Teresa Padro

Scopus Publications

Circulating miR-6821-5p levels and coronary calcification in asymptomatic familial hypercholesterolemia patients
Rafael Escate, Teresa Padró, Leopoldo Pérez de Isla, Francisco Fuentes, Rodrigo Alonso, Pedro Mata, and Lina Badimon
Elsevier BV

C-reactive protein modifies lipoprotein(a)-related risk for coronary heart disease: the BiomarCaRE project
Natalie Arnold, Christopher Blaum, Alina Goßling, Fabian J Brunner, Benjamin Bay, Marco M Ferrario, Paolo Brambilla, Giancarlo Cesana, Valerio Leoni, Luigi Palmieri,et al.
Oxford University Press (OUP)
Abstract Background and Aims Recent investigations have suggested an interdependence of lipoprotein(a) [Lp(a)]-related risk for cardiovascular disease with background inflammatory burden. The aim the present analysis was to investigate whether high-sensitive C-reactive protein (hsCRP) modulates the association between Lp(a) and coronary heart disease (CHD) in the general population. Methods Data from 71 678 participants from 8 European prospective population-based cohort studies were used (65 661 without/6017 with established CHD at baseline; median follow-up 9.8/13.8 years, respectively). Fine and Gray competing risk-adjusted models were calculated according to accompanying hsCRP concentration (&lt;2 and ≥2 mg/L). Results Among CHD-free individuals, increased Lp(a) levels were associated with incident CHD irrespective of hsCRP concentration: fully adjusted sub-distribution hazard ratios [sHRs (95% confidence interval)] for the highest vs. lowest fifth of Lp(a) distribution were 1.45 (1.23–1.72) and 1.48 (1.23–1.78) for a hsCRP group of &lt;2 and ≥2 mg/L, respectively, with no interaction found between these two biomarkers on CHD risk (Pinteraction = 0.82). In those with established CHD, similar associations were seen only among individuals with hsCRP ≥ 2 mg/L [1.34 (1.03–1.76)], whereas among participants with a hsCRP concentration &lt;2 mg/L, there was no clear association between Lp(a) and future CHD events [1.29 (0.98–1.71)] (highest vs. lowest fifth, fully adjusted models; Pinteraction = 0.024). Conclusions While among CHD-free individuals Lp(a) was significantly associated with incident CHD regardless of hsCRP, in participants with CHD at baseline, Lp(a) was related to recurrent CHD events only in those with residual inflammatory risk. These findings might guide adequate selection of high-risk patients for forthcoming Lp(a)-targeting compounds.

Perivascular and epicardial adipose tissue
Lina Badimon, Gemma Arderiu, Gemma Vilahur, Teresa Padro, Alberto Cordero, and Guiomar Mendieta
Elsevier BV

Canonical Wnt pathway and the LDL receptor superfamily in neuronal cholesterol homeostasis and function
Maria Borrell-Pages, Aureli Luquero, Gemma Vilahur, Teresa Padró, and Lina Badimon
Oxford University Press (OUP)
Abstract Aims There is little information on the regulation of cholesterol homeostasis in the brain. Whether cholesterol crosses the blood–brain barrier is under investigation, but the present understanding is that cholesterol metabolism in the brain is independent from that in peripheral tissues. Lipoprotein receptors from the LDL receptor family (LRPs) have key roles in lipid particle accumulation in cells involved in vascular and cardiac pathophysiology; however, their function on neural cells is unknown. Methods and results The expression of LRP5 and the components and targets of its downstream signalling pathway, the canonical Wnt pathway, including β-catenin, LEF1, VEGF, OPN, MMP7, and ADAM10, is analysed in the brains of Wt and Lrp5−/− mice and in a neuroblastoma cell line. LRP5 expression is increased in a time- and dose-dependent manner after lipid loading in neuronal cells; however, it does not participate in cholesterol homeostasis as shown by intracellular lipid accumulation analyses. Neurons challenged with staurosporin and H2O2 display an anti-apoptotic protective role for LRP5. Conclusions For the first time, it has been shown that neurons can accumulate intracellular lipids and lipid uptake is performed mainly by the LDLR, while CD36, LRP1, and LRP5 do not play a major role. In addition, it has been shown that LRP5 triggers the canonical Wnt pathway in neuronal cells to generate pro-survival signals. Finally, Lrp5−/− mice have maintained expression of LRP5 only in the brain supporting the biological plausible concept of the need of brain LRP5 to elicit pro-survival processes and embryonic viability.

