An extremely wide QRS complex tachycardia induced by anamorelin.

Anamorelin, a ghrelin receptor agonist, is used for cancer-related cachexia but can induce life-threatening arrhythmias. A case study illustrates an extremely wide QRS tachycardia, posing diagnostic challenges. Anamorelin cessation led to normalization, highlighting the importance of ECG monitoring, particularly in liver-compromised patients, and hemodynamic support are crucial during suspected toxicity.

Sex differences in achieving guideline-recommended heart rate control among a large sample of patients at risk for sudden cardiac arrest.

Background: Despite known clinical benefits, guideline-recommended heart rate (HR) control is not achieved for a significant proportion of patients with HF with reduced ejection fraction. The wearable cardioverter-defibrillator (WCD) provides continuous HR monitoring and alerts that could aid medication titration. Objective: This study sought to evaluate sex differences in achieving guideline-recommended HR control during a period of WCD use. Methods: Data from patients fitted with a WCD from 2015 to 2018 were obtained from the manufacturer's database (ZOLL). The proportion of patients with adequate nighttime resting HR control at the beginning of use (BOU) and at the end of use (EOU) were compared by sex. Adequate HR control was defined as having a nighttime median HR <70 beats/min. Results: A total of 21,440 women and a comparative sample of 17,328 men (median 90 [IQR 59-116] days of WCD wear) were included in the final dataset. Among patients who did not receive a shock, over half had insufficient HR control at BOU (59% of women, 53% of men). Although the proportion of patients with resting HR ≥70 beats/min improved by EOU, 43% of women and 36% of men did not achieve guideline-recommended HR control. Conclusion: A significant proportion of women and men did not achieve adequate HR control during a period of medical therapy optimization. Compared with men, a greater proportion of women receiving WCD shocks had insufficiently controlled HR in the week preceding ventricular tachyarrhythmia/ventricular fibrillation and 43% of nonshocked women, compared with 36% of men, did not reach adequate HR control during the study period. The WCD can be utilized as a remote monitoring tool to record HR and inform adequate uptitration of beta-blockers, with particular focus on reducing the treatment gap in women.

Loss of protein phosphatase 2A regulatory subunit PPP2R5A is associated with increased incidence of stress-induced proarrhythmia.

Background: Protein 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. Methods: The 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 (I K). Results: ECG 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. Conclusion: These 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.

Activation of PKC affects the ventricular restitution properties and arrhythmogenesis through L-type Ca+ current.

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.

Digoxin and Risk of Ventricular Tachyarrhythmia and Death in ICD Recipients.

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.

Histological and functional assessment of a Takotsubo cardiomyopathy model established by immobilization stress.

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.

Metabolomics Profiling Predicts Ventricular Arrhythmia in Patients with an Implantable Cardioverter Defibrillator.

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.

Syncope and loss of consciousness after implantation of a cardioverter-defibrillator in patients with Brugada syndrome: Prevalence and characteristics in long-term follow-up.

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.

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

Background: 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. Objective: The study sought to investigate whether caffeine and binge drinking synergistically affect cardiac arrhythmogenesis. Methods: 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. Results: 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. Conclusion: Co-consumption of caffeine and binge drinking synergistically promote spontaneous ventricular tachyarrhythmias in rats. Dantrolene treatment can decrease alcohol-enhanced Ca2+ sparks in vitro and prevented alcohol and caffeine induced ventricular tachyarrhythmias in vivo.

RyR2 C-terminal truncating variants identified in patients with arrhythmic phenotypes exert a dominant negative effect through formation of wildtype-truncation heteromers.

Gain-of-function missense variants in the cardiac ryanodine receptor (RyR2) are linked to catecholaminergic polymorphic ventricular tachycardia (CPVT), whereas RyR2 loss-of-function missense variants cause Ca2+ release deficiency syndrome (CRDS). Recently, truncating variants in RyR2 have also been associated with ventricular arrhythmias (VAs) and sudden cardiac death. However, there are limited insights into the potential clinical relevance and in vitro functional impact of RyR2 truncating variants. We performed genetic screening of patients presenting with syncope, VAs, or unexplained sudden death and in vitro characterization of the expression and function of RyR2 truncating variants in HEK293 cells. We identified two previously unknown RyR2 truncating variants (Y4591Ter and R4663Ter) and one splice site variant predicted to result in a frameshift and premature termination (N4717 + 15Ter). These 3 new RyR2 truncating variants and a recently reported RyR2 truncating variant, R4790Ter, were generated and functionally characterized in vitro. Immunoprecipitation and immunoblotting analyses showed that all 4 RyR2 truncating variants formed heteromers with the RyR2-wildtype (WT) protein. Each of these C-terminal RyR2 truncations was non-functional and suppressed [3H]ryanodine binding to RyR2-WT and RyR2-WT mediated store overload induced spontaneous Ca2+ release activity in HEK293 cells. The expression of these RyR2 truncating variants in HEK293 cells was markedly reduced compared with that of the full-length RyR2 WT protein. Our data indicate that C-terminal RyR2 truncating variants are non-functional and can exert a dominant negative impact on the function of the RyR2 WT protein through formation of heteromeric WT/truncation complex.

