A significant presence in atherosclerotic cardiovascular disease: Remnant cholesterol: A review.

The current first-line treatment for atherosclerotic cardiovascular disease (ASCVD) involves the reduction of a patient's low-density lipoprotein cholesterol (LDL-C) levels through the use of lipid-lowering drugs. However, even when other risk factors such as hypertension and diabetes are effectively managed, there remains a residual cardiovascular risk in these patients despite achieving target LDL-C levels with statins and new lipid-lowering medications. This risk was previously believed to be associated with lipid components other than LDL, such as triglycerides. However, recent studies have unveiled the crucial role of remnant cholesterol (RC) in atherosclerosis, not just triglycerides. The metabolized product of triglyceride-rich lipoproteins is referred to as triglyceride-rich remnant lipoprotein particles, and its cholesterol component is known as RC. Numerous pieces of evidence from epidemiological investigations and genetic studies demonstrate that RC plays a significant role in predicting the incidence of ASCVD. As a novel marker for atherosclerosis prediction, when LDL-C is appropriately controlled, RC should be prioritized for attention and intervention among individuals at high risk of ASCVD. Therefore, reducing RC levels through the use of various lipid-lowering drugs may yield long-term benefits. Nevertheless, routine testing of RC in clinical practice remains controversial, necessitating further research on the treatment of elevated RC levels to evaluate the advantages of reducing RC in patients at high risk of ASCVD.

Associations of tissue factor and tissue factor pathway inhibitor with organ dysfunctions in septic shock.

Coagulopathy, microvascular alterations and concomitant organ dysfunctions are hallmarks of sepsis. Attempts to attenuate coagulation activation with an inhibitor of tissue factor (TF), i.e. tissue factor pathway inhibitor (TFPI), revealed no survival benefit in a heterogenous group of sepsis patients, but a potential survival benefit in patients with an international normalized ratio (INR) < 1.2. Since an increased TF/TFPI ratio determines the procoagulant activity specifically on microvascular endothelial cells in vitro, we investigated whether TF/TFPI ratio in blood is associated with INR alterations, organ dysfunctions, disseminated intravascular coagulation (DIC) and outcome in septic shock. Twenty-nine healthy controls (HC) and 89 patients with septic shock admitted to a tertiary ICU were analyzed. TF and TFPI in blood was analyzed and related to organ dysfunctions, DIC and mortality. Patients with septic shock had 1.6-fold higher levels of TF and 2.9-fold higher levels of TFPI than HC. TF/TFPI ratio was lower in septic shock compared to HC (0.003 (0.002-0.005) vs. 0.006 (0.005-0.008), p < 0.001). Non-survivors had higher TFPI levels compared to survivors (43038 (29354-54023) vs. 28041 (21675-46582) pg/ml, p = 0.011). High TFPI levels were associated with acute kidney injury, liver dysfunction, DIC and disease severity. There was a positive association between TF/TFPI ratio and troponin T (b = 0.531 (0.309-0.754), p < 0.001). A high TF/TFPI ratio is exclusively associated with myocardial injury but not with other organ dysfunctions. Systemic TFPI levels seem to reflect disease severity. These findings point towards a pathophysiologic role of TF/TFPI in sepsis-induced myocardial injury.

Associations between Serum Kallistatin Levels and Markers of Glucose Homeostasis, Inflammation, and Lipoprotein Metabolism in Patients with Type 2 Diabetes and Nondiabetic Obesity.

Kallistatin is an endogenous serine proteinase inhibitor with various functions, including antioxidative, anti-inflammatory, and anti-atherosclerotic properties. To date, associations between kallistatin and lipoprotein subfractions are poorly investigated. In this study, we enrolled 62 obese patients with type 2 diabetes (T2D), 106 nondiabetic obese (NDO) subjects matched in gender, age, and body mass index, as well as 49 gender- and age-matched healthy, normal-weight controls. Serum kallistatin levels were measured with ELISA, and lipoprotein subfractions were analyzed using Lipoprint® (Quantimetrix Corp., Redondo Beach, CA, USA) gel electrophoresis. Kallistatin concentrations were significantly higher in T2D patients compared to NDO and control groups. We found significant positive correlations between very-low-density lipoprotein (VLDL), small high-density lipoprotein (HDL) subfractions, glucose, hemoglobin A1c (HbA1c), betatrophin, and kallistatin, while negative correlations were detected between mean low-density lipoprotein (LDL) size, large and intermediate HDL subfractions, and kallistatin in the whole study population. The best predictor of kallistatin was HbA1c in T2D patients, high-sensitivity C-reactive protein (hsCRP) and betatrophin in NDO patients, and hsCRP in controls. Our results indicate that kallistatin expression might be induced by persistent hyperglycemia in T2D, while in nondiabetic subjects, its production might be associated with systemic inflammation. The correlation of kallistatin with lipid subfractions may suggest its putative role in atherogenesis.

