Elevated Low-density Lipoprotein Cholesterol Research Articles

12369 Clinical Experience With Inclisiran At An Academic Center

Abstract Disclosure: L. Chavez Marin: None. M. Gonzalez: None. M.F. Linton: None. B.G. Carranza Leon: None. Background: Inclisiran, a small interfering RNA (siRNA) molecule designed to inhibit proprotein convertase subtilisin/kexin type 9 (PCSK9), is the only siRNA approved for management of elevated low-density lipoprotein cholesterol (LDL-C) in both primary (for patients with familial hypercholesterolemia) and secondary prevention of cardiovascular disease. In clinical trials, Inclisiran has been shown to reduce LDL-C by more than 50% in populations at high cardiovascular risk. However, real world data about its tolerability and efficacy is still limited. Methods: We conducted an electronic medical record search to identify subjects who were prescribed Inclisiran at a lipid clinic within Vanderbilt University Medical Center (Nashville, USA). Subjects were included if they received at least one dose of Inclisiran and had pre- and post- LDL-C levels. Subjects taking other LDL-C lowering medications like statins, ezetimibe, bempedoic acid, and PCSK-9 inhibitors were included. Pre- and post- LDL-C averages were calculated and analyzed with 95% confidence intervals. The reasons for medication discontinuation were also examined. Results: Out of 69 subjects identified, only 19 met criteria for inclusion, while 32 never received a dose due to cost burden and insurance denial. The other 18 subjects were not included due to inadequate lab results at the time of data collection. In subjects who received at least one dose of Inclisiran, average pre-LDL-C was 142 mg/dL [CI: 34.7] while post-LDL-C was 77 mg/dL [CI: 24.0], notable for a 46% decrease in LDL-C levels. These subjects were also receiving another lipid lowering agent, like a statin, or had previously used a monoclonal antibody-PCSK-9 inhibitor. Those without prior use of PCSK-9 inhibitors were also analyzed. Average pre-LDL-C was 109.5 mg/dL [CI: 15.8] while post-LDL-C was 39.8 mg/dL [CI: 17.2], which revealed a 64% decrease in LDL-C levels. The main reason for discontinuation of Inclisiran was insurance denial followed by individual preference. Only one subject discontinued Inclisiran due to experiencing a generalized rash. Conclusions: Inclisiran is an effective and overall well-tolerated medication indicated for the management of elevated LDL cholesterol. Our study revealed that for individuals with above goal LDL-C, despite maximum tolerated therapy with a statin, additional LDL-C lowering benefits can be seen with Inclisiran use. However, insurance approval and cost burden seem to be the main barriers for access. Presentation: 6/3/2024

8702 Age-Sex Differences in Global Burden of Ischemic Heart Disease Attributable to High LDL in the Last 3 Decades:Global, Regional, National Variations, Age Dynamics, and Implications for Global Health

Abstract Disclosure: V. Adedara: None. K. Maddineni: None. A. Dekhne: None. M. Chinthapalli: None. G. Potluri: None. A. Parisapogu: None. K. Markandu: None. H. Desai: None. Background: Ischemic Heart Disease (IHD) stands as the foremost cause of mortality globally, contributing to 9.6 million deaths. Elevated levels of low-density lipoprotein cholesterol (LDL-C) consistently feature among the risk factors associated with IHD. Methods: Employing the Global Burden of Disease framework, we computed mortality and DALYs linked to IHD attributable to LDL-C, stratified by age-sex, year, and covering 204 countries and territories during the period from 1990 to 2019. Non-fatal health outcomes were estimated using DISMOD MR 2.1, Bayesian meta-regression tool for epidemiological modelling. Results were expressed in absolute counts and age-standardized rates (ASR) per 100,000 person-years. Results: The total number of deaths attributed to IHD due to elevated LDL-C increased from 2.5 million (95% Uncertainty Interval: 2-3.1 million) in 1990 to 3.7 million (95% UI: 2.8-4.8 million) in 2019. Concurrently, DALYs increased from 60.4 million (95% UI: 50.4-70.7 million) in 1990 to 84.9 million (95% UI: 69.5-101.3 million) in 2019. In terms of ASR, the annual percentage change (APC) in death rates decreased by 36%, and DALY rates decreased by 32% from 1990 to 2019. Regionally, East Asia exhibited the highest increase in APC in death counts by 191%, followed by Commonwealth Low-Income countries at 164%, and Oceania at 160% during the same period. Conversely, the Commonwealth High-Income region experienced the highest decrease at 41%. Males displayed higher APC in death (48% vs. 44%) and DALYs (42% vs. 38%) compared to females over the last three decades. In terms of ASR, males observed a higher decrease compared to females. In 2019, the age group 80-84 years had the highest number of deaths at 534,079 (264,177-813,898), while DALYs were most pronounced in the 55-59 year age group, reaching 10.6 million (8.9-12.3 million). Conclusion: IHD remains a significant global health challenge, with high LDL-C levels being a crucial modifiable risk factor. Age-sex disparities in the burden of IHD are evident, driven by variations in LDL-C metabolism, hormonal changes, and lifestyle factors. Recognizing and addressing these disparities is essential for developing effective prevention and treatment strategies tailored to different populations and age groups. Presentation: 6/2/2024

