Amplifying hepatic L-aspartate levels suppresses CCl4-induced liver fibrosis by reversing glucocorticoid receptor ß-mediated mitochondrial malfunction.

Liver fibrosis is a determinant-stage process of many chronic liver diseases and affected over 7.9 billion populations worldwide with increasing demands of ideal therapeutic agents. Discovery of active molecules with anti-hepatic fibrosis efficacies presents the most attacking filed. Here, we revealed that hepatic L-aspartate levels were decreased in CCl4-induced fibrotic mice. Instead, supplementation of L-aspartate orally alleviated typical manifestations of liver injury and fibrosis. These therapeutic efficacies were alongside improvements of mitochondrial adaptive oxidation. Notably, treatment with L-aspartate rebalanced hepatic cholesterol-steroid metabolism and reduced the levels of liver-impairing metabolites, including corticosterone (CORT). Mechanistically, L-aspartate treatment efficiently reversed CORT-mediated glucocorticoid receptor ß (GRß) signaling activation and subsequent transcriptional suppression of the mitochondrial genome by directly binding to the mitochondrial genome. Knockout of GRß ameliorated corticosterone-mediated mitochondrial dysfunction and hepatocyte damage which also weakened the improvements of L-aspartate in suppressing GRß signaling. These data suggest that L-aspartate ameliorates hepatic fibrosis by suppressing GRß signaling via rebalancing cholesterol-steroid metabolism, would be an ideal candidate for clinical liver fibrosis treatment.

Dysregulation of cholesterol homeostasis is an early signal of beta cell proteotoxicity characteristic of type 2 diabetes.

Type 2 diabetes (T2D) is a common metabolic disease due to insufficient insulin secretion by pancreatic beta cells in the context of insulin resistance. Islet molecular pathology reveals a role for protein misfolding in beta cell dysfunction and loss with islet amyloid derived from islet amyloid polypeptide (IAPP), a protein co-expressed and co-secreted with insulin. The most toxic form of misfolded IAPP is intracellular membrane disruptive toxic oligomers present in beta cells in T2D and in beta cells of mice transgenic for human IAPP (hIAPP). Prior work revealed a high degree of overlap of transcriptional changes in islets from T2D and pre-diabetic 9-10-week-old mice transgenic for hIAPP with most changes being pro-survival adaptations and therefore of limited therapeutic guidance. Here we investigated islets from hIAPP transgenic mice at an earlier age (6 weeks) to screen for potential mediators of hIAPP toxicity that precede predominance of pro-survival signaling. We identified early suppression of cholesterol synthesis and trafficking along with aberrant intra-beta cell cholesterol and lipid deposits, and impaired cholesterol trafficking to cell membranes. These findings align with comparable lipid deposits present in beta cells in T2D and increased vulnerability to develop T2D in individuals taking medications that suppress cholesterol synthesis.

The Association Between Neutrophil/High-Density Lipoprotein Cholesterol Ratio and Non-Alcoholic Fatty Liver Disease in a Healthy Population.

Objective: Non-alcoholic fatty liver disease (NAFLD) is characterized by abnormal lipid metabolism and inflammation. This study aimed to investigate the relationship between neutrophil-HDL cholesterol ratio (NHR) and NAFLD in a healthy population. Methods: 1881 healthy people who underwent a physical examination from August to December 2023 at the Hebei General Hospital were chosen for this cross-sectional study. 936 individuals were ultimately included thanks to propensity matching and exclusion criteria. Ultrasound was used to diagnose fatty liver and a t-test or Mann-Whitney test was used to compare the clinical characteristics of participants between groups with and without fatty liver. Logistic regression was used to construct a new model that included NHR. The predictive value of NHR as well as the new model for NAFLD in a healthy population was assessed using logistic regression and subject work characteristic curves. Results: NHR levels were higher among participants in the NAFLD group than those without NAFLD(P<0.05). NHR is a risk factor for NAFLD in a healthy population(P<0.05). The odds ratios (ORs) of NHR for predicting NAFLD in Model I (adjusted for sex, age, and BMI) and Model II (adjusted for sex, age, BMI, HbA1c, TC, TG, and ALT) were 1.166 (1.022, 1.331) and 1.248 (1.110, 1.402)(P<0.05). The new model created by logistic regression predicted NAFLD with an area under the curve of 0.676 (0.645, 0.706). Compared to participants in the low NHR group, the high NHR group exhibited a higher prevalence of NAFLD(p<0.05). Conclusion: NHR is associated with NAFLD, which is a good predictor of NAFLD in a healthy population.