Mechanical properties of blood exosomes and lipoproteins after the rat whole blood irradiation with X-rays in vitro explored by atomic force microscopy.

Blood is a two-component system with two levels of hierarchy: the macrosystem of blood formed elements and the dispersed system of blood nanoparticles. Biological nanoparticles are the key participants in communication between the irradiated and non-irradiated cells and inducers of the non-targeted effects of ionizing radiation. The work aimed at studying by atomic force microscopy the structural, mechanical, and electrical properties of exosomes and lipoproteins (LDL/VLDL) isolated from rat blood after its exposure to X-rays in vitro. MATERIALS AND METHODS: The whole blood of Wistar rats fed with a high-fat diet was irradiated with X-rays (1 and 100 Gy) in vitro. The structural and mechanical properties (the elastic modulus and nonspecific adhesion force) of exosome and lipoprotein isolates from the blood by ultracentrifugation method were studied using Bruker Bioscope Resolve atomic force microscope in PF QNM mode, their electric properties (the zeta-potential) was measured by electrophoretic mobility. RESULTS: Lipoproteins isolated from non-irradiated blood were softer (Me(LQ; UQ): 7.8(4.9;12.1) MPa) compared to blood nanoparticles of its exosome fraction (34.8(22.6;44.9) MPa) containing both exosomes and non-membrane nanoparticles. X-ray blood irradiation with a dose of 1 Gy significantly weakened the elastic properties of lipoproteins. Exposure of the blood to 100 Gy X-rays made lipoproteins stiffer and their nonspecific adhesive properties stronger. The radiation effects on the mechanical parameters of exosomes and non-membrane nanoparticles in exosome fractions differed. The significant radiation-induced change in electric properties of the studied nanoparticles was detected only for lipoproteins in the blood irradiated with 1 Gy X-rays. The low-dose radiation-induced changes in zeta-potential and increase in lipoprotein size with the appearance of a soft thick surface layer indicate the formation of the modified lipoproteins covered with a corona from macromolecules of irradiated blood. CONCLUSION: Our data obtained using the nanomechanical mapping mode of AFM are the first evidence of the significant radiation-induced changes in the structural and mechanical properties of the dispersed system of blood nanoparticles after the X-ray irradiation of the blood.

Serum Levels of Adiponectin Are Strongly Associated with Lipoprotein Subclasses in Healthy Volunteers but Not in Patients with Metabolic Syndrome.

Metabolic syndrome (MS) is a widespread disease in developed countries, accompanied, among others, by decreased adiponectin serum levels and perturbed lipoprotein metabolism. The associations between the serum levels of adiponectin and lipoproteins have been extensively studied in the past under healthy conditions, yet it remains unexplored whether the observed associations also exist in patients with MS. Therefore, in the present study, we analyzed the serum levels of lipoprotein subclasses using nuclear magnetic resonance spectroscopy and examined their associations with the serum levels of adiponectin in patients with MS in comparison with healthy volunteers (HVs). In the HVs, the serum levels of adiponectin were significantly negatively correlated with the serum levels of large buoyant-, very-low-density lipoprotein, and intermediate-density lipoprotein, as well as small dense low-density lipoprotein (LDL) and significantly positively correlated with large buoyant high-density lipoprotein (HDL). In patients with MS, however, adiponectin was only significantly correlated with the serum levels of phospholipids in total HDL and large buoyant LDL. As revealed through logistic regression and orthogonal partial least-squares discriminant analyses, high adiponectin serum levels were associated with low levels of small dense LDL and high levels of large buoyant HDL in the HVs as well as high levels of large buoyant LDL and total HDL in patients with MS. We conclude that the presence of MS weakens or abolishes the strong associations between adiponectin and the lipoprotein parameters observed in HVs and disturbs the complex interplay between adiponectin and lipoprotein metabolism.

Cardiovascular outcomes in patients with homozygous familial hypercholesterolaemia on lipoprotein apheresis initiated during childhood: long-term follow-up of an international cohort from two registries.

