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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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Abstract
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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Effect of a dietary intervention including minimal and unprocessed foods, high in natural saturated fats, on the lipid profile of children, pooled evidence from randomized controlled trials and a cohort study.
Hendriksen, RB, van der Gaag, EJ
PloS one. 2022;(1):e0261446
Abstract
AIM: To study the possible effects of a dietary intervention with minimal and unprocessed foods, high in natural saturated fats on the lipid profile and body mass index of children. METHOD This study combines three intervention studies; one non-randomized retrospective cohort study and two randomized controlled trials, to a pooled analysis. The intervention group received a dietary intervention of minimal and unprocessed foods for three to six months, consisting of five times per week green vegetables, three times per week beef, daily 200-300 mL whole cow's milk (3.4% fat) and whole dairy butter (80% fat) on each slice of bread. The control group continued their usual dietary habits. Raw data of the three intervention studies where combined into one single dataset for data analysis, using mixed effects analysis of covariance to test the effects of the dietary advice on the main study outcomes, which are measurements of the lipid profile. RESULTS In total, 267 children aged 1 to 16 years were followed. 135 children were included in the intervention group and 139 children in the control group. Characteristics (age, gender and follow-up period) were equally distributed between the groups at baseline. In the intervention group HDL-cholesterol increased significantly from 1.22 mmol/L, 95% confidence interval (CI) 1.14-1.32 to 1.42 mmol/L 95% CI 1.30-1.65 (p = 0.007). The increase over time in HDL cholesterol in the intervention group was significantly different compared to the increase in the control group (from 1.26 mmol/L, 95% CI 1.19-1.35, to 1.30 mmol/L, 95% CI 1.26-1.37) (p = 0.04). Due to the increased HDL concentration in the intervention group, the total cholesterol/HDL cholesterol ratio decreased significantly from 3.70 mmol/L, 95% CI 3.38-3.87, to 3.25 mmol/L, 95% CI 2.96-3.31 (p = 0.05). CONCLUSION Consumption of minimal and unprocessed foods (high in natural saturated fats) has favourable effects on HDL cholesterol in children. Therefore, this dietary advice can safely be recommended to children.
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Virgin Olive Oil Phenolic Compounds Modulate the HDL Lipidome in Hypercholesterolaemic Subjects: A Lipidomic Analysis of the VOHF Study.
Fernández-Castillejo, S, Pedret, A, Catalán, Ú, Valls, RM, Farràs, M, Rubió, L, Castañer, O, Macià, A, Fitó, M, Motilva, MJ, et al
Molecular nutrition & food research. 2021;(9):e2001192
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Abstract
SCOPE The lipidomic analysis of high-density lipoprotein (HDL) could be useful to identify new biomarkers of HDL function. METHODS AND RESULTS A randomized, controlled, double-blind, crossover trial (33 hypercholesterolaemic subjects) is performed with a control virgin olive oil (VOO), VOO enriched with its own phenolic compounds (FVOO), or VOO enriched with additional phenolic compounds from thyme (FVOOT) for 3 weeks. HDL lipidomic analyses are performed using the Lipidyzer platform. VOO and FVOO intake increase monounsaturated-fatty acids (FAs) and decrease saturated and polyunsaturated FAs in triacylglyceride (TAG) species, among others species. In contrast, FVOOT intake does not induce these FAs changes. The decrease in TAG52:3(FA16:0) after VOO intake and the decrease in TAG52:5(FA18:2) after FVOO intake are inversely associated with changes in HDL resistance to oxidation. After FVOO intake, the decrease in TAG54:6(FA18:2) in HDL is inversely associated with changes in HDL cholesterol efflux capacity. CONCLUSION VOO and FVOO consumption has an impact on the HDL lipidome, in particular TAG species. Although TAGs are minor components of HDL mass, the observed changes in TAG modulated HDL functionality towards a cardioprotective mode. The assessment of the HDL lipidome is a valuable approach to identify and characterize new biomarkers of HDL function.
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Twelve weeks' treatment with a polyphenol-rich seaweed extract increased HDL cholesterol with no change in other biomarkers of chronic disease risk in overweight adults: A placebo-controlled randomized trial.
