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Resumen Introduccion y objetivos La amiloidosis hereditaria por transtirretina (ATTRv) es una enfermedad causada por mutaciones en el gen de la transtirretina que frecuentemente presenta afeccion cardiaca debido al deposito de amiloide en el miocardio. Nuestro objetivo es describir esta afeccion en una cohorte espanola. Metodos Estudio retrospectivo multicentrico de pacientes con ATTRv y afeccion cardiaca provenientes de centros espanoles. Se recogieron datos demograficos, clinicos y geneticos. Resultados En 26 centros se incluyo a 181 pacientes, el 65,2% varones, con una mediana de edad al diagnostico de 62 anos. Las mutaciones mas frecuentes fueron Val50Met (67,7%) y Val142Ile (12,4%). El principal motivo de consulta fue extracardiaco (69%), principalmente neurologico. La media de la fraccion aminoterminal del propeptido natriuretico cerebral (NT-proBNP) fue 2.145 ± 3.586 pg/ml. Lo mas caracteristico del electrocardiograma fueron el patron de seudoinfarto (25,9%) y el bloqueo auriculoventricular (25,3%). El grosor ventricular medio fue 15,4 ± 4,1 mm. El strain longitudinal estaba reducido en segmentos basales en el 29,4%. Se observo realce tardio subendocardico difuso en el 58,8%. En la gammagrafia habia captacion de grados 2-3 en un 75%. En el seguimiento, el 24,9% ingreso por insuficiencia cardiaca, el 34,3% preciso marcapasos y el 31,6%, trasplante hepatico. El 32,5% fallecio, principalmente por insuficiencia cardiaca (28,8%). Las mutaciones diferentes de Val50Met se asociaron en general con un peor pronostico. Conclusiones La ATTRv cardiaca en Espana tiene un espectro genetico y de afeccion heterogeneo. El pronostico es malo principalmente por las complicaciones cardiacas, por lo que son esenciales un diagnostico y un tratamiento precoces.

Introduction and objectives Hereditary transthyretin amyloidosis (hATTR) is a disease caused by mutations in the transthyretin gene that frequently shows cardiac involvement due to amyloid deposition in the myocardium. Our objective was to identify cardiac involvement in a Spanish cohort. Methods Retrospective multicenter study of patients diagnosed with hATTR with cardiac involvement from Spanish centers. We collected demographic, clinical, and genetic data. Results A total of 181 patients from 26 centers were included (65.2% men, with a median age at diagnosis of 62 years). The most frequent mutations were Val50Met (67.7%) and Val142Ile (12.4%). The main reason for consultation was extracardiac symptoms (69%), mainly neurological. The mean N-terminal pro-B-type natriuretic peptide level was 2145±3586 pg/mL. The most characteristic electrocardiogram findings were a pseudoinfarct pattern (25.9%) and atrioventricular block (25.3%). Mean ventricular thickness was 15.4±4.1mm. Longitudinal strain was reduced in basal segments by 29.4%. Late diffuse subendocardial enhancement was observed in 58.8%. Perugini grade 2 or 3 uptake was observed in 75% of scintigraphy scans. During follow-up, 24.9% of the patients were admitted for heart failure, 34.3% required a pacemaker, and 31.6% required a liver transplant. One third (32.5%) died during follow-up, mainly due to heart failure (28.8%). The presence of non-Val50Met mutations was associated with a worse prognosis. Conclusions HATTR cardiac amyloidosis in Spain shows heterogeneous genetic and clinical involvement. The prognosis is poor, mainly due to cardiac complications. Consequently early diagnosis and treatment are vital.

