MicroRNA in cardiometabolic health and disease: The perspectives of sex, gender and personalised medicine.

BACKGROUND: Personalized medicine represents a novel and integrative approach that focuses on an individual's genetics and epigenetics, precision medicine, lifestyle and exposures as key players of health status and disease phenotypes. METHODS: In this narrative review, we aim to carefully discuss the current knowledge on gender disparities in cardiometabolic diseases, and we consider the sex- specific expression of miRNAs and their role as promising tool in precision medicine. RESULTS: Personalised medicine overcomes the restricted care of patient based on a binomial sex approach, by enriching itself with a holistic and dynamic gender integration. Recognized as a major worldwide health emergency, cardiometabolic disorders continue to rise, impacting on health systems and requiring more effective and targeted strategies. Several sex and gender drivers might affect the onset and progression of cardiometabolic disorders in males and females at multiple levels. In this respect, distinct contribution of genetic and epigenetic mechanisms, molecular and physiological pathways, sex hormones, visceral fat and subcutaneous fat and lifestyle lead to differences in disease burden and outcomes in males and females. CONCLUSIONS: Sex and gender play a pivotal role in precision medicine because the influence the physiology of each individual and the way they interact with environment from intrauterine life.

Circulating miR-6821-5p levels and coronary calcification in asymptomatic familial hypercholesterolemia patients.

BACKGROUND AND AIMS: Premature atherosclerotic cardiovascular disease (CVD) is a clinic characteristic of familial hypercholesterolemia (FH). Coronary calcium score (CCS) is a highly used imaging modality to evidence atherosclerotic plaque burden. microRNAs (miRNAs) are non-coding RNAs that epigenetically regulate gene expression. Here, we investigated whether CCS associates with a specific miRNA-signature in FH-patients. METHODS: Patients with genetic diagnosis of FH (N = 86) from the nationwide SAFEHEART-cohort were investigated by computed tomography angiography imaging and classified depending on the presence of coronary calcification in FH-CCS (+) and FH-CCS (-) groups by the Agatston score. Differential miRNA profiling was performed in two stages: first by Affymetrix microarray technology (high-throughput differential profiling-studies) and second by RT-PCR using TaqMan-technology (analytical RT-qPCR study) in plasma of the two patient groups. RESULTS: miR-193a-5p, miR-30e-5p and miR-6821-5p levels were significantly higher in FH-CCS (+) compared to FH-CCS (-). miR-6821-5p was the best miRNA to discriminate FH-patients CCS(+), according to receiver operating characteristic (ROC) analysis (AUC: 0.70 ± 0.06, p = 0.006). High miR-6821-5p levels were associated with older age (p = 0.03) and high LDL-burden (p = 0.014) using a ROC-derived cut-off value. However, miR-6821-5p did not correlate with age in either the CCS- or CCS + group. Genes involved in calcification processes were identified by in silico analysis. The relation of cell-calcification and expression levels of miR-6821-5p, BMP2 and SPP1 was validated experimentally in human vascular smooth muscle cell cultures. CONCLUSIONS: Up-regulated levels of miR-6821-5p are found in the plasma of asymptomatic FH-patients with coronary calcified atherosclerotic plaques, as well as in isolated human vascular smooth muscle cells expressing the pro-calcification genes BMP2 and SPP1. These findings highlight the impact of epigenetic regulation on the development of subclinical atherosclerosis.

miR-619-5p and cardiogenic shock in patients with ST-segment elevation myocardial infarction.

BACKGROUND: Cardiogenic 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. METHODS: STEMI-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. RESULTS: Of 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). CONCLUSIONS: Up-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.

C-reactive protein modifies lipoprotein(a)-related risk for coronary heart disease: the BiomarCaRE project.

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 (<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 <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 <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.

Update of HDL in atherosclerotic cardiovascular disease / Nuevos conceptos de las HDL en la enfermedad cardiovascular aterosclerótica

Epidemiologic evidence supported an inverse association between HDL (high-density lipoprotein) cholesterol (HDL-C) levels and atherosclerotic cardiovascular disease (ASCVD), identifying HDL-C as a major cardiovascular risk factor and postulating diverse HDL vascular- and cardioprotective functions beyond their ability to drive reverse cholesterol transport. However, the failure of several clinical trials aimed at increasing HDL-C in patients with overt cardiovascular disease brought into question whether increasing the cholesterol cargo of HDL was an effective strategy to enhance their protective properties. In parallel, substantial evidence supports that HDLs are complex and heterogeneous particles whose composition is essential for maintaining their protective functions, subsequently strengthening the “HDL quality over quantity” hypothesis. The following state-of-the-art review covers the latest understanding as per the roles of HDL in ASCVD, delves into recent advances in understanding the complexity of HDL particle composition, including proteins, lipids and other HDL-transported components and discusses on the clinical outcomes after the administration of HDL-C raising drugs with particular attention to CETP (cholesteryl ester transfer protein) inhibitors. (AU)

