Low-density Lipoprotein Subclasses Research Articles

Impact of Distinct Anti-Androgen Exposures on the Plasma Metabolome in Feminizing Gender-Affirming Hormone Therapy.

The plasma metabolome is a functional readout of metabolic activity and is associated with phenotypes exhibiting sexual dimorphism, such as cardiovascular disease. Sex hormones are thought to play a key role in driving sexual dimorphism. Gender-affirming hormone therapy (GAHT) is a cornerstone of transgender care, but longitudinal changes in the plasma metabolome with feminizing GAHT have not been described. Blood samples were collected at baseline and after three and six months of GAHT from transgender women (n = 53). Participants were randomized to different anti-androgens, cyproterone acetate or spironolactone. NMR-based metabolomics was used to measure 249 metabolic biomarkers in plasma. Additionally, we used metabolic biomarker data from an unrelated cohort of children and their parents (n = 3,748) to identify sex- and age-related metabolite patterns. We identified 43 metabolic biomarkers altered after six months in both anti-androgen groups, most belonging to the very low- or low-density lipoprotein subclasses, with all but one showing a decrease. We observed a cyproterone acetate-specific decrease in glutamine, glycine, and alanine levels. Notably, of the metabolic biomarkers exhibiting the most abundant 'sex- and age-related' pattern (higher in assigned female children and lower in assigned female adults, relative to assigned males), 80% were significantly lowered after GAHT, reflecting a shift toward the adult female profile. Our results suggest an anti-atherogenic signature in the plasma metabolome after the first six months of feminizing GAHT, with cyproterone acetate also reducing specific plasma amino acids. This study provides novel insight into the metabolic changes occurring across feminizing GAHT.

Role of low-density lipoprotein electronegativity and sexual dimorphism in contributing early ventricular tachyarrhythmias following ST-elevation myocardial infarction.

Early ventricular tachycardia/fibrillation (VT/VF) in patients with ST-elevation myocardial infarction (STEMI) has higher morbidity and mortality. This study examines gender-differentiated risk factors and underlying mechanisms for early onset VT/VF in STEMI. We analyzed data from 2,964 consecutive STEMI patients between January 1, 2008 and December 31, 2021. Early VT/VF was defined as occurrence of spontaneous VT/VF of ≥30 s or requirement of immediate cardioversion/defibrillation within the first 48 h after symptoms. An ex vivo ischemic-reperfusion experiments were conducted in 8-week-old ApoE-/- mice fed a high-fat diet to explore the underlying mechanisms of early VT/VF. In 255 of out 2,964 STEMI patients who experienced early VT/VF, the age was younger (58.6 ± 13.8 vs. 61.0 ± 13.0 years old, P = 0.008) with a male predominance. The plasma levels of L5, the most electronegative subclass of low-density lipoprotein, was higher in early VT/VF patients compared to those without early VT/VF (n = 21, L5: 14.1 ± 22.6% vs. n = 46, L5: 4.3 ± 9.9%, P = 0.016). In the experimental setup, all male mice (n = 4) developed VT/VF post sham operation, whereas no such incidence was observed in the female mice (n = 3). Significantly, male mice exhibited considerably slower cardiac conduction velocity as compared to their female counterparts in whole heart preparations (25.01 ± 0.93 cm/s vs.42.32 ± 5.70 cm/s, P < 0.001), despite analogous action potential durations. Furthermore, isolated ventricular myocytes from male mice showed a distinctly lower sodium current density (-29.20 ± 3.04 pA/pF, n = 6) in comparison to female mice (-114.05 ± 6.41 pA/pF, n = 6, P < 0.001). This decreased sodium current density was paralleled by a reduced membrane expression of Nav1.5 protein (0.38 ± 0.06 vs. 0.89 ± 0.09 A.U., P < 0.001) and increased cytosolic Nav1.5 levels (0.59 ± 0.06 vs. 0.29 ± 0.04 A.U., P = 0.001) in male mice. Furthermore, it was observed that the overall expressions of sorting nexin 27 (SNX27) and vacuolar protein sorting 26 (VPS26) were significantly diminished in male mice as compared to female littermates (0.91 ± 0.15 vs. 1.70 ± 0.28, P = 0.02 and 0.74 ± 0.09 vs. 1.57 ± 0.13, P < 0.01, respectively). Our findings reveal that male STEMI patients with early VT/VF are associated with elevated L5 levels. The gender-based discrepancy in early VT/VF predisposition might be due to compromised sodium channel trafficking, possibly linked with increased LDL electronegativity.

