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.

Reprint of: Fibrinolytic and Non-fibrinolytic Roles of Tissue-type Plasminogen Activator in the Ischemic Brain.

The neurovascular unit (NVU) is assembled by endothelial cells (ECs) and pericytes, and encased by a basement membrane (BM) surveilled by microglia and surrounded by perivascular astrocytes (PVA), which in turn are in contact with synapses. Cerebral ischemia induces the rapid release of the serine proteinase tissue-type plasminogen activator (tPA) from endothelial cells, perivascular astrocytes, microglia and neurons. Owning to its ability to catalyze the conversion of plasminogen into plasmin, in the intravascular space tPA functions as a fibrinolytic enzyme. In contrast, the release of astrocytic, microglial and neuronal tPA have a plethora of effects that not always require the generation of plasmin. In the ischemic brain tPA increases the permeability of the NVU, induces microglial activation, participates in the recycling of glutamate, and has various effects on neuronal survival. These effects are mediated by different receptors, notably subunits of the N-methyl-D-aspartate receptor (NMDAR) and the low-density lipoprotein receptor-related protein-1 (LRP-1). Here we review data on the role of tPA in the NVU under non-ischemic and ischemic conditions, and analyze how this knowledge may lead to the development of potential strategies for the treatment of acute ischemic stroke patients.

Comparative Cardiovascular Benefits of Bempedoic Acid and Statin Drugs.

BACKGROUND: In the CLEAR (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) Outcomes trial, treatment of statin-intolerant patients with bempedoic acid produced a 21% decrease in low-density lipoprotein cholesterol (LDL-C) relative to placebo and a 13% relative reduction in the risk of major adverse cardiovascular events. OBJECTIVES: This study sought to determine whether the relationship between LDL-C lowering and cardiovascular benefit achieved with bempedoic acid resembles that observed with statins when standardized per unit change in LDL-C. METHODS: To compare the treatment effect of bempedoic acid with statins, the methodology of the Cholesterol Treatment Trialists' Collaboration (CTTC) was applied to outcomes among the 13,970 patients enrolled in the CLEAR Outcomes trial. The CTTC endpoint of "major vascular event" was a composite of coronary heart disease death, nonfatal myocardial infarction, fatal or nonfatal stroke, or coronary revascularization. HRs for CTTC-defined endpoints were normalized to 1 mmol/L differences in LDL-C levels between bempedoic acid and placebo groups. RESULTS: A first major vascular event occurred in 703 (10.1%) patients in the bempedoic acid group and 816 (11.7%) patients in the placebo group (HR: 0.85; 95% CI: 0.77-0.94). When normalized per 1 mmol/L reduction in LDL-C, the HR was 0.75 (95% CI: 0.63-0.90), comparable to the rate ratio of 0.78 reported for statins in the CTTC meta-analysis. Normalized risk reductions were similar for bempedoic acid and statins for the endpoints of major coronary events, nonfatal myocardial infarction, and coronary revascularization. CONCLUSIONS: Cardiovascular risk reduction with bempedoic acid is similar to that achieved with statins for a given absolute magnitude of LDL-C lowering. (Evaluation of Major Adverse Cardiovascular Events in Participants With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated with Bempedoic Acid [ETC-1002] or Placebo [CLEAR Outcomes]; NCT02993406).

Impact of Lipoprotein(a) Level on Low-Density Lipoprotein Cholesterol- or Apolipoprotein B-Related Risk of Coronary Heart Disease.

