Increase In non-HDL Cholesterol Research Articles

Prospective associations of non-HDL cholesterol with premature structural and functional cardiac damage progression in British youth: the ALSPAC study

Abstract Background Non high-density lipoprotein (non-HDL) cholesterol from childhood has been associated with signs of cardiac damage and subclinical atherosclerosis in middle age adults. Cumulative non-HDL cholesterol has been associated with subclinical atherosclerosis during growth from mid-adolescence through young adulthood. Due to the scarcity of repeated measures of cardiac structure and function, there is limited knowledge regarding the independent associations of non-HDL cholesterol with premature cardiac damage in youth. Purpose To investigate the longitudinal association of changes in non-HDL cholesterol with structural and functional cardiac damage progression during growth from adolescence through young adulthood. Methods From the Avon Longitudinal Study of Parents and Children (ALSPAC), UK birth cohort, 1595 adolescents aged 17 years who had fasting plasma non-HDL cholesterol computed from the difference between total cholesterol and HDL cholesterol at 17- and 24-year clinic visits were included. Repeated echocardiography measured LVM indexed for height2.7 (LVMI2.7), relative wall thickness (RWT), LV diastolic function from mitral E/A ratio (LVDF), and LV filling pressure from E/e´ ratio (LVFP) were available at baseline and follow-up. LVMI2.7 ≥51g/m2.7, RWT ≥0.44, LVDF <1.5, and LVFP ≥8 were categorised as LV hypertrophy, high RWT, LVD dysfunction, and high LVFP, respectively. Multivariable adjusted associations were examined using generalized linear mixed-effect models and generalized logit mixed-effect models and adjusted for sex, and time-varying covariates measured at both baseline and follow-up such as age, insulin, high-sensitivity C-reactive protein, heart rate, systolic blood pressure, glucose, fat mass, lean mass, smoking status, family history of hypertension/diabetes/high cholesterol/vascular disease, socioeconomic status, sedentary time, light physical activity, and moderate to vigorous physical activity. Results Among 1595 adolescents (mean [SD] age at baseline, 17.74 [0.38] years; 955 [59.8%] females]) mean non-HDL cholesterol values increased in males from 2.34mmol/L to 2.82mmol/L and in females from 2.60mmol/L to 2.77mmol/L, over 7 years. The prevalence of LV hypertrophy increased in males from 3.6% to 11.9% and in females from 1.6% to 4% over 7 years. The prevalence of LVD dysfunction increased in males from 7.8% to 16.6% and in females from 10.3% to 15.4%. In a fully adjusted model, 1 mmol increase in non-HDL cholesterol was significantly associated with higher odds of LV hypertrophy progression (odds ratio 1.21; [95% CI, 1.11 – 1.33], p<0.0001), high RWT (1.16; [1.07 – 1.29], p=0.005), and high LVFP (1.15; [1.06 – 1.25], p=0.001) but not LVD dysfunction (1.05 [0.95 – 1.18], p=0.342), over 7 years. Conclusion Increased non-HDL cholesterol during growth from adolescence through young adulthood was prospectively associated with worsening structural and functional cardiac damage in asymptomatic youth.

“A Comparative Study of Efficacy of Atorvastatin Alone and Atorvastatin with Omega-3 Fatty Acids Combination in Patients with Hyperlipidaemia Attending Tertiary Care Hospital”

Background: Current treatment with statins has become an integral part of vascular diseases but monotherapy has a significant residual event rate. Due to particularly one of the factor associated with atherogenic lipid phenotype that is characterized by a low high-density lipoprotein (HDL) cholesterol and increase in non-HDL cholesterol like Low-Density Lipoprotein (LDL). Omega-3 Fatty acids have demonstrated a preventiverole in primary and, particularly secondary cardiovascular diseases. Hence this study was planned to compare the efficacy of Atorvastatin alone with Atorvastatin and Omega-3 fatty acids in treatment in hyperlipidaemia patients.
 Methods: The study was comparative, randomized, and prospective and open labeled conducted in MI patients. A total of 100 patients were selected based on inclusion and exclusion criteria. They were divided randomly into two Groups (Group–A and Group-B). Group-A was given Atorvastatin 10mg/day and Group-B was given Atorvastatin 10mg/day and Omega-3 fatty acids 600mg/day for 6 months. Follow up was done every month and efficacy was measured by assessing the lipoprotein levels in serum.
 Results: The results were compared before treatment and after 6 months treatment.The levels were significantly decreased Total Cholesterol (TC), LDL, Low-Density Lipoprotein (VLDL), Triglycerides (TG) and HDL levels were increased in Group–A and Group-B. When these results compared between two Groups the HDL levels were increased also it shown high significance (<0.001) but there were no significance changes in other cholesterol levels.
 Conclusion: The present study results showed that Atorvastatin and Omega-3 fatty acids treatment was more effective than Atorvastatin alone treatment in improving HDL-C levels from base line and it may have a additive effect in major coronary artery diseases.

