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BackgroundChronic diseases have a negative impact on quality of life (QOL) and psychological health. There are limited related data regarding this topic in Brugada syndrome (BrS). We evaluated the effects of the diagnosis of BrS on health-related QOL and psychological status among patients and their relatives.MethodsPatients with BrS and their relatives underwent psychological evaluation at diagnosis (T0), 1 and 2 years after diagnosis (T1 and T2) using questionnaires on mental QOL, anxiety, depression, stress, post-traumatic stress, and resilience resources.ResultsSixty-one patients and 39 relatives were enrolled. Compared with controls, patients showed increased physical QOL (54.1 ± 6.5 vs. 50.1 ± 8.0, p = 0.014), reduced mental QOL (43.2 ± 11.8 vs. 49.6 ± 9.1, p = 0.018) and increased anxiety (9.9 ± 6.6 vs. 6.9 ± 7.7, p = 0.024) at T0; reduced resilience scores (3.69 ± 0.40 vs. 3.96 ± 0.55, p = 0.008) at T1; and reduced resilience (3.69 ± 0.35 vs. 3.96 ± 0.55, p = 0.019) and increased anxiety scores (16.4 ± 12.8 vs. 6.9 ± 7.7, p = 0.006) at T2. Relatives presented higher stress (17.63 ± 3.77 vs. 12.90 ± 6.0, p = 0.02) at T0 and higher anxiety scores at T0 (13.5 ± 7.6 vs. 6.9 ± 7.7, p

Brugada syndrome (BrS) is an inherited cardiac channelopathy with variable expressivity that can lead to sudden cardiac arrest (SCA). Studies worldwide suggest that BrS and Brugada pattern (BrP) have low prevalences in general. However, studies also note that BrS is most prevalent among certain Asian populations. Among the different global regions, the highest prevalence is believed to be in Southeast Asia, followed by the Middle East, South Asia, East Asia, Europe, and North America. It is not only important to recognize such varying degrees of BrS prevalence within Asia but also to understand that there may be significant differences in terms of presenting symptoms, occult risk factors, and the impact on clinical outcomes. The importance of identifying such differences lies in the necessity to develop improved risk assessment strategies to guide secondary prevention and treatment for these patients. Specifically, the decision to pursue placement of an implantable cardiac defibrillator (ICD) can be lifesaving for high-risk BrS patients. However, there remains a significant lack of consensus on how to best risk stratify BrS patients. While the current guidelines recommend ICD implantation in patients with spontaneous Type 1 ECG pattern BrS who present with syncope, there may still exist additional clinical factors that may serve as better predictors or facilitate more refined risk stratification before malignant arrhythmias occur. This carries huge relevance given that BrS patients often do not have any preceding symptoms prior to SCA. This review seeks to delineate the differences in BrS presentation and prevalence within the Asian continent in the hope of identifying potential risk factors to guide better prognostication and management of BrS patients in the future.

Brugada syndrome is a rare hereditary disorder characterized by distinct ECG findings, complex genetics, and a high risk of sudden cardiac death. Recognition of the syndrome is crucial as it represents a paradigm of sudden death tragedy in individuals at the peak of their lives. Notably, Brugada syndrome accounts for more than 20% of sudden cardiac deaths in individuals with structurally normal hearts. Although this syndrome follows an autosomal dominant inheritance pattern, it is more prevalent and severe in males. Diagnosis is primarily based on the characteristic ECG pattern observed in the right precordial leads. Mutations in the SCN5A gene, resulting in loss of function, are the most common genetic cause. We presented a 36-year-old proband with a family history of sudden cardiac death. Although the patient was asymptomatic for Brugada syndrome, his father had experienced sudden death at the age of 36. The proband was admitted to St. Catherine's Specialty Hospital where blood was taken and subjected to next-generation sequencing (NGS) using a “Sudden cardiac death” panel. The analysis identified a pathogenic variant in the SCN5A gene [c.4222G > A(p.Gly1408Arg)], which is associated with autosomal dominant Brugada syndrome. Based on the positive genetic test result, the patient was referred for further examination. ECG with modified precordial lead positioning confirmed the presence of the Brugada phenotype, displaying the type-2 and type-1 ECG patterns. Therefore, we made the diagnosis and decided to implant an implantable cardioverter-defibrillator (ICD) based on the results of broad genetic NGS testing, diagnostic criteria (ECG), and considering the high burden of sudden cardiac death in the patient's family, as well as his concerns that limited his everyday activities. This case shows that genetics and personalized medicine hold immense potential in the primary prevention, diagnosis, and treatment of Brugada syndrome and sudden cardiac death.

