ABSTRACT
BACKGROUND: The familial hypercholesterolemia (FH) diagnosis is based on clinical and genetic criteria. A relevant proportion of FH patients fulfilling the criteria for definite FH have negative genetic testing. Increasing the identification of true genetic-based FH is a clinical challenge. Deepening the analysis of lipoprotein alterations could help increase the yield of genetic testing. We evaluated whether the number, size, and composition of lipoproteins assessed by 1H-NMR could increase the identification of FH patients with pathogenic gene variants. METHODS: We studied 294 clinically definite FH patients, 222 (75.5%) with positive genetic testing, as the discovery cohort. As an external validation cohort, we studied 88 children with FH, 72 (81%) with positive genetic testing. The advanced lipoprotein test based on 1H-NMR (Liposcale®) was performed at baseline after a lipid-lowering drug wash-out of at least 6 weeks. The association of variables with genetic variants was evaluated by random forest and logistic regression. Areas under the curve (AUCs) were calculated. A predictive formula was developed and applied to the validation cohort. RESULTS: A formula derived from NMR lipoprotein analyses improved the identification of genetically positive FH patients beyond LDL-C levels (AUC=0.87). The parameters contributing the most to the identification formula were LDL particle number, HDL size and remnant cholesterol. The formula also increases the classification of FH children with a pathogenic genetic variation. CONCLUSIONS: NMR lipoprotein profile analysis identifies differences beyond standard lipid parameters that help identify FH with a positive pathogenic gene variant, increasing the yield of genetic testing in FH patients.
ABSTRACT
BACKGROUND: The diabetogenic effect of statins has been well established by clinical trials, Mendelian randomisation studies and meta-analyses. According to large clinical trials, PCSK9 inhibitors (PCSK9i) have no deleterious impact on glucose metabolism. However, few real-life studies have yet evaluated the long-term effects of these drugs on glucose homeostasis and their impact on new-onset diabetes (NODM). METHODS: We studied 218 patients treated with either alirocumab or evolocumab (70% with familial hypercholesterolemia) for at least three years (PCSK9iG). We studied the NODM rate in the nondiabetic group at baseline (168) and overall glucose metabolism control in the whole group. Incidental DM was compared with two groups. The first was a propensity score matching (PSM)-selected group (n = 168) from the database of patients attending the Reus lipid unit (Metbank, n = 745) who were not on PCSK9i (PSMG). The second was a subgroup with a similar age range (n = 563) of the Di@bet.es study (Spanish prospective study on diabetes development n = 5072) (D@G). The incidence was reported as the percentage of NODM cases per year. RESULTS: The fasting glucose (FG) level of the subjects with normoglycaemia at baseline increased from 91 (86-95.5) to 93 (87-101) mg/dL (p = 0.014). There were 14 NODM cases in the PCSK9i group (2.6%/y), all among people with prediabetes at baseline. The incidence of NODM in PSMG and D@G was 1.8%/y (p = 0.69 compared with the PCSK9iG). The incidence among the subjects with prediabetes was 5.1%/y in the PCSK9iG, 4.8%/y in the PSMG and 3.9%/y in the D@G (p = 0.922 and p = 0.682, respectively). In the multivariate analysis, only the FG level was associated with the development of NODM in the PCSK9iG (OR 1.1; 95% CI: 1.0-1.3; p = 0.027). Neither FG nor A1c levels changed significantly in patients with DM at baseline. CONCLUSION: A nonsignificant increase in NODM occurred in the PCSK9iG, particularly in patients with prediabetes, compared with the PSMG and D@G groups. Baseline FG levels were the main variable associated with the development of DM. In the subjects who had DM at baseline, glucose control did not change. The impact of PCSK9i on glucose metabolism should not be of concern when prescribing these therapies.
Subject(s)
Diabetes Mellitus , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Prediabetic State , Humans , PCSK9 Inhibitors , Proprotein Convertase 9 , Glycemic Control , Prospective Studies , Diabetes Mellitus/diagnosis , Diabetes Mellitus/drug therapy , Diabetes Mellitus/epidemiology , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Glucose , Risk FactorsABSTRACT
BACKGROUND AND AIM: Triglyceride-rich lipoproteins (TRLs) can have an important role in atherosclerosis development due to their size and ability to penetrate the endothelium. While high plasma triglyceride (TG) levels and chronic inflammation are relevant in metabolic diseases, it remains unclear whether TGs are atherogenic or which TRL-TG-derived metabolites are responsible for inflammation. Here, we aimed to study the lipidome modifications of TRL particles enriched in TG in patients with hyperlipidemia and their associations with a proinflammatory status both in vivo and in vitro. METHODS: Using proton nuclear magnetic resonance (1 H-NMR), we analysed the plasma levels of glycoprotein acetyls and the TRL lipidomic profile of 307 patients with dyslipidemia. THP-1-derived macrophages were used as an in vitro model to explore the molecular inflammatory effects mediated by TRL. RESULTS: In vivo, higher TRL-TG levels were associated with higher circulating levels of NMR-measured glycoproteins (Glyc-A, Glyc-B and Glyc-F; p < .001). Lipidomic analysis showed that TRL-TG enrichment led to decreased cholesterol and phospholipid content (p < .01), an increase in omega-9, and a decrease in saturated fatty acids (p < .001). THP-1 macrophages exposed to increasing TRL particle concentrations augmented the secretion of IL-1ß and TNF-α, which varied based on particle composition. Particles with higher cholesterol and phospholipid contents exerted higher cytokine secretion. The activation of MAPK, Akt/NFκB, and caspase-1 was concurrent with this proinflammatory response. CONCLUSIONS: High TRL-TG levels are associated with a higher systemic inflammatory status and increased particle concentrations. In vitro, higher particle numbers increase proinflammatory cytokine secretion, with cholesterol and phospholipid-rich TRL being more proinflammatory.
