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Nuclear Magnetic Resonance Derived Biomarkers for Evaluating Cardiometabolic Risk in Youth and Young Adults Across the Spectrum of Glucose Tolerance.
Chung, ST, Matta, ST, Meyers, AG, Cravalho, CK, Villalobos-Perez, A, Dawson, JM, Sharma, VR, Sampson, ML, Otvos, JD, Magge, SN
Frontiers in endocrinology. 2021;:665292
Abstract
UNLABELLED Youth with obesity have an increased risk for cardiometabolic disease, but identifying those at highest risk remains a challenge. Four biomarkers that might serve this purpose are "by products" of clinical NMR LipoProfile® lipid testing: LPIR (Lipoprotein Insulin Resistance Index), GlycA (inflammation marker), BCAA (total branched-chain amino acids), and glycine. All are strongly related to insulin resistance and type 2 diabetes (T2DM) in adults (glycine inversely) and are independent of biological and methodological variations in insulin assays. However, their clinical utility in youth is unclear. We compared fasting levels of these biomarkers in 186 youth (42 lean normal glucose tolerant (NGT), 88 obese NGT, 23 with prediabetes (PreDM), and 33 with T2DM. All four biomarkers were associated with obesity and glycemia in youth. LPIR and GlycA were highest in youth with PreDM and T2DM, whereas glycine was lowest in youth with T2DM. While all four were correlated with HOMA-IR (Homeostatic Model Assessment for Insulin Resistance), LPIR had the strongest correlation (LPIR: r = 0.6; GlycA: r = 0.4, glycine: r = -0.4, BCAA r = 0.2, all P < 0.01). All four markers correlated with HbA1c (LPIR, GlycA, BCAA r ≥ 0.3 and glycine: r = -0.3, all P < 0.001). In multi-variable regression models, LPIR, GlycA, and glycine were independently associated with HOMA-IR (Adjusted R2 = 0.473, P < 0.001) and LPIR, glycine, and BCAA were independently associated with HbA1c (Adjusted R2 = 0.33, P < 0.001). An LPIR index of >44 was associated with elevated blood pressure, BMI, and dyslipidemia. Plasma NMR-derived markers were related to adverse markers of cardiometabolic risk in youth. LPIR, either alone or in combination with GlycA, should be explored as a non-insulin dependent predictive tool for development of insulin resistance and diabetes in youth. CLINICAL TRIAL REGISTRATION Clinicaltrials.gov, identifier NCT:02960659.
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Evaluation of atherogenic lipoprotein-cholesterol to HDL cholesterol ratio as a prognostic test for ST-segment elevation myocardial infarction.
Li, JY, Xu, WJ, Zhou, Z, Zhang, RL, Sun, T, Xu, H, Wu, J
International journal of medical sciences. 2021;(13):2897-2904
Abstract
Background: The detectable component of triglyceride-rich lipoproteins (TGRLs), remnant lipoprotein cholesterol (RLP-c), has been proven being correlated with the progression of atherosclerosis and myocardial infarction. However, when taken as a risk predictor, the prognostic and diagnostic potential of RLP-c remains controversial in studies. In this study, we evaluated the hypothesis that atherogenic lipoprotein-cholesterol (AL-c), representing the sum of RLP-c and the sd-LDL-c, to the HDL-c ratio, could represent a better predictive indicator than RLP-c alone in ST-segment elevation myocardial infarction (STEMI). Methods: The 316 consecutive patients suffering from persistent chest discomfort admitted to the Shanghai General Hospital between January 2018 and June 2018 were enrolled. 149 STEMI patients (62% men, mean age 69.6 ± 13.3 years) were included as the study cohort. The AL-c/HDL-c ratio was calculated on admission in a cohort of electrocardiogram-confirmed STEMI patients and compared to other lipid profiles as a predictive indicator. Results: The AL-c/HDL-c ratio was significantly increased in STEMI patients compared with apparently healthy adults (0.93; IQR [0.71-1.18] vs 0.70; IQR [0.45-1.04]; p < 0.001). Gender dependency existed, and the male and female patients had median AL-c/HDL-c ratios of 1.01 and 0.79, respectively (p < 0.001). Compared to RLP-c, the AL-c/HDL-c ratio had a better prognostic value to predict STEMI risk in both sexes (AUC of 0.672 with a sensitivity of 0.794 in males and 0.613 with a sensitivity of 0.684 in females). Conclusions: The AL-c/HDL-c ratio could represent a convenient and sensitive biomarker for screening and predicting STEMI risk.
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Prognostic impact of estimated remnant-like particle cholesterol in patients with differing glycometabolic status: an observational cohort study from China.
