Novel risk predictor of arrhythmias for patients with potassium channel-related congenital long QT syndrome.

Background: Congenital long QT syndrome (LQTS) is characterized by delayed ventricular repolarization, predisposing to potentially lethal ventricular arrhythmias. The variability in disease severity among patients remains largely unexplored, underscoring the limitations of current risk stratification methods.

Objective: We aimed to evaluate the potential utility of electrocardiographic markers from the exercise stress test (EST) in identifying patients with high-risk LQTS.

ECG-only explainable deep learning algorithm predicts the risk for malignant ventricular arrhythmia in phospholamban cardiomyopathy.

Background: Phospholamban (PLN) p.(Arg14del) variant carriers are at risk for development of malignant ventricular arrhythmia (MVA). Accurate risk stratification allows timely implantation of intracardiac defibrillators and is currently performed with a multimodality prediction model.

Multicentre experience with valve-sparing aortic root replacement by means of combined remodelling and external aortic ring annuloplasty in patients with Marfan syndrome.

Objectives: The most recent valve-sparing root replacement technique combines the advantages of the reimplantation (David) and remodelling (Yacoub) techniques. The aortic root is reconstructed according to the remodelling technique, the aortic valve is repaired according to the principle of effective height, and an external ring provides annular support. The purpose of this study was to evaluate operative and mid-term outcomes using this technique in patients with Marfan syndrome.

Deep neural network-based clustering of deformation curves reveals novel disease features in PLN pathogenic variant carriers.

Echocardiographic deformation curves provide detailed information on myocardial function. Deep neural networks (DNNs) may enable automated detection of disease features in deformation curves, and improve the clinical assessment of these curves. We aimed to investigate whether an explainable DNN-based pipeline can be used to detect and visualize disease features in echocardiographic deformation curves of phospholamban (PLN) p.

SCN5A-1795insD founder variant: a unique Dutch experience spanning 7 decades.

The SCN5A-1795insD founder variant is a unique SCN5A gene variant found in a large Dutch pedigree that first came to attention in the late 1950s. To date, this is still one of the largest and best described SCN5A founder families worldwide. It was the first time that a single pathogenic variant in SCN5A proved to be sufficient to cause a sodium channel overlap syndrome.

Exercise does not influence development of phenotype in PLN p.(Arg14del) cardiomyopathy.

Background: Endurance and frequent exercise are associated with earlier onset of arrhythmogenic right ventricular cardiomyopathy (ARVC) and ventricular arrhythmias (VA) in desmosomal gene variant carriers. Individuals with the pathogenic c.40_42del; p.

A Systematic Analysis of the Clinical Outcome Associated with Multiple Reclassified Desmosomal Gene Variants in Arrhythmogenic Right Ventricular Cardiomyopathy Patients.

The presence of multiple pathogenic variants in desmosomal genes (DSC2, DSG2, DSP, JUP, and PKP2) in patients with arrhythmogenic right ventricular cardiomyopathy (ARVC) has been linked to a severe phenotype. However, the pathogenicity of variants is reclassified frequently, which may result in a changed clinical risk prediction. Here, we present the collection, reclassification, and clinical outcome correlation for the largest series of ARVC patients carrying multiple desmosomal pathogenic variants to date (n = 331).

Variant Location Is a Novel Risk Factor for Individuals With Arrhythmogenic Cardiomyopathy Due to a Desmoplakin () Truncating Variant.

Background: Truncating variants in desmoplakin (tv) are an important cause of arrhythmogenic cardiomyopathy; however the genetic architecture and genotype-specific risk factors are incompletely understood. We evaluated phenotype, risk factors for ventricular arrhythmias, and underlying genetics of tv cardiomyopathy.

Methods: Individuals with tv and any cardiac phenotype, and their gene-positive family members were included from multiple international centers.

KBTBD13 is a novel cardiomyopathy gene.

KBTBD13 variants cause nemaline myopathy type 6 (NEM6). The majority of NEM6 patients harbors the Dutch founder variant, c.1222C>T, p.

Longitudinal Prediction of Ventricular Arrhythmic Risk in Patients With Arrhythmogenic Right Ventricular Cardiomyopathy.

Background: The arrhythmogenic right ventricular cardiomyopathy (ARVC) risk calculator stratifies risk for incident sustained ventricular arrhythmias (VA) at the time of ARVC diagnosis. However, included risk factors change over time, and how well the ARVC risk calculator performs at follow-up is unknown.

Methods: This was a retrospective analysis of patients with definite ARVC and without prior sustained VA.

Towards a Better Understanding of Genotype-Phenotype Correlations and Therapeutic Targets for Cardiocutaneous Genes: The Importance of Functional Studies above Prediction.

Genetic variants in gene-encoding proteins involved in cell−cell connecting structures, such as desmosomes and gap junctions, may cause a skin and/or cardiac phenotype, of which the combination is called cardiocutaneous syndrome. The cardiac phenotype is characterized by cardiomyopathy and/or arrhythmias, while the skin particularly displays phenotypes such as keratoderma, hair abnormalities and skin fragility. The reported variants associated with cardiocutaneous syndrome, in genes DSP, JUP, DSC2, KLHL24, GJA1, are classified by interpretation guidelines from the American College of Medical Genetics and Genomics.

A cross-sectional study on fatigue, anxiety, and symptoms of depression and their relation with medical status in adult patients with Marfan syndrome. Psychological consequences in Marfan syndrome.