Background and Objectives: Left atrial (LA) remodelling and dilatation predicts atrial fibrillation (AF) recurrences after catheter ablation. However, whether right atrial (RA) remodelling and dilatation predicts AF recurrences after ablation has not been fully evaluated. Materials and Methods: This is an observational study of 85 consecutive patients (aged 57 ± 9 years; 70 [82%] men) who underwent cardiac magnetic resonance before first catheter ablation for AF (40 [47.1%] persistent AF). Four-chamber cine-sequence was selected to measure LA and RA area, and ventricular end-systolic image phase to obtain atrial 3D volumes. The effect of different variables on event-free survival was investigated using the Cox proportional hazards model. Results: In patients with persistent AF, combined LA and RA area indexed to body surface area (AILA + RA) predicted AF recurrences (HR = 1.08, 95% CI 1.00–1.17, p = 0.048). An AILA + RA cut-off value of 26.7 cm2/m2 had 72% sensitivity and 73% specificity for predicting recurrences in patients with persistent AF. In this group, 65% of patients with AILA + RA > 26.7 cm2/m2 experienced AF recurrence within 2 years of follow-up (median follow-up 11 months), compared to 25% of patients with AILA + RA ≤ 26.7 cm2/m2 (HR 4.28, 95% CI 1.50–12.22; p = 0.007). Indices of LA and RA dilatation did not predict AF recurrences in patients with paroxysmal AF. Atrial 3D volumes did not predict AF recurrences after ablation. Conclusions: In this pilot study, the simple measurement of AILA + RA may predict recurrences after ablation of persistent AF, and may outperform measurements of atrial volumes. In paroxysmal AF, atrial dilatation did not predict recurrences. Further studies on the role of RA and LA remodelling are needed.

Background: Laminopathies are caused by rare alterations in LMNA, leading to a wide clinical spectrum. Though muscular dystrophy begins at early ages, disease progression is different in each patient. We investigated variability in laminopathy phenotypes by performing a targeted genetic analysis of patients diagnosed with LMNA-related muscular dystrophy to identify rare variants in alternative genes, thereby explaining phenotypic differences.Methods: We analyzed 105 genes associated with muscular diseases by targeted sequencing in 26 pediatric patients of different countries, diagnosed with any LMNA-related muscular dystrophy. Family members were also clinically assessed and genetically analyzed.Results: All patients carried a pathogenic rare variant in LMNA. Clinical diagnoses included Emery-Dreifuss muscular dystrophy (EDMD, 13 patients), LMNA-related congenital muscular dystrophy (L-CMD, 11 patients), and limb-girdle muscular dystrophy 1B (LGMD1B, 2 patients). In 9 patients, 10 additional rare genetic variants were identified in 8 genes other than LMNA. Genotype-phenotype correlation showed additional deleterious rare variants in five of the nine patients (3 L-CMD and 2 EDMD) with severe phenotypes.Conclusion: Analysis f known genes related to muscular diseases in close correlation with personalized clinical assessments may help identify additional rare variants of LMNA potentially associated with early onset or most severe disease progression.