miR-619-5p and cardiogenic shock in patients with ST-segment elevation myocardial infarction
Rafael Escate, Teresa Padró, Rosa Suades, Jordi Sans‐Roselló, Yvan Devaux, Päivi Lakkisto, Veli‐Pekka Harjola, Alessandro Sionis, and Lina Badimon
Wiley
AbstractBackgroundCardiogenic shock (CS) is a severe myocardial dysfunction secondary to various cardiac conditions including ST‐segment elevation acute myocardial infarction (STEMI) and associated with a high risk of death. Little is known on epigenetic determinants in CS. Here, we investigated plasma miRNAs in relation to CS stratification in STEMI‐patients.MethodsSTEMI‐patients (n = 49), with (CS, n = 25) and without CS (non‐CS, n = 24) fulfilling inclusion criteria were included from HSCSP‐cohort (Derivation‐cohort). CS‐miRNAs were analysed by Affymetrix‐microarray and RT‐PCR. Results were validated in a second cohort of CS‐patients (CardShock: n = 35) with similar inclusion/exclusion criteria as the derivation cohort. In silico analysis were performed to identify potential miRNA target genes.ResultsOf the 5‐miRNA signature obtained from microarray analysis, miR‐619‐5p showed higher levels in CS than in Non‐CS patients (p = .003) and discriminating power for CS by ROC (AUC: .752, p = .003). miR‐619‐5p directly associated with risk scores [GRACE, p = .001; CardShock, p < .001]. Furthermore, miR‐619‐5p showed discrimination power for death in CS. Thus, miRNA levels were significantly higher in patients with mortality outcome both in the Derivation HSCSP‐cohort (p = .02; AUC: .78 ± .095) and the Validation CardShock‐cohort (p = .017; AUC: .737 ± .086) By in silico analysis, miR‐619‐5p target genes and TNF‐alpha were involved in the regulation of inflammation. miR‐619‐5p and TNF‐alpha levels discriminated mortality outcome in CS‐patients during 30‐day follow‐up (Validation‐Cohort: ROC: .812, p = .002; HR: 9.99, p = .003).ConclusionsUp‐regulation of miR‐619‐5p is found in the plasma of STEMI‐patients with CS and mortality outcome. These findings highlight the specificity of epigenetic regulation of inflammation on the disease severity of MI.

The ESC Working Group on Coronary Pathophysiology and Microcirculation
Teresa Padro, Edina Cenko, and Dimitris Tousoulis
Oxford University Press (OUP)

Vascular and Platelet Effects of Tomato Soffritto Intake in Overweight and Obese Subjects
Anallely López-Yerena, Teresa Padro, Victoria de Santisteban Villaplana, Natàlia Muñoz-García, Antonio Pérez, Gemma Vilahur, and Lina Badimon
MDPI AG
Tomatoes are known for their numerous health benefits, including antioxidants, anti-cancer, antimicrobial, anti-inflammatory, anti-neurodegenerative, antiplatelet, and cardio-protective properties. However, their potential health benefits in the Mediterranean diet’s popular soffritto remain largely unexplored in scientific research. The objective was to evaluate the effects of soffritto intake on platelet activity, vascular endothelial function, weight, lipid profile, and blood parameters. In a prospective, controlled, randomized two-arm longitudinal cross-over trial, 40 overweight and obese individuals received 100 g/day of soffritto, or a control, for 42 days. The primary outcome was the effect on vascular endothelial function and platelet activity. As exploratory secondary outcomes, anthropometric measures, serum lipid profile, and hemogram profile were measured before and after a 6-week intervention with or without soffritto supplementation. Compared with the control group, soffritto supplementation for six weeks improved collagen-induced (−5.10 ± 3.06%) platelet aggregation (p < 0.05). In addition, after six weeks, a reduction in ADP-induced aggregation (−3.67 ± 1.68%) was also only observed in the soffritto group (p < 0.05). No significant effects of the soffritto intake were observed on vascular endothelial function, anthropometric measures, serum lipid profile, or blood parameters (p > 0.05). In conclusion, as a basic culinary technique, soffritto may have a role in the primary prevention of cardiovascular disease by reducing platelet activation, which could contribute to a reduction in thrombotic events.

