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

Carotid ultrasound is useful for the cardiovascular risk stratification in patients with hidradenitis suppurativa

INTRODUCTION: Hidradenitis suppurativa (HS) is a chronic inflammatory cutaneous disease which has been associated with an increased risk of adverse cardiovascular (CV) outcomes. Adequate stratification of the CV risk is an issue of major importance in patients with HS. To analyze the usefulness of carotid ultrasound (US) assessment for the CV disease risk stratification compared with a traditional score, the Framingham risk score (FRS), in a series of patients with HS. METHODS: Cross-sectional study of 60 patients with HS without history of CV events, diabetes mellitus or chronic kidney disease. Information on CV risk factors was collected and the FRS was calculated. Thus, the patients were classified into low, intermediate and high-CV disease risk categories based on FRS. Carotid US was performed in all participants, and the presence of atherosclerotic plaques was considered as a marker of high CV risk. RESULTS: HS patients had a mean age of 45.1±10.2 years, and 55% were female. The median FRS was 5.7 (IQR: 3.1-14.7). Twenty-four (40%) of the patients were classified into the low risk group, 28 (46.7%) in the intermediate risk group, and 8 (13.3%) into the FRS-high risk category. Noteworthy, carotid US revealed that about one-third of the patients (17/52; 32.6%) in the FRS-based low and intermediate risk categories had carotid plaques, and, therefore, they were reclassified into a high-risk category. CONCLUSION: CV risk in HS patients may be underestimated by using the FRS. Carotid US may be useful to improve the CV risk stratification of patients with HS.This study was funded through an unrestricted grant provided by AbbVie to MGL. AbbVie has not played any role in study design, data collection and analysis, decision to publish or preparation of the manuscript

Protective Role of the Interleukin 33 rs3939286 Gene Polymorphism in the Development of Subclinical Atherosclerosis in Rheumatoid Arthritis Patients

OBJECTIVES: To determine whether the interleukin-33 (IL-33)-interleukin-1 receptor like 1 (IL-1RL1) signaling pathway is implicated in the risk of subclinical atherosclerosis in patients with rheumatoid arthritis (RA). METHODS: A total of 576 Spanish RA patients from Northern Spain were genotyped for 6 well-known IL33-IL1RL1 polymorphisms (IL33 rs3939286, IL33 rs7025417, IL33 rs7044343, IL1RL1 rs2058660, IL1RL1 rs2310173 and IL1RL1 rs13015714) by TaqMan genotyping assay. The presence of subclinical atherosclerosis was determined by the assessment of carotid intima-media thickness (cIMT) by carotid ultrasound (US). RESULTS: RA patients carrying the TT genotype of the IL33 rs3939286 polymorphism had lower cIMT values than those homozygous for the CC genotype (mean ± standard deviation (SD): 0.71 ± 0.14 mm versus 0.76 ± 0.16 mm, respectively) while patients carrying the CT genotype had intermediate cIMT values (mean ± SD: 0.73 ± 0.17 mm). Moreover, RA patients carrying the mutant allele T of the IL33 rs3939286 polymorphism exhibited significantly lower cIMT values than those carrying the wild allele C (mean ± SD: 0.72 ± 0.16 mm versus 0.75 ± 0.18 mm respectively; p = 0.04). The association of both genotype and allele frequencies of IL33 rs3939286 and cIMT levels remained statistically significant after adjustment for sex, age at the time of US study, follow-up and center (p = 0.006 and p = 0.0023, respectively), evidencing that the potential effect conferred by IL33 rs3939286 may be independent of confounder factors. No association with other IL33-IL1RL1 genetic variants was observed. CONCLUSIONS: In conclusion, our results may suggest a potential protective effect of the IL33 rs3939286 allele T in the risk of subclinical atherosclerosis in patients with RA

Detection of high cardiovascular risk patients with ankylosing spondylitis based on the assessment of abdominal aortic calcium as compared to carotid ultrasound

