Lower Triglyceride Levels Research Articles

ASGR1 deficiency improves atherosclerosis but alters liver metabolism in ApoE-/- mice

The asialoglycoprotein receptor 1 (ASGR1), a multivalent carbohydrate-binding receptor that primarily is responsible for recognizing and eliminating circulating glycoproteins with exposed galactose (Gal) or N-acetylgalactosamine (GalNAc) as terminal glycan residues, has been implicated in modulating the lipid metabolism and reducing cardiovascular disease burden. In this study, we investigated the impact of ASGR1 deficiency (ASGR1−/−) on atherosclerosis by evaluating its effects on plaque formation, lipid metabolism, circulating immunoinflammatory response, and circulating N-glycome under the hypercholesterolemic condition in ApoE-deficient mice. After 16 weeks of a western-type diet, ApoE−/−/ASGR1−/− mice presented lower plasma cholesterol and triglyceride levels compared to ApoE−/−. This was associated with reduced atherosclerotic plaque area and necrotic core formation. Interestingly, ApoE−/−/ASGR1−/− mice showed increased levels of circulating immune cells, increased AST/ALT ratio, and no changes in the N-glycome profile and liver morphology. The liver of ApoE−/−/ASGR1−/− mice, however, presented alterations in the metabolism of lipids, xenobiotics, and bile secretion, indicating broader alterations in liver homeostasis beyond lipids. These data suggest that improvements in circulating lipid metabolism and atherosclerosis in ASGR1 deficiency is paralleled by a deterioration of liver injury. These findings point to the need for additional evaluation before considering ASGR1 as a pharmacological target for dyslipidemia and cardiovascular disorders.Graphical abstract

Metabolic syndrome in association with novel dietary index, metabolic parameters, nesfatin-1 and omentin-1

BackgroundMetabolic syndrome is a prevalent and common health problem and numerous studies have revealed the role of diet and lifestyle change in prevention of metabolic syndrome. However, the novel dietary index, cardioprotective index (CPI) and its association with metabolic syndrome is not investigated yet. In the current study, we evaluated the association between metabolic syndrome and its components, CPI, Nesfatin-1 and Omentin-1in a cross-sectional study.MethodsThree hundred forty eight overweight and obese individuals with metabolic syndrome were recruited. Subjects underwent anthropometric and laboratory assays including metabolic markers, Nesfatin-1 and Omentin-1 with commercial kits.ResultsThose at the first tertile of CPI had lower high density lipoprotein concentrations (HDL) and higher low density lipoprotein concentrations (LDL), triglyceride (TG), systolic and diastolic blood pressures (SBP, DBP) levels compared with those at the highest tertiles (P < 0.05). After adjustment for the confounding effects of age, sex, body mass index, physical activity and total calorie intake, LDL lost its significance across CPI tertiles. Moreover, serum total cholesterol, insulin and insulin resistance were not significant across CPI tertiles neither in crude nor in adjusted models (P > 0.05). Additionally, being at the third tertile of CPI was accompanied with significantly higher Nesfatin-1 and Omentin-1 levels compared with lowest tertiels (P < 0.05) in crude and confounder – adjusted models. Conclusions: To our findings, CPI was in positive relationship with metabolic parameters, blood pressure, Nesfatin-1 and Omentin-1 levels in metabolic syndrome. Further future studies will help to elaborate the causality.Clinical trial numberNot applicable.

Association Between Lifestyle Patterns and Abdominal Obesity with Biochemical and Inflammatory Biomarkers in Adolescents with Down Syndrome: The UP&DOWN Study.

The main objective of this study was to examine the association between lifestyle patterns (physical activity, screen and sleep time and diet) and abdominal obesity, and endocrine, metabolic, and immunological biomarkers in adolescents with Down syndrome (DS). Eighty-three DS adolescents (38.6% girls), aged 11 to 18 years, from the UP&DOWN study were included. Cluster analysis was performed by including the compliance of recommendations of lifestyle variables, such as moderate to vigorous physical activity (MVPA), screen and sleep time and adherence to the Mediterranean diet (AMD). The waist-to-height ratio was used as an indicator of abdominal obesity. Haematological, biochemical and inflammatory biomarkers were analysed. A three-cluster solution was identified: Cluster 1: adolescents with low compliance; Cluster 2: youth with medium compliance; and Cluster 3: adolescents with high compliance. Significant differences in MVPA (p = 0.000), screen time (p = 0.004), sleep time (p = 0.0001), AMD (p = 0.000) and abdominal obesity (p = 0.003) were found. Clusters 2 and 3 had lower levels of triglycerides and LDL-cholesterol than Cluster 1. Cluster 2, in which all adolescents met the MVPA recommendations, had the lowest levels of galactin 3. Compliance with lifestyle recommendations (PA, screen and sleep time and AMD) and the absence of abdominal obesity seem to be associated with better biochemical and inflammatory values.