BACKGROUND: Homozygous familial hypercholesterolaemia (HoFH) is a rare genetic disease characterised by extremely high plasma LDL cholesterol from birth, causing atherosclerotic cardiovascular disease at a young age. Lipoprotein apheresis in combination with lipid-lowering drugs effectively reduce LDL cholesterol, but long-term health outcomes of such treatment are unknown. We aimed to investigate the long-term cardiovascular outcomes associated with lipoprotein apheresis initiated in childhood or adolescence. METHODS: In this cohort study, data were drawn from the HoFH International Clinical Collaboration (HICC) and the international registry for Children with Homozygous Hypercholesterolemia on Lipoprotein Apheresis (CHAIN). An overall cohort included patients diagnosed with HoFH aged 0-18 years who were alive and in follow-up between Jan 1, 2010, and Nov 8, 2021, and whose high plasma LDL cholesterol concentrations made them eligible for lipoprotein apheresis. To compare cardiovascular outcomes, patients who initiated lipoprotein apheresis in childhood (lipoprotein apheresis group) and patients who only received lipid-lowering drugs (pharmacotherapy-only group) were matched by sex and untreated plasma LDL cholesterol concentrations. The primary outcome was a composite of cardiovascular death, myocardial infarction, ischaemic stroke, percutaneous coronary intervention, coronary artery bypass grafting, aortic valve replacement, peripheral artery disease, carotid endarterectomy, angina pectoris, and supra-aortic or aortic stenosis (collectively referred to as atherosclerotic cardiovascular disease), for which survival analyses were performed in the matched cohort. Cox regression analyses were used to compare disease-free survival between cohorts and to calculate hazard ratio (HR) and 95% CI adjusted for sex, age at diagnosis, untreated plasma LDL cholesterol concentration, and number of lipid-lowering therapies other than lipoprotein apheresis. FINDINGS: The overall cohort included 404 patients with a median age at diagnosis of 6·0 years (IQR 3·0-9·5) and median untreated plasma LDL cholesterol of 17·8 mmol/L (14·7-20·8). The matched cohorts included 250 patients (125 patients per group), with a median untreated LDL cholesterol of 17·2 mmol/L (14·8-19·7). Mean reduction in plasma LDL cholesterol concentrations between baseline and final follow-up was greater in the lipoprotein apheresis group (-55% [95% CI -60 to -51] vs -31% [-36 to -25]; p<0·0001). Patients in the lipoprotein apheresis group had longer atherosclerotic cardiovascular disease-free survival (adjusted HR 0·52 [95% CI 0·32-0·85]) and longer cardiovascular death-free survival (0·0301 [0·0021-0·4295]). Cardiovascular death was more common in the pharmacotherapy-only group than in the lipoprotein apheresis group (ten [8%] vs one [1%]; p=0·010), whereas median age at coronary artery bypass grafting was lower in the lipoprotein apheresis group than in the pharmacotherapy-only group (15·0 years [IQR 12·0-24·0] vs 30·5 years [19·0-33·8]; p=0·037). INTERPRETATION: Among patients with HoFH, lipoprotein apheresis initiated during childhood and adolescence is associated with reduced long-term risk of atherosclerotic cardiovascular disease and death, and clear benefits of early initiation of high-frequency treatment on reducing plasma cholesterol were found. Consensus recommendations are now needed to guide more widespread and timely use of lipoprotein apheresis for children with HoFH, and research is required to further optimise treatment and ensure benefits of early and aggressive treatment delivery are balanced against effects on quality of life. FUNDING: Amsterdam University Medical Centers, Location Academic Medical Center; Perelman School of Medicine at the University of Pennsylvania; European Atherosclerosis Society; and the US National Heart, Lung, and Blood Institute, National Institutes of Health.

Effects of phytosterol supplementation on lipoprotein subfractions and LDL particle quality.

