First time ACS in patients with on-target lipid levels: Inflammation at admission and re-event rate at follow-up.

BACKGROUND: Dyslipidaemia, inflammation and elevated Lp(a) levels are associated with the progression of atherosclerosis. This study investigates whether patients with a first-time presentation of chest pain and on-target LDL-C levels and intermediate FRS/ESC-Score risks, display a high inflammatory burden linked to myocardial injury and whether inflammation at admission affects the re-event rate up to 6 years follow-up. METHODS: Blind assessments of novel inflammatory markers such as Glycoprotein A and B via nuclear magnetic resonance (NMR), cytokines, hsCRP, Neutrophil-to-Lymphocyte ratio (NLR) and Lipoprotein(a) levels were examined. Out of 198 chest pain patients screened, 97 met the inclusion criteria at admission. RESULTS: cTnI(+) patients (>61 ng/L) with elevated Lipoprotein(a), showed significantly increased levels of Glycoprotein A and B, hsCRP, IL-6, a high NLR and a reduced left ventricular ejection fraction (%) compared to cTnI(-) individuals. Those patients, with a higher inflammatory burden at hospital admission (hsCRP, IL-6, Glycoprotein A and B, and Lipoprotein(a)) had a higher re-event rate at follow-up. CONCLUSIONS: Inflammation and Lipoprotein(a) levels were particularly prominent in patients presenting with reduced left ventricular ejection fraction. Notably, Glycoproteins A/B emerge as novel markers of inflammation in these patients. Our study highlights the significantly higher impact of inflammatory burden in patients with chest pain and high level of myocardial damage than in those with lower myocardial affectation, even when they all had lipid levels well controlled. Inflammation at the time of admission influenced the re-event rate over a follow-up period of up to 6 years.

Long-term sex differences in atherosclerotic cardiovascular disease in individuals with heterozygous familial hypercholesterolaemia in Spain: a study using data from SAFEHEART, a nationwide, multicentre, prospective cohort study.

BACKGROUND: Sex differences in atherosclerotic cardiovascular disease (ASCVD) in familial hypercholesterolaemia have been reported but are not fully established. We aimed to assess sex differences in the risk of ASCVD and life-time burden of ASCVD in patients with heterozygous familial hypercholesterolaemia. METHODS: SAFEHEART is a nationwide, multicentre, long-term prospective cohort study conducted in 25 tertiary care hospitals and one regional hospital in Spain. Participants in the SAFEHEART study aged 18 years or older with genetically confirmed familial hypercholesterolaemia were included in our analysis. Data were obtained between Jan 26, 2004, and Nov 30, 2022. ASCVD and age at onset were documented at enrolment and at follow-up. Our aim was to investigate the differences by sex in the risk and burden of ASCVD in patients with heterozygous familial hypercholesterolaemia, over the study follow-up and over the life course. The SAFEHEART study is registered with ClinicalTrials.gov, NCT02693548. FINDINGS: Of the 5262 participants in SAFEHEART at the time of analysis, 3506 (1898 [54·1%] female and 1608 [45·9%] male participants) met the inclusion criteria and were included in the current study. Mean age was 46·1 years (SD 15·5) and median follow-up was 10·3 years (IQR 6·4-13·0). Mean on-treatment LDL-cholesterol at follow-up was 3·1 mmol/L (SD 1·4) in females and 3·0 mmol/L (1·5) in males. LDL-cholesterol reductions over time were similar in both sexes (1·39 mmol/L [95% CI 1·30-1·47] absolute reduction in females vs 1·39 mmol/L [1·29-1·48] in males; p=0·98). At enrolment, 130 (6·8%) females and 304 (18·9%) males (p<0·0001) had cardiovascular disease. During follow-up, 134 (7·1%) females and 222 (13·8%) males (p<0·0001) had incident cardiovascular events. Median age at first ASCVD event (mostly due to coronary artery disease) was 61·6 years (IQR 50·0-71·4) in females and 50·6 years (42·0-58·6) in males (p<0·0001). The adjusted hazard ratio for ASCVD in males compared with females during follow-up was 1·90 (95% CI 1·49-2·42) and for cardiovascular death was 1·74 (1·11-2·73). Major adverse cardiovascular disease event (MACE)-free survival from birth was lower in males than females (hazard ratio 3·52 [95% CI 2·98-4·16]; p<0·0001). Median MACE-free survival time was 90·1 years (95% CI 86·5-not estimable) in females and 71·0 years (69·2-74·6) in males. The age at which 25% of female participants have had a MACE event was 74·9 years, this figure was 55·5 years in male participants. INTERPRETATION: Our findings suggest that the burden and risk of ASCVD are markedly lower in females than males with familial hypercholesterolaemia. The impact of sex needs to be considered to improve risk stratification and personalised management in patients with heterozygous familial hypercholesterolaemia. FUNDING: Fundación Hipercolesterolemia Familiar, the Instituto de Salud Carlos III, and Next Generation EU funds from the Recovery and Resilience Mechanism Program. TRANSLATION: For the Spanish translation of the abstract see Supplementary Materials section.

