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Association of Serum Low-Density Lipoprotein, High-Density Lipoprotein, and Total Cholesterol With Development of Knee Osteoarthritis.
Schwager, JL, Nevitt, MC, Torner, J, Lewis, CE, Matthan, NR, Wang, N, Sun, X, Lichtenstein, AH, Felson, D, ,
Arthritis care & research. 2022;(2):274-280
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Abstract
OBJECTIVE Studies suggest an association between elevated total serum cholesterol, particularly low-density lipoprotein (LDL), and osteoarthritis (OA). The present study was undertaken to evaluate the association between total cholesterol, LDL, and high-density lipoprotein (HDL) and risk of knee OA. METHODS We studied participants from the Multicenter Osteoarthritis study (MOST) cohort at risk of developing knee OA. From baseline through 7 years, repeated knee radiographs and magnetic resonance images (MRIs) were obtained, and knee symptoms were queried. From baseline fasting blood samples, lipids and lipoproteins were analyzed using standard assays. After excluding participants with baseline OA, we defined 2 sets of patients: those developing radiographic OA, and those developing symptomatic OA (knee pain and radiographic OA). Controls did not develop these outcomes. Additionally, we examined worsening of cartilage loss and synovitis on MRI and of knee pain using the Western Ontario and McMaster Universities Osteoarthritis Index scale. We carried out logistic regression adjusting for age, sex, body mass index, education, baseline pain, and depressive symptoms, testing total cholesterol and lipoproteins as continuous measures, and we performed sensitivity analyses examining whether commonly used thresholds for high cholesterol, LDL, or low HDL increased risk. RESULTS We studied 337 patients with incident symptomatic OA and 283 patients with incident radiographic OA. The mean age at baseline was 62 years (55% women). Neither total cholesterol, LDL, nor HDL showed a significant association with radiographic or symptomatic OA. Additionally, we found no association of these lipid measures with cartilage loss, worsening synovitis, or worsening knee pain. CONCLUSION Our data do not support an association between total cholesterol, LDL, or HDL with OA outcomes.
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High-Density Lipoprotein Cholesterol and Cardiovascular Events in Patients with Stable Coronary Artery Disease Treated with Statins: An Observation from the REAL-CAD Study.
Omote, K, Yokota, I, Nagai, T, Sakuma, I, Nakagawa, Y, Kamiya, K, Iwata, H, Miyauchi, K, Ozaki, Y, Hibi, K, et al
Journal of atherosclerosis and thrombosis. 2022;(1):50-68
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AIM: The association between high-density lipoprotein cholesterol (HDL-C) level after statin therapy and cardiovascular events in patients with stable coronary artery disease (CAD) remains unclear. Thus, in this study, we sought to determine how HDL-C level after statin therapy is associated with cardiovascular events in stable CAD patients. METHODS From the REAL-CAD study which had shown the favorable prognostic effect of high-dose pitavastatin in stable CAD patients with low-density lipoprotein cholesterol (LDL-C) <120 mg/dL, 9,221 patients with HDL-C data at baseline and 6 months, no occurrence of primary outcome at 6 months, and reported non-adherence for pitavastatin, were examined. The primary outcome was a composite of cardiovascular death, non-fatal myocardial infarction, non-fatal ischemic stroke, or unstable angina requiring emergent admission after 6 months of randomization. Absolute difference and ratio of HDL-C levels were defined as (those at 6 months-at baseline) and (absolute difference/baseline)×100, respectively. RESULTS During a median follow-up period of 4.0 (IQR 3.2-4.7) years, the primary outcome occurred in 417 (4.5%) patients. The adjusted risk of all HDL-C-related variables (baseline value, 6-month value, absolute, and relative changes) for the primary outcome was not significant (hazard ratio [HR] 0.99, 95% confidence interval [CI] 0.91-1.08, HR 1.03, 95% CI 0.94-1.12, HR 1.05, 95% CI 0.98-1.12, and HR 1.08, 95% CI 0.94-1.24, respectively). Furthermore, adjusted HRs of all HDL-C-related variables remained non-significant for the primary outcome regardless of on-treatment LDL-C level at 6 months. CONCLUSIONS After statin therapy with modestly controlled LDL-C, HDL-C level has little prognostic value in patients with stable CAD.
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Non-High-Density Lipoprotein Cholesterol Predicts Adverse Outcomes in Acute Ischemic Stroke.
