevention of SCD may be warranted to harmonize clinical practice especially in debated indications.. [ABSTRACT FROM AUTHOR]

Abstract Background The clinical implications of chronic kidney disease (CKD) and cardiac sympathetic nervous activity (CSNA) regarding lethal arrhythmic events have not yet been fully elucidated in patients with chronic heart failure (CHF). We hypothesized that the combination of CKD and abnormal CSNA, assessed by 123I‐metaiodobenzylguanidine (123I‐MIBG) scintigraphy, may provide useful prognostic information for lethal arrhythmic events. Methods We studied 165 consecutive hospitalized CHF patients without dialysis. Cardiac 123I‐MIBG scintigraphy was performed in a clinically stable condition, and abnormal CSNA was defined as a late heart‐to‐mediastinum ratio of

Background: Some studies have shown digoxin use to be associated with adverse outcomes, including increased mortality. There are limited data on whether digoxin use is associated with increased risk of ventricular tachycardia/ventricular fibrillation (VT/VF) in heart failure patients with an implantable cardioverter-defibrillator (ICD)., Objectives: This study sought to assess whether digoxin use is associated with increased risk of VT/VF in patients with heart failure with reduced ejection fraction with a primary prevention ICD in landmark clinical trials., Methods: The study cohort consisted of patients with an ICD or cardiac resynchronization therapy-defibrillator who were enrolled in 4 landmark MADIT trials (Multicenter Automatic Defibrillator Implantation Trials). We employed propensity score quintile stratification for treatment with digoxin as well as additional multivariable adjustment to assess the risk of digoxin vs no-digoxin therapy for the endpoints of first and recurrent VT/VF and all-cause mortality. The proportional hazards regression models for arrhythmia-specific endpoints incorporated adjustments for the competing risk of death., Results: At baseline, 1,155 of 4,499 patients were on digoxin (26%). After propensity score quintile stratification, patients prescribed digoxin were shown to exhibit a statistically significant 48% increased risk of VT/VF (P < 0.001), 42% increased risk of the composite of VT/VF or death (P < 0.001), and a 37% increased risk of all-cause mortality (P = 0.006). Digoxin use was also associated with increased risk of appropriate ICD shocks (HR: 1.91; P < 0.001) and with increased burden of VT/VF events (HR: 1.46; P = 0.001)., Conclusions: Our findings suggests that digoxin use is associated with ventricular tachyarrhythmia and death in heart failure with reduced ejection fraction patients with an ICD., Competing Interests: Funding Support and Author Disclosures The MADIT-RISK study was supported by NIH grant HL077478. Dr Aktas has received research funding from AstraZeneca. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2024 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Aims The aim of this study was to examine the effect of dapagliflozin on the incidence of ventricular arrhythmias and sudden death in patients with heart failure and reduced ejection fraction (HFrEF). Methods and results In a post hoc analysis of DAPA-HF, we examined serious adverse event reports related to ventricular arrhythmias or cardiac arrest, in addition to adjudicated sudden death. The effect of dapagliflozin, compared with placebo, on the composite of the first occurrence of any serious ventricular arrhythmia, resuscitated cardiac arrest, or sudden death was examined using Cox proportional hazards models. A serious ventricular arrhythmia was reported in 115 (2.4%) of the 4744 patients in DAPA-HF (ventricular fibrillation in 15 patients, ventricular tachycardia in 86, 'other' ventricular arrhythmia/tachyarrhythmia in 12, and torsade de pointes in 2 patients). A total of 206 (41%) of the 500 cardiovascular deaths occurred suddenly. Eight patients survived resuscitation from cardiac arrest. Independent predictors of the composite outcome (first occurrence of any serious ventricular arrhythmia, resuscitated cardiac arrest or sudden death), ranked by chi-square value, were log-transformed N-terminal pro-B-type natriuretic peptide, history of ventricular arrhythmia, left ventricular ejection fraction, systolic blood pressure, history of myocardial infarction, male sex, body mass index, serum sodium concentration, non-white race, treatment with dapagliflozin, and cardiac resynchronization therapy. Of participants assigned to dapagliflozin, 140/2373 patients (5.9%) experienced the composite outcome compared with 175/2371 patients (7.4%) in the placebo group [hazard ratio 0.79 (95% confidence interval 0.63–0.99), P  = 0.037], and the effect was consistent across each of the components of the composite outcome. Conclusions Dapagliflozin reduced the risk of any serious ventricular arrhythmia, cardiac arrest, or sudden death when added to conventional therapy in patients with HFrEF. Clinical trial registration  ClinicalTrials.gov unique identifier: NCT03036124 (DAPA-HF). [ABSTRACT FROM AUTHOR]