Phytosterols are natural components of plant-based foods used as supplements because of their known cholesterol-lowering effect. However, their effects on lipoprotein subfractions and the quality of the LDL particle have not been studied in greater detail. We aimed to evaluate the effects of phytosterols supplements on lipids, lipoproteins subfractions, and on the quality of LDL. A prospective, pilot-type, open label, cross-over study, randomized 23 males in primary prevention of hypercholesterolemia to receive diet or diet plus phytosterol (2.6 g in 2 doses, with meals) for 12 weeks, when treatments were switched for another 12 weeks. Lipoprotein subfractions were analyzed by electrophoresis in polyacrylamide gel (Lipoprint System®). The Sampson equation estimated the small and dense (sd) and large and buoyant (lb) LDL subfractions from the lipid profile. Quality of LDL particle was analyzed by Z-scan and UV-vis spectroscopy. Primary outcome was the comparison of diet vs. diet plus phytosterols. Secondary outcomes assessed differences between baseline, diet and diet plus phytosterol. Non-parametric statistics were performed with p < 0.05. There was a trend to reduction on HDL-7 (p = 0.05) in diet plus phytosterol arm, with no effects on the quality of LDL particles. Heatmap showed strong correlations (ρ > 0.7) between particle size by different methods with both interventions. Diet plus phytosterol reduced TC, increased HDL-c, and reduced IDL-B, whereas diet increased HDL7, and reduced IDL-B vs. baseline (p < 0.05, for all). Phytosterol supplementation demonstrated small beneficial effects on HDL-7 subfraction, compared with diet alone, without effects on the quality of LDL particles.This trial is registered in Clinical Trials (NCT06127732) and can be accessed at https://clinicaltrials.gov .

Blood Lipids, Lipoproteins, and Apolipoproteins With Risk of Coronary Heart Disease: A Prospective Study Among Racially Diverse Populations.

BACKGROUND: Comprehensive blood lipoprotein profiles and their association with incident coronary heart disease (CHD) among racially and geographically diverse populations remain understudied. METHODS AND RESULTS: We conducted nested case-control studies of CHD among 3438 individuals (1719 pairs), including 1084 White Americans (542 pairs), 1244 Black Americans (622 pairs), and 1110 Chinese adults (555 pairs). We examined 36 plasma lipids, lipoproteins, and apolipoproteins, measured by nuclear magnetic resonance spectroscopy, with incident CHD among all participants and subgroups by demographics, lifestyle, and metabolic health status using conditional or unconditional logistic regression adjusted for potential confounders. Conventionally measured blood lipids, that is, total cholesterol, triglycerides, low-density lipoprotein-cholesterol, and high-density lipoprotein-cholesterol, were each associated with incident CHD, with odds ratios (ORs) being 1.33, 1.32, 1.24, and 0.79 per 1-SD increase among all participants. Seventeen lipoprotein biomarkers showed numerically stronger associations than conventional lipids, with ORs per 1-SD among all participants ranging from 1.35 to 1.57 and a negative OR of 0.78 (all false discovery rate <0.05), including apolipoprotein B100 to apolipoprotein A1 ratio (OR, 1.57 [95% CI, 1.45-1.7]), low-density lipoprotein-triglycerides (OR, 1.55 [95% CI, 1.43-1.69]), and apolipoprotein B (OR, 1.49 [95% CI, 1.37-1.62]). All these associations were significant and consistent across racial groups and other subgroups defined by age, sex, smoking, obesity, and metabolic health status, including individuals with normal levels of conventionally measured lipids. CONCLUSIONS: Our study highlighted several lipoprotein biomarkers, including apolipoprotein B/ apolipoprotein A1 ratio, apolipoprotein B, and low-density lipoprotein-triglycerides, strongly and consistently associated with incident CHD. Our results suggest that comprehensive lipoprotein measures may complement the standard lipid panel to inform CHD risk among diverse populations.

Protective effect of phospholipids in lipoproteins against diabetic kidney disease: A Mendelian randomization analysis.

BACKGROUND: The etiology of diabetic kidney disease is complex, and the role of lipoproteins and their lipid components in the development of the disease cannot be ignored. However, phospholipids are an essential component, and no Mendelian randomization studies have yet been conducted to examine potential causal associations between phospholipids and diabetic kidney disease. METHODS: Relevant exposure and outcome datasets were obtained through the GWAS public database. The exposure datasets included various phospholipids, including those in LDL, IDL, VLDL, and HDL. IVW methods were the primary analytical approach. The accuracy of the results was validated by conducting heterogeneity, MR pleiotropy, and F-statistic tests. MR-PRESSO analysis was utilized to identify and exclude outliers. RESULTS: Phospholipids in intermediate-density lipoprotein (OR: 0.8439; 95% CI: 0.7268-0.9798), phospholipids in large low- density lipoprotein (OR: 0.7913; 95% CI: 0.6703-0.9341), phospholipids in low- density lipoprotein (after removing outliers, OR: 0.788; 95% CI: 0.6698-0.9271), phospholipids in medium low- density lipoprotein (OR: 0.7682; 95% CI: 0.634-0.931), and phospholipids in small low-density lipoprotein (after removing outliers, OR: 0.8044; 95% CI: 0.6952-0.9309) were found to be protective factors. CONCLUSIONS: This study found that a higher proportion of phospholipids in intermediate-density lipoprotein and the various subfractions of low-density lipoprotein, including large LDL, medium LDL, and small LDL, is associated with a lower risk of developing diabetic kidney disease.

