Roberto Barriales-Villa

Truncating FLNC Mutations Are Associated With High-Risk Dilated and Arrhythmogenic Cardiomyopathies

BACKGROUND Filamin C (encoded by the FLNC gene) is essential for sarcomere attachment to the plasmatic membrane. FLNC mutations have been associated with myofibrillar myopathies, and cardiac involvement has been reported in some carriers. Accordingly, since 2012, the authors have included FLNC in the genetic screening of patients with inherited cardiomyopathies and sudden death. OBJECTIVES The aim of this study was to demonstrate the association between truncating mutations in FLNC and the development of high-risk dilated and arrhythmogenic cardiomyopathies. METHODS FLNC was studied using next-generation sequencing in 2,877 patients with inherited cardiovascular diseases. A characteristic phenotype was identified in probands with truncating mutations in FLNC. Clinical and genetic evaluation of 28 affected families was performed. Localization of filamin C in cardiac tissue was analyzed in patients with truncating FLNC mutations using immunohistochemistry. RESULTS Twenty-three truncating mutations were identified in 28 probands previously diagnosed with dilated, arrhythmogenic, or restrictive cardiomyopathies. Truncating FLNC mutations were absent in patients with other phenotypes, including 1,078 patients with hypertrophic cardiomyopathy. Fifty-four mutation carriers were identified among 121 screened relatives. The phenotype consisted of left ventricular dilation (68%), systolic dysfunction (46%), and myocardial fibrosis (67%); inferolateral negative T waves and low QRS voltages on electrocardiography (33%); ventricular arrhythmias (82%); and frequent sudden cardiac death (40 cases in 21 of 28 families). Clinical skeletal myopathy was not observed. Penetrance was >97% in carriers older than 40 years. Truncating mutations in FLNC cosegregated with this phenotype with a dominant inheritance pattern (combined logarithm of the odds score: 9.5). Immunohistochemical staining of myocardial tissue showed no abnormal filamin C aggregates in patients with truncating FLNC mutations. CONCLUSIONS Truncating mutations in FLNC caused an overlapping phenotype of dilated and left-dominant arrhythmogenic cardiomyopathies complicated by frequent premature sudden death. Prompt implantation of a cardiac defibrillator should be considered in affected patients harboring truncating mutations in FLNC.

Transient left ventricular apical ballooning and outflow tract obstruction.

In the interesting syndrome of transient left ventricular apical ballooning (TLVAB) without coronary artery stenosis mimicking acute myocardial infarction, originally described by Tsuchihashi et al. [(1)][1], clinical manifestations in most patients were preceded by severe physical or emotional

Congenital Coronary Artery Anomalies With Origin in the Contralateral Sinus of Valsalva: Which Approach Should We Take?

Recent years have witnessed a change in our perception of congenital coronary artery anomalies. From being regarded as simple coronary angiographic observations of little clinical significance, they have come to be seen as potential causes of sudden death in young people and of myocardial ischemia in adults. Diagnostic difficulties, a lack of knowledge about the mechanisms through which they produce myocardial ischemia, and their highly variable incidence have made congenital coronary artery anomalies of great interest to cardiologists. This article focuses on the group of coronary artery anomalies that is responsible for most clinical events: anomalies that have their origin in the contralateral sinus of Valsalva. Coronary artery anomalies are defined, their incidence is discussed, diagnostic criteria are given, and finally a treatment algorithm based on current knowledge is proposed.

Anomalías congénitas de las arterias coronarias con origen en el seno de Valsalva contralateral: ¿qué actitud se debe seguir?