Abstract 4137713: Epsin-Mediated PCSK9-LDLR Interaction: A New Therapeutic Target for Atherosclerosis

Introduction: Atherosclerosis, a leading cause of cardiovascular diseases, causes about 17.9 million deaths annually. It is driven by high levels of LDL cholesterol (LDL-C). The liver's LDL receptor (LDLR) removes LDL-C from the bloodstream, but its degradation by PCSK9 exacerbates the condition. Epsin, an endocytic adaptor protein crucial for clathrin-mediated endocytosis, plays a significant role in atherosclerosis, particularly lipid metabolism. Hypothesis: We propose that hepatic epsins significantly contribute to atherosclerosis by facilitating the PCSK9-induced degradation of LDLR, thus impeding LDL-C clearance. Objectives: This study aims to investigate hepatic epsins' role in PCSK9-mediated LDLR degradation and its effects on LDL-C levels and atherosclerosis development. Using bioinformatics, we will analyze enriched pathways and networks to study epsins modulation, which will be validated through biochemical assays and in vivo experiments. Methods: Liver-specific double knockout (DKO) mice lacking epsin1 and epsin2 were created on an ApoE -/- background. Atherosclerosis was induced using a Western diet (WD), and blood cholesterol and triglyceride levels were monitored. We employed high-resolution single-cell RNA sequencing (scRNA-seq) to analyze cellular transitions, intercellular interactions, and Gene Ontology pathway enrichment within hepatocyte-derived data. Results: RNA velocity reveals the transition from lipogenic Alb hi Hepatocytes to glucogenic Hnf4a hi Hepatocytes in Liver-DKO mice on an ApoE -/- background on a WD. Liver-DKO mice on an ApoE -/- background on a WD exhibited significantly reduced atherogenesis and lower blood cholesterol and triglyceride levels compared with wild-type on an ApoE -/- background on a WD. Gene Ontology enrichment analysis showed elevated pathways for LDL particle clearance and enhanced LDLR-cholesterol communication scores in Liver-DKO mice, suggesting improved LDL-C clearance. Nanoparticle-encapsulated siRNAs targeting liver epsins effectively inhibited atherosclerosis. Conclusion: Epsin depletion in the liver upregulated LDLR protein levels, and PCSK9-triggered LDLR degradation was abolished, preventing atheroma progression. Targeting liver epsins presents a novel therapeutic strategy for atherosclerosis, supported by network analysis and predictive modeling for effective interventions.

Abstract 4146303: A Single-Dose of a Novel CasX-Editor Lowers APOC3 Levels In Vivo

Background: Apolipoprotein C-III (APOC3) is a key regulator of lipid metabolism that inhibits the catabolism and clearance of triglyceride (TG)-rich lipoproteins in the blood. Loss-of-function APOC3 variants are associated with significantly lower TG levels and a reduced risk of heart disease, underscoring the potential of APOC3 inactivation as a therapeutic strategy for patients with familial chylomicronemia syndrome (FCS) and severe hypertriglyceridemia (SHTG). Here, we developed STX-1400 lead molecules as a novel investigational gene editing treatment using a highly engineered CRISPR-CasX mRNA and a guide RNA (gRNA) encapsulated into lipid nanoparticles (LNPs) to edit the APOC3 gene and knock out its hepatic expression. Methods: STX-1400 lead molecules were evaluated for editing potency and resulting functional effects on APOC3 reduction in vitro in primary human hepatocytes (PHHs) and primary cynomolgus hepatocytes (PCHs). In vivo studies were conducted in PXB mice, a humanized liver mouse model. Liver biopsies and serum samples were collected at two weeks post-dose. Human APOC3 mRNA and APOC3 protein levels were measured in liver biopsies and serum samples, respectively. Lipid profile evaluation, which included measuring TGs and total cholesterol (TC) levels, was also performed. Results: Treatment of PHHs with LNPs containing STX-1400 lead molecules showed a dose-dependent increase in editing activity; up to 90% editing at the APOC3 locus was associated with &gt;70% reduction in secreted APOC3 protein levels. Potency was also observed in PCHs, with up to 70% editing. A single dose of LNPs encapsulating STX-1400 lead molecules delivered into PXB humanized mice resulted in &gt;60% editing at the APOC3 locus in the liver, which was associated with &gt;90% reduction of serum hAPOC3 protein levels, accompanied by reduction in TG and TC levels. Conclusions: These data demonstrate that the STX-1400 lead molecules efficiently knock down hepatic expression of APOC3 in preclinical models. This work suggests that the CRISPR-CasX-based editor approach could be developed as a single dose therapy for the treatment of hypertriglyceridemia.

