[Design and rationale: Observational Study of the Argentine Group for the Study of Lipoprotein (a)]. / Diseño y racional estudio observacional del Grupo Argentino Estudio Lipoproteína (a).

INTRODUCTION: Elevated levels of Lipoprotein(a) [Lp(a)] have been linked to increased cardiovascular risk globally. However, comprehensive studies on Lp(a) levels and their impact on cardiovascular health in Argentina are lacking. The Argentine Group for the Study of Lipoprotein (a) [GAELp(a)] aims to address this gap through an observational study designed to evaluate the prevalence and consequences of elevated Lp(a) levels in the Argentine population. METHODS: The GAELp(a) study will recruit participants from diverse regions across Argentina. Eligible individuals will undergo comprehensive assessments, including demographic data collection, medical history review, and laboratory analyses to measure Lp(a) levels. The study will employ rigorous statistical analyses to explore the association between elevated Lp(a) levels and cardiovascular outcomes, considering potential confounding variables. RESULTS: Anticipated outcomes of the GAELp(a) study include a detailed characterization of Lp(a) levels within the Argentine population and their correlation with cardiovascular diseases. By elucidating these relationships, the study aims to provide valuable insights into the prevalence and impact of elevated Lp(a) on cardiovascular health in Argentina. CONCLUSION: The GAELp(a) observational study holds promise for enhancing our understanding of Lp(a)-related cardiovascular risk in Argentina. Findings from this study may contribute to the development of targeted interventions, clinical guidelines, and public health policies aimed at reducing cardiovascular morbidity and mortality associated with elevated Lp(a) levels. Through collaborative efforts, the GAELp(a) study seeks to advance cardiovascular research and improve healthcare outcomes in Argentina.

Aspirin use in patients with elevated lipoprotein(a): Impact on cardiovascular events and bleeding.

The role of aspirin in cardiovascular primary prevention remains controversial. There are physiological reasons to explore its potential benefits in patients with high levels of lipoprotein(a) [Lp(a)], mainly due to its antifibrinolytic properties and interactions with platelets. The primary objective of this systematic review was to evaluate the cardiovascular benefits and bleeding risks associated with aspirin use in patients who have elevated Lp(a) levels but no history of cardiovascular disease. This systematic review was conducted following PRISMA guidelines. We performed a literature search to identify studies assessing the cardiovascular benefits and bleeding risks of aspirin use in patients with elevated Lp(a) levels (or a related genetic variant) who have no history of cardiovascular disease. Five studies (49,871 individuals) were considered for this systematic review. Three studies assessed the impact of aspirin use in relation to genetic variants associated with elevated Lp(a) levels (SNP rs379822), while the remaining two studies directly measured plasma levels of Lp(a). The endpoints evaluated varied among the studies. Overall, the findings consistently show that carriers of the apolipoprotein(a) variant or patients with Lp(a) levels > 50 mg/dL experience a reduction in cardiovascular risk with aspirin use. No significant bleeding issues were observed, although such events were reported in only two studies. This systematic review suggests that aspirin use in patients with elevated Lp(a) levels and no prior cardiovascular history may reduce cardiovascular risk. The available data on bleeding risk is insufficient.

The impact of cholesteryl ester transfer protein on the progression of cutaneous leishmaniasis.

Introduction: Pathogenesis of cutaneous leishmaniases involves parasite growth, persistent inflammation, and likely participation of lipoproteins (LP). The cholesteryl ester transfer protein (CETP), involved in LP remodeling, has been shown to participate in the inflammatory response and the evolution of infectious conditions. Methods: We evaluated the impact of the presence of CETP on infection by Leishmania (L.) amazonensis in an experimental model of cutaneous leishmaniasis using C57BL6/J mice transgenic for human CETP (CETP), having as control their littermates that do not express the protein, wild-type (WT) mice. The progression of the lesion after infection in the footpad was monitored for 12 weeks. Two groups of animals were formed to collect the plantar pad in the 4th and 12th week post-infection. Results: The lesion increased from the 3rd week onwards, in both groups, with a gradual decrease from the 10th week onwards in the CETP group compared to the WT group, showing a reduction in parasitism and an improvement in the healing process, a reduction in CD68+ cells, and an increase in CD163+ and CD206, characterizing a population of M2 macrophages. A reduction in ARG1+ cells and an increase in INOS+ cells were observed. During infection, the LP profile showed an increase in triglycerides in the VLDL fraction in the CETP group at 12 weeks. Gene expression revealed a decrease in the CD36 receptor in the CETP group at 12 weeks, correlating with healing and parasite reduction. In vitro, macrophages derived from bone marrow cells from CETP mice showed lower parasite load at 48 h and, a reduction in arginase activity at 4 h accompanied by increased NO production at 4 and 24 h compared to WT macrophages, corroborating the in vivo findings. Discussion: The data indicate that the presence of CETP plays an important role in resolving Leishmania (L.) amazonensis infection, reducing parasitism, and modulating the inflammatory response in controlling infection and tissue repair.