Introduction: LMNA-related muscular dystrophy is a rare entity that produce “laminopathies” such as Emery–Dreifuss muscular dystrophy (EDMD), limb–girdle muscular dystrophy type 1B (LGMD1B), and LMNA-related congenital muscular dystrophy (L-CMD). Heart failure, malignant arrhythmias, and sudden death may occur. No consensus exists on cardiovascular management in pediatric laminopathies. The aim was to perform an exhaustive cardiologic follow-up in pediatric patients diagnosed with LMNA-related muscular dystrophy.Methods: Baseline cardiac work-up consisted of clinical assessment, transthoracic Doppler echocardiography, 12-lead electrocardiogram, electrophysiological study, and implantation of a long-term implantable cardiac loop recorder (ILR).Results: We enrolled twenty-eight pediatric patients diagnosed with EDMD (13 patients), L-CMD (11 patients), LGMD1B (2 patients), and LMNA-related mild weakness (2 patients). Follow-up showed dilated cardiomyopathy (DCM) in six patients and malignant arrhythmias in five (four concomitant with DCM) detected by the ILR that required implantable cardioverter defibrillator (ICD) implantation. Malignant arrhythmias were detected in 20% of our cohort and early-onset EDMD showed worse cardiac prognosis.Discussion: Patients diagnosed with early-onset EDMD are at higher risk of DCM, while potentially life-threatening arrhythmias without DCM appear earlier in L-CMD patients. Early onset neurologic symptoms could be related with worse cardiac prognosis. Specific clinical guidelines for children are needed to prevent sudden death.

Background Left atrial structural remodeling contributes to the arrhythmogenic substrate of atrial fibrillation (AF), but the role of the right atrium (RA) remains unknown. Our aims were to comprehensively characterize right atrial structural remodeling in AF and identify right atrial parameters predicting recurrences after ablation. Methods and Results A 3.0 T late gadolinium enhanced–cardiac magnetic resonance was obtained in 109 individuals (9 healthy volunteers, 100 patients with AF undergoing ablation). Right and left atrial volume, surface, and sphericity were quantified. Right atrial global and regional fibrosis burden was assessed with validated thresholds. Patients with AF were systematically followed after ablation for recurrences. Progressive right atrial dilation and an increase in sphericity were observed from healthy volunteers to patients with paroxysmal and persistent AF; fibrosis was similar among the groups. The correlation between parameters recapitulating right atrial remodeling was mild. Subsequently, remodeling in both atria was compared. The RA was larger than the left atrium (LA) in all groups. Fibrosis burden was higher in the LA than in the RA of patients with AF, whereas sphericity was higher in the LA of patients with persistent AF only. Fibrosis, volume, and surface of the RA and LA, but not sphericity, were strongly correlated. Tricuspid regurgitation predicted right atrial volume and shape, whereas diabetes was associated with right atrial fibrosis burden; sex and persistent AF also predicted right atrial volume. Fibrosis in the RA was mostly located in the inferior vena cava–RA junction. Only right atrial sphericity is significantly associated with AF recurrences after ablation (hazard ratio, 1.12 [95% CI, 1.01–1.25]). Conclusions AF progression associates with right atrial remodeling in parallel with the LA. Right atrial sphericity yields prognostic significance after ablation.

ABSTRACT Background: We aimed to describe the morphology of the border zone of viable myocardium surrounded by scarring in patients with Chagas heart disease and study their association with clinical events. Methods: Adult patients with Chagas heart disease (n=22; 55% females; 65.5 years, SD 10.1) were included. Patients underwent high-resolution contrast-enhanced cardiac magnetic resonance using myocardial delayed enhancement with postprocessing analysis to identify the core scar area and border zone channels number, mass, and length. The association between border zone channel parameters and the combined end-point (cardiovascular mortality or internal cardiac defibrillator implantation) was tested by multivariable Cox proportional hazard regression analyses. The significance level was set at 0.05. Data are presented as the mean (standard deviation [SD]) or median (interquartile range). Results: A total of 44 border zone channels (1[1-3] per patient) were identified. The border zone channel mass per patient was 1.25 (0.48-4.39) g, and the extension in layers of the border zone channels per patient was 2.4 (1.0-4.25). Most border zone channels were identified in the midwall location. Six patients presented the studied end-point during a mean follow-up of 4.9 years (SD 1.6). Border zone channel extension in layers was associated with the studied end-point independent from left ventricular ejection fraction or fibrosis mass (HR=2.03; 95% CI 1.15-3.60). Conclusions: High-resolution contrast-enhanced cardiac magnetic resonance can identify border zone channels in patients with Chagas heart disease. Moreover, border zone channel extension was independently associated with clinical events.