Subject(s)
Hyperlipidemias , Lipidomics , Humans , Lipoproteins , Triglycerides , Cholesterol , Inflammation , Phospholipids , CytokinesABSTRACT
Rheumatoid arthritis (RA) is associated with problems beyond the joints such as cardiovascular (CV) disease. MicroRNA-24, -146 and -Let7a are associated with carotid plaque presence in RA patients. We evaluated whether these microRNAs were involved in the inflammatory state of RA, and we studied their gene targets to understand their role in inflammation and atherosclerosis. A total of 199 patients with RA were included. Inflammatory variables such as disease activity score 28 (DAS28) and erythrocyte sedimentation rate (ESR) were quantified. MicroRNAs were extracted from plasma and quantified with qPCR. Multivariate models and classification methods were used for analysis. The multivariate models showed that diminished expression of microRNA-146 was associated with inferior levels of DAS28-ESR, and the decreased expression of microRNA-24, -146 and -Let7a were associated with lowered ESR in the overall cohort. When microRNAs were evaluated globally, a global increase was associated with increased DAS28-ESR and ESR in the overall cohort. Sex-stratified analyses showed different associations of these microRNAs with the inflammatory variables. Finally, random forest models showed that microRNAs have a pivotal role in classifying patients with high and low inflammation. Plasmatic expressions of microRNA-24, -146 and -Let7a were associated with inflammatory markers of RA. These microRNAs are associated with both inflammation and atherosclerosis and are potential therapeutic targets for RA.
Subject(s)
Arthritis, Rheumatoid , Atherosclerosis , Cardiovascular Diseases , MicroRNAs , Plaque, Atherosclerotic , Humans , MicroRNAs/genetics , C-Reactive Protein/metabolism , Inflammation/genetics , Inflammation/complications , Plaque, Atherosclerotic/genetics , Plaque, Atherosclerotic/complications , Atherosclerosis/complications , Cardiovascular Diseases/complicationsABSTRACT
Introducción y objetivos: La estrategia de prevención cardiovascular en las comunidades autónomas (CCAA) puede ser variable, al estar transferidas las competencias en sanidad. El objetivo del estudio fue conocer el control de la dislipemia y la terapia hipolipemiante utilizada en pacientes de alto/muy alto riesgo cardiovascular (RCV) por CCAA. Métodos: Estudio descriptivo, transversal, multicéntrico no aleatorizado basado en una metodología de consenso. Se recogió información de práctica clínica en 145 áreas sanitarias de 17CCAA españolas mediante reuniones presenciales y cuestionarios realizados a los 435 médicos participantes. Se recopilaron datos agregados no identificables de 10 pacientes dislipémicos consecutivos que cada participante hubiera visitado recientemente. Resultados: De los 4.010 pacientes compilados, 649 (16%) eran de alto y 2.458 (61%) de muy alto RCV. La distribución de los 3.107 pacientes de alto/muy alto RCV fue equilibrada entre regiones, pero hubo diferencias interterritoriales (p<0,0001) en la consecución del objetivo de cLDL<70 e <55mg/dl, respectivamente. Las estatinas de alta intensidad en monoterapia o combinadas con ezetimiba y/o inhibidores PCSK9 se utilizaron en el 44, el 21 y el 4% de los pacientes de alto RCV, mientras que en los de muy alto RCV era del 38, del 45 y del 6%, respectivamente. El uso de estas terapias hipolipemiantes a nivel nacional fue significativamente diferente entre regiones (p=0,0079). Conclusiones: A pesar de que la distribución de los pacientes de alto/muy alto RCV fue similar entre CCAA, se identificaron diferencias interterritoriales en el grado de consecución del objetivo terapéutico en cLDL y de utilización de la terapia hipolipemiante. (AU)
Introduction and objective: The cardiovascular prevention strategy by autonomous communities can be variable since the competences in health are transferred. The objective of the study was to determine the degree of dyslipidaemia control and the lipid-lowering pharmacological therapy used in patients at high/very high cardiovascular risk (CVR) by autonomous communities. Methods: Observational, cross-sectional, descriptive study based on a consensus methodology. Information on the clinical practice of 145 health areas belonging to 17 Spanish autonomous communities was collected through face-to-face meetings and questionnaires administered to the 435 participating physicians. Furthermore, aggregate non-identifiable data were compiled from 10 consecutive dyslipidaemic patients that each participant had recently visited. Results: Of the 4010 patients collected, 649 (16%) had high and 2458 (61%) very high CVR. The distribution of the 3107 high/very high CVR patients was balanced across regions, but there were inter-regional differences (P<.0001) in the achievement of target LDL-C <70 and <55mg/dL, respectively. High-intensity statins in monotherapy or in combination with ezetimibe and/or PCSK9 inhibitors were used in 44, 21 and 4% of high CVR patients, while in those at very high CVR it rose to 38, 45 and 6%, respectively. The use of these lipid-lowering therapies at national level was significantly different between regions (P=.0079). Conclusions: Even though the distribution of patients at high/very high CVR was similar between autonomous communities, inter-territorial differences were identified in the degree of achievement of LDL cholesterol therapeutic goal and use of lipid-lowering therapy. (AU)