Metabolic Changes Induced by Bariatric Surgery May be Mediated by PAI-1 and PCSK9 Crosstalk.

BACKGROUND: Adiposity favors several metabolic disorders with an exacerbated chronic pro-inflammatory status and tissue damage, with high levels of plasminogen activator inhibitor type 1 (PAI-1) and proprotein convertase subtilisin/kexin type 9 (PCSK9). OBJECTIVE: To demonstrate the influence of bariatric surgery on the crosstalk between PAI-1 and PCSK9 to regulate metabolic markers. METHODS: Observational and longitudinal study of 190 patients with obesity and obesity-related comorbidities who underwent bariatric surgery. We measured, before and after bariatric surgery, the anthropometric variables and we performed biochemical analysis by standard methods (glucose, insulin, triglycerides [TG], total cholesterol, high-density lipoprotein cholesterol [HDL-C], low-density lipoprotein cholesterol [LDL-C] and TG/HDL-C ratio, PAI-1 and PCSK9 were measured by ELISA). RESULTS: PAI-1 levels decreased significantly after bariatric surgery, and were positively correlated with lipids, glucose, and TG, with significance on PCSK9 and TG/HDL-C alleviating the insulin resistance (IR) and inducing a state reversal of type 2 diabetes (T2D) with a significant decrease in body weight and BMI (p <0.0001). Multivariate regression analysis predicted a functional model in which PAI-1 acts as a regulator of PCSK9 (p <0.002), TG (p <0.05), and BMI; at the same time, PCSK9 modulates LDL-C HDL-C and PAI-1. CONCLUSIONS: After bariatric surgery, we found a positive association and crosstalk between PAI-1 and PCSK9, which modulates the delicate balance of cholesterol, favoring the decrease of circulating lipids, TG, and PAI-1, which influences the glucose levels with amelioration of IR and T2D, demonstrating the crosstalk between fibrinolysis and lipid metabolism, the two main factors involved in atherosclerosis and cardiovascular disease in human obesity.

Very Low Calorie Ketogenic Diet: What Effects on Lipid Metabolism?

PURPOSE OF REVIEW: This review aims to critically examine how VLCKD affects plasma lipoprotein, lipid and cholesterol metabolism. Cardiovascular disease is a worldwide health problem affecting millions of people and leading to high rates of mortality and morbidity. There is a well-established association between cardiovascular disease and circulating cholesterol. Various dietary recommendations are currently available for the management of dyslipidemia. RECENT FINDINGS: The very low-calorie ketogenic diet (VLCKD) is becoming increasingly popular as a treatment option for several pathological conditions, including dyslipidemia. In addition to being low in calories, the VLCKD's main feature is its unique calorie distribution, emphasizing a reduction in carbohydrate consumption in favor of fat as the primary calorie source. Lowering calorie intake through a VLCKD can reduce the endogenous production of cholesterol. However, if the foods consumed are from animal sources, dietary cholesterol intake may increase due to the higher fat content of animal products. When combined, these dietary practices may have opposing effects on plasma cholesterol levels. Studies investigating the impact of VLCKD on plasma cholesterol and low-density lipoprotein cholesterol levels report contradictory findings. While some studies found an increase in low-density lipoprotein cholesterol levels, others showed a decrease in total cholesterol and low-density lipoprotein cholesterol, along with an increase in high-density lipoprotein cholesterol.

Cholesterol transfer to high-density lipoprotein in obesity and the effects of weight loss after bariatric surgery.