Determinants of Cardiovascular Risk in 7000 Youth With Type 1 Diabetes in the Australasian Diabetes Data Network.

Cardiovascular disease occurs prematurely in type 1 diabetes. The additional risk of overweight is not well characterized. The primary aim was to measure the impact of body mass index (BMI) in youth with type 1 diabetes on cardiovascular risk factors. The secondary aim was to identify other determinants of cardiovascular risk. Observational longitudinal study of 7061 youth with type 1 diabetes followed for median 7.3 (interquartile range [IQR] 4-11) years over 41 (IQR 29-56) visits until March 2019. 15 tertiary care diabetes centers in the Australasian Diabetes Data Network.Participants were aged 2 to 25 years at baseline, with at least 2 measurements of BMI and blood pressure. Standardized systolic and diastolic blood pressure scores and non-high-density lipoprotein (HDL) cholesterol were co-primary outcomes. Urinary albumin/creatinine ratio was the secondary outcome. BMI z-score related independently to standardized blood pressure z- scores and non-HDL cholesterol. An increase in 1 BMI z-score related to an average increase in systolic/diastolic blood pressure of 3.8/1.4 mmHg and an increase in non-HDL cholesterol (coefficient + 0.16 mmol/L, 95% confidence interval [CI], 0.13-0.18; P < 0.001) and in low-density lipoprotein (LDL) cholesterol. Females had higher blood pressure z-scores, higher non-HDL and LDL cholesterol, and higher urinary albumin/creatinine than males. Indigenous youth had markedly higher urinary albumin/creatinine (coefficient + 2.15 mg/mmol, 95% CI, 1.27-3.03; P < 0.001) and higher non-HDL cholesterol than non-Indigenous youth. Continuous subcutaneous insulin infusion was associated independently with lower non-HDL cholesterol and lower urinary albumin/creatinine. BMI had a modest independent effect on cardiovascular risk. Females and Indigenous Australians in particular had a more adverse risk profile.

Investigating the Association of Metabolic Biomarkers With Knee Cartilage Composition and Structural Abnormalities Using MRI: A Pilot Study.

The goal of this study was to explore the metabolic syndrome-associated phenotype of osteoarthritis by investigating the cross-sectional associations of glycemic markers and serum lipids with knee cartilage composition and structural abnormalities in middle-aged adults. Twenty participants between 40 to 70 years of age with Kellgren-Lawrence score 0-1 in at least one knee were recruited at a single center. Knee cartilage composition was assessed using 3.0 T cartilage T2 and T1ρ mapping. Evaluation of structural knee abnormalities was performed using the modified Whole-Organ Magnetic Resonance Imaging Score (WORMS). Linear regression was used to assess the associations of standardized fasting glucose (FG), hemoglobin A1c (HbA1c), insulin, total cholesterol, high-density lipoprotein (HDL), low-density lipoprotein (LDL), non-HDL cholesterol, and triglycerides with cartilage T2 and T1ρ as well as WORMS subscores, adjusting for body mass index. Higher FG and higher HbA1c were associated with higher WORMS meniscus sum (beta coefficient 1.31 [95% confidence interval (CI): 0.57, 2.05], P = 0.002 per standard deviation [SD] increase in FG; beta coefficient 0.90 [95% CI: 0.07, 1.73], P = 0.035 per SD increase in HbA1c). Also, higher total cholesterol and higher non-HDL cholesterol were associated with higher WORMS cartilage sum (beta coefficient 0.94 [95% CI: 0.01, 1.86], P = 0.048 per SD increase in total cholesterol; beta coefficient 1.05 [95% CI: 0.14, 1.96], P = 0.03 per SD increase in non-HDL cholesterol). Higher FG and HbA1c were associated with increased meniscal degeneration while higher total and non-HDL cholesterol were associated with increased cartilage degeneration.

Genetic variability in the absorption of dietary sterols affects the risk of coronary artery disease.

AimsTo explore whether variability in dietary cholesterol and phytosterol absorption impacts the risk of coronary artery disease (CAD) using as instruments sequence variants in the ABCG5/8 genes, key regulators of intestinal absorption of dietary sterols.Methods and resultsWe examined the effects of ABCG5/8 variants on non-high-density lipoprotein (non-HDL) cholesterol (N up to 610 532) and phytosterol levels (N = 3039) and the risk of CAD in Iceland, Denmark, and the UK Biobank (105 490 cases and 844 025 controls). We used genetic scores for non-HDL cholesterol to determine whether ABCG5/8 variants confer greater risk of CAD than predicted by their effect on non-HDL cholesterol. We identified nine rare ABCG5/8 coding variants with substantial impact on non-HDL cholesterol. Carriers have elevated phytosterol levels and are at increased risk of CAD. Consistent with impact on ABCG5/8 transporter function in hepatocytes, eight rare ABCG5/8 variants associate with gallstones. A genetic score of ABCG5/8 variants predicting 1 mmol/L increase in non-HDL cholesterol associates with two-fold increase in CAD risk [odds ratio (OR) = 2.01, 95% confidence interval (CI) 1.75–2.31, P = 9.8 × 10−23] compared with a 54% increase in CAD risk (OR = 1.54, 95% CI 1.49–1.59, P = 1.1 × 10−154) associated with a score of other non-HDL cholesterol variants predicting the same increase in non-HDL cholesterol (P for difference in effects = 2.4 × 10−4).ConclusionsGenetic variation in cholesterol absorption affects levels of circulating non-HDL cholesterol and risk of CAD. Our results indicate that both dietary cholesterol and phytosterols contribute directly to atherogenesis.