Cardiometabolic risk factors are affected by interaction between FADS1 rs174556 variant and dietary vegetable oils in patients with diabetes: a randomized controlled trial

FADS1 rs174556 polymorphism influences on dietary fats metabolism and type 2 diabetes (T2DM). This study aimed to compare the effect of three oils of sesame, canola and sesame-canola on cardio metabolic factors across genotypes of rs174556 variant in patients with type 2 of diabetes. This study was a randomized triple-blind three-way cross-over clinical trial. 95 Subjects with T2DM replaced their regular dietary oil with sesame oil, canola oil, or sesame-canola oil for three 9-week phases and completed the study. There were three anthropometric measurements, blood sampling and biochemical assessments at the beginning, middle, and at the end of each phase for assessments. Genotyping was conducted using the polymerase chain reaction-restriction fragment length polymorphism (PCR–RFLP) method. In the crude model, there was an interaction between consumed oils and rs174556 variant on serum concentration of Apolipoprotein A-I (ApoA-1). During intake of sesame oil, lower levels of triglycerides (TG) were observed in individuals with TT genotype compared to C allele carriers’ allele, which remained significant in adjusted models. Compared to C allele carrier’s, the people with TT genotype experienced significant increase and decrease in serum levels of HDL and TG, respectively in adjusted models. Also, the subjects who consumed sesame-canola oil had lower serum concentrations of fasting blood glucose than those who received sesame and canola oils, regardless of used oils and genotypes. FADS1 Gene variant (rs174556) might modify cardiometabolic changes following dietary vegetable oils. Larger longitudinal studies especially randomized clinical trials are needed to clarify these associations.

Improvements in Insulin Resistance and Glucose Metabolism Related to Breastfeeding Are Not Mediated by Subclinical Inflammation.

Background: Lactation is known to improve insulin resistance, but this phenomenon remains poorly understood. Our goal was to evaluate whether subclinical inflammation could mediate the association between breastfeeding (BF) and improvement in glucose metabolism and markers of insulin resistance (MIRs) in the postpartum. Methods: A total of 95 adult women (≥18 years) with a BMI ≥ 25 kg/m2 from the outpatient clinic of the Federal University of São Paulo were followed from early pregnancy until 60 to 180 days postpartum. The patients were divided based on their BF status: BF and non-BF groups. A latent variable termed SubInf was created incorporating inflammation-related biomarkers: adiponectin, E-selectin, branched-chain amino acids, zonulin, copeptin, and lipopolysaccharides. The association of BR with MIRs in the postpartum was evaluated through linear regression analysis, and mediation analysis was performed to evaluate the role of SubInf in this association. Results: The groups were similar regarding gestational diabetes mellitus (GDM) prevalence, pre-gestational BMI, caloric intake, physical activity, and postpartum weight loss. The BF group presented lower levels of triglycerides (TGs), fasting glucose, fasting insulin, TG/HDLcholesterol ratio (TG/HDL), TyG index, and HOMA-IR compared to the non-BF group. A linear regression analysis adjusted for scholarity, parity, pre-gestational BMI, GDM, weight gain during pregnancy, and mode of delivery revealed an inverse association between BF and fasting glucose [-6.30 (-10.71 to -1.89), p = 0.005), HOMA-IR [-0.28 (-0.50 to -0.05), p = 0.017], TyG index [-0.04 (-0.06 to -0.01), p = 0.002], and TG/HDL ratio [-0.23 (-0.46 to -0.01), p = 0.001]. In the mediation analysis, SubInf did not mediate the indirect effect of BF on MIRs. Conclusions: In overweight and obese women, an association between BF and improvement in MIRs in the postpartum was seen, corroborating that BF should be stimulated, especially in these cardiometabolic high-risk women. Subclinical inflammation did not seem to mediate this association.

Increased risk of vascular complications in patients with type 2 diabetes and fatty liver disease

BackgroundThe prevalence of steatotic liver disease (SLD) in patients with type 2 diabetes (T2DM) exceeds 50%. This study aimed to investigate the clinical characteristics of SLD and liver fibrosis in Chinese patients with T2DM.MethodsInpatients from 2021 to 2023 were included in the study. Fatty liver index (FLI) and fibrosis-4 (FIB-4) were calculated to assess hepatic steatosis and fibrosis respectively. Statistical analysis was completed by SPSS v25 and GraphPad Prism v8.0.1.ResultsOf the 1466 participants, about one-third of the patients in T2DM-SLD group were diagnosed with liver fibrosis (LF), and the percentage of patients over 50 years old was 85.9%. Patients with SLD had higher levels of BMI, blood pressure, liver enzymes, fasting blood glucose (FBG), HbA1c, C-peptide, total cholesterol (TC) and triglyceride (TG) (P<0.05 for all). Patients with liver fibrosis had lower TC, TG, hemoglobin (Hb), erythrocyte count (RBC), leukocyte count (WBC) and platelet (PLT) levels (P<0.05 for all). Compared with simple T2DM and SLD-NLF (non-liver fibrosis) groups, for patients over 50 years old, the prevalence of coronary heart disease, stroke, tumor, and diabetic nephropathy was higher in patients with liver fibrosis. Liver fibrosis might be the risk factor of arterial stiffness, stroke, coronary heart disease and numbness based on multivariable logistic regression analysis.ConclusionHepatic steatosis and fibrosis were common in patients with T2DM. Liver fibrosis was relevant to many macrovascular and microvascular diabetic complications.

Efficacy and Safety of Pemafibrate Extended-Release Tablet: a Phase 3, Multicenter, Randomized, Double-Blind, Active-Controlled, Parallel-Group Comparison Trial.