Effects of Recombinant Human Lecithin Cholesterol Acyltransferase on Lipoprotein Metabolism in Humans.

BACKGROUND: LCAT (lecithin cholesterol acyl transferase) catalyzes the conversion of unesterified, or free cholesterol, to cholesteryl ester, which moves from the surface of HDL (high-density lipoprotein) into the neutral lipid core. As this iterative process continues, nascent lipid-poor HDL is converted to a series of larger, spherical cholesteryl ester-enriched HDL particles that can be cleared by the liver in a process that has been termed reverse cholesterol transport. METHODS: We conducted a randomized, placebocontrolled, crossover study in 5 volunteers with atherosclerotic cardiovascular disease, to examine the effects of an acute increase of recombinant human (rh) LCAT via intravenous administration (300-mg loading dose followed by 150 mg at 48 hours) on the in vivo metabolism of HDL APO (apolipoprotein)A1 and APOA2, and the APOB100-lipoproteins, very low density, intermediate density, and low-density lipoproteins. RESULTS: As expected, recombinant human LCAT treatment significantly increased HDL-cholesterol (34.9 mg/dL; P≤0.001), and this was mostly due to the increase in cholesteryl ester content (33.0 mg/dL; P=0.014). This change did not affect the fractional clearance or production rates of HDL-APOA1 and HDL-APOA2. There were also no significant changes in the metabolism of APOB100-lipoproteins. CONCLUSIONS: Our results suggest that an acute increase in LCAT activity drives greater flux of cholesteryl ester through the reverse cholesterol transport pathway without significantly altering the clearance and production of the main HDL proteins and without affecting the metabolism of APOB100-lipoproteins. Long-term elevations of LCAT might, therefore, have beneficial effects on total body cholesterol balance and atherogenesis.

Lipoproteins and metabolites in diagnosing and predicting Alzheimer's disease using machine learning.

BACKGROUND: Alzheimer's disease (AD) is a chronic neurodegenerative disorder that poses a substantial economic burden. The Random forest algorithm is effective in predicting AD; however, the key factors influencing AD onset remain unclear. This study aimed to analyze the key lipoprotein and metabolite factors influencing AD onset using machine-learning methods. It provides new insights for researchers and medical personnel to understand AD and provides a reference for the early diagnosis, treatment, and early prevention of AD. METHODS: A total of 603 participants, including controls and patients with AD with complete lipoprotein and metabolite data from the Alzheimer's disease Neuroimaging Initiative (ADNI) database between 2005 and 2016, were enrolled. Random forest, Lasso regression, and CatBoost algorithms were employed to rank and filter 213 lipoprotein and metabolite variables. Variables with consistently high importance rankings from any two methods were incorporated into the models. Finally, the variables selected from the three methods, with the participants' age, sex, and marital status, were used to construct a random forest predictive model. RESULTS: Fourteen lipoprotein and metabolite variables were screened using the three methods, and 17 variables were included in the AD prediction model based on age, sex, and marital status of the participants. The optimal random forest modeling was constructed with "mtry" set to 3 and "ntree" set to 300. The model exhibited an accuracy of 71.01%, a sensitivity of 79.59%, a specificity of 65.28%, and an AUC (95%CI) of 0.724 (0.645-0.804). When Mean Decrease Accuracy and Gini were used to rank the proteins, age, phospholipids to total lipids ratio in intermediate-density lipoproteins (IDL_PL_PCT), and creatinine were among the top five variables. CONCLUSIONS: Age, IDL_PL_PCT, and creatinine levels play crucial roles in AD onset. Regular monitoring of lipoproteins and their metabolites in older individuals is significant for early AD diagnosis and prevention.

Worldwide Increasing Use of Nonfasting Rather Than Fasting Lipid Profiles.