A naturalistic study of plasma lipid alterations in female patients with anorexia nervosa before and after weight restoration treatment.

BACKGROUND: Plasma lipid concentrations in patients with anorexia nervosa (AN) seem to be altered. METHODS: We conducted a naturalistic study with 75 adult female patients with AN and 26 healthy female controls (HC). We measured plasma lipid profile, sex hormones and used self-report questionnaires at admission and discharge. RESULTS: Total cholesterol (median (IQR): 4.9 (1.2)) and triglycerides (TG) (1.2 (0.8)) were elevated in AN at admission (BMI 15.3 (3.4)) compared with HC (4.3 (0.7), p = 0.003 and 0.9 (0.3), p = 0.006) and remained elevated at discharge (BMI 18.9 (2.9)) after weight restoration treatment. Estradiol (0.05 (0.1)) and testosterone (0.5 (0.7)) were lower in AN compared with HC (0.3 (0.3), p = < 0.001 and 0.8 (0.5), p = 0.03) and remained low at discharge. There was no change in eating disorder symptoms. Depression symptoms decreased (33 (17) to 30.5 (19), (p = 0.007)). Regression analyses showed that illness duration was a predictor of TG, age was a predictor of total cholesterol and LDL, while educational attainment predicted LDL and TG. CONCLUSION: Lipid concentrations remained elevated following weight restoration treatment, suggesting an underlying, premorbid dysregulation in the lipid metabolism in AN that persists following weight restoration. Elevated lipid concentrations may be present prior to illness onset in AN. LEVEL OF EVIDENCE: III: Evidence obtained from well-designed cohort or case-control analytic studies.

Fat is essential for the human body. Too much fat in the blood can be a sign of underlying illness including heart disease. This study investigated how plasma lipids (fats) are affected in individuals with anorexia nervosa (AN). We included 75 adult female individuals with AN and 26 healthy female controls, and measured lipids, sex hormones, and used questionnaires upon admission and discharge from treatment. We found that low-weight individuals with AN had higher lipids than the healthy controls, and these lipids remained elevated after weight restoration treatment. Additionally, individuals with AN had lower levels of sex hormones (estradiol and testosterone) at their low weight, and they stayed low even after weight restoration treatment. Eating disorder symptoms remained unchanged, but depression symptoms decreased during treatment. In conclusion, the study suggests that individuals with AN have changes in their lipid metabolism, which persists even after weight restoration treatment. We don't know the reason behind these elevated lipids, and therefore, this should be investigated further in future study.

Increased high-density lipoprotein cholesterol in patients with type 2 diabetes and its correlates: a cross-sectional, matched case-control survey.

BACKGROUND: So far, high-density lipoprotein cholesterol (HDL-C) levels and mortality were shown to have a U-shaped relationship. Additionally, high HDL-C levels increase the risk of developing a variety of diseases. However, a paucity of data exists regarding the characteristics of people with high HDL-C levels. The aim of this study was to assess the demographics and characteristics of patients with high HDL-C levels and compare their features with normal and low HDL-C groups. METHODS: As a cross-sectional, matched case-control study, a total of 510 patients with type 2 diabetes (T2D) were enrolled in the study and categorized into three matched groups according to their HDL-C concentrations. The studied groups were matched by their age and gender. Restricted cubic spline (RCS) curves were designed to evaluate the relationship between height, blood pressure, triglyceride, and vitamin D concentrations with the probability of having high HDL-C levels. Furthermore, violin plots were conducted to illustrate the distribution of continuous variables within each group. RESULTS: This study showed that having high HDL-C (more than 70 mg/dL) compared to having low HDL-C (less than 40 mg/dL in men and 50 mg/dL in women) was significantly associated with height (OR 0.918, 95% CI 0.866-0.974), systolic blood pressure (SBP) (0.941, 0.910-0.972), vitamin D (0.970, 0.941-0.999), and triglyceride (0.992, 0.987-0.998) serum concentrations. Further analysis investigated that having high HDL-C levels compared to desired HDL-C levels (40 ≤ HDL-C levels < 70 in men and 50 ≤ HDL-C levels < 70 in women) was inversely associated with having SPB values greater than 130 mmHg. Besides, sufficient vitamin D levels (above 20 ng/ml) could 0.349 times decrease the odds of having high HDL-C versus normal HDL-C levels. CONCLUSION: Sufficient vitamin D levels, SPB values higher than 130 mmHg, as well as increased triglyceride levels, were inversely associated with having high HDL levels. However, higher height values were associated with a decreased likelihood of having high HDL.

