Sex-related differences of fatty acid-binding protein 4 and leptin levels in atrial fibrillation

Aims: Adiposity plays a key role in the pathogenesis of atrial fibrillation (AF). Our aim was to study the sex differences in adipokines levels according to AF burden. Methods and results: Two independent cohorts of patients were studied: (i) consecutive patients with AF undergoing catheter ablation (n = 217) and (ii) a control group (n = 105). (i) Adipokines, oxidative stress, indirect autonomic markers, and leucocytes mRNA levels were analysed; (ii) correlation between biomarkers was explored with heatmaps and Kendall correlation coefficients; and (iii) logistic regression and random forest model were used to determine predictors of AF recurrence after ablation. Our results showed that: (i) fatty acid-binding protein 4 (FABP4) and leptin levels were higher in women than in men in both cohorts (P < 0.01). In women, FABP4 levels were higher on AF cohort (20 ± 14 control, 29 ± 18 paroxysmal AF and 31 ± 17 ng/mL persistent AF; P < 0.01). In men, leptin levels were lower on AF cohort (22 ± 15 control, 13 ± 16 paroxysmal AF and 13 ± 11 ng/mL persistent AF; P < 0.01). (ii) In female with paroxysmal AF, there was a lower acetylcholinesterase and higher carbonic anhydrase levels with respect to men (P < 0.05). (iii) Adipokines have an important role on discriminate AF recurrence after ablation. In persistent AF, FABP4 was the best predictor of recurrence after ablation (1.067, 95% confidence interval 1-1.14; P = 0.046). Conclusion: The major finding of the present study is the sex-based differences of FABP4 and leptin levels according to AF burden. These adipokines are associated with oxidative stress, inflammatory and autonomic indirect markers, indicating that they may play a role in AF perpetuation.This study was supported by projects (PI16/01282 and PI18/01584) integrated in the Plan Estatal de I+D+I 2016–2019 and cofounded by ISCIII-Subdirección General de Evaluación y Fomento de la Investigación del Fondo Europeo de Desarrollo Regional (FEDER). J.N.L.-C. and M.R.-M. were a recipient of a Sociedade Galega de Cardioloxía (SOGACAR) research grant. D.d.G.-C. was a recipient of a Juan de la Cierva-Incorporación grant from the Ministry of Science Innovation and Universities (IJCI-2016-29393). CIBER Cardiovascular (CB16/11/00403 to V.Ll.-C. and D.d.G.-C.) is a project from Carlos III Health Institute.Peer reviewe

Biophysical and lipidomic biomarkers of cardiac remodeling post-myocardial infarction in humans

Few studies have analyzed the potential of biophysical parameters as markers of cardiac remodeling post-myocardial infarction (MI), particularly in human hearts. Fourier transform infrared spectroscopy (FTIR) illustrates the overall changes in proteins, nucleic acids and lipids in a single signature. The aim of this work was to define the FTIR and lipidomic pattern for human left ventricular remodeling post-MI. A total of nine explanted hearts from ischemic cardiomyopathy patients were collected. Samples from the right ventricle (RV), left ventricle (LV) and infarcted left ventricle (LV INF) were subjected to biophysical (FTIR and differential scanning calorimetry, DSC) and lipidomic (liquid chromatography–high-resolution mass spectrometry, LC–HRMS) studies. FTIR evidenced deep alterations in the myofibers, extracellular matrix proteins, and the hydric response of the LV INF compared to the RV or LV from the same subject. The lipid and esterified lipid FTIR bands were enhanced in LV INF, and both lipid indicators were tightly and positively correlated with remodeling markers such as collagen, lactate, polysaccharides, and glycogen in these samples. Lipidomic analysis revealed an increase in several species of sphingomyelin (SM), hexosylceramide (HexCer), and cholesteryl esters combined with a decrease in glycerophospholipids in the infarcted tissue. Our results validate FTIR indicators and several species of lipids as useful markers of left ventricular remodeling post-MI in humans

Identification of new biophysical markers for pathological ventricular remodelling in tachycardia-induced dilated cardiomyopathy

