Implantable cardioverter defibrillator use in arrhythmogenic right ventricular cardiomyopathy in North America and Europe.

BACKGROUND AND AIMS: Implantable cardioverter-defibrillators (ICDs) are critical for preventing sudden cardiac death (SCD) in arrhythmogenic right ventricular cardiomyopathy (ARVC). This study aims to identify cross-continental differences in utilization of primary prevention ICDs and survival free from sustained ventricular arrhythmia (VA) in ARVC. METHODS: This was a retrospective analysis of ARVC patients without prior VA enrolled in clinical registries from 11 countries throughout Europe and North America. Patients were classified according to whether they received treatment in North America or Europe and were further stratified by baseline predicted VA risk into low- (<10%/5 years), intermediate- (10%-25%/5 years), and high-risk (>25%/5 years) groups. Differences in ICD implantation and survival free from sustained VA events (including appropriate ICD therapy) were assessed. RESULTS: One thousand ninety-eight patients were followed for a median of 5.1 years; 554 (50.5%) received a primary prevention ICD, and 286 (26.0%) experienced a first VA event. After adjusting for baseline risk factors, North Americans were more than three times as likely to receive ICDs {hazard ratio (HR) 3.1 [95% confidence interval (CI) 2.5, 3.8]} but had only mildly increased risk for incident sustained VA [HR 1.4 (95% CI 1.1, 1.8)]. North Americans without ICDs were at higher risk for incident sustained VA [HR 2.1 (95% CI 1.3, 3.4)] than Europeans. CONCLUSIONS: North American ARVC patients were substantially more likely than Europeans to receive primary prevention ICDs across all arrhythmic risk strata. A lower rate of ICD implantation in Europe was not associated with a higher rate of VA events in those without ICDs.

A new model for predicting adverse outcomes in arrhythmogenic right ventricular cardiomyopathy.

INTRODUCTION: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is a progressive disease leading to ventricular arrhythmias and heart failure. Determining optimal time for heart transplantation (HTx) is challenging; therefore, it is necessary to identify risk factors for disease progression. OBJECTIVES: The study aimed to identify predictors of end­stage heart failure and to evaluate the role of biomarkers in predicting adverse outcomes in ARVC. PATIENTS AND METHODS: A total of 91 individuals with ARVC (59 men; mean [SD] age, 47 [16] years) were included. In all patients, information on medical history was collected, electrocardiography and echocardiography were performed, and serum levels of selected biomarkers (soluble form of the ST2 protein [sST2], galectin­3 [Gal­3], extracellular matrix metalloproteinases [MMP­2 and MMP­9], N­terminal pro-B­type natriuretic peptide [NT­proBNP], and high­sensitivity troponin T [hs­TnT]) were measured. Thereafter, the participants were followed for the primary end point of death or HTx, as well as the secondary end point of major arrhythmic events (MAEs), defined as sudden cardiac death, ventricular fibrillation, sustained ventricular tachycardia, or appropriate implantable cardioverter­defibrillator intervention. RESULTS: During the median (interquartile range) follow­up of 36.4 (29.8-41.2) months, 13 patients (14%) reached the primary end point of death or HTx, and 27 (30%) experienced MAEs. The patients who achieved the primary end point had higher levels of sST2, MMP­2, NT­proBNP, and hs­TnT, but not of Gal-3 and MMP-9. Three factors turned out to be independent predictors of death or HTx: higher NT­proBNP concentration (≥890.3 pg/ml), greater right ventricular end­diastolic area (≥39 cm2), and a history of atrial tachycardia. None of the biomarkers predicted MAEs. CONCLUSIONS: An NT­proBNP concentration greater than or equal to 890.3 pg/ml, right ventricular end-diastolic area of 39 cm2 or greater, and a history of atrial tachycardia were identified as risk factors for death or HTx in ARVC. Higher levels of sST2, MMP­2, NT­proBNP, and hs­TnT were associated with reaching the primary end point of death or HTx. The biomarkers had no value in predicting ventricular arrhythmias.

Implantable cardiac defibrillator events in patients with arrhythmogenic right ventricular cardiomyopathy.