Demographic Predictors of Elevated LDL Cholesterol in Type 1 Diabetes: A Cross-Sectional Study

Demographic Predictors of Elevated LDL Cholesterol in Type 1 Diabetes: A Cross-Sectional Study

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Background: Dyslipidaemia has been proposed as a potential risk factor for breast cancer. This study aimed to evaluate the association between serum lipid profiles and breast cancer among women, comparing lipid levels between breast cancer patients and healthy controls. Methods: A hospital-based cross-sectional observational study was conducted at SMS Medical College and Hospital, Jaipur, from ethics committee approval until June 2024. The study included 100 breast cancer patients and 100 matched healthy controls. Inclusion criteria were individuals aged 18 years or older with informed consent, while exclusion criteria included critically ill patients, those with malignancies other than breast cancer, and those on lipid-lowering therapy. The lipid profile was assessed according to the National Cholesterol Education Program (NCEP) Adult Treatment Panel III (ATP III) guidelines. Data collection involved clinical examination, anthropometric measurements, and biochemical analysis of serum lipid levels. Results: The mean age of participants was 48.5 years for the Case Group and 45.92 years for the Control Group. Serum lipid profiles showed significantly higher levels of total cholesterol (TC), low-density lipoprotein cholesterol (LDL), and triglycerides (TG) in breast cancer patients compared to controls, with TC at 197 ± 42.2 mg/dl vs. 174.06 ± 38.46 mg/dl, LDL at 152.65 ± 32.57 mg/dl vs. 121.09 ± 24.56 mg/dl, and TG at 162.12 ± 15.64 mg/dl vs. 138.23 ± 22.99 mg/dl. High-density lipoprotein cholesterol (HDL) was significantly lower in breast cancer patients (36.0 ± 16.60 mg/dl vs. 50.60 ± 17.64 mg/dl). Subgroup analysis by age showed similar trends across different age groups. No significant differences were observed between premenopausal and postmenopausal women in lipid levels. Conclusion: Elevated serum lipid levels, particularly TC, LDL, and TG, are associated with breast cancer. Monitoring and managing lipid levels may offer potential benefits in breast cancer prevention and treatment strategies.

Complex Dyslipidemia Induced by Lorlatinib Therapy: A Case Study

ContextLorlatinib is an anaplastic lymphoma kinase (ALK) inhibitor, which is currently used for the treatment of ALK-positive metastatic non-small cell lung cancer (NSCLC). Previous reports have noticed an association between lorlatinib and hyperlipidemia, however the specific mechanisms for this side effect remain unknown. Some investigators have reported nephrotic syndrome to be the underlying cause of lorlatinib-induced hyperlipidemia. Case ReportA 59-year-old female with NSCLC presented with marked elevation of lipid levels, including total cholesterol, triglycerides, low-density lipoprotein-cholesterol (LDL-C), and high-density lipoprotein-cholesterol (HDL-C), after initiation of lorlatinib therapy. Despite high dose atorvastatin and ezetimibe, lipid levels remained elevated. A 24-hour urine collection revealed only 226 mg of protein excretion. ConclusionsLorlatinib induced a complex dyslipidemia in our patient with elevations of both LDL-C and HDL-C. The underlying mechanism of lorlatinib-induced hyperlipidemia remains unknown and is unlikely to be secondary to nephrotic syndrome in many patients.

Serum levels of per- and poly-fluoroalkyl substances among middle-aged and elderly populations in Beijing and their association with dyslipidemia

Per- and poly-fluoroalkyl substances (PFAS), ubiquitous environmental pollutants, have been reported as possible contributors to human dyslipidemia. However, evidence for emerging PFAS remains scarce. Using a nested case-control study (n = 357) in a middle-aged and elderly population from Beijing, we investigated the serum concentrations of eight traditional and fourteen emerging PFAS and their potential links with dyslipidemia. Perfluorooctanesulfonic acid (PFOS) and perfluorooctanoic acid (PFOA) were found to be the dominant PFAS. Serum levels of perfluorohexanesulfonic acid (PFHxS) and 6:2 chlorinated polyfluoroalkyl ether sulfonate (6:2 Cl-PFESA/F53B) were associated with higher risk of elevated low-density lipoprotein cholesterol (LDL-C) with odds ratios (OR) of 3.88 (95% CI: 1.44–10.51) and 2.71 (95% CI: 1.11–6.57), respectively. These compounds also positively correlated with high total cholesterol (TC). PFOA, perfluorodecanoic acid (PFDA), and 6:2 Fluorotelomer phosphate monoester (6:2 PAP) were linked to increased risk of high triglycerides (TG) with OR of 2.79 (95% CI: 1.30–6.01), 2.41 (95% CI: 1.27–4.60), and 1.53 (95% CI: 1.05–2.22), respectively. Conversely, perfluorooctane sulfonamidoacetic acid (FOSAA) was negatively associated with high TG levels. These findings indicate that both traditional and emerging PFAS may induce dyslipidemia, emphasizing the potentially serious impact of emerging PFAS on human health.