Contribution of cytokine-mediated prolongation of QTc interval to the multi-hit theory of Torsade de Pointes.

BACKGROUND: 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). METHODS: 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 (APD90) and arrhythmia inducibility. Computer simulations (MATLAB) were performed to investigate IKr inhibition at varying IL-6 and quetiapine concentrations. RESULTS: 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 APD90:179.67 ± 2.47 ms vs 153.5 ± 7.86 ms, p = .0357). When hypokalemia was introduced, the APD90 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 IKr inhibition. CONCLUSIONS: 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.

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

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

Bail-out Ablation of Ventricular Tachycardia Electrical Storm in a Patient with a Durable Left Ventricular Assist Device.

The therapeutic strategy for sustained ventricular tachycardia (VT) during left ventricular assist device usage remains unclear. We encountered a patient with durable left ventricular assist device who presented sustained VT. Electrophysiological mapping was able to be established appropriately owing to the robust mechanical hemodynamics support despite inter-device interference. The three-dimensional activation map of clinically documented VT demonstrated that the propagation exited from the right ventricular apex through the critical isthmus located at the epicardium or interventricular septum, which was successfully treated by catheter ablation at the exit site. Further experiences like ours should be accumulated to establish a therapeutic strategy.

Timing of cardioverter-defibrillator implantation in patients with cardiac laminopathies-External validation of the LMNA-risk ventricular tachyarrhythmia calculator.

BACKGROUND: 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. OBJECTIVE: The purpose of this study was to validate the LMNA-risk VTA calculator. METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Genetic Biomarkers of Antipsychotic-Induced Prolongation of the QT Interval in Patients with Schizophrenia.

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.

Prognostic Impact of Different Types of Ventricular Tachyarrhythmias Stratified by Underlying Cardiac Disease.

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.

Arrhythmogenic right-ventricular cardiomyopathy with plakophilin-2 genetic variant concomitant with early manifestation of ventricular tachyarrhythmia: a case series.

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.

Long-term outcome of repaired tetralogy of Fallot: Survival, tachyarrhythmia, and impact of pulmonary valve replacement.

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.

Risks of Ventricular Tachyarrhythmia and Mortality in Patients with Amyloidosis - A Long-Term Cohort Study.

Background: The presence of ventricular tachycardia (VT) is associated with higher mortality. The annual incidence of VT after a diagnosis of amyloidosis and the associated cardiovascular (CV) outcomes have not been well assessed in a large cohort. Methods: A total of 12,139 amyloidosis patients were identified from the Taiwan National Health Insurance Research Database. Non-amyloidosis group was matched 1:1 for age, gender, hypertension, and diabetes mellitus (DM) to the amyloidosis group using a propensity score. Analysis of the risk of CV outcomes was conducted. We also analyzed the incidence of cardiac amyloidosis (CA). Results: The incidence rates of amyloidosis and CA were 6.54 and 0.61 per 100,000 person-years, respectively. Multivariable analysis revealed that the risk of VT was higher in both the amyloidosis [hazard ratio (HR): 7.90; 95% confidence interval (CI): 4.49-13.9] and CA (HR: 153.3, 95% CI: 54.3-432.7) groups. In the amyloidosis group, the risk of heart failure (HF)-related hospitalization, CV death, and all-cause death was also higher. Amyloidosis was associated with a higher CV mortality rate following VT (HR: 1.50; 95% CI: 1.07-2.12). The onset of a new VT event in patients with amyloidosis was associated with HF, DM, chronic liver disease, and anti-arrhythmic drug use. Conclusions: In this nationwide cohort study, the incidence rates of amyloidosis and CA were 6.54 and 0.61 per 100,000 person-years, respectively. The long-term risks of VT and CV mortality were higher in the patients with amyloidosis and CA. The patients with amyloidosis had a poorer prognosis following VT events, highlighting the importance of continuous monitoring in these patients.