Wang, G, Jing, J, Wang, A, Zhang, X, Zhao, X, Li, Z, Wang, C, Li, H, Liu, L, Wang, Y, et al
Stroke. 2021;(6):2035-2042
Abstract
BACKGROUND AND PURPOSE Non–high-density lipoprotein cholesterol (non–HDL-C) was significantly related to adverse outcomes in patients with cardiovascular disease. We aim to investigate the associations of non-HDL-C and adverse outcomes in acute ischemic stroke. METHODS Among 19 604 patients with acute ischemic stroke admitted to the China National Stroke Registry II, 16 113 with both total cholesterol and HDL-C were analyzed. Patients were classified into 5 groups by quintiles of non-HDL-C. The outcomes included recurrent ischemic stroke, intracranial hemorrhage, and all-cause death within 1 year. The relationship of non-HDL-C with the risk of outcomes was analyzed by Cox regression models. RESULTS Among the 16 113 patients, the median (interquartile range) of non-HDL-C was 3.41 (2.78–4.10) mmol/L. After adjustment for confounding variables, patients in the top quintile of non-HDL-C were associated with higher risk of recurrent ischemic stroke within 1 year (adjusted hazard ratio, 1.46 [95% CI, 1.20–1.77]), compared with those in the third quintile. Patients in the bottom and top quintile of non-HDL-C were associated with higher risk of all-cause death within 1 year (adjusted hazard ratio, 1.22 [95% CI, 1.01–1.47] and adjusted hazard ratio, 1.40 [95% CI, 1.15–1.70], respectively), compared with those in the third quintile. However, non-HDL-C levels were not significantly predictive in intracranial hemorrhage. CONCLUSIONS Non-HDL-C may be a qualified predictor for recurrent ischemic stroke and all-cause death within 1 year in patients with acute ischemic stroke.
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Association of Serum Alkaline Phosphatase with the TG/HDL Ratio and TyG Index in Korean Adults.
Son, DH, Ha, HS, Lee, YJ
Biomolecules. 2021;(6)
Abstract
Alkaline phosphatase (ALP) has long been considered a marker of hepatobiliary and bone disorders, but recent studies have shown that increased ALP activity is correlated with various cardio-metabolic diseases. Thus, we investigated the association of serum ALP level with surrogate markers of insulin resistance such as triglyceride to high-density lipoprotein cholesterol ratio (TG/HDL-C ratio) and triglyceride and glucose (TyG) index in the general population. The study included 12,868 men and women aged 19 years and older. Participants were categorized into four groups based on serum ALP level (U/L) as follows: Q1: 55-190 U/L, Q2: 191-224 U/L, Q3: 225-265 U/L, and Q4: 266-923 U/L for men, Q1: 48-161 U/L, Q2: 162-198 U/L, Q3: 199-245 U/L, Q4: 246-790 U/L for women. The insulin resistance cut-off levels were defined corresponding to the 75th percentile of the TyG index and TG/HDL-C ratio in the current samples. Odds ratios (ORs) with 95% confidence intervals (CIs) of insulin resistance according to quartile of serum ALP level were calculated using weighted multivariate logistic regression analysis. Compared with Q1, the adjusted OR (95% CI) for insulin resistance of the Q4 serum ALP group was 1.517 (1.234-1.866) in men and 1.881 (1.399-2.528) in women using the TG/HDL-C ratio and 1.374 (1.093-1.728) in men and 2.047 (1.468-2.855) in women using the TyG index after adjusting for confounding variables. Serum ALP levels are independently and positively associated with surrogate markers of insulin resistance in Korean adults.
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Atherogenic index of plasma is associated with major adverse cardiovascular events in patients with type 2 diabetes mellitus.