Bioinformatic platforms for clinical stratification of natural history of atherosclerotic cardiovascular diseases
Giuditta Benincasa, Rosa Suades, Teresa Padró, Lina Badimon, and Claudio Napoli
Oxford University Press (OUP)
Abstract Although bioinformatic methods gained a lot of attention in the latest years, their use in real-world studies for primary and secondary prevention of atherosclerotic cardiovascular diseases (ASCVD) is still lacking. Bioinformatic resources have been applied to thousands of individuals from the Framingham Heart Study as well as health care-associated biobanks such as the UK Biobank, the Million Veteran Program, and the CARDIoGRAMplusC4D Consortium and randomized controlled trials (i.e. ODYSSEY, FOURIER, ASPREE, and PREDIMED). These studies contributed to the development of polygenic risk scores (PRS), which emerged as novel potent genetic-oriented tools, able to calculate the individual risk of ASCVD and to predict the individual response to therapies such as statins and proprotein convertase subtilisin/kexin type 9 inhibitor. ASCVD are the first cause of death around the world including coronary heart disease (CHD), peripheral artery disease, and stroke. To achieve the goal of precision medicine and personalized therapy, advanced bioinformatic platforms are set to link clinically useful indices to heterogeneous molecular data, mainly epigenomics, transcriptomics, metabolomics, and proteomics. The DIANA study found that differential methylation of ABCA1, TCF7, PDGFA, and PRKCZ significantly discriminated patients with acute coronary syndrome from healthy subjects and their expression levels positively associated with CK-MB serum concentrations. The ARIC Study revealed several plasma proteins, acting or not in lipid metabolism, with a potential role in determining the different pleiotropic effects of statins in each subject. The implementation of molecular high-throughput studies and bioinformatic techniques into traditional cardiovascular risk prediction scores is emerging as a more accurate practice to stratify patients earlier in life and to favour timely and tailored risk reduction strategies. Of note, radiogenomics aims to combine imaging features extracted for instance by coronary computed tomography angiography and molecular biomarkers to create CHD diagnostic algorithms useful to characterize atherosclerotic lesions and myocardial abnormalities. The current view is that such platforms could be of clinical value for prevention, risk stratification, and treatment of ASCVD.

Update of HDL in atherosclerotic cardiovascular disease
Leonie Schoch, Sebastián Alcover, Teresa Padró, Soumaya Ben-Aicha, Guiomar Mendieta, Lina Badimon, and Gemma Vilahur
Elsevier BV

Perivascular adipose tissue as a source of therapeutic targets and clinical biomarkers
Charalambos Antoniades, Dimitris Tousoulis, Marija Vavlukis, Ingrid Fleming, Dirk J Duncker, Etto Eringa, Olivia Manfrini, Alexios S Antonopoulos, Evangelos Oikonomou, Teresa Padró,et al.
Oxford University Press (OUP)
Abstract Obesity is a modifiable cardiovascular risk factor, but adipose tissue (AT) depots in humans are anatomically, histologically, and functionally heterogeneous. For example, visceral AT is a pro-atherogenic secretory AT depot, while subcutaneous AT represents a more classical energy storage depot. Perivascular adipose tissue (PVAT) regulates vascular biology via paracrine cross-talk signals. In this position paper, the state-of-the-art knowledge of various AT depots is reviewed providing a consensus definition of PVAT around the coronary arteries, as the AT surrounding the artery up to a distance from its outer wall equal to the luminal diameter of the artery. Special focus is given to the interactions between PVAT and the vascular wall that render PVAT a potential therapeutic target in cardiovascular diseases. This Clinical Consensus Statement also discusses the role of PVAT as a clinically relevant source of diagnostic and prognostic biomarkers of vascular function, which may guide precision medicine in atherosclerosis, hypertension, heart failure, and other cardiovascular diseases. In this article, its role as a ‘biosensor’ of vascular inflammation is highlighted with description of recent imaging technologies that visualize PVAT in clinical practice, allowing non-invasive quantification of coronary inflammation and the related residual cardiovascular inflammatory risk, guiding deployment of therapeutic interventions. Finally, the current and future clinical applicability of artificial intelligence and machine learning technologies is reviewed that integrate PVAT information into prognostic models to provide clinically meaningful information in primary and secondary prevention.

Biomarker-based prediction of fatal and non-fatal cardiovascular outcomes in individuals with diabetes mellitus
Paul M Haller, Alina Goßling, Christina Magnussen, Hermann Brenner, Ben Schöttker, Licia Iacoviello, Simona Costanzo, Frank Kee, Wolfgang Koenig, Allan Linneberg,et al.
Oxford University Press (OUP)
Abstract Aims The role of biomarkers in predicting cardiovascular outcomes in high-risk individuals is not well established. We aimed to investigate benefits of adding biomarkers to cardiovascular risk assessment in individuals with and without diabetes. Methods and results We used individual-level data of 95 292 individuals of the European population harmonized in the Biomarker for Cardiovascular Risk Assessment across Europe consortium and investigated the prognostic ability of high-sensitivity cardiac troponin I (hs-cTnI), N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and high-sensitivity C-reactive protein (hs-CRP). Cox-regression models were used to determine adjusted hazard ratios of diabetes and log-transformed biomarkers for fatal and non-fatal cardiovascular events. Models were compared using the likelihood ratio test. Stratification by specific biomarker cut-offs was performed for crude time-to-event analysis using Kaplan–Meier plots. Overall, 6090 (6.4%) individuals had diabetes at baseline, median follow-up was 9.9 years. Adjusting for classical risk factors and biomarkers, diabetes [HR 2.11 (95% CI 1.92, 2.32)], and all biomarkers (HR per interquartile range hs-cTnI 1.08 [95% CI 1.04, 1.12]; NT-proBNP 1.44 [95% CI 1.37, 1.53]; hs-CRP 1.27 [95% CI 1.21, 1.33]) were independently associated with cardiovascular events. Specific cut-offs for each biomarker identified a high-risk group of individuals with diabetes losing a median of 15.5 years of life compared to diabetics without elevated biomarkers. Addition of biomarkers to the Cox-model significantly improved the prediction of outcomes (likelihood ratio test for nested models P &lt; 0.001), accompanied by an increase in the c-index (increase to 0.81). Conclusion Biomarkers improve cardiovascular risk prediction in individuals with and without diabetes and facilitate the identification of individuals with diabetes at highest risk for cardiovascular events.