CD66b+/CD68+ circulating extracellular vesicles, lactate dehydrogenase and neutrophil-to-lymphocyte ratio can differentiate coronavirus disease 2019 severity during and after infection.

Coronavirus disease 2019 (COVID-19) has been a major public health burden. We hypothesised that circulating extracellular vesicles (cEVs), key players in health and disease, could trace the cell changes during COVID-19 infection and recovery. Therefore, we studied the temporal trend of cEV and inflammatory marker levels in plasma samples of COVID-19 patients that were collected within 24 h of patient admission (baseline, n = 80) and after hospital discharge at day-90 post-admission (n = 59). Inflammatory markers were measured by standard biochemical methods. cEVs were quantitatively and phenotypically characterized by high-sensitivity nano flow cytometry. In patients recovered from COVID-19 lower levels of inflammatory markers were detected. cEVs from vascular (endothelial cells) and blood (platelets, distinct immune subsets) cells were significantly reduced at day-90 compared to admission levels, a pattern also observed for cEVs from progenitor, perivascular and epithelial cells. The best discriminatory power for COVID-19 severity was found for inflammatory markers lactate dehydrogenase and neutrophil-to-lymphocyte ratio and for granulocyte/macrophage-released CD66b+/CD68+-cEVs. Albeit inflammatory markers were good indicators of systemic inflammatory response and discriminators of COVID-19 remission, they do not completely reveal cell stress and organ damage states. cEVs reaching baseline pre-infection levels at 90 days post-infection in recovered patients discriminate parental cells affected by disease.

Development of a long noncoding RNA-based machine learning model to predict COVID-19 in-hospital mortality.

Tools for predicting COVID-19 outcomes enable personalized healthcare, potentially easing the disease burden. This collaborative study by 15 institutions across Europe aimed to develop a machine learning model for predicting the risk of in-hospital mortality post-SARS-CoV-2 infection. Blood samples and clinical data from 1286 COVID-19 patients collected from 2020 to 2023 across four cohorts in Europe and Canada were analyzed, with 2906 long non-coding RNAs profiled using targeted sequencing. From a discovery cohort combining three European cohorts and 804 patients, age and the long non-coding RNA LEF1-AS1 were identified as predictive features, yielding an AUC of 0.83 (95% CI 0.82-0.84) and a balanced accuracy of 0.78 (95% CI 0.77-0.79) with a feedforward neural network classifier. Validation in an independent Canadian cohort of 482 patients showed consistent performance. Cox regression analysis indicated that higher levels of LEF1-AS1 correlated with reduced mortality risk (age-adjusted hazard ratio 0.54, 95% CI 0.40-0.74). Quantitative PCR validated LEF1-AS1's adaptability to be measured in hospital settings. Here, we demonstrate a promising predictive model for enhancing COVID-19 patient management.

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.

Lactiplantibacillus plantarum strains KABP011, KABP012, and KABP013 modulate bile acids and cholesterol metabolism in humans.