LDL electronegativity and male predominance in early ventricular tachyarrhythmias following ST-elevation myocardial infarction: evidence of sexual dimorphism associated reduction of sodium currents

Abstract Background Early ventricular tachycardia/fibrillation (VT/VF) in patients with ST-elevation myocardial infarction (STEMI) was associated with a higher morbidity and mortality rate. We sought to investigate the gender-specific risk and explore the underlying mechanisms of early VT/VF in STEMI patients. Methods We analyzed the clinical and laboratory data among 2965 consecutive STEMI patients between Jan 1, 2008 and Dec 31, 2021. Early VT/VF was defined as occurrence of spontaneous VT/VF of ≥30 seconds or requirement of immediate cardioversion/defibrillation due to hemodynamic compromise within the first 48 hours after onset of symptoms. To explore the mechanisms underlying early VT/VF, ex vivo ischemic-reperfusion experiments were conducted in 8-week-old ApoE-/- mice fed a high-fat diet for 8 weeks to promote atherogenesis. Results Of the 2965 STEMI patients studied, 256 (8.6%) experienced early VT/VF. Patients who developed early VT/VF were younger (58±13 vs. 61±13 years old, P=0.012) and had a higher proportion of males (87% vs. 83%, P=0.043). Notably, some patients with early VT/VF had significantly higher plasma levels of L5, the most electronegative subclass of low-density lipoprotein (LDL), compared to those without early VT/VF (n=19, L5: 10.14±3.09% vs. n=43, L5: 2.11±0.23%, P=0.006). In animal study, we have previously showed that male mice have higher plasma L5 concentrations than female mice. In this study, all male mice (n=4) developed VT/VF following the sham operation, whereas none of the female mice (n=3) did. Moreover, male mice had significantly slower heart conduction velocity than female mice in whole heart preparations (13.37±3.81 cm/s vs. 40.70±4.97 cm/s, P&amp;lt;0.001), despite having similar action potential duration (61.00±7.07 vs. 50.33±4.16 ms, P=0.999). In addition, isolated ventricular myocytes from male mice exhibited markedly lower sodium current density (-29.20±3.04 pA/pF, n=6) compared to those from female mice (-114.05±6.41 pA/pF, n=6, P&amp;lt;0.001). The reduced sodium current density was accompanied by lower membranous Nav1.5 protein expression (0.38±0.06 vs. 0.89±0.09 A.U., P&amp;lt;0.001) and higher cytosolic Nav1.5 levels (0.59±0.06 vs. 0.29±0.04 A.U., P&amp;lt;0.01) in male mice. Conclusions Our study demonstrates that male STEMI patients with early VT/VF have higher levels of L5, the most electronegative LDL subclass. This gender disparity in the susceptibility of early VT/VF may be caused by compromised sodium channel trafficking, likely linked to increased LDL electronegativity.

Association of LDL-cholesterol subfractions with cardiovascular disorders: a systematic review

BackgroundCardiovascular disorders (CVDs) are the leading cause of death worldwide. This study aimed to evaluate the association between low-density lipoprotein (LDL) subfractions and cardiovascular disorders.MethodsTo ensure the rigor of the systematic review, the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines were used. For this systematic review, a comprehensive search strategy was performed in important databases including PubMed, Scopus, Embase, International Statistical Institute (ISI) Web of Science, and google scholar from 2009 to February 2021. The following terms were used for systematic search: low-density lipoprotein, LDL, subfractions, subclasses, nuclear magnetic resonance, NMR, chromatography, high-pressure liquid, HPLC, cardiovascular disease, cerebrovascular, and peripheral vascular disease. Also, for evaluating the risk of bias, the Newcastle-Ottawa scale was employed.ResultsAt the end of the search process, 33 articles were included in this study. The results of most of the evaluated studies revealed that a higher LDL particle number was consistently associated with increased risk for cardiovascular disease, independent of other lipid measurements. Also, small dense LDL was associated with an increased risk of CVDs. There was no association between LDL subfraction and CVDs in a small number of studies.ConclusionsOverall, it seems that the evaluation of LDL subclasses can be used as a very suitable biomarker for the assessment and diagnosis of cardiovascular diseases. However, further studies are required to identify the mechanisms involved.

Low-density lipoprotein subclasses over the menopausal transition and risk of coronary calcification and carotid atherosclerosis: the SWAN Heart and HDL ancillary studies.