Pemafibrate, a selective peroxisome proliferator-activated receptor α modulator that lowers serum triglyceride levels and increases high-density lipoprotein cholesterol levels, is approved for treating dyslipidemia as twice-daily immediate-release (IR) tablets. A once-daily extended-release (XR) tablet has also been developed. We aimed to confirm the non-inferiority of XR (0.2 or 0.4 mg/day; once daily) to IR (0.2 mg/day; twice daily) in lowering triglyceride levels in patients with hypertriglyceridemia. This phase 3, multicenter, randomized, double-blind study included patients with fasting triglycerides ≥ 200 mg/dL who received IR (0.2 mg/day) or XR (0.2 or 0.4 mg/day). The primary efficacy endpoint was the percentage change in fasting triglyceride levels from baseline to 4, 8, and 12 weeks. Common treatment effects at weeks 4 through 12 were compared between groups using repeated analysis of covariance. In 356 randomized patients, fasting triglyceride levels decreased by 48.0%, 43.8%, and 48.0% with IR 0.2, XR 0.2, and XR 0.4 mg/day, respectively, confirming the non-inferiority of both XR regimens to IR. The proportion of patients who achieved fasting triglycerides ＜150 mg/dL was 45.7%, 37.4%, and 51.7%, while the percentage change of triglycerides in the subgroup with baseline triglycerides ≥ 500 mg/dL was -59.3%, -52.2%, and -66.3% with IR 0.2, XR 0.2, and XR 0.4 mg/day, respectively. XR (0.2 and 0.4 mg/day) was non-inferior to IR (0.2 mg/day). XR 0.4 mg/day demonstrated a more potent triglyceride-lowering effect than XR 0.2 mg/day and should be considered for patients with high triglyceride levels.

Organophosphorus Flame Retardants and Metabolic Disruption: An in Silico, in Vitro, and in Vivo Study Focusing on Adiponectin Receptors.

Environmental chemical exposures have been associated with metabolic outcomes, and typically, their binding to nuclear hormone receptors is considered the molecular initiating event (MIE) for a number of outcomes. However, more studies are needed to understand the influence of such exposures on cell membrane-bound adiponectin receptors (AdipoRs), which are critical metabolic regulators. We aimed to clarify the potential interactions between AdipoRs and environmental chemicals, specifically organophosphorus flame retardants (OPFRs), and the resultant effects. Employing in silico simulation, cell thermal shift, and noncompetitive binding assays, we screened eight OPFRs for interactions with AdipoR1 and AdipoR2. We tested two key events underlying AdipoR modulation upon OPFR exposure in a liver cell model. The Toxicological Prioritization Index (ToxPi)scoring scheme was used to rank OPFRs according to their potential to disrupt AdipoR-associated metabolism. We further examined the inhibitory effect of OPFRs on AdipoR signaling activation in mouse models. Analyses identified pi-pi stacking and pi-sulfur interactions between the aryl-OPFRs 2-ethylhexyl diphenyl phosphate (EHDPP), triphenyl phosphate (TPhP), and tricresyl phosphate (TCP) and the transmembrane cavities of AdipoR1 and AdipoR2. Cell thermal shift assays showed a rightward shift in the AdipoR proteins' melting curves upon exposure to these three compounds. Although the binding sites differed from adiponectin, results suggest that aryl-OPFRs noncompetitively inhibited the binding of the endogenous peptide ligand ADP355 to the receptors. Analyses of key events underlying AdipoR modulation revealed that glucose uptake was notably lower, whereas lipid content was higher in cells exposed to aryl-OPFRs. EHDPP, TCP, and TPhP were ranked as the top three disruptors according to the ToxPi scores. A noncompetitive binding between these aryl-OPFRs and AdipoRs was also observed in wild-type (WT) mice. In db/db mice, the finding of lower blood glucose levels after ADP355 injection was diminished in the presence of a typical aryl-OPFR (TCP). WT mice exposed to TCP demonstrated lower AdipoR1 signaling, which was marked by lower phosphorylated AMP-activated protein kinase (pAMPK) and a higher expression of gluconeogenesis-related genes. Moreover, WT mice exposed to ADP355 demonstrated higher levels of pAMPK protein and peroxisome proliferator-activated receptor- messenger RNA. This was accompanied by higher glucose disposal and by lower levels of long-chain fatty acids and hepatic triglycerides; these metabolic improvements were negated upon TCP co-treatment. In silico, in vitro, and invivo assays suggest that aryl-OPFRs act as noncompetitive inhibitors of AdipoRs, preventing their activation by adiponectin, and thus function as antagonists to these receptors. Our study describes a novel MIE for chemical-induced metabolic disturbances and highlights a new pathway for environmental impact on metabolic health. https://doi.org/10.1289/EHP14634.

Sodium Orthovanadate Mitigates Nonalcoholic Fatty Liver Disease by Enhancing Autophagy.