Additional mechanism for selective absorption of cholesterol and Phytosterols.

Phytosterols are structurally similar to cholesterol but they are much less absorbed (<2%) than cholesterol (>50%) in the intestine. We hypothesize that phytosterols are poor substrates of intestinal acyl-CoA: cholesterol acyltransferase 2 (ACAT2), and thus minimal phytosterol esters are formed and packed into chylomicrons, leading to their low absorption. Two isotope tracing models, including a radioactive hamster microsomal ACAT2 reaction model and a differentiated Caco-2 cell model, were established to examine the specificity of ACAT2 to various sterols, including cholesterol, sitosterol, stigmasterol, and campesterol. Both models consistently demonstrated that only cholesterol but not phytosterols could be efficiently esterified by ACAT2 in a time- and dose-dependent manner. Molecular docking further suggested that unfavorable interactions existed between ACAT2 and phytosterols. In conclusion, phytosterols are poor substrates of ACAT2 and thus minimally absorbed. This work provides a theoretical basis for the use of phytosterol-based supplements in treating dyslipidemia and preventing heart diseases.

Cardiovascular Risk Estimation and Stratification Among Individuals with Hypercholesterolemia.

PURPOSE OF THE REVIEW: This review aims to assess the variability in considering hypercholesterolemia for cardiovascular risk stratification in the general population. Recent literature on the integration of hypercholesterolemia into clinical risk scores and its interaction with other risk factors will be explored. RECENT FINDINGS: The impact of hypercholesterolemia on risk estimation varies among different cardiovascular risk calculators. Elevated lipid levels during early life stages contribute to atherosclerotic plaque development, influencing disease severity despite later treatment initiation. The interplay between low-density lipoprotein cholesterol (LDLc), inflammatory markers and non-LDL lipid parameters enhances cardiovascular risk stratification. Studies have also examined the role of coronary artery calcium (CAC) score as a negative risk marker in populations with severe hypercholesterolemia. Furthermore, polygenic risk scores (PRS) may aid in diagnosing non-monogenic hypercholesterolemia, refining cardiovascular risk stratification and guiding lipid-lowering therapy strategies. Understanding the heterogeneity in risk estimation and the role of emerging biomarkers and imaging techniques is crucial for optimizing cardiovascular risk prediction and guiding personalized treatment strategies in individuals with hypercholesterolemia.

Elevated remnant cholesterol was associated with the increased metabolically unhealthy obesity risk in Chinese youth.

BACKGROUND AND OBJECTIVES: Metabolically unhealthy obesity is characterized by the presence of cardiovascular metabolic risks such as hypertension, dyslipidemia, and hyperglycemia. Research has shown a correlation between remnant cholesterol (RC) concentrations and abdominal obesity in children. However, the effect of RC concentration on metabolically unhealthy obesity remains unclear. METHODS AND STUDY DESIGN: This study included 3114 Chinese adolescents who received health check-ups. We used logistic regression models and receiver operating characteristic analysis to evaluate the correlation between RC concentration and metabolically unhealthy obesity in a cross-sectional design. RESULTS: After controlling for possible confounding variables, we found that individuals in the top and fourth quintiles of RC concentrations had a significantly higher likelihood of developing metabolically unhealthy obesity compared to those in the bottom quintile (ORs, 4.810 and 1.836; 95% CIs, 3.209-7.212 and 1.167-2.890, respectively). The risk of metabolically unhealthy obesity tended to increase with RC concentration (ptrend<0.001). In addition, boys showed positive associations between RC concentration and both BMI (r = 0.305, p<0.001) and waist circumference (r = 0.306, p<0.001). According to the analysis, the predictive accuracy of metabolically unhealthy obesity was 0.736 (95% CI, 0.690-0.781) for boys and 0.630 (95% CI, 0.573-0.687) for girls. The ideal prediction threshold was 0.66 for boys and 0.59 for girls. CONCLUSIONS: Our findings indicate that elevated RC concen-tration is linked to a higher likelihood of developing metabolically unhealthy obesity in young individuals, regardless of other known risk factors.

