Proyecto de cooperación de un equipo de cirugía cardiaca infantil en Etiopía. Organización y resultados

Introducción y objetivos: Las cardiopatías en la población infantil son una causa común de morbimortalidad en países subdesarrollados. La mayoría de estos niños con un diagnóstico y tratamiento adecuados podrían alcanzar la vida adulta con un desarrollo normal. Nuestro objetivo ha sido analizar nuestra experiencia en el tratamiento quirúrgico de cardiopatías congénitas en niños en un centro de Etiopía. Métodos: En el 2009 se inaugura en Adis Abeba un centro hospitalario dedicado exclusivamente a la atención de niños con cardiopatías, financiado por varias organizaciones internacionales. El equipo humano estuvo formado por: 9 facultativos, 3 enfermeras y un1 perfusionista. El material fungible, así como la medicación necesaria, fueron obtenidos gracias a donaciones de la industria farmacéutica. Resultados: Desde enero del 2010 hasta noviembre del 2013 hemos realizado 6 campañas quirúrgicas con un objetivo doble: asistencial y docente. Las campañas tuvieron una duración efectiva entre 8 y 10 días cada una. Realizamos 106 intervenciones en 103 niños portadores de cardiopatías congénitas. El 80% presentaba hipertensión pulmonar (HTP) severa. La mayoría de los diagnósticos fueron comunicación interauricular (CIV) n = 26 (con HTP, estenosis del tracto de salida de ventrículo derecho o ductus), CIA n = 29 (con estenosis pulmonar, ductus, insuficiencia mitral o drenaje venoso pulmonar anómalo), y estenosis subaórtica (n = 14). El 92% de los niños fueron extubados en las primeras 3 h. La estancia media en UCI fue de 1,8 días. El riesgo medio según la escala de Aristóteles básica fue de 5,01 (mortalidad esperada 0-5%). La mortalidad observada fue del 3,8%. El seguimiento fue realizado por los médicos del hospital de origen sin que hubiera complicaciones durante el mismo. Conclusiones: El desarrollo de un programa de cirugía cardiaca pediátrica en países subdesarrollados es posible con buen resultado, aunque por escasez de recursos y problemas asociados, ni la patología a tratar ni los resultados obtenidos pueden ser equiparables a los observados en nuestro medio

Comprehensive genetic characterization of a Spanish Brugada Syndrome cohort

BACKGROUND: Brugada syndrome (BrS) is a rare genetic cardiac arrhythmia that can lead to sudden cardiac death in patients with a structurally normal heart. Genetic variations in SCN5A can be identified in approximately 20-25% of BrS cases. The aim of our work was to determine the spectrum and prevalence of genetic variations in a Spanish cohort diagnosed with BrS. METHODOLOGY/PRINCIPAL FINDINGS: We directly sequenced fourteen genes reported to be associated with BrS in 55 unrelated patients clinically diagnosed. Our genetic screening allowed the identification of 61 genetic variants. Of them, 20 potentially pathogenic variations were found in 18 of the 55 patients (32.7% of the patients, 83.3% males). Nineteen of them were located in SCN5A, and had either been previously reported as pathogenic variations or had a potentially pathogenic effect. Regarding the sequencing of the minority genes, we discovered a potentially pathogenic variation in SCN2B that was described to alter sodium current, and one nonsense variant of unknown significance in RANGRF. In addition, we also identified 40 single nucleotide variations which were either synonymous variants (four of them had not been reported yet) or common genetic variants. We next performed MLPA analysis of SCN5A for the 37 patients without an identified genetic variation, and no major rearrangements were detected. Additionally, we show that being at the 30-50 years range or exhibiting symptoms are factors for an increased potentially pathogenic variation discovery yield./nCONCLUSIONS: In summary, the present study is the first comprehensive genetic evaluation of 14 BrS-susceptibility genes and MLPA of SCN5A in a Spanish BrS cohort. The mean pathogenic variation discovery yield is higher than that described for other European BrS cohorts (32.7% vs 20-25%, respectively), and is even higher for patients in the 30-50 years age range.This work was supported by Obra social “la Caixa” (www.obrasocial.lacaixa.es/), Centro Nacional de Investigaciones Cardiovasculares (CNIC-03-2008; www.cnic.es/), and Instituto de Salud Carlos III (FISPI08/1800 and Fondo Europeo de Desarrollo Regional; www.isciii.es/). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript

Comprehensive Genetic Characterization of a Spanish Brugada Syndrome Cohort

Brugada syndrome (BrS) is a rare genetic cardiac arrhythmia that can lead to sudden cardiac death in patients with a structurally normal heart. Genetic variations in SCN5A can be identified in approximately 20-25% of BrS cases. The aim of our work was to determine the spectrum and prevalence of genetic variations in a Spanish cohort diagnosed with BrS. Methodology/Principal Findings: We directly sequenced fourteen genes reported to be associated with BrS in 55 unrelated patients clinically diagnosed. Our genetic screening allowed the identification of 61 genetic variants. Of them, 20 potentially pathogenic variations were found in 18 of the 55 patients (32.7% of the patients, 83.3% males). Nineteen of them were located in SCN5A, and had either been previously reported as pathogenic variations or had a potentially pathogenic effect. Regarding the sequencing of the minority genes, we discovered a potentially pathogenic variation in SCN2B that was described to alter sodium current, and one nonsense variant of unknown significance in RANGRF. In addition, we also identified 40 single nucleotide variations which were either synonymous variants (four of them had not been reported yet) or common genetic variants. We next performed MLPA analysis of SCN5A for the 37 patients without an identified genetic variation, and no major rearrangements were detected. Additionally, we show that being at the 30-50 years range or exhibiting symptoms are factors for an increased potentially pathogenic variation discovery yield. In summary, the present study is the first comprehensive genetic evaluation of 14 BrSsusceptibility genes and MLPA of SCN5A in a Spanish BrS cohort. The mean pathogenic variation discovery yield is higher than that described for other European BrS cohorts (32.7% vs 20-25%, respectively), and is even higher for patients in the 30-50 years age rang

Characteristics of the Spanish BrS patients carrying rare genetic variations.

<p>The table shows the clinical characteristics of the probands who carried rare genetic variations in <i>SCN5A</i>, <i>SCN2B</i>, or <i>RANGRF</i>. All of them are potentially pathogenic except that found in <i>RANGRF</i>, which is of unknown significance (see <a href="http://www.plosone.org/article/info:doi/10.1371/journal.pone.0132888#sec014" target="_blank">discussion</a>). All the potentially pathogenic variations (PPVs) that had been previously reported, except p.P1725L and p.R1898C, had been identified in BrS patients. p.P1725L had been associated with Long QT Syndrome and p.R1898C was found in Exome Variant Server with a MAF of 0.0079%. No rare variations were identified in the control population. Patient’s age is expressed in years. Bold identifies the patients carrying variations that had not been described previously. M, male; F, female; S, syncope; ICD, intracardiac cardioverter defibrillator; UK, unknown; EPS, electrophysiological studies (+, positive response;-, negative response; N/P, not performed). The two patients who carried two PPVs each are identified by ^a and ^b, respectively.</p

Na_v1.5 channel scheme showing the relative position of the <i>SCN5A</i> PPVs identified in our cohort.

<p>Open symbols indicate already described variations and closed symbols locate novel variations reported in this study. DI to DIV designate the 4 domains of the protein, and numbers 1–6 identify the different segments within each domain. Crosses mark the voltage sensor.</p

Influence of the phenotype on PPV discovery yield.

<p>Bar graph comparing the PPV detection yield in 8 different clinical categories (stated below the graph). Each bar shows the total number of patients for each clinical category divided in those with a PPV (black) and those without an identified PPV (white). The number of patients (in brackets) and percentages are given. Pos, positive; Neg, negative; Spont, spontaneous type 1 BrS ECG; Drug, drug-induced type 1 BrS ECG; <i>n</i>, number of patients.</p

Demographics of the 55 Spanish BrS patients included in the study.

<p>The table shows the demographic characteristics of all the patients included in the study. Numbers in parentheses represent the relative percentages for each condition. T1 ECG refers to Type 1 BrS diagnostic electrocardiogram (ECG), obtained either spontaneously, or after drug challenge. The information regarding both the electrophysiological studies (EPS) and the treatment was not available for all the patients. Two of the patients that didn’t receive any treatment died, and were not taken into account for the calculations of percentages (+2 dead). ICD, intracardiac cardioverter defibrillator.</p

Influence of the age on PPVs discovery yield.

<p><b>(A)</b> Pie charts showing the distribution of patients in the overall population as well as in the categories of symptomatic and asymptomatic patients regarding PPV discovery. The percentage and the number of patients (in brackets) are given for each group. The small pie charts correspond to the age distribution of patients with an identified PPV. <b>(B)</b> Bar graphs of the PPV detection yields obtained for each of the age groups (< 30 years, 30–50 years and > 50 years). Numbers inside each bar correspond to the number of patients carrying a PPV for each category and the percentages represent the variation detection yield.</p

Characteristics of the probands carrying non-reported potentially pathogenic variations (PPVs) in <i>SCN5A</i> and their families.

<p><i>Left</i>: Electrocardiograms of the probands: <b>(A)</b> patient carrying the p.R569Pfs*151 variation, showing the ST elevation characteristic of BrS in V1 at the time of the flecainide test; <b>(B)</b> patient carrying the p.E625Rfs*95 variation, showing the spontaneous ST elevation characteristic of BrS in V1 and V2; and <b>(C)</b> patient carrying the p.R1623Efs*7 variation, showing the spontaneous ST elevation characteristic of BrS in V1 and V2. <i>Middle</i>: Family pedigrees. Open symbols designate clinically normal subjects, filled symbols mark clinically affected individuals and question marks identify subjects without an available clinical diagnosis. Plus signs indicate the carriers of the PPVs and minus signs, non-carriers. The crosses mark deceased individuals and arrows identify the proband. <i>Right</i>: Detail of the electropherograms obtained after <i>SCN5A</i> sequence analysis of a control subject (left panels) and of the probands (right panels).</p