BACKGROUND: Conventional low-density lipoprotein cholesterol (LDL-C) quantification includes cholesterol attributable to lipoprotein(a) (Lp(a)-C) due to their overlapping densities. OBJECTIVES: The purposes of this study were to compare the association between LDL-C and LDL-C corrected for Lp(a)-C (LDLLp(a)corr) with incident coronary heart disease (CHD) in the general population and to investigate whether concomitant Lp(a) values influence the association of LDL-C or apolipoprotein B (apoB) with coronary events. METHODS: Among 68,748 CHD-free subjects at baseline LDLLp(a)corr was calculated as "LDL-C-Lp(a)-C," where Lp(a)-C was 30% or 17.3% of total Lp(a) mass. Fine and Gray competing risk-adjusted models were applied for the association between the outcome incident CHD and: 1) LDL-C and LDLLp(a)corr in the total sample; and 2) LDL-C and apoB after stratification by Lp(a) mass (≥/<90th percentile). RESULTS: Similar risk estimates for incident CHD were found for LDL-C and LDL-CLp(a)corr30 or LDL-CLp(a)corr17.3 (subdistribution HR with 95% CI) were 2.73 (95% CI: 2.34-3.20) vs 2.51 (95% CI: 2.15-2.93) vs 2.64 (95% CI: 2.26-3.10), respectively (top vs bottom fifth; fully adjusted models). Categorization by Lp(a) mass resulted in higher subdistribution HRs for uncorrected LDL-C and incident CHD at Lp(a) ≥90th percentile (4.38 [95% CI: 2.08-9.22]) vs 2.60 [95% CI: 2.21-3.07]) at Lp(a) <90th percentile (top vs bottom fifth; Pinteraction0.39). In contrast, apoB risk estimates were lower in subjects with higher Lp(a) mass (2.43 [95% CI: 1.34-4.40]) than in Lp(a) <90th percentile (3.34 [95% CI: 2.78-4.01]) (Pinteraction0.49). CONCLUSIONS: Correction of LDL-C for its Lp(a)-C content provided no meaningful information on CHD-risk estimation at the population level. Simple categorization of Lp(a) mass (≥/<90th percentile) influenced the association between LDL-C or apoB with future CHD mostly at higher Lp(a) levels.

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.

Metagenome-derived SusD-homologs affiliated with Bacteroidota bind to synthetic polymers.

Starch utilization system (Sus)D-homologs are well known for their carbohydrate-binding capabilities and are part of the sus operon in microorganisms affiliated with the phylum Bacteroidota. Until now, SusD-like proteins have been characterized regarding their affinity toward natural polymers. In this study, three metagenomic SusD homologs (designated SusD1, SusD38489, and SusD70111) were identified and tested with respect to binding to natural and non-natural polymers. SusD1 and SusD38489 are cellulose-binding modules, while SusD70111 preferentially binds chitin. Employing translational fusion proteins with superfolder GFP (sfGFP), pull-down assays, and surface plasmon resonance (SPR) has provided evidence for binding to polyethylene terephthalate (PET) and other synthetic polymers. Structural analysis suggested that a Trp triad might be involved in protein adsorption. Mutation of these residues to Ala resulted in an impaired adsorption to microcrystalline cellulose (MC), but not so to PET and other synthetic polymers. We believe that the characterized SusDs, alongside the methods and considerations presented in this work, will aid further research regarding bioremediation of plastics. IMPORTANCE: SusD1 and SusD38489 can be considered for further applications regarding their putative adsorption toward fossil-fuel based polymers. This is the first time that SusD homologs from the polysaccharide utilization loci (PUL), largely described for the phylum Bacteroidota, are characterized as synthetic polymer-binding proteins.

Oxidized Low-Density Lipoprotein: Preparation, Validation, and Use in Cell Models.