Brugada syndrome is a rare hereditary arrhythmia disorder characterized by a distinctive electrocardiogram pattern and an elevated risk of ventricular arrhythmias and sudden cardiac death in young adults. Despite recent advances, it remains a complex condition, encompassing mechanisms, genetics, diagnosis, arrhythmia risk stratification, and management. The underlying electrophysiological mechanism of Brugada syndrome requires further investigation, with current theories focusing on abnormalities in repolarization, depolarization, and current-load match. The genetic basis of the syndrome is strong, with mutations found in genes encoding subunits of cardiac sodium, potassium, and calcium channels, as well as genes involved in channel trafficking and regulation. While the initial discovery of mutations in the SCN5A gene provided valuable insights, Brugada syndrome is now recognized as a multifactorial disease influenced by several loci and environmental factors, challenging the traditional autosomal dominant inheritance model. This comprehensive review aims to provide a current understanding of Brugada syndrome, focusing on its pathophysiology, genetic mechanisms, and novel models of risk stratification. Advancements in these areas hold the potential to facilitate earlier diagnosis, improve risk assessments, and enable more targeted therapeutic interventions.

Background: Vasovagal syncope (VVS) is the most common cause of syncope. Some stages of its pathophysiological mechanisms remain unclear. Vasoactive substances such as nitric oxide metabolites (NOx) and endothelin (ET) may be involved during acute orthostatic stress. Objective: To analyze plasma changes in NOx and ET and heart rate variability (HRV) in the supine positions (T1) and during the head-up tilt test (HUTT) (T2), in patients with VVS (case group) and control group. Methods: Thirty-seven patients (17 in the case group and 20 in the control group), matched for age and sex (mean aged 31.8 years) underwent HUTT with simultaneous HRV recording and venipuncture. Blood samples were collected during phases T1 and T2 and the analysis was performed without knowledge of the HUTT result. Results: In the total sample, there was an increase in NOx values ( P = .014), however there was no increase in ET values from phase T1 to phase T2. Patients with VVS tended to increase plasma NOx values ( P = .057) and had significantly higher plasma values compared to ET ( P = .033) between phases T1 to T2. In the control group, there was no significant change in the values of these vasoactive substances. Regarding HRV, there were a decrease in the component HF (high frequency) and increased of the LF (low frequency)/HF ratio during HUTT. Conclusions: There was an increase in ET during HUTT occurred only in the case group. These patients are more likely to have an imbalance between antagonistic vasoactive biomarkers during orthostatic stress.

BackgroundSubstrate-based ablation has become a successful technique for ventricular tachycardia (VT) ablation. High-density (HD) mapping catheters provide high-resolution electroanatomical maps and better discrimination of local abnormal electrograms. The HD Grid Mapping Catheter is an HD catheter with the ability to map orthogonal signals on top of conventional bipolar signals, which could provide better discrimination of the arrhythmic substrate. On the other hand, conventional mapping techniques, such as activation mapping, when possible, help to identify the isthmus of the tachycardia.AimThe purpose of this study was to compare clinical outcomes after using two different VT ablation strategies: one based on extensive mapping with the HD Grid Mapping Catheter, including VT isthmus analysis, and the other based on pure substrate ablation.MethodsForty consecutive patients undergoing VT ablation with extensive HD mapping method in the hospital clinic (November 2018–November 2019) were included. Clinical outcomes were compared with a historical cohort of 26 consecutive patients who underwent ablation using a scar dechanneling technique before 2018.ResultsThe density of mapping points was higher in the extensive mapping group (2370.24 ± 920.78 vs. 576.45 ± 294.46; p < 0.001). After 1 year of follow-up, VT recurred in 18.4% of patients in the extensive mapping group vs. 34.6% of patients in the historical control group (p = 0.14), with a significantly greater reduction of VT burden: VT episodes (81.7 ± 7.79 vs. 43.4 ± 19.9%, p < 0.05), antitachycardia pacing (99.45 ± 2.29 vs. 33.9 ± 102.5%, p < 0.001), and implantable cardioverter defibrillator (ICD) shocks (99 ± 4.5 vs. 64.7 ± 59.9%, p = 0.02).ConclusionThe use of a method based on extensive mapping with the HD Grid Mapping Catheter and VT isthmus analysis allows better discrimination of the arrhythmic substrate and could be associated with a greater decrease in VT burden.