World Heart Federation Cholesterol Roadmap: The Portuguese Case.

Atherosclerotic cardiovascular disease (ASCVD) remains the major cause of premature death and disability; effective cardiovascular (CV) risk prevention is fundamental. The World Heart Federation (WHF) Cholesterol Roadmap provides a framework for national policy development and aims to achieve ASCVD prevention.At the invitation of the WHF, a group of experts from the Portuguese Society of Cardiology (SPC), addressed the cholesterol burden at the national level and discussed possible strategies to include in a Portuguese cholesterol roadmap. The literature review showed that the cholesterol burden in Portugal is high and especially uncontrolled in those with the highest CV risk. An infographic, scorecard, was built to include in the WHF collection, for a clear idea about CV risk and cholesterol burden in Portugal, which would also be useful for health policy advocacy.The expert discussion and preventive strategies proposal followed the five pillars of the WHF document: Awareness improvement; Population-based approaches for CV risk and cholesterol; Risk assessment /population screening; System-level approaches; Surveillance of cholesterol and ASCVD outcomes. These strategies were debated by all the expert participants, with the goal of creating a national cholesterol roadmap to be used for advocacy and as a guide for CV prevention.Several key recommendations were made: Include all stakeholders in a multidisciplinary national program; Create a structured activities plan to increase awareness in the population; Improve the quality of continuous CV health education; Increase the interaction between different health professionals and non-health professionals; Increment the referral of patients to cardiac rehabilitation; Screen cholesterol levels in the general population, especially high-risk groups; Promote patients' self-care, engaging with patients' associations; Use specific social networks to spread information widely; Create a national database of cholesterol levels with systematic registry of CV events; Redefine strategies based on the evaluation of results; Create and involve more patients' associations - invert the pyramid order. In conclusion: ASCVD and the cholesterol burden remain a strong global issue in Portugal, requiring the involvement of multiple stakeholders in prevention. The Portuguese cholesterol roadmap can provide some solutions to help mitigate the problem urgently. Population-based approaches to improve awareness and CV risk assessment and surveillance of cholesterol and ASCVD outcomes are key factors in this change. A call to action is clearly needed to fight hypercholesterolemia and ASCVD burden.

SCD1 promotes the stemness of gastric cancer stem cells by inhibiting ferroptosis through the SQLE/cholesterol/mTOR signalling pathway.

Cancer stem cells (CSCs) play a substantial role in cancer onset and recurrence. Anomalous iron and lipid metabolism have been documented in CSCs, suggesting that ferroptosis, a recently discovered form of regulated cell death characterised by lipid peroxidation, could potentially exert a significant influence on CSCs. However, the precise role of ferroptosis in gastric cancer stem cells (GCSCs) remains unknown. To address this gap, we screened ferroptosis-related genes in GCSCs using The Cancer Genome Atlas and corroborated our findings through quantitative polymerase chain reaction and western blotting. These results indicate that stearoyl-CoA desaturase (SCD1) is a key player in the regulation of ferroptosis in GCSCs. This study provides evidence that SCD1 positively regulates the transcription of squalene epoxidase (SQLE) by eliminating transcriptional inhibition of P53. This mechanism increases the cholesterol content and the elevated cholesterol regulated by SCD1 inhibits ferroptosis via the mTOR signalling pathway. Furthermore, our in vivo studies showed that SCD1 knockdown or regulation of cholesterol intake affects the stemness of GCSCs and their sensitivity to ferroptosis inducers. Thus, targeting the SCD1/squalene epoxidase/cholesterol signalling axis in conjunction with ferroptosis inducers may represent a promising therapeutic approach for the treatment of gastric cancer based on GCSCs.

