Negative Autopsy in Infant and Juvenile Population: Role of Cardiac Arrhythmias

Negative autopsy is a post-mortem examination in which a comprehensive analysis does not provide a cause of death. These include situation of death, anatomical and histological analysis, toxicology and microbiological study. A low part of autopsies remain without a conclusive cause of death, but all these cases are usually seen in young population, apparently healthy who died suddenly and unexpectedly. In these situations a cardiac arrhythmia is suspected as cause of death and genetic testing is recommended despite not regularly performed. Sudden death is a natural and unexpected decease that occurs in apparently healthy people, or whose disease was not severe enough to expect a fatal outcome. It can be due to several pathologies, usually of cardiac cause and called sudden cardiac death. In infants and young people, both long QT syndrome and catecholaminergic polymorphic ventricular tachycardia are main causes in negative autopsies. These genetic diseases lead to ventricular fibrillation, syncope and sudden cardiac death in a normal heart. Unfortunately, sudden cardiac death could be the first manifestation of the diseases, being early identification and prevention a crucial point in current medical practice. This chapter focuses on sudden death and negative autopsy in young population, mainly due to cardiac arrhythmias

Recent Advances in Short QT Syndrome

Short QT syndrome is a highly malignant inherited cardiac disease characterized by ventricular tachyarrhythmias leading to syncope and sudden cardiac death. It is responsible of lethal episodes in young people, mainly infants. International guidelines establish diagnostic criteria with the presence of a QTc ≤ 340 ms in the electrocardiogram despite clinical diagnostic values remain controversial. In last years, clinical diagnosis, risk stratification as well as preventive therapies have been improved due to identification of pathophysiological mechanisms. The only effective option is implantation of a defibrillator despite Quinidine may be at times an effective option. Currently, a limited number of rare variants have been identified in seven genes, which account for nearly 20–30% of families. However, some of these variants are associated with phenotypes showing a shorter QT interval but no conclusive diagnosis of Short QT syndrome. Therefore, an exhaustive interpretation of each variant and a close genotype-phenotype correlation is necessary before clinical translation. Here, we review the main clinical and genetic hallmarks of this rare entity

316 Percutaneous right outflow tract valve implantation: when should we pre-stent?

IntroductionPercutaneous pulmonary valve insertion has been recently introduced in clinical setting. Patient selection is widely accepted. Initial results demonstrated early and differed stent fractures that make consider pre-stenting as a previous step for the procedure. To date, differed or intra-procedure pre-stenting are both accepted techniques.Patients and methodsWe reviewed patients included over the last 6 months in the prospective study (REVALV) for patients undergoing RVOT intervention for severe stenosis and/or insufficiency. Only valved stent group is analyzed here. All patients undergoing valved stent implantation are previously pre-stented with a bare metal stent according to present recommendations. Thirty-seven patients were included, distributed in two gropus according moment of pre-stenting: differed pre-stenting (bare metal stent implantation several days before valved stent implantation -20 patients-) and same procedure pre-stenting (bare metal stent implantation at the same procedure of valved stent implantation-17 patients-). For analytical purposes, we considered RVOT anatomy (homograft, synthetic tube, patch-extended RVOT or native outflow tract).ResultsOverall, no differences were found regarding mean procedure times (77,35 vs 96,88, p=NS) and time of hospitalization (2,95 vs 3,63, p=NS). Mean delay time from pre-stenting to valvulation was 196,5 + −68 days. Rv to Ao ratio improvement from basal to valvulation was significantly better in intra-procedure pre-stenting group (0,172 vs 0,373, p=0,009). Concerning complications, bare metal stent mobilization happened just after implantation while trying to place valved stent delivery gain. Two pelvic hematomas were observed (one of each group).ConclusionsIntra-procedure pre-stenting influences final result when considering RV-to-Ao ratio improvement, probably related to increase radial strength. The risk, however, remains higher as freshly implanted bare metal stent can mobilize, especially in native RVOT. Stratification of patient should be considered while choosing candidates for valved stent implantation