Fu, L, Zhou, Y, Sun, J, Zhu, Z, Xing, Z, Zhou, S, Wang, Y, Tai, S
Cardiovascular diabetology. 2021;(1):201
Abstract
BACKGROUND Previous studies reported the prognostic value of the atherogenic index of plasma (AIP) in the course of atherosclerosis and other cardiovascular diseases (CVDs). Still, the predictive utility of the AIP is unknown among patients with type 2 diabetes mellitus (T2DM). METHODS This was a secondary analysis of the Action to Control Cardiovascular Risk in Diabetes (ACCORD) study, which randomized 10,251 patients with long-lasting T2DM. ROC curve analysis was used to determine an optimal threshold for AIP, and the study population was divided into high and low AIP groups. Univariable and multivariable Cox proportional hazards regression analyses were used to determine the association between AIP and primary (major adverse cardiovascular events [MACEs], including nonfatal myocardial infarction, nonfatal stroke, and/or death from cardiovascular causes) and secondary outcomes (all-cause mortality). Stratified analyses were performed to control for the confounding factors. RESULTS AIP was an independent risk factor for the prognosis of T2DM (HR = 1.309; 95% CI 1.084-1.581; P = 0.005). The threshold for AIP was determined to be 0.34 in the study population. After adjustments for confounding factors, multivariable analysis showed that AIP was associated with the risk of MACEs (Model 1: HR = 1.333, 95% CI 1.205-1.474, P < 0.001; Model 2: HR = 1.171, 95% CI 1.030-1.333, P = 0.016; Model 3: HR = 1.194, 95% CI 1.049-1.360, P = 0.007), all-cause mortality (Model 1: HR = 1.184, 95% CI 1.077-1.303, P < 0.001), cardiovascular death (Model 1: HR = 1.422, 95% CI 1.201-1.683, P < 0.001; Model 3: HR = 1.264, 95% CI 1.015-1.573, P = 0.036), and nonfatal myocardial infarction (Model 1: HR = 1.447, 95% CI 1.255-1.669, P < 0.001; Model 2: HR = 1.252, 95% CI 1.045-1.499, P = 0.015; Model 3: HR = 1.284, 95% CI 1.071-1.539, P = 0.007). Subgroup stratified analyses showed that AIP might interact with sex, a classical risk factor of cardiovascular events. CONCLUSIONS This study showed that AIP might be a strong biomarker that could be used to predict the risk of cardiovascular events in patients with T2DM. TRIAL REGISTRATION URL: http://www.clinicaltrials.gov . Unique identifier: NCT00000620.
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Inflammation Alters Relationship Between High-Density Lipoprotein Cholesterol and Cardiovascular Risk in Patients With Chronic Kidney Disease: Results From KNOW-CKD.
Kim, JY, Park, JT, Kim, HW, Chang, TI, Kang, EW, Ahn, C, Oh, KH, Lee, J, Chung, W, Kim, YS, et al
Journal of the American Heart Association. 2021;(16):e021731
Abstract
Background The function of high-density lipoprotein can change from protective to proatherosclerotic under inflammatory conditions. Herein, we studied whether inflammation could modify the relationship between high-density lipoprotein level and risk of adverse outcomes in patients with chronic kidney disease . Methods and Results In total, 1864 patients from the prospective KNOW-CKD (Korean Cohort Study for Outcome in Patients With Chronic Kidney Disease) were enrolled. The main predictor was high-density lipoprotein cholesterol (HDL-C) level. Presence of inflammation was defined by hs-CRP (high-sensitivity C-reactive protein) level of ≥1.0 mg/L. The primary outcome was extended major adverse cardiovascular events. During 9231.2 person-years of follow-up, overall incidence of the primary outcome was 15.8 per 1000 person-years. In multivariable Cox analysis after adjusting for confounders, HDL-C level was not associated with the primary outcome. There was a significant interaction between the inflammatory status and HDL-C for risk of extended major adverse cardiovascular events (P=0.003). In patients without inflammation, the hazard ratios (HRs) (95% CIs) for HDL-C levels <40, 50 to 59, and ≥60 mg/dL were 1.10 (0.50-1.82), 0.95 (0.50-1.82), and 0.42 (0.19-0.95), respectively, compared with HDL-C of 40 to 49 mg/dL. However, the significant association for HDL-C ≥60 mg/dL was not seen after Bonferroni correction. In patients with inflammation, we observed a trend toward increased risk of extended major adverse cardiovascular events in higher HDL-C groups (HRs [95% CIs], 0.73 [0.37-1.43], 1.24 [0.59-2.61], and 1.56 [0.71-3.45], respectively), but without statistical significance. Conclusions The association between HDL-C level and adverse cardiovascular outcomes showed reverse trends based on inflammation status in Korean patients with chronic kidney disease. Registration URL: https://www.clinicaltrials.gov; Unique identifier: NCT01630486.
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Effect of Probucol and/or Cilostazol on Carotid Intima Media Thickness in Patients with Coronary Heart Disease: A Randomized, Multicenter, Multinational Study.