Dietary ω3 Fatty Acids and Phytosterols in the Modulation of the HDL Lipidome: A Longitudinal Crossover Clinical Study
Teresa Padro, Anallely López-Yerena, Antonio Pérez, Gemma Vilahur, and Lina Badimon
MDPI AG
High-density lipoproteins (HDLs) are complex particles composed of a wide range of lipids, proteins, hormones and vitamins that confer to the HDL particles multiple cardiovascular protective properties, mainly against the development of atherosclerosis. Among other factors, the HDL lipidome is affected by diet. We hypothesized that diet supplementation with ω3 (docosahexaenoic acid: DHA and eicosapentaenoic acid: EPA) and phytosterols (PhyS) would improve the HDL lipid profile. Overweight subjects (n = 20) were enrolled in a two-arm longitudinal crossover study. Milk (250 mL/day), supplemented with either ω3 (EPA + DHA, 375 mg) or PhyS (1.6 g), was administered to the volunteers over two consecutive 28-day intervention periods, followed by HDL lipidomic analysis. The comprehensive lipid pattern revealed that the HDL lipidome is diet-dependent. ω3-milk supplementation produced more changes than PhyS, mainly in cholesteryl esters (CEs). After ω3-milk intake, levels of DHA and EPA within phosphatylcholines, triglycerides and CE lipids in HDLs increased (p < 0.05). The correlation between lipid species showed that lipid changes occur in a coordinated manner. Finally, our analysis revealed that the HDL lipidome is also sex-dependent. The HDL lipidome is affected by diet and sex, and the 4 weeks of ω3 supplementation induced HDL enrichment with EPA and DHA.

Dysfunctional antioxidant capacity of high-density lipoprotein in rheumatoid arthritis
María Carmen García‐Gómez, Teresa Padró, Natàlia Muñoz‐García, María Bianchi, Lorenzo Álvarez, Lina Badimon, Emili Corbella, and Xavier Pintó
Wiley
BACKGROUND High-density lipoprotein (HDL) present atheroprotective functions not readily reflected by plasma HDL-cholesterol levels. The aim of this study was to investigate HDL antioxidant function in patients with rheumatoid arthritis (RA). METHODS This pilot and cross-sectional study included 50 RA patients and 50 controls matched by age, gender, cardiovascular risk factors and drug therapy. The antioxidant capacity of HDL was assessed by the total radical-trapping antioxidative potential test (TRAP-assay) and the susceptibility of low-density lipoprotein (LDL) to oxidation by the Conjugated Dienes Assay (Dmax). A carotid ultrasound was performed in all participants to detect subclinical atherosclerosis. RESULTS HDL from RA patients showed lower antioxidant capacity than those from controls [oxidized-LDL%: 35.8(27-42) vs. 24.4(20-32), p<0.001] when analysed with the TRAP-assay. In addition, the time to achieve 50% of maximal LDL oxidation (Lag-time) was shorter in RA-patients than in matched controls [57.2(42-71) vs. 69.5(55-75) minutes, (p=0.003)]. RA patients showed a higher atherosclerotic burden than controls. The pro-oxidant pattern in RA was irrespective of the presence of carotid atherosclerosis. On the contrary, there was a positive correlation between inflammatory parameters (erythrocyte sedimentation rate, ultrasensitive C-reactive protein and fibrinogen) and the loss of HDL-anti-oxidant capacity measured by the TRAP-assay (rho=0.211, p=0.035; rho=0.231, p=0.021 and rho=0.206, p=0.041, respectively). Furthermore, the glucocorticoid dose at recruitment was negatively associated with the Lag-time in RA patients (rho=-0.387, p=0.026). CONCLUSION RA patients present reduced HDL antioxidant capacity and a lower resistance of LDL particles to oxidation, mainly related to the degree of inflammation.