BACKGROUND: Historically, lipids and lipoproteins were measured in the fasting state for cardiovascular risk prediction; however, since 2009 use of nonfasting lipid profiles has increased substantially worldwide. For patients, nonfasting lipid profiles are convenient and avoid any risk of hypoglycemia. For laboratories, blood sampling in the morning and extra visits for patients who have not fasted are avoided. For patients, clinicians, hospitals, and society, nonfasting sampling allows same-day visits with first blood sampling followed by a short wait for test results before clinical consultation. Therefore, nonfasting compared to fasting lipid profiles will save money and time and may improve patient compliance with cardiovascular prevention programs. CONTENT: We report on the progression of endorsement and implementation of nonfasting lipid profiles for cardiovascular risk prediction worldwide and summarize the recommendations from major medical societies and health authorities in different countries. We also describe practical advantages and disadvantages for using nonfasting lipid profiles. Further, we include a description of why fasting has been the standard historically, the barriers against implementation of nonfasting lipid profiles, and finally we suggest the optimal content of a nonfasting lipid profile. SUMMARY: Lipid, lipoprotein, and apolipoprotein concentrations vary minimally in response to normal food intake and nonfasting lipid profiles are equal or superior to fasting profiles for cardiovascular risk prediction. Major guidelines and consensus statements in Europe, the United States, Canada, Brazil, Japan, India, and Australia now endorse use of nonfasting lipid profiles in some or all patients; however, there are still gaps in endorsement and implementation of nonfasting lipid profiles worldwide.

Profile of Lipoprotein Subclasses in Chinese Primary Open-Angle Glaucoma Patients.

To investigate the plasma lipoprotein subclasses in patients with primary open-angle glaucoma (POAG), a total of 20 Chinese POAG patients on intraocular pressure (IOP)-lowering treatment and 20 age-matched control subjects were recruited. Based on the levels of total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C), the study subjects were divided into elevated- and normal-level subgroups. The plasma lipoprotein, lipoprotein subclasses, and oxidized LDL (oxLDL) levels were quantitatively measured. The discrimination potential of the lipoproteins was evaluated using the area under the receiver operating characteristic curve (AUC), and their correlation with clinical parameters was also evaluated. Compared to the control subjects with elevated TC and/or LDL-C levels, the levels of TC, LDL-C, non-high-density lipoprotein cholesterol (non-HDL), LDL subclass LDL3 and small dense LDL (sdLDL), and oxLDL were significantly higher in POAG patients with elevated TC and/or LDL-C levels. No differences in any lipoproteins or the subclasses were found between the POAG patients and control subjects with normal TC and LDL-C levels. Moderate-to-good performance of TC, LDL-C, non-HDL, LDL3, sdLDL, and oxLDL was found in discriminating between the POAG patients and control subjects with elevated TC and/or LDL-C levels (AUC: 0.710-0.950). Significant negative correlations between LDL3 and sdLDL with retinal nerve fiber layer (RNFL) thickness in the superior quadrant and between LDL3 and average RNFL thickness were observed in POAG patients with elevated TC and/or LDL-C levels. This study revealed a significant elevation of plasma lipoproteins, especially the LDL subclasses, in POAG patients with elevated TC and/or LDL-C levels, providing insights on monitoring specific lipoproteins in POAG patients with elevated TC and/or LDL-C.

Plasma tissue factor pathway inhibitor levels in coronavirus disease 2019 patients: a systematic review and meta-analysis.

Studies have suggested a relationship between tissue factor pathway inhibitor (TFPI) and coronavirus disease 2019 (COVID-19) severity. However, there is inconsistency in the findings of the studies. To enhance comprehension of this relationship, a meta-analysis was conducted. PubMed, Web of Science, and Scopus databases were searched to identify eligible studies. The mean difference was employed as effect measures and the standardized mean difference (SMD) and the 95% confidence interval (CI) were utilized as a summary statistic. Heterogeneity was assessed through the application of the chi-square test and the I2 statistic. The included studies' quality and risk of bias were assessed using the Newcastle-Ottawa assessment scale, adapted for case-control studies. A total of six studies were included with 684 cases and healthy controls (180 healthy controls and 504 COVID-19 patients with different severity, 76 mild, 292 moderate, and 136 severe). The analysis revealed a significant increase in the TFPI level in COVID-19 patients with moderate severity compared with healthy controls (SMD = 0.95 ng/ml, 95% confidence interval (CI) 0.27, 1.63 ng/ml; I2 : 87.2%). The increased TFPI level in mild and moderate COVID-19 was not significant, SMD = 0.68 ng/ml, 95% CI -0.64 to 2.0 ng/ml; I2 92.9% and SMD = 0.62 ng/ml, 95% CI -0.62 to 1.86 ng/ml; I2 91.5%, respectively. In addition, most studies indicate an association of the increased TFPI concentrations with increased markers of inflammation, endothelial damage, and hypercoagulation. Considering the anticoagulant and anti-inflammatory roles of TFPI, its increase seems to be aimed at modulating COVID-19-induced hyper-inflammation and hyper-coagulation state. SYSTEMATIC REVIEW REGISTRATION: PROSPERO CRD42023437353.