Our aim was to identify biophysical biomarkers of ventricular remodelling in tachycardia‐induced dilated cardiomyopathy (DCM). Our study includes healthy controls (N = 7) and DCM pigs (N = 10). Molecular analysis showed global myocardial metabolic abnormalities, some of them related to myocardial hibernation in failing hearts, supporting the translationality of our model to study cardiac remodelling in dilated cardiomyopathy. Histological analysis showed unorganized and agglomerated collagen accumulation in the dilated ventricles and a higher percentage of fibrosis in the right (RV) than in the left (LV) ventricle (P = .016). The Fourier Transform Infrared Spectroscopy (FTIR) 1st and 2nd indicators, which are markers of the myofiber/collagen ratio, were reduced in dilated hearts, with the 1st indicator reduced by 45% and 53% in the RV and LV, respectively, and the 2nd indicator reduced by 25% in the RV. The 3rd FTIR indicator, a marker of the carbohydrate/lipid ratio, was up‐regulated in the right and left dilated ventricles but to a greater extent in the RV (2.60‐fold vs 1.61‐fold, P = .049). Differential scanning calorimetry (DSC) showed a depression of the freezable water melting point in DCM ventricles – indicating structural changes in the tissue architecture – and lower protein stability. Our results suggest that the 1st, 2nd and 3rd FTIR indicators are useful markers of cardiac remodelling. Moreover, the 2nd and 3rd FITR indicators, which are altered to a greater extent in the right ventricle, are associated with greater fibrosis

El microRNA circulante miR-130a-3p es un potencial biomarcador de aterosclerosis coronaria: una aproximación traslacional

Trabajo presentado en el 29º Congreso Nacional de la Sociedad Española de Arteriosclerosis (SEA), celebrado del 18 al 20 de mayo de 2017 en GranadaPeer reviewe

Diagnostic value of circulating miRNAs: association with the presence and extension of coronary atherosclerosis in patients with suspected ischemic heart disease

[Aim] Circulating miRNAs have been proposed as biomarkers of ischemic heart disease (IHD). Nonetheless, most studies are based on small case-control approaches, with inadequate consideration of comorbidities and medications, and no comparison with established biomarkers. We have previously demonstrated the potential of miR-24-3p and miR-130a-3p as indicators of coronary atherosclerosis. Here, we determined the diagnostic value of both miRNAs in a real-world cohort of patients with suspected IHD.[Methods] Plasma samples were collected from 105 consecutive patients referred for computed tomography angiography (CCTA) for evaluation of suspected IHD. Presence and extension of coronary atherosclerosis were evaluated as previously described. Circulating miRNAs were analyzed using RT-qPCR.[Results] Circulating levels of miR-130a-3p were significantly reduced in patients with significant coronary stenosis (narrowing > 50 % of the reference luminal diameter) compared to patients without stenosis or non-significant stenosis (narrowing 1-49 % of the reference luminal diameter) (P 5] (P < 0.050). After adjustment for potential confounders (risk factors and medications), circulating miR-130a-3p levels were inversely associated with the extension of coronary atherosclerosis (P < 0.050 for all regression models). No association was observed with miR-24-3p or us-CRP. The addition of miR-130a-3p to a model of coronary atherosclerosis resulted in a higher area under the ROC curve.[Conclusions] Circulating miR-130a-3p is a potential biomarker of coronary atherosclerosis in patients with clinically suspected of IHD.Peer reviewe

Soluble LRP1 is an independent biomarker of epicardial fat volume in patients with type 1 diabetes mellitus