Introduction and objectives Sudden cardiac death (SCD) in young people often has a genetic cause. Consequently, the results of “molecular autopsy” may have important implications for their relatives. Our objective was to evaluate the diagnostic yield of a molecular autopsy program using next-generation sequencing. Methods We performed a prospective study of a cohort of consecutive patients who died from nonviolent SCD, aged ≤ 50 years, and who underwent molecular autopsy using large panels of next-generation sequencing, with subsequent clinical and genetic family screening. We analyzed demographic, clinical, toxicological, and genetic data. Results We studied 123 consecutive cases of SCD in persons aged ≤ 50 years. The incidence of SCD was 5.8 cases/100 000 individuals/y, mean age was 36.15 ± 12.7 years, and 95 were men (77%). The cause was cardiac in 53%, unexplained SCD in 24%, toxic in 10.6%, and infant SCD in 4%. Among cardiac causes, ischemic heart disease accounted for 38% of deaths, arrhythmogenic cardiomyopathy for 7%, hypertrophic cardiomyopathy for 5%, and idiopathic left ventricular hypertrophy for 11%. Genetic analysis was performed in 62 cases (50.4%). Genetic variants were found in 42 cases (67.7%), with a mean of 3.4 ± 4 genetic variants/patient, and the variant found was considered to be pathogenic or probably pathogenic in 30.6%. In unexplained SCD, 70% showed some genetic variant. Family screening diagnosed 21 carriers or affected individuals, 5 of whom were at risk, indicating an implantable cardiac defibrillator. Conclusions Protocol-based and exhaustive study of SCD from cardiac causes in persons aged ≤ 50 years is feasible and necessary. In a high percentage of cases, the cause is genetic, indicating the existence of relatives at risk who could benefit from early diagnosis and treatment to avoid complications.

Resumen Introduccion y objetivos La muerte subita (MS) de personas jovenes suele tener una causa genetica, por lo cual la «autopsia molecular» puede tener implicaciones importantes para los familiares. El objetivo del estudio es evaluar el rendimiento diagnostico de un programa de autopsia molecular mediante secuenciacion masiva. Metodos Estudio prospectivo de una cohorte de pacientes consecutivos de edad ≤ 50 anos y fallecidos por MS no violenta, a los que se realizo autopsia molecular mediante paneles amplios por secuenciacion masiva, con posterior cribado familiar clinico y genetico. Se analizan datos demograficos, clinicos, toxicologicos y geneticos. Resultados Se estudiaron 123 casos consecutivos de MS a edades ≤ 50 anos. La incidencia de MS fue de 5,8 casos/100.000 individuos/ano, a una media de edad de 36,15 ± 12,7 anos; 95 (77%) eran varones. La causa fue cardiaca en el 53%; MS inexplicada en el 24%, toxicos en el 10,6% y MS del lactante en el 4%. De las cardiacas, el 38% por cardiopatia isquemica, el 7% por miocardiopatia arritmogenica, el 5% por miocardiopatia hipertrofica y el 11% por hipertrofia ventricular izquierda idiopatica. Se indico analisis genetico en 62 casos (50,4%). Se hallaron variantes geneticas en 42 (67,7%), con una media de 3,4 ± 4 variantes/paciente, que se consideraron patogenicas o probablemente patogenicas en el 30,6%. De las MS inexplicadas, hasta el 70% presento alguna variante genetica. El estudio familiar permitio detectar a 21 portadores o afectos, 5 de ellos estaban en riesgo, por lo que se indico implante de desfibrilador. Conclusiones El estudio protocolizado y exhaustivo de la MS cardiaca de personas jovenes es factible y necesario. En un alto porcentaje la causa es genetica y, por lo tanto, existen familiares en riesgo que pueden beneficiarse de un diagnostico y un tratamiento precoces para evitar complicaciones.

Hypertrophic cardiomyopathy (HCM) is a genetic disease characterised by increased left ventricle (LV) wall thickness caused by mutations in sarcomeric genes. Finding a causal mutation can help to better assess the proband's risk, as it allows the presence of the mutation to be evaluated in relatives and the follow-up to be focused on carriers. We performed an observational study of patients with HCM due to the novel p.Arg652Lys variant in the

Hypertrophic cardiomyopathy (HCM) is a genetic disease characterised by increased left ventricle (LV) wall thickness caused by mutations in sarcomeric genes. Finding a causal mutation can help to better assess the proband’s risk, as it allows the presence of the mutation to be evaluated in relatives and the follow-up to be focused on carriers. We performed an observational study of patients with HCM due to the novel p.Arg652Lys variant in the MYH7 gene. Eight families and 59 patients are described in the follow-up for a median of 63 months, among whom 39 (66%) carry the variant. Twenty-five (64%) of carriers developed HCM. A median maximum LV wall thickness of 16.5 mm was described. The LV hypertrophy was asymmetric septal in 75% of cases, with LV outflow tract obstruction in 28%. The incidence of a composite of serious adverse cardiovascular events (sudden death, aborted sudden death, appropriate implantable cardiac defibrillator discharge, an embolic event, or admission for heart failure) was observed in five (20%) patients. Given the finding of the p.Arg652Lys variant in patients with HCM, but not in controls, with evident segregation in patients with HCM from eight families and the location in an active site of the protein, we can define this variant as likely pathogenic and associated with the development of HCM.