Inhibition of PCSK9 with evolocumab modulates lipoproteins and monocyte activation in high-risk ASCVD subjects.

BACKGROUND: Mechanistic studies suggest that proprotein convertase subtilisin/kexin type 9 inhibitors can modulate inflammation. METHODS: Double-blind, placebo-controlled trial randomized 41 ASCVD subjects with type 2 diabetes with microalbuminuria and LDL-C level >70 mg/dL on maximum tolerated statin therapy received subcutaneous evolocumab 420 mg every 4 weeks or matching placebo. The primary outcomes were change in circulating immune cell transcriptional response, lipoproteins and blood viscosity at 2 weeks and 12 weeks. Safety was assessed in all subjects who received at least one dose of assigned treatment and analyses were conducted in the intention-to-treat population. RESULTS: All 41 randomized subjects completed the 2-week visit. Six subjects did not receive study medication consistently after the 2-week visit due to COVID-19 pandemic suspension of research activities. The groups were well-matched with respect to age, comorbidities, baseline LDL-C, white blood cell counts, and markers of systemic inflammation. Evolocumab reduced LDL-C by -68.8% (p < 0.0001) and -52.8% (p < 0.0001) at 2 and 12 weeks, respectively. There were no differences in blood viscosity at baseline nor at 2 and 12 weeks. RNA-seq was performed on peripheral blood mononuclear cells with and without TLR4 stimulation ("Stress" transcriptomics). "Stress" transcriptomics unmasked immune cell phenotypic differences between evolocumab and placebo groups at 2 and 12 weeks. CONCLUSIONS: This trial is the first to demonstrate that PCSK9 mAB with evolocumab can modulate circulating immune cell properties and highlights the importance of "stress" profiling of circulating immune cells that more clearly define immune contributions to ASCVD.

Relationship between plasma tissue Factor Pathway Inhibitor (TFPI) levels, thrombin generation and clinical risk of bleeding in patients with severe haemophilia A or B.

INTRODUCTION: Bleeding severity in severe haemophilic patients, with low thrombin generation (TG) capacity, can vary widely between patients, possibly reflecting differences in tissue factor pathway inhibitor (TFPI) level. AIM: To compare free TFPI (fTFPI) levels in patients with severe haemophilia A (sHA) and severe haemophilia B (sHB) and to investigate in these patients as a whole the relationships between bleeding and TG potential, between TG potential and fTFPI level and between fTFPI level and bleeding tendency. METHODS: Data on bleeding episodes retrospectively recorded during follow-up visits over 5-10 years were collected and used to calculate the annualised joint bleeding rate (AJBR). fTFPI levels and basal TG parameters were determined in platelet-poor plasma (PPP) and platelet-rich plasma (PRP) using calibrated automated tomography (CAT). RESULTS: Mean fTFPI levels did not differ significantly between sHA (n = 34) and sHB (n = 19) patients. Mean values of endogenous thrombin potential (ETP) and thrombin peak (peak) in PPP and PRP were two-fold higher when fTFPI levels < 9.4 versus > 14.3 ng/mL. In patients treated on demand, ETP and peak in PRP were doubled when AJBR was ≤ 4.9 $ \le 4.9$ , AJBR being halved in patients with a low fTFPI level (9.4 ng/mL). In patients on factor prophylaxis, no association was found between TG parameters and either fTFPI level or AJBR. CONCLUSION: In patients treated on demand, bleeding tendency was influenced by fTFPI levels, which in turn affected basal TG potential. In patients on prophylaxis, bleeding tendency is probably determined primarily by the intensity of this treatment.

Clinical practice recommendations on lipoprotein apheresis for children with homozygous familial hypercholesterolaemia: An expert consensus statement from ERKNet and ESPN.