Obesity increases serum triglycerides and decreases high-density lipoprotein cholesterol (HDL-C). The objective is to explore some functions of HDL, cholesterol transfers and antioxidant, in subjects with grade I (G1-OB) and III (G3-OB) obesity and effects of bariatric surgery on G3-OB. Fifteen G3-OB patients (43 ± 6 years, BMI 49 ± 3 kg/m2) were studied before and 1 year after bariatric surgery; 15 G1-OB (32 ± 2 years, 32 ± 2 kg/m2) and 15 normal weight (NW) (38 ± 6 years, 22 ± 1 kg/m2) were also studied. HDL diameter, cholesterol transfer to HDL and antioxidant capacity of HDL were determined. G3-OB had higher triglycerides and lower HDL-C; G1-OB had higher triglycerides than NW but HDL-C was equal. Compared to NW, HDL size was smaller in G3-OB but equal in G1-OB. One year after bariatric surgery, BMI and triglycerides of G3-OB decreased (p < .0001 and p = .0012, respectively) and HDL-C increased (p < .0001), equalling of NW group. Antioxidant capacity and cholesterol transfers were not different in groups and were unchanged 1 year after bariatric surgery in G3-OB. HDL antioxidant capacity and transfer of cholesterol to HDL were not defective in obesity despite HDL-C reduction and smaller HDL size. In addition, pronounced weight loss by bariatric surgery did not change those protective functions.

Lipophorin: The Lipid Shuttle.

Insects need to transport lipids through the aqueous medium of the hemolymph to the organs in demand, after they are absorbed by the intestine or mobilized from the lipid-producing organs. Lipophorin is a lipoprotein present in insect hemolymph, and is responsible for this function. A single gene encodes an apolipoprotein that is cleaved to generate apolipophorin I and II. These are the essential protein constituents of lipophorin. In some physiological conditions, a third apolipoprotein of different origin may be present. In most insects, lipophorin transports mainly diacylglycerol and hydrocarbons, in addition to phospholipids. The fat body synthesizes and secretes lipophorin into the hemolymph, and several signals, such as nutritional, endocrine, or external agents, can regulate this process. However, the main characteristic of lipophorin is the fact that it acts as a reusable shuttle, distributing lipids between organs without being endocytosed or degraded in this process. Lipophorin interacts with tissues through specific receptors of the LDL receptor superfamily, although more recent results have shown that other proteins may also be involved. In this chapter, we describe the lipophorin structure in terms of proteins and lipids, in addition to reviewing what is known about lipoprotein synthesis and regulation. In addition, we reviewed the results investigating lipophorin's function in the movement of lipids between organs and the function of lipophorin receptors in this process.

Impact of Lipoprotein(a) Levels on Cardiovascular Risk Estimation.

INTRODUCTION: A new cardiovascular risk (CVR) calculator that incorporates Lipoprotein(a) [Lp(a)] levels has recently been designed. AIMS: To estimate CVR using the new score and to identify the reduction in low-density lipoprotein cholesterol (LDL-C) or systolic blood pressure (SBP) necessary to balance the risk attributable to Lp(a). METHODS: CVR throughout life and at 10 years was estimated with the new score in patients in primary prevention, both considering and not considering the value of Lp(a). When the estimated risk considering Lp(a) levels exceeded the baseline risk, the reduction in LDL-C levels or SBP necessary to balance the risk attributable to Lp(a) was calculated. RESULTS: In total, 671 patients (mean age 54.2 years, 47.2% women) were included. Globally, 22.7% of the population had high Lp(a) values (> 50 mg/dL or > 125 nmol/L). When calculating CVR throughout life and considering the Lp(a) value, the global risk increased in 66.7% of cases (median 19.3%). Similar results were observed when we assessed the 10-year risk. The risk associated with Lp(a) could be completely compensated by decreasing LDL-C (average 21 mg/dL) or SBP (average 6.3 mmHg) in 79.2% and 74.7% of cases, respectively. CONCLUSION: When calculating the CVR with the new score, two-thirds and one-third of the population were bidirectionally recategorized as 'up' or 'down,' respectively. The decrease in LDL-C or SBP mitigated the increased risk caused by Lp(a) levels across a substantial proportion of patients.

Exploring the Interplay between Diabetes and Lp(a): Implications for Cardiovascular Risk.