Epicardial adipose tissue (EAT) is a metabolically active tissue intimately associated with metabolic syndrome and cardiovascular disease. Quantification of EAT volume is an interesting clinical tool for the evaluation of cardiometabolic disease. Nevertheless, current methodology presents serious disadvantages. The soluble form of the receptor LRP1 (sLRP1) is a non-invasive biomarker of EAT in general population. Here, we analysed the potential of circulating sLRP1 as biomarker of EAT volume in patients with type 1 diabetes mellitus (T1DM). The study included a well-characterized cohort of T1DM patients without clinical cardiovascular disease (N = 73). EAT volume was assessed by a multidetector computed tomography (MDCT). sLRP1 and panel of inflammatory and endocrine mediators were measured using commercially available ELISA. EAT volume showed a direct association with circulating sLRP1 (β = 0.398, P = 0.001) in univariate linear regression analysis. This association was higher than that observed for other potential inflammatory and endocrine biomarkers. Using multivariate linear regression analyses, we demonstrated that the association between EAT volume and circulating sLRP1 was independent of potential confounding factors, including age, sex, body mass index, CRP, HbA1c and LDL-C (P < 0.050 for all multivariate linear regression models). In conclusion, sLRP1 is an independent biomarker of EAT in T1DM patients.Tis work was supported by FIS PI14/01729 and FIS PI13/00364 from the Instituto Salud Carlos III, co-fnanced by the European Fund for Regional Development (E.F.R.D), Fundació Marató TV3 (201521 10) and Ayudas Sociedad Española de Diabetes (SED) de Investigación Básica y Clínica en Diabetes 2011. CIBER Cardiovascular (CB16/11/00403) and CIBERDEM (CB07/08/0016) are Instituto de Salud Carlos III Projects. DdG-C was a recipient of a Sara Borrell grant from the Instituto de Salud Carlos III (CD14/00109). AR-U, MP-C and JLS-Q are members of the Quality Research Group 2014-SGR-0246 and VLL-C, DdG-C are members of the Quality Research Group 2014-SGR-00170 from Generalitat de Catalunya.Peer reviewe

Circulating microRNAs as biomarkers of stable CAD

Objectives: To explore the diagnostic performance of circulating microRNAs (miRNAs) as biomarkers in patients with suspected stable coronary artery disease (CAD). Methods: Plasma samples were collected from 237 consecutive patients referred for coronary computed tomography angiography (CCTA). Presence, extension and severity of coronary stenosis were evaluated using the indexes: presence of diameter stenosis ≥ 50%, segment involvement score (SIS), segment stenosis score (SSS) and 3-vessel plaque score. A panel of 10 miRNAs previously associated with CAD was analysed using RT-qPCR. Multivariate analyses were used to analyse the associations between biomarkers and indexes. Discrimination was evaluated using the area under the ROC curve (AUC). Decision trees were generated using chi-squared Automatic Interaction Detector (CHAID) prediction models. Results: After comprehensive adjustment including cardiovascular risk factors, medication use, confounding factors and protein-based biomarkers (hs-TnT and hs-CRP), several circulating miRNAs were inversely associated with coronary atherosclerosis extension (SIS and 3-vessel plaque score) and severity (SSS). In the whole population, circulating miRNAs showed a poor discrimination value for all indexes (AUC = 0.539–0.644) and did not increase the discrimination capacity of a clinical model of coronary stenosis presence, extension and severity based on conventional cardiovascular risk factors. Conversely, the inclusion of circulating miRNAs in decision trees produces models that improve the classification of cases and controls in specific patient subgroups. Conclusions: This study identifies a group of circulating miRNAs that failed to improve the discrimination capacity of cardiovascular risk factors but that has the potential to define specific subpopulations of patients with suspected stable CAD.DdG‐C was a recipient of a Juan de la Cierva‐Incorporación grant from the Ministerio de Economía y Competitividad (IJCI‐2016‐29393). This work was funded by FIS PI14/01729 & FIS PI18/01584 grant from Instituto de Salud Carlos III, co‐financed by the European Fund for Regional Development (E.F.R.D.) and by Project 201521‐10 from Fundació MARATÓ TV3. CIBER Cardiovascular (CB16/11/00403 to DdG‐C and VL‐C) is a project from Instituto de Salud Carlos III

Plasma circular RNA hsa_circ_0001445 and coronary artery disease: Performance as a biomarker