Subject(s)
Humans , Hyperlipidemias/prevention & control , Cardiovascular Diseases/therapy , Hypolipidemic Agents/therapeutic use , Cross-Sectional Studies , Epidemiology, Descriptive , Spain , Cardiovascular Diseases/prevention & controlABSTRACT
BACKGROUND AND AIM: Circulating biomarkers of metabolic and cardiovascular diseases can help in the early detection and prevention of those diseases. Using proton nuclear magnetic resonance (1H-NMR), we aimed to study the plasma levels of low-molecular-weight metabolites (LMWMs) in a cohort of 307 patients with metabolic diseases to assess their relationships with type-2 diabetes (T2D) and incident atherosclerotic cardiovascular disease (ASCVD). METHODS: We conducted a cross-sectional and prospective study. We included 307 patients attending the Lipid Unit of our University Hospital for the treatment of the following metabolic disturbances and associated disorders: T2D (73.9%), obesity (58.7%), and hypertension (55.1%). 1H-NMR was used to study the plasma levels of 13 LMWMs. LMWM serum concentrations were evaluated in patients with and without T2D. and the correlations with several parameters and their associations with T2D were analyzed. The association between LMWM levels at baseline and the development of ASCVD in patients with T2D after 10 years of follow-up was also evaluated. RESULTS: Among the LMWMs measured, the branched-chain amino acids (BCAAs) valine, leucine and isoleucine showed a positive association with several clinical and lipid-related biochemical parameters and inflammatory markers (p < 0.05). Likewise, these three BCAAS were associated with diabetes even after adjusting for covariates (p < 0.05). During the follow-up period of 10 years, 29 of the 185 patients with diabetes at baseline (15.68%) developed ASCVD. After adjusting for clinical covariates, baseline levels of valine and alanine were associated with the development of ASCVD (p < 0.05). CONCLUSION: Overall, our results indicated that plasma levels of LMWMs measured by 1H-NMR could be potential biomarkers associated with T2D. Moreover, alanine and valine can help in the early detection of the cardiovascular risk associated with this metabolic disease.
Subject(s)
Atherosclerosis , Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Humans , Diabetes Mellitus, Type 2/diagnosis , Diabetes Mellitus, Type 2/epidemiology , Cardiovascular Diseases/diagnosis , Cardiovascular Diseases/epidemiology , Cross-Sectional Studies , Prospective Studies , Alanine , Atherosclerosis/diagnosis , Atherosclerosis/epidemiology , LipidsABSTRACT
BACKGROUND AND AIMS: Both Nordic and Mediterranean diets are considered healthy despite notable regional differences. Although these dietary patterns may lower cardiovascular risk, it is unclear if they improve the lipoprotein phenotype in children with familial hypercholesterolemia (FH). The aim is to determine the impact of Nordic and Mediterranean diets on the advanced lipoprotein profile in children with heterozygous FH (HeFH). METHODS: This was a cross-sectional study performed in children with FH recruited from the Lipid Clinics at Sant Joan University Hospital in Reus (Spain) and Oslo University Hospital (Norway). Two-hundred fifty-six children (mean age 10 y/o; 48% girls): 85 Spanish and 29 Norwegian FH children, and 142 non-FH healthy controls (119 from Spain and 23 from Norway) were included in the study. A pathogenic FH-associated genetic variant was present in 81% of Spanish children with FH and all Norwegian children with FH. An 1H NMR based advanced lipoprotein test (Nightingale®) providing information on the particle number, size and lipid composition of 14 lipoprotein subclasses was performed and correlated to the dietary components. RESULTS: Levels of LDL-C, HDL-C and triglycerides were not significantly different between the Nordic and Mediterranean FH groups. Spanish children with FH had more LDL particles, mainly of the large and medium LDL subclasses, than Norwegian FH children. Spanish FH children also had more HDL particles, mainly medium and small, than Norwegian FH children. The mean LDL size of Spanish FH children was larger, while the HDL size was smaller than that of the Norwegian FH children. The HDL particle number and size were the main determinants of differences between the two groups. In Norwegian children with FH, dietary total fat and MUFAs showed a significant correlation with all apolipoprotein B-containing lipoproteins and LDL size, whereas there was no correlation to SFA. A weaker association pattern was observed in the Spanish children. CONCLUSIONS: The lipoprotein profiles of Spanish and Norwegian children showed differences when studied by 1H NMR. These differences were in part associated with differences in dietary patterns.