Marfan syndrome (MFS) is a connective tissue disorder affecting the cardiovascular, ocular, and skeletal system, which may be accompanied by psychological features. This study aimed to determine the prevalence of fatigue, anxiety, and symptoms of depression in MFS patients, and to assess the degree to which sociodemographic and clinical variables are associated with fatigue and psychological aspects. The prevalence of fatigue, anxiety, and symptoms of depression were assessed in two cohorts of MFS patients and compared with healthy controls.

Value of genetic testing in the diagnosis and risk stratification of arrhythmogenic right ventricular cardiomyopathy.

Background: Arrhythmogenic right ventricular cardiomyopathy (ARVC) is characterized by risk of malignant ventricular arrhythmia (VA). ARVC is diagnosed using an array of clinical tests in the consensus-based Task Force Criteria (TFC), one of which is genetic testing.

Objective: The purpose of this study was to investigate the value of genetic testing in diagnosing ARVC and its relation to the occurrence of first malignant VA.

A new prediction model for ventricular arrhythmias in arrhythmogenic right ventricular cardiomyopathy.

Aims: Arrhythmogenic right ventricular dysplasia/cardiomyopathy (ARVC) is characterized by ventricular arrhythmias (VAs) and sudden cardiac death (SCD). We aimed to develop a model for individualized prediction of incident VA/SCD in ARVC patients.

Methods And Results: Five hundred and twenty-eight patients with a definite diagnosis and no history of sustained VAs/SCD at baseline, aged 38.

Clinical Characteristics and Follow-Up of Pediatric-Onset Arrhythmogenic Right Ventricular Cardiomyopathy.

Objectives: The goal of this study was to describe characteristics, cascade screening results, and predictors of adverse outcome in pediatric-onset arrhythmogenic right ventricular cardiomyopathy (ARVC).

Background: Although ARVC is increasingly recognized in children, pediatric ARVC cohorts remain underrepresented in the literature.

Methods: This study included 12 probands with pediatric-onset ARVC (aged <18 years at diagnosis) and 68 pediatric relatives (aged <18 years at first evaluation) referred for cascade screening.

Functional investigation of two simultaneous or separately segregating DSP variants within a single family supports the theory of a dose-dependent disease severity.

Desmoplakin (DP) is an important component of desmosomes, essential in cell-cell connecting structures in stress-bearing tissues. Over the years, many hundreds of pathogenic variants in DSP have been associated with different cutaneous and cardiac phenotypes or a combination, known as a cardiocutaneous syndrome. Of less than 5% of the reported DSP variants, the effect on the protein has been investigated.

Genome-wide methylation patterns in Marfan syndrome.

Background: Marfan syndrome (MFS) is a connective tissue disorder caused by mutations in the Fibrillin-1 gene (FBN1). Here, we undertook the first epigenome-wide association study (EWAS) in patients with MFS aiming at identifying DNA methylation loci associated with MFS phenotypes that may shed light on the disease process.

Methods: The Illumina 450 k DNA-methylation array was used on stored peripheral whole-blood samples of 190 patients with MFS originally included in the COMPARE trial.

An International Multicenter Cohort Study on β-Blockers for the Treatment of Symptomatic Children With Catecholaminergic Polymorphic Ventricular Tachycardia.

Background: Symptomatic children with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for recurrent arrhythmic events. β-Blockers decrease this risk, but studies comparing individual β-blockers in sizeable cohorts are lacking. We aimed to assess the association between risk for arrhythmic events and type of β-blocker in a large cohort of symptomatic children with CPVT.

Sex-specific aspects of phospholamban cardiomyopathy: The importance and prognostic value of low-voltage electrocardiograms.

Background: A pathogenic variant in the gene encoding phospholamban (PLN), a protein that regulates calcium homeostasis of cardiomyocytes, causes PLN cardiomyopathy. It is characterized by a high arrhythmic burden and can progress to severe cardiomyopathy. Risk assessment guides implantable cardioverter-defibrillator therapy and benefits from personalization.

Aortic distensibility in Marfan syndrome: a potential predictor of aortic events?

Objectives: Patients with Marfan syndrome (MFS) are prone to develop aortic aneurysms due to fragmentation of elastic fibres, resulting in reduced distensibility of the aorta. Reduced distensibility was previously shown to predict progressive descending aorta dilatation. Here, we investigated longitudinal changes in distensibility, as a potential predictor of aortic events.

Pathophysiological pathways in patients with heart failure and atrial fibrillation.

Aims: Atrial fibrillation (AF) and heart failure (HF) are two growing epidemics that frequently co-exist. We aimed to gain insights into the underlying pathophysiological pathways in HF patients with AF by comparing circulating biomarkers using pathway overrepresentation analyses.

Methods And Results: From a panel of 92 biomarkers from different pathophysiological domains available in 1620 patients with HF, we first tested which biomarkers were dysregulated in patients with HF and AF (n = 648) compared with patients in sinus rhythm (n = 972).

Optimal echocardiographic assessment of myocardial dysfunction for arrhythmic risk stratification in phospholamban mutation carriers.

Aims: Phospholamban (PLN) p.Arg14del mutation carriers are at risk of developing malignant ventricular arrhythmias (VAs) and/or heart failure. Currently, left ventricular ejection fraction (LVEF) plays an important role in risk assessment for VA in these individuals.