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[ES] Existen varios estudios sobre la morfogénesis del corazón en el embrión de los vertebrados, y en particular sobre cómo durante el desarrollo del tubo cardíaco se rompe la simetría bilateral dando lugar a una morfogénesis con asimetría izquierda-derecha. A pesar de los hallazgos clínicos y experimentales, todavía no está del todo claro cómo el patrón izquierda-derecha impulsa la morfogénesis asimétrica, ya que el enfoque se ha centrado generalmente en una simple descripción de la dirección del bucle. Una forma de afrontar los enigmas de la investigación clínica es utilizar modelos computacionales predictivos que ayuden a explorar las variaciones de forma durante el desarrollo del corazón, en función de la anomalía congénita que se quiera estudiar. La heterotaxia, como conjunto de patologías que afectan a la estructura espacial del corazón debido a la asimetría izquierda-derecha (entre otras), puede dar lugar a enfermedades cardiovasculares, por lo que es de especial relevancia encontrar el origen de esta anomalía y las diferentes configuraciones que pueden dar lugar a su aparición. Una de ellas se conoce como "Transposición de las grandes arterias (TGA)" y se sospecha que se debe a una torsión del tracto de salida (TF) durante la morfogénesis. Para este estudio nos propusimos predecir, mediante simulaciones computacionales y utilizando métodos de discretización y mallado de elementos finitos, la morfogénesis de un modelo de corazón desarrollado tras el bucle del tubo cardíaco cuando la región del OFT no crece, principalmente utilizando la cuantificación del ángulo de torsión. Los resultados proporcionan una visión del mecanismo del bucle cardíaco, en el que la tendencia a la torsión es hacia la derecha, lo que conduce a una reorganización de los ventrículos como primer hallazgo. Esto es relevante para los defectos cardíacos congénitos, así como para la estimación del patrón izquierda-derecha en la morfogénesis del corazón con el fin de obtener una mejor clasificación en las diferentes clases de síndrome de heterotaxia., [EN] There are several studies on the heart morphogenesis in the vertebrate embryo, and in particular on how during the development of the heart tube bilateral symmetry is broken leading to morphogenesis with left-right asymmetry. Despite clinical and experimental findings, it is still not entirely clear how left-right patterning drives asymmetric morphogenesis, as the focus has generally been on a simple description of the direction of the loop. One way to overcome the conundrums in clinical research is to use predictive computational models to help explore shape variations during heart development, depending on the congenital anomaly to be studied. Heterotaxy, as a set of pathologies affecting the spatial structure of the heart due to left-right asymmetry (among others), can lead to cardiovascular diseases, so it is of particular relevance to find the origin of this anomaly and the different configurations that can lead to its emergence. One of them is known as "Transposition of the great arteries (TGA)" and is suspected to be due to a twist of the outflow tract (OFT) during morphogenesis. For this study we aimed to predict, through computational simulations and using discretization and finite element meshing methods, the morphogenesis of a heart model developed after the heart tube loop when the OFT region does not grow, mainly using the quantification of the twist angle. The results provide an insight into the mechanism of the cardiac loop, where the flipping tendency is to the right leading to a re-organization of the ventricles as the first finding. This is relevant for congenital heart defects as well as for the estimation of the left-right pattern in the morphogenesis of the heart in order to get a better classification in the different classes of heterotaxy syndrome.

Arrhythmogenic cardiomyopathy is a heritable heart disease associated with desmosomal mutations, especially premature termination codon (PTC) variants. It is known that PTC triggers the nonsense-mediated decay (NMD) mechanism. It is also accepted that PTC in the last exon escapes NMD; however, the mechanisms involving NMD escaping in 5′-PTC, such as reinitiation of translation, are less known. The main objective of the present study is to evaluate the likelihood that desmosomal genes carrying 5′-PTC will trigger reinitiation. HL1 cell lines were edited by CRISPR/Cas9 to generate isogenic clones carrying 5′-PTC for each of the five desmosomal genes. The genomic context of the ATG in-frame in the 5′ region of desmosomal genes was evaluated by in silico predictions. The expression levels of the edited genes were assessed by Western blot and real-time PCR. Our results indicate that the 5′-PTC in PKP2, DSG2 and DSC2 acts as a null allele with no expression, whereas in the DSP and JUP gene, N-truncated protein is expressed. In concordance with this, the genomic context of the 5′-region of DSP and JUP presents an ATG in-frame with an optimal context for the reinitiation of translation. Thus, 5′-PTC triggers NMD in the PKP2, DSG2* and DSC2 genes, whereas it may escape NMD through the reinitiation of the translation in DSP and JUP genes, with no major effects on ACM-related gene expression.