Subject(s)
Diet, Mediterranean , Hyperlipoproteinemia Type II , Humans , Cross-Sectional Studies , Hyperlipoproteinemia Type II/diagnosis , Hyperlipoproteinemia Type II/genetics , Lipoproteins/genetics , Phenotype , Dietary FatsABSTRACT
BACKGROUND: Alzheimer's disease (AD) and type 2 diabetes mellitus (T2DM) share metabolic alterations such as abnormal insulin and lipid metabolism and have some common genetic factors such as APOE genotype. Taking this into account, we hypothesized that we could identify common genetic factors involved in the development of diabetes and cardiovascular diseases. METHODOLOGY: We first genotyped 48 single nucleotide polymorphisms (SNPs) previously associated with AD in a cohort composed of 330 patients with cognitive impairment (CI) to assess their association with plasma lipids. Second, we conducted pleiotropy-informed conjunctional false discovery rate (FDR) analysis designed to identify shared variants between AD and plasma lipid levels. Finally, we used the SNPs to be found associated with lipid parameters and AD to search for associations with lipoprotein parameters in 281 patients with cardiometabolic risk. RESULTS: Five SNPs were significantly associated with lower levels of cholesterol transported in remnant lipoprotein particles (RLPc) in subjects with CI; among these SNPs was the rs73572039 variant in PVRL2. Stratified QQ-plots were conducted on GWAS designed for AD and triglycerides (TG). The cross-trait analysis resulted in a total of 22 independent genomic loci associated with both AD and TG levels with a conjFDR < 0.05. Among these loci, two pleiotropic variants were located in PVRL2 (rs12978931 and rs11667640). The three SNPs in PVRL2 were significantly associated with RLPc, TG, and number of circulating VLDL and HDL particles in subjects with cardiometabolic risk. CONCLUSIONS: We have identified three variants in PVRL2 that predispose individuals to AD that also influence the lipid profile that confers cardiovascular risk in T2DM subjects. PVRL2 is a potential new modulating factor of atherogenic dyslipidemia.
Subject(s)
Alzheimer Disease , Cardiovascular Diseases , Diabetes Mellitus, Type 2 , Dyslipidemias , Metabolic Syndrome , Humans , Alzheimer Disease/genetics , Alzheimer Disease/complications , Cardiovascular Diseases/genetics , Cholesterol , Diabetes Mellitus, Type 2/complications , Diabetes Mellitus, Type 2/genetics , Dyslipidemias/genetics , Dyslipidemias/complications , Genome-Wide Association Study , Metabolic Syndrome/genetics , Metabolic Syndrome/complications , Polymorphism, Single Nucleotide , TriglyceridesABSTRACT
INTRODUCTION AND OBJECTIVE: The cardiovascular prevention strategy by autonomous communities can be variable since the competences in health are transferred. The objective of the study was to determine the degree of dyslipidaemia control and the lipid-lowering pharmacological therapy used in patients at high/very high cardiovascular risk (CVR) by autonomous communities. METHODS: Observational, cross-sectional, descriptive study based on a consensus methodology. Information on the clinical practice of 145 health areas belonging to 17 Spanish autonomous communities was collected through face-to-face meetings and questionnaires administered to the 435 participating physicians. Furthermore, aggregate non-identifiable data were compiled from 10 consecutive dyslipidaemic patients that each participant had recently visited. RESULTS: Of the 4010 patients collected, 649 (16%) had high and 2458 (61%) very high CVR. The distribution of the 3107 high/very high CVR patients was balanced across regions, but there were inter-regional differences (P<.0001) in the achievement of target LDL-C <70 and <55mg/dL, respectively. High-intensity statins in monotherapy or in combination with ezetimibe and/or PCSK9 inhibitors were used in 44, 21 and 4% of high CVR patients, while in those at very high CVR it rose to 38, 45 and 6%, respectively. The use of these lipid-lowering therapies at national level was significantly different between regions (P=.0079). CONCLUSIONS: Even though the distribution of patients at high/very high CVR was similar between autonomous communities, inter-territorial differences were identified in the degree of achievement of LDL cholesterol therapeutic goal and use of lipid-lowering therapy.
Subject(s)
Anticholesteremic Agents , Dyslipidemias , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Hypercholesterolemia , Hyperlipidemias , Humans , Hypercholesterolemia/drug therapy , Hypercholesterolemia/epidemiology , Proprotein Convertase 9 , Spain , Cross-Sectional Studies , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Ezetimibe/therapeutic use , Hyperlipidemias/drug therapy , Cholesterol, LDL , Dyslipidemias/complications , Dyslipidemias/drug therapy , Dyslipidemias/epidemiology , Anticholesteremic Agents/therapeutic useABSTRACT
Statins have contributed to the prevention of numerous atherosclerotic cardiovascular (CV) events and cardiovascular deaths in the past three decades. The benefit of statins is mainly mediated by the lowering of LDLc. According to scientific evidence, the current international guidelines recommend very low LDLc goals in patients at high/very high cardiovascular risk because they are associated with fewer CV events and improvements in atherosclerotic plaques. However, these goals often cannot be obtained with statins alone. Recent RCTs have demonstrated that these CV benefits can also be obtained with nonstatin LDLc-lowering drugs such as PCSK9 inhibitors (alirocumab and evolocumab), ezetimibe and bempedoic acid, while evidence with inclisiran is upcoming. Icosapent ethyl, a lipid metabolism modifier, has also shown an effect on event reduction. Physicians should take advantage of the currently available lipid-lowering therapies, choosing the drug or combination of drugs that is most appropriate for each patient according to his or her CV risk and baseline LDLc concentration. Strategies implementing combination therapies from early stages or even from the outset may increase the number of patients attaining LDLc goals, thereby preventing new CV episodes and improving existing atherosclerotic lesions.