PURPOSE OF REVIEW: The objective of this manuscript is to review and describe the relationship between Lp(a) and diabetes, exploring both their association and synergy as cardiovascular risk factors, while also describing the current evidence regarding the potential connection between low levels of Lp(a) and the presence of diabetes. RECENT FINDINGS: Epidemiological studies suggest a potential relationship between low to very low levels of Lp(a) and diabetes. Lipoprotein(a), or Lp(a), is an intriguing lipoprotein of genetic origin, yet its biological function remains unknown. Elevated levels of Lp(a) are associated with an increased risk of cardiovascular atherosclerosis, and coexisting diabetes status confers an even higher risk. On the other hand, epidemiological and genetic studies have paradoxically suggested a potential relationship between low to very low levels of Lp(a) and diabetes. While new pharmacological strategies are being developed to reduce Lp(a) levels, the dual aspects of this lipoprotein's behavior need to be elucidated in the near future.

Comparison of the Friedewald and Vujovic methods with the calculated LDL concentration in a biochemical auto-analyzer.

Objective: To compare the concentration of Low-Density Lipoprotein (LDL-c) obtained using the Friedewald formula with those obtained directly with the RAYTO CHEMRAY 120 autoanalyzer. Methods: Cross-sectional study. We evaluated outpatients with a medical request for a lipid profile study (total cholesterol, triglycerides, LDL, and HDL). The analyses were carried out in a RAYTO CHEMRAY 120 autoanalyzer under the principle of spectrophotometry. We obtained LDL-c using the Friedewald and Vujovic formulas. Results: We evaluated 199 individuals whose direct LDL concentration averages were measured by the RAYTO CHEMRAY 120 equipment. Those calculated by the Friedewald and Vujovic formulas were 129.97 ± 32.66, 119.28 ± 30.44, and 127.01 ± 32.01, respectively, and in all cases, significant differences (P < 0.001) were observed with the RAYTO analyzer. In both cases a low positive bias was found with the RAYTO analyzer.. The Passing-Bablok and Deming's regressions showed a linear correlation between both methods (Friedewald and Vujovic) with the LDL values obtained with the Rayto autoanalyzer. Conclusions: Our study found that the Friedewald and Vujovic methods are good predictors of LDL cholesterol levels and have a low level of bias. Therefore, they could be used as potential predictors.

Objetivo: Comparar las concentraciones de Lipoproteínas de Baja Densidad (LDL-c) obtenidas mediante la fórmula de Friedewald con las obtenidas directamente con el autoanalizador RAYTO CHEMRAY 120. Métodos: Estudio transversal. Se evaluaron pacientes ambulatorios con solicitud médica de perfil lipídico (colesterol total, triglicéridos, LDL y HDL). Los análisis se realizaron con un autoanalizador RAYTO CHEMRAY 120 bajo el principio de espectrofotometría. Obtuvimos el LDL-c usando las fórmulas de Friedewald y Vujovic. Resultados: Se evaluaron 199 individuos cuyos promedios directos de concentración de LDL fueron medidos con el equipo RAYTO CHEMRAY 120. Las concentraciones calculadas por las fórmulas de Friedewald y Vujovic fueron de 129,97 ± 32,66, 119,28 ± 30,44, y de 127,01 ± 32,01, respectivamente, y en todos los casos se observaron diferencias significativas (P < 0,001) con el analizador RAYTO. En ambos casos se encontró un sesgo positivo bajo en el analizador RAYTO. Las regresiones de Passing-Bablok y Deming mostraron una correlación lineal entre ambos métodos (Friedewald y Vujovic) con los valores de LDL obtenidos con el autoanalizador Rayto. Conclusión: Nuestro estudio encontro que los métodos de Friedewald y Vujovic son buenos predictores de los niveles de colesterol LDL y presentan un nivel de sesgo bajo. Por lo que podrían usarse como potenciales predictores.

Comparación de los métodos de Friedewald y Vujovic con la concentración de LDL calculada en un autoanalizador bioquímico / Comparison of the Friedewald and Vujovic methods with the calculated LDL concentration in a biochemical auto-analyzer

Objective To compare the concentration of Low-Density Lipoprotein (LDL-c) obtained using the Friedewald formula with those obtained directly with the RAYTO CHEMRAY 120 autoanalyzer. Methods Cross-sectional study. We evaluated outpatients with a medical request for a lipid profile study (total cholesterol, triglycerides, LDL, and HDL). The analyses were carried out in a RAYTO CHEMRAY 120 autoanalyzer under the principle of spectrophotometry. We obtained LDL-c using the Friedewald and Vujovic formulas. Results We evaluated 199 individuals whose direct LDL concentration averages were measured by the RAYTO CHEMRAY 120 equipment. Those calculated by the Friedewald and Vujovic formulas were 129.97 ± 32.66, 119.28 ± 30.44, and 127.01 ± 32.01, respectively, and in all cases, significant differences (P < 0.001) were observed with the RAYTO analyzer. In both cases a low positive bias was found with the RAYTO analyzer.. The Passing-Bablok and Deming's regressions showed a linear correlation between both methods (Friedewald and Vujovic) with the LDL values obtained with the Rayto autoanalyzer. Conclusions Our study found that the Friedewald and Vujovic methods are good predictors of LDL cholesterol levels and have a low level of bias. Therefore, they could be used as potential predictors.