En los ultimos anos se esta produciendo un cambio en la actitud hacia las anomalias congenitas de las arterias coronarias. De simples hallazgos de las coronariografias, sin mayor trascendencia clinica, han pasado a considerarse como causa de muerte subita en jovenes y possible causa de isquemia en la poblacion adulta. La dificultad en su diagnostico, el desconocimiento de los mecanismos implicados en la produccion de isquemia y la gran variabilidad en su incidencia hacen de las anomalias congenitas de las arterias coronarias un tema de gran interes para el cardiologo. En este articulo nos centraremos en el grupo de anomalies coronarias causante de la mayor parte de eventos clinicos, que son las que tienen su origen en el seno de Valsalva contralateral. Definiremos que se considera una anomalia coronaria y analizaremos cual es su incidencia, como se diagnostican y, finalmente, propondremos un algoritmo para su tratamiento basado en los conocimientos actuales.

Screening mutations in myosin binding protein C3 gene in a cohort of patients with Hypertrophic Cardiomyopathy

BackgroundMyBPC3 mutations are amongst the most frequent causes of hypertrophic cardiomyopathy, however, its prevalence varies between populations. They have been associated with mild and late onset disease expression. Our objectives were to establish the prevalence of MyBPC3 mutations and determine their associated clinical characteristics in our patients.MethodsScreening by Single Strand Conformation Polymorphisms (SSCP) and sequencing of the fragments with abnormal motility of the MyBPC3 gene in 130 unrelated consecutive HCM index cases. Genotype-Phenotype correlation studies were done in positive families.Results16 mutations were found in 20 index cases (15%): 5 novel [D75N, V471E, Q327fs, IVS6+5G>A (homozygous), and IVS11-9G>A] and 11 previously described [A216T, R495W, R502Q (2 families), E542Q (3 families), T957S, R1022P (2 families), E1179K, K504del, K600fs, P955fs and IVS29+5G>A]. Maximum wall thickness and age at time of diagnosis were similar to patients with MYH7 mutations [25(7) vs. 27(8), p = 0.16], [46(16) vs. 44(19), p = 0.9].ConclusionsMutations in MyBPC3 are present in 15% of our hypertrophic cardiomyopathy families. Severe hypertrophy and early expression are compatible with the presence of MyBPC3 mutations. The genetic diagnosis not only allows avoiding clinical follow up of non carriers but it opens new possibilities that includes: to take preventive clinical decisions in mutation carriers than have not developed the disease yet, the establishment of genotype-phenotype relationship, and to establish a genetic diagnosis routine in patients with familial HCM.

Registro de anomalías congénitas de las arterias coronarias con origen en el seno de Valsalva contralateral en 13 hospitales españoles (RACES)

Este registro estudio la incidencia, la clinica asociada, el trayecto, los metodos diagnosticos de imagen y el tratamiento de las anomalias coronarias con origen en el seno coronario contralateral en 13 hospitales durante 2003. En 23.300 coronariografias se describieron 98 anomalias (incidencia del 0,4%): 46 circunflejas (47%), 25 coronarias derechas (25,5%), 10 coronarias izquierdas (10,2%), 3 descendentes anteriores (3,1%), 6 coronarias unicas (6,1%) y 8 incluidas en el apartado «otras» (8,2%). El motivo de la coronariografia mas frecuente fue la angina (43,9%). El trayecto inicial de la coronaria anomala no fue identificado en el 40,8% de los casos. En 2 pacientes (2%) se emplearon metodos de imagen asociados. El 51% tenia enfermedad coronaria asociada y el 18,4%, valvular; la valvula aortica era la mas afectada (15,2%). El 16,3% recibio tratamiento para la anomalia. Se observo una incidencia similar a la de series previas, y las anomalias de la circunfleja fueron las mas frecuentes. Los metodos de imagen asociados para el diagnostico del trayecto inicial fueron infrautilizados.