Brugada syndrome (BrS) was initially described in 1992 by Josep and Pedro Brugada as an arrhythmogenic disease characterized by ST segment elevation in the right precordial leads and increased risk of sudden cardiac death (SCD). Alterations in the SCN5A gene are responsible for approximately 30% of cases of BrS, following an autosomal dominant pattern of inheritance. However, despite its autosomal transmission, sex-related differences are widely accepted. BrS is more prevalent in males than in females (8–10 times), with males having a 5.5-fold higher risk of SCD. There are also differences in clinical presentation, with females being more frequently asymptomatic and older than males at the time of diagnosis. Some factors have been identified that could explain these differences, among which testosterone seems to play an important role. However, only 30% of the available publications on the syndrome include sex-related information. Therefore, current findings on BrS are based on studies conducted mainly in male population, despite the wide acceptance of gender differences. The inclusion of complete clinical and demographic information in future publications would allow a better understanding of the phenotypic variability of BrS in different age and sex groups helping to improve the diagnosis, management and risk management of SCD.

Introducción: un evento de muerte súbita supone un gran impacto para la sociedad, siendo importante su estudio para aportar conocimiento y fortalecer estrategias de promoción y prevención. Objetivo: determinar la prevalencia de los diagnósticos anatomopatológicos cardiacos definitivos y los hallazgos histopatológicos asociados con la muerte súbita de origen cardíaco en los pacientes sometidos a autopsias clínicas realizadas en el Hospital de San José de Bogotá DC, Colombia, durante el período 2015 a 2018. Métodos: estudio descriptivo de corte transversal retrospectivo en pacientes a quienes se les realizó autopsia con diagnóstico de muerte súbita de origen cardiovascular en el servicio de patología del Hospital de San José, Bogotá DC, Colombia. Resultados: se incluyeron 178 autopsias con diagnóstico de muerte súbita cardíaca. El promedio global de edad fue 56.1 años (DE: 15.06) con una relación hombre-mujer de 3:1. El hallazgo macroscópico más frecuente fue cardiomegalia (promedio 428.1 g (DE 112.8), acompañado de la presencia de coronariopatía esclerótica (p=0.000) con obstrucción de la luz de las arterias coronarias mayores de 80% (p=0.037). Conclusiones: los diagnósticos anatomopatológicos definitivos prevalentes en la muerte súbita cardiaca fueron cardiopatía isquémica crónica complicada (65%) e infarto agudo de miocardio (16%), datos similares a los reportados a nivel mundial. La cardiomegalia es un hallazgo frecuente que debe valorarse en forma cuidadosa.

High-level sports competition is popular among Swiss youth. Even though preparticipation evaluation for competitive athletes is widespread, screening strategies for diseases responsible for sudden death during sport are highly variable. Hence, we sought to develop age-specific preparticipation cardiovascular evaluation (PPCE) proposals for Swiss paediatric and adolescent athletes (under 18 years of age). We recommend that all athletes practising in a squad with a training load of at least 6 hours per week should undergo PPCE based on medical history and physical examination from the age of 12 years on. Prior to 12 years, individual judgement of athletic performance is required. We suggest the inclusion of a standard 12-lead electrocardiogram (ECG) evaluation for all post-pubertal athletes (or older than 15 years) with analysis in accordance with the International Criteria for ECG Interpretation in Athletes. Echocardiography should not be a first-line screening tool but rather serve for the investigation of abnormalities detected by the above strategies. We recommend regular follow-up examinations, even for those having normal history, physical examination and ECG findings. Athletes with an abnormal history (including family history), physical examination and/or ECG should be further investigated and pathological findings discussed with a paediatric cardiologist. Importantly, the recommendations provided in this document are not intended for use among patients with congenital heart disease who require individualised care according to current guidelines.