Objetivo Comparar las concentraciones de Lipoproteínas de Baja Densidad (LDL-c) obtenidas mediante la fórmula de Friedewald con las obtenidas directamente con el autoanalizador RAYTO CHEMRAY 120. Métodos Estudio transversal. Se evaluaron pacientes ambulatorios con solicitud médica de perfil lipídico (colesterol total, triglicéridos, LDL y HDL). Los análisis se realizaron con un autoanalizador RAYTO CHEMRAY 120 bajo el principio de espectrofotometría. Obtuvimos el LDL-c usando las fórmulas de Friedewald y Vujovic. Resultados Se evaluaron 199 individuos cuyos promedios directos de concentración de LDL fueron medidos con el equipo RAYTO CHEMRAY 120. Las concentraciones calculadas por las fórmulas de Friedewald y Vujovic fueron de 129,97 ± 32,66, 119,28 ± 30,44, y de 127,01 ± 32,01, respectivamente, y en todos los casos se observaron diferencias significativas (P < 0,001) con el analizador RAYTO. En ambos casos se encontró un sesgo positivo bajo en el analizador RAYTO. Las regresiones de Passing-Bablok y Deming mostraron una correlación lineal entre ambos métodos (Friedewald y Vujovic) con los valores de LDL obtenidos con el autoanalizador Rayto. Conclusión Nuestro estudio encontro que los métodos de Friedewald y Vujovic son buenos predictores de los niveles de colesterol LDL y presentan un nivel de sesgo bajo. Por lo que podrían usarse como potenciales predictores.

Modulatory actions of Echinococcus granulosus antigen B on macrophage inflammatory activation.

Cestodes use own lipid-binding proteins to capture and transport hydrophobic ligands, including lipids that they cannot synthesise as fatty acids and cholesterol. In E. granulosus s.l., one of these lipoproteins is antigen B (EgAgB), codified by a multigenic and polymorphic family that gives rise to five gene products (EgAgB8/1-5 subunits) assembled as a 230 kDa macromolecule. EgAgB has a diagnostic value for cystic echinococcosis, but its putative role in the immunobiology of this infection is still poorly understood. Accumulating research suggests that EgAgB has immunomodulatory properties, but previous studies employed denatured antigen preparations that might exert different effects than the native form, thereby limiting data interpretation. This work analysed the modulatory actions on macrophages of native EgAgB (nEgAgB) and the recombinant form of EgAg8/1, which is the most abundant subunit in the larva and was expressed in insect S2 cells (rEgAgB8/1). Both EgAgB preparations were purified to homogeneity by immunoaffinity chromatography using a novel nanobody anti-EgAgB8/1. nEgAgB and rEgAgB8/1 exhibited differences in size and lipid composition. The rEgAgB8/1 generates mildly larger lipoproteins with a less diverse lipid composition than nEgAgB. Assays using human and murine macrophages showed that both nEgAgB and rEgAgB8/1 interfered with in vitro LPS-driven macrophage activation, decreasing cytokine (IL-1ß, IL-6, IL-12p40, IFN-ß) secretion and ·NO generation. Furthermore, nEgAgB and rEgAgB8/1 modulated in vivo LPS-induced cytokine production (IL-6, IL-10) and activation of large (measured as MHC-II level) and small (measured as CD86 and CD40 levels) macrophages in the peritoneum, although rEgAgB8/1 effects were less robust. Overall, this work reinforced the notion that EgAgB is an immunomodulatory component of E. granulosus s.l. Although nEgAgB lipid's effects cannot be ruled out, our data suggest that the EgAgB8/1 subunit contributes to EgAgB´s ability to regulate the inflammatory activation of macrophages.

Effect of Empagliflozin with or without the Addition of Evolocumab on HDL Subspecies in Individuals with Type 2 Diabetes Mellitus: A Post Hoc Analysis of the EXCEED-BHS3 Trial.