Sodium orthovanadate (SOV) has been investigated in recent research for its therapeutic efficacy in treating metabolic disorders. Considering the rising prevalence of non-alcoholic fatty liver disease (NAFLD), the effects of SOV on NAFLD remain to be further investigated. The aim of this study was to investigate the role and mechanism of SOV in NAFLD. Two mouse models were established by induction with high fat diet (HFD) and Western diet supplemented with the sugar in drinking water (WDS), respectively. We searched for the downstream molecules of SOV by RNA sequencing, followed by rescue experiments with an autophagy inhibitor (3-MA) in HepG2 cells as well as in animal models. The results showed that in HFD and WDS-induced NAFLD models, SOV significantly reduced body weight, inhibited lipid deposition, lowered serum triglyceride and cholesterol levels. Then RNA sequencing and RT-PCR found that the effect of SOV might be related to the activation of autophagy coregulated by hypoxia-inducible factor 1 and autophagy-related gene 5. The protective effects of SOV-activated autophagy were blocked by 3-MA, leading to the restoration of lipid deposition in vitro and in vivo. We conclude that SOV could activate liver cell autophagy, thereby improving lipid deposition and metabolism during the course of NAFLD. Our findings revealed the potential of SOV for controlling NAFLD.

Study Design and Protocol for a Randomized Controlled Trial to Assess Long-Term Efficacy and Safety of a Triple Combination of Ezetimibe, Fenofibrate, and Moderate-Intensity Statin in Patients with Type 2 Diabetes and Modifiable Cardiovascular Risk Factors (ENSEMBLE).

Atherogenic dyslipidemia, which is frequently associated with type 2 diabetes (T2D) and insulin resistance, contributes to the development of vascular complications. Statin therapy is the primary approach to dyslipidemia management in T2D, however, the role of non-statin therapy remains unclear. Ezetimibe reduces cholesterol burden by inhibiting intestinal cholesterol absorption. Fibrates lower triglyceride levels and increase high-density lipoprotein cholesterol (HDL-C) levels via peroxisome proliferator- activated receptor alpha agonism. Therefore, when combined, these drugs effectively lower non-HDL-C levels. Despite this, few clinical trials have specifically targeted non-HDL-C, and the efficacy of triple combination therapies, including statins, ezetimibe, and fibrates, has yet to be determined. This is a multicenter, prospective, randomized, open-label, active-comparator controlled trial involving 3,958 eligible participants with T2D, cardiovascular risk factors, and elevated non-HDL-C (≥100 mg/dL). Participants, already on moderate-intensity statins, will be randomly assigned to either Ezefeno (ezetimibe/fenofibrate) addition or statin dose-escalation. The primary end point is the development of a composite of major adverse cardiovascular and diabetic microvascular events over 48 months. This trial aims to assess whether combining statins, ezetimibe, and fenofibrate is as effective as, or possibly superior to, statin monotherapy intensification in lowering cardiovascular and microvascular disease risk for patients with T2D. This could propose a novel therapeutic approach for managing dyslipidemia in T2D.

Growth performance, serum metabolites, plasma protein fraction, meat lipid profile and antioxidant activities of breast meat of broiler chicken fed diets containing Cinnamomum ceylon powder, Zingiber officinale powder and Moringa oleifera leafmeal supplem

An experiment was conducted to determine growth performance, serum metabolites, plasma protein fraction, meat lipid profile and antioxidant activities of meat of broilers as affected by Cinnamomium ceylon, Zingiber officinale and Moringa oleifera supplementation. A total of 112 day old chicks were allotted into four treatments replicated four times with seven birds per replicate in a completely randomized design (CRD). Basal diets were formulated for broiler starters (0-28days) and finisher phase (29-56) days. The basal diets were divided into 4 diets : diet 1- control diet without supplementation; diet 2- contained 0.2% Cinnamomum ceylon supplementation (CCS); diet 3- contained 0.2% Zingiber officinale supplementation (ZOS), diet 4-contained 0.2% Moringa oleifera leafmeal (MOLM) supplementation. The experiment lasted for 56 days. Results showed an improvement in final liveweight, weight gain, feed intake and feed conversion ratio of birds on 0.2% MOLM. Birds on phytogenic feed additives have lower values of urea, cholesterol, glucose, high density lipoprotein and low density lipoprotein. Birds administered phytogenic supplements exhibited much greater plasma albumin levels. Low levels of meat cholesterol, triglycerides and low density lipoprotein were found in birds fed phytogenic feed additives while high levels of high density lipoprotein were recorded for birds on phytogenic feed additives. The supplementation of broilers diets with phytogenic feed additives increased the glutathione peroxidase and superoxide dismutase and decreased lipid peroxidation. It was concluded that supplementation of broiler diets with Moringa oleifera leaf meal enhanced body weight gain, antioxidant activities also reduced cholesterol level in both serum metabolites and meat.

Impact of Triglyceride Levels on the Long-term Clinical Outcomes in Patients With Acute Myocardial Infarction.