AIMS: Probiotics with high bile salt hydrolase (BSH) activity have shown to promote cardiovascular health. However, their mechanism(s) of action remain poorly understood. Here, we performed a pilot exploratory study to investigate effects of a 4-week intervention with escalating doses of a BSH-active formula containing Lactiplantibacillus plantarum strains KABP011, KABP012, and KABP013 on bile acid (BA), lipid profile, and lipoprotein function. METHODS AND RESULTS: Healthy overweight individuals were included in this study. The probiotic intake was associated with a progressive decrease of conjugated BAs in serum, due to the reduction of tauro- and glyco-conjugated forms. Plasma levels of fibroblast growth factor-19 were significantly reduced and correlated with BA changes. The probiotic induced significant changes in serum lipids, with reduction in non-HDL cholesterol (non-HDLc) and LDL cholesterol (LDLc) levels. The largest decrease was evidenced in the subgroup with higher baseline LDLc levels (LDLc > 130 mg/dL). Fasting levels of circulating apolipoprotein(Apo) B100 and ApoB48 were significantly reduced. Importantly, the decrease in non-HDLc levels was associated with a significant reduction in small LDL particles. Functional testing indicated that LDL particles had a significantly lower susceptibility to oxidation, while HDL particles gained antioxidant capacity after the probiotic intake. The microbiota profile in faeces collected at the end of the study was enriched with members of class Desulfovibrio, a taurine-consuming bacteria, likely because of the increase in free taurine in the gut due to the BSH activity of the probiotic. CONCLUSION: The intervention with L. plantarum strains induces beneficial effects on BA signature and lipoprotein profile. It reduces ApoB and small LDL levels and LDL susceptibility to oxidation and increases HDL antioxidant capacity. These metabolic profile changes suggest increased protection against atherosclerotic disease.

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.

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 / 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)

Incidencia de eventos cardiovasculares y cambios en el riesgo estimado y en el tratamiento de la hipercolesterolemia familiar: registro SAFEHEART / Incidence of cardiovascular events and changes in the estimated risk and treatment of familial hypercholesterolemia: the SAFEHEART registry

INTRODUCCIÓN Y OBJETIVOS: El estudio SAFEHEART se diseñó para analizar la situación y mejorar el conocimiento de la hipercolesterolemia familiar heterocigota (HFH) en España. Nuestro objetivo es determinar la tasa de incidencia de eventos cardiovasculares, el riesgo estimado de sufrir un evento y su modificación, el empleo de tratamiento hipolipemiante y la consecución de objetivos de colesterol unido a lipoproteínas de baja densidad en pacientes con HFH. MÉTODOS: El SAFEHEART es un estudio prospectivo de cohorte, abierto, multicéntrico, de escala nacional, con seguimiento protocolizado a largo plazo en una población de HFH caracterizada molecularmente. Se analizó a los pacientes mayores de 18 años con seguimiento completo. RESULTADOS: El análisis en este estudio se hizo con 2.648 pacientes con HFH. La mediana de seguimiento fue de 6,6 (4,8-9,7) años. La tasa de incidencia general de eventos cardiovasculares fue de 1,3 eventos/100 pacientes-año. El riesgo estimado de sufrir un evento cardiovascular a 10 años se redujo en el seguimiento, y pasó del 1,6 al 1,3% (p <0,001). En el último seguimiento, el 20,6 y el 22,2% de los pacientes en prevención primaria y secundaria consiguieron un colesterol unido a lipoproteínas de baja densidad <100 y <70 mg/dl respectivamente. CONCLUSIONES: En este estudio se muestra la tasa de incidencia de eventos cardiovasculares, el riesgo estimado de sufrir un evento cardiovascular en la mayor población de pacientes con HF en España, así como su modificación, la consecución de objetivos en colesterol unido a lipoproteínas de baja densidad y su tratamiento. Aunque el riesgo cardiovascular de la HFH es elevado, un adecuado tratamiento reduce la probabilidad de sufrir un evento

INTRODUCTION AND OBJECTIVES: The SAFEHEART study was designed to analyze the situation of familial heterozygous hypercholesterolemia (FHH) and improve knowledge of this disease in Spain. Our objective was to determine the incidence rate of cardiovascular events, the estimated risk of developing an event and its modification, the use of lipid-lowering treatment, and the achievement of low-density lipoprotein cholesterol targets in patients with FHH. METHODS: SAFEHEART is a prospective, open, multicenter, nationwide cohort study, with long-term protocol-based follow-up in a population of individuals with molecularly-characterized FHH. We analyzed patients older than 18 years with complete follow-up. RESULTS: We included 2648 patients with FHH. The median follow-up was 6.6 (4.8-9.7) years. The overall incidence rate of cardiovascular events was 1.3 events/100 patient-years. After the follow-up, the 10-year estimated risk of developing a cardiovascular event was reduced from 1.6% to 1.3% (P <.001). In the last follow-up, 20.6% and 22.2% of the patients in primary and secondary prevention achieved low-density lipoprotein cholesterol values <100mg/dL and <70mg/dL, respectively. CONCLUSIONS: This study was performed in the largest population of patients with FHH in Spain. We identified the incidence rate of cardiovascular events, the estimated risk of developing a cardiovascular event and its modification, the achievement of low-density lipoprotein cholesterol targets, and the therapeutic management in this population. Although the cardiovascular risk of FHH is high, appropriate treatment reduces the likelihood of an event