Murray, M, Dordevic, AL, Cox, K, Scholey, A, Ryan, L, Bonham, MP
The Journal of nutritional biochemistry. 2021;:108777
Abstract
Cardiovascular diseases (CVD) are the leading global cause of death. Strategies to reduce CVD risk are urgently needed. Polyphenols represent a class of bioactive compounds with potential to moderate biochemical risk factors for CVD (cholesterol, triglycerides, glucose, and inflammation). This double-blind, placebo-controlled, randomized parallel-groups trial investigated the effect of a polyphenol-rich seaweed (Fucus vesiculosus) extract on biochemical markers of CVD risk. Thirty-four overweight and obese adults (21 female, 13 male) with elevated low-density lipoprotein cholesterol (>2.0 mmol/L) were randomized to either the seaweed extract (2000 mg/d) or placebo for twelve weeks. Fasting blood samples were collected at baseline, week six and week twelve to assess biochemical markers. Tests of cognitive performance and mood were performed at baseline, week six and week twelve. A 9.5% (-2.3, 12.9) increase in high-density lipoprotein (HDL) cholesterol was identified following the seaweed extract (baseline: mean (SD) 1.28 (0.23) mmol/L, week 12: 1.35 (0.24) mmol/L) which was different to placebo (baseline: 1.38 (0.54) mmol/L, week 12: 1.35 (0.59) mmol/L) (P=.045). No changes were identified in low-density lipoprotein cholesterol, total cholesterol, triglycerides, glucose, insulin, interleukin (IL)-2, IL-6, IL-8, IL-10, or tumour necrosis factor-alpha levels in the blood, or in cognitive performance or mood between the treatment and placebo groups. Despite the small increase observed in HDL cholesterol, the polyphenol-rich seaweed extract did not change CVD risk factors in adults with high fasting lipids. A larger sample size would be required to confirm the clinical relevance of the changes in HDL cholesterol.
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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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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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Effects of Living High-Training Low and High on Body Composition and Metabolic Risk Markers in Overweight and Obese Females.
Gao, H, Xu, J, Zhang, L, Lu, Y, Gao, B, Feng, L
BioMed research international. 2020;:3279710
Abstract
This study examined the effects of 4 weeks of living high-training low and high (LHTLH) under moderate hypoxia on body weight, body composition, and metabolic risk markers of overweight and obese females. Nineteen healthy overweight or obese females participated in this study. Participants were assigned to the normoxic training group (NG) or the LHTLH group (HG). The NG participants lived and trained at sea level. The HG participants stayed for approximately 10 hours in a simulated 2300 m normobaric state of hypoxia for six days a week and trained for 2 hours 3 times a week under the same simulated hypoxia. The interventions lasted for 4 weeks. All groups underwent dietary restriction based on resting metabolic rate. The heart rate of the participants was monitored every ten minutes during exercise to ensure that the intensity was in the aerobic range. Compared with the preintervention values, body weight decreased significantly in both the NG and the HG (-8.81 ± 2.09% and -9.09 ± 1.15%, respectively). The fat mass of the arm, leg, trunk, and whole body showed significant reductions in both the NG and the HG, but no significant interaction effect was observed. The percentage of lean soft tissue mass loss in the total body weight loss tended to be lower in the HG (27.61% versus 15.94%, P=0.085). Between the NG and the HG, significant interaction effects of serum total cholesterol (-12.66 ± 9.09% versus -0.05 ± 13.36%,) and apolipoprotein A1 (-13.66 ± 3.61% versus -5.32 ± 11.07%, P=0.042) were observed. A slight increase in serum high-density lipoprotein cholesterol (HDL-C) was observed in the HG (1.12 ± 12.34%) but a decrease was observed in the NG (-11.36 ± 18.91%). The interaction effect of HDL-C between NG and HG exhibited a significant trend (P=0.055). No added effects on serum triglycerides (TGs), low-density lipoprotein cholesterol (LDL-C), or APO-B were observed after 4 weeks of LHTLH. In conclusion, 4 weeks of LHTLH combined with dietary restriction could effectively reduce the body weight and body fat mass of overweight and obese females. Compared with training and sleeping under normoxia, no additive benefit of LHTLH on the loss of body weight and body fat mass was exhibited. However, LHTLH may help to relieve the loss of lean soft tissue mass and serum HDL-C.