ABSTRACT: Background: This study aimed to determine whether, besides carotid ultrasound (US), a lateral lumbar spine radiography may also help identify ankylosing spondylitis (AS) patients at high risk of cardiovascular (CV) disease. Methods: A set of 125 AS patients older than 35 years without a history of CV events, diabetes mellitus, or chronic kidney disease was recruited. Carotid US and lateral lumbar spine radiography were performed in all of them. The CV risk was calculated according to the total cholesterol systematic coronary risk evaluation (TC- CORE) algorithm. Presence of carotid plaques was defined following the Mannheim Carotid Intima-media Thickness and Plaque Consensus. Abdominal aortic calcium (AAC) in a plain radiography was defined as calcific densities visible in an area parallel and anterior to the lumbar spine. Results: Carotid US showed higher sensitivity than lateral lumbar spine radiography to detect high CV risk in the 54 patients with moderate TC-SCORE (61% versus 38.9%). Using carotid plaques as the gold standard test, a predictive model that included a TC-SCORE >= 5% or the presence of AAC in the lateral lumbar spine radiography in patients with both moderate and low CV risk (< 5%) according to the TC-SCORE yielded a sensitivity of 50.9% with a specificity of 95.7% to identify high/very high CV-risk AS patients. A positive correlation between AAC and carotid plaques was observed (r2 = 0.49, p < 0.001). Conclusions: A lateral lumbar spine radiography is a useful tool to identify patients with AS at high risk of CV disease

A 3-Biomarker 2-Point-Based Risk Stratification Strategy in Acute Heart Failure

Altres ajuts: ISCIII/RD06-0003-0000Altres ajuts: ISCIII/RD12/0042/0002Introduction and Objectives: Most multi-biomarker strategies in acute heart failure (HF) have only measured biomarkers in a single-point time. This study aimed to evaluate the prognostic yielding of NT-proBNP, hsTnT, Cys-C, hs-CRP, GDF15, and GAL-3 in HF patients both at admission and discharge. Methods: We included 830 patients enrolled consecutively in a prospective multicenter registry. Primary outcome was 12-month mortality. The gain in the C-index, calibration, net reclassification improvement (NRI), and integrated discrimination improvement (IDI) was calculated after adding each individual biomarker value or their combination on top of the best clinical model developed in this study (C-index 0.752, 0.715-0.789) and also on top of 4 currently used scores (MAGGIC, GWTG-HF, Redin-SCORE, BCN-bioHF). Results: After 12-month, death occurred in 154 (18.5%) cases. On top of the best clinical model, the addition of NT-proBNP, hs-CRP, and GDF-15 above the respective cutoff point at admission and discharge and their delta during compensation improved the C-index to 0.782 (0.747-0.817), IDI by 5% (p < 0.001), and NRI by 57% (p < 0.001) for 12-month mortality. A 4-risk grading categories for 12-month mortality (11.7, 19.2, 26.7, and 39.4%, respectively; p < 0.001) were obtained using combination of these biomarkers. Conclusion: A model including NT-proBNP, hs-CRP, and GDF-15 measured at admission and discharge afforded a mortality risk prediction greater than our clinical model and also better than the most currently used scores. In addition, this 3-biomarker panel defined 4-risk categories for 12-month mortality

Renal Function Impact in the Prognostic Value of Galectin-3 in Acute Heart Failure