El ácido acetilsalicílico reduce la liberación de micropartículas eritrocitarias, monocitarias y de células del músculo liso vascular en pacientes diabéticos / Microparticle shedding by erythrocytes, monocytes and vascular smooth muscular cells is reduced by aspirin in diabetic patients

Introducción y objetivos: La diabetes mellitus está asociada a mayor riesgo de enfermedad cardiovascular y su prevalencia está en aumento. La diabetes mellitus induce estrés metabólico a las células vasculares, lo cual promueve la activación plaquetaria y la disfunción vascular. El grado de activación de las células vasculares se puede medir con el número y el fenotipo de las micropartículas circulantes. El objetivo de este estudio es investigar el efecto de una dosis de ácido acetilsalicílico con acción inhibidora plaquetaria en el número y el tipo de las micropartículas liberadas a la circulación. Métodos: Se inscribió a 43 pacientes diabéticos que recibieron una dosis diaria de 100 mg de ácido acetilsalicílico durante 10 días, con objeto de cubrir el periodo medio de vida de las plaquetas en la circulación. Antes y después del periodo de intervención, se caracterizaron y cuantificaron las micropartículas circulantes mediante citometría de flujo. Resultados: Respecto a los pacientes con diabetes mellitus tipo 2, aquellos con diabetes mellitus tipo 1 presentaron el doble de micropartículas circulantes positivas para factor tisular (derivadas de plaquetas y monocitos) y micropartículas positivas para selectina E de origen endotelial. El tratamiento con ácido acetilsalicílico inhibió significativamente las plaquetas, puesto que la generación de tromboxano derivado de la ciclooxigenasa 1 disminuyó un 99%. Se produjo una reducción significativa de las micropartículas derivadas de eritrocitos, monocitos activados y células de músculo liso tras 10 días de administración de ácido acetilsalicílico. Conclusiones: Estos resultados indican que: a) las células vasculares y hemáticas de los pacientes con diabetes mellitus tipo 1 están expuestas a un mayor estrés continuo, que se refleja en el origen y la cantidad de sus micropartículas; b) el tratamiento con ácido acetilsalicílico inhibe la activación de las células de la pared vascular y la liberación de micropartículas, y c) los efectos del ácido acetilsalicílico son similares en la diabetes mellitus tipos 1 y 2 (AU)

Introduction and objectives: Diabetes mellitus is associated with an enhanced risk for cardiovascular disease and its prevalence is increasing. Diabetes induces metabolic stress on blood and vascular cells, promoting platelet activation and vascular dysfunction. The level of vascular cell activation can be measured by the number and phenotype of microparticles found in the circulation. The aim of this study was to investigate the effect of a platelet-inhibitory dose of aspirin on the number and type of microparticles shed to the circulation. Methods: Forty-three diabetic patients were enrolled in the study and received a daily dose of 100 mg of aspirin for 10 days to cover the average platelet life-span in the circulation. Before and after the intervention period, circulating microparticles were characterized and quantified by flow cytometry. Results: Type 1 diabetic patients had about twice the number of tissue factor-positive circulating microparticles (derived both from platelets and monocytes) and endothelial-derived E-selectin positive microparticles than type 2 diabetic patients. Aspirin therapy significantly inhibited platelets since cyclooxygenase 1 derived thromboxane generation levels were reduced by 99%. Microparticles derived from erythrocytes, activated monocytes, and smooth muscle cells were significantly reduced after 10 days of aspirin administration. Conclusions: These results indicate that: a) vascular and blood cells in type 1 diabetic patients are exposed to more sustained stress shown by their specific microparticle origin and levels; b) aspirin therapy inhibits vascular wall cell activation and microparticle shedding, and c) the effects of aspirin are similar in type 1 and 2 diabetes (AU)

El polimorfismo rs11613352 (genotipo TT) se asocia con disminución de triglicéridos y aumento de HDL en pacientes con hipercolesterolemia familiar / rs11613352 polymorphism (TT Genotype) associates with a decrease of triglycerides and an increase of HDL in familial hypercholesterolemia patients