OBJECTIVE: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is associated with a risk of sudden cardiac death. Optimal risk stratification is still under debate. The main purpose of this long-term, single-centre observation was to analyse predictors of appropriate and inappropriate implantable cardioverter-defibrillator (ICD) interventions in the population of patients with ARVC with a high risk of life-threatening arrhythmias. METHODS: The study comprised 65 adult patients (median age 40 years, 48 men) with a definite diagnosis of ARVC who received ICD over a time span of 20 years in primary (40%) or secondary (60%) prevention of sudden cardiac death. The study endpoints were first appropriate and inappropriate ICD interventions (shock or antitachycardia pacing) after device implantation. RESULTS: During a median follow-up of 7.75 years after ICD implantation, nine patients died and six individuals underwent heart transplantation. Appropriate ICD interventions occurred in 43 patients (66.2%) and inappropriate ICD interventions in 18 patients (27.7%). Multivariable analysis using cause-specific hazard model identified three predictors of appropriate ICD interventions: right ventricle dysfunction (cause-specific HR 2.85, 95% CI 1.56 to 5.21, p<0.001), age <40 years at ICD implantation (cause-specific HR 2.37, 95% CI 1.13 to 4.94, p=0.022) and a history of sustained ventricular tachycardia (cause-specific HR 2.55, 95% CI 1.16 to 5.63, p=0.020). Predictors of inappropriate ICD therapy were not found. Complications related to ICD implantation occurred in 12 patients. CONCLUSIONS: Right ventricle dysfunction, age <40 years and a history of sustained ventricular tachycardia were predictors of appropriate ICD interventions in patients with ARVC. The results may be used to improve risk stratification before ICD implantation.

Pathogenic variants in plakophilin-2 gene (PKP2) are associated with better survival in arrhythmogenic right ventricular cardiomyopathy.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is mainly caused by mutations in genes encoding desmosomal proteins. Variants in plakophilin-2 gene (PKP2) are the most common cause of the disease, associated with conventional ARVC phenotype. The study aims to evaluate the prevalence of PKP2 variants and examine genotype-phenotype correlation in Polish ARVC cohort. All 56 ARVC patients fulfilling the current criteria were screened for genetic variants in PKP2 using denaturing high-performance liquid chromatography or next-generation sequencing. The clinical evaluation involved medical history, electrocardiogram, echocardiography, and follow-up. Ten variants (5 frameshift, 2 nonsense, 2 splicing, and 1 missense) in PKP2 were found in 28 (50%) cases. All truncating variants are classified as pathogenic/likely pathogenic, while the missense variant is classified as variant of uncertain significance. Patients carrying a PKP2 mutation were younger at diagnosis (p = 0.003), more often had negative T waves in V1-V3 (p = 0.01), had higher left ventricular ejection fraction (p = 0.04), and were less likely to present symptoms of heart failure (p = 0.01) and left ventricular damage progression (p = 0.04). Combined endpoint of death or heart transplant was more frequent in subgroup without PKP2 mutation (p = 0.03). Pathogenic variants in PKP2 are responsible for 50% of ARVC cases in the Polish population and are associated with a better prognosis. ARVC patients with PKP2 mutation are less likely to present left ventricular involvement and heart failure symptoms. Combined endpoint of death or heart transplant was less frequent in this group.

Prolonged left ventricular contraction duration in apical segments as a marker of arrhythmic risk in patients with long QT syndrome.

AIMS: Long QT syndrome (LQTS) is an inherited cardiac ion channelopathy predisposing to life-threatening ventricular arrhythmias and sudden cardiac death. The aim of this study was to investigate left ventricular mechanical abnormalities in LQTS patients and establish a potential role of strain as a marker of arrhythmic risk. METHODS AND RESULTS: We included 47 patients with genetically confirmed LQTS (22 LQT1, 20 LQT2, 3 LQT3, and 2 SCN3B) and 25 healthy controls. A history of cardiac events was present in 30 LQTS subjects. Tissue Doppler and speckle tracking echocardiography were performed and contraction duration was measured by radial and longitudinal strain. The radial strain characteristic was subdivided into two planes - the basal and the apical. Left ventricular ejection fraction and global longitudinal strain were normal in LQTS patients. Mean contraction duration was longer in LQTS patients compared with controls in regard to basal radial strain (491 ± 57 vs. 437 ± 55 ms, P < 0.001), apical radial strain (450 ± 53 vs. 407 ± 53 ms, P = 0.002), and longitudinal strain (445 ± 34 vs. 423 ± 43 ms, P = 0.02). Moreover, contraction duration obtained from apical radial strain analysis was longer in symptomatic compared with asymptomatic LQTS mutation carriers (462 ± 49 vs. 429 ± 55 ms, P = 0.024), as well as in subject with mutations other than LQT1 considered to be at higher risk (468 ± 50 vs. 429 ± 49 ms, P = 0.01). CONCLUSION: Myocardial contraction duration is prolonged for both radial and longitudinal directions in LQTS patients. Regional left ventricular function analysis may contribute to risk stratification. Apical radial deformation seems to select subjects at higher risk of arrhythmic events.