Zhao, Q, Zhang, TY, Cheng, YJ, Ma, Y, Xu, YK, Yang, JQ, Zhou, YJ
Lipids in health and disease. 2020;(1):179
Abstract
BACKGROUND It is uncertain whether estimated remnant-like particle cholesterol (RLP-C) could predict residual risk in patients with different glycometabolic status. This study aimed to evaluate the relationship between estimated RLP-C and adverse prognosis in patients with non-ST-segment elevation acute coronary syndrome (NSTE-ACS) treated with percutaneous coronary intervention (PCI) and to identify the potential impact of glycometabolism on the predictive value of estimated RLP-C. METHODS The study assessed 2419 participants with NSTE-ACS undergoing PCI at Beijing Anzhen Hospital from January to December 2015. Estimated RLP-C was calculated as follows: total cholesterol (TC) minus low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C). The adverse events included all-cause death, non-fatal myocardial infarction (MI), and ischemia-driven revascularization. RESULTS Estimated RLP-C was prominently associated with adverse prognosis in the total population [hazard ratio (HR) 1.291 per 1-SD increase, 95% confidence interval (CI) 1.119-1.490, P < 0.001], independent of confounding risk factors. However, subgroup analysis showed that increasing estimated RLP-C was related to a higher risk of adverse events in the diabetic population only [HR 1.385 per 1-SD increase, 95% CI 1.183-1.620, P < 0.001]. Estimated RLP-C failed to be a significant determinant of adverse prognosis in non-diabetic and pre-diabetic subgroups. The addition of estimated RLP-C to a baseline model including traditional risk factors enhanced the predictive performance both in total and diabetic populations. CONCLUSIONS High estimated RLP-C level is a significant predictor for recurrent adverse events in patients with diabetes and NSTE-ACS treated with PCI.
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Beverage Consumption and Longitudinal Changes in Lipoprotein Concentrations and Incident Dyslipidemia in US Adults: The Framingham Heart Study.
Haslam, DE, Peloso, GM, Herman, MA, Dupuis, J, Lichtenstein, AH, Smith, CE, McKeown, NM
Journal of the American Heart Association. 2020;(5):e014083
Abstract
Background Limited data are available on the prospective relationship between beverage consumption and plasma lipid and lipoprotein concentrations. Two major sources of sugar in the US diet are sugar-sweetened beverages (SSBs) and 100% fruit juices. Low-calorie sweetened beverages are common replacements. Methods and Results Fasting plasma lipoprotein concentrations were measured in the FOS (Framingham Offspring Study) (1991-2014; N=3146) and Generation Three (2002-2001; N=3584) cohorts. Beverage intakes were estimated from food frequency questionnaires and grouped into 5 intake categories. Mixed-effect linear regression models were used to examine 4-year changes in lipoprotein measures, and Cox proportional hazard models were used to estimate hazard ratios for incident dyslipidemia, adjusting for potential confounding factors. We found that regular (>1 serving per day) versus low (<1 serving per month) SSB consumption was associated with a greater mean decrease in high-density lipoprotein cholesterol (β±standard error -1.6±0.4 mg/dL; Ptrend<0.0001) and increase in triglyceride (β±standard error: 4.4±2.2 mg/dL; Ptrend=0.003) concentrations. Long-term regular SSB consumers also had a higher incidence of high triglyceride (hazard ratio, 1.52; 95% CI, 1.03-2.25) compared with low consumers. Although recent regular low-calorie sweetened beverage consumers had a higher incidence of high non-high-density lipoprotein cholesterol (hazard ratio, 1.40; 95% CI, 1.17-1.69) and low-density lipoprotein cholesterol (hazard ratio, 1.27; 95% CI, 1.05-1.53) concentrations compared with low consumers, cumulative average intakes of low-calorie sweetened beverages were not associated with changes in non-high-density lipoprotein cholesterol, low-density lipoprotein cholesterol concentrations, or incident dyslipidemias. Conclusions SSB intake was associated with adverse changes in high-density lipoprotein cholesterol and triglyceride concentrations, along with a higher risk of incident dyslipidemia, suggesting that increased SSB consumption may contribute to the development of dyslipidemia.
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Remnant cholesterol as a risk factor for cardiovascular, cancer or other causes mortality: A competing risks analysis.