Red Blood Cells and Endothelium Derived Circulating Extracellular Vesicles in Health and Chronic Heart Failure: A Focus on Phosphatidylserine Dynamics in Vesiculation
Rosa Suades, Alba Vilella-Figuerola, Teresa Padró, Sonia Mirabet, and Lina Badimon
MDPI AG
Circulating extracellular microvesicles (cEVs) are characterised by presenting surface antigens of parental cells. Since their biogenesis involves the translocation of phosphatidylserine (PS) from the inner to the outer leaflet of the plasma membrane, exposed PS has been considered as a recognition hallmark of cEVs. However, not all cEVs externalise PS. In this study, we have phenotypically and quantitatively characterised cEVs by flow cytometry, paying special attention to the proportions of PS in chronic heart failure patients (cHF; n = 119) and a reference non-HF group (n = 21). PS−-cEVs were predominantly found in both groups. Parental markers showed differential pattern depending on the PS exposure. Endothelium-derived and connexin 43-rich cEVs were mainly PS−-cEVs and significantly increased in cHF. On the contrary, platelet-derived cEVs were mostly PS+ and were increased in the non-HF group. We observed similar levels of PS+- and PS−-cEVs in non-HF subjects when analysing immune cell-derived Evs, but there was a subset-specific difference in cHF patients. Indeed, those cEVs carrying CD45+, CD29+, CD11b+, and CD15+ were mainly PS+-cEVs, while those carrying CD14+, CD3+, and CD56+ were mainly PS−-cEVs. In conclusion, endothelial and red blood cells are stressed in cHF patients, as detected by a high shedding of cEVs. Despite PS+-cEVs and PS−-cEVs representing two distinct cEV populations, their release and potential function as both biomarkers and shuttles for cell communication seem unrelated to their PS content.

Alirocumab and Coronary Atherosclerosis in Asymptomatic Patients with Familial Hypercholesterolemia: The ARCHITECT Study
Leopoldo Pérez de Isla, Jose L. Díaz-Díaz, Manuel J. Romero, Ovidio Muñiz-Grijalvo, Juan D. Mediavilla, Rosa Argüeso, Juan F. Sánchez Muñoz-Torrero, Patricia Rubio, Pilar Álvarez-Baños, Paola Ponte,et al.
Ovid Technologies (Wolters Kluwer Health)
Background: The effect of alirocumab, a PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor, on coronary plaque burden in patients with familial hypercholesterolemia has not been addressed. Our aim was to assess changes in coronary plaque burden and its characteristics after treatment with alirocumab by quantification and characterization of atherosclerotic plaque throughout the coronary tree on the basis of a noninvasive analysis of coronary computed tomographic angiography in asymptomatic subjects with familial hypercholesterolemia receiving optimized and stable treatment with maximum tolerated statin dose with or without ezetimibe. Methods: This study is a phase IV, open-label, multicenter, single-arm clinical trial to assess changes in coronary plaque burden and its characteristics after 78 weeks of treatment with alirocumab in patients with familial hypercholesterolemia without clinical atherosclerotic cardiovascular disease. Participants underwent an initial coronary computed tomographic angiography at baseline and another at 78 weeks. Every patient received 150 mg of alirocumab subcutaneiously every 14 days in addition to high-intensity statin therapy. The main outcome was the change on coronary plaque burden and its characteristics by quantification and characterization of atherosclerotic plaque throughout the coronary tree on the basis of analysis of coronary computed tomographic angiography. Results: The study was completed by 104 patients. The median age was 53.3 (46.2–59.4) years. Of these patients, 54 were women (51.9%). Median low-density lipoprotein cholesterol was 138.9 (117.5–175.3) mg/dL at entry and 45.0 (36.0–65.0) mg/dL at follow-up ( P <0.001). Coronary plaque burden changed from 34.6% (32.5%–36.8%) at entry to 30.4% (27.4%–33.4%) at follow-up ( P <0.001). A significant change in the characteristics of the coronary atherosclerosis was also found: an increase in the proportion of calcified (+0.3%; P <0.001) and mainly fibrous (+6.2%; P <0.001) plaque, accompanied by a decrease in the percentage of fibro-fatty (–3.9%; P <0.001) and necrotic plaque (–0.6%; P <0.001). Conclusions: Treatment with alirocumab in addition to high-intensity statin therapy resulted in significant regression of coronary plaque burden and plaque stabilization on coronary computed tomographic angiography over 78 weeks in these groups of patients with familial hypercholesterolemia without clinical atherosclerotic cardiovascular disease. ARCHITECT (Effect of Alirocumab on Atherosclerotic Plaque Volume, Architecture and Composition) could link and explain ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment With Alirocumab) results. Registration: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT05465278.