Subject(s)
Anticholesteremic Agents , Atherosclerosis , Cardiovascular Diseases , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Plaque, Atherosclerotic , Humans , Male , Female , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Proprotein Convertase 9/metabolism , Anticholesteremic Agents/therapeutic use , Plaque, Atherosclerotic/drug therapy , Cholesterol, LDL , Atherosclerosis/drug therapy , Atherosclerosis/prevention & control , Cardiovascular Diseases/drug therapyABSTRACT
Atherosclerosis is a chronic inflammatory disease caused by the accumulation of cholesterol in the intima. Proprotein convertase subtilisin/kexin type 9 inhibitors (iPCSK9) can reduce low-density lipoprotein (LDL) cholesterol levels by 60%, but there is still no evidence that they can lower markers of systemic inflammation such as high-sensitivity C-reactive protein (hsCRP). Acute-phase serum glycoproteins are upregulated in the liver during systemic inflammation, and their role as inflammatory biomarkers is under clinical evaluation. In this observational study, we evaluate the effects of iPCSK9 on glycoproteins (Glyc) A, B and F. Thirty-nine patients eligible for iPCSK9 therapy were enrolled. One sample before and after one to six months of iPCSK9 therapy with alirocumab was obtained from each patient. Lipids, apolipoproteins, hsCRP and PCSK9 levels were measured by biochemical analyses, and the lipoprotein and glycoprotein profiles were measured by 1H nuclear magnetic resonance (1H-NMR). The PCSK9 inhibitor reduced total (36.27%, p < 0.001), LDL (55.05%, p < 0.001) and non-high-density lipoprotein (HDL) (45.11%, p < 0.001) cholesterol, apolipoprotein (apo) C-III (10%, p < 0.001), triglycerides (9.92%, p < 0.001) and glycoprotein signals GlycA (11.97%, p < 0.001), GlycB (3.83%, p = 0.017) and GlycF (7.26%, p < 0.001). It also increased apoA-I (2.05%, p = 0.043) and HDL cholesterol levels (11.58%, p < 0.001). Circulating PCSK9 levels increased six-fold (626.28%, p < 0.001). The decrease in Glyc signals positively correlated with the decrease in triglycerides and apoC-III. In conclusion, in addition to LDL cholesterol, iPCSK9 therapy also induces a reduction in systemic inflammation measured by 1H-NMR glycoprotein signals, which correlates with a decrease in triglycerides and apoC-III.
Subject(s)
Cardiovascular Diseases , Proprotein Convertase 9 , Humans , Proprotein Convertase 9/metabolism , PCSK9 Inhibitors , Apolipoprotein C-III , Cardiovascular Diseases/etiology , C-Reactive Protein , Proton Magnetic Resonance Spectroscopy , Risk Factors , Cholesterol , Cholesterol, LDL , Triglycerides , Magnetic Resonance Spectroscopy/adverse effects , Lipoproteins , Inflammation/drug therapy , Inflammation/complications , Anti-Inflammatory Agents , Glycoproteins , Heart Disease Risk FactorsABSTRACT
Familial hypercholesterolemia (FH) is an autosomal dominant disease that has a prevalence of approximately 1/250 inhabitants and is the most frequent cause of early coronary heart disease (CHD). We included 1.343.973 women and 1.210.671 men with at least one LDL-c measurement from the Catalan primary care database. We identified 14.699 subjects with Familial hypercholesterolemia-Phenotype (FH-P) based on LDL-c cut-off points by age (7.033 and 919 women, and 5.088 and 1659 men in primary and secondary prevention, respectively). Lipid lower therapy (LLT), medication possession ratio (MPR) as an indicator of adherence, and number of patients that reached their goal on lipid levels were compared by sex. In primary and secondary prevention, 69% and 54% of women (P = 0.001) and 64% and 51% of men (P = 0.001) were on low-to-moderate-potency LLT. Adherence to LLT was reduced in women older than 55 years, especially in secondary prevention (P = 0.03), where the percentage of women and men with LDL-c > 1.81 mmol/L were 99.9% and 98.9%, respectively (P = 0.001). Women with FH-P are less often treated with high-intensity LLT, less adherent to LLT, and have a lower probability of meeting their LDL-c goals than men, especially in secondary prevention.
Subject(s)
Coronary Disease , Hyperlipoproteinemia Type II , Female , Humans , Cholesterol, LDL/genetics , Coronary Disease/epidemiology , Hyperlipoproteinemia Type II/drug therapy , Hyperlipoproteinemia Type II/epidemiology , Hyperlipoproteinemia Type II/complications , Phenotype , MaleABSTRACT
BACKGROUND: Patients with hypertension present a permanent state of low-grade inflammation, as the disease activates several pro-inflammatory cells and inflammatory pathways. Glycoproteins A, B, and F, determined by proton nuclear magnetic resonance, provide a highly sensitive method for determining a group of liver-derived pro-inflammatory proteins, and their role has not yet been explored in patients with hypertension. In this study, we evaluated the impact of plasma concentrations of these glycoproteins in patients with hypertension. METHODS: This cross-sectional study involved 340 patients attending our vascular and metabolism medicine unit. Of them, 129 were normotensive and 211 were hypertensive. Standard biochemistry and carotid ultrasound measures were performed. Serum concentrations of glycoproteins A, B, and F were determined by proton nuclear magnetic resonance. RESULTS: Hypertensive patients presented a higher prevalence of obesity, metabolic syndrome, and diabetes and higher glycoprotein A, B, and F concentrations. Glycoproteins A, B, and F were positively correlated with systolic and diastolic blood pressure. Multivariate logistic models showed that glycoproteins A, B, and F were associated with higher odds of being hypertensive. Machine learning methods corroborated the relationship between glycoproteins and high blood pressure. The higher prevalence of carotid plaques in patients with high blood pressure was partially mediated by glycoproteins A and F. CONCLUSIONS: Patients with hypertension present systemic, subclinical inflammation as assessed by liver-derived glycoprotein A, B, and F serum levels. These results support the effect of hypertension on the mechanisms of systemic inflammation. Hypertension-associated systemic inflammation plays a role in hypertension-associated vascular injury and probably in hypertension-induced damage to other organs.