[Abstract] Introduction: Galectin-3 (Gal-3) is an inflammatory marker associated with the development and progression of heart failure (HF). A close relationship between Gal-3 levels and renal function has been observed, but data on their interaction in patients with acute HF (AHF) are scarce. We aim to assess the prognostic relationship between renal function and Gal-3 during an AHF episode. Materials and methods: This is an observational, prospective, multicenter registry of patients hospitalized for AHF. Patients were divided into two groups according to estimated glomerular filtration rate (eGFR): preserved renal function (eGFR ≥ 60 mL/min/1.73 m2) and renal dysfunction (eGFR <60 mL/min/1.73 m2). Cox regression analysis was performed to evaluate the association between Gal-3 and 12-month mortality. Results: We included 1,201 patients in whom Gal-3 values were assessed at admission. The median value of Gal-3 in our population was 23.2 ng/mL (17.3-32.1). Gal-3 showed a negative correlation with eGFR (rho = -0.51; p < 0.001). Gal-3 concentrations were associated with higher mortality risk in the multivariate analysis after adjusting for eGFR and other prognostic variables [HR = 1.010 (95%-CI: 1.001-1.018); p = 0.038]. However, the prognostic value of Gal-3 was restricted to patients with renal dysfunction [HR = 1.010 (95%-CI: 1.001-1.019), p = 0.033] with optimal cutoff point of 31.5 ng/mL, with no prognostic value in the group with preserved renal function [HR = 0.990 (95%-CI: 0.964-1.017); p = 0.472]. Conclusions: Gal-3 is a marker of high mortality in patients with acute HF and renal dysfunction. Renal function influences the prognostic value of Gal-3 levels, which should be adjusted by eGFR for a correct interpretation.Grant No. RD06-0003-0000 Grant No. RD12/0042/000

SMAD3 rs17228212 Gene Polymorphism Is Associated with Reduced Risk to Cerebrovascular Accidents and Subclinical Atherosclerosis in Anti-CCP Negative Spanish Rheumatoid Arthritis Patients

Rheumatoid arthritis (RA) is a complex polygenic inflammatory disease associated with accelerated atherosclerosis and increased risk of cardiovascular (CV) disease. Previous genome-wide association studies have described SMAD3 rs17228212 polymorphism as an important signal associated with CV events. The aim of the present study was to evaluate for the first time the relationship between this gene polymorphism and the susceptibility to CV manifestations and its potential association with the presence of subclinical atherosclerosis assessed by the evaluation of carotid intima-media thickness (cIMT) in patients with RA

Influence of elevated-CRP level-related polymorphisms in non-rheumatic Caucasians on the risk of subclinical atherosclerosis and cardiovascular disease in rheumatoid arthritis

Association between elevated C-reactive protein (CRP) serum levels and subclinical atherosclerosis and cardiovascular (CV) events was described in rheumatoid arthritis (RA). CRP, HNF1A, LEPR, GCKR, NLRP3, IL1F10, PPP1R3B, ASCL1, HNF4A and SALL1 exert an influence on elevated CRP serum levels in non-rheumatic Caucasians. Consequently, we evaluated the potential role of these genes in the development of CV events and subclinical atherosclerosis in RA patients. Three tag CRP polymorphisms and HNF1A, LEPR, GCKR, NLRP3, IL1F10, PPP1R3B, ASCL1, HNF4A and SALL1 were genotyped in 2,313 Spanish patients by TaqMan. Subclinical atherosclerosis was determined in 1,298 of them by carotid ultrasonography (by assessment of carotid intima-media thickness-cIMT-and presence/absence of carotid plaques). CRP serum levels at diagnosis and at the time of carotid ultrasonography were measured in 1,662 and 1,193 patients, respectively, by immunoturbidimetry. Interestingly, a relationship between CRP and CRP serum levels at diagnosis and at the time of the carotid ultrasonography was disclosed. However, no statistically significant differences were found when CRP, HNF1A, LEPR, GCKR, NLRP3, IL1F10, PPP1R3B, ASCL1, HNF4A and SALL1 were evaluated according to the presence/absence of CV events, carotid plaques and cIMT after adjustment. Our results do not confirm an association between these genes and CV disease in RA

Persistent Pulmonary Hypertension in Corrected Valvular Heart Disease: Hemodynamic Insights and Long-Term Survival.