Perimenopausal women experience a steep increase in low-density lipoprotein cholesterol (LDL-C) that is related to a higher risk of carotid plaque later in life. Low-density lipoprotein subclasses have been linked to cardiovascular diseases beyond LDL-C, promising a better risk stratification. We aim to characterize changes in LDL subclasses and assess their associations with presence of coronary artery calcium (CAC score ≥10) and carotid intima-media thickness (cIMT) over the menopausal transition (MT) and by menopause stage. Nuclear magnetic resonance spectroscopy LDL subclasses were measured for a maximum of five time points. Coronary artery calcification and cIMT were measured for a maximum of two time points. LOESS (locally weighted regression with scatter smoothing) plots, linear mixed-effects models, and generalized estimating equations were used for analyses. The study included 471 women (baseline: age, 50.2 ± 2.7 years; 79.0% premenopausal/early perimenopausal), of whom 221 had data on CAC or cIMT. Low-density lipoprotein subclasses increased over the MT, whereas intermediate density-lipoprotein particles declined. In adjusted models, higher total LDL particles (LDL-P) and apolipoprotein B were associated with greater CAC prevalence and greater cIMT. Although none of the associations were modified by menopause stage, higher LDL-C, apolipoprotein B, and total LDL-P were associated with greater cIMT during the perimenopause or postmenopause stages, whereas higher LDL-C and small LDL-P were associated with greater CAC prevalence, mainly during perimenopause. During the MT, women experience significant increases in LDL subclasses found to be related to greater cIMT levels and CAC prevalence. Whether these changes could better predict future risk of hard cardiovascular disease events beyond LDL-C remains a research question to address.

Measurement of cholesterol levels of lipoprotein subclasses in human serum using anion-exchange high-performance liquid chromatography with a linear concentration gradient of sodium perchlorate.

Relationships between the subclasses of high-density lipoprotein (HDL) or low-density lipoprotein (LDL) and the risk of atherosclerotic cardiovascular disease have been studied, and using various methods, such as ultracentrifugation, electrophoresis, and nuclear magnetic resonance, for analysing lipoprotein subclasses. We established a method for HDL and LDL subclasses using anion-exchange high-performance liquid chromatography (AEX-HPLC) with a linear concentration gradient of sodium perchlorate (NaClO4). In the AEX-HPLC, the subclasses of HDL and LDL were separated, and detected using a post-column reactor with an enzymatic cholesterol reagent, that contained cholesterol esterase, cholesterol oxidase, and peroxidase as major ingredients. LDL subclasses were divided based on the absolute value of first-derivative chromatogram. Three HDL subclasses, HDL-P1, HDL-P2, and HDL-P3, and three LDL subclasses, LDL-P1, LDL-P2, and LDL-P3, were separated by AEX-HPLC, and detected in order. The major components of HDL-P2 and HDL-P3 were HDL3 and HDL2, respectively. The linearity was determined for each lipoprotein subclass. The coefficients of variation of cholesterol concentration of the subclasses for within-day assay (n = 10) and between-day assay (n = 10) ranged between 3.08-8.94% and 4.52-9.97%, respectively. Cholesterol levels in HDL-P1 of diabetic patients were positively correlated with oxidized LDL levels (r = 0.409, p = 0.002). Moreover, cholesterol levels in LDL-P2 and LDL-P3 were positively correlated with oxidized LDL levels (r = 0.393, p = 0.004 and r = 0.561, p < 0.001, respectively). AEX-HPLC may be highly suitable as an assay to clinically assess lipoprotein subclasses.

Low-density lipoprotein particles in atherosclerosis.

Among the diseases causing human death, cardiovascular disease (CVD) remains number one according to the World Health Organization report in 2021. It is known that atherosclerosis is the pathological basis of CVD. Low-density lipoprotein (LDL) plays a pivotal role in the initiation and progression of atherosclerotic CVD (ASCVD). LDL cholesterol (LDL-C) is the traditional biological marker of LDL. However, large numbers of patients who have achieved the recommended LDL-C goals still have ASCVD risk. In multiple prospective studies, LDL particle (LDL-P) is reported to be more accurate in predicting CVD risk than LDL-C. LDL-Ps differ in size, density and chemical composition. Numerous clinical studies have proved that the atherogenic mechanisms of LDL-Ps are determined not only by LDL number and size but also by LDL modifications. Of note, small dense LDL (sdLDL) particles possess stronger atherogenic ability compared with large and intermediate LDL subfractions. Besides, oxidized LDL (ox-LDL) is another risk factor in atherosclerosis. Among the traditional lipid-lowering drugs, statins induce dramatic reductions in LDL-C and LDL-P to a lesser extend. Recently, proprotein convertase subtilsin/kexin type 9 inhibitors (PCSK9i) have been demonstrated to be effective in lowering the levels of LDL-C, LDL-P, as well as CVD events. In this article, we will make a short review of LDL metabolism, discuss the discordance between LDL-C and LDL-P, outline the atherogenic mechanisms of action of LDL by focusing on sdLDL and ox-LDL, summarize the methods used for measurement of LDL subclasses, and conclude the advances in LDL-lowering therapies using statins and PCSK9i.