Subject(s)
Hypertension , Protons , Humans , Proton Magnetic Resonance Spectroscopy , Cross-Sectional Studies , Hypertension/complications , Blood Pressure , Glycoproteins , InflammationABSTRACT
OBJECTIVE: Patients with RA present increased risk of cardiovascular (CV) disease compared with the general population. Moreover, CV risk factors that have a causal relationship with atherosclerosis do not seem to fully explain the accelerated process that they exhibit. We evaluated the association of a 10 microRNAs panel with surrogate markers of subclinical arteriosclerosis [carotid intima-media thickness (cIMT), carotid plaque presence (cPP), pulse wave velocity (PWV) and distensibility] in a cohort of RA patients. MATERIAL AND METHODS: A total of 199 patients with RA were included. Surrogate markers of arteriosclerosis were measured with My Lab 60 X-Vision sonographer. MicroRNAs were extracted from plasma and quantified with qPCR. Multivariate models and classification methods were performed. RESULTS: Multivariate models showed that microRNAs-24 (ß = 15.48), 125a (ß = 9.93), 132 (ß = 11.52), 146 (ß = 15.12), 191 (ß = 13.25) and 223 (ß = 13.30) were associated with cIMT globally. MicroRNA-24 [odds ratio (OR) = 0.41], 146 (OR = 0.36) and Let7a (OR = 0.23) were associated with cPP in men. Including the microRNAs in a partial least square discriminant analysis model properly classified men with and without cPP. MicroRNA-96 (ß = -0.28) was associated with PWV in male patients. Finally, several miRNAs were also associated with cIMT, cPP and arterial stiffness in the high DAS28 group and in the earlier tertile groups of disease duration. CONCLUSION: Plasmatic expression of microRNA-24, 96, 103, 125a, 132, 146, 191, 223 and Let7a were associated with surrogate markers of CV disease and could be predictors of CV risk in patients with RA.
Subject(s)
Arthritis, Rheumatoid , Atherosclerosis , Cardiovascular Diseases , MicroRNAs , Humans , Male , Carotid Intima-Media Thickness , Risk Factors , Cardiovascular Diseases/epidemiology , Pulse Wave Analysis/adverse effects , Arthritis, Rheumatoid/complications , Arthritis, Rheumatoid/genetics , Atherosclerosis/etiology , BiomarkersABSTRACT
Introducción: Los estudios clínicos reflejan que los pacientes con riesgo cardiovascular elevado todavía están lejos de alcanzar los objetivos terapéuticos, especialmente de los niveles de cLDL. Si el manejo de estos pacientes en unidades especializadas difiere de otros escenarios no es conocido. Pacientes y métodos: Se seleccionaron 61 Unidades de Lípidos certificadas en el Registro de Dislipemias de la Sociedad Española de Arteriosclerosis para la recogida de datos del estudio. Se incluyeron 3.58 sujetos > 18 años que cumplían los criterios de hipercolesterolemia (colesterol LDL ≥ 160 mg/dL o colesterol no HDL ≥ 190 mg/dL) sin hipercolesterolemia familiar. Un total de 1.665 sujetos fueron estudiados con un tiempo medio de seguimiento de 4,2 años. Resultados y conclusiones: Un total de 42 sujetos tuvieron un evento cardiovascular desde su inclusión en el Registro, que supone 0,6%. No hubo diferencias en el tratamiento utilizado al inicio del seguimiento entre los sujetos con y sin evento prospectivo. El cLDL mejoró durante el seguimiento, pero 50% de los pacientes no alcanzaron los objetivos terapéuticos en la visita final del seguimiento. Se observó un aumento del uso de tratamiento hipolipemiante de alta potencia, incluyendo los inhibidores de PCSK9 en un 16,7% de los sujetos con recurrencias.(AU)
Introduction: Clinical studies show that patients with high cardiovascular risk are still far from reaching the therapeutic objectives, especially of the levels of LDL cholesterol. If the management of these patients in specialized units differs from other scenarios is known. Patients and methods: 61 certified Lipid Units were selected in the Registry of Dyslipemias of the Spanish Arteriosclerosis Society for the collection of study data. The study included 3958 subjects >18 years of age who met the criteria for hypercholesterolemia (LDL cholesterol ≥160 mg/dL or non-HDL cholesterol ≥190 mg/dL) without familial hypercholesterolemia. A total 1,665 subjects were studied with a mean follow-up time of 4.2 years. Results and conclusions: A total of 42 subjects had a cardiovascular event since their inclusion in the Registry, which represents 0.6%. There were no differences in the treatment used at follow-up, but 50% of the patients did not reach the therapeutic goals at the visit end of follow-up. An increase in the potency of the lipid-lowering treatment was observed, including PCSK9 inhibitors use in 16.7% of subjects with recurrences.(AU)
Subject(s)
Humans , Male , Female , Primary Prevention , Secondary Prevention , Dyslipidemias , Lipids , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Research , ArteriosclerosisABSTRACT
INTRODUCTION: Clinical studies show that patients with high cardiovascular risk are still far from reaching the therapeutic objectives, especially of the levels of LDL cholesterol. If the management of these patients in specialized units differs from other scenarios is known. PATIENTS AND METHODS: 61 certified Lipid Units were selected in the Registry of Dyslipemias of the Spanish Arteriosclerosis Society for the collection of study data. The study included 3958 subjects >18 years of age who met the criteria for hypercholesterolemia (LDL cholesterol ≥160 mg/dL or non-HDL cholesterol ≥190 mg/dL) without familial hypercholesterolemia. A total 1,665 subjects were studied with a mean follow-up time of 4.2 years. RESULTS AND CONCLUSIONS: A total of 42 subjects had a cardiovascular event since their inclusion in the Registry, which represents 0.6%. There were no differences in the treatment used at follow-up, but 50% of the patients did not reach the therapeutic goals at the visit end of follow-up. An increase in the potency of the lipid-lowering treatment was observed, including PCSK9 inhibitors use in 16.7% of subjects with recurrences.
