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.

Caso clínico 1: manejo del paciente con cardiopatía isquémica y comorbilidades relacionadas / Case report I: treatment of a patient with ischemic heart disease and associated comorbidities

Las comorbilidades son frecuentes en los pacientes con cardiopatía isquémica crónica. Se presenta el caso de un varón de 70 años, en seguimiento por cardiopatía isquémica crónica estable, con una plétora de factores de riesgo vascular (incluida la diabetes mellitus) y múltiples comorbilidades. Tras una historia inicial de eventos agudos y revascularización percutánea, este artículo se centra en el seguimiento en los últimos 6 años en tratamiento médico. La respuesta terapéutica ha sido excelente, si bien se describen complicaciones evolutivas no inhabituales en este tipo de pacientes. Se discute el impacto de las comorbilidades tanto en el pronóstico como en los aspectos terapéuticos (AU)

Patients with chronic ischemic heart disease frequently have comorbid conditions. We present the case of a 70-year-old man with a range of vascular risk factors, including diabetes, and numerous associated comorbidities who was being followed up for chronic stable ischemic heart disease. His early history included a series of acute episodes and percutaneous revascularization. This report focuses on follow-up during the last 6 years of medical treatment. Although the response to treatment was excellent, a number of complications developed that are not unusual for this type of patient. The effect of associated comorbidities on both prognosis and therapy are discussed (AU)

Impacto pronóstico del abordaje intervencionista en el paciente muy anciano con síndrome coronario agudo sin elevación del segmento ST / Prognostic impact of interventional approach in non-ST segment elevation acute coronary syndrome in very elderly patients

Introducción y objetivos. En el síndrome coronario agudo sin elevación del segmento ST de riesgo intermedio o alto, las guías de actuación clínica recomiendan la realización de coronariografía con intención de revascularizar. Sin embargo, para los pacientes muy ancianos la evidencia que avala esta recomendación es muy escasa. Métodos. Analizamos retrospectivamente a todos los pacientes con síndrome coronario agudo sin elevación del segmento ST y edad ≥ 85 años ingresados en un único centro entre 2004 y 2009. Mediante propensity score, emparejamos 1:1 a los pacientes con abordaje intervencionista con aquellos en que se decidió manejo conservador. Se comparó la supervivencia y la supervivencia libre de eventos isquémicos. Resultados. Se incluyó a 228 pacientes consecutivos (media de edad 88 [intervalo, 85-101] años). Se decidió abordaje intervencionista en 100 pacientes (128 con manejo conservador). Los enviados a abordaje intervencionista eran más jóvenes y más frecuentemente varones y tenían menos comorbilidad, menos demencia y menos frecuentemente elevación de troponina. Se emparejó a 63 pacientes del grupo de abordaje intervencionista con 63 del grupo de manejo conservador mediante propensity score. En el seguimiento a 3 años de los pacientes emparejados, el grupo de abordaje intervencionista presentó mayor supervivencia (log rank test=4,24; p=0,039) y mayor supervivencia libre de eventos isquémicos (log rank test=8,63; p=0,003). En la población total, ajustando por quintiles de propensity score, el abordaje intervencionista se relacionó con mayor supervivencia (hazard ratio=0,52; intervalo de confianza del 95%, 0,32-0,85) y mayor supervivencia libre de eventos isquémicos (hazard ratio=0,48; intervalo de confianza del 95%, 0,32-0,74). Conclusiones. Casi todos los pacientes muy ancianos ingresados por síndrome coronario agudo sin elevación del segmento ST están en riesgo intermedio-alto. En estos pacientes, el abordaje intervencionista se relaciona con mayor supervivencia y mayor supervivencia libre de eventos isquémicos (AU)

Introduction and objectives. In moderate or high risk non-ST segment elevation acute coronary syndrome, clinical practice guidelines recommend a coronary angiography with intent to revascularize. However, evidence to support this recommendation in very elderly patients is poor. Methods. All patients over 85 years old admitted to our hospital between 2004 and 2009 with a diagnosis of non-ST segment elevation acute coronary syndrome were retrospectively included. Using a propensity score, patients undergoing the interventional approach and those undergoing conservative management were matched and compared for survival and survival without ischemic events. Results. We included 228 consecutive patients with a mean age of 88 years (range: 85 to 101). Those in the interventional approach group (n=100) were younger, with a higher proportion of males and less comorbidity, less cognitive impairment and lower troponin I levels compared with patients in the conservative management group (n=128). We matched 63 patients from the interventional approach group and 63 from the conservative management group using propensity score. In the matched patients, the interventional approach group exhibited better survival (log rank 4.24; P=.039) and better survival free of ischemic events (log rank 8.63; P=.003) at the 3-year follow-up. In the whole population, adjusted for propensity score quintiles, the interventional approach group had lower mortality (hazard ratio 0.52; 95% confidence interval: 0.32-0.85) and a better survival free of ischemic events (hazard ratio 0.48; 95% confidence interval: 0.32-0.74). Conclusions. Nearly all the very elderly patients admitted with non-ST segment elevation acute coronary syndrome were of moderate or high risk. In these patients, the interventional approach was associated with overall better survival and better survival free of ischemic events (AU)

[Prognostic impact of interventional approach in non-ST segment elevation acute coronary syndrome in very elderly patients]. / Impacto pronóstico del abordaje intervencionista en el paciente muy anciano con síndrome coronario agudo sin elevación del segmento ST.

INTRODUCTION AND OBJECTIVES: In moderate or high risk non-ST segment elevation acute coronary syndrome, clinical practice guidelines recommend a coronary angiography with intent to revascularize. However, evidence to support this recommendation in very elderly patients is poor. METHODS: All patients over 85 years old admitted to our hospital between 2004 and 2009 with a diagnosis of non-ST segment elevation acute coronary syndrome were retrospectively included. Using a propensity score, patients undergoing the interventional approach and those undergoing conservative management were matched and compared for survival and survival without ischemic events. RESULTS: We included 228 consecutive patients with a mean age of 88 years (range: 85 to 101). Those in the interventional approach group (n=100) were younger, with a higher proportion of males and less comorbidity, less cognitive impairment and lower troponin I levels compared with patients in the conservative management group (n=128). We matched 63 patients from the interventional approach group and 63 from the conservative management group using propensity score. In the matched patients, the interventional approach group exhibited better survival (log rank 4.24; P=.039) and better survival free of ischemic events (log rank 8.63; P=.003) at the 3-year follow-up. In the whole population, adjusted for propensity score quintiles, the interventional approach group had lower mortality (hazard ratio 0.52; 95% confidence interval: 0.32-0.85) and a better survival free of ischemic events (hazard ratio 0.48; 95% confidence interval: 0.32-0.74). CONCLUSIONS: Nearly all the very elderly patients admitted with non-ST segment elevation acute coronary syndrome were of moderate or high risk. In these patients, the interventional approach was associated with overall better survival and better survival free of ischemic events.