Bonfiglio, C, Leone, CM, Silveira, LVA, Guerra, R, Misciagna, G, Caruso, MG, Bruno, I, Buongiorno, C, Campanella, A, Guerra, VMB, et al
Nutrition, metabolism, and cardiovascular diseases : NMCD. 2020;(11):2093-2102
Abstract
BACKGROUND AND AIMS Cardiovascular diseases (CVDis) are leading causes of morbidity and mortality. Even after the introduction of pharmacological therapy to lower Cholesterol, there is still a residual risk that may be ascribed to remnant cholesterol (RC). We aimed, by analyzing two prospective cohort studies, to estimate the effect of RC on risk and hazard of cardiovascular deaths (CVDs), while accounting for competing risks such as cancer (CDs) and other-causes deaths (OCDs). METHODS AND RESULTS Cohorts were enrolled in 1992 and 2005. Personal data history was recorded. A fasting venous blood sample was obtained, and RC was calculated at baseline. Cause of Death was coded by using ICD-10th version. Follow-up ended on December 31, 2017. Flexible parametric competing-risks models were applied, with age at death as time-axis. In total, 5729 subjects were enrolled. There were 861 (15.1%) deaths: 234 CVDs (27.2%), 245 CDs (28.5%), 271 OCDs (31.5%) and 111 unknown causes of death (12.8%). RC exposure was a strong risk factor only for CVDs (Risk 2.54, 95% Confidence Interval 1.21; 5.34; Trend 1.26 (1.00; 1.58) for ≥1.29 mmol/L). CONCLUSIONS RC is a strong independent risk factor for cardiovascular mortality. Competing risk analysis is demonstrably a useful tool to disentangle associations among different competing events with a common risk factor.
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Triglyceride-Rich Lipoprotein Cholesterol, Small Dense LDL Cholesterol, and Incident Cardiovascular Disease.
Duran, EK, Aday, AW, Cook, NR, Buring, JE, Ridker, PM, Pradhan, AD
Journal of the American College of Cardiology. 2020;(17):2122-2135
Abstract
BACKGROUND Elevated triglyceride-rich lipoprotein (TRL) and small-dense low-density lipoprotein (sdLDL) particles are hallmarks of atherogenic dyslipidemia, and their cholesterol content is hypothesized to drive atherosclerotic risk. Prospective epidemiological data pertaining to cholesterol content of TRLs and sdLDL in primary prevention populations are mostly limited to coronary heart disease. OBJECTIVES The purpose of this study was to prospectively evaluate whether triglyceride-rich lipoprotein cholesterol (TRL-C) and small-dense low-density lipoprotein cholesterol (sdLDL-C) concentrations associate with composite and individual incident cardiovascular disease (CVD) outcomes including myocardial infarction (MI), ischemic stroke (IS), and peripheral artery disease (PAD). METHODS In a prospective case-cohort study within the Women's Health Study, TRL-C and sdLDL-C (mg/dl) were directly measured in baseline blood specimens of case subjects (n = 480) and the reference subcohort (n = 496). Risk associations were evaluated for total CVD (MI, IS, PAD, and CVD death), coronary and cerebrovascular disease (MI, IS, CVD death), and individual outcomes (MI, IS, and PAD). Models were adjusted for traditional risk factors, low-density lipoprotein cholesterol, and high-sensitivity C-reactive protein. RESULTS The risk of both composite outcomes significantly increased across quartiles of TRL-C and sdLDL-C. TRL-C was significantly associated with MI and PAD (MI hazard ratio [HR]Q4: 3.05 [95% confidence interval (CI): 1.46 to 6.39]; ptrend = 0.002; PAD HRQ4: 2.58 [95% CI: 1.18 to 5.63]; ptrend = 0.019), whereas sdLDL-C was significantly associated with MI alone (HRQ4: 3.71 [95% CI: 1.59 to 8.63]; ptrend < 0.001). Both markers weakly associated with IS. Association patterns were similar for continuous exposures and, for TRL-C, among subjects with low atherogenic particle concentrations (apolipoprotein B <100 mg/dl). CONCLUSIONS TRL-C strongly associates with future MI and PAD events, whereas sdLDL-C strongly associates with MI alone. These findings signal that the cholesterol content of TRLs and sdLDL influence atherogenesis independently of low-density lipoprotein cholesterol, and high sensitivity C-reactive protein, with potentially different potency across vascular beds. (Women's Health Study; NCT00000479).
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Remnant lipoproteins play an important role of in-stent restenosis in type 2 diabetes undergoing percutaneous coronary intervention: a single-centre observational cohort study.