Cardiotrophin-1 plasma levels are associated with the severity of hypertrophy in hypertrophic cardiomyopathy

Aims Cardiotrophin-1 (CT-1) is a cytokine that induces hypertrophy in cardiomyocytes and is associated with left ventricular hypertrophy (LVH) in hypertensive patients. The objective of this study was to evaluate whether plasma CT-1 is associated with hypertrophic cardiomyopathy (HCM). Methods and results The study was performed in 124 patients with HCM. All patients underwent a full clinical evaluation and an echocardiogram. Left ventricular hypertrophy was evaluated by the measurement of the maximal LV wall thickness and the Spiritos LVH score. Plasma CT-1 was measured by an enzyme-linked immunosorbent assay. Compared with controls, patients with HCM exhibited higher (P < 0.001) plasma CT-1 levels. Significant correlations were found between CT-1 and maximal LV wall thickness (r = 0.284, P = 0.001) and the Spiritos LVH score (r = 0.287, P = 0.006) in HCM patients. In addition, the levels of CT-1 were higher (P = 0.02) in patients with severe LVH (maximal LV wall thickness ≥30 mm) than in patients with mild or moderate LVH (maximal LV wall thickness <30 mm). Conclusions These findings show that plasma CT-1 is associated with the severity of LVH in patients with HCM. Further studies are required to ascertain whether CT-1 is a diagnostic biomarker of this cardiomyopathy.

Genetics of Cardiomyopathies: Novel Perspectives with Next Generation Sequencing

Cardiomyopathies are a heterogeneous group of primary diseases of the myocardium usually of genetic origin and with familial presentation. The identification of multiple genetic causes for these diseases has opened a new window for early diagnosis, understanding of their natural history and improvement in risk stratification and management. However, in the past years, the clinical application of genetics has been limited by the prohibiting cost and restricted yield of the available genotyping technologies. The emergence of Next Generation Sequencing (NGS) has completely changed this scenario. This group of sequencing technologies allow the evaluation of hundreds or even thousands of genes in parallel at an affordable cost. Now the challenge is not genotyping per se but the interpretation of the complex results that NGS generates. In this paper we review the main aspects related to the application and impact of Next Generation Sequencing in the study of cardiomyopathies: technology, analysis procedures, bioinformatics, clinical validation and interpretation of results.

Mutación en homocigosis en el gen MYBPC3 asociada a fenotipos severos y alto riesgo de muerte súbita en una familia con miocardiopatía hipertrófica

El estudio genetico puede resultar una pieza clave en la evaluacion integral de la miocardiopatia hipertrofica familiar y en el desarrollo de una medicina individualizada. Hay pocos casos descritos, pero existe un grupo de pacientes con genotipos complejos asociados a manifestacion severa de la enfermedad y alto riesgo de muerte subita. Presentamos una familia caracterizada por evolucion precoz a disfuncion sistolica y diastolica en algunos de sus integrantes y muerte subita a edades tempranas en otros. Se detecto una mutacion en homocigosis (IVS6+5G>A) en el gen de la proteina C de union a la miosina, no descrita previamente, que nos permitio explicar el fenotipo de los afectados, estimar el riesgo en otros familiares y ofrecer consejo genetico.

Phenotype and prognostic correlations of the converter region mutations affecting the β myosin heavy chain

Objectives The prognostic value of genetic studies in cardiomyopathies is still controversial. Our objective was to evaluate the outcome of patients with cardiomyopathy with mutations in the converter domain of β myosin heavy chain (MYH7). Methods Clinical characteristics and survival of 117 affected members with mutations in the converter domain of MYH7 were compared with 409 patients described in the literature with mutations in the same region. Results Twenty-five mutations were evaluated (9 in our families including 3 novel (Ile730Asn, Asp717Gly and Arg719Pro)). Clinical diagnoses were hypertrophic (n=407), dilated (n=15), non-compaction (n=4) and restrictive (n=5) cardiomyopathies, unspecified cardiomyopathy (n=11), sudden death (n=50) and 35 healthy carriers. One hundred eighty-four had events (cardiovascular death or transplant). Median event-free survival was 50±2 years in our patients and 53±3 years in the literature (p=0.27). There were significant differences in the outcome between mutation: Ile736Thr had fewer events than other mutations in the region (p=0.01), while Arg719Gln (p<0.01) had reduced event-free survival. Conclusions Mutations in the converter region are generally associated with adverse prognosis although there are differences between mutations. The identification of a mutation in this particular region provides important prognostic information that should be considered in the clinical management of affected patients.