[eng] Objective: To evaluate the impact of clinical pharmacist interventions in the management of patients with cardiovascular diseases in a tertiary care hospital. Methodology: The Present Study was a Prospective Interventional study conducted over a minimum period of 6 months from October 2019 to March 2020 in Cardiology and General Medicine Departments In a Tertiary Care Hospital, India. 220 prescription was evaluated out of which 140 prescription had pDDIs. The patient demographics and all medically relevant information were noted in a predefined data collection form. Alternatively, these case charts were reviewed for potential drug interactions, drugs involved in interactions, laboratory investigations, followed up for assessing observed adverse drug interaction, and pharmacist’s intervention. Result: Out of 220 prescriptions analyzed, 140 prescriptions comprised of potential drug interactions and it was found that 234 drug interactions were present. The incidence of potential drug interaction was 63.64%, A total of 28 adverse drug reactions were recorded among 234 pDDI. Conclusion: This study attempted to assess the potential drug-drug interaction in the prescription of cardiac patients in the inpatient hospital setting. This study also examined patient, drug characteristics, causality, and severity of pDDIs. This study shows that DDIs are frequent among hospitalized cardiac patients. About 234 drug interactions were reported during the study period with a median number of 1.67 pDDIs in the cardiac patients. This study emphasizes the need to consider pDDIs during therapeutic planning, protect patients from the consequence of drug interactions. In addition, providing DDI-related information to the prescribers and drug interaction alert software to the dispensing pharmacist can play a vital role in minimizing the incidence rate of DDI., [spa] Objetivo: Evaluar el impacto de las intervenciones del farmacéutico clínico en el manejo de pacientes con enfermedades cardiovasculares en un hospital de tercer nivel. Metodología: El presente estudio fue un estudio prospectivo de intervención realizado durante un período mínimo de 6 meses desde octubre de 2019 hasta marzo de 2020 en los departamentos de cardiología y medicina general en un hospital de atención terciaria, India. Se evaluaron 220 prescripciones de las cuales 140 tenían pDDIs. Los datos demográficos del paciente y toda la información médicamente relevante se anotaron en un formulario de recogida de datos predefinido. Además, se revisaron las historias clínicas para determinar las posibles interacciones farmacológicas, los fármacos implicados en las interacciones, las investigaciones de laboratorio, el seguimiento para evaluar la interacción farmacológica adversa observada y la intervención del farmacéutico. Resultado: De las 220 prescripciones analizadas, 140 incluían posibles interacciones farmacológicas y se descubrió que había 234 interacciones farmacológicas. La incidencia de interacciones farmacológicas potenciales fue del 63,64%, y se registraron un total de 28 reacciones farmacológicas adversas entre las 234 pDDI. Conclusión: Este estudio trató de evaluar la potencial interacción farmacológica en la prescripción de pacientes cardíacos en el ámbito hospitalario. Este estudio también examinó las características del paciente, del fármaco, la causalidad y la gravedad de las pDDI. Este estudio muestra que las IDP son frecuentes entre los pacientes cardíacos hospitalizados. Se notificaron unas 234 interacciones farmacológicas durante el periodo de estudio, con una mediana de 1,67 IDP en los pacientes cardíacos. Este estudio enfatiza la necesidad de considerar las pDDIs durante la planificación terapéutica, para proteger a los pacientes de las consecuencias de las interacciones farmacológicas. Además, el suministro de información relacionada con las IDP a los prescriptores y el software de alerta de interacciones farmacológicas al farmacéutico dispensador pueden desempeñar un papel vital para minimizar la tasa de incidencia de las IDP.

[eng] Background: To assess the use of heart age as new tool to evaluate cardiovascular risk, measuring correlation with classical tools (REGICOR, SCORE) and with other cardio-vascular parameters. Methods: An observational, transversal and descriptive study was conducted in 6788 volunteers (3885 women and 2903 men, 35 - 65 years) between January 2018 and December 2019. The “Heart age calculator” considered the following parameters: age, sex, height, weight, waist perimeter, familiar history of cardiovascular disease, presence of diabetes, tobacco consumption, levels of total and HDL cholesterol and systolic blood pressure values. Cardiovascular risk was assessed using Framingham calibrated for Spanish population (REGICOR) and SCORE models. Results: Overweight, obesity, adiposity, metabolic syndrome and diabetes were significantly more prevalent in men than in women (p < 0.05). A high correlation was observed between heart age and cardiovascular risk (absolute and relative) measured according to REGICOR model, with correlation coefficients of 0.6 - 0.8, higher in men than in women. As relative risk increased, heart age was worsening. Finally, a relationship between heart age and cardiovascular parameters (waist perimeter, BMI, adiposity and metabolic syndrome) was also established. Conclusions: Heart age can be a useful tool to assess the cardiovascular risk, at least in these peruvian population., [spa] Introducción: Para evaluar el uso de la edad del corazón como nueva herramienta para valorar el riesgo cardiovascular, se determina la correlación con las herramientas clásicas (REGICOR y SCORE) y con otros parámetros cardiovasculares. Métodos: Estudio observacional, transversal y descriptivo, realizado en 6.788 voluntarios (3.885 mujeres y 2.903 hombres) de 35 a 65 años entre Enero de 2018 y diciembre de 2019. La “Calculadora de edad del Corazón” considera los siguientes parámetros: edad, sexo, altura, peso, perímetro de la cintura, historia familiar de enfermedad cardiovascular, presencia de diabetes, consumo de tabaco, niveles de colesterol total y HDL y presión sistólica. El riesgo cardiovascular se evaluó a través de Framingham calibrada para la población española (REGICOR) y el modelo SCORE. Resultados: El sobrepeso, la obesidad, la grasa corporal, el síndrome metabólico y la diabetes fueron significativamente más frecuente en hombres que en mujeres (p