Evolocumab and empagliflozin yield a modest rise in plasma high-density lipoprotein cholesterol (HDL-C) through unknown mechanisms. This study aims to assess the effect of evolocumab plus empagliflozin vs. empagliflozin alone on HDL subspecies isolated from individuals with type 2 diabetes mellitus (T2D). This post hoc prespecified analysis of the EXCEED-BHS3 trial compared the effects of a 16-week therapy with empagliflozin (E) alone or in combination with evolocumab (EE) on the lipid profile and cholesterol content in HDL subspecies in individuals with T2D divided equally into two groups of 55 patients. Both treatments modestly increased HDL-C. The cholesterol content in HDL subspecies 2a (7.3%), 3a (7.2%) and 3c (15%) increased from baseline in the E group, while the EE group presented an increase from baseline in 3a (9.3%), 3b (16%) and 3c (25%). The increase in HDL 3b and 3c was higher in the EE group when compared to the E group (p < 0.05). No significant interactive association was observed between changes in hematocrit and HDL-C levels after treatment. Over a 16-week period, empagliflozin with or without the addition of evolocumab led to a modest but significant increase in HDL-C. The rise in smaller-sized HDL particles was heterogeneous amongst the treatment combinations.

Gasto energético en reposo y concentración sérica de lipoproteínas de baja densidad en adultos con hipotiroidismo subclínico leve

La alta prevalencia de hipotiroidismo subclínico en Chile puede deberse a que el límite superior normal de la hormona estimulante del tiroides (TSH) sérica es bajo. Personas con TSH levemente mayor al límite superior pueden ser metabólicamente similares a personas sanas. Se compararon marcadores de acción tiroidea (gasto energético en reposo [GER] y lipoproteína de baja densidad [LDL]) en adultos con hipotiroidismo subclínico leve y con función tiroidea normal con o sin tratamiento con levotiroxina. Se midió GER, perfil lipídico y tiroideo en personas sanas con función tiroidea normal (TSH ≥0,4-<4,5 µUI/ml; n=91); con hipotiroidismo subclínico leve (TSH ≥4,5-≤6,5 µUI/ml; n=5); y con hipotiroidismo clínico tratado con levotiroxina y TSH normal (n=13). Se analizó la LDL en 838 personas sanas con función tiroidea normal y 89 con hipotiroidismo subclínico leve de la Encuesta Nacional de Salud 2016/17 (ENS). El GER, ajustado por peso, sexo y edad, fue similar entre grupos (p=0,71). La LDL fue similar entre personas con función tiroidea normal e hipotiroidismo subclínico leve (91±24 vs. 101±17 mg/dl; p=0,67), y menor en hipotiroidismo tratado (64±22 mg/dl; p<0,01). La LDL no se asoció con TSH pero si inversamente con T4L en mujeres (r=-0,33; p=0,02; n=53). En la ENS, ambos grupos tuvieron similar LDL (p=0,34), la que se asoció inversamente con T4L en mujeres (r=-0,12; p=0,01; n=569) pero no con TSH. Personas sanas con función tiroidea normal y con hipotiroidismo subclínico leve tienen similar GER y LDL. Esto apoya la idea de redefinir el límite superior normal de TSH.

The high prevalence of subclinical hypothyroidism in Chile may be due to the low normal upper limit of serum thyroid-stimulating hormone (TSH). People with TSH slightly higher than the upper limit may be metabolically similar to healthy people. Thyroid action markers (resting energy expenditure [REE] and low-density lipoprotein [LDL]) were compared in adults with mild subclinical hypothyroidism and with normal thyroid function with or without levothyroxine treatment. REE, lipid and thyroid profile were measured in healthy people with normal thyroid function (TSH ≥0,4-<4,5 µUI/ml (n=91); with mild subclinical hypothyroidism (TSH ≥4,5-≤6 µUI/ml; n=5); and with clinical hypothyroidism treated with levothyroxine and normal TSH (n=13). LDL was analyzed in 838 healthy people with normal thyroid function and 89 with mild subclinical hypothyroidism from the 2016/17 National Health Survey (NHS). REE, adjusted for weight, sex and age, was similar between the groups (p=0,71). LDL was similar between people with normal thyroid function and mild subclinical hypothyroidism (91±24 vs. 101±17 mg/dl; p=0,67), and lower in treated hypothyroidism (64±22 mg/dl; p<0,01). LDL was not associated with TSH but was inversely with FT4 in women (r=-0,33; p=0,02; n=53). In the NHS, both groups had similar serum LDL (p=0,34), which was inversely associated with FT4 in women (r=-0,12; p=0,01; n=569), but not with TSH. Healthy people with normal thyroid function and mild subclinical hypothyroidism have similar REE and LDL. These results support the idea of redefining the normal upper limit of TSH.