Introducción y objetivos Estudios recientes de asociación de genoma completo han identificado un locus en el cromosoma 12q.13.3 asociado con las concentraciones plasmáticas de triglicéridos y colesterol unido a lipoproteínas de alta densidad; rs11613352 es el polimorfismo de un solo nucleótido líder en dicho locus. El objetivo del estudio es investigar la implicación de rs11613352 en una población con elevado riesgo cardiovascular por hipercolesterolemia familiar. Métodos Se genotipificó mediante análisis Taqman® el polimorfismo de un solo nucleótido en una cohorte de 601 pacientes con hipercolesterolemia familiar no relacionados, y se analizó su asociación genética con las concentraciones plasmáticas de triglicéridos y colesterol unido a lipoproteínas de alta densidad, mediante métodos multivariables basados en regresión lineal. Resultados La frecuencia alélica mínima fue de 0,17 y las frecuencias genotípicas, 0,69, 0,27 y 0,04 para los genotipos CC, CT y TT respectivamente. El polimorfismo se asoció de manera recesiva (genotipo TT) con disminución de los triglicéridos (p = 0,002) y aumento de colesterol unido a lipoproteínas de alta densidad (p = 0,021) tras ajustar por edad y sexo. Conclusiones El polimorfismo rs11613352 puede contribuir a modular el riesgo cardiovascular al modificar las concentraciones plasmáticas de lípidos en los pacientes con hipercolesterolemia familiar (AU)

Introduction and objectives: Recent genome-wide association studies have identified a locus on chromosome 12q13.3 associated with plasma levels of triglyceride and high-density lipoprotein cholesterol, with rs11613352 being the lead single nucleotide polymorphism in this genome-wide association study locus. The aim of the study is to investigate the involvement of rs11613352 in a population with high cardiovascular risk due to familial hypercholesterolemia. Methods: The single nucleotidepoly morphism was genotyped by Taqman W assay in a cohortof601unrelated familial hypercholesterolemia patients and its association with plasma triglyceride and high-density lipoprotein cholesterol levels was analyzed by multivariate methods based on linear regression. Results: Minimal allele frequency was 0.17 and genotype frequencies were 0.69, 0.27, and 0.04 for CC, CT, and TT genotypes, respectively. The polymorphism is associated in a recessive manner (TT genotype) with a decrease in triglyceride levels (P = .002) and with an increase in high-density lipoprotein cholesterol levels (P = .021) after adjusting by age and sex. Conclusions: The polymorphism rs11613352 may contribute to modulate the cardiovascular risk by modifying plasma lipid levels in familial hypercholesterolemia patients (AU)

El enriquecimiento de la dieta con polifenoles previene la disfunción endotelial coronaria mediante la activación de la vía de Akt/eNOS / Polyphenol-enriched diet prevents coronary endothelial dysfunction by activating the akt/enos pathway

Introducción y objetivos La dieta mediterránea rica en polifenoles se ha demostrado cardioprotectora, pero se desconocen los mecanismos implicados. Se ha investigado los efectos de un extracto de granada rico en polifenoles en la función coronaria de un modelo porcino. Métodos Los animales ingirieron durante 10 días una dieta normocolesterolémica o hipercolesterolémica. La mitad de los cerdos recibieron un suplemento de 625 mg/día de un extracto de granada (Pomanox®; 200 mg punicalaginas/día). Se analizó (flujo-Doppler) la vasodilatación tras la administración coronaria de acetilcolina, ionóforo de calcio, nitroprusiato de sodio y L-NG-monometilarginina (inhibidor de la enzima óxido nítrico sintasa endotelial) y la activación del eje Akt/óxido nítrico sintasa endotelial, la expresión de proteína quimiotáctica de monocitos–1 y el daño oxidativo coronario del ácido desoxirribonucleico y la oxidación de las lipoproteínas. Resultados Pomanox® redujo la disfunción endotelial inducida por la dieta hipercolesterolémica a valores de animales normocolesterolémicos tras la estimulación con acetilcolina y/o ionóforo de calcio. Este efecto se asoció con mayor actividad coronaria de Akt/óxido nítrico sintasa endotelial, menor expresión de proteína quimioatáctica de monocitos–1 y menor daño oxidativo. Las lipoproteínas de alta densidad mostraron mayor capacidad antioxidante y las lipoproteínas de baja densidad fueron más resistentes a la oxidación. Pomanox® no afectó a la vasorrelajación de los animales normocolesterolémicos. Todos los animales mostraron similar vasodilatación tras la administración de nitroprusiato de sodio y la L-NG-monometilarginina bloqueó la vasorrelajación de todos los agentes vasoactivos, a excepción del nitroprusiato de sodio. Conclusiones La toma de Pomanox® previene la disfunción endotelial coronaria inducida por la hiperlipemia, al preservar el eje Akt/óxido nítrico sintasa endotelial y contrarrestar la inflamación y el daño oxidativo vascular (AU)