Review of p.(Val429Met), a Variant of LDLR That Is Associated with Familial Hypercholesterolemia

Patients affected by familial hypercholesterolemia possess elevated low-density lipoprotein cholesterol and therefore have greater risk for cardiovascular disease. About 90% of familial hypercholesterolemia cases are associated with aberrant LDLR. Over 3500 LDLR variants have been identified, 15% of which are considered “pathogenic.” Given the genetic diversity of LDLR variants, specific variants rarely receive attention. However, investigators have proposed the critical evaluation of individual variants as a method to clarify knowledge and to resolve discrepancies in the literature. This article reviews p.(Val429Met) (rs28942078) in the areas of pathology, epidemiology, lipid-lowering therapy, and genetic testing. The p.(Val429Met) variant is associated with a missense point substitution in exon 9 of chromosome 19. Biochemical studies have found severely reduced low-density lipoprotein receptor protein in autologous and heterologous expression systems. Additionally, there are inconsistencies regarding the functional classification of p.(Val429Met). Considered to be of European origin, p.(Val429Met) is found in extant populations due to founder effects. Evidence from clinical trials have also demonstrated variable responses to newer lipid-lowering therapies in patients with a p.(Val429Met) variant. Proper clinical detection and adequate genetic testing have been shown to greatly improve outcomes. Future research may be aimed at resolving discrepancies to better comprehend the implications of familial hypercholesterolemia.

Prevalence of genetically diagnosed familial hypercholesterolemia in Vietnamese patients with premature acute myocardial infarction.

Familial hypercholesterolemia (FH) is a genetic disorder that results in elevated low-density lipoprotein cholesterol (LDL-C) levels, which manifest early in the first decades of life. It is a major cause of premature coronary artery disease worldwide, leading to significant public health challenges. The prevalence of genetically determined FH in patients with premature coronary artery disease remains underestimated, particularly in developing countries. This study aimed to assess the prevalence of genetically defined FH in Vietnamese patients with premature acute myocardial infarction (AMI) in the Vietnamese population. This cross-sectional study enrolled 218 consecutive patients diagnosed with premature AMI who underwent coronary angiography. The low-density lipoprotein receptor (LDLR), apolipoprotein B, and proprotein convertase subtilisin-kexin type 9 genes were analyzed by next-generation sequencing. FH was diagnosed according to Dutch Lipid Clinic Network criteria. Among the patients with premature AMI who underwent coronary angiography, the mean age was 46.9 ± 6.1 years, with a predominance of males (83.9%). The prevalence of potential FH diagnosed using Dutch Lipid Clinic Network criteria was 14.7% (definite FH, 6.0%; probable FH, 8.7%). Pathogenic or likely pathogenic variants in LDLR, apolipoprotein B, and proprotein convertase subtilisin-kexin type 9 were found in 9 of 218 patients (4.1%), all of which were causative mutations in LDLR. Patients with premature AMI and FH had significantly greater LDL-C levels (217.6 vs 125.7 mg/dL) and more severe coronary artery lesions, as assessed by the Gensini score (100.3 vs 60.5), than did those in the No FH group. The prevalence of genetically determined FH among Vietnamese patients with premature AMI is relatively high. Screening and diagnosis of hereditary conditions in patients with premature AMI are essential to improve early detection and management and reduce the burden of coronary artery disease in this population.

Clinical Expression of Familial Hypercholesterolemia in Patients from France and French Canada Carrying Identical-by-Descent Pathogenic LDLR Gene Variants: A Proof-of-Concept Study.