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Lower levels of high-density lipoprotein cholesterol are associated with increased cardiovascular events in patients with acute coronary syndrome.
Nakazawa, M, Arashi, H, Yamaguchi, J, Ogawa, H, Hagiwara, N
Atherosclerosis. 2020;:21-28
Abstract
BACKGROUND AND AIMS This study aimed to elucidate whether high-density lipoprotein cholesterol (HDL-C) at 3-month follow-up for patients receiving contemporary lipid-lowering therapy after acute coronary syndrome (ACS) could predict cardiac events. METHODS The HIJ-PROPER study was a multicenter, prospective, randomized trial comparing intensive lipid-lowering therapy (pitavastatin + ezetimibe) and conventional lipid-lowering therapy (pitavastatin monotherapy) after ACS. The entire cohort was divided into three groups according to tertiles of HDL-C levels at 3-month follow-up (Group 1, HDL-C ≤43 mg/dL; Group 2, HDL-C >43, <53.6 mg/dL; Group 3; HDL-C ≥53.6 mg/dL). Baseline characteristics and incidence of the primary endpoint (a composite of all-cause death, non-fatal myocardial infarction, non-fatal stroke, unstable angina pectoris, or ischemia-driven revascularization) were compared among the three groups. RESULTS The primary endpoint event occurred in 34.8%, 30.1%, and 24.6% of patients in Groups 1, 2, and 3, respectively, and its incidence was significantly higher in Group 1 than in Group 3 (hazard ratio [HR], 1.5; 95% confidence interval [CI], 1.19-1.9; p = 0.001). Irrespective of the treatment regimen, Group 1 had significantly higher rates of the primary endpoint than Group 3 (pitavastatin + ezetimibe therapy: HR, 1.6; 95% CI, 1.12-2.22; p = 0.01 and pitavastatin monotherapy: HR, 1.4; 95% CI, 1.05-1.98; p = 0.02). These trends remained even after adjustment for baseline characteristics and lipid profiles. Multivariate analysis revealed that lower body mass index, prevalence of diabetes mellitus, higher levels of high-sensitivity C reactive protein at baseline, and lower levels of HDL-C at 3-month follow-up were independent predictors of the incidence of primary endpoint. CONCLUSIONS Lower levels of HDL-C at 3-month follow-up are independently associated with higher incidence of cardiovascular events in ACS patients receiving contemporary lipid-lowering therapy.
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Testosterone concentrations and risk of cardiovascular events in androgen-deficient men with atherosclerotic cardiovascular disease.
Boden, WE, Miller, MG, McBride, R, Harvey, C, Snabes, MC, Schmidt, J, McGovern, ME, Fleg, JL, Desvigne-Nickens, P, Anderson, T, et al
American heart journal. 2020;:65-76
Abstract
BACKGROUND Whether androgen deficiency among men increases the risk of cardiovascular (CV) events or is merely a disease marker remains a subject of intense scientific interest. OBJECTIVES Among male subjects in the AIM-HIGH Trial with metabolic syndrome and low baseline levels of high-density lipoprotein (HDL)-cholesterol who were randomized to niacin or placebo plus simvastatin, we examined the relationship between low baseline testosterone (T) concentrations and subsequent CV outcomes during a mean 3-year follow-up. METHODS In this post hoc analysis of men with available baseline plasma T concentrations, we examined the relationship between clinical/demographic characteristics and T concentrations both as a continuous and dichotomous variable (<300 ng/dL ["low T"] vs. ≥300 ng/dL ["normal T"]) on rates of pre-specified CV outcomes, using Cox proportional hazards models. RESULTS Among 2118 male participants in whom T concentrations were measured, 643 (30%) had low T and 1475 had normal T concentrations at baseline. The low T group had higher rates of diabetes mellitus, hypertension, elevated body mass index, metabolic syndrome, higher blood