Lipoproteins in plasma are constituted by the least dense chylomicron, very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), and high-density lipoprotein (HDL) that can be separated using commercially available medium such as iodixanol. Iodixanol constitutes the self-generated density gradient to fractionate lipoproteins by rapid ultracentrifugation method, replacing time-consuming protocols. Filling the centrifuge tubes is technically easier and faster than layering salt gradients and is reproducible. The separated lipoproteins by this method are closest to the native state with 80 to 100% recovery possible. Low-density lipoprotein is the major carrier of cholesterol in systemic circulation. The plasma isolated LDL is purified to be used as native LDL and for the preparation of oxidized LDL (oxLDL). The oxLDL is characterized for its oxidation, by various methods based on assay of the lipid and protein oxidation products such as TBARS, conjugated diene formation, and by other methods such as agarose gel electrophoresis. Rapid isolation of LDL particles from human plasma is useful for lipid peroxidation studies, characterization of subclass for functional studies and clinical correlation especially in cardiovascular diseases apart from lipidomic, and proteomic studies. OxLDL preparations are done in vitro chiefly based on copper-induced oxidation; glucose and other prooxidants. Which are used for various studies using animal model and in vitro cell models especially to understand macrophage-mediated atheroma formation, vascular endothelial cell dysfunction, cell signaling studies has scope for extensive research in metabolic dysfunction of various cells.  This chapter deals with one of the applications in the in vitro cell models using macrophage (THP-1 cell line) and human retinal pigment epithelial cell (ARPE-19 cell line) to study the oxLDL uptake using fluorescently labeled oxidized LDL (DiI-oxLDL).

Bariatric Surgery Effect on the Crosstalk of PAI-1 and PCSK9 to Regulate the Metabolic Changes in Patients with Obesity.

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

The clinical impact of estimating low-density lipoprotein cholesterol (LDL-C) using different equations in the general population.

BACKGROUND: Low-density lipoprotein cholesterol (LDL-C) is associated with atherosclerotic cardiovascular disease (ASCVD). Friedewald, Sampson, and Martin-Hopkins equations are used to calculate LDL-C. This study compares the impact of switching between these equations in a large geographically defined population. MATERIALS AND METHODS: Data for individuals who had a lipid panel ordered clinically between 2010 and 2019 were included. Comparisons were made across groups using the two-sample t-test or chi-square test as appropriate. Discordances between LDL measures based on clinically actionable thresholds were summarized using contingency tables. RESULTS: The cohort included 198,166 patients (mean age 54 years, 54% female). The equations perform similarly at the lower range of triglycerides but began to diverge at a triglyceride level of 125 mg/dL. However, at triglycerides of 175 mg/dL and higher, the Martin-Hopkins equation estimated higher LDL-C values than the Samson equation. This discordance was further exasperated at triglyceride values of 400 to 800 mg/dL. When comparing the Sampson and Friedewald equations, at triglycerides are below 175 mg/dL, 9% of patients were discordant at the 70 mg/dL cutpoint, whereas 42.4% were discordant when triglycerides are between 175 and 400 mg/dL. Discordance was observed at the clinically actionable LDL-C cutpoint of 190 mg/dL with the Friedewald equation estimating lower LDL-C than the other equations. In a high-risk subgroup (ASCVD risk score > 20%), 16.3% of patients were discordant at the clinical cutpoint of LDL-C < 70 mg/dL between the Sampson and Friedewald equations. CONCLUSIONS: Discordance at clinically significant LDL-C cutpoints in both the general population and high-risk subgroups were observed across the three equations. These results show that using different methods of LDL-C calculation or switching between different methods could have clinical implications for many patients.

Oxidized LDL Accelerates Cartilage Destruction and Inflammatory Chondrocyte Death in Osteoarthritis by Disrupting the TFEB-Regulated Autophagy-Lysosome Pathway.

Osteoarthritis (OA) involves cartilage degeneration, thereby causing inflammation and pain. Cardiovascular diseases, such as dyslipidemia, are risk factors for OA; however, the mechanism is unclear. We investigated the effect of dyslipidemia on the development of OA. Treatment of cartilage cells with low-density lipoprotein (LDL) enhanced abnormal autophagy but suppressed normal autophagy and reduced the activity of transcription factor EB (TFEB), which is important for the function of lysosomes. Treatment of LDL-exposed chondrocytes with rapamycin, which activates TFEB, restored normal autophagy. Also, LDL enhanced the inflammatory death of chondrocytes, an effect reversed by rapamycin. In an animal model of hyperlipidemia-associated OA, dyslipidemia accelerated the development of OA, an effect reversed by treatment with a statin, an anti-dyslipidemia drug, or rapamycin, which activates TFEB. Dyslipidemia reduced the autophagic flux and induced necroptosis in the cartilage tissue of patients with OA. The levels of triglycerides, LDL, and total cholesterol were increased in patients with OA compared to those without OA. The C-reactive protein level of patients with dyslipidemia was higher than that of those without dyslipidemia after total knee replacement arthroplasty. In conclusion, oxidized LDL, an important risk factor of dyslipidemia, inhibited the activity of TFEB and reduced the autophagic flux, thereby inducing necroptosis in chondrocytes.