Implementation of risk-based lipid-lowering therapies in older (age ≥ 65 years) and very-old adults (age ≥ 75 years) with ischemic heart disease in the greater Salzburg region.

Introduction: European guidelines recommend the implementation of lipid-lowering therapies (LLTs) in adults (≥ 65 years) with established atherosclerotic cardiovascular disease (ASCVD) and for risk-based primary prevention in older adults (≤ 75 years), yet their use in very-old adults (> 75 years) is controversial, discretionary, and oriented on the presence of risk factors. The aim of this retrospective study is to assess guideline-directed LLT implementation and low-density lipoprotein cholesterol (LDL-C) target achievement in high-/very-high-risk older/very-old adults (65-74 and ≥ 75 years) at presentation for ST-segment elevation myocardial infarction (STEMI) and also to assess evidence-based care delivery to older adults in our region. Methods: All STEMI patients with available LDL-C and total cholesterol presenting for treatment at a large tertiary center in Salzburg, Austria, 2018-2020, were screened (n = 910). High-risk/very-high-risk patients (n = 369) were classified according to European guidelines criteria and divided into cohorts by age: < 65 years (n = 152), 65-74 years (n = 104), and ≥ 75 years (n = 113). Results: Despite being at high-/very-high-risk, prior LLT use was < 40% in the total cohort, with no significant difference by age. Statin monotherapy predominated; 20%-23% of older/very-old adults in the entire cohort were using low-/moderate-intensity stains, 11%-13% were using high-intensity statins, 4% were on ezetimibe therapy, and none were taking proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors. In the secondary prevention cohort, 53% of older/very-old patients used prior LLTs. Significantly higher percentages of older/oldest ASCVD patients (43% and 49%) met LDL-C targets < 70 mg/dL compared to patients < 65 years (29%; p = 0.033), although just 22% and 30% of these older groups attained stricter LDL-C targets of < 55 mg/dL. Low LLT uptake (16%) among older adults aged 64-74 years for primary prevention resulted in 17% and 10% attainment of risk-based LDL-C targets < 70 mg/dL and < 55 mg/dL, respectively. Oldest adults (≥ 75 years) in both primary and secondary prevention groups more often met risk-based targets than older and younger adults, despite predominantly receiving low-/moderate-intensity statin monotherapy. Conclusion: Secondary prevention was sub-optimal in our region. Less than half of older/very-old adults with established ASCVD met LDL-C targets at the time of STEMI, suggesting severe care-delivery deficits in LLT implementation. Shortcomings in initiation of risk-based LLTs were also observed among high-/very-high-risk primary prevention patients < 75 years, with the achievement of risk-based LDL-C targets in 10%-48% of these patients.

LncRNA DANCR promotes macrophage lipid accumulation through modulation of membrane cholesterol transporters.

The progression of atherosclerosis (AS), the pathological foundation of coronary artery disease (CAD), is featured by massive lipid deposition in the vessel wall. LncRNAs are implicated in lipid disorder and AS, whereas the specific role of lncRNA DANCR in atherogenesis remains unknown. Here, we demonstrated that DANCR promotes macrophage lipid accumulation by regulating the expression of membrane cholesterol transport proteins. qPCR showed that compared to control groups, CAD patients and atherosclerotic mice had higher DANCR levels. Treating human THP-1 macrophages and mouse RAW264.7 macrophages with ox-LDL significantly upregulated the expression levels of DANCR. Oil Red O staining showed that the silence of DANCR robustly reduced, while overexpression of DANCR significantly increased the numbers and size of lipid droplets in ox-LDL-treated THP-1 macrophages. In contrast, the opposite phenomena were observed in DANCR overexpressing cells. The expression of ABCA1, ABCG1, SR-BI, and NBD-cholesterol efflux was increased obviously by DANCR inhibition and decreased by DANCR overexpression, respectively. Furthermore, transfection with DANCR siRNA induced a robust decrease in the levels of CD36, SR-A, and Dil-ox-LDL uptake, while DANCR overexpression amplified the expression of CD36, SR-A and the uptake of Dil-ox-LDL in lipid-laden macrophages. Lastly, we found that the effects of DANCR on macrophage lipid accumulation and the expression of membrane cholesterol transport proteins were not likely related to miR-33a. The present study unraveled the adverse role of DANCR in foam cell formation and its relationship with cholesterol transport proteins. However, the competing endogenous RNA network underlying these phenomena warrants further exploration.