Background: Studying patients carrying identical-by-descent (IBD) pathogenic gene variants allows us to control for the disease-causing genetic background and to more accurately document the impact of modifiers. Familial hypercholesterolemia (FH) is characterized by elevated low-density lipoprotein cholesterol (LDL-c) levels and premature atherosclerosis and is often caused by defects in the LDLR gene. There is a high prevalence of FH in French Canada as a result of a founder effect from France in the 17th century. Several FH patients currently living in French Canada (founder population) and in France (colonizing population) carry IBD FH-causing variants. The expression of FH is affected by environmental and genetic modifiers, and patients with IBD variants may present different characteristics. Methods: In this study, we compared FH clinical expression patients carrying IBD LDLR pathogenic variants living in France or Canada. Four IBD variants, namely c.259T>G p.(Trp87Gly), c.2000G>A p.(Cys667Tyr), c.682G>A p.(Glu228Lys), and c.1048C>T p.(Arg350*), were selected. Untreated plasma lipid profiles, the apolipoprotein E (APOE) genotype, cardiovascular risk factors, and the occurrence of symptomatic ASCVD were compared in 105 adult carriers (30 from France and 75 from French Canada). Results: All parameters were similar between the two populations, except for untreated total cholesterol (10.14 ± 1.89 mmol/L vs. 8.65 ± 1.84 mmol/L, p = 0.0006) and LDL-c concentrations (7.94 ± 1.86 mmol/L vs. 6.93 ± 1.78 mmol/L, p = 0.016), which were significantly higher in FH patients living in France, an observation that was revealed across all studied LDLR variants. Conclusions: This study illustrates that FH patients sharing IBD pathogenic LDLR variants that have evolved in different geographic, cultural, and socio-economic environments for hundreds of years differ in terms of cholesterol levels, highlighting the importance of better understanding the interplay between genetic and environmental modulators of FH expression.

Exploring the causal effects of serum lipids and lipidomes on lewy body dementia: a Mendelian randomization study.

Lewy body dementia (LBD) is a neurodegenerative disorder characterized by the accumulation of Lewy bodies, which primarily composed of misfolded alpha-synuclein (αS). The development of LBD and APOE4 subtypes is thought to be associated with disorders of lipid metabolism. In this study, we investigated the causal relationship between serum lipids, liposomes and LBD using a two-sample Mendelian randomization (TSMR) method. A TSMR analysis of genome-wide association study (GWAS) data for 8 serum lipids, 179 lipidomes components, LBD and its subtypes was performed, using inverse variance weighted as the primary outcome. To ensure robustness, the sensitivity analyses including MR Pleiotropy RESidual Sum and Outlier, Cochran's test, leave-one-out method and funnel plots were performed. In this study, we found that low-density lipoprotein cholesterol (LDL-C) (OR=1.45, 95% CI=1.19-1.77, P<0.001) and remnant cholesterol (RC) (OR=2.64, 95% CI=1.64-4.28, P<0.001) had significant positive causal effects on LBD, and RC also had a positive effect on LBD in carriers of the APOE4 gene. The results of lipidome analysis showed that phosphatidylcholine (PC) (O-16:0_20:4) levels (OR=0.86, 95% CI=0.75-0.98, P=0.02) and PC (O-18:1_20:4) levels (OR=0.76, 95% CI=0.65-0.89, P <0.001) had negative causal effects on LBD, whereas phosphatidylinositol (PI) (18:1_20:4) levels had a positive causal effect on LBD (OR=1.19, 95% CI=1.02-1.39, P=0.03). For LBD with APOE4 carriers, high levels of PC (16:1_18:0) and PC (O-18:2_18:1) had a significant positive effect, while high levels of PC (O-16:1_18:0), phosphatidylethanolamine (PE) (O-18:2_18:1), sphingomyelin (SM) (d38:2), and triacylglycerol (TAG) (56:5) significantly reduced the risk. No heterogeneity and horizontal pleiotropy were observed in sensitivity analysis. Elevated LDL-C and RC levels are significant risk factors for LBD, with RC also impacting APOE4-carrying LBD. Glycerophospholipids play a crucial role in the pathogenesis of LBD, but the specific components that play a role differ from those with the APOE4 carries. These findings highlight the importance of lipid metabolism in LBD and APOE4 subtypes.

The effect of the modified Atkins diet and anti-seizure medications on lipid marker levels in adults with epilepsy.

Some anti-seizure medications (ASMs) are known to induce liver enzymes and impact lipid values that include total cholesterol (TC), low density lipoprotein cholesterol (LDL), high density lipoprotein cholesterol (HDL), and triglyceride (TG). In addition, use of ketogenic diet therapies, including the modified Atkins diet (MAD), has also influenced lipids. Here, we explored the combined impact of enzyme inducing ASMs (EIASMs) and MAD on lipid values in adults with epilepsy. Diet-naïve adults with epilepsy who began MAD were divided into three groups based on ASM use: EIASMs, non-EIASMs, and those on no ASMs. Demographic information, epilepsy-specific clinical history, anthropometrics and lipid values were obtained through retrospective chart review at baseline and after a minimum of 12 months of MAD use. Forty-two adults on MAD had baseline and follow up 12-month lipid outcomes. There was a significant increase in median levels of TC, LDL, non-HDL, and HDL after 12 months of MAD use. There was no change in median levels of TG. When separated according to ASM category, adults on non-EIASMs showed significant elevations in TC, HDL, and LDL after 12 months of MAD use. In contrast, adults on EIASMs only showed a significant increase in HDL after 12 months of MAD use. The increase in atherogenic cholesterol levels observed after 12 months of MAD use was most pronounced in adults with epilepsy on non-EIASMs and not observed in adults with epilepsy on EIASMs despite a higher proportion of abnormal cholesterol levels at baseline in those on EIASMs.