Introduction: Long QT syndrome is the main arrhythmogenic disease responsible for sudden death in infants, especially in the first days of life. Performing an electrocardiogram in newborns could enable early diagnosis and adoption of therapeutic measures focused on preventing lethal arrhythmogenic events. However, the inclusion of an electrocardiogram in neonatal screening protocols still remains a matter of discussion. To comprehensively analyse the potential clinical value of performing an electrocardiogram and subsequent follow-up in a cohort of newborns.Methods: Electrocardiograms were performed in 685 neonates within the first week of life. One year follow-up was performed if QTc > 450 ms identified. Comprehensive genetic analysis using massive sequencing was performed in all cases with QTc > 470 ms.Results: We identified 54 neonates with QTc > 450 ms/ 480 ms at birth and, if persistent, pharmacological treatment was administrated during follow-up. A rare variant was identified as the potential cause of long QT syndrome in five cases. Three cases showed a family history of sudden arrhythmogenic death.Conclusions: Our prospective study identifies 0.14% of cases with a definite long QT, supporting implementation of electrocardiograms in routine pediatric protocols. It is an effective, simple and non-invasive approach that can help prevent sudden death in neonates and their relatives. Genetic analyses help to unravel the cause of arrhythmogenic disease in diagnosing neonates. Further, clinical assessment and genetic analysis of relatives allowed early identification of family members at risk of arrhythmias helping to adopt preventive personalized measures.

In the Cardiology Masters section of European Cardiology Review, we bring you an insight into the career of a key contributor to the field of cardiology. In this edition, we feature Josep Brugada.

Aims: Riata® implantable cardioverter-defibrillator (ICD) leads from St. Jude Medical are prone to malfunction. This study aimed to describe the rate of this lead's malfunction in a very long-term follow-up. Methods: This single-centre observational study included 50 patients who received a Riata 7Fr dual-coil lead between 2003 and 2008. Follow-up was conducted both in person and remotely, and analysed at 8-month intervals. We evaluated the rates of cable externalization (CE), electrical failure (EF), and the interaction of these two complications. Structural lead failure was defined as radiographic CE. Oversensing of non-cardiac signal or sudden changes in impedance, sensing, or pacing thresholds constituted EF. Results: During a mean follow-up of 10.2 ± 2.9 years, 16 patients (32%) died. We observed lead malfunction in 13 patients (26%): three (23%) due to CE, six (46%) to EF and four (31%) to both complications. Of the malfunctioning leads, 77% failed after seven years of follow-up. The incidence rate (IR) of overall malfunction per 100 patients per year was 0.9 during the first seven years post-implantation, increased to 7.0 after the 7th year and more than doubled (to 16.7) after 10 years. Beyond seven years post-implantation, IR per 100 patient-years increased in both EF and CE (from 0.6 to 5.6 vs. 0.3 to 4.2, respectively). Presence of CE was associated with a 4-fold increase in the proportion of EF. Conclusion: The incidence of Riata ICD lead malfunction, both for EF and CE, increased dramatically after seven years and then more than doubled after 10 years post-implantation. Keywords: Implantable cardioverter-defibrillator, Long-term follow-up, Malfunction, Cable externalization, Electrical failure

Summary: Genome-wide association studies (GWASs) are instrumental in identifying loci harboring common single-nucleotide variants (SNVs) that affect human traits and diseases. GWAS hits emerge in clusters, but the focus is often on the most significant hit in each trait- or disease-associated locus. The remaining hits represent SNVs in linkage disequilibrium (LD) and are considered redundant and thus frequently marginally reported or exploited. Here, we interrogate the value of integrating the full set of GWAS hits in a locus repeatedly associated with cardiac conduction traits and arrhythmia, SCN5A-SCN10A. Our analysis reveals 5 common 7-SNV haplotypes (Hap1–5) with 2 combinations associated with life-threatening arrhythmia—Brugada syndrome (the risk Hap1/1 and protective Hap2/3 genotypes). Hap1 and Hap2 share 3 SNVs; thus, this analysis suggests that assuming redundancy among clustered GWAS hits can lead to confounding disease-risk associations and supports the need to deconstruct GWAS data in the context of haplotype composition.