Estimated small dense low-density lipoprotein-cholesterol and the risk of kidney and cardiovascular outcomes in diabetic kidney disease.

AIMS: This study aimed to investigate the correlations between estimated small dense low-density lipoprotein-cholesterol (esd-LDL-c) and the development of end-stage kidney disease (ESKD), cardiovascular mortality, and all-cause mortality in individuals with diabetic kidney disease (DKD) or diabetes mellitus (DM) concomitant chronic kidney disease (CKD). METHODS: We analyzed the data from a biopsy-proven DKD cohort conducted at West China Hospital of Sichuan University between 2009 and 2021 (the DKD cohort) and participants with DM and CKD in the National Health and Nutrition Examination Survey (NHANES) 2011-2014 (the NHANES DM-CKD cohort). Cox regression analysis was also used to estimate associations between esd-LDL-c and the incidence of ESKD, cardiovascular mortality, and all-cause mortality. RESULTS: There were 175 ESKD events among 338 participants in the DKD cohort. Patients were divided into three groups based on esd-LDL-c tertiles (T1 < 33.7 mg/dL, T2 ≥ 33.7 mg/dL to <45.9 mg/dL, T3 ≥ 45.9 mg/dL). The highest tertile of esd-LDL-c was associated with ESKD (adjusted HR 2.016, 95% CI 1.144-3.554, p = .015). Furthermore, there were 99 deaths (39 cardiovascular) among 293 participants in the NHANES DM-CKD cohort. Participants were classified into three groups in line with the tertile values of esd-LDL-c in the DKD cohort. The highest tertile of esd-LDL-c was associated with cardiovascular mortality (adjusted HR 3.95, 95% CI 1.3-12, p = .016) and all-cause mortality (adjusted HR 2.37, 95% CI 1.06-5.32, p = .036). CONCLUSIONS: Higher esd-LDL-c was associated with increased risk of ESKD in people with biopsy-proven DKD, and higher cardiovascular and all-cause mortality risk among those with DM-CKD.

Relationships of the Surface Charge of Low-Density Lipoprotein (LDL) with the Serum LDL-Cholesterol and Atherosclerosis Levels in a Japanese Population: The DOSANCO Health Study.

AIM: This study investigated the associations of the surface charge of low-density lipoprotein (LDL) with the serum LDL-cholesterol and atherosclerosis levels in a community-based Japanese population. METHODS: The study had a cross-sectional design and included 409 community residents aged 35-79 years who did not take medications for dyslipidemia. The potential electric charge of LDL and the zeta potential, which indicate the surface charge of LDL, were measured by laser Doppler microelectrophoresis. The correlations of the zeta potential of LDL (-mV) with the serum LDL-cholesterol levels (mg/dL), cardio-ankle vascular index (CAVI), and serum high-sensitivity C-reactive protein (hsCRP) levels (log-transformed values, mg/L) were examined using Pearson's correlation coefficient (r). Linear regression models were constructed to examine these associations after adjusting for potential confounding factors. RESULTS: A total of 201 subjects with correctly stored samples were included in the primary analysis for zeta potential measurement. An inverse correlation was observed between the LDL zeta potential and the serum LDL-cholesterol levels (r=-0.20; p=0.004). This inverse association was observed after adjusting for sex, age, dietary cholesterol intake, smoking status, alcohol intake, body mass index, and the serum levels of the major classes of free fatty acids (standardized ß=-6.94; p=0.005). However, the zeta potential of LDL showed almost no association with CAVI or the serum hsCRP levels. Similar patterns were observed in the 208 subjects with compromised samples as well as all the original 409 subjects. CONCLUSION: A higher electronegative surface charge of LDL was associated with lower serum LDL-cholesterol levels in the general Japanese population.