Altres ajuts: Fondo Europeo de Desarrollo Regional (FEDER). Some lipoprotein disorders related to the residual risk of premature cardiovascular disease (PCVD) are not detected by the conventional lipid profile. In this case-control study, the predictive power of PCVD of serum sdLDL-C, measured using a lipoprotein precipitation method, and of the physicochemical properties of serum lipoproteins, analyzed by nuclear magnetic resonance (NMR) techniques, were evaluated. We studied a group of patients with a first PCVD event (n = 125) and a group of control subjects (n = 190). Conventional lipid profile, the size and number of Very Low Density Lipoproteins (VLDL), Low Density Lipoproteins (LDL), High Density Lipopro-teins (HDL) particles, and the number of particles of their subclasses (large, medium, and small) were measured. Compared to controls, PCVD patients had lower concentrations of all LDL parti-cles, and smaller and larger diameter of LDL and HDL particles, respectively. PCVD patients also showed higher concentrations of small dense LDL-cholesterol (sdLDL), and triglycerides (Tg) in LDL and HDL particles (HDL-Tg), and higher concentrations of large VLDL particles. Multivariate logistic regression showed that sdLDL-C, HDL-Tg, and large concentrations of LDL particles were the most powerful predictors of PCVD. A strong relationship was observed between increased HDL-Tg concentrations and PCVD. This study demonstrates that beyond the conventional lipid profile, PCVD patients have other atherogenic lipoprotein alterations that are detected by magnetic resonance imaging (MRI) analysis.

We report a case of unusual and unexplained cardiac death in an 18-years old female patient with congenital neurosensorial deafness. The fatal event was characterized by an initial syncopal episode, associated with a wide QRS tachycardia (around 110 bpm) but stable hemodynamic conditions. The patient, however, subsequently developed severe hypotension and progressive bradyarrhythmias until asystole and lack of cardiac response to resuscitation maneuvers and ventricular pacing

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.

The SCN5A gene encodes the α-subunit of the voltage-gated cardiac sodium channel (NaV1.5), a key player in cardiac action potential depolarization. Genetic variants in protein-coding regions of the human SCN5A have been largely associated with inherited cardiac arrhythmias. Increasing evidence also suggests that aberrant expression of the SCN5A gene could increase susceptibility to arrhythmogenic diseases, but the mechanisms governing SCN5A expression are not yet well understood. To gain insights into the molecular basis of SCN5A gene regulation, we used rat gastrocnemius muscle four days following denervation, a process well known to stimulate Scn5a expression. Our results show that denervation of rat skeletal muscle induces the expression of the adult cardiac Scn5a isoform. RNA-seq experiments reveal that denervation leads to significant changes in the transcriptome, with Scn5a amongst the fifty top upregulated genes. Consistent with this increase in expression, ChIP-qPCR assays show enrichment of H3K27ac and H3K4me3 and binding of the transcription factor Gata4 near the Scn5a promoter region. Also, Gata4 mRNA levels are significantly induced upon denervation. Genome-wide analysis of H3K27ac by ChIP-seq suggest that a super enhancer recently described to regulate Scn5a in cardiac tissue is activated in response to denervation. Altogether, our experiments reveal that similar mechanisms regulate the expression of Scn5a in denervated muscle and cardiac tissue, suggesting a conserved pathway for SCN5A expression among striated muscles This research was funded by the University of Girona, grant number MPCUdG2016/039 and Obra Social La Caixa. D.C. acknowledges a predoctoral fellowship from the Agència de Gesitó d’Ajusts Universitaris I de Recerca-Generalitat de Catalunya (2018FI_B00969) and European Social Fund (ESF)

The voltage‐gated sodium (NaV) channel is essential for cardiomyocyte function. It is responsible for generating the rising phase of the cardiac action potential. The channel consists of a pore‐forming, α‐subunit, whose main cardiac isoform is NaV1.5, and one or two associated β‐subunits. Moreover, it is part of a macromolecular complex including a diverse set of interacting proteins, some of which are implicated in regulating its localization to specialized membrane domains of the cardiomyocyte sarcolemma

