Pilar Molina

Deregulated hepatic microRNAs underlie the association between non-alcoholic fatty liver disease and coronary artery disease

Non‐alcoholic fatty liver disease (NAFLD) appears to be a new risk factor for the development of coronary artery disease (CAD). Members of a class of non‐coding RNAs, termed microRNAs (miRNAs), have been identified as post‐transcriptional regulators of cholesterol homoeostasis and can contribute to the development of NAFLD. The aims of this study were to (i) to assess the relationship between NAFLD and sudden cardiac death (SCD) from severe CAD in forensic autopsies and (ii) to quantify several hepatic miRNAs previously associated with lipid metabolism and NAFLD to correlate their expression with the presence of NAFLD, CAD, obesity parameters and postmortem lipid profile.

Phenotypic Patterns of Cardiomyopathy Caused by Mutations in the Desmin Gene. A Clinical and Genetic Study in Two Inherited Heart Disease Units

Desminopathies are a largely autosomal dominant group of rare diseases caused by mutations in the desmin gene. Because desmin is the main component of intermediate filaments in cardiac, skeletal, and smooth muscle and of Purkinje fibers, these conditions are characterized by skeletal myopathy and cardiomyopathy (mainly restrictive) with arrhythmias or conduction disorders. The aim of our present study was to analyze the genotype and phenotype of patients with desmin mutation-related cardiomyopathy. Because published series normally include few patients, any further contributions will boost our understanding of this disease. In 2 centers with 819 studied families, we analyzed all individuals found to have a desmin mutation after a phenotypeguided genetic study (restrictive cardiomyopathy/dilated cardiomyopathy with a restrictive pattern, families with high rates of pacemaker implants, skeletal myopathy, and/or creatine kinase elevation). Gene sequencing was performed using Sanger or nextgeneration sequencing. A pathogenic mutation was defined as any mutation involving an amino acid change from the reference sequence that met 3 criteria: it segregated with affected members of the family, it was not present in 200 chromosomes of healthy unrelated individuals, and the affected residue was conserved among species and desmin isoforms. We studied 20 patients from 4 families, identifying 3 pathogenic mutations: Ile367Phe (2 families, Sanger), Pro419Ser (Sanger), and Arg415Gln (next-generation sequencing). Of these, 16 had desminopathy (including 2 obligate carriers who died of cardiomyopathy, without genetic confirmation) and 4 were young unaffected carriers (Table). The mean age at diagnosis was 35 15 years. Two Rev Esp Cardiol. 2015;68(11):1027–1038

The Cerebellum of Patients with Steatohepatitis Shows Lymphocyte Infiltration, Microglial Activation and Loss of Purkinje and Granular Neurons

Peripheral inflammation contributes to minimal hepatic encephalopathy in chronic liver diseases, which could be mediated by neuroinflammation. Neuroinflammation in cerebellum of patients with chronic liver diseases has not been studied in detail. Our aim was to analyze in cerebellum of patients with different grades of liver disease, from mild steatohepatitis to cirrhosis and hepatic encephalopathy: (a) neuronal density in Purkinje and granular layers; (b) microglial activation; (c) astrocyte activation; (d) peripheral lymphocytes infiltration; (e) subtypes of lymphocytes infiltrated. Steatohepatitis was classified as SH1, SH2 and SH3. Patients with SH1 show Th17 and Tfh lymphocytes infiltration in the meninges, microglia activation in the molecular layer and loss of 16 ± 4% of Purkinje and 19 ± 2% of granular neurons. White matter remains unaffected. With the progression of liver disease to worse stages (SH2, SH3, cirrhosis) activation of microglia and astrocytes extends to white matter, Bergman glia is damaged in the molecular layer and there is a further loss of Purkinje neurons. The results reported show that neuroinflammation in cerebellum occurs at early stages of liver disease, even before reaching cirrhosis. Neuroinflammation occurs earlier in the molecular layer than in white matter, and is associated with infiltration of peripheral Th17 and Tfh lymphocytes.

Thickness and an Altered miRNA Expression in the Epicardial Adipose Tissue Is Associated With Coronary Heart Disease in Sudden Death Victims

INTRODUCTION AND OBJECTIVES An increased epicardial adipose tissue (EAT) thickness has become a new risk factor for coronary heart disease (CHD). We aimed to study the role of EAT dysfunction as a CHD marker by focusing on its thickness and microRNA (miRNA) expression profile, and the potential factors possibly influencing them. METHODS One hundred and fifty-five CHD sudden cardiac death victims and 84 non-CHD-sudden death controls were prospectively enrolled at autopsy. A representative subset underwent EAT thickness measurements and EAT miRNA expression profiling. RESULTS Epicardial adipose tissue thickness was increased and allowed an accurate diagnosis of patient status (among other measurements, EAT score area under the curve 0.718, P < .001). Epicardial adipose tissue from patients showed 14 up- and 14 down-regulated miRNAs and miR-34a-3p, -34a-5p, -124-3p, -125a-5p, 628-5p, -1303 and -4286 were validated by quantitative real-time polymerase chain reaction. Patients exhibited higher EAT levels of miR-34a-3p and -34a-5p than controls (with a positive trend considering EAT from coronaries without stenosis, with stable stenosis and complicated plaques) and correlated with age only in controls. The mild positive correlation between liver and EAT miR-34a-5p levels in patients (r = 0.295, P = .020) dramatically increased in EAT from complicated plaques (r = 0.799, P = .017). Similar correlations were observed for high-sensitivity-C-reactive protein levels and miR-34a-5p levels both in EAT and liver extracts. CONCLUSIONS Increased age-independent levels of miR-34a-3p and -34a-5p characterize the EAT miRNA expression profile of CHD regardless of EAT thickness, anthropometric parameters, and the presence of underlying atherosclerotic plaques.