Kang, HJ, Kim, MH, Sung, J, Kim, SH, Kim, CH, Park, JE, Ge, J, Oh, BH, ,
Journal of atherosclerosis and thrombosis. 2021;(2):124-136
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AIM: In a prospective randomized multinational open blinded endpoint study, the long-term effects of probucol or probucol and cilostazol with statin on carotid mean intima media thickness (IMT) were evaluated for the first time. METHODS Hypercholesterolemic patients with coronary artery disease were randomized to three groups and received study drugs for 3 years: the control with statin alone; the probucol group with statin and probucol; and the combo group with statin, probucol, and cilostazol. Primary efficacy endpoint was changes of mean carotid IMT at 3 years. Biomarkers, major adverse cerebro-cardiovascular events (MACCEs) and safety were secondary endpoints. RESULTS Two hundred eighty-one patients were randomized into three groups. All three groups showed significant regression of carotid IMT at 3 years compared with baseline. Decrease in mean carotid IMT was significantly greater in the combo group than in the control group at 1 year. However, there were no significant differences in changes of mean carotid IMT between groups at 3 years (control; -0.12±0.36 mm vs. probucol; -0.11 ±0.32 mm vs. combo; -0.16±0.38 mm). MACCEs were frequent in the control group, but the difference was not significant (control; 10.8% vs. probucol; 4.4% vs. combo; 6.9%, p=0.35). Probucol and cilostazol were well tolerated in long-term treatment without serious drug-related adverse reactions. CONCLUSION Probucol or probucol and cilostazol with statin did not reduce carotid IMT in comparison with statin alone in this study. However, the clinical outcome of probucol-based treatment with current standard statin treatment may need further studies.
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Relationship between serum lipid levels and ischemic stroke in patients with atrial fibrillation: a nested case-control study based on the China Atrial Fibrillation Registry.
Li, F, Du, X, He, L, Jiang, C, Xia, S, Ma, C, Dong, J
BMC cardiovascular disorders. 2021;(1):424
Abstract
BACKGROUND Atrial fibrillation (AF) is an important risk factor for acute ischemic stroke. METHODS A nested case-control study was conducted among patients diagnosed with AF, whose information was acquired from the prospective China Atrial Fibrillation Registry (China-AF), from August 2011 to December 2018. RESULTS This study compared patients with stroke group (n = 145) with a matched control group (n = 577). Demographic data were similar except for body mass index (BMI), diastolic blood pressure (DBP) which were higher, and new oral anticoagulant (NOAC) treatment rate which was lower in the stroke group (all P < 0.05). Baseline median [IQR] levels of including triglyceride (TG) were higher in the stroke group (21.96 [16.74, 21.52], mg/dL) than the control group (19.62 [14.76, 27.36], mg/dL) (P = 0.012), while the total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) were similar between the two groups. Elevated TG and HDL-C were positively associated with ischemic stroke (OR 1.01, 95% CI 1.00-1.02, P = 0.032; OR 1.03, 95% CI 1.00-1.05, P = 0.025), after adjustment for BMI, systolic blood pressure, DBP, CHA2DS2-VASc score, HAS-BLED score, NOAC, LDL-C and HDL-C. However, NOAC (OR 0.20, 95% CI 0.05-0.84, P = 0.029) could decrease the likelihood of ischemic stroke in patients with AF. In subgroup analysis, higher TG level remained significantly associated with ischemic stroke for AF patients without a history of smoking (OR 1.26, 95% CI 1.02-1.55, P = 0.028). CONCLUSION Higher level of TG and HDL-C were positively associated with ischemic stroke in patients with AF.
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Probucol Trial for Secondary Prevention of Atherosclerotic Events in Patients with Coronary Heart Disease (PROSPECTIVE).