Aim: To perform a comprehensive phenotype-genotype correlation of all rare variants in Triadin leading to malignant arrhythmias in pediatrics.Methods: Triadin knockout syndrome is a rare entity reported in pediatric population. This syndrome is caused by rare variants in the TRDN gene. Malignant ventricular arrhythmias and sudden cardiac death can be a primary manifestation of disease. Although pharmacological measures are effective, some patients require an implantable defibrillator due to high risk of arrhythmogenic episodes.Main Results: Fourteen rare genetic alterations in TRDN have been reported to date. All of these potentially pathogenic alterations are located in a specific area of TRDN, highlighting this hot spot as an arrhythmogenic gene region.Conclusions: Early recognition and comprehensive interpretation of alterations in Triadin are crucial to adopt preventive measures and avoid malignant arrhythmogenic episodes in pediatric population.

We report a pediatric patient with persistent left superior vena cava and a D-transposition of great arteries, which is an uncommon relation. It is crucial to know the anatomy of the persistent left superior vena cava and the dilated coronary sinus to plan the mapping techniques in cases of posterior accessory pathways.

ABSTRACT: Background: Accurate interpretation of rare genetic variants is a challenge for clinical translation. Updates in recommendations for rare variant classification require the reanalysis and reclassification. We aim to perform an exhaustive re-analysis of rare variants associated with inherited arrhythmogenic syndromes, which were classified ten years ago, to determine whether their classification aligns with current standards and research findings. Methods: In 2010, the rare variants identified through genetic analysis were classified following recommendations available at that time. Nowadays, the same variants have been reclassified following current American College of Medical Genetics and Genomics recommendations. Findings: Our cohort included 104 cases diagnosed with inherited arrhythmogenic syndromes and 17 post-mortem cases in which inherited arrhythmogenic syndromes was cause of death. 71.87% of variants change their classification. While 65.62% of variants were classified as likely pathogenic in 2010, after reanalysis, only 17.96% remain as likely pathogenic. In 2010, 18.75% of variants were classified as uncertain role but nowadays 60.15% of variants are classified of unknown significance. Interpretation: Reclassification occurred in more than 70% of rare variants associated with inherited arrhythmogenic syndromes. Our results support the periodical reclassification and personalized clinical translation of rare variants to improve diagnosis and adjust treatment. Funding: Obra Social ''La Caixa Foundation'' (ID 100010434, LCF/PR/GN16/50290001 and LCF/PR/GN19/50320002), Fondo Investigacion Sanitaria (FIS PI16/01203 and FIS, PI17/01690), Sociedad Española de Cardiología, and “Fundacio Privada Daniel Bravo Andreu”. Keywords: Sudden cardiac death, Arrhythmias, Pathogenicity, Genetics

BackgroundElectrocardiographic QT interval prolongation is the most widely used risk marker for ventricular arrhythmia potential and thus an important component of drug cardiotoxicity assessments. Several antimalarial medicines are associated with QT interval prolongation. However, interpretation of electrocardiographic changes is confounded by the coincidence of peak antimalarial drug concentrations with recovery from malaria. We therefore reviewed all available data to characterise the effects of malaria disease and demographic factors on the QT interval in order to improve assessment of electrocardiographic changes in the treatment and prevention of malaria.Methods and findingsWe conducted a systematic review and meta-analysis of individual patient data. We searched clinical bibliographic databases (last on August 21, 2017) for studies of the quinoline and structurally related antimalarials for malaria-related indications in human participants in which electrocardiograms were systematically recorded. Unpublished studies were identified by the World Health Organization (WHO) Evidence Review Group (ERG) on the Cardiotoxicity of Antimalarials. Risk of bias was assessed using the Pharmacoepidemiological Research on Outcomes of Therapeutics by a European Consortium (PROTECT) checklist for adverse drug events. Bayesian hierarchical multivariable regression with generalised additive models was used to investigate the effects of malaria and demographic factors on the pretreatment QT interval. The meta-analysis included 10,452 individuals (9,778 malaria patients, including 343 with severe disease, and 674 healthy participants) from 43 studies. 7,170 (68.6%) had fever (body temperature ≥ 37.5°C), and none developed ventricular arrhythmia after antimalarial treatment. Compared to healthy participants, patients with uncomplicated falciparum malaria had shorter QT intervals (-61.77 milliseconds; 95% credible interval [CI]: -80.71 to -42.83) and increased sensitivity of the QT interval to heart rate changes. These effects were greater in severe malaria (-110.89 milliseconds; 95% CI: -140.38 to -81.25). Body temperature was associated independently with clinically significant QT shortening of 2.80 milliseconds (95% CI: -3.17 to -2.42) per 1°C increase. Study limitations include that it was not possible to assess the effect of other factors that may affect the QT interval but are not consistently collected in malaria clinical trials.ConclusionsAdjustment for malaria and fever-recovery-related QT lengthening is necessary to avoid misattributing malaria-disease-related QT changes to antimalarial drug effects. This would improve risk assessments of antimalarial-related cardiotoxicity in clinical research and practice. Similar adjustments may be indicated for other febrile illnesses for which QT-interval-prolonging medications are important therapeutic options.