Introduction and objectives: The Mediterranean diet, rich in polyphenols, has shown to be cardioprotective. However the mechanisms involved remain unknown. We investigated whether supplementation with a pomegranate extract rich in polyphenols renders beneficial effects on coronary function in a clinically relevant experimental model and characterized the underlying mechanisms. Methods: Pigs were fed a 10-day normocholesterolemic or hypercholesterolemic diet. Half of the animals were given a supplement of 625 mg/day of a pomegranate extract (PomanoxW; 200 mg punicalagins/day). Coronary responses to escalating doses of vasoactive drugs (acetylcholine, calciumionophore, and sodium nitroprusside) and L-NG-monomethylarginine (endothelial nitric oxide synthase inhibitor) were measured using flow Doppler. Akt/endothelial nitric oxide-synthase axis activation, monocyte chemoattractant protein-1 expression, oxidative deoxyribonucleic acid damage in the coronary artery, and lipoprotein resistance to oxidation were evaluated. Results: In dyslipidemic animals, PomanoxW supplementation prevented diet-induced impairment of endothelial relaxation, reaching vasodilatory values comparable to normocholesterolemic animals upon stimulation with acetylcholine and/or calcium ionophore. These beneficial effects were associated with vascular Akt/endothelial nitric oxide-synthase activation and lower monocyte chemoattractant protein-1 expression. PomanoxW supplementation reduced systemic oxidative stress (higher high-density (..) (AU)

Los polimorfismos del gen LRP1 se asocian al riesgo prematuro de enfermedad cardiovascular en pacientes con hipercolesterolemia familiar / LRP1 gene polymorphisms are associated with premature risk of cardiovascular disease in patients with familial hypercholesterolemia

Introducción y objetivos. La expresión del gen LRP1, muy acentuada en la placa aterosclerótica, se asocia con un aumento en la incorporación de lípidos por la pared vascular. Nuestro objetivo es analizar si el gen LRP1 modula el riesgo genético de aparición de enfermedad cardiovascular prematura en pacientes con hipercolesterolemia familiar mediante asociación de polimorfismos. Métodos. Se genotipificaron 10 polimorfismos de un solo nucleótido del gen LRP1 (rs715948, rs1799986, rs1800127, rs7968719, rs1800176, rs1800194, rs1800181, rs1140648, rs1800164 y rs35282763) en 339 pacientes (77 con enfermedad cardiovascular y 262 sin enfermedad) pertenecientes al estudio SAFEHEART. Resultados. Se halló una asociacion significativa con el polimorfismo c.677C>T (rs1799986) tras ajustar por sexo, edad, índice de masa corporal y efecto de la mutación del receptor de lipoproteínas de baja densidad con el modelo dominante (CT+TT frente a CC: odds ratio=1,94; intervalo de confianza del 95%, 1,08-3,48; p=0,029). Tras ampliar la población a 648 individuos (133 con enfermedad y 515 sin ella), se obtuvieron resultados similares (odds ratio=1,83; intervalo de confianza del 95%, 1,16-2,88; p=0,011). Conclusiones. El polimorfismo c.677C>T se asocia con aumento del riesgo de enfermedad cardiovascular prematura en la hipercolesterolemia familiar. Aunque su implicación en la alteración de un patrón normal de procesamiento del ARNm no se ha corroborado, no se descarta que dicho polimorfismo se halle en desequilibrio de ligamento con otro polimorfismo funcional en el que resida la relación causa-efecto con la enfermedad cardiovascular. Serían necesarios más estudios para corroborar los resultados y localizar las variantes genéticas relacionadas con dicho polimorfismo implicadas en conferir riesgo de enfermedad cardiovascular (AU)