A systematic review and meta-analysis of serum lipid concentrations in people with Down syndrome.

BACKGROUND: Down syndrome (DS) is the most prevalent chromosomal disorder, being the leading cause of intellectual disability. The increased life expectancy of individuals with DS has led to a shift in the incidence of non-communicable chronic diseases, resulting in new concerns, particularly cardiovascular disease (CVD) and Alzheimer's disease. This study aimed to analyse the blood lipid profile of a large DS cohort to establish a baseline for evaluating health risk parameters. METHODS: A comprehensive literature search was conducted on PubMed and Virtual Health Library databases to identify original articles published before July 2022. Selected studies were included in the meta-analysis. RESULTS: Fifteen studies reporting serum lipid levels in individuals with DS were incorporated into the analysis. The meta-analysis used the means and standard deviations extracted from the selected studies. The analysis encompassed 671 participants in the DS group and 898 euploid controls. The results indicated significant differences in total cholesterol [C] (mean difference [MD]: -3.34; CI: 95%: -4.94 to -1.73; P < 0.0001), HDL-C (MD: -3.39; CI: 95%: -6.72 to -0.06; P = 0.05) and triglycerides (MD: 21.48; CI: 95%: 9.32 to 33.65; P = 0.0005) levels between individuals with DS and their control counterparts. CONCLUSIONS: Individuals with DS have less favourable blood lipid concentrations than their controls, particularly HDL-C, triglycerides, and total-C, even when grouped by age. These findings underscore the importance of closer monitoring of lipid profiles in people with DS and the necessity for specific cut-offs for this population, considering the risk for ischemic heart and Alzheimer's diseases.

Early Initiation of PCSK9 Inhibitor Therapy Versus Placebo in Patients With Acute Coronary Syndrome: A Systematic Review and Meta-Analysis.

In patients with stable atherosclerotic cardiovascular disease, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9is) have shown a 50% to 60% reduction in low-density lipoprotein cholesterol (LDL-C) from baseline when added to high-intensity statin therapy. However, less is known about the impact of PCSK9is in the setting of an acute coronary syndrome (ACS). Therefore, we performed a systematic review and meta-analysis comparing PCSK9is with placebo in the setting of ACS added to guideline-directed high-intensity or maximally tolerated statin therapy. We included randomized controlled trials with initiation of a PCSK9i or placebo within 1 week of presentation or percutaneous coronary intervention for ACS. PubMed, EMBASE, and Cochrane Central were searched. This study followed the Cochrane and Preferred Reporting Items for Systematic Reviews and Meta-Analysis (PRISMA) recommendations. A total of 6 randomized controlled trials were included, with a total of 996 patients, of whom 503 (50.5%) received PCSK9is. The mean follow-up ranged from 4 to 52 weeks. The LDL-C (mean difference [MD] -44.0 mg/100 ml, CI -54.3 to -33.8, p <0.001) and lipoprotein (a) levels (MD -24.0 nmol/L, confidence interval [CI] -43.0 to -4.9, p = 0.01) were significantly lower at follow-up with PCSK9is. Similarly, the total cholesterol (MD -49.2 mg/100 ml, CI -59.0 to -39.3), triglycerides (MD -19.0 mg/100 ml, CI -29.9 to -8.2), and apolipoprotein B (MD -33.3 mg/100 ml, CI -44.4 to -22.1) were significantly reduced with PCSK9is. In conclusion, in patients with ACS, early initiation of PCSK9i added to statin significantly reduces LDL-C and lipoprotein (a) levels compared with placebo. Whether the differences in these atherogenic lipoproteins translate into a reduction in clinical end points is yet to be determined.

Evolocumab in paediatric heterozygous familial hypercholesterolaemia: cognitive function during 80 weeks of open-label extension treatment.