glucose, hemoglobin A1c, and triglyceride levels, but lower levels of both low-density lipoprotein and HDL-cholesterol, and a lower rate of prior myocardial infarction (MI). Men with low T had a higher risk of the primary composite outcome of coronary heart disease (CHD) death, MI, stroke, hospitalization for acute coronary syndrome, or coronary or cerebral revascularization (20.1%) compared with the normal T group (15.2%); final adjusted HR 1.23, P = .07, and a higher risk of the CHD death, MI, and stroke composite endpoint (11.8% vs. 8.2%; final adjusted HR 1.37, P = .04), respectively. CONCLUSIONS In this post hoc analysis, there was an association between low baseline testosterone concentrations and increased risk of subsequent CV events in androgen-deficient men with established CV disease and metabolic syndrome, particularly for the composite secondary endpoint of CHD death, MI, and stroke. CONDENSED ABSTRACT In this AIM-HIGH Trial post hoc analysis of 2118 men with metabolic syndrome and low HDL-cholesterol with available baseline plasma testosterone (T) samples, 643 males (30%) had low T (mean: 229 ng/dL) and 1475 (70%) had normal T (mean: 444 ng/dL) concentrations. The "low T" group had a 24% higher risk of the primary 5-component endpoint (20.1%) compared with the normal T group (15.2%); final adjusted HR 1.23, P = .07). There was also a 31% higher risk of the secondary composite endpoint: coronary heart disease death, myocardial infarction, and stroke (11.8% vs. 8.2%, final adjusted HR 1.37, P = .04) in the low vs. normal T group, respectively.
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HDL-apoA-I kinetics in response to 16 wk of exercise training in men with nonalcoholic fatty liver disease.
Whyte, MB, Shojaee-Moradie, F, Sharaf, SE, Cuthbertson, DJ, Kemp, GJ, Barrett, M, Jackson, NC, Herring, RA, Wright, J, Thomas, EL, et al
American journal of physiology. Endocrinology and metabolism. 2020;(6):E839-E847
Abstract
Nonalcoholic fatty liver disease (NAFLD) is characterized by low-circulating concentration of high-density lipoprotein cholesterol (HDL-C) and raised triacylglycerol (TAG). Exercise reduces hepatic fat content, improves insulin resistance and increases clearance of very-low-density lipoprotein-1 (VLDL1). However, the effect of exercise on TAG and HDL-C metabolism is unknown. We randomized male participants to 16 wk of supervised, moderate-intensity aerobic exercise (n = 15), or conventional lifestyle advice (n = 12). Apolipoprotein A-I (apoA-I) and VLDL-TAG and apolipoprotein B (apoB) kinetics were investigated using stable isotopes (1-[13C]-leucine and 1,1,2,3,3-2H5 glycerol) pre- and postintervention. Participants underwent MRI/spectroscopy to assess changes in visceral fat. Results are means ± SD. At baseline, there were no differences between exercise and control groups for age (52.4 ± 7.5 vs. 52.8 ± 10.3 yr), body mass index (BMI: 31.6 ± 3.2 vs. 31.7 ± 3.6 kg/m2), and waist circumference (109.3 ± 7.5 vs. 110.0 ± 13.6 cm). Percentage of liver fat was 23.8 (interquartile range 9.8-32.5%). Exercise reduced body weight (101.3 ± 10.2 to 97.9 ± 12.2 kg; P < 0.001) and hepatic fat content [from 19.6%, interquartile range (IQR) 14.6-36.1% to 8.9% (4.4-17.8%); P = 0.001] and increased the fraction HDL-C concentration (measured following ultracentrifugation) and apoA-I pool size with no change in the control group. However, plasma and VLDL1-TAG concentrations and HDL-apoA-I fractional catabolic rate (FCR) and production rate (PR) did not change significantly with exercise. Both at baseline (all participants) and after exercise there was an inverse correlation between apoA-I pool size and VLDL-TAG and -apoB pool size. The modest effect of exercise on HDL metabolism may be explained by the lack of effect on plasma and VLDL1-TAG.