Hypertriglyceridemia is a known cardiovascular risk factor. However, the relationship between serum triglyceride (TG) levels and the clinical outcomes in patients with acute myocardial infarction (AMI) is unclear. We conducted a single-center, retrospective observational study involving 538 consecutive patients with AMI who underwent emergent percutaneous coronary intervention within 12 hours of onset. Patients were categorized into three groups based on their serum TG levels at admission as follows: T1 group (TG <78 mg/dl, n=172), T2 group (78≤TG<141 mg/dl, n=177), and T3 group (141 mg/dl ≤TG, n=176). The primary endpoint was major adverse cardiovascular events (MACEs) defined as a composite of cardiovascular death, non-fatal MI, and non-fatal stroke. The median follow-up period was 2.4 (1.5-4.2) years. Patients in the T1 group were older, had a higher proportion of females, and had fewer cardiovascular risk factors. However, they also had a higher prevalence of multi-vessel coronary artery disease and severely calcified culprit lesions. The T1 group had a significantly higher rate of MACEs (20.4% in T1, 12.4% in T2 and 8.5% in T3, p<0.05 by Log-rank test, respectively). Multivariate analysis revealed that T1 was an independent predictor of MACEs (hazard ratio=2.19, 95% confidence interval=1.16-4.14, p<0.05). Although patients with AMI with low TG levels at admission had fewer coronary risk factors, they had more severe calcified culprit lesions and worse clinical outcomes.

Efficacy and severity of side-effects of rosuvastatin compared to other statins post-heart-transplantation

Abstract Introduction The International Society of Heart and Lung Transplantation (ISHLT) 2022 guideline recommends statin therapy in heart transplantation (HTx) patients, with the therapeutic low-density lipoprotein (LDL) target being &amp;lt;2.5 mmol/L. Particularly pravastatin is recommended, given proven beneficial effects on long-term clinical outcome and the low prevalence of side effects. Yet, in the general population, rosuvastatin has been shown to be even more potent. Purpose We investigated the lipid-lowering effect and severity of side-effects of rosuvastatin compared to less potent statins in HTx patients. Methods In this before-after study, we included all HTx patients whom were prescribed a change from the statin they were using to rosuvastatin, for better cardiovascular risk management and/or because of side-effects, between February 2018 and February 2023. We evaluated the weight, lipid profile and side-effects (including myalgia, cramps, stiffness and weakness) of these patients up to one year prior to and after the statin change. At the same time, side-effects were measured in a visual analogue scale (VAS) ranging from 0-10, with the average score of side-effects utilized for analysis. We compared the differences using a Wilcoxon signed rank test. Results Out of 299 HTx patients, we included 114 patients, with a median age of 58 [IQR 50-67] years at switch of whom 31 (27%) were females. Median time since HTx was 9 [IQR 5-15] years. The distribution and dosage of prescribed statins before and after switch can be found in Table 1. Compared to statins used prior to therapy change, rosuvastatin was associated with lower total cholesterol, LDL- and triglyceride levels, with high density lipoprotein (HDL) levels remaining the same (Table 2). No difference in bodyweight was found (Table 2). Before switch, 41 (36%) patients achieved the target of LDL-levels below 2.5 mmol/L. After switch, 86 (75%) patients achieved the target of LDL levels below 2.5 mmol/L. Rosuvastatin shows a trend towards a lower prevalence of side-effects (Table 2). Conclusion In HTx patients that were prescribed a change of statin due to better cardiovascular risk management and/or complaints of side-effects, rosuvastatin is related to a more favorable lipid profile, without additional side-effects, compared to other statins. Furthermore, many more patients achieve the guideline recommended LDL-target. Ongoing research should determine whether this translates to a better clinical outcome.

The Triglycerides - Glucose Index: An independent predictor of late subclinical cardiotoxicity in adult survivors of childhood, adolescent and young adult cancer

Abstract Introduction The Triglycerides - Glucose index (TyG index) has been identified as a reliable alternative for estimating insulin resistance (IR). Numerous recent studies have provided strong statistical evidence suggesting that this index is associated with the development and prognosis of cardiovascular pathologies. Objectives The aim of this study was to investigate the predictive role of the TyG index on the decrease in left ventricular longitudinal global strain (GLS) assessed on two-dimensional echocardiography in asymptomatic adult survivors of childhood, adolescent and young adult cancer. Methods The study included patients aged 18 years and older, asymptomatic cardiovascular survivors of childhood, adolescent and young adult cancer treated with anthracyclines with or without mediastinal radiotherapy. Anthropometric characteristics, cardiovascular risk factors and cancer treatment-related characteristics were collected. The TyG index was calculated using the formula: ln [fasting triglycerides (mg/dl) × fasting glucose (mg/dl)/2]. GLS was assessed and expressed as an absolute value. A GLS equal to 17.3% was retained as the threshold value after calculation in a referent group matched to patients according to age and gender. Cardiac biomarkers GDF 15, ultra-sensitive troponin I and NT-proBNP levels were measured in addition to fasting blood glucose and lipid profiles. Multivariate analysis using linear regression was performed to identify associations between these different parameters. Results A total of 105 cancer survivors from childhood, adolescence and young adulthood were included. The sex ratio was 1.3. The mean age of the patients was 25 years, the mean time since completion of cancer treatment was 10.6 years, the mean cumulative doses of anthracyclines and mediastinal radiotherapy were successively 245.75 ± 75.14 mg/m2 and 34.6 ± 6.19 Gy. Mean GLS was 18.5 ± 2.83%, mean LVEF 60.6 ± 5.69%. None of the patients had any known diabetes or treatment to lower blood glucose or triglyceride levels. No patient had a history of cardiovascular disease. In the univariate study, the factors associated with lower GLS were patient age at recruitment (p = 0.03), mean time since completion of cancer treatment when this was greater than ten years (p = 0.005), dyslipidemia (p = 0.012), obesity (p = 0.037) and TyG (p = 0.037). In multivariate analysis, lower GLS was related to mean time since completion of cancer treatment (p = 0.015) and TyG index (p = 0.002). Conclusion Our results suggest that the TyG index, as a simple and inexpensive marker of insulin resistance, could help identify cancer survivors from childhood, adolescence and young adulthood who would be at risk of subclinical cardiac dysfunction. Prospective studies with larger numbers are needed to confirm these findings.