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Background: Night-time heart rate (HR) is expected to reflect more accurately the cardiac autonomic function of modulating cardiovascular activity. Few studies have been conducted on the predictive values of night-time HR in relation to cardioverter-defibrillator therapies.Aims: To explore the associations of night-time HR with the ventricular tachyarrhythmias (VTAs), appropriate and inappropriate implantable cardioverter-defibrillator (ICD) shocks.Methods: Patients from the SUMMIT registry receiving ICD or cardiac resynchronization therapy with defibrillator (CRT-D) implantation were retrospectively analyzed using archived home monitoring data. Night-time HR was recorded from 2:00 am to 6:00 am during the first 30 to 60 days after implantation. VTA events and ICD shocks were identified using the intracardiac electrograms by two independent physicians. Restricted cubic splines and smooth curve fitting were conducted to address the non-linear associations between night-time HR and adjusted hazards for clinical outcomes.Results: Over a mean follow-up duration of 55.8 ± 22.7 months, 187 deaths were observed among 730 patients. VTAs, appropriate and inappropriate ICD shocks were observed in 422 (57.8%), 293 (40.1%), and 72 (10.0%) patients, respectively. Apparent U-shaped non-linear associations of night-time HR with VTAs (P for non-linearity = 0.007), appropriate ICD shocks (P for non-linearity = 0.003) and inappropriate ICD shocks (P for non-linearity = 0.014) were detected. When night-time HR was beyond 60 bpm, every 1 bpm increase in night-time HR could result in 3.2, 3.3, and 4.9% higher risks of VTAs and appropriate and inappropriate ICD shocks, respectively; when night-time HR was lower than 60 bpm, every 1 bpm increase in night-time HR could result in 6.0 and 10.7% lower risks of appropriate and inappropriate ICD shocks. Compared to night-time HR of ≤ 50 or ≥70 bpm, night-time HR of 50–70 bpm was associated with 24.9, 30.2, 63.5, and 31.5% reduced incidences of VTA events, appropriate ICD shocks, inappropriate ICD shocks, and all-cause mortality, respectively.Conclusion: Apparent non-linear associations of night-time HR with VTAs and ICD shocks were detected. An increasing incidence of VTAs and ICD shocks was observed at both low and high levels of night-time HR. Night-time HR of 50–70 bpm might be the optimal therapeutics target for the management of ICD/CRT-D recipients.

Background: The clinical significance and outcomes of ventricular tachyarrhythmias (VTa) in patients undergoing valve replacement have rarely been reported.Objective: This study aimed to investigate the incidence and outcome of VTa after surgical valve replacement.Methods: We conducted a population-based retrospective cohort study using data obtained from the Taiwan National Health Insurance Research Database. In total, 10,212 patients were selected after 1:1 propensity-score matching based on the type of prosthetic valve used (mechanical vs. bioprosthetic). Various outcomes during long-term follow-up were analyzed.Results: After a median follow-up period of 59.6 months, the crude incidence rate of VTa after surgical valve replacement was 4.8/1,000 person-years, and the cumulative incidence of VTa persistently increased after surgery. Furthermore, the occurrences of VTa after valve replacement significantly increased the risk of cardiovascular (CV) death (P < 0.001, HR 1.67, 95% CI 1.41–1.96), stroke- (P < 0.001, HR 1.66, 95% CI 1.37–2.01), atrial fibrillation- (P < 0.001, HR 2.80, 95% CI 2.42–3.24), and congestive heart failure-related hospitalization (P < 0.001, HR 2.61, 95% CI 2.30–2.95). Among patients with VTa, all-cause mortality (P = 0.001, HR 0.49, 95% CI 0.32–0.75) and CV death (P = 0.047, HR 0.58, 95% CI 0.34–0.99) in those with implantable cardioverter-defibrillator (ICD) implantation were lower than those without.Conclusion: The crude incidence rate of VTa after surgical valve replacement was 4.8/1,000 person-years, and the cumulative incidence of VTa persistently increased during follow-up. The presence of VTa after surgical valve replacement increases hospitalization and CV death, while ICD implantation reduced the mortality rate in these patients.