AIMS: PCSK9 inhibition intensively lowers low density lipoprotein cholesterol and is well tolerated in adults and paediatric patients with familial hypercholesterolaemia (FH). HAUSER-RCT showed that 24 weeks of treatment with evolocumab in paediatric patients did not affect cognitive function. This study determined the effects of 80 additional weeks of evolocumab treatment on cognitive function in paediatric patients with heterozygous FH. METHODS AND RESULTS: HAUSER-OLE was an 80-week open-label extension of HAUSER-RCT, a randomized, double-blind, 24-week trial evaluating the efficacy and safety of evolocumab in paediatric patients (ages 10-17 years) with FH. During the OLE, all patients received monthly 420 mg subcutaneous evolocumab injections. Tests of psychomotor function, attention, visual learning, and executive function were administered at baseline and Weeks 24 and 80 of the OLE. Changes over time were analysed descriptively and using analysis of covariance. Cohen's d statistic was used to evaluate the magnitude of treatment effects. Analysis of covariance results indicated no decrease in performance across visits during 80 weeks of evolocumab treatment for Groton Maze Learning, One Card Learning accuracy, Identification speed, or Detection speed (all P > 0.05). Performance on all tasks was similar for those who received placebo or evolocumab in the RCT (all P > 0.05). For all tests, the least square mean differences between patients who received placebo vs. evolocumab in the parent study were trivial (all Cohen's d magnitude < 0.2). CONCLUSION: In paediatric patients with FH, 80 weeks of open-label evolocumab treatment had no negative impact on cognitive function. REGISTRATION: ClinicalTrials.gov identifier: NCT02624869.

Some children are born with a genetic disorder that causes high cholesterol, which leads to heart disease. Children with high cholesterol can be treated with evolocumab, a medication that lowers blood cholesterol. Because cholesterol is important for development and adequate function of the brain, there is a concern that lowering cholesterol in children may affect mental ability. In this study, we tested whether treating children with evolocumab for 80 weeks affected mental ability in performing several tasks. A battery of tests that measure executive function (Groton Maze Learning Test), visual learning (One Card Learning Test), visual attention (Identification Test), and psychomotor function (Detection Test) showed no decrease in performance across visits during 80 weeks of evolocumab treatment. Performance on all tasks was similar for the children who received placebo for the first 24 weeks then received evolocumab for an additional 80 weeks (placebo/evolocumab) and those who received evolocumab for 24 weeks then received evolocumab for an additional 80 weeks (evolocumab/evolocumab).

Triglyceride/HDL cholesterol ratio and lipoprotein insulin resistance Score: Associations with subclinical atherosclerosis and incident cardiovascular disease.

BACKGROUND: The triglyceride/HDL cholesterol (TG/HDL-C) ratio and the Lipoprotein Insulin Resistance (LP-IR) score are lipid markers of insulin resistance. Their associations with carotid intima media thickness (cIMT; subclinical atherosclerosis) and incident cardiovascular disease (CVD) have not been thoroughly investigated. METHODS: In a cross-sectional cohort (89 subjects without type 2 diabetes (T2D) and 81 subjects with T2D we determined cIMT (ultrasound), homeostasis model assessment of insulin resistance (HOMA-IR) and the TG/HDL-C ratio. The LP-IR score, based on 6 lipoprotein characteristics determined by nuclear magnetic resonance spectroscopy, was measured in 123 participants. A prospective study was carried out among 6232 participants (Prevention of REnal and Vascular ENd-stage Disease study). RESULTS: Cross-sectionally, the adjusted associations of HOMA-IR, the TG/HDL-C ratio and the LP-IR score with cIMT were approximately similar (standardized ß = 0.34 (95 % CI 0.19-0.48), 0.24 (95 % CI 0.09-039) and 0.41 (95 % CI 0.23--0.59), respectively). Prospectively, 507 new cases of CVD were observed after a median follow-up of 8.2 (interquartile range 7.5-8.8) years. HOMA-IR, the TG/HDL-C ratio and LP-IR were each associated with incident CVD independent of potential confounders (HR 1.12, 95 % CI 1.02-1.24;1.22, 95 % CI 1.11-1.35 and 1.15. 95 % CI 1.01-1.31, respectively). The association of the TG/HDL-C ratio with incident CVD was somewhat stronger than that of HOMA-IR. CONCLUSION: Lipoprotein-based markers of insulin resistance are at least as strongly associated with subclinical atherosclerosis and clinical atherosclerosis development as HOMA-IR, obviating the need to measure insulin to determine the impact of insulin resistance. For practical purposes, the easily obtainable TG/HDL-C ratio may suffice.