Alterations in calmodulin-cardiac ryanodine receptor molecular recognition in congenital arrhythmias.

Calmodulin (CaM), a ubiquitous and highly conserved Ca2+-sensor protein involved in the regulation of over 300 molecular targets, has been recently associated with severe forms of lethal arrhythmia. Here, we investigated how arrhythmia-associated mutations in CaM localized at the C-terminal lobe alter the molecular recognition with Ryanodine receptor 2 (RyR2), specifically expressed in cardiomyocytes. We performed an extensive structural, thermodynamic, and kinetic characterization of the variants D95V/H in the EF3 Ca2+-binding motif and of the D129V and D131H/E variants in the EF4 motif, and probed their interaction with RyR2. Our results show that the specific structural changes observed for individual CaM variants do not extend to the complex with the RyR2 target. Indeed, some common alterations emerge at the protein-protein interaction level, suggesting the existence of general features shared by the arrhythmia-associated variants. All mutants showed a faster rate of dissociation from the target peptide than wild-type CaM. Integration of spectroscopic data with exhaustive molecular dynamics simulations suggests that, in the presence of Ca2+, functional recognition involves allosteric interactions initiated by the N-terminal lobe of CaM, which shows a lower affinity for Ca2+ compared to the C-terminal lobe in the isolated protein.

The Emergence of Human Induced Pluripotent Stem Cell-Derived Cardiomyocytes (hiPSC-CMs) as a Platform to Model Arrhythmogenic Diseases.

There is a need for improved in vitro models of inherited cardiac diseases to better understand basic cellular and molecular mechanisms and advance drug development. Most of these diseases are associated with arrhythmias, as a result of mutations in ion channel or ion channel-modulatory proteins. Thus far, the electrophysiological phenotype of these mutations has been typically studied using transgenic animal models and heterologous expression systems. Although they have played a major role in advancing the understanding of the pathophysiology of arrhythmogenesis, more physiological and predictive preclinical models are necessary to optimize the treatment strategy for individual patients. Human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) have generated much interest as an alternative tool to model arrhythmogenic diseases. They provide a unique opportunity to recapitulate the native-like environment required for mutated proteins to reproduce the human cellular disease phenotype. However, it is also important to recognize the limitations of this technology, specifically their fetal electrophysiological phenotype, which differentiates them from adult human myocytes. In this review, we provide an overview of the major inherited arrhythmogenic cardiac diseases modeled using hiPSC-CMs and for which the cellular disease phenotype has been somewhat characterized.

Current Interventional and Surgical Management of Congenital Heart Disease: Specific Focus on Valvular Disease and Cardiac Arrhythmias.

Successful outcome in the care of patients with congenital heart disease depends on a comprehensive multidisciplinary team. Surgery is offered for almost every heart defect, despite complexity. Early mortality for cardiac surgery in the neonatal period is ≈10% and beyond infancy is <5%, with 90% to 95% of patients surviving with a good quality of life into the adult years. Advances in imaging have facilitated accurate diagnosis and planning of interventions and surgical procedures. Similarly, advances in the perioperative medical management of patients, particularly with intensive care, has also contributed to improving outcomes. Arrhythmias and heart failure are the most common late complications for the majority of defects, and reoperation for valvar problems is common. Lifelong surveillance for monitoring of recurrent or residual structural heart defects, as well as periodic assessment of cardiac function and arrhythmia monitoring, is essential for all patients. The field of congenital heart surgery is poised to incorporate new innovations such as bioengineered cells and scaffolds that will iteratively move toward bioengineered patches, conduits, valves, and even whole organs.

Plasma natriuretic peptide levels in fetuses with congenital heart defect and/or arrhythmia.