Purpose: The purpose of this study was to establish a nomogram to predict the risk of complicating ventricular tachyarrhythmia (VTA) in patients with acute myocardial infarction (AMI) during hospitalization and to verify the accuracy of the model.Clinical Information and Method: The authors enrolled the information of 503 patients who were diagnosed as AMI from January 2017 to December 2019. The cohort was randomly divided into a training set and a testing set at a ratio of 70%:30%. A total of 13 clinical indicators were screened by the least absolute shrinkage and selection operator (LASSO) regression and Boruta arithmetic independently in order to figure out the optimal feature variables. Multivariable logistic regression analysis was applied to establish the prediction model represented by a nomogram incorporating the selected feature variables. The performance of the nomogram was assessed by discrimination, calibration and clinical usefulness. C-Statistics with the area under the receiver operating characteristic curve (AUC), calibration curve and decision curve analysis were used to evaluate the identification ability, calibration and clinical practicability respectively. The prediction model was verified on the testing set to ensure its accuracy.Results: Five feature variables as percutaneous coronary intervention (PCI) timing after hospitalization, ejection fraction (EF), high-sensitive troponin T (hsTnT) score, infection and estimated glomerular filtration rate (eGFR) were selected by both LASSO regression and Boruta arithmetic. C-statistics with AUC was 0.764 (95% confidence interval: 0.690-0.838) in the training set while a slight increasing to 0.804 (95% confidence interval: 0.673-0.935) in the testing set. Calibration curve illustrated that the predicted and actually diagnosis of VTA probabilities were satisfactory on both training set and testing validation. Decision curve analysis indicated that the nomogram can be used in clinical settings as it has a threshold of between 4% to 90% along with a net benefit.Conclusion: The nomogram with five variables is practical to clinicians in estimating the risk of complicating VTA after AMI during hospitalization. [ABSTRACT FROM AUTHOR]

Objective: Ventricular tachyarrhythmia is the leading cause of death in post-infarction patients. Big endothelin-1 (ET-1) is a potent vasoconstrictor peptide and plays a role in ventricular tachyarrhythmia development. The aim of this study was to investigate the association between the serum concentration of big ET-1 and ventricular tachyarrhythmia in post-infarction left ventricular aneurysm (PI-LVA) patients. Methods: A total of 222 consecutive PI-LVA patients who had received medical therapy were enrolled in the study. There were 43 (19%) patients who had ventricular tachycardia/ventricular fibrillation (VT/VF) at the time of admission. The clinical characteristics were observed and the plasma big ET-1 level was measured. Associations between big ET-1 and the presence of VT/VF were assessed. Patients were followed up to check for outcomes related to cardiovascular mortality, VT/VF attack, and all-cause mortality. Results: The median concentration of big ET-1 was 0.635 pg/mL. Patients with big ET-1 concentrations above the median were more likely to have higher risk clinical features. There was a positive correlation between the level of big ET-1 with VT/VF attack (r=0.354, p

Abstract This case concerns a 24‐year‐old female who developed malignant ventricular tachyarrhythmia a few weeks after pacemaker implantation for complete heart block. Apparently, right ventricular pacing caused significant repolarization abnormalities in both native and paced rhythms with marked QT prolongation and substantial electrical instability. This case highlights other intriguing phenomena in the puzzle of cardiac repolarization and how pacing therapy may alter this complex process providing arrhythmic substrate in vulnerable subjects. Though such arrhythmic events are clinically rare, vulnerable patients or with suspected myocardial disease that may cause QT prolongation should be carefully followed in the course of pacing therapy.

Abstract It is important to consider calcium and parathyroid hormone levels in patients with recurrent VT/VF without any obvious cause of arrhythmia. In similar cases to gain rhythm control using isoprenaline and do comprehensive molecular‐genetic. Diagnosis and surgery in case of parathyroid adenoma may be needed to obtain definite arrhythmia control.

Abstract Background Little is known about the ICD performance using enhanced detection algorithms in unselected, non-trial patients. Performance of recent generation ICD equipped with SmartShock™ technology (SST) for detection and conversion of ventricular tachyarrhythmias (VTA) was investigated. Methods 4P was a prospective, multicenter, observational study conducted in 10 Swiss implanting centers. Patients with a Class I indication according to international guidelines were included and received an ICD with SST. ICD discrimination capability was assessed by evaluating SST performance; therapy efficacy was assessed by rate of VTA conversions by ATP and by rescue shocks. Results Overall, 196 patients were included in the analysis with a mean duration of follow-up of 27.7 months (452 patient-years of observation). Patient-specific rather than recommended programming was preferred. Device-detected episodes were frequent (5147 episodes in 146 patients, 74.5%). In 44 patients (22.4%), 1274 episodes were categorized as VTA; only 215 episodes were symptomatic. ATP was the first-line therapy and highly effective (99.9% success rate at the episode level, 100.0% at the patient level). Rescue shocks were rare (66 episodes in 28 patients); 7 shocks in 5 patients (2.6%) were inappropriate. Death and hospitalization rates were low. Conclusions In a cohort of non-trial, unselected ICD patients, VTA episodes were frequent. The 4P results confirm the robustness of VTA detection by SST and the effectiveness of ATP treatment, hence limiting overall ICD shock burden.