Yamashita, S, Arai, H, Bujo, H, Masuda, D, Ohama, T, Ishibashi, T, Yanagi, K, Doi, Y, Nakagawa, S, Yamashiro, K, et al
Journal of atherosclerosis and thrombosis. 2021;(2):103-123
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AIMS: Although intensive statin therapy reduced cardiovascular risks, cardiovascular events have not been completely prevented. Probucol is a potent antioxidant and reduces tendon xanthomas in familial hypercholesterolemia patients despite reduction of high-density lipoprotein (HDL)-cholesterol (HDL-C). We investigated whether probucol can reduce cardiovascular events on top of conventional lipid-lowering therapy in patients with coronary heart disease (CHD). METHODS PROSPECTIVE is a multicenter, randomized, prospective study that recruited 876 Japanese patients with CHD and dyslipidemia with a low-density lipoprotein (LDL)-cholesterol (LDL-C) level of ≥ 140 mg/dL without medication or those treated with lipid-lowering drugs. Lipid-lowering agents were administered during the study period in the control group (n=438), and probucol 500 mg/day was added to lipid-lowering therapy in the probucol group (n=438). Patients were randomly assigned to two treatment groups by adjusting the LDL-C level and presence of diabetes and hypertension and followed up for more than 3 years. The primary end point was a composite of cerebrovascular and cardiovascular events (cardiovascular disease death including sudden death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for unstable angina, hospitalization for heart failure, or coronary revascularization). The secondary end point was carotid intima-media thickness in a subset of patients. RESULTS The incidence of the primary end point showed a trend to be lower in the probucol group compared with that in the control group despite reduced HDL-C without serious adverse events. Anti-atherogenic effects of probucol may be attributed to its potent antioxidative function and enhancement of reverse cholesterol transport. CONCLUSION Since there was no statistical significance between the probucol and control groups despite a marked reduction of HDL-C, further studies on the clinical outcomes of probucol on top of conventional therapy may be necessary in the future (UMIN000003307).
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Independent association of atherogenic dyslipidaemia with all-cause mortality in individuals with type 2 diabetes and modifying effect of gender: a prospective cohort study.
Orsi, E, Penno, G, Solini, A, Bonora, E, Fondelli, C, Trevisan, R, Vedovato, M, Cavalot, F, Morano, S, Baroni, MG, et al
Cardiovascular diabetology. 2021;(1):28
Abstract
BACKGROUND Atherogenic dyslipidaemia has been implicated in the residual risk for cardiovascular morbidity and mortality, which remains despite attainment of LDL cholesterol goals especially in individuals with type 2 diabetes. However, its relationship with all-cause death has not been sufficiently explored. This analysis evaluated the independent association of increased triglycerides and triglyceride:HDL cholesterol ratio (TG:HDL) and decreased HDL cholesterol with total mortality and the possible modifying effect of gender in a large cohort of patients with type 2 diabetes. METHODS This observational, prospective study enrolled 15,773 patients in 19 Diabetes Clinics throughout Italy in the years 2006-2008. Triglycerides and total and HDL cholesterol were measured by colorimetric enzymatic methods. Vital status was retrieved on 31 October 2015 for 15,656 patients (99.3%). Participants were stratified by quartiles of triglycerides, HDL cholesterol, and TG:HDL. RESULTS There were 3,602 deaths over a follow-up 7.42 ± 2.05 years (31.0 × 1000 person-years). In the unadjusted analyses, the highest TG:HDL (but not triglyceride) and the lowest HDL cholesterol quartile were associated with increased death rate and mortality risk. When sequentially adjusting for confounders, including total, LDL, or non-HDL cholesterol and lipid-lowering treatment, mortality risk was significantly higher in the highest triglyceride (hazard ratio 1.167 [95% confidence interval 1.055-1.291], p = 0.003) and TG:HDL (1.192 [1.082-1.314], p < 0.0001) and the lowest HDL cholesterol (1.232 [1.117-1.360], p < 0.0001) quartile, though the association of triglycerides and HDL cholesterol disappeared after further adjustment for each other. Interaction with gender was significant only for HDL cholesterol (p = 0.0009). The relationship with death was stronger for triglycerides in males and HDL cholesterol in females, with these associations remaining significant even after adjustment for HDL cholesterol (1.161 [1.019-1.324], p = 0.025, for the highest vs the lowest triglyceride quartile) and triglycerides (1.366 [1.176-1.587], p < 0.0001, for the lowest vs the highest HDL cholesterol quartile). CONCLUSIONS In patients with type 2 diabetes, higher triglycerides and TG:HDL and lower HDL cholesterol were independently associated with increased all-cause mortality, with a modifying effect of gender for triglycerides and HDL cholesterol. These data suggest that atherogenic dyslipidaemia, especially TG:HDL, may serve as predictor of all-cause death in these individuals. Trial registration ClinicalTrials.gov, NCT00715481, 15 July, 2008.