Clinical Deep Data Accumulation System (CLIDAS) reveals a "Lipid paradox" of hypertriglyceridemia in Japanese patients

Abstract Background The association between triglycerides (TG), HDL cholesterol (HDL-C) and the prognosis of cardiovascular disease has not been established. Purpose The aim of this study was to elucidate the relationships between the combination of TG and HDL-C levels and the risk of a major adverse cardiac and cerebral events (MACCE) and to verify the usefulness of TG and HDL-C as a risk stratification factor using the Clinical Deep Data Accumulation System (CLIDAS) database. Methods CLIDAS is a database that accumlates electronic medical records in seven tertiary hospitals in Japan including patient characteristics, medications, laboratory test, physiological test, cardiac catheterization, and PCI treatment. We analyzed 9,690 patients who underwent PCI between April 2014 and March 2020. These patients were stratified into the acute coronary syndrome (ACS) group (N=4,135; 43%) and the chronic coronary syndrome (CCS) group (N=5,555; 57%). Furthermore, patients were divided into four groups based on mean serum TG levels (175 mg/dL) and HDL-C levels (40 mg/dL) as cutoff values: high TG/low HDL-C, low TG/low HDL-C, high TG/high HDL-C, and low TG/high HDL-C, and compared for major adverse cardiac and cerebrovascular events (MACCE). The median follow-up duration was 2.5 years. Results The patients with high TG/low HDL-C showed the highest event rates in myocardial infarction among the ACS group. The hazard ratio for high TG/low HDL-C versus low TG/high HDL-C was 1.76 (95% CI, 1.08 to 2.87, P &amp;lt; 0.05) after adjustment for age, sex, eGFR, and mean LDL-C levels, while we observed no risk stratification by the combination of TG and HDL-C levels in the CCS group (Figure 1). In contrast, the patients with low TG levels showed the paradoxically higher event rates of MACCE in both the ACS and CCS groups, as well as cardiovascular death in the CCS group, compared to those with high TG levels (Figure 2). The hazard ratio for low TG/low HDL-C versus high TG/low HDL-C was 3.21 (95% CI, 1.44 to 7.13, P &amp;lt;0.005), and the hazard ratio for low TG/high HDL-C versus high TG/high HDL-C was 2.23 (95% CI, 1.03 to 4.84, P &amp;lt; 0.05) in the CCS group after adjustment for age, sex, eGFR, and mean LDL-C levels. Conclusion In the CLIDAS database, while high TG and low HDL-C levels stratified the risk of ACS, low TG levels showed worsening prognosis for CV death, suggesting a "Lipid paradox" in the real world.Figure 1Figure 2

Twenty-Week Dietary Supplementation with Beeswax Alcohol (BWA; Raydel®) Ameliorates High-Cholesterol-Induced Long-Term Dyslipidemia and Organ Damage in Hyperlipidemic Zebrafish in a Dose-Dependent Manner: A Comparative Analysis Between BWA and Coenzyme Q10.

Beeswax alcohol (BWA; Raydel®) is a blend of six long-chain aliphatic alcohols extracted from honeybee wax and is well known for its diverse functionality and health benefits. Herein, the efficacy of a BWA dietary intervention for 20 weeks was assessed to ameliorate high-cholesterol diet (HCD)-induced dyslipidemia and adverse effects on the vital organs of adult zebrafish. Adult zebrafish were fed different high-cholesterol diets (HCDs; final concentration of 4%, w/w) supplemented with BWA (final concentrations of 0.1%, 0.5% and 1.0%, w/w) or CoQ10 (final concentration of 1.0%). Following 20 weeks of supplementation, blood and different organs (liver, kidney, testes and ovaries) were collected, and biochemical, histological and immunohistochemical analyses were performed. The results demonstrate a dose-dependent effect of BWA of mitigating HCD-induced mortality in zebrafish over the 20-week supplementation period, which was noticeably better than the effect exerted by coenzyme Q10 (CoQ10). Consistently, a dose-dependent effect of BWA consumption of curtailing HCD-induced total cholesterol (TC) and triglyceride (TG) levels and increasing high-density-lipoprotein cholesterol (HDL-C) levels was noticed. Compared with CoQ10 (final concentration of 1.0%, w/w), BWA (final concentration of 1.0%, w/w) displayed a significantly better effect of mitigating HCD-induced dyslipidemia, as evidenced by 1.2-fold (p < 0.05) and 2.0-fold (p < 0.05) lower TC and TG levels and 2.4-fold (p < 0.01) higher HDL-C levels. The histological analysis revealed substantial prevention of fatty liver changes, reactive oxygen species (ROS) generation, cellular senescence and interleukin (IL)-6 production in the hepatic tissue of BWA zebrafish, which was significantly better than the effect exerted by CoQ10. Consistently, compared with CoQ10, significant 25% (p < 0.05) and 35% (p < 0.01) reductions in the HCD-induced elevated levels of the hepatic function biomarkers aspartate aminotransferase and alanine aminotransferase was observed in the BWA group. Likewise, BWA consumption efficiently ameliorated HCD-induced kidney, ovary and testis damage by inhibiting ROS generation, cellular senescence and lipid accumulation. Supplementation with BWA demonstrated higher therapeutic potential than that with CoQ10 to prevent dyslipidemia and organ damage associated with long-term consumption of HCDs.