Review of Laboratory Methods to Determine HDL and LDL Subclasses and Their Clinical Importance

Given the high prevalence of cardiovascular disease, accurate identification of methods for assessing lipoprotein subclasses, mainly low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subfractions, can play an essential role in predicting the incidence of cardiovascular disease such as heart attack. LDL and HDL subclasses differ in size, surface charge, lipid and protein compositions, and biological role. There is no “gold standard” method for measuring the LDL and HDL subclasses or standardizing the different methods used to measure their subfractions. Over the past decades, various techniques have been introduced to evaluate and measure subclasses of these two lipoproteins, each with its own advantages and disadvantages. Development of laboratory methods that accurately HDL and LDL function must be developed and validated to high-throughput for clinical usage. In this review study, we tried to examine different methods of evaluating various subclasses of LDL and HDL by mentioning the strengths and weaknesses of each.

Anorexia Nervosa Is Associated with a Shift to Pro-Atherogenic Low-Density Lipoprotein Subclasses.

Anorexia nervosa (AN) is a severe eating disorder affecting primarily female adolescents and younger adults. The energy deprivation associated with AN has been shown to alter lipoprotein metabolism, which may affect cardiovascular risk. However, the mechanisms leading to alterations in the composition, structure, and function of lipoproteins in AN patients are not well-understood yet. Here, we investigated the lipid abnormalities associated with AN, particularly changes in the distribution, composition, metabolism, and function of lipoprotein subclasses. In this exploratory study, we analyzed serum samples of 18 women diagnosed with AN (BMI < 17.5 kg/m2) and 24 normal-weight women (BMI from 18.5–24.9 kg/m2). Using the Quantimetrix Lipoprint® system, we determined low-density lipoprotein (LDL) subclass distribution, including quantitative measurements of very low-density lipoprotein (VLDL), intermediate density lipoprotein (IDL) and high-density lipoprotein (HDL) subclass distribution. We quantified the most abundant apolipoproteins of HDL and assessed lecithin-cholesterol acyltransferase (LCAT) and cholesteryl-ester transfer protein (CETP) activities. In addition, anti-oxidative capacity of apoB-depleted serum and functional metrics of HDL, including cholesterol efflux capacity and paraoxonase activity were assessed. The atherogenic lipoprotein subclasses VLDL and small LDL particles were increased in AN. Levels of VLDL correlated significantly with CETP activity (rs = 0.432, p = 0.005). AN was accompanied by changes in the content of HDL-associated apolipoproteins involved in triglyceride catabolism, such as apolipoprotein C-II (+24%) and apoA-II (−27%), whereas HDL-associated cholesterol, phospholipids, and triglycerides were not altered. Moreover, AN did not affect HDL subclass distribution, cholesterol efflux capacity, and paraoxonase activity. We observed a shift to more atherogenic lipoprotein subclasses in AN patients, whereas HDL functionality and subclass distribution were not altered. This finding underpins potential detrimental effects of AN on lipid metabolism and the cardiovascular system by increasing atherosclerotic risk factors.

Clinical Utility of Small, Dense LDL as an Atherogenic Risk Marker

Low-density lipoprotein (LDL) has a major role in the origination and development of atherosclerosis and Cardio Vascular Diseases (CVD). Over the past few years, many studies have been concerned with different subclasses of LDLs and their atherogenicity. Low-density lipoproteins (LDLs) include many subclasses. The most common are large buoyant (LB), intermediate and small dense (sd) low-density lipoprotein particles. Small dense low-density lipoproteins attracted a lot of attention. Small dense LDL (sdLDL) has recently been proven to be more atherogenic than other lipoproteins containing apolipoprotein B, which have the potential to trigger atherosclerotic reactions. Many researchers have reported that small dense low-density lipoproteins are the superior biomarker for the prediction of atherosclerosis and CVDs regarding all other markers, including total low-density lipoprotein cholesterol(LDL-C), and total serum cholesterol, non-high-density lipoprotein (non-HDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride content. Circulating small dense, low-density lipoproteins go through several modifications in the blood, rendering them more atherogenic. These modifications may include glycation, oxidation, and desialylation. Modified particles are strong inducers of inflammation resulting in many cardiovascular diseases, making them the primary target during the treatment of coronary artery disease. This article will elaborate on the clinical utility of sdLDL as an early marker to predict atherosclerosis and CVDs, and why it is considered superior to other atherosclerotic markers.