Background The determinants and consequences of pulmonary hypertension after successfully corrected valvular heart disease remain poorly understood. We aim to clarify the hemodynamic bases and risk factors for mortality in patients with this condition. Methods and Results We analyzed long-term follow-up data of 222 patients with pulmonary hypertension and valvular heart disease successfully corrected at least 1 year before enrollment who had undergone comprehensive hemodynamic and imaging characterization as per the SIOVAC (Sildenafil for Improving Outcomes After Valvular Correction) clinical trial. Median (interquartile range) mean pulmonary pressure was 37 mm Hg (32-44 mm Hg) and pulmonary artery wedge pressure was 23 mm Hg (18-26 mm Hg). Most patients were classified either as having combined precapillary and postcapillary or isolated postcapillary pulmonary hypertension. After a median follow-up of 4.5 years, 91 deaths accounted for 4.21 higher-than-expected mortality in the age-matched population. Risk factors for mortality were male sex, older age, diabetes mellitus, World Health Organization functional class III and higher pulmonary vascular resistance-either measured by catheterization or approximated from ultrasound data. Higher pulmonary vascular resistance was related to diabetes mellitus and smaller residual aortic and mitral valve areas. In turn, the latter correlated with prosthetic nominal size. Six-month changes in the composite clinical score and in the 6-minute walk test distance were related to survival. Conclusions Persistent valvular heart disease-pulmonary hypertension is an ominous disease that is almost universally associated with elevated pulmonary artery wedge pressure. Pulmonary vascular resistance is a major determinant of mortality in this condition and is related to diabetes mellitus and the residual effective area of the corrected valve. These findings have important implications for individualizing valve correction procedures. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT00862043.This study was funded by the Instituto de Salud Carlos III, Ministerio de Ciencia e Innovación, Spain, the European Union–European Regional Development Fund (EC07/90772 and PI19/00649), and the Consorcio de Investigación Biomédica en Red de Enfermedades Cardiovasculares (CIBERCV).S

Differences in MEF2 and NFAT Transcriptional Pathways According to Human Heart Failure Aetiology

BACKGROUND:Ca(2+) handling machinery modulates the activation of cardiac transcription pathways involved in heart failure (HF). The present study investigated the effect of HF aetiology on Ca(+2) handling proteins and NFAT1, MEF2C and GATA4 (transcription factors) in the same cardiac tissue. METHODOLOGY AND PRINCIPAL FINDINGS:A total of 83 hearts from ischemic (ICM, n = 43) and dilated (DCM, n = 31) patients undergoing heart transplantation and controls (CNT, n = 9) were analyzed by western blotting. Subcellular distribution was analyzed by fluorescence and electron microscopy. When we compared Ca(+2) handling proteins according to HF aetiology, ICM showed higher levels of calmodulin (24%, p<0.01), calcineurin (26%, p<0.01) and Ca(2+)/Calmodulin-dependent kinase II (CaMKIIδ(b) nuclear isoform 62%, p<0.001) than the CNT group. However, these proteins in DCM did not significantly increase. Furthermore, ICM showed a significant elevation in MEF2C (33%, p<0.01), and GATA4 (49%, p<0.05); also NFAT1 (66%, p<0.001) was increased, producing the resultant translocation of this transcriptional factor into the nuclei. These results were supported by fluorescence and electron microscopy analysis. Whereas, DCM only had a significant increase in GATA4 (52%, p<0.05). Correlations between NFAT1 and MEF2C in both groups (ICM r = 0.38 and DCM r = 0.59, p<0.05 and p<0.01, respectively) were found; only ICM showed a correlation between GATA4 and NFAT1 (r = 0.37, p<0.05). CONCLUSIONS/SIGNIFICANCE:This study shows an increase of Ca(2+) handling machinery synthesis and their cardiac transcription pathways in HF, being more markedly increased in ICM. Furthermore, there is a significant association between MEF2, NFAT1 and GATA4. These proteins could be therapeutic targets to improve myocardial function