Sudden death is a rare event in the pediatric population but with a social shock due to its presentation as the first symptom in previously healthy children. Comprehensive autopsy in pediatric cases identify an inconclusive cause in 40–50% of cases. In such cases, a diagnosis of sudden arrhythmic death syndrome is suggested as the main potential cause of death. Molecular autopsy identifies nearly 30% of cases under 16 years of age carrying a pathogenic/potentially pathogenic alteration in genes associated with any inherited arrhythmogenic disease. In the last few years, despite the increasing rate of post-mortem genetic diagnosis, many families still remain without a conclusive genetic cause of the unexpected death. Current challenges in genetic diagnosis are the establishment of a correct genotype–phenotype association between genes and inherited arrhythmogenic disease, as well as the classification of variants of uncertain significance. In this review, we provide an update on the state of the art in the genetic diagnosis of inherited arrhythmogenic disease in the pediatric population. We focus on emerging publications on gene curation for genotype–phenotype associations, cases of genetic overlap and advances in the classification of variants of uncertain significance. Our goal is to facilitate the translation of genetic diagnosis to the clinical area, helping risk stratification, treatment and the genetic counselling of families.

Cardiomyopathies are a heterogeneous group of inherited cardiac diseases characterized by progressive myocardium abnormalities associated with mechanical and/or electrical dysfunction. Massive genetic sequencing technologies allow a comprehensive genetic analysis to unravel the cause of disease. However, most identified genetic variants remain of unknown clinical significance due to incomplete penetrance and variable expressivity. Therefore, genetic interpretation of variants and translation into clinical practice remain a current challenge. We performed retrospective comprehensive clinical assessment and genetic analysis in six families, four diagnosed with arrhythmogenic cardiomyopathy, and two diagnosed with hypertrophic cardiomyopathy (HCM). Genetic testing identified three rare variants (two non-sense and one small indel inducing a frameshift), each present in two families. Although each variant is currently classified as pathogenic and the cause of the diagnosed cardiomyopathy, the onset and/or clinical course differed in each patient. New genetic technology allows comprehensive yet cost-effective genetic analysis, although genetic interpretation, and clinical translation of identified variants should be carefully done in each family in a personalized manner.

The persistence of inflammatory processes in the myocardium in varying degrees of chronic Chagas heart disease has been poorly investigated. We hypothesized that edema could occur in patients with chronic chagasic cardiomyopathy and corresponds to the persistence of inflammatory processes in the myocardium. Eighty-two Chagas disease (CD) seropositive patients (64.6% females; age = 58.9 ± 9.9) without ischemic heart disease or conditions that cause myocardial fibrosis and dilation were considered. Late gadolinium enhancement (LGE) and T2-weighted magnetic resonance imaging of edema were obtained and represented using a 17-segment model. Patients were divided into three clinical groups according to the left ventricular (LV) ejection fraction (EF) as G1 (EF > 60%; n=37), G2 (35% > EF 35% (p