Is lipoprotein(a) measurement important for cardiovascular risk stratification in children and adolescents?

BackgroundElevated lipoprotein (Lp(a)) levels are associated with increased risk of atherosclerotic processes and cardiovascular events in adults. The amount of Lp(a) is mainly genetically determined. Therefore, it is important to identify individuals with elevated Lp(a) as early as possible, particularly if other cardiovascular risk factors are present. The purpose of the study was to investigate whether, in a population of children and adolescents already followed for the presence of one or more cardiovascular risk factors (elevated blood pressure (BP), and/or excess body weight, and/or dyslipidemia), the measurement of Lp(a) can be useful for better stratifying their risk profile.MethodsIn a sample of 195 children and adolescents, height, body weight, waist circumference and systolic (SBP) and diastolic (DBP) BP were measured. Body Mass Index (BMI) and SBP and DBP z-scores were calculated. Plasma Lp(a), total cholesterol, high-density lipoprotein (HDL), triglycerides, glucose, insulin, uric acid and creatinine were assessed. Low-density lipoprotein (LDL) cholesterol was calculated with the Friedewald formula. High Lp(a) was defined as ≥ 75 nmol/L and high LDL cholesterol as ≥ 3.37 mmol/L.ResultsOur sample of children and adolescents (54.4% males, mean age 11.5 years) had median LDL cholesterol and Lp(a) values equal to 2.54 (interquartile range, IQR: 2.07–3.06) mmol/L and 22 (IQR: 7.8–68.6) nmol/L respectively. 13.8% of children had LDL cholesterol ≥ 3.37 mmol/L and 22.6 Lp(a) values ≥ 75 nmol/L. Lp(a) values were higher in children of normal weight than in those with excess weight (p = 0.007), but the difference disappeared if normal weight children referred for dyslipidemia only were excluded from the analysis (p = 0.210). 69.4% of children had normal Lp(a) and LDL cholesterol values and only 6.2% showed both elevated Lp(a) and LDL cholesterol levels. However, 16.6% of the sample, despite having normal LDL cholesterol, had elevated Lp(a) values. Multivariable analyses showed a significant association of LDL cholesterol both with Lp(a) values, and with the presence of elevated Lp(a) levels. For each mmol/L increase in LDL cholesterol the risk of having an elevated Lp(a) value increased by 73%. There was an inverse correlation between BMI z-score and Lp(a). Neither BP z-scores, nor other biochemical parameters were associated with Lp(a).ConclusionsIn our population more than one out of five children had elevated Lp(a) values, and in about 17% of children elevated Lp(a) values were present in the absence of increased LDL cholesterol. Our results suggest that Lp(a) measurement can be useful to better define the cardiovascular risk profile in children and adolescents already followed for the presence of other cardiovascular risk factors such as elevated BP, excess body weight and high LDL cholesterol.

The therapeutic effect of liver transplantation in 14 children with homozygous familial hypercholesterolemia: a prospective cohort: Liver transplant for familial hypercholesterolemia

ObjectivesHomozygous familial hypercholesterolemia (HoFH) is characterized by elevated low-density lipoprotein cholesterol (LDL-C) and early-onset cardiovascular disease. To assess the therapeutic effects of liver transplantation (LT) on HoFH patients, we observed and analyzed the outcomes of HoFH children after LT. Study designThis prospective cohort study included all LT candidates under 18 years old diagnosed with HoFH at Ren Ji Hospital between November 2017 and July 2021. The patients were followed until October 2023. They were treated according to the standard protocol at our center. We collected data on changes in lipid profiles, clinical manifestations, and cardiovascular complications at different time points, and recorded postoperative recipient and graft survival. ResultsFourteen HoFH patients with a median age of 7 (2-12) years were included. Preoperatively, xanthomas and arcus corneas occurred in 14 and 3 patients, respectively, with 10 patients showing mild cardiovascular disease. All patients underwent LT. Recipient and graft survival rates were 100 % over a median follow-up duration of 35 (27-71) months. Median LDL-C levels dropped from 11.83 (7.99-26.14) mmol/L preoperatively to 2.3 (1.49-3.39) mmol/L postoperative at the last measurement. Thirteen patients discontinued lipid-lowering treatment after LT, while only one patient resumed statins 6 months post-operation. Xanthomas and arcus corneas significantly improved. Cardiovascular complications regressed in five patients, with no progression observed in the others. ConclusionsLT is a safe and effective treatment for severe HoFH patients beyond lipid-lowering control. Early LT improves prognosis and quality of life while minimizing the risk of cardiovascular complications.