Aim. To assess the role of stimulating growth factor 2 (ST-2) and galectin-3 in predicting the ventricular tachyarrhythmias (VTA) in patients with coronary artery disease (CAD) and left ventricular ejection fraction (LVEF) 22,48 ng/ml (p=0,02) and galectin-3 >10,95 ng/ml (p=0,009) corresponded to appropriate ICD discharge. Multivariate ROC analysis demonstrated that the only independent predictor of VTA was ST-2 elevation (odds ratio, 1,11; 95% CI, 1,01-1,21; p=0,023).Conclusion. An increase in the concentration of both ST-2 >22,48 ng/ml and galectin-3 >10,95 ng/ml had a high predictive value in assessing the VTA risk in patients with ischemic cardiomyopathy. In multivariate analysis, an increase in ST-2 >22,48 ng/ml was an independent predictor of VTA.

Aims The benefit of prophylactic implantable cardioverter-defibrillator (ICD) is not uniform due to differences in the risk of life-threatening ventricular tachycardia (VT)/ventricular fibrillation (VF) and non-arrhythmic mortality. We aimed to develop an ICD benefit prediction score that integrates the competing risks. Methods and results The study population comprised all 4531 patients enrolled in the MADIT trials. Best-subsets Fine and Gray regression analysis was used to develop prognostic models for VT (≥200 b.p.m.)/VF vs. non-arrhythmic mortality (defined as death without prior sustained VT/VF). Eight predictors of VT/VF (male, age < 75 years, prior non-sustained VT, heart rate > 75 b.p.m. systolic blood pressure < 140 mmHg, ejection fraction ≤ 25%, myocardial infarction, and atrialarrhythmia) and 7 predictors of non-arrhythmic mortality (age ≥ 75 years, diabetes mellitus, body mass index < 23 kg/m2, ejection fraction ≤ 25%, New York Heart Association ≥II, ICD vs. cardiac resynchronization therapy with defibrillator, and atrial arrhythmia) were identified. The two scores were combined to create three MADIT-ICD benefit groups. In the highest benefit group, the 3-year predicted risk of VT/VF was three-fold higher than the risk of non-arrhythmic mortality (20% vs. 7%, P  < 0.001). In the intermediate benefit group, the difference in the corresponding predicted risks was attenuated (15% vs. 9%, P  < 0.01). In the lowest benefit group, the 3-year predicted risk of VT/VF was similar to the risk of non-arrhythmic mortality (11% vs. 12%, P  = 0.41). A personalized ICD benefit score was developed based on the distribution of the two competing risks scores in the study population (https://is.gd/madit). Internal and external validation confirmed model stability. Conclusions We propose the novel MADIT-ICD benefit score that predicts the likelihood of prophylactic ICD benefit through personalized assessment of the risk of VT/VF weighed against the risk of non-arrhythmic mortality. [ABSTRACT FROM AUTHOR]

Background: A low appropriate therapy rate indicates that a minority of patients will benefit from their implantable cardioverter defibrillator (ICD). Quantitative measurements from 18F-fluorodeoxyglucose positron emission tomography (18F-FDG PET) may predict ventricular arrhythmia (VA) occurrence after ICD placement.Methods: We performed a prospective observational study and recruited patients who required ICD placement. Pre-procedure image scans were performed. Patients were followed up for VA occurrence. Associations between image results and VA were analyzed.Results: In 51 patients (33 males, 53.9 ± 17.2 years) analyzed, 17 (33.3%) developed VA. Compared with patients without VA, patients with VA had significantly larger values in scar area (17.7 ± 12.4% vs. 7.0 ± 7.9%), phase standard deviation (51.4° ± 14.0° vs. 34.0° ± 15.0°), bandwidth (172.9° ± 39.8° vs. 128.7° ± 49.9°), sum thickening score (STS, 29.5 ± 11.1 vs. 17.8 ± 13.2), and sum motion score (42.9 ± 11.5 vs. 33.0 ± 19.0). Cox regression analysis and receiver operating characteristic curve analysis showed that scar size, dyssynchrony, and STS were associated with VA occurrence (HR, 4.956, 95% CI 1.70-14.46).Conclusion: Larger left ventricular scar burden, increased dyssynchrony, and higher STS quantified by 18F-FDG PET may indicate a higher VA incidence after ICD placement. [ABSTRACT FROM AUTHOR]