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.

Impact of dietary n-6/n-3 fatty acid ratio of atherosclerosis risk: A review.

Atherosclerosis is a causative factor associated with cardiovascular disease (CVD). Over the past few decades, extensive research has been carried out on the relationship between the n-6/n-3 fatty acid ratio of ingested lipids and the progression of atherosclerosis. However, there are still many uncertainties regarding the precise nature of this relationship, which has led to challenges in providing sound dietary advice to the general public. There is therefore a pressing need to review our current understanding of the relationship between the dietary n-6/n-3 fatty acid ratio and atherosclerosis, and to summarize the underlying factors contributing to the current uncertainties. Initially, this article reviews the association between the n-6/n-3 fatty acid ratio and CVDs in different countries. A summary of the current understanding of the molecular mechanisms of n-6/n-3 fatty acid ratio on atherosclerosis is then given, including inflammatory responses, lipid metabolism, low-density lipoprotein cholesterol oxidation, and vascular function. Possible reasons behind the current controversies on the relationship between the n-6/n-3 fatty acid ratio and atherosclerosis are then provided, including the precise molecular structures of the fatty acids, diet-gene interactions, the role of fat-soluble phytochemicals, and the impact of other nutritional factors. An important objective of this article is to highlight areas where further research is needed to clarify the role of n-6/n-3 fatty acid ratio on atherosclerosis.

Association of lipid-lowering drugs with risk of sarcopenia: a drug target mendelian randomization study and meta-analysis.

BACKGROUND: Lipid-lowering drugs are widely used among the elderly, with some studies suggesting links to muscle-related symptoms. However, the causality remains uncertain. METHODS: Using the Mendelian randomization (MR) approach, we assessed the causal effects of genetically proxied reduced low-density lipoprotein cholesterol (LDL-C) through inhibitions of hydroxy-methyl-glutaryl-CoA reductase (HMGCR), proprotein convertase subtilisin/kexin type 9 (PCSK9), and Niemann-Pick C1-like 1 (NPC1L1) on sarcopenia-related traits, including low hand grip strength, appendicular lean mass, and usual walking pace. A meta-analysis was conducted to combine the causal estimates from different consortiums. RESULTS: Using LDL-C pooled data predominantly from UK Biobank, genetically proxied inhibition of HMGCR was associated with higher appendicular lean mass (beta = 0.087, P = 7.56 × 10- 5) and slower walking pace (OR = 0.918, P = 6.06 × 10- 9). In contrast, inhibition of PCSK9 may reduce appendicular lean mass (beta = -0.050, P = 1.40 × 10- 3), while inhibition of NPC1L1 showed no causal impact on sarcopenia-related traits. These results were validated using LDL-C data from Global Lipids Genetics Consortium, indicating that HMGCR inhibition may increase appendicular lean mass (beta = 0.066, P = 2.17 × 10- 3) and decelerate walking pace (OR = 0.932, P = 1.43 × 10- 6), whereas PCSK9 inhibition could decrease appendicular lean mass (beta = -0.048, P = 1.69 × 10- 6). Meta-analysis further supported the robustness of these causal associations. CONCLUSIONS: Genetically proxied HMGCR inhibition may increase muscle mass but compromise muscle function, PCSK9 inhibition could result in reduced muscle mass, while NPC1L1 inhibition is not associated with sarcopenia-related traits and this class of drugs may serve as viable alternatives to sarcopenia individuals or those at an elevated risk.

Aggravating effect of abnormal low-density protein cholesterol level on coronary atherosclerotic plaque in type 2 diabetes mellitus patients assessed by coronary computed tomography angiography.