Introduction and objectives. LRP1 gene overexpression in atherosclerotic plaque is associated with increased lipid uptake through the vascular wall. The aim of the study was to analyze whether LRP1 modulates the genetic risk of developing premature cardiovascular disease in familial hypercholesterolemia, using single nucleotide polymorphism association analysis. Methods. Ten polymorphisms of the LRP1 gene (rs715948, rs1799986, rs1800127, rs7968719, rs1800176, rs1800194, rs1800181, rs1140648, rs1800164, and rs35282763) were genotyped in 339 patients (77 with premature cardiovascular disease and 262 without) in the SAFEHEART study. Results. The c.677C>T (rs1799986) polymorphism showed a significant association with premature cardiovascular disease after adjusting by sex, age, body mass index, and the effect of the low-density lipoprotein receptor mutation in the dominant model (CT+TT vs CC: odds ratio=1.94; 95% confidence interval, 1.08-3.48; P=.029). Similar results were observed after increasing the sample to 648 subjects (133 with premature cardiovascular disease vs 515 without [odds ratio=1.83; 95% confidence interval, 1.16-2.88; P=.011]). Conclusions. The c.677C>T polymorphism is associated with increased rates of premature cardiovascular disease in familial hypercholesterolemia. Although we were unable to show that this polymorphism was involved in the alteration of normal mRNA splicing patterns, the possibility that it is in strong linkage disequilibrium with another functional polymorphism cannot be ruled out and would explain the cause-effect relationship with cardiovascular disease risk in this population. Further studies are needed to replicate the results and to localize the putative genetic variants associated with this polymorphism (AU)

Effects of rosuvastatin on the coordinated proteomic response ofhuman coronary smooth muscle cells to low density lipoproteins

Introducción: El beneficio de las estatinas en la reducción de eventos coronarios se ha asociado con la repoblación por células musculares lisas (CML) de centros acelulares de placas de ateroma y su estabilización. Las LDL de la intima modulan el fenotipo de las CML e inducen desestabilización de las placas. Nosotros hemos demostrado que las LDL inhiben el remodelado vascular debido a un efecto sobre proteínas citoesqueléticas. Aquí, mediante una aproximación proteómica hemos estudiado si la rosuvastatina revierte los efectos de concentraciones aterógena sde LDL en las CML humanas. Métodos y Resultados: CML tratadas con/sin 10 M rosuvastatina se incubaron en presencia/ausencia de 100 g/mL LDL (24 h). Mediante 2DE y MALDI-ToF MS identificamos 39 proteínas no redundantes (52 spots) con expresión diferencial en CML tratadas con LDL. La rosuvastatina revirtió el efecto de las LDL en 13 de estas proteínas. Así, 4 proteínas disminuyeron su intensidad, 6 aumentaron y 3 proteínas multispot cambiaron su patrón proteómico. Estas proteínas se localizaron en el retículo endoplasmático, mitocondria, núcleo, membrana celular, citoesqueleto y citoplasma. La rosuvastatina afectó a proteínas involucradas en diversas funciones como regulación del citoesqueleto, actividad chaperona, metabolismo de carbohidratos, síntesis y plegamiento de proteínas, actividad cinasa, procesos redox, citoproteccióny proliferación celular. Conclusiones: Los resultados demuestran que la rosuvastatina revierte el efecto de las LDL en CML a través de su efecto sobre proteínas funcionales, relevantes para el metabolismo y dinámica celular, lo que podría contribuir al efecto beneficioso de las estatinas en la estabilización de placas ateroscleróticas ricas en lípidos en la aterosclerosis humana (AU)

Introduction: The clinical benefits of statins in reducing coronary events have been related to repopulation of the acellular core of atheromatous plaques with vascular smooth muscle cells(VSMC) and plaque stabilization. Intimal low-density lipoproteins (LDL) have been associated with VSMC phenotypic modulation and plaque destabilization. We have recently reported that LDL impair vascular remodelling because of changes affecting cytoskeleton proteins. Here, we used a proteomic approach to study whether rosuvastatin reverses the effects induced by atherogenic concentrations of LDL in human VSMC. Methods and Results: VSMC treated with/without 10 M (..) (AU)

El consumo de futas y hortalizas ayuda a prevenir el daño endotelial / Consumption of fruits and vegetables in the prevention of endothelial damage

The endothelium helps to maintain the normal structure and homeostasis of the vasculature. However, chronic exposure to cardiovascular (CV) risk factors causes endothelial dysfunction, a phenomenon that is characterized by inflammation, reduced bioavailability of nitric oxide (NO) and a prothrombotic state. Epidemiological studies have shown that regular consumption of fruits and vegetables reduces CV risk, which has caused interest in knowing the bioactive compounds and the mechanisms involved. Among the components that protect the endothelium are antioxidants (vitamin C, vitamin E and poly phenols) and polyunsaturated fatty acids. Vitamin C and E promote vasodilatation protecting NO by blocking the reactive oxygen species (ROS). Poly phenols improve endothelial function primarily by increasing levels of NO, and inhibition of angiogenesis and platelet activation. Diets rich in poly-unsaturated fatty acids have shown beneficial effects by reducing the gene expression of cyclooxygenase-2 and the expression of cell adhesion molecules. This review mainly highlights the current understanding of endothelial dysfunction and the protective effect of endothelial cells by bioactive components of fruits and vegetables.