Subject(s)
Anticholesteremic Agents , Arteriosclerosis , Dyslipidemias , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Humans , Cholesterol, LDL , Proprotein Convertase 9 , Secondary Prevention , Dyslipidemias/complications , Dyslipidemias/drug therapy , Registries , Arteriosclerosis/drug therapy , Hydroxymethylglutaryl-CoA Reductase Inhibitors/therapeutic use , Anticholesteremic Agents/therapeutic useABSTRACT
ANTECEDENTES:Las quilomicronemias generalmente se diagnostican genéticamente mediante secuenciación genómica o cribado de mutaciones en genes causales con un gran efecto fenotípico. Esta estrategia ha permitido mejorar la caracterización de estos pacientes, pero aún tenemos un 30% de ellos sin un diagnóstico genético concluyente. Es por esto que hipotetizamos que añadiendo el componente epigenético podemos mejorar el diagnóstico genético y para ello hemos explorado el grado de metilación en el ADN de pacientes hipertrigliceridémicos. METODOLOGÍA: El ADN de células sanguíneas fue obtenido de 16 pacientes hipertrigliceridémicos y de 16 sujetos control emparejados por edad y sexo. El grado de metilación en el ADN de todo el genoma fue determinado mediante el Illumina® Infinium MethylationEPIC Array Analysis. RESULTADOS: Identificamos 31 citosinas diferencialmente metiladas al comparar los patrones de metilación que presentaban los pacientes hipertrigliceridémicos vs. los sujetos control. La cg03636183 en el gen F2RL3 estaba un 10% hipometilada en los pacientes hipertrigliceridémicos, y ha sido previamente asociada a un mayor riesgo cardiovascular. La cg13824500 está un 10% hipometilada en pacientes hipertrigliceridémicos y se localiza en VTI1A, que es un gen limitante en el tránsito de los quilomicrones en el enterocito a través del retículo endoplásmico y el aparato de Golgi. La cg26468118 en el gen RAB20 (13% hipometilada) y la cg21560722 en el gen SBF2 (33% hipermetilada) están implicadas en la regulación de vesículas del aparato de Golgi. CONCLUSIONES: Nuestros resultados evidencian que existen regiones diferencialmente metiladas relacionadas con la formación de los quilomicrones en pacientes hipertrigliceridémicos.
BACKGROUND: Chylomicronemias are generally diagnosed genetically by genomic sequencing or screening for mutations in causal genes with a large phenotypic effect. This strategy has allowed to improve the characterization of these patients, but we still have 30% of the patients without a conclusive genetic diagnosis. This is why we hypothesize that by adding the epigenetic component we can improve the genetic diagnosis, and for this we have explored the degree of methylation in the DNA of hypertriglyceridemic patients. METHODOLOGY: Blood cell DNA was obtained from 16 hypertriglyceridemic patients and from 16 age- and sex-matched control subjects. The degree of methylation in genome-wide DNA was determined using the Illumina® Infinium Methylation EPIC Array Analysis. RESULTS: We identified 31 differentially methylated cytosines by comparing the methylation patterns presented by hypertriglyceridemic patients vs. control subjects. The cg03636183 in the F2RL3 gene was 10% hypomethylated in hypertriglyceridemic patients, and has previously been associated with an increased cardiovascular risk. Cg13824500 is 10% hypomethylated in hypertriglyceridemic patients and is located in VTI1A, which is a limiting gene in the transit of chylomicrons in the enterocyte through the endoplasmic reticulum and the Golgi apparatus. Cg26468118 in the RAB20 gene (13% hypomethylated) and cg21560722 in the SBF2 gene (33% hypermethylated) are involved in the regulation of Golgi apparatus vesicles. CONCLUSIONS: Our results suggest that there are differentially methylated regions related to the formation of chylomicrons in hypertriglyceridemic patients.