Uticaj metaboličkih parametara na veličinu i subklasu LDL i HDL kod adolescenata sa dijabetesom tip 1

Alterations in the serum of low-density lipoprotein (LDL) and high-density lipoprotein (HDL) size and subclass contribute to the atherogenesis in coronary artery disease in diabetic patients. The purpose of this study is to evaluate the effect of metabolic parameters on LDL and HDL size and subclasses in adolescents with type 1 diabetes. The cross-sectional study included 43 adolescents (23 females, 20 males) with type 1 diabetes of mean age 15.09±1.94 years, with mean disease duration of 5.86 ± 3.08 years. LDL and HDL particles were separated by polyacrylamide gradient gel electrophoresis, while serum lipid parameters were determined by routine laboratory methods. Patients with inadequate metabolic control (HbA1c ≥ 7.5%) had a higher mean value of triglycerides (TG) (p = 0.041), higher proportions of small, dense LDL particles (p = 0.045), higher proportions of LDL IIA subclasses (p=0.03) and smaller LDL diameter (p = 0.02) and HDL diameter (p = 0.04) than patients with optimal metabolic control (HbA1c &lt; 7.5%). Higher HbA1c and higher TG levels were statistically significantly related to small, dense LDL (r=0.341, p=0.025; r= 0.394, p= 0.009) and HDL particles (r=0.684, p=0.000; r=0.421, p=0.005). Predictors of small, dense LDL and HDL particles, which contribute to atherogenesis, were high HbA1c (HR = 1.52, 95% CI: 0.97-2.40; HR 3.87, 95% CI: 2.11-7.10) and elevated TG (HR= 1.10, 95% CI: 1.00-1.20; HR 1.85, 95% CI: 1.07-3.21). Diabetic adolescents require particular attention in order to minimize factors such as high HbA1c and elevated TGs in the development of future cardiovascular events.

Effects of Apnea, Obesity, and Statin Therapy on Proprotein Convertase Subtilisin/Kexin 9 Levels in Patients with Obstructive Sleep Apnea

Objectives: Obstructive sleep apnea (OSA) is a common condition closely related to obesity, insulin resistance, dyslipidemia, and cardiovascular disease. The aim of this study was to explore the possible relationship between OSA and proprotein convertase subtilisin/kexin type 9 (PCSK9). Methods: Full-night polysomnography was performed on 150 participants who were divided into three groups: controls, OSA patients on statin therapy, and OSA patients not on statin therapy. Biochemical markers, plasma low-density lipoprotein (LDL) and high-density lipoprotein (HDL) subclasses, and PCSK9 were determined. Results: PCSK9 was highest in OSA patients on statins compared to the control group and to OSA patients not on statins (p = 0.036 and p = 0.039, respectively), after adjustment for body mass index (BMI). LDL diameter was greater in OSA patients not on statins compared to OSA patients on statins (p = 0.032). PCSK9 was highest in the group of patients with all three risk factors (diagnosed OSA, statins, BMI ≥25 kg/m²) compared to groups with no, one, and two risk factors (p = 0.031, p = 0.001, and p = 0.029, respectively). Presence of OSA, statin therapy, and BMI ≥25 kg/m² when combined were independently associated with higher levels of PCSK9 when adjusted for antihypertensive therapy, small dense LDL, and HDL 3c subclass (odds ratio = 2.849; interquartile range [1.026–7.912], p = 0.044). Conclusion: Statin therapy was closely related to PCSK9. OSA along with obesity and statin use induces elevation of PCSK9.

Higher thyrotropin leads to unfavorable lipid profile and somewhat higher cardiovascular disease risk: evidence from multi-cohort Mendelian randomization and metabolomic profiling