OBJECTIVE: Diagnosing fetal heart failure remains challenging because it is difficult to know how well the fetal myocardium will perform as loading conditions change. In adult cardiology, natriuretic peptides (NPs) are established markers of heart failure. However, the number of studies investigating NP levels in fetuses is quite limited. The aim of this study was to evaluate the significance of plasma NP levels in the assessment of heart failure in fetuses with a congenital heart defect (CHD) and/or arrhythmia. METHODS: This was a prospective observational study conducted at a tertiary pediatric cardiac center. A total of 129 singletons with CHD and/or arrhythmia and 127 controls were analyzed between 2012 and 2015. Umbilical cord plasma atrial NP, brain NP and N-terminal pro-brain NP levels at birth were compared with ultrasonography findings indicating fetal heart failure, such as cardiovascular profile (CVP) score and morphological characteristics. RESULTS: Fetuses with CHD and/or arrhythmia had higher NP levels than did controls (P < 0.01). NP levels of fetuses with CHD and/or arrhythmia were correlated inversely with CVP score (P for trend < 0.01). No differences in NP levels were found in fetuses with CHD and/or arrhythmia and a CVP score of ≥ 8 in comparison to controls. Multivariate analysis showed that a CVP score of ≤ 5, tachy- or bradyarrhythmia at birth, preterm birth and umbilical artery pH < 7.15 were associated independently with high NP levels (P < 0.01). Among fetuses with a CVP score of ≤ 7, abnormal venous Doppler sonography findings were significantly more common and more severe in fetuses with tachy- or bradyarrhythmia than in those with CHD, and those with tachy- or bradyarrhythmia had higher NP levels than did those with CHD (P = 0.01). Fetuses with right-heart defect and moderate or severe tricuspid valve regurgitation had significantly higher NP levels than did fetuses with other types of CHD (P < 0.01). CONCLUSIONS: Plasma NP levels in fetuses with CHD and/or arrhythmia are correlated with the severity of fetal heart failure. Elevated NP levels are attributed mainly to an increase in central venous pressure secondary to arrhythmia or atrioventricular valve regurgitation due to CHD, rather than to the morphological abnormality itself. Copyright © 2017 ISUOG. Published by John Wiley & Sons Ltd.

The mental health of adolescents and pre-adolescents living with inherited arrhythmia syndromes: a systematic review of the literature.

Potentially fatal arrhythmias add to the mental health challenges of adolescence. This systematic review sought to summarise current knowledge regarding the mental health of adolescents and pre-adolescents diagnosed with inherited arrhythmia syndromes. Searches combining psychological problems with inherited cardiac arrhythmia diagnoses identified 16 studies with paediatric (<18 years) inherited arrhythmia patients. All studies were cross-sectional; 8/16 required an implantable cardioverter defibrillator. Methods were quantitative (n=11), qualitative (n=4), or mixed (n=1), with 14-100% of participants having an inherited arrhythmia syndrome. Mean/median age in 13/16 studies was 12-16 years. Patients and parents reported lower quality of life, particularly in relation to physical function, social relationships, restriction of peer activities, bodily pain, and mental and emotional health. Self-perceptions and behaviour were similar to healthy populations. Rates of anxiety and depression (15-33% of these patients) were not increased in these studies where patients were assessed 2+ years after diagnosis. Higher mental health risk occurred among patients who have a diagnosed sibling, those with cardiomyopathy, and those who report decreased quality of life. Mental health research among youth with inherited arrhythmias is extremely limited and of low quality. Data, primarily from patients 2-4 years after diagnosis or treatment with an implantable cardioverter defibrillator, indicate that quality of life may be decreased and 15-33% experience mental health issues. Future research is required to examine the mental health and quality of life of paediatric patients with inherited arrhythmia syndromes, whether or not they have an implantable cardioverter defibrillator, from time of diagnosis.

Avoiding sports-related sudden cardiac death in children with congenital channelopathy : Recommendations for sports activities.

For the past few years, children affected by an inherited channelopathy have been counseled to avoid (recreational) sports activities and all competitive sports so as to prevent exercise-induced arrhythmia and sudden cardiac death. An increased understanding of the pathophysiological mechanisms, better anti-arrhythmic strategies, and, in particular, more epidemiological data on exercise-induced arrhythmia in active athletes with channelopathies have changed the universal recommendation of "no sports," leading to revised, less strict, and more differentiated guidelines (published by the American Heart Association/American College of Cardiology in 2015). In this review, we outline the disease- and genotype-specific mechanisms of exercise-induced arrhythmia; give an overview of trigger-, symptom-, and genotype-dependent guidance in sports activities for children with long QT syndrome (LQTS), Brugada syndrome (BrS), catecholaminergic polymorphic ventricular tachycardia (CPVT), or short QT syndrome (SQTS); and highlight the novelties in the current guidelines compared with previous versions. While it is still recommended for patients with LQT1 and CPVT (even when asymptomatic) and all symptomatic LQTS patients (independent of genotype) to avoid any competitive and high-intensity sports, other LQTS patients successfully treated with anti-arrhythmic therapies and phenotype-negative genotype-positive patients may be allowed to perform sports at different activity levels - provided they undergo regular, sophisticated evaluations to detect any changes in arrhythmogenic risk.