286 – Percutaneous right outflow tract valve implantation: substrate matters

IntroductionPercutaneous pulmonary valve insertion has been recently introduced in clinical setting. Patient selection is widely accepted. These candidates are however heterogeneous, in regard of heart defects, and type of surgical right ventricular outflow tract (RVOT) reconstruction. It is presently unclear in the literature if type of surgical reconstruction matters for the success of the pulmonary valve insertion. Our goal was to compare the hemodynamic results of percutaneous pulmonary valve in patients with homografts, prosthetic conduit or RVOT reconstructed with patch.Patients and methodsWe reviewed patients included over the last 6 months in the prospective study (REVALV) for patients undergoing RVOT intervention for severe stenosis and/or insufficiency. Only valved stent group is analyzed here. All patients undergoing valved stent implantation are previously pre-stented with a bare metal stent according to present recommendations. Thirty-seven patients were included, distributed in three groups according to type of RVOT reconstruction (homograft REVALV is a multicentric prospective study for patients undergoing RVOT intervention for severe stenosis and/or insufficiency. Patients are distributed in three groups according to type of RVOT reconstruction (homograft, n = 10; prosthetic conduit, n = 20; RVOT enlargement by patch, n = 7).ResultsOverall, all groups were similar in RV to AP gradient improvement (after pre-stenting mean 30,79 vs 28 p = NS; final result mean 23,71 vs 28,17, p = NS), RV to aorta pressures ratio (after pre-stenting 0,187 vs 0,3117 p = NS; final result man 0,315 vs 0,317, p = NS). If considering non-extensible synthetic tubes we observe that RV-to-AP improvement is significantly worst to the rest of the group (mean 7,07 vs 0,17, p = 0,005). When focusing on outflow tract diameter, results did not differ in homograft group and patch group. In contrast, diameter did play a role in those patients having a synthetic tube, with a cut-off at 20mm diameter. Below 20mm, relieve of outflow tract gradient was significantly worse than for bigger conduits.DiscussionPulmonary valve insertion is efficient in all type of RVOT reconstruction at least in the short term. The diameter of the conduits did not play a role in RVOT obstruction relief as long as surgical substrates are homografts or patch enlargement. In patients with prosthetic conduits, size matters. In non-extensible synthetic tubes results are worst. Reduced distensibility and progressive diameter reduction may lead to not consider these patients as good candidates for this procedure

Generation of four induced pluripotent stem cell lines from a family harboring a single nucleotide variant in SCN5A

Patient-derived induced pluripotent stem cells (iPSC) are a valuable approach to model cardiovascular diseases. We nucleofected non-integrating episomal vectors in skin fibroblasts of three family members carrying a single nucleotide variant (SNV) in SCN5A, which encodes the cardiac-type sodium channel, and of a related healthy control. The SNV SCN5A_c.4573G > A had been previously identified in a Brugada Syndrome patient. The resulting iPS cell lines differentiate into cells of the 3 germ layers, display normal karyotypes and express pluripotency surface markers and genes. Thus, they are a reliable source to study the effect of the identified mutation in a physiologically relevant environment

Update on Genes Associated with Arrhythmogenic Cardiomyopathy

Arrhythmogenic cardiomyopathy is a rare genetic entity characterized by progressive fibro-fatty replacement of myocardium leading to malignant arrhythmias, syncope, and sudden cardiac death. Mostly it affects the right ventricle, but cases have also been described with biventricular and even isolated left ventricular involvement. The disease affects mainly young males and arrhythmias are usually induced by exercise. Arrhythmogenic cardiomyopathy has a genetic origin and is basically caused by deleterious alterations in genes encoding desmosomal proteins, especially plakophilin-2. To date, more than 400 rare genetic alterations have been identified in 18 genes, mainly with autosomal dominant inheritance, but some recessive forms have also been reported (Naxos disease and Carvajal syndrome). A comprehensive genetic analysis identifies a rare variant as potential cause of the disease in around 60% of patients, suggesting the existence of unknown genes as well as other genome alterations not yet discovered. Genetic interpretation classifies some of these rare variants as ambiguous, playing an uncertain role in arrhythmogenic cardiomyopathy. This makes a proper translation of genetic data into clinical practice difficult. Moreover, incomplete penetrance and variable phenotypic expression makes it difficult to arrive at the correct diagnosis. In the present chapter, we focus on recent advances in the knowledge regarding the genetic basis of arrhythmogenic cardiomyopathy