BackgroundObservational studies suggest interconnections between thyroid status, metabolism, and risk of coronary artery disease (CAD), but causality remains to be proven. The present study aimed to investigate the potential causal relationship between thyroid status and cardiovascular disease and to characterize the metabolomic profile associated with thyroid status.MethodsMulti-cohort two-sample Mendelian randomization (MR) was performed utilizing genome-wide significant variants as instruments for standardized thyrotropin (TSH) and free thyroxine (fT4) within the reference range. Associations between TSH and fT4 and metabolic profile were investigated in a two-stage manner: associations between TSH and fT4 and the full panel of 161 metabolomic markers were first assessed hypothesis-free, then directional consistency was assessed through Mendelian randomization, another metabolic profile platform, and in individuals with biochemically defined thyroid dysfunction.ResultsCirculating TSH was associated with 52/161 metabolomic markers, and fT4 levels were associated with 21/161 metabolomic markers among 9432 euthyroid individuals (median age varied from 23.0 to 75.4 years, 54.5% women). Positive associations between circulating TSH levels and concentrations of very low-density lipoprotein subclasses and components, triglycerides, and triglyceride content of lipoproteins were directionally consistent across the multivariable regression, MR, metabolomic platforms, and for individuals with hypo- and hyperthyroidism. Associations with fT4 levels inversely reflected those observed with TSH. Among 91,810 CAD cases and 656,091 controls of European ancestry, per 1-SD increase of genetically determined TSH concentration risk of CAD increased slightly, but not significantly, with an OR of 1.03 (95% CI 0.99–1.07; p value 0.16), whereas higher genetically determined fT4 levels were not associated with CAD risk (OR 1.00 per SD increase of fT4; 95% CI 0.96–1.04; p value 0.59).ConclusionsLower thyroid status leads to an unfavorable lipid profile and a somewhat increased cardiovascular disease risk.

Main differences between two highly effective lipid-lowering therapies in subclasses of lipoproteins in patients with acute myocardial infarction

BackgroundLarge observational studies have shown that small, dense LDL subfractions are related to atherosclerotic cardiovascular disease. This study assessed the effects of two highly effective lipid-lowering therapies in the atherogenic subclasses of lipoproteins in subjects with ST-segment elevation myocardial infarction (STEMI).MethodsPatients of both sexes admitted with their first myocardial infarction and submitted to pharmacoinvasive strategy (N = 101) were included and randomized using a central computerized system to receive a daily dose of simvastatin 40 mg plus ezetimibe 10 mg or rosuvastatin 20 mg for 30 days. Intermediate-density lipoprotein (IDL) and low-density lipoprotein (LDL) subfractions were analysed by polyacrylamide gel electrophoresis (Lipoprint System) on the first (D1) and 30th days (D30) of lipid-lowering therapy. Changes in LDL and IDL subfractions between D1 and D30 were compared between the lipid-lowering therapies (Mann-Whitney U test).ResultsThe classic lipid profile was similar in both therapy arms at D1 and D30. At D30, the achievement of lipid goals was comparable between lipid-lowering therapies. Cholesterol content in atherogenic subclasses of LDL (p = 0.043) and IDL (p = 0.047) decreased more efficiently with simvastatin plus ezetimibe than with rosuvastatin.ConclusionsLipid-lowering therapy with simvastatin plus ezetimibe was associated with a better pattern of lipoprotein subfractions than rosuvastatin monotherapy. This finding was noted despite similar effects in the classic lipid profile and may contribute to residual cardiovascular risk.Trial registrationClinicalTrials.gov, NCT02428374, registered on 28/09/2014.

Subclass distribution of low-density lipoprotein triglyceride and the clustering of metabolic syndrome components in Japanese children.

Recent studies demonstrated that low-density lipoprotein-tryglyceride (LDL-TG) may represent another marker of cardiovascular risks. We therefore measured LDL-TG including the low-density lipoprotein (LDL) subclass distribution and investigated the association between LDL-TG subclass profile and the clustering of metabolic syndrome (MetS) components and insulin resistance in Japanese children. The study included 237 schoolchildren (boys 115, girls 122). Four subclasses of low-density lipoprotein-tryglyceride (large, medium, small, and very small) was quantified using high-performance liquid chromatography. Total LDL-TG and TG levels in LDL subclasses were evaluated among four MetS component groups; non-abdominal obesity, abdominal obesity, pre-MetS, and MetS. Total LDL-TG (P = 0.0003, P = 0.0175) and triglyceride levels in LDL subclasses were significantly different among four MetS component groups (large: P = 0.0002, P = 0.0084; medium: P = 0.0009, P = 0.0491; small: P =0.0025, P = 0.0509; very small: P = 0.0808, P = 0.0228; boys and girls, respectively). Total LDL-TG (r = 0.411, P < 0.0001, r = 0.378. P < 0.0001) and triglyceride levels in LDL subclasses correlated positively with the homeostasis model of assessment ratio (large: r = 0.396, P < 0.0001, r = 0.346, P < 0.0001; medium: r = 0.274, P = 0.0030, r = 0.228, P = 0.0115; small: r = 0.342, P = 0.0002, r = 0.292, P = 0.0011; very small: r = 0.385, P < 0.0001, r = 0.426, P < 0.0001, boys and girls, respectively). Subclass distribution of LDL-TG was significantly associated with the clustering of MetS components in both sexes, and insulin resistance is a significant determinant of LDL-TG in all LDL subclasses. Lipoprotein-tryglyceride subclass analysis, rather than LDL-C, may provide a precise evaluation for cardiovascular disease risks in children with MetS.