Ferritin-based disruptor nanoparticles: A novel strategy to enhance LDL cholesterol clearance via multivalent inhibition of PCSK9-LDL receptor interaction.

Hypercholesterolemia, characterized by elevated low-density lipoprotein (LDL) cholesterol levels, is a significant risk factor for cardiovascular disease. Proprotein convertase subtilisin/kexin type 9 (PCSK9) plays a crucial role in cholesterol metabolism by regulating LDL receptor degradation, making it a therapeutic target for mitigating hypercholesterolemia-associated risks. In this context, we aimed to engineer human H ferritin as a scaffold to present 24 copies of a PCSK9-targeting domain. The rationale behind this protein nanoparticle design was to disrupt the PCSK9-LDL receptor interaction, thereby attenuating the PCSK9-mediated impairment of LDL cholesterol clearance. The N-terminal sequence of human H ferritin was engineered to incorporate a 13-amino acid linear peptide (Pep2-8), which was previously identified as the smallest PCSK9 inhibitor. Exploiting the quaternary structure of ferritin, engineered nanoparticles were designed to display 24 copies of the targeting peptide on their surface, enabling a multivalent binding effect. Extensive biochemical characterization confirmed precise control over nanoparticle size and morphology, alongside robust PCSK9-binding affinity (KD in the high picomolar range). Subsequent efficacy assessments employing the HepG2 liver cell line demonstrated the ability of engineered ferritin's ability to disrupt PCSK9-LDL receptor interaction, thereby promoting LDL receptor recycling on cell surfaces and consequently enhancing LDL uptake. Our findings highlight the potential of ferritin-based platforms as versatile tools for targeting PCSK9 in the management of hypercholesterolemia. This study not only contributes to the advancement of ferritin-based therapeutics but also offers valuable insights into novel strategies for treating cardiovascular diseases.

Characteristics of Patients With Atherosclerotic Cardiovascular Disease in Belgium and Current Treatment Patterns for the Management of Elevated LDL-C Levels.

Dyslipidemia remains the major cause of atherosclerotic cardiovascular disease (ASCVD). Lipid management in patients with increased cardiovascular (CV) risk needs improvement across Europe, and data gaps are noticeable at the country level. We described the current treatment landscape in Belgium, hypothesizing that lipid management in patients with ASCVD remains inadequate and aiming to understand the reasons. Using data from an anonymized primary care database in Belgium derived from 494 750 individuals, we identified those with any CV risk factor between November 2019 and October 2022 and described the clinical features of patients with ASCVD. The main outcomes were the proportion of patients (i) receiving lipid-lowering therapies (LLTs), (ii) per low-density lipoprotein cholesterol (LDL-C) threshold, stratified per LLT, (iii) reaching the 2021 ESC recommended LDL-C goals, and (iv) LDL-C reduction per type of LLT was also determined. Among 40 888 patients with very high CV risk, 24 859 had established ASCVD. Most patients with ASCVD were either receiving monotherapy (59.6%) or had no documented LLT (25.1%). Further, 64.2% of those with no documented LLT exhibited LDL-C levels ≥ 100 mg/dL. Among common treatment options, one of the greatest improvements in LDL-C levels was achieved with combination therapy of statin and ezetimibe, reducing LDL-C levels by 41.5% (p < 0.0001). Yet, in this group, 24.8% of patients had still LDL-C levels ≥ 100 mg/dL and only 20.7% were at goal. Our study emphasizes the importance of developing strategies to help patients achieve their LDL-C goals, with a focus on supporting the implementation of combination LLT in routine clinical practice.

Prevalence and Risk Factors of Chronic Kidney Disease in Patients With Type 2 Diabetes in China: Cross-Sectional Study.