Prevalence and Clinical Characteristics of Familial Hypercholesterolemia in Patients with Acute Coronary Syndrome according to the Current Japanese Guidelines: Insight from the EXPLORE-J study.

AIMS: Little data exists for evaluating the prevalence and patient characteristics of familial hypercholesterolemia (FH) according to the latest 2022 guidelines for FH published by the Japan Atherosclerosis Society (JAS), which revised the Achilles tendon thickness (ATT) threshold from 9.0 mm in both sexes to 8.0 mm in men and 7.5 mm in women. This study used a nationwide registry of patients with acute coronary syndrome (ACS) to evaluate the prevalence of FH according to the latest diagnostic criteria for FH and to investigate the application of Achilles tendon imaging in the diagnosis of FH.A previous prospective observational study at 59 Japanese centers involving consecutive patients with ACS who were managed between April 2015 and August 8, 2016 was conducted to explore lipid management and persistent risk in patients hospitalized for ACS (EXPLORE-J). The study population consisted of 1,944 EXPLORE-J enrollees. RESULTS: According to the diagnostic criteria for FH in the 2022 JAS guidelines, the prevalence of probable or definite was among patients with ACS was 6.6% (127/1944). Among patients with premature ACS (male, age ＜55 years; female, age ＜65 years), the prevalence of FH was 10.1% (43/427). The mean ages were of the probable FH and definite FH groups were 59.9 and 61.0 years, respectively, while the mean age of the possible-or-unlikely FH group was 66.4 years (significantly older). Relative to the possible-or-unlikely FH group, the low-density lipoprotein cholesterol (LDL-C) levels were similar in the probable FH group and and significantly higher in the definite FH group. CONCLUSIONS: The prevalence of FH was considerably higher than previously reported, especially for patients with premature ACS. The age and LDL-C levels of the patients in the probable FH and definite FH groups were similar.

Alirocumab and cardiovascular outcomes according to sex and lipoprotein(a) after acute coronary syndrome: a report from the ODYSSEY OUTCOMES study.

BACKGROUND: The ODYSSEY OUTCOMES trial (NCT01663402) compared the effects of the proprotein convertase subtilisin/kexin type 9 inhibitor alirocumab with placebo on major adverse cardiovascular events (MACE) in patients with recent acute coronary syndrome (ACS). OBJECTIVE: We assessed efficacy and safety of alirocumab versus placebo according to sex and lipoprotein(a) level. METHODS: This prespecified analysis compared the effects of alirocumab versus placebo on lipoproteins, MACE (coronary heart disease death, non-fatal myocardial infarction, fatal/non-fatal ischemic stroke, unstable angina requiring hospitalization), death, total cardiovascular events, and adverse events in 4762 women and 14,162 men followed for a median of 2.8 years. In post-hoc analysis, we evaluated total cardiovascular events according to sex, baseline lipoprotein(a), and treatment. RESULTS: Women were older, had higher baseline LDL-C levels (89.6 vs 85.3 mg/dL) and lipoprotein(a) (28.0 vs 19.3 mg/dL) and had more co-morbidities than men. At 4 months, alirocumab lowered LDL-C by 49.4 mg/dL in women and 54.0 mg/dL in men and lipoprotein(a) by 9.7 and 8.1 mg/dL, respectively (both p < 0.0001). Alirocumab reduced MACE, death, and total cardiovascular events similarly in both sexes. In the placebo group, lipoprotein(a) was a risk factor for total cardiovascular events in women and men. In both sexes, reduction of total cardiovascular events was greater at higher baseline lipoprotein(a), but this effect was more evident in women than men (pinteraction=0.08). Medication adherence and adverse event rates were similar in both sexes. CONCLUSIONS: Alirocumab improves cardiovascular outcomes after ACS irrespective of sex. Reduction of total cardiovascular events was greater at higher baseline lipoprotein(a).