Long-term fasting improves lipoprotein-associated atherogenic risk in humans

PurposeDyslipidemia is a major health concern associated with an increased risk of cardiovascular mortality. Long-term fasting (LF) has been shown to improve plasma lipid profile. We performed an in-depth investigation of lipoprotein composition.MethodsThis observational study included 40 volunteers (50% men, aged 32–65 years), who underwent a medically supervised fast of 14 days (250 kcal/day). Changes in lipid and lipoprotein levels, as well as in lipoprotein subclasses and particles, were measured by ultracentrifugation and nuclear magnetic resonance (NMR) at baseline, and after 7 and 14 fasting days.ResultsThe largest changes were found after 14 fasting days. There were significant reductions in triglycerides (TG, − 0.35 ± 0.1 mmol/L), very low-density lipoprotein (VLDL)-TG (− 0.46 ± 0.08 mmol/L), VLDL-cholesterol (VLDL-C, − 0.16 ± 0.03 mmol/L) and low-density lipoprotein (LDL)-C (− 0.72 ± 0.14 mmol/L). Analysis of LDL subclasses showed a significant decrease in LDL1-C (− 0.16 ± 0.05 mmol/L), LDL2-C (− 0.30 ± 0.06 mmol/L) and LDL3-C (− 0.27 ± 0.05 mmol/L). NMR spectroscopy showed a significant reduction in large VLDL particles (− 5.18 ± 1.26 nmol/L), as well as large (− 244.13 ± 39.45 nmol/L) and small LDL particles (− 38.45 ± 44.04 nmol/L). A significant decrease in high-density lipoprotein (HDL)-C (− 0.16 ± 0.04 mmol/L) was observed. By contrast, the concentration in large HDL particles was significantly raised. Apolipoprotein A1 decreased significantly whereas apolipoprotein B, lipoprotein(a), fibrinogen and high-sensitivity C-reactive protein were unchanged.ConclusionOur results suggest that LF improves lipoprotein levels and lipoprotein subclasses and ameliorates the lipoprotein-associated atherogenic risk profile, suggesting a reduction in the cardiovascular risk linked to dyslipidemia.Trial RegistrationStudy registration number: DRKS-ID: DRKS00010111 Date of registration: 03/06/2016 “retrospectively registered”.

Investigation of IgG anti-oxLDL antibody levels and HDL and LDL subclasses in patients with ST-segment elevation acute myocardial infarction

IntroductionDyslipidemia, inflammation and immunological processes play a key role in the development of atherosclerosis. This study investigates the relationship of different phenotypes of low-density lipoprotein (LDL) and high-density lipoprotein (HDL), human antibodies G classes against oxLDL (IgG anti-oxLDL antibodies) and inflammatory marker pentraxin-3 (PTX3) in patients with ST-segment elevation acute myocardial infarction (STEMI). Among STEMI patients with different Synergy Between Percutaneous Coronary Intervention With Taxus and Cardiac Surgery (SYNTAX) score, we analyzed predictive abilities of these biomarkers to assess disease outcome.Material and methodsIn 69 STEMI, 21 patients with stable angina pectoris (AP) and 67 healthy controls, IgG anti-oxLDL antibodies and PTX3 were determined by ELISA. Gradient gel electrophoresis was used for lipoprotein subclasses separation.ResultsWe found significantly lower HDL and LDL diameters (p&lt;0.001 and p&lt;0.001, respectively) and higher PTX3 concentration (p&lt;0.001) in patients than in controls. Control subjects with small-sized HDL and LDL B phenotype had significantly higher IgG anti-oxLDL antibody levels (p=0.015), whereas STEMI patients with the same profile had higher PTX3 concentration (p=0.005). STEMI patients with intermediate SYNTAX score had lower levels of IgG anti-oxLDL antibodies (p=0.008). Multivariate logistic regression analysis showed that smaller LDL diameter was an independent predictor of intermediate SYNTAX score (OR=0.370; p=0.019).ConclusionsSmaller LDL and HDL particles are associated with elevated IgG anti-oxLDL antibodies in healthy subjects, but with increased PTX3 level in STEMI patients. In addition, we found that smaller LDL size was independent predictor of higher SYNTAX score. Further studies are needed to expand our preliminary observations.

Genetic and Epigenetic Biomarkers for Diagnosis, Prognosis and Treatment of Metabolic Syndrome.