Use of Lupinus albus as a Local Protein Source in the Production of High-Quality Iberian Pig Products.

The replacement of soybean meal with sweet white lupin (Lupinus albus L.) seeds was investigated in the diets of Iberian pigs during the growing and fattening phases, evaluating its effects on growth performance, carcass traits, and meat quality. Iberian pigs (n = 50) were divided into two dietary groups (n = 25 per group), receiving either a lupin-based concentrate or a soybean meal-based concentrate. The data were analysed using one-way analysis of variance (ANOVA), with a significance level of p < 0.05. The results showed that lupin substitution had no adverse effect on body weight, average daily gain, or carcass characteristics. No significant differences were observed in meat quality parameters such as pH, colour, and texture. However, significantly (p = 0.007) lower levels of saturated fatty acids (SFA) content were found in the intramuscular fat of pre-finishing (primor) pigs fed lupin-based diets. In addition, these pigs had lower plasma triglyceride levels at the end of the growing phase. Overall, the results suggest that sweet white lupin is a viable alternative protein source in Iberian pig production, offering potential health benefits in line with consumer preferences for sustainably produced, healthier meat products, without compromising production efficiency or product quality.

Clinical reality and challenges with familial hypercholesterolemia patients' management. 2024 results from the Regional Center for Rare Diseases (RCRD) Registry in Poland

BackgroundDespite advancements in early diagnosis and effective medications in last decade, most heterozygous familial hypercholesterolemia (heFH) patients still fail to achieve their low-density lipoprotein cholesterol (LDL-C) goals and remain at residual cardiovascular disease risk. We present recent data from the regional FH registry in Poland, highlighting the challenges and real-life clinical management of FH patients. MethodsThe registry is held at the Regional Centre for Rare Diseases, founded in 2016, at the 2nd largest, supraregional hospital in Poland, where >80 different rare diseases in patients from all over Poland are diagnosed and treated, including phenotypically or genetically diagnosed FH patients. Our analysis focused on both children and adult FH patients, excluding those treated with inclisiran due to a small sample size (n = 5). ResultsWe studied 173 consecutive heFH patients, median age for adult population was 40 years (range: 27–57), of whom 56.14 % were women. Among the population, 82.1 % were adults (n = 142), and 31 were children (17.92 %; median age 9 (8–13), females 58.16 %). Children exhibited lower total cholesterol and triglyceride levels compared to adults, with no significant differences in LDL-C and high-density lipoprotein cholesterol (HDL-C) levels. Molecular diagnosis in the whole population revealed that 76.6 % had an LDL receptor (LDLR) mutation, while 23.4 % had an apolipoprotein B (APOB) mutation. Risk assessment categorized patients into high (70.7 %), very high (22.1 %), and extremely high (7.1 %) risk groups. Triple therapy achieved treatment goals in 61.76 % of adults and 70.97 % of children. At baseline, 36.62 % of adult patients were not using statins. High-intensity statin therapy combined with ezetimibe was initiated for the remaining patients. Only 3.33 % of patients avoided statins due to complete intolerance. Ezetimibe was used in 57.27 % of patients (mostly in combination therapy), and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors were prescribed for 28.17 % FH patients. In adults receiving statin and ezetimibe therapy, median achieved LDL-C was 141 mg/dl (107–184). For triple therapy, median achieved LDL-C was 52.5 mg/dL (32–86.5). Overall median achieved LDL-C in the study population was 99.5 mg/dl (57.5–145.4). PCSK9 inhibitors reduced LDL-C by 165.6 mg/dl. Combination therapy did not significantly alter baseline lipoprotein(a) (Lp(a)) levels (p = 0.134), and PCSK9 inhibitors led to a mean Lp(a) reduction of 18.66 mg/dl (45 % reduction; p = 0.013). Multivariable regression analysis identified key factors for achieving LDL-C targets in FH patients: DLCN total score, DLCN category, ezetimibe use, and PCSK9 inhibitors. ConclusionsIn Poland, FH patients are often diagnosed too late (usually over 40 years of age), and many still do not reach their LDL-C goals. Combination LLT double or triple therapy significantly increases the likelihood of achieving LDL-C targets – even up to fivefold. Therefore, unrestricted access to PCSK9 inhibitors for all FH patients is crucial, without the current limitations imposed by drug reimbursement programs like B101.