Effects of Antioxidants in Fermented Beverages in Tissue Transcriptomics: Effect of Beer Intake on Myocardial Tissue after Oxidative Injury
Alex Gallinat, Gemma Vilahur, Teresa Padro, and Lina Badimon
MDPI AG
Fermented beverages, such as wine and beer, are rich in polyphenols that have been shown to have protective effects against oxidative stress. Oxidative stress plays a central role in the pathogenesis and progression of cardiovascular disease. However, the potential benefits of fermented beverages on cardiovascular health need to be fully investigated at a molecular level. In this study, we aimed at analyzing the effects of beer consumption in modulating the transcriptomic response of the heart to an oxidative stress challenge induced by myocardial ischemia (MI) in the presence of hypercholesterolemia in a pre-clinical swine model. Previous studies have shown that the same intervention induces organ protective benefits. We report a dose-dependent up-regulation of electron transport chain members and the down-regulation of spliceosome-associated genes linked to beer consumption. Additionally, low-dose beer consumption resulted in a down-regulation of genes associated with the immune response, that was not shown for moderate-dose beer consumption. These findings, observed in animals having demonstrated beneficial effects at the organ-level, indicate that the antioxidants in beer differentially affect the myocardial transcriptome in a dose-dependent manner.

HDL Function and Size in Patients with On-Target LDL Plasma Levels and a First-Onset ACS
Alberto Cordero, Natàlia Muñoz-García, Teresa Padró, Gemma Vilahur, Vicente Bertomeu-González, David Escribano, Emilio Flores, Pilar Zuazola, and Lina Badimon
MDPI AG
Patients admitted for acute coronary syndrome (ACS) usually have high cardiovascular risk scores with low levels of high-density lipoprotein cholesterol (HDL-C) and high low-density lipoprotein cholesterol (LDL-C) levels. Here, we investigated the role of lipoprotein functionality as well as particle number and size in patients with a first-onset ACS with on-target LDL-C levels. Ninety-seven patients with chest pain and first-onset ACS with LDL-C levels of 100 ± 4 mg/dL and non-HDL-C levels of 128 ± 4.0 mg/dL were included in the study. Patients were categorized as ACS and non-ACS after all diagnostic tests were performed (electrocardiogram, echocardiogram, troponin levels and angiography) on admission. HDL-C and LDL-C functionality and particle number/size by nuclear magnetic resonance (NMR) were blindly investigated. A group of matched healthy volunteers (n = 31) was included as a reference for these novel laboratory variables. LDL susceptibility to oxidation was higher and HDL-antioxidant capacity lower in the ACS patients than in the non-ACS individuals. ACS patients had lower HDL-C and Apolipoprotein A-I levels than non-ACS patients despite the same prevalence of classical cardiovascular risk factors. Cholesterol efflux potential was impaired only in the ACS patients. ACS-STEMI (Acute Coronary Syndrome—ST-segment-elevation myocardial infarction) patients, had a larger HDL particle diameter than non-ACS individuals (8.4 ± 0.02 vs. 8.3 ± 0.02 and, ANOVA test, p = 0.004). In conclusion, patients admitted for chest pain with a first-onset ACS and on-target lipid levels had impaired lipoprotein functionality and NMR measured larger HDL particles. This study shows the relevance of HDL functionality rather than HDL-C concentration in ACS patients.

Cardiovascular residual risk: aetiology, lipids and inflammation

A comprehensive and longitudinal cardiac magnetic resonance imaging study of the impact of coronary ischemia duration on myocardial damage in a highly translatable animal model
Monika Radike, Pablo Sutelman, Soumaya Ben‐Aicha, Manuel Gutiérrez, Guiomar Mendieta, Sebastià Alcover, Laura Casaní, Gemma Arderiu, María Borrell‐Pages, Teresa Padró,et al.
Wiley
We performed a comprehensive assessment of the effect of myocardial ischemia duration on cardiac structural and functional parameters by serial cardiac magnetic resonance (CMR) and characterized the evolving scar.