Subject(s)
Humans , Health Sciences , DNA Methylation , Epigenesis, Genetic , Mutation/genetics , rab GTP-Binding Proteins/geneticsABSTRACT
BACKGROUND: Chylomicronemias are generally diagnosed genetically by genomic sequencing or screening for mutations in causal genes with a large phenotypic effect. This strategy has allowed to improve the characterization of these patients, but we still have 30% of the patients without a conclusive genetic diagnosis. This is why we hypothesize that by adding the epigenetic component we can improve the genetic diagnosis, and for this we have explored the degree of methylation in the DNA of hypertriglyceridemic patients. METHODOLOGY: Blood cell DNA was obtained from 16 hypertriglyceridemic patients and from 16 age- and sex-matched control subjects. The degree of methylation in genome-wide DNA was determined using the Illumina® Infinium Methylation EPIC Array Analysis. RESULTS: We identified 31 differentially methylated cytosines by comparing the methylation patterns presented by hypertriglyceridemic patients vs. control subjects. The cg03636183 in the F2RL3 gene was 10% hypomethylated in hypertriglyceridemic patients, and has previously been associated with an increased cardiovascular risk. Cg13824500 is 10% hypomethylated in hypertriglyceridemic patients and is located in VTI1A, which is a limiting gene in the transit of chylomicrons in the enterocyte through the endoplasmic reticulum and the Golgi apparatus. Cg26468118 in the RAB20 gene (13% hypomethylated) and cg21560722 in the SBF2 gene (33% hypermethylated) are involved in the regulation of Golgi apparatus vesicles. CONCLUSIONS: Our results suggest that there are differentially methylated regions related to the formation of chylomicrons in hypertriglyceridemic patients.
Subject(s)
DNA Methylation , Epigenesis, Genetic , Humans , Mutation , rab GTP-Binding Proteins/geneticsABSTRACT
PURPOSE: Low-density lipoprotein (LDL) cholesterol reduction by statin therapy is dose-dependent, varies among different statins, and has wide inter-individual variability. The present study aimed to compare mean LDL cholesterol reduction and its variability achieved with different doses of the three statins most frequently used in monotherapy or combined with ezetimibe in a real clinical setting. METHODS: Of 5620 cases with primary hypercholesterolemia on the Spanish Arteriosclerosis Society Registry, 1004 with non-familial hypercholesterolemia and complete information on drug therapy and lipid profile were included. RESULTS: The lowest mean percentage LDL cholesterol reduction was observed with simvastatin 10 mg (32.5 ± 18.5%), while the highest mean percentage LDL reduction was obtained with rosuvastatin 40 mg (58.7 ± 18.8%). As to combined treatment, the lowest and highest mean percentage LDL cholesterol reductions were obtained with simvastatin 10 mg combined with ezetimibe (50.6 ± 24.6%) and rosuvastatin 40 mg combined with ezetimibe (71.6 ± 11.1%), respectively. Factors associated with a suboptimal response were male sex, lower age, body mass index, and baseline LDL cholesterol levels. Combined treatment was associated with less variability in LDL cholesterol reduction (OR 0.603, p < 0.001). CONCLUSION: In a real clinical setting, rosuvastatin was superior to the other statins in lowering LDL cholesterol, both as monotherapy or combined with ezetimibe. Factors associated with a suboptimal response in LDL cholesterol decline were male sex, age, body mass index, and baseline LDL cholesterol levels. Combined treatment was associated with less variability in LDL cholesterol improvement.
Subject(s)
Anticholesteremic Agents , Arteriosclerosis , Dyslipidemias , Hydroxymethylglutaryl-CoA Reductase Inhibitors , Hypercholesterolemia , Anticholesteremic Agents/adverse effects , Arteriosclerosis/drug therapy , Cholesterol, LDL , Drug Therapy, Combination , Dyslipidemias/diagnosis , Dyslipidemias/drug therapy , Ezetimibe/adverse effects , Female , Humans , Hydroxymethylglutaryl-CoA Reductase Inhibitors/adverse effects , Hypercholesterolemia/diagnosis , Hypercholesterolemia/drug therapy , Male , Registries , Rosuvastatin Calcium/adverse effects , Simvastatin/adverse effectsABSTRACT
BACKGROUND AND AIMS: Lipoprotein(a) [Lp(a)] concentration in heterozygous familial hypercholesterolemia (heFH) is not well established. Whether the genetic defect responsible for heFH plays a role in Lp(a) concentration is unknown. We aimed to compare Lp(a) in controls from a healthy population, in genetically diagnosed heFH and mutation-negative hypercholesterolemia subjects, and to assess the influence on Lp(a) of the genetic defect responsible for heFH. METHODS: We conducted a cross-sectional study, performed in a lipid clinic in Spain. We studied adults with suspected heFH and a genetic study of FH genes (LDLR, APOB, APOE and PCSK9) and controls from de Aragon Workers' Health Study. HeFH patients from the Dyslipidemia Registry of the Spanish Atherosclerosis Society (SEA) were used as validation cohort. RESULTS: Adjusted geometric means (95% confidence interval) of Lp(a) in controls (n = 1059), heFH (n = 500), and mutation-negative subjects (n = 860) were 14.9 mg/dL (13.6, 16.4), 21.9 mg/dL (18.1, 25.6) and 37.4 mg/dL (33.3, 42.1), p < 0.001 in all comparisons. Among heFH subjects, APOB-dependent FH showed the highest Lp(a), 36.5 mg/dL (22.0, 60.8), followed by LDLR-dependent FH, 21.7 mg/dL (17.9, 26.4). These differences were also observed in heFH from the SEA cohort. The number of plasminogen-like kringle IV type-2 repeats of LPA, the hypercholesterolemia polygenic score or LDLc concentration did not explain these differences. In LDLR-dependent FH, Lp(a) levels were not different depending on the affected protein domain. CONCLUSIONS: Lp(a) is elevated in mutation-negative subjects and in heFH. The concentration of Lp(a) in heFH varies in relation to the responsible gene. Higher Lp(a) in heFH is not explained by their higher LDLc.