Qin, Z, Zhou, K, Li, YP, Wang, JL, Cheng, WJ, Hu, CP, Shi, C, He, H, Zhou, YJ
Cardiovascular diabetology. 2019;(1):11
Abstract
BACKGROUND Increasing evidence has suggested that the presence of remnant lipoproteins is a significant risk factor for atherosclerosis. Remnant lipoproteins are lipoproteins that are rich in triglycerides (TGs), and the main components include very-low-density lipoprotein (VLDL) in the fasting state. Diabetic patients often have hypertriglyceridemia with elevated levels of VLDL cholesterol but normal levels of low-density lipoprotein cholesterol (LDL-C). The aim of the present study was to elucidate the potential role of remnant lipoproteins-induced atherosclerosis in the occurrence and development of in-stent restenosis (ISR) in diabetic patients with coronary artery disease. METHODS The present study enrolled 2312 patients with type 2 diabetes mellitus who underwent percutaneous coronary intervention from January 2013 to December 2014 and who were followed up by angiography. Patients were divided into two groups based on the presence or absence of ISR, and multivariate Cox's proportional hazards regression modelling showed that remnant-like particle cholesterol (RLP-C) was an independent risk factor for ISR. According to the receiver operating characteristic curve, the optimal cutoff point of the RLP-C was identified, and the patients were further divided into 2 groups. Propensity score matching analysis was performed, and 762 pairs were successfully matched. Log-rank tests were used to compare Kaplan-Meier curves for overall follow-up to assess ISR. RESULTS The multivariate Cox's proportional hazards regression analysis showed that RLP-C was independently associated with ISR, and the baseline RLP-C level at 0.505 mmol/L was identified as the optimal cutoff point to predict ISR. Patients were divided into 2 groups by RLP levels. After propensity score matching analysis, a total of 762 pairs matched patients were generated. Kaplan-Meier curves showed that the estimated cumulative rate of ISR was significantly higher in patients with RLP-C levels ≥ 0.505 mmol/L (log-rank P < 0.001; HR equal to 4.175, 95% CI = 3.045-5.723, P < 0.001) compared to patients with RLP-C levels < 0.505 mmol/L. CONCLUSIONS The present study emphasized the importance of remnant-like particle cholesterol in cardiovascular pathology in diabetic patients. Physicians should take measures to control RLP-C below the level of 0.505 mmol/L to better prevent of in-stent restenosis in diabetic patients.
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Triglyceride-Rich Lipoprotein Cholesterol and Risk of Cardiovascular Events Among Patients Receiving Statin Therapy in the TNT Trial.
Vallejo-Vaz, AJ, Fayyad, R, Boekholdt, SM, Hovingh, GK, Kastelein, JJ, Melamed, S, Barter, P, Waters, DD, Ray, KK
Circulation. 2018;(8):770-781
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Abstract
BACKGROUND Mendelian randomization data suggest that the genetic determinants of lifetime higher triglyceride-rich lipoprotein-cholesterol (TRL-C) are causally related to cardiovascular disease and therefore a potential therapeutic target. The relevance of TRL-C among patients receiving statins is unknown. We assessed the relationship between TRL-C and cardiovascular risk, and whether this risk was modifiable among patients receiving statins in the TNT trial (Treating to New Targets). METHODS Patients with coronary heart disease and low-density lipoprotein cholesterol (LDL-C) 130 to 250 mg/dL entered an 8-week run-in phase with atorvastatin 10 mg/d (ATV10). After this period, participants with LDL-C <130 mg/dL entered the randomized phase with ATV10 (n=5006) versus atorvastatin 80 mg/d (ATV80, n=4995). The primary end point was coronary heart disease death, nonfatal myocardial infarction, resuscitated cardiac arrest, or stroke (major adverse cardiovascular events [MACE]). TRL-C was calculated as total cholesterol minus high-density lipoprotein cholesterol minus LDL-C. The effect of atorvastatin on TRL-C was assessed during the run-in phase (ATV10) and randomized phase (ATV80 versus ATV10). The risk of MACE was assessed across quintiles (Q) of baseline TRL-C (and, for comparison, by baseline triglycerides and non-high-density lipoprotein cholesterol) during the randomized period. Last, the association between TRL-C changes with atorvastatin and cardiovascular risk was assessed by multivariate Cox regression. RESULTS ATV10 reduced TRL-C 10.7% from an initial TRL-C of 33.9±16.6 mg/dL. ATV80 led to an additional 15.4% reduction. Cardiovascular risk factors positively correlated with TRL-C. Among patients receiving ATV10, higher TRL-C was associated with higher 5-year MACE rates (Q1=9.7%, Q5=13.8%; hazard ratio Q5-versus-Q1, 1.48; 95% confidence interval, 1.15-1.92; P-trend<0.0001). ATV80 (versus ATV10) did not significantly alter the risk of MACE in Q1-Q2, but significantly reduced risk in Q3-Q5 (relative risk reduction, 29%-41%; all P<0.0250), with evidence of effect modification ( P-homogeneity=0.0053); results were consistent for triglycerides ( P-homogeneity=0.0101) and directionally similar for non-high-density lipoprotein cholesterol ( P-homogeneity=0.1387). Last, in adjusted analyses, a 1 SD percentage reduction in TRL-C with atorvastatin resulted in a significant lower risk of MACE (hazard ratio, 0.93; 95% confidence interval, 0.86-1.00; P=0.0482) independent of the reduction in LDL-C and of similar magnitude to that per 1 SD lowering in LDL-C (hazard ratio, 0.89; 95% confidence interval, 0.83-0.95; P=0.0008). CONCLUSIONS The present post hoc analysis from TNT shows that increased TRL-C levels are associated with an increased cardiovascular risk and provides evidence for the cardiovascular benefit of lipid lowering with statins among patients who have coronary heart disease with high TRL-C. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov . Unique identifier: NCT00327691.