Estudios epidemiológicos respaldan una asociación inversa entre los niveles de colesterol de lipoproteínas de alta densidad (c-HDL) y la enfermedad cardiovascular aterosclerótica (ECVA), identificando el c-HDL como un importante factor de riesgo cardiovascular y postulando diversas funciones vasculares y cardioprotectoras de las HDL más allá de su capacidad para promover el transporte reverso del colesterol. Sin embargo, el fracaso de varios ensayos clínicos dirigidos a aumentar el c-HDL en pacientes con enfermedad cardiovascular manifiesta, puso en duda el concepto que incrementar la carga de c-HDL fuera una estrategia eficaz para potenciar sus propiedades protectoras. Paralelamente, numerosos estudios han evidenciado que las HDL son partículas complejas y heterogéneas cuya composición es esencial para mantener sus funciones protectoras, lo que refuerza la hipótesis de que «la calidad de las HDL prima sobre la cantidad». En el siguiente manuscrito revisamos el estado del arte sobre los últimos avances en torno a las funciones de las HDL en la ECVA, nos adentramos en los avances recientes en la comprensión de la complejidad de la composición de las partículas de HDL, incluidas las proteínas, los lípidos y otros componentes transportados por las HDL, y revisamos los resultados clínicos tras la administración de inductores del c-HDL, especialmente los inhibidores de la proteína transportadora del colesterol esterificado (CETP). (AU)

Vascular and Platelet Effects of Tomato Soffritto Intake in Overweight and Obese Subjects.

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.

Update of HDL in atherosclerotic cardiovascular disease.

Epidemiologic evidence supported an inverse association between HDL (high-density lipoprotein) cholesterol (HDL-C) levels and atherosclerotic cardiovascular disease (ASCVD), identifying HDL-C as a major cardiovascular risk factor and postulating diverse HDL vascular- and cardioprotective functions beyond their ability to drive reverse cholesterol transport. However, the failure of several clinical trials aimed at increasing HDL-C in patients with overt cardiovascular disease brought into question whether increasing the cholesterol cargo of HDL was an effective strategy to enhance their protective properties. In parallel, substantial evidence supports that HDLs are complex and heterogeneous particles whose composition is essential for maintaining their protective functions, subsequently strengthening the "HDL quality over quantity" hypothesis. The following state-of-the-art review covers the latest understanding as per the roles of HDL in ASCVD, delves into recent advances in understanding the complexity of HDL particle composition, including proteins, lipids and other HDL-transported components and discusses on the clinical outcomes after the administration of HDL-C raising drugs with particular attention to CETP (cholesteryl ester transfer protein) inhibitors.

Canonical Wnt pathway and the LDL receptor superfamily in neuronal cholesterol homeostasis and function.

OBJECTIVE: 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. APPROACH AND RESULTS: The expression of LRP5 and components and targets of its downstream signaling pathway, the canonical WNT pathway including ß-catenin, LEF1, VEGF, OPN MMP7 and ADAM10 is analyzed in brains of Wt and Lrp5-/- mice and in a neuroblastoma cell line. LRP5 expression is increased in a time-dependent 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 stausporin and H2O2 display an anti-apoptotic protective role for LRP5. CONCLUSIONS: We show for the first time that neurons can accumulate intracellular lipids and that lipid uptake is performed mainly by the LDLR while CD36, LRP1, and LRP5 do not play a major role. We also show that LRP5 triggers the canonical WNT pathway in neuronal cells to generate pro-survival signals. Finally we show, that 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.

Perivascular adipose tissue as a source of therapeutic targets and clinical biomarkers.

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.

Dietary ω3 Fatty Acids and Phytosterols in the Modulation of the HDL Lipidome: A Longitudinal Crossover Clinical Study.

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.

Bioinformatic platforms for clinical stratification of natural history of atherosclerotic cardiovascular diseases.

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.

Red Blood Cells and Endothelium Derived Circulating Extracellular Vesicles in Health and Chronic Heart Failure: A Focus on Phosphatidylserine Dynamics in Vesiculation.

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.

Effects of Antioxidants in Fermented Beverages in Tissue Transcriptomics: Effect of Beer Intake on Myocardial Tissue after Oxidative Injury.

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.

Platelet-Released Extracellular Vesicle Characteristics Differ in Chronic and in Acute Heart Disease.

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.

Biomarker-based prediction of fatal and non-fatal cardiovascular outcomes in individuals with diabetes mellitus.

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 < 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.

In this work, the role of cardiac biomarkers measured from blood to predict cardiovascular events and death is tested in individuals of the general population and particularly in those with known diabetes. The work is based on a cooperation of different population studies across Europe and includes more than 90 000 individuals, with more than 6000 having diabetes. We could demonstrate that the determination of three cardiac biomarkers helps to identify individuals at highest risk for cardiovascular events (e.g. myocardial infarction or stroke) and death, despite accounting for known cardiovascular risk factors in these individuals. Therefore, these biomarkers should be considered for routine risk assessment for cardiovascular diseases and could improve the early identification of high-risk individuals, consequently leading to an earlier initiation of preventive therapies.

Alirocumab and Coronary Atherosclerosis in Asymptomatic Patients with Familial Hypercholesterolemia: The ARCHITECT Study.

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.

Dysfunctional antioxidant capacity of high-density lipoprotein in rheumatoid arthritis.

BACKGROUND: High-density lipoprotein (HDL) presents 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: High-density lipoprotein from RA patients showed lower antioxidant capacity than those from controls [oxidized-LDL%: 35.8 (27-42) vs. 24.4 (20-32), p < .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 = .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 = .211, p = .035; rho = .231, p = .021 and rho = .206, p = .041, respectively). Furthermore, the glucocorticoid dose at recruitment was negatively associated with the Lag-time in RA patients (rho = -.387, p = .026). CONCLUSION: Rheumatoid arthritis patients present reduced HDL antioxidant capacity and a lower resistance of LDL particles to oxidation, mainly related to the degree of inflammation.

HDL Function and Size in Patients with On-Target LDL Plasma Levels and a First-Onset ACS.

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.