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.Instituto de Salud Carlos III [PI11/0699, PI14/0967, PI14/01477, RD012/0042/0029, RD012/0042/0049, RD012/0042/0066, RD12/0042/0069]; Spanish Ministry of Economy and Competitiveness [SAF2015-71863-REDT]; Plan Nacional de I+D+I; Plan Estatalde I+D+I, European Regional Development Fund; Health in Code SLS

Shortage of influential factors in the evolution of ischemic cardiogenic shock.

Objective: To evaluate the influence of age on long-term prognosis of patients with ischemic cardiogenic shock who were treated with early coronary revascularization. Methods: Prospective observational study of patients that were admitted to the Coronary Care Unit between 1 January 2006 and 1 January 2011 with diagnosis of ischemic cardiogenic shock who were treated by coronary revascularization in the first 72 hours. There was a follow up of the patients during hospitalization and after discharge, completing a follow-up of 5 years. Results: 97 patients diagnosed with ischemic cardiogenic shock were admitted , of whom 44 were patients aged 75 years or older. Males in group of patients ≥ 75 years was 56 %, significantly lower vs males in group of patients < 75 years (81 %, p: 0.009). No significant differences were found between both groups with regard to the history of hypertension, dyslipidemia, atherosclerotic disease or associated pathologies (chronic obstructive pulmonary disease, ACV or chronic renal failure). There were a greater number of diabetic patients (20.4 % vs 49 %, p: 0.004) and fewer smokers (4.5 % vs 39.6 %, p: 0.001) in group of patients ≥ 75 years. No differences were found in type or location of myocardial infarction, being similar incidence of left main coronary artery disease or multivessel disease. Percutaneous coronary revascularization was performed in all patients. No differences were found in TIMI pre- and post- revascularization or multivessel revascularization (20.4 % of patients ≥ 75 years vs 15 % of younger patients, p = 0.3). Use of glycoprotein IIb/IIIa inhibitors and intra-aortic balloon pump were similar between two groups. There was no difference in mortality during hospitalization according to the sex of patients, but there was a clear influence in prognosis of LVEF. The patients who died during follow-up, 73.8 % had a LVEF <35 %, p 0.02). Performing an analysis of survival by age groups stratified by LVEF, again it shows that regardless of LVEF, patients aged ≥ 75 years have lower survival compared to younger patients. Conclusions: Only age ≥ 75 years , LVEF <35 % and previous atherosclerotic disease were independent variables associated with mortality during follow-u