Molecular autopsy in sudden cardiac death

Actualmente hay un porcentaje importante de autopsias que quedan sin un diagnóstico concluyente del fallecimiento, especialmente cuando este evento letal se produce súbitamente. El análisis genético se ha ido incorporando recientemente al campo de la medicina forense, sobre todo en aquellos pacientes que han fallecido de forma repentina, y donde no se identifica causa concluyente del fallecimiento tras una autopsia médico-legal completa. En estos casos las enfermedades eléctricas primarias son las principales responsables del fallecimiento. Hasta la fecha se han descrito más de 40 genes asociados a afecciones arritmogénicas causantes de muerte súbita cardiaca. Las principales enfermedades arritmogénicas son el síndrome de QT largo y la taquicardia ventricular; estudios genéticos post-mortem no solo permiten llevar a cabo un diagnóstico de la causa del fallecimiento, sino que también permiten una traslación clínica hacia los familiares, focalizado en la identificación precoz de individuos en riesgo de síncope, así como adopción de medidas terapéuticas personalizadas para la prevención de un episodio arrítmico letal.Currently, there are a significant percentage of autopsies left without a conclusive diagnosis of death, especially when this lethal event occurs suddenly. Genetic analysis has been recently incorporated into the field of forensic medicine, especially in patients with sudden death and where no conclusive cause of death is identified after a complete medicallegal autopsy. Inherited arrhythmogenic diseases are the main cause of death in these cases. To date, more than 40 genes have been associated with arrhythmogenic disease, and causing sudden cardiac death has been described. The main arrhythmogenic diseases are Long QT Syndrome, Catecholaminergic Polymorphic Ventricular Tachycardia, Brugada Syndrome, and Short QT Syndrome. These post-mortem genetic studies, not only allow a diagnosis of the cause of death, but also allow a clinical translation in relatives, focusing on the early identification of individuals at risk of syncope, as well as adopting personalised therapeutic measures for the prevention of a lethal arrhythmic episode

Personalized Genetic Diagnosis of Congenital Heart Defects in Newborns

Congenital heart disease is a group of pathologies characterized by structural malformations of the heart or great vessels. These alterations occur during the embryonic period and are the most frequently observed severe congenital malformations, the main cause of neonatal mortality due to malformation, and the second most frequent congenital malformations overall after malformations of the central nervous system. The severity of different types of congenital heart disease varies depending on the combination of associated anatomical defects. The causes of these malformations are usually considered multifactorial, but genetic variants play a key role. Currently, use of high-throughput genetic technologies allows identification of pathogenic aneuploidies, deletions/duplications of large segments, as well as rare single nucleotide variants. The high incidence of congenital heart disease as well as the associated complications makes it necessary to establish a diagnosis as early as possible to adopt the most appropriate measures in a personalized approach. In this review, we provide an exhaustive update of the genetic bases of the most frequent congenital heart diseases as well as other syndromes associated with congenital heart defects, and how genetic data can be translated to clinical practice in a personalized approach.This work was supported by Obra Social "La Caixa Foundation" (LCF/PR/GN16/50290001, and LCF/PR/GN19/50320002). Funders had no role in study design, data collection, data analysis, interpretation, or writing of the report

Malignant Arrhythmogenic Role Associated with RBM20: A Comprehensive Interpretation Focused on a Personalized Approach

The RBM20 gene encodes the muscle-specific splicing factor RNA-binding motif 20, a regulator of heart-specific alternative splicing. Nearly 40 potentially deleterious variants in RBM20 have been reported in the last ten years, being found to be associated with highly arrhythmogenic events in familial dilated cardiomyopathy. Frequently, malignant arrhythmias can be a primary manifestation of disease. The early recognition of arrhythmic genotypes is crucial in avoiding lethal episodes, as it may have an impact on the adoption of personalized preventive measures. Our study performs a comprehensive update of data concerning rare variants in RBM20 that are associated with malignant arrhythmogenic phenotypes with a focus on personalized medicine.This work was supported by Obra Social "La Caixa Foundation" (LCF/PR/GN16/50290001 and LCF/PR/GN19/50320002), Fondo Investigacion Sanitaria (FIS PI16/01203 and FIS, PI17/01690) from Instituto Salud Carlos III (ISCIII), and "Fundacio Privada Daniel Bravo Andreu". CIBERCV is an initiative of the ISCIII, Spanish Ministry of Economy and Competitiveness

Personalized Interpretation and Clinical Translation of Genetic Variants Associated With Cardiomyopathies

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