El endotelio normal ayuda a mantener la estructura y la hemostasia vascular. Sin embargo, la exposición crónica a factores de riesgo cardiovascular (CV) produce disfunción endotelial, fenómeno que se caracteriza por inflamación, disminución en la biodisponibilidad de óxido nítrico (NO) y un estado protrombótico. Estudios epidemiológicos han demostrado que el consumo regular de frutas y hortalizas disminuye el riesgo CV, lo que ha causado interés en conocer los compuestos bioactivos y los mecanismos involucrados. Entre los componentes que protegen el endotelio se encuentran las moléculas antioxidantes (vitamina C, vitamina E y polifenoles) y ácidos grasos poliinsaturados. Las vitaminas C y E favorecen la vasodilatación protegiendo el NO al bloquear las especies reactivas del oxigeno (ROS). Los polifenoles mejoran la función endotelial principalmente por el aumento de los niveles de NO, y la inhibición de la angiogénesis y de la activación plaquetaria. Dietas ricas en ácidos grasos poliinsaturados han mostrado efectos beneficiosos, mediante la reducción de la expresión géni-ca de la ciclooxigenasa-2 y de la expresión de moléculas de adhesión celular. Esta revisión principalmente señala los conocimientos actuales de la disfunción endotelial y el efecto protector de las células endoteliales por componentes bioactivos de frutas y hortalizas.

Serum proteome in acute myocardial infarction

Introduction: Acute myocardial infarction (AMI) is one of the major causes of mortality and morbidity worldwide. Despite the efforts being made, there is a lack of early markers for the prevention, diagnosis and treatment of ischemic syndromes. Proteomic expression profiling technologies are a highly important tool for research into new serum biomarkers for the diagnosis and prognosis of acute coronary syndromes. Methods: Serum samples were sub-fractionated with different methods for the depletion of high-abundance proteins. The low-abundance fraction was analyzed by two-dimensional electrophoresis(2-DE), followed by protein identification with mass-spectrometry (MALDI-TOF).The proteomic profiles of serum samples from AMI patients and controls were analyzed and compared. Results: Through depletion of six high-abundance proteins in 2-DE analysis of serum samples,569 spots were detected, of which 131 spots were only detected in the AMI group and 27 were only detected in controls. The comparative analysis between AMI-patients and controls revealed a group of differential protein spots involved in seven different biological functions. The main changes were found in proteins involved in the immune system and lipid metabolism. Conclusions: In this study, by using a 2-DE differential approach, we developed a highly reproducible methodology for the analysis of coordinated changes in serum proteome patterns that occur within the first 6 hours after the onset of an AMI (AU)

Introducción El infarto agudo de miocardio (IAM) es una de las mayores causas de mortalidad y morbilidad en el mundo. A pesar de todos los esfuerzos hay una falta de marcadores para la prevención, el diagnóstico y el tratamiento de la fase temprana de los síndromes isquémicos. Las técnicas proteómicas son una herramienta muy importante para la búsqueda de nuevos biomarcadores para el diagnóstico y el pronóstico de los síndromes coronarios agudos. Métodos Las muestras de suero se sub-fraccionaron mediante diferentes métodos para eliminar las proteínas mayoritarias. La fracción de proteínas de menor abundancia se analizó mediante electroforesis bidimensional (2-DE), seguida de la identificación de proteínas mediante espectrometría de masas (MALDI-TOF). Se analizó y comparó el patrón proteómico de los pacientes IAM y el grupo control. Resultados Mediante la eliminación de las seis proteínas mayoritarias en el análisis por 2-DE se detectaron un total de 569 spots, de los cuales 131 sólo se detectaron en el grupo infarto y 27 sólo en el grupo control. El análisis comparativo entre los pacientes IAM y los controles reveló un grupo de spots proteicos con un patrón de (..) (AU)