BACKGROUND: The abnormal low-density protein cholesterol (LDL-C) level in the development of atherosclerosis is often comorbid in individuals with type 2 diabetes mellitus(T2DM). This study aimed to investigate the aggravating effect of abnormal LDL-C levels on coronary artery plaques assessed by coronary computed tomography angiography (CCTA) in T2DM. MATERIALS AND METHODS: This study collected 3439 T2DM patients from September 2011 to February 2022. Comparative analysis of differences in coronary plaque characteristics was performed for the patients between the normal LDL-C level group and the abnormal LDL-C level group. Factors with P < 0.1 in the univariable linear regression analyses were included in the multivariable linear stepwise regression. RESULTS: A total of 2820 eligible T2DM patients were included and identified as the normal LDL-C level group (n = 973) and the abnormal LDL-C level group (n = 1847). Compared with the normal LDL-C level group, both on a per-patient basis and per-segment basis, patients with abnormal LDL-C level showed more calcified plaques, partially calcified plaques, low attenuation plaques, positive remodellings, and spotty calcifications. Multivessel obstructive disease (MVD), nonobstructive stenosis (NOS), obstructive stenosis (OS), plaque involvement degree (PID), segment stenosis score (SSS), and segment involvement scores (SIS) were likely higher in the abnormal LDL-C level group than that in the normal LDL-C level group (P < 0.001). In multivariable linear stepwise regression, the abnormal LDL-C level was validated as an independent positive correlation with high-risk coronary plaques and the degree and extent of stenosis caused by plaques (low attenuation plaque: ß = 0.116; positive remodelling: ß = 0.138; spotty calcification: ß = 0.091; NOS: ß = 0.427; OS: ß = 0.659: SIS: ß = 1.114; SSS: ß = 2.987; PID: ß = 2.716, all P value < 0.001). CONCLUSIONS: Abnormal LDL-C levels aggravate atherosclerotic cardiovascular disease (ASCVD) in patients with T2DM. Clinical attention deserves to be caught by the tailored identification of cardiovascular risk categories in T2DM individuals and the achievement of the corresponding LDL-C treatment goal.

A Cost-Effective Sulfide Solid Electrolyte Li7P3S7.5O3.5 with Low Density and Excellent Anode Compatibility.

The commercialization of all-solid-state Li batteries (ASSLBs) demands solid electrolytes with strong cost-competitiveness, low density (for enabling satisfactory energy densities), and decent anode compatibility (the need for cathode compatibility can be circumvented by the cathode coating techniques that are widely applied in sulfide-based ASSLBs). However, none of the reported oxide, sulfide, or chloride solid electrolytes meets these requirements simultaneously. Here, we design a Li7P3S7.5O3.5 (LPSO) solid electrolyte, which shows a combination of all the aforementioned characteristics. The synthesis of this material does not need the expensive Li2S, so the raw materials cost is only $14.42/kg, which, unlike most solid electrolytes, lies below the $50/kg threshold for commercialization. The density of LPSO is 1.70 g cm-3, considerably lower than those of the oxide (typically above 5 g cm-3) and chloride (around 2.5 g cm-3) solid electrolytes. Besides, LPSO also shows excellent anode compatibility. The Li | LPSO | Li cell cycles stably with a potential of ~50 mV under 0.1 mA cm-2 for over 4200 h at 25 °C, and the all-solid-state pouch cell with the Si anode shows a capacity retention of 89.29% after 200 cycles under 88.6 mA g-1 at 60 °C.

Evolving Concepts of the SCORE System: Subtracting Cholesterol from Risk Estimation: A Way for a Healthy Longevity?