Metabolic syndrome is a clinical condition that deserves special attention because it puts the individual at high cardiovascular risk, especially heart attack and stroke. Considering precision medicine, it would be advisable to evaluate the individual cardio-metabolic risk by estimating the coexistence of risk factors (abdominal obesity, low level of High-Density Lipoprotein Cholesterol, High Triglycerides, and small dense Low-Density Lipoproteins sub-classes, hypertension, and elevated fasting glycemia), which could engrave on metabolism increasing cardiovascular mortality. To identify genetic and epigenetic biomarkers may assist in the possibility of helping follow-up strategies and other measures of prevention and in metabolic risk. We searched for studies that valued the combination between epigenetic biomarkers and all factors of cardio-metabolic risk. Numerous researches have investigated the molecular start of metabolic alterations, focusing on the epigenetic mark, as methylation of DNA, histone modifications and non.coding RNAs. It has been found that DNA methylation is the most searched epigenetic sign in the human genome concerning the control of gene expression. For the screening, diagnosis, and prognosis of metabolic syndrome and the prescription of personalized medicine, the DNA methylation biomarkers specify for subjects have been recognized as an ensuring tool. While these results are promising, further investigations are needed to unravel the complicated synergic association of the genome, epigenome and the situations related to metabolic pathology.

Achievement of the Targets of the 20-Year Infancy-Onset Dietary Intervention-Association with Metabolic Profile from Childhood to Adulthood.

The Special Turku Coronary Risk Factor Intervention Project (STRIP) is a prospective infancy-onset randomized dietary intervention trial targeting dietary fat quality and cholesterol intake, and favoring consumption of vegetables, fruit, and whole-grains. Diet (food records) and circulating metabolites were studied at six time points between the ages of 9–19 years (n = 549–338). Dietary targets for this study were defined as (1) the ratio of saturated fat (SAFA) to monounsaturated and polyunsaturated fatty acids (MUFA + PUFA) < 1:2, (2) intake of SAFA < 10% of total energy intake, (3) fiber intake ≥ 80th age-specific percentile, and (4) sucrose intake ≤ 20th age-specific percentile. Metabolic biomarkers were quantified by high-throughput nuclear magnetic resonance metabolomics. Better adherence to the dietary targets, regardless of study group allocation, was assoiated with higher serum proportion of PUFAs, lower serum proportion of SAFAs, and a higher degree of unsaturation of fatty acids. Achieving ≥ 1 dietary target resulted in higher low-density lipoprotein (LDL) particle size, lower circulating LDL subclass lipid concentrations, and lower circulating lipid concentrations in medium and small high-density lipoprotein subclasses compared to meeting 0 targets. Attaining more dietary targets (≥2) was associated with a tendency to lower lipid concentrations of intermediate-density lipoprotein and very low-density lipoprotein subclasses. Thus, adherence to dietary targets is favorably associated with multiple circulating fatty acids and lipoprotein subclass lipid concentrations, indicative of better cardio-metabolic health.

Association of Coronary Calcium, Carotid Wall Thickness, and Carotid Plaque Progression With Low-Density Lipoprotein and High-Density Lipoprotein Particle Concentration Measured by Ion Mobility (From Multiethnic Study of Atherosclerosis [MESA

Current risk stratification strategies do not fully explain cardiovascular disease (CVD) risk. We aimed to evaluate the association of low-density lipoprotein (LDL-P) and high-density lipoprotein (HDL-P) particles with progression of coronary artery calcium and carotid wall injury. All participants in the Multi-Ethnic Study Atherosclerosis (MESA) with LDL-P and HDL-P measured by ion mobility, coronary artery calcium score (CAC), carotid intima-media thickness (IMT), and carotid plaque data available at Exam 1 and 5 were included in the study. CAC progression was annualized and treated as a categorical or continuous variable. Carotid IMT and plaque progression were treated as continuous variables. Fully adjusted regression models included established CVD risk factors, as well as traditional lipids. Mean (±SD) follow-up duration was 9.6 ± 0.6 years. All LDL-P subclasses as well as large HDL-P at baseline were positively and significantly associated with annualized CAC progression, however, after adjustment for established risk factors and traditional lipids, only the association with medium and very small LDL-P remained significant (β -0.02, p = 0.019 and β 0.01, p = 0.003, per 1 nmol/l increase, respectively). Carotid plaque score progression was positively associated with small and very small LDL-P (p <0.01 for all) and non-HDL-P (p = 0.013). Only the association with very small LDL-P remained significant in a fully adjusted model (p = 0.035). Mean IMT progression was not associated with any of the lipid particles. In conclusion, in the MESA cohort, LDL-P measured by ion mobility was significantly associated with CAC progression as well as carotid plaque progression beyond the effect of traditional lipids.