Large conductance calcium-activated potassium (BK) channels are widely expressed in the nervous system. We have recently shown that principal neurons from canine intracardiac ganglia (ICG) express a paxilline- and TEA-sensitive BK current, which increases neuronal excitability. In the present work, we further explore the molecular constituents of the BK current in canine ICG. We found that the β1 and β4 regulatory subunits are expressed in ICG. Single channel voltage-dependence at different calcium concentrations suggested that association of the BKα with a particular β subunit was not enough to explain the channel activity in this tissue. Indeed, we detected the presence of several splice variants of the BKα subunit. In conclusion, BK channels in canine ICG may result from the arrangement of different BKα splice variants, plus accessory β subunits. The particular combinations expressed in canine IC neurons likely rule the excitatory role of BK current in this tissue This work was supported in part by a National Institute of Health grant HL073161 to GJP, an American Heart Association grant 0335446T to FSS, a grant from the Obra Social “La Caixa” to RB and a Sara Borrell postdoctoral fellowship CD11/00063 from the Instituto de Salud Carlos III to ES

The voltage-gated sodium (NaV ) channel is required for cardiomyocyte function. In heart, its major, pore-forming, α-subunit is NaV 1.5, encoded by SCN5A, which maps to chromosome 3p21. The NaV channel plays a key role in myocardial excitability, since it is responsible for generating the rising phase of the cardiac action potential. NaV 1.5 often shows alterations in inherited channelopathies causing cardiac arrhythmias. Two well-known arrhythmias in which pathogenic variants of NaV 1.5 are implicated are Brugada syndrome (BrS) and Long QT syndrome (LQTS) type 3 (LQT3), which are due, respectively, to loss- and gain-of-function of the channel

Aberrant expression of the sodium channel gene (SCN5A) has been proposed to disrupt cardiac action potential and cause human cardiac arrhythmias, but the mechanisms of SCN5A gene regulation and dysregulation still remain largely unexplored. To gain insight into the transcriptional regulatory networks of SCN5A, we surveyed the promoter and first intronic regions of the SCN5A gene, predicting the presence of several binding sites for GATA transcription factors (TFs). Consistent with this prediction, chromatin immunoprecipitation (ChIP) and sequential ChIP (Re-ChIP) assays show co-occupancy of cardiac GATA TFs GATA4 and GATA5 on promoter and intron 1 SCN5A regions in fresh-frozen human left ventricle samples. Gene reporter experiments show GATA4 and GATA5 synergism in the activation of the SCN5A promoter, and its dependence on predicted GATA binding sites. GATA4 and GATA6 mRNAs are robustly expressed in fresh-frozen human left ventricle samples as measured by highly sensitive droplet digital PCR (ddPCR). GATA5 mRNA is marginally but still clearly detected in the same samples. Importantly, GATA4 mRNA levels are strongly and positively correlated with SCN5A transcript levels in the human heart. Together, our findings uncover a novel mechanism of GATA TFs in the regulation of the SCN5A gene in human heart tissue. Our studies suggest that GATA5 but especially GATA4 are main contributors to SCN5A gene expression, thus providing a new paradigm of SCN5A expression regulation that may shed new light into the understanding of cardiac disease.

INTRODUCTION: Drowning incidents are the cause of the 52’7 % of all the death in people under 15 years (372.000 deaths per year). For each child dead by a drowning episode, it is estimated than another four children experience a serious non-fatal drowning event. In comparison with other activities, swimming is now a well-stablished trigger of arrhythmia in people who have LQTS or CPVT. HYPOTHESIS AND OBJECTIVES: The aim of this retrospective descriptive study is to discover if there are underlying cardiac channelopathies in drowning and near-drowning incidents that happened between 1997 and 2017 in patients registered in Emergencies and Intensive Care Units of SJD Hospital. METHODS: A registry of 155 patients listed for having suffered a drowning or near-drowning event was described and analysed, attending to epidemiological data, clinical aspects, familiar background, all diagnostic tools used and their results. RESULTS: ECG was performed in 26,5% patients of those 155 patients registered, five of them were positive for LQTS, what supposes a 12,2% of these 41 performed ECG. Five patients did have a genetic test performed, all of them resulted positive. CONCLUSIONS: Because ECGs and genetic tests are not performed as part of the drowning and near-drowning events protocol, there is a potential underestimation in the diagnosis of these channelopathies in cases of drowning and near-drowning events. ECGs and genetic tests are both fundamental in the diagnosis of both LQTS and CPVT diseases. Due to this fact, it is essential to proceed to do both of them when a patient has suffered from a drowning or near-drowning event, apart from a stress test to unmask a possible underlying CPVT once patients have recovered from the incident