[Arrhythmogenic left ventricular cardiomyopathy]. / Arytmogenní kardiomyopatie levé komory.

Arrhythmogenic left ventricular cardiomyopathy (ALVC) is a rare condition characterised by progressive fibrofatty replacement of the myocardium of the left ventricle in combination with arrhythmias of left ventricular origin. ALVC has been linked to autosomal dominant mutations of genes encoding desmosomal proteins, similarly to the classic arrhythmogenic right ventricular cardiomyopathy with which it also shares pathological and prognostic features. It seems that isolated left or right ventricular abnormalities represent two extremes of the spectrum of clinical manifestations of a single disease: arrhythmogenic cardiomyopathy. In addition to arrhythmias originating from the left ventricle, the diagnosis of ALVC is based on identification of morphological changes of the left ventricle including late gadolinium enhancement with subepicardial to midwall distribution, corresponding to fibrous or fibrofatty replacement on histopathology. The diagnosis is confirmed by detection of a causal mutation. ALVC should be kept in mind in the differential diagnosis of ventricular tachycardia of non-ischemic origin.Key words: arrhythmogenic cardiomyopathy - cardiac magnetic resonance - late gadolinium enhancement - ventricular tachycardia.

[Fetal magnetocardiography: a promising way to diagnose fetal arrhytmia and to study fetal heart rate variability?]. / Fetálna magnetokardiografia: Slubný spôsob diagnostiky fetálnych arytmií a stúdia fetálnej srdcovej variability?

OBJECTIVE: An overwiev of the new diagnostic method of fetal wellbeing - fetal magnetocardiography (fMCG). DESIGN: A review article. SETTING: Department of Gynecology and Obstetrics, Jessenius Faculty of Medicine in Martin, Comenius University in Bratislava, Slovak Republic. METHODS: An analysis of the literature using database search engines PubMed, and SCOPE in field of fMCG. RESULTS: Fetal magnetocardiography is a non-invasive technique able to monitor the spontaneous electrophysiological activity of the fetal heart. Compared to cardiotocography and fetal electrocardiography, this is a more effective method with a higher resolution. The signal obtained from the fetal heart is sufficiently precise and the quality allows an assessment of PQRST complex alterations, and to detect fetal arrhythmia. Thanks to early diagnosis of fetal arrhythmia, there is the possibility for appropriate therapeutic intervention and the reduction of unexplained fetal death in late gestation. fMCG with high temporal resolution also increases the level of clinical trials which record fetal heart rate (FHR) variability. According to the latest theories, FHR variability is a possible indicator of fetal status and enables the study of the fetal autonomic nervous system indirectly. fMCG is an experimental method that requires expensive equipment. It is yet to be shown in the future, if this method will get any application in clinical practice.

[Congenital Cardiac Conduction Abnormalities].

Abnormalities in cardiac conduction can occur due to a variety of factors. So called "idiopathic", conduction system degeneration develops without evident causes and may have hereditary basis. In the majority of cases it has no clinical manifestation, do not require treatment and have overall good prognosis. In this review we focus on congenital complete atrioventricular block and progressive cardiac conduction defect - rare but malignant and potentially lethal conditions that can be caused by genetic mutations and may be isolated or associated with structural heart disease. Cardiac involvement is relatively common in rare hereditary diseases - myodystrophies and mitochondrial cytopathies. Conduction abnormalities are among the most severe manifestations that may determine prognosis in these rare genetic disorders. These conditions deserve special consideration because of rapid progression of conduction defects and high prevalence of sudden cardiac death if no appropriate treatment applied.

Sudden unexplained death in infants and children: the role of undiagnosed inherited cardiac conditions.