Influence of geographical latitude on vitamin D status: cross-sectional results from the BiomarCaRE consortium
Viktor Oskarsson, Mats Eliasson, Veikko Salomaa, Jaakko Reinikainen, Satu Männistö, Luigi Palmieri, Chiara Donfrancesco, Susana Sans, Simona Costanzo, Giovanni de Gaetano,et al.
Cambridge University Press (CUP)
AbstractEven though sunlight is viewed as the most important determinant of 25-hydroxyvitamin D (25(OH)D) status, several European studies have observed higher 25(OH)D concentrations among north-Europeans than south-Europeans. We studied the association between geographical latitude (derived from ecological data) and 25(OH)D status in six European countries using harmonised immunoassay data from 81 084 participants in the Biomarkers for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project (male sex 48·9 %; median age 50·8 years; examination period 1984–2014). Quantile regression models, adjusted for age, sex, decade and calendar week of sampling and time from sampling to analysis, were used for between-country comparisons. Up until the median percentile, the ordering of countries by 25(OH)D status (from highest to lowest) was as follows: Sweden (at 65·6–63·8°N), Germany (at 48·4°N), Finland (at 65·0–60·2°N), Italy (at 45·6–41·5°N), Scotland (at 58·2–55·1°N) and Spain (at 41·5°N). From the 75th percentile and upwards, Finland had higher values than Germany. As an example, using the Swedish cohort as a comparator, the median 25(OH)D concentration was 3·03, 3·28, 5·41, 6·54 and 9·28 ng/ml lower in the German, Finnish, Italian, Scottish and Spanish cohort, respectively (P-value < 0·001 for all comparisons). The ordering of countries was highly consistent in subgroup analyses by sex, age, and decade and season of sampling. In conclusion, we confirmed the previous observation of a north-to-south gradient of 25(OH)D status in Europe, with higher percentile values among north-Europeans than south-Europeans.

Platelet-Released Extracellular Vesicle Characteristics Differ in Chronic and in Acute Heart Disease
Alba Vilella-Figuerola, Alberto Cordero, Sònia Mirabet, Natàlia Muñoz-García, Rosa Suades, Teresa Padró, and Lina Badimon
Georg Thieme Verlag KG
Background Extracellular vesicles (EVs), shed in response to cell activation, stress, or injury, are increased in the blood of patients with cardiovascular disease. EVs are characterized by expressing parental-cell antigens, allowing the determination of their cellular origin. Platelet-derived EVs (pEVs) are the most abundant in blood. Although not universally given, EVs generally express phosphatidylserine (PS) in their membrane. Objectives To investigate pEVs in chronic and acute conditions, such as chronic heart failure (CHF) and first-onset acute coronary syndrome (ACS), in patients treated as per guidelines. Methods EVs in CHF patients (n = 119), ACS patients (n = 58), their respective controls (non-CHF [n = 21] and non-ACS [n = 24], respectively), and a reference control group (n = 31) were characterized and quantified by flow cytometry, using monoclonal antibodies against platelet antigens, and annexin V (AV) to determine PS exposure. Results CHF patients had higher EVs-PS− numbers, while ACS had predominantly EVs-PS+. In contrast to ACS, CHF patients had significantly reduced numbers of pEVs carrying PECAM and αIIb-integrin epitopes (CD31+/AV+, CD41a+/AV+, and CD31+/CD41a+/AV+), while no differences were observed in P-selectin-rich pEVs (CD62P+/AV+) compared with controls. Additionally, background etiology of CHF (ischemic vs. nonischemic) or ACS type (ST-elevation myocardial infarction [STEMI] vs. non-STEMI [NSTEMI]) did not affect pEV levels. Conclusion PS exposure in EV and pEV-release differ between CHF and ACS patients, with tentatively different functional capacities beyond coagulation to inflammation and cross-talk with other cell types.

Systems Biology in Chronic Heart Failure—Identification of Potential miRNA Regulators
Alba Vilella-Figuerola, Alex Gallinat, Rafael Escate, Sònia Mirabet, Teresa Padró, and Lina Badimon
MDPI AG
Heart failure (HF) is a complex disease entity with high clinical impact, poorly understood pathophysiology and scantly known miRNA-mediated epigenetic regulation. We have analysed miRNA patterns in patients with chronic HF (cHF) and a sex- and age-matched reference group and pursued an in silico system biology analysis to discern pathways involved in cHF pathophysiology. Twenty-eight miRNAs were identified in cHF that were up-regulated in the reference group, and eight of them were validated by RT-qPCR. In silico analysis of predicted targets by STRING protein-protein interaction networks revealed eight cluster networks (involving seven of the identified miRNAs) enriched in pathways related to cell cycle, Ras, chemokine, PI3K-AKT and TGF-β signaling. By ROC curve analysis, combined probabilities of these seven miRNAs (let-7a-5p, miR-107, miR-125a-5p, miR-139-5p, miR-150-5p, miR-30b-5p and miR-342-3p; clusters 1–4 [C:1–4]), discriminated between HF with preserved ejection fraction (HFpEF) and HF with reduced ejection fraction (HFrEF), and ischaemic and non-ischaemic aetiology. A combination of miR-107, miR-139-5p and miR-150-5p, involved in clusters 5 and 7 (C:5+7), discriminated HFpEF from HFrEF. Pathway enrichment analysis of miRNAs present in C:1–4 (let-7a-5p, miR-125a-5p, miR-30b-5p and miR-342-3p) revealed pathways related to HF pathogenesis. In conclusion, we have identified a differential signature of down-regulated miRNAs in the plasma of HF patients and propose novel cellular mechanisms involved in cHF pathogenesis.