Chronic kidney disease (CKD) is a significant long-term complication of diabetes and is a primary contributor to end-stage kidney disease. This study aimed to report comprehensive nationwide data on the prevalence, screening, and awareness rates of CKD in Chinese patients with type 2 diabetes, along with associated risk factors. Baseline data analysis of the ongoing prospective, observational IMPROVE study was conducted. The study cohort comprised patients who had been diagnosed with type 2 diabetes more than 12 months prior, received at least 1 hypoglycemic medication, and were aged ≥18 years. The participants completed questionnaires and underwent laboratory assessments, including blood and urine samples. The data encompassed patient demographics, medical history, concurrent medications, and comorbidities. Comprehensive evaluations involved physical examinations, urinary albumin-to-creatinine ratio (UACR), estimated glomerular filtration rate (eGFR), glycated hemoglobin (HbA1c), fasting blood glucose, 2-hour postprandial blood glucose, fasting blood lipid profile, and urinalysis. Descriptive statistics were applied for data interpretation, and logistic regression analyses were used to identify the CKD-associated risk factors in patients with type 2 diabetes. A national study from December 2021 to September 2022 enlisted 9672 participants with type 2 diabetes from 45 hospitals that had endocrinology departments. The enrollees were from diverse regions in China, as follows: central (n=1221), east (n=3269), south (n=1474), north (n=2219), and west (n=1489). The prevalence, screening, and awareness rates of CKD among patients with type 2 diabetes were 31% (2997/9672), 27% (810/2997), and 54.8% (5295/9672), respectively. Multivariate binary regression analysis revealed that the CKD risk factors were screening, awareness, smoking, age, diabetes duration, concurrent antihypertensive and microcirculation medications, diabetic complications (foot, retinopathy, and neuropathy), hypertension, elevated low-density lipoprotein (LDL) cholesterol, and suboptimal glycemic control. Subgroup analysis highlighted an increased CKD prevalence among older individuals, those with prolonged diabetes durations, and residents of fourth-tier cities. Residents of urban areas that had robust educational and economic development exhibited relatively high awareness and screening rates. Notably, 24.2% (1717/7107) of patients with an eGFR ≥90 mL/min/1.73 m2 had proteinuria, whereas 3.4% (234/6909) who had a UACR <30 mg/g presented with an eGFR <60 mL/min/1.73 m2. Compared with patients who were cognizant of CKD, those who were unaware of CKD had increased rates of HbA1c ≥7%, total cholesterol >5.18 μmol/L, LDL cholesterol >3.37 μmol/L, BMI ≥30 kg/m2, and hypertension. In a Chinese population of adults with type 2 diabetes, the CKD prevalence was notable, at 31%, coupled with low screening and awareness rates. Multiple risk factors for CKD have been identified. ClinicalTrials.gov NCT05047471; https://clinicaltrials.gov/study/NCT05047471.

Cholesterol 7 alpha-hydroxylase (CYP7A1) gene polymorphisms are associated with increased LDL-cholesterol levels and the incidence of subclinical atherosclerosis.

The cholesterol 7 alpha-hydroxylase (CYP7A1) enzyme plays an important role in the conversion of cholesterol to bile acid, contributing to the reduction of cholesterol plasma levels in normal conditions. Nonetheless, recent studies have shown that some genetic variants in the enhancer and promoter regions of the CYP7A1 gene reduce the expression of the CYP7A1 enzyme, increasing plasma lipid levels, as well as the risk of developing coronary heart disease. The aim of this work was to explore whether the genetic variants (rs2081687, rs9297994, rs10107182, rs10504255, rs1457043, rs8192870, and rs3808607) of the CYP7A1 gene are involved in subclinical atherosclerosis and plasma lipid levels. We included 416 patients with subclinical atherosclerosis (SA) with coronary artery calcium (CAC) greater than zero, and 1046 controls with CAC = 0. According to the inheritance models (co-dominant, dominant, recessive, over-dominant and additive), the homozygosity of the minor allele frequencies of 7 analyzed polymorphisms showed a high incidence of SA (P < 0.05). In a sub-analysis performed including only the patients with SA, the same SNPs were associated with increased low-density lipoprotein cholesterol (LDL-C) levels. On the other hand, our findings showed that the haplotype (TGCGCTG) increases the risk of developing SA (P < 0.05). In conclusion, the rs2081687, rs9297994, rs10107182, rs10504255, rs1457043, rs8192870, and rs3808607 polymorphisms of CYP7A1 confer a risk of developing SA and elevated LDL-C levels. Our results suggest that the CYP7A1 is involved in the incidence of SA through the increase in the plasma lipid profile.

Established and Emerging Nucleic Acid Therapies for Familial Hypercholesterolemia.

Familial hypercholesterolemia (FH) is a genetic disease that leads to elevated low-density lipoprotein cholesterol levels and risk of coronary heart disease. Current therapeutic options for FH remain relatively limited and only partially effective in both lowering low-density lipoprotein cholesterol and modifying coronary heart disease risk. The unique characteristics of nucleic acid therapies to target the underlying cause of the disease can offer solutions unachievable with conventional medications. DNA- and RNA-based therapeutics have the potential to transform the care of patients with FH. Recent advances are overcoming obstacles to clinical translation of nucleic acid-based medications, including greater stability of the formulations as well as site-specific delivery, making gene-based therapy for FH an alternative approach for treatment of FH.

Targeting Liver Epsins Ameliorates Dyslipidemia in Atherosclerosis.