Inhibition of protein disulfide isomerase induces differentiation of acute myeloid leukemia cells.

A cute myeloid leukemia is a malignant disease of immature myeloid cells. Despite significant therapeutic effects of differentiation-inducing agents in some acute myeloid leukemia subtypes, the disease remains incurable in a large fraction of patients. Here we show that SK053, a thioredoxin inhibitor, induces differentiation and cell death of acute myeloid leukemia cells. Considering that thioredoxin knock-down with short hairpin RNA failed to exert antiproliferative effects in one of the acute myeloid leukemia cell lines, we used a biotin affinity probe-labeling approach to identify potential molecular targets for the effects of SK053. Mass spectrometry of proteins precipitated from acute myeloid leukemia cells incubated with biotinylated SK053 used as a bait revealed protein disulfide isomerase as a potential binding partner for the compound. Biochemical, enzymatic and functional assays using fluorescence lifetime imaging confirmed that SK053 binds to and inhibits the activity of protein disulfide isomerase. Protein disulfide isomerase knockdown with short hairpin RNA was associated with inhibition of cell growth, increased CCAAT enhancer-binding protein α levels, and induction of differentiation of HL-60 cells. Molecular dynamics simulation followed by the covalent docking indicated that SK053 binds to the fourth thioredoxin-like domain of protein disulfide isomerase. Differentiation of myeloid precursor cells requires the activity of CCAAT enhancer-binding protein α, the function of which is impaired in acute myeloid leukemia cells through various mechanisms, including translational block by protein disulfide isomerase. SK053 increased the levels of CCAAT enhancer-binding protein α and upregulated mRNA levels for differentiation-associated genes. Finally, SK053 decreased the survival of blasts and increased the percentage of cells expressing the maturation-associated CD11b marker in primary cells isolated from bone marrow or peripheral blood of patients with acute myeloid leukemia. Collectively, these results provide a proof-of-concept that protein disulfide isomerase inhibition has potential as a therapeutic strategy for the treatment of acute myeloid leukemia and for the development of small-molecule inhibitors of protein disulfide isomerase.

Ablation of atrial tachyarrhythmias late after surgical correction of tetralogy of Fallot: long-term follow-up.

BACKGROUND: After the surgical correction of tetralogy of Fallot, surgical scars and natural obstacles form pathways capable of supporting an atrial tachyarrhythmia (AT). Radiofrequency (RF) ablation is effective, although the few studies published on this topic had relatively short follow-up periods. AIM: The aims of the study were to evaluate the acute and long-term effects of RF ablation of AT and examine the charac-teristics of arrhythmia recurrence. METHODS: Tetralogy of Fallot patients (n = 16, age 44.7 ± 10.7 years) referred for ablation of ATs, appearing 25.7 ± 9.6 years after repair, were studied. RESULTS: Twenty-five ATs were ablated, including 16 cavo-tricuspid isthmus atrial flutters (CTI-AFLs) and nine intraatrial reentrant tachycardia (IART). In one patient with paroxysmal atrial fibrillation (PAF), pulmonary vein isolation was also performed. Ten patients had permanent, and six had paroxysmal arrhythmia prior to the first ablation. Four patients had PAF. Regardless of the type of first ablated arrhythmia, all 16 patients required CTI-AFL ablation. The effectiveness of the first RF ablation reached 88%. The acute efficacy of RF ablation was 100% for CTI-AFL and 78% for IART. Long-term follow-up was possible in 15 out of 16 patients (mean follow-up 68.8 ± 36.6 months). Four patients were free of sustained arrhythmia, nine (60%) had AF. After the last RF ablation, an episode suggestive of CTI-AFL/IART was documented only in one patient. CONCLUSIONS: Ablation of CTI-AFL/IART in tetralogy of Fallot patients is safe and effective. AF was observed in most patients during the long-term follow-up. Regardless of the type of the first ablated arrhythmia, all patients required CTI-AFL ablation.