Mechanisms, therapeutic implications, and methodological challenges of gut microbiota and cardiovascular diseases: a position paper by the ESC Working Group on Coronary Pathophysiology and Microcirculation
Dimitris Tousoulis, Tomasz Guzik, Teresa Padro, Dirk J Duncker, Giuseppe De Luca, Etto Eringa, Marija Vavlukis, Alexios S Antonopoulos, Themistoklis Katsimichas, Edina Cenko,et al.
Oxford University Press (OUP)
AbstractThe human gut microbiota is the microbial ecosystem in the small and large intestines of humans. It has been naturally preserved and evolved to play an important role in the function of the gastrointestinal tract and the physiology of its host, protecting from pathogen colonization, and participating in vitamin synthesis, the functions of the immune system, as well as glucose homeostasis and lipid metabolism, among others. Mounting evidence from animal and human studies indicates that the composition and metabolic profiles of the gut microbiota are linked to the pathogenesis of cardiovascular disease, particularly arterial hypertension, atherosclerosis, and heart failure. In this review article, we provide an overview of the function of the human gut microbiota, summarize, and critically address the evidence linking compositional and functional alterations of the gut microbiota with atherosclerosis and coronary artery disease and discuss the potential of strategies for therapeutically targeting the gut microbiota through various interventions.

New factors in heart failure pathophysiology: Immunity cells release of extracellular vesicles
Alba Vilella-Figuerola, Teresa Padró, Eulàlia Roig, Sònia Mirabet, and Lina Badimon
Frontiers Media SA
Leukocyte-shed extracellular vesicles (EVs) can play effector roles in the pathophysiological mechanisms of different diseases. These EVs released by membrane budding of leukocytes have been found in high amounts locally in inflamed tissues and in the circulation, indicating immunity cell activation. These EVs secreted by immune cell subsets have been minimally explored and deserve further investigation in many areas of disease. In this study we have investigated whether in heart failure there is innate and adaptive immune cell release of EVs. Patients with chronic heart failure (cHF) (n = 119) and in sex- and age-matched controls without this chronic condition (n = 60). Specifically, EVs were quantified and phenotypically characterized by flow cytometry and cell-specific monoclonal antibodies. We observed that even in well medically controlled cHF patients (with guideline-directed medical therapy) there are higher number of blood annexin-V+ (phosphatidylserine+)-EVs carrying activated immunity cell-epitopes in the circulation than in controls (p &lt; 0.04 for all cell types). Particularly, EVs shed by monocytes and neutrophils (innate immunity) and by T-lymphocytes and natural-killer cells (adaptive immunity) are significantly higher in cHF patients. Additionally, EVs-shed by activated leukocytes/neutrophils (CD11b+, p = 0.006; CD29+/CD15+, p = 0.048), and T-lymphocytes (CD3+/CD45+, p &lt; 0.02) were positively correlated with cHF disease severity (NYHA classification). Interestingly, cHF patients with ischemic etiology had the highest levels of EVs shed by lymphocytes and neutrophils (p &lt; 0.045, all). In summary, in cHF patients there is a significant immune cell activation shown by high-release of EVs that is accentuated by clinical severity of cHF. These activated innate and adaptive immunity cell messengers may contribute by intercellular communication to the progression of the disease and to the common affectation of distant organs in heart failure (paracrine regulation) that contribute to the clinical deterioration of cHF patients.

Extracellular vesicles in atherothrombosis: From biomarkers and precision medicine to therapeutic targets
Lina Badimon, Teresa Padro, Gemma Arderiu, Gemma Vilahur, Maria Borrell‐Pages, and Rosa Suades
Wiley
Atherosclerotic cardiovascular disease (ASCVD) remains the leading cause of global mortality. Extracellular vesicles (EVs) are small phospholipid vesicles that convey molecular bioactive cargoes and play essential roles in intercellular communication and, hence, a multifaceted role in health and disease. The present review offers a glimpse into the current state and up‐to‐date concepts on EV field. It also covers their association with several cardiovascular risk factors and ischemic conditions, being subclinical atherosclerosis of utmost relevance for prevention. Interestingly, we show that EVs hold promise as prognostic and diagnostic as well as predictive markers of ASCVD in the precision medicine era. We then report on the role of EVs in atherothrombosis, disentangling the mechanisms involved in the initiation, progression, and complication of atherosclerosis and showing their direct effect in the context of arterial thrombosis. Finally, their potential use for therapeutic intervention is highlighted.

Teresa Padro

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