Sudden unexplained death in childhood is a traumatic event for both the immediate family and medical professionals. This is termed sudden unexplained or arrhythmic death syndrome (SUDS/SADS) for children over 1 year of age while sudden unexplained death in infancy or sudden infant death syndrome (SUDI/SIDS) refers to unexplained deaths in the first year of life. There is increasing evidence for the role of undiagnosed inherited cardiac conditions, particularly channelopathies, as the cause of these deaths. This has far-reaching implications for the family regarding the potential risk to other family members and future pregnancies, providing a challenge not only in the counselling but also in the structured assessment and management of immediate relatives. This review will discuss the cardiac risk involved in sudden unexplained deaths of infants and children, the role of molecular autopsy, family cardiological screening, current management strategies, and future directions in this area.

Does low birth weight affect P-wave and QT dispersion in childhood?

BACKGROUND: The aim of our study is to investigate the effects of low birth weight (LBW) on atrial conduction and ventricular repolarization in children by using P-wave dispersion (Pw-d) and QT dispersion (QT-d) analyses. These effects have not yet been studied in detail in LBW children. METHODS: Fifty LBW children and 70 normal birth weight (NBW) children were enrolled in this cross-sectional controlled study. The Pw-d and QT-d of the LBW and NBW children were investigated. Independent Student's t-test, Mann-Whitney U test, and χ(2) test were performed to compare these two groups. Stepwise multiple regression analysis was performed to investigate whether there was a relationship between P-wave indices, QT derivatives, anthropometric and clinical features, and echocardiographic parameters. RESULTS: Age, gender, body mass index, waist circumferences, systolic and diastolic blood pressure, and echocardiographic measurements were similar between the LBW group and the NBW group (all P values > 0.05). The following findings were recorded for the LBW and NBW groups, respectively: the Pw-d (30 [10-50] ms vs 30 [10-50] ms, P = 0.977), QT-d (20 [10-50] ms vs 30 [15-50] ms, P = 0.561), and QTc-d (26 [14-54] ms vs 33 [17-62] ms, P = 0.866). No significant difference was found in Pw-d, QT-d, and QTc-d in comparison between the groups (all P values > 0.05). Pw-d was related to left atrial diameter and QTc-d was associated with left ventricle mass index even though they were within the normal range. CONCLUSION: Compared with the NBW group, no significant difference was found in both atrial conduction and ventricular repolarization features in LBW children.

Congenital long and short QT syndromes.

Congenital long and short QT syndromes are familial arrhythmias characterized by derangement of repolarization and a high risk of sudden cardiac death due to ventricular tachyarrhythmias. With growing understanding of these syndromes in both the medical and lay communities, diagnostic and therapeutic difficulties are increasingly faced by health care providers. Modern genomics has determined the mechanism of arrhythmia induction in these patients, resulting in specific medical therapies and improved risk stratification. This paper reviews the common presentations, genetic etiology, basic evaluation, risk stratification, and therapeutic approach for both syndromes. Particular attention is paid to the effect of the individual syndrome on the cardiac action potential and its correlate the surface 12 lead ECG. In conclusion, patients with long and short QT syndromes are at risk for sudden death, with accurate diagnosis, risk stratification, and resulting appropriate therapy favorably altering their outcome.

Fetal magnetocardiography (fMCG): moving forward in the establishment of clinical reference data by advanced biomagnetic instrumentation and analysis.

Cardiotocography and echocardiography are currently standard for fetal heart monitoring. However, both do not provide adequate temporal resolution to measure fetal cardiac time intervals and detect arrhythmias, which can occur during normal sinus rhythm. Fetal magnetocardiography (fMCG) is a non-invasive technique measuring magnetic signals generated by fetal heart activity. Most fMCG devices are installed in research institutions limiting the implementation of this method in a clinical setting. Several institutions made a step forward by installing devices, in particular for fetal investigations, in hospital sites to evaluate the clinical benefit. Based on instrumentation differences which can affect signal quality, there is still no established reference database for fetal cardiac time intervals. A new magnetograph dedicated to fetal recordings was implemented with improved patient comfort. The setting was optimized to establish a standard. A total of 103 healthy fetuses starting as early as possible after the first trimester were recorded and fMCG values of cardiac time intervals were compared to former studies. Data allowed high and reliable detection for all fMCG components starting at 17 weeks. The data were comparable to fMCG multicenter studies, fetal electrocardiography and neonatal ECG results and could serve as a database of norm values for further investigation of fetal arrhythmias.