The role of cholesterol, mainly low-density lipoproteins (LDL-C), as a causal risk factor for atherosclerotic cardiovascular disease (ASCVD) is now established and accepted by the international scientific community. Based on this evidence, the European and American guidelines recommend early risk stratification and "rapid" achievement of the suggested target according to the risk estimation to reduce the number of major cardiovascular events. Prolonged exposure over the years to high levels of LDL-C is one of the determining factors in the development and progression of atherosclerotic plaque, on which the action of conventional risk factors (cigarette smoking, excess weight, sedentary lifestyle, arterial hypertension, diabetes mellitus) as well as non-conventional risk factors (gut microbiota, hyperuricemia, inflammation), alone or in combination, favors the destabilization of the atherosclerotic lesion with rupture/fissuration/ulceration and consequent formation of intravascular thrombosis, which leads to the acute clinical manifestations of acute coronary syndromes. In the current clinical practice, there is a growing number of cases that, although extremely common, are emblematic of the concept of long-term exposure to the risk factor (LDL hypercholesterolemia), which, not adequately controlled and in combination with other risk factors, has favored the onset of major cardiovascular events. The triple concept of "go lower, start earlier and keep longer!" should be applied in current clinical practice at any level of prevention. In the present manuscript, we will review the current evidence and documents supporting the causal role of LDL-C in determining ASCVD and whether it is time to remove it from any score.

Association between serum lipid and all-cause mortality in asthmatic populations: a cohort study.

BACKGROUND: Presently, the majority of investigations primarily evaluate the association between lipid profiles and asthma. However, few investigations explore the connection between lipids and mortality related to the disease. This study aims to explore the association of serum lipids with all-cause mortality within asthmatic adults. METHODS: The investigation included 3233 eligible patients with asthma from the NHANES (2011-2018). The potential associations were explored using three Cox proportional hazards models, restricted cubic splines (RCS), threshold effect models, and CoxBoost models. In addition, subgroup analyses were conducted to investigate these associations within distinct populations. RESULTS: After controlling all covariables, the Cox proportional hazards model proved a 17% decrease in the probability of death for each increased unit of low-density lipoprotein-cholesterol (LDL-C) (mmol/L). Yet, there was no association seen between blood high-density lipoprotein cholesterol (HDL-C), total cholesterol, or triglyceride and all-cause mortality in asthmatics. The application of RCS and threshold effect models verified an inverse and linear association of LDL-C with all-cause mortality. According to the results from the CoxBoost model, LDL-C exhibited the most substantial impact on the follow-up status of asthmatics among the serum lipids. CONCLUSION: Our investigation concluded that in American asthmatic populations, LDL-C levels were inversely and linearly correlated with mortality. However, no independent relationship was found between triglycerides, total cholesterol, or HDL-C and mortality.

LDLR c.89_92dup: a novel frameshift variation in familial hypercholesterolemia.

BACKGROUND: Familial hypercholesterolemia (FH) is a common inherited metabolic disease that causes premature atherosclerosis, cardiovascular disease, and even death at a young age. Approximately 95% of FH-causing genetic variants that have been identified are in the LDLR gene. However, only 10% of the FH population worldwide has been diagnosed and adequately treated, due to the existence of numerous unidentified variants, uncertainties in the pathogenicity scoring of many variants, and a substantial number of individuals lacking access to genetic testing. OBJECTIVE: The aim of this study was to identify a novel variant in the LDLR gene that causes FH in a Chinese family, thereby expanding the spectrum of FH-causing variants. METHODS: Patients were recruited from Beijing Anzhen Hospital, Capital Medical University. FH diagnosis was made according to the Dutch Lipid Clinical Network (DLCN) criteria. Whole-exome sequencing (WES) was conducted to identify the FH-causing variant in the proband, and amplicon sequencing was used to verify the variant in his family members. RESULTS: A three-generation Chinese family was recruited, and two FH patients were clinically diagnosed, both without known FH-causing variants. These two FH patients and another possible patient carried a novel variant, NC_000019.9(NM_000527.5):c.89_92dup (NP_000518.1:p.Phe32Argfs*21), in the ligand-binding domain of the low-density lipoprotein (LDL) receptor that led to a frameshift. The FH adults in the family showed severe clinical symptoms and statin therapy resistance. CONCLUSION: This study identified a novel pathogenic LDLR variant, c.89_92dup, associated with severe FH clinical manifestations and statin therapy resistance.