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The relationship between migraine and lipid sub-fractions among individuals without cardiovascular disease: A cross-sectional evaluation in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil).
Goulart, AC, Lotufo, PA, Santos, IS, Bittencourt, MS, Santos, RD, Blaha, MJ, Jones, S, Toth, PP, Kulkarni, K, Benseñor, IM
Cephalalgia : an international journal of headache. 2018;(3):528-542
Abstract
Introduction Recent studies have explored the relationship between dyslipidemia and migraine in a cardiovascular context. Thus, we aimed to evaluate the possible association between lipids, lipoprotein subfractions and migraine according to aura symptoms in the Brazilian Longitudinal Study of Adult Health (ELSA-Brasil). Methods 1,560 women and 1,595 men, without CVD or lipid disorders requiring medication, underwent a baseline clinical assessment. Total-cholesterol and its sub-fractions (LDL, VLDL and HDL subclass cholesterol); triglycerides and triglyceride-rich lipoprotein cholesterol [TRL-C (VLDL1+2-C VLDL3-C + IDL-C)] were determined by vertical auto profile (VAP). We also calculated logarithmic LDL density ratio [LLDR = ln ((LDL3-C + LDL4-C)/(LDL1-C + LDL2-C))], T-Chol/HDL-C and triglycerides/HDL-C ratios. Odds ratios (OR) with 95% confidence intervals (CI) were obtained to evaluate the relationship between lipids tertiles and migraine for both sexes. Results Main findings revealed positive associations between migraine without aura (MO) and the highest tertiles of VLDL-C (OR, 1.61; 95%CI, 1.07-2.40) and TRL-C (OR, 1.55; 95% CI, 1.03-2.34) in women. In men, the highest tertile of VLDL3-C (OR, 3.87; 95%CI, 1.23-12.19) was positively associated with MO, as well. Conclusions In middle-aged participants without CVD or lipid disorders requiring medication, the worst lipid profile was determined by the highest levels of TRL-C and their cholesterol-rich remnants in migraineurs without aura for both sexes.
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Metabolic Syndrome Modulates Association between Endothelial Lipase and Lipid/Lipoprotein Plasma Levels in Acute Heart Failure Patients.
Potočnjak, I, Trbušić, M, Terešak, SD, Radulović, B, Pregartner, G, Berghold, A, Tiran, B, Marsche, G, Degoricija, V, Frank, S
Scientific reports. 2017;(1):1165
Abstract
We hypothesised that the established association of endothelial lipase (EL) plasma levels with atherogenic lipid profile is altered in acute heart failure (AHF) and additionally affected by overlapping metabolic syndrome (MetS). We examined the association of EL plasma levels and lipid/lipoprotein plasma levels in AHF patients without and with overlapping MetS. The study was performed as a single-centre, observational study on 152 AHF patients, out of which 85 had overlapping MetS. In the no-MetS group, EL plasma levels were significantly positively correlated with plasma levels of atherogenic lipids/lipoproteins, including total cholesterol, low-density lipoprotein (LDL)-cholesterol, total LDL particles and triglycerides, but also with plasma levels of antiatherogenic high-density lipoprotein (HDL)-cholesterol, total HDL particles and small HDL particles. In the MetS group, EL plasma levels were positively correlated with triglyceride and small LDL-particle levels, and significantly negatively correlated with plasma levels of large HDL particles as well as with LDL- and HDL-particle size, respectively. EL- and lipid/lipoprotein- plasma levels were different in the no-MetS patients, compared to MetS patients. The association of EL with atherogenic lipid profile is altered in AHF and additionally modified by MetS, which strongly modulates EL- and lipid/lipoprotein-plasma levels in AHF.