The role of circular RNAs (circRNAs) as biomarkers remains poorly characterized. Here, we investigated the performance of the circRNA hsa_circ_0001445 as a biomarker of coronary artery disease (CAD) in a real‐world clinical practice setting. Plasma hsa_circ_0001445 was measured in a study population of 200 consecutive patients with suspected stable CAD who had undergone coronary computed tomographic angiography (CTA). Multivariable logistic models were constructed combining conventional risk factors with established biomarkers and hsa_circ_0001445. Model robustness was internally validated by the bootstrap technique. Biomarker accuracy was evaluated using the C‐index. The integrated discrimination improvement (IDI) and net reclassification improvement (NRI) were also calculated. Risk groups were developed via classification tree models. The stability of plasma hsa_circ_0001445 was evaluated under different clinical conditions. hsa_circ_0001445 levels were associated with higher coronary atherosclerosis extent and severity with a 2‐fold increase across tertiles (28.4%‐50.0%). Levels of hsa_circ_0001445 were proportional to coronary atherosclerotic burden, even after comprehensive adjustment for cardiovascular risk factors, medications, and established biomarkers (fully adjusted OR = 0.432 for hsa_circ_0001445 as a continuous variable and fully adjusted OR = 0.277 for hsa_circ_0001445 as a binary variable). The classification of patients was improved with the incorporation of hsa_circ_0001445 into a base clinical model (CM) composed of conventional cardiovascular risk factors, showing an IDI of 0.047 and NRI of 0.482 for hsa_circ_0001445 as a continuous variable and an IDI of 0.056 and NRI of 0.373 for hsa_circ_0001445 as a binary variable. A trend toward higher discrimination capacity was also observed (C‐indexCM = 0.833, C‐indexCM+continuous hsa_circ_0001445 = 0.856 and C‐indexCM+binary hsa_circ_0001445 = 0.855). Detailed analysis of stability showed that hsa_circ_0001445 was present in plasma in a remarkably stable form. In vitro, hsa_circ_0001445 was downregulated in extracellular vesicles secreted by human coronary smooth muscle cells upon exposure to atherogenic conditions. In patients with suspected stable CAD referred for coronary CTA, plasma hsa_circ_0001445 improves the identification of coronary artery atherosclerosis.N

Plasma microRNA profiling reveals novel biomarkers of epicardial adipose tissue: A multidetector computed tomography study

Epicardial adipose tissue (EAT) constitutes a novel parameter for cardiometabolic risk assessment and a target for therapy. Here, we evaluated for the first time the plasma microRNA (miRNA) profile as a source of biomarkers for epicardial fat volume (EFV). miRNAs were profiled in plasma samples from 180 patients whose EFV was quantified using multidetector computed tomography. In the screening study, 54 deregulated miRNAs were identified in patients with high EFV levels (highest tertile) compared with matched patients with low EFV levels (lowest tertile). After filtering, 12 miRNAs were selected for subsequent validation. In the validation study, miR-15b-3p, miR-22-3p, miR-148a-3p miR-148b-3p and miR-590-5p were directly associated with EFV, even after adjustment for confounding factors (p value < 0.05 for all models). The addition of miRNA combinations to a model based on clinical variables improved the discrimination (area under the receiver-operating-characteristic curve (AUC) from 0.721 to 0.787). miRNAs correctly reclassified a significant proportion of patients with an integrated discrimination improvement (IDI) index of 0.101 and a net reclassification improvement (NRI) index of 0.650. Decision tree models used miRNA combinations to improve their classification accuracy. These results were reproduced using two proposed clinical cutoffs for epicardial fat burden. Internal validation corroborated the robustness of the models. In conclusion, plasma miRNAs constitute novel biomarkers of epicardial fat burden.D.d.G.-C. was a recipient of a Juan de la Cierva-Incorporación grant from the Ministerio de Economía y Competitividad (IJCI-2016-29393). O.B. (Project 201521-10) and N.P. (Project 201716) were recipients of Fundació Marató TV3. S.B. and J.L.S.-Q. (2017-SGR-1149) and D.d.G.-C., L.N., À.V., D.V., R.L. and V.L.-C. (2017-SGR-946) are members of Quality Research Groups from Generalitat de Catalunya. S.B., J.L.S.-Q., N.P., V.L.-C. and D.d.G.-C. are members of the Group of Vascular Biology of the Spanish Society of Atherosclerosis (SEA). This work was funded by FIS PI14/01729 (to V.L.-C.), FIS PI16/00471 (to J.L.S.-Q.) & FIS PI18/01584 (to V.L.-C.) grants from Instituto Salud Carlos III, co-financed by the European Fund for Regional Development (EFRD) and by Project 201521-10 from Fundació MARATÓ TV3 (to V.L.-C.). CIBERCV (CB16/11/00403 to V.L.-C. and D.d.G.-C. and CB16/11/00276 to A.F.-G.) and CIBERDEM (CB07/08/0016 to J.L.S.-Q.) are projects from Instituto de Salud Carlos III.Peer reviewe