Prenatal pharmacotherapy for fetal anomalies: a 2011 update.

Fetal therapy can be defined as any prenatal treatment administered to the mother with the primary indication to improve perinatal or long-term outcomes for the fetus or newborn. This review provides an update of the pharmacological therapies that are solely directed at the fetus with anomalies and outlines a future transcriptomic approach. Fetal anomalies targeted with prenatal pharmacotherapy are a heterogeneous group of structural, endocrine, and metabolic conditions, including congenital cystic adenomatoid malformation (CCAM), congenital adrenal hyperplasia, congenital heart block, fetal tachyarrhythmias, inborn errors of metabolism, fetal thyroid disorders, and polyhydramnios. To date, the majority of pharmacotherapies for fetal anomalies have been evaluated only in retrospective, uncontrolled studies. The way forward will be with an evidence-based approach to prenatal pharmacological interventions.

Arrhythmias presenting in neonatal lupus.

Perfusion of human foetal heart with anti-Ro/SSA antibodies induces transient heart block. Anti-Ro/SSA antibodies may cross-react with T- and L-type calcium channels, and anti-p200 antibodies may cause calcium to accumulate in rat heart cells. These actions may explain a direct electrophysiological effect of these antibodies. Congenital complete heart block is the more severe manifestation of so-called "Neonatal Lupus". In clinical practice, it is important to distinguish in utero complete versus incomplete atrioventricular (AV) block, as complete AV block to date is irreversible, while incomplete AV block has been shown to be potentially reversible after fluorinated steroid therapy. Another issue is the definition of congenital AV block, as cardiologists have considered congenital blocks detected months or years after birth. We propose as congenital blocks detected in utero or within the neonatal period (0-27 days after birth). The possible detection of first degree AV block in utero, with different techniques, might be a promising tool to assess the effects of these antibodies. Other arrhythmias have been described in NL or have been linked to anti-Ro/SSA antibodies: first degree AV block, in utero and after birth, second degree (i.e. incomplete block), sinus bradycardia and QT prolongation, both in infants and in adults, ventricular arrhythmias (in adults). Overall, these arrhythmias have not a clinical relevance, but are important for research purposes.

Spectrum of cardiac involvement in neonatal lupus.

'Neonatal' lupus erythematosus (NLE) describes a clinical spectrum of cardiac and non-cardiac abnormalities observed in neonates and foetuses whose mothers have the auto-antibodies anti-SSA/Ro (anti-Ro) and anti-SSB/La (anti-La). Of the cardiac abnormalities, congenital AVB is the most common cardiovascular abnormality found in affected foetuses and infants. Many other cardiovascular manifestations of NLE have been more recently recognized including atrial and ventricular arrhythmias and other conduction abnormalities, myocarditis, cardiomyopathy often with endocardiofibroelastosis and structural heart disease, particularly valvar lesions. In this report, the spectrum of cardiovascular manifestations observed in foetuses and infants with NLE are reviewed and the pathogenesis, diagnosis and clinical outcomes are briefly discussed.

[Cardiotocography in fetal heart arrhythmia--analysis of cases]. / Zapisy kardiotokograficzne u plodów z zaburzeniami rytmu serca--analiza przypadków.

Cardiotocography (CTG) is routinely used in obstetric units to monitor fetal well-being during pregnancy and labor Nevertheless the use of CTG is limited in cases of fetal arrhythmia, because it truncates the FHR if faster than 210 bpm and slower than 50 bpm. In fetal arrhythmias, with the heart rate between 50 bpm and 210 bpm, CTG may be nonconclusive, difficult to interpret and should not be taken into consideration when making the decision to end the pregnancy especially when it is premature. Until now the usefulness of CTG in the fetal arrhythmia has not been sufficiently described. The following study evaluates typical cases of fetal arrhythmia diagnosed by fetal echocardiography with corresponding cardiotocography and reviews the decision that had been made in each case.