Low density cholesterol receptor (LDLR) in the liver is critical for the clearance of low-density lipoprotein cholesterol (LDL-C) in the blood. In atherogenic conditions, proprotein convertase subtilisin/kexin 9 (PCSK9) secreted by the liver, in a nonenzymatic fashion, binds to LDLR on the surface of hepatocytes, preventing its recycling and enhancing its degradation in lysosomes, resulting in reduced LDL-C clearance. Our recent studies demonstrate that epsins, a family of ubiquitin-binding endocytic adaptors, are critical regulators of atherogenicity. Given the fundamental contribution of circulating LDL-C to atherosclerosis, we hypothesize that liver epsins promote atherosclerosis by controlling LDLR endocytosis and degradation. We will determine the role of liver epsins in promoting PCSK9-mediated LDLR degradation and hindering LDL-C clearance to propel atherosclerosis. We generated double knockout mice in which both paralogs of epsins, namely, epsin-1 and epsin-2, are specifically deleted in the liver (Liver-DKO) on an ApoE -/- background. We discovered that western diet (WD)-induced atherogenesis was greatly inhibited, along with diminished blood cholesterol and triglyceride levels. Mechanistically, using scRNA-seq analysis on cells isolated from the livers of ApoE-/- and ApoE-/- /Liver-DKO mice on WD, we found lipogenic Alb hi hepatocytes to glycogenic HNF4α hi hepatocytes transition in ApoE-/- /Liver-DKO. Subsequently, gene ontology analysis of hepatocyte-derived data revealed elevated pathways involved in LDL particle clearance and very-low-density lipoprotein (VLDL) particle clearance under WD treatment in ApoE-/- /Liver-DKO, which was coupled with diminished plasma LDL-C levels. Further analysis using the MEBOCOST algorithm revealed enhanced communication score between LDLR and cholesterol, suggesting elevated LDL-C clearance in the ApoE-/- Liver-DKO mice. In addition, we showed that loss of epsins in the liver upregulates of LDLR protein level. We further showed that epsins bind LDLR via the ubiquitin-interacting motif (UIM), and PCSK9-triggered LDLR degradation was abolished by depletion of epsins, preventing atheroma progression. Finally, our therapeutic strategy, which involved targeting liver epsins with nanoparticle-encapsulated siRNAs, was highly efficacious at inhibiting dyslipidemia and impeding atherosclerosis. Liver epsins promote atherogenesis by mediating PCSK9-triggered degradation of LDLR, thus raising the circulating LDL-C levels. Targeting epsins in the liver may serve as a novel therapeutic strategy to treat atherosclerosis by suppression of PCSK9-mediated LDLR degradation.

Hyperuricemia and associated factors among hypertensive patients attending an academic hospital of Ethiopia: A cross-sectional study

BackgroundHypertension is a major public health problem in developing countries. Globally, nearly 1.13 billion adults had hypertension in 2015 and this is estimated to increase to 1.56 billion by 2025. Hyperuricemia is an important predictor of the progression of hypertension and is common in hypertensive patients. Hypertensive patients with hyperuricemia are at higher risk of cardiovascular disease. ObjectiveTo assess the prevalence of hyperuricemia and its associated factors among hypertensive patients attending the University of Gondar Comprehensive Specialized Hospital (UGCSH). MethodAn institutional-based cross-sectional study was conducted on 248 hypertensive patients attending the University of Gondar Comprehensive Specialized Hospital from January 2020 to February 2021. A convenient sampling technique was employed to select study participants. Socio-demographic and clinical characteristics were collected using a structured questionnaire via face-to-face interviews and reviewing medical records respectively. The biochemical parameters were measured by using a Mindray BS-200E chemistry analyzer. Data was entered using EpiData version 4.6.0.0 and analyzed using STATA vs. 14.0. Bivariable and multivariable binary logistic regression were fitted to identify factors associated with hyperuricemia. The odds ratio and 95 % CI were calculated to assess the strength of the association and a P-value <0.05 in the multivariable was considered statistically significant. ResultsA total of 248 patients were enrolled; 140 (56.5 %) were female. The mean age of patients was 57.9 ± 10.5 years. The overall prevalence of hyperuricemia was 42.3 %; males had a prevalence of 36.1 % and females of 47.1 %. High waist circumference, high body mass index, dyslipidemia, low estimated Glomerular Filtration Rate, elevated fasting blood glucose, elevated total cholesterol, elevated triglycerides, elevated Low-Density Lipoprotein cholesterol, and Low High-Density Lipoprotein cholesterol were found to be significantly associated with hyperuricemia. ConclusionThis study demonstrated the predominant existence of hyperuricemia in hypertensive patients. Therefore, early diagnosis and monitoring of hyperuricemia are required before further complications occur.