Homozygous familial hypercholesterolaemia is a life-threatening genetic condition, which causes extremely elevated LDL-C levels and atherosclerotic cardiovascular disease very early in life. It is vital to start effective lipid-lowering treatment from diagnosis onwards. Even with dietary and current multimodal pharmaceutical lipid-lowering therapies, LDL-C treatment goals cannot be achieved in many children. Lipoprotein apheresis is an extracorporeal lipid-lowering treatment, which is used for decades, lowering serum LDL-C levels by more than 70% directly after the treatment. Data on the use of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia mainly consists of case-reports and case-series, precluding strong evidence-based guidelines. We present a consensus statement on lipoprotein apheresis in children based on the current available evidence and opinions from experts in lipoprotein apheresis from over the world. It comprises practical statements regarding the indication, methods, treatment goals and follow-up of lipoprotein apheresis in children with homozygous familial hypercholesterolaemia and on the role of lipoprotein(a) and liver transplantation.

Lipoprotein Insulin Resistance Score and Mortality Risk Stratification in Heart Failure.

BACKGROUND: Higher total serum cholesterol is associated with lower mortality in heart failure. Evaluating associations between lipoprotein subfractions and mortality among people with heart failure may provide insights into this observation. METHODS: We prospectively enrolled a community cohort of people with heart failure from 2003 to 2012 and assessed vital status through 2021. Plasma collected at enrollment was used to measure lipoprotein subfractions via nuclear magnetic resonance spectroscopy. A composite score of 6 lipoprotein subfractions was generated using the lipoprotein insulin resistance index (LP-IR) algorithm. Using covariate-adjusted proportional hazards regression models, we evaluated associations between LP-IR score and all-cause mortality. RESULTS: Among 1382 patients with heart failure (median follow-up 13.9 years), a one-standard-deviation (SD) increment in LP-IR score was associated with lower mortality (hazard ratio [HR] 0.93; 95% confidence interval [CI], 0.97-0.99). Among LP-IR parameters, mean high-density lipoprotein (HDL) particle size was significantly associated with lower mortality (HR per 1-SD decrement in mean HDL particle size = 0.83; 95% CI, 0.78-0.89), suggesting that the inverse association between LP-IR score and mortality may be driven by smaller mean HDL particle size. CONCLUSIONS: LP-IR score was inversely associated with mortality among patients with heart failure and may be driven by smaller HDL particle size.

Coagulation activity and thrombotic risk following high-volume endurance exercise in recreationally active cyclists.

Despite the prognostic effect of physical activity, acute bouts of high-volume endurance exercise can induce cardiac stress and postexercise hypercoagulation associated with increased thrombotic risk. The aim of this study was to explore the effect of high-volume endurance exercise on coagulation and thrombotic activity in recreational cyclists. Thirty-four recreational cyclists completed 4.8 ± 0.3 h of cycling at 45 ± 5% of maximal power output on a bicycle ergometer. Intravenous blood samples were collected preexercise, immediately postexercise, 24 and 48 h postexercise, and analyzed for brain natriuretic peptide (BNP), cardiac troponin (cTn), C-reactive protein (CRP), D-dimer, thrombin-antithrombin (TAT) complex, tissue factor (TF), tissue factor pathway inhibitor (TFPI), and TF-to-TFPI ratio (TF:TFPI). An increase in cTn was observed postexercise (P < 0.001). CRP concentrations were increased at 24 and 48 h postexercise compared with preexercise concentrations (P ≤ 0.001). TF was elevated at 24 h postexercise (P < 0.031) and TFPI was higher immediately postexercise (P < 0.044) compared with all other time points. TF:TFPI was increased at 24 and 48 h postexercise compared with preexercise (P < 0.025). TAT complex was reduced at 48 h postexercise compared with preexercise (P = 0.015), D-dimer was higher immediately postexercise compared with all other time points (P ≤ 0.013). No significant differences were observed in BNP (P > 0.05). High-volume endurance cycling induced markers of cardiac stress among recreational cyclists. However, plasma coagulation and fibrinolytic activity suggest no increase in thrombotic risk after high-volume endurance exercise.NEW & NOTEWORTHY In this study, a high-volume endurance exercise protocol induced markers of cardiac stress and altered plasma coagulation and fibrinolytic activity for up to 48 h in recreationally active cyclists. However, analysis of coagulation biomarkers indicates no increase in thrombotic risk when appropriate hydration and rest protocols are implemented.