A Positive Association Between Dietary Intake of Higher Cow's Milk-Fat Percentage and Non−High-Density Lipoprotein Cholesterol in Young Children

To determine the association between cow's milk-fat and non-high-density lipoprotein (non-HDL) cholesterol, a marker of cardiovascular disease (CVD) risk in young children, and whether this association is mediated by the typical volume of cow's milk consumed. A longitudinal study in 2- to 8-year-old children (n=2890) was conducted through The Applied Research Group for Kids (TARGet Kids!), a practice-based research network in Toronto, Canada. Generalized estimating equations were used to examine the relationship between parent-reported cow's milk-fat percentage intake and serum non-HDL cholesterol concentrations as well as having high non-HDL cholesterol (≥3.75mmol/L [145mg/dL]), adjusting for covariates including age, sex, body mass index z score, breastfeeding duration, mother's ethnicity, and parental history of CVD. Bootstrap resampling (10 000 repetitions) was used to assess whether typical volume consumed mediated the association between cow's milk-fat percentage and non-HDL cholesterol. In total, 156 (5.4%) had high non-HDL cholesterol. Each percent increase in cow's milk-fat was associated with a 0.035mmol/L (1.35mg/dL) (P<.001) and 0.024mmol/L (0.92mg/dL) (P=.01) increase in non-HDL cholesterol, unadjusted and adjusted for covariates respectively. Cow's milk-fat percentage was not associated with greater odds of having high non-HDL cholesterol. Volume of cow's milk partially mediated the association between cow's milk-fat percentage and non-HDL cholesterol, accounting for 28% of the relationship (P<.001). Consumption of higher-fat cow's milk was associated with a small increase in non-HDL cholesterol but not greater odds of having high non-HDL cholesterol. Further research is needed to assess this relationship with other CVD risk factors in young children. ClinicalTrials.gov: NCT01869530.

Ezetimibe/statin combination therapy to treat patients with type 2 diabetes

Patients with diabetes represent a population at higher risk for cardiovascular disease. Diabetic dyslipidemia is characterized by the so-called atherogenic lipid triad, consisting of an increase in small dense low density lipoprotein particles and in triglyceride-rich lipoproteins, and a decrease in high-density lipoprotein cholesterol, with an increase in non-HDL cholesterol. Numerous trials have investigated the efficacy of add-on ezetimibe therapy for patients with type 2 diabetes and not controlled by statin therapy. The published data highly suggest that patients with type 2 diabetes may be more likely to benefit from ezetimibe/statin combination therapy. However, evidence specifically addressing hard clinical endpoints and prospective trials addressing differences in response between patients with or without diabetes are still needed.

Early onset intrauterine growth restriction in a mouse model of gestational hypercholesterolemia and atherosclerosis.

The susceptibility to develop atherosclerosis is increased by intrauterine growth restriction and prenatal exposure to maternal hypercholesterolemia. Here, we studied whether mouse gestational hypercholesterolemia and atherosclerosis affected fetal development and growth at different stages of gestation. Female LDLR KO mice fed a proatherogenic, high cholesterol (HC) diet for 3 weeks before conception and during pregnancy exhibited a significant increase in non-HDL cholesterol and developed atherosclerosis. At embryonic days 12.5 (E12.5), E15.5, and E18.5, maternal gestational hypercholesterolemia and atherosclerosis were associated to a 22–24% reduction in male and female fetal weight without alterations in fetal number/litter or morphology nor placental weight or structure. Feeding the HC diet exclusively at the periconceptional period did not alter fetal growth, suggesting that maternal hypercholesterolemia affected fetal weight only after implantation. Vitamin E supplementation (1,000 UI of α-tocopherol/kg) of HC-fed females did not change the mean weight of E18.5 fetuses but reduced the percentage of fetuses exhibiting body weights below the 10th percentile of weight (HC: 90% vs. HC/VitE: 68%). In conclusion, our results showed that maternal gestational hypercholesterolemia and atherosclerosis in mice were associated to early onset fetal growth restriction and that dietary vitamin E supplementation had a beneficial impact on this condition.

Gender differences in blood lipids and the risk of ischemic stroke among the hypertensive adults in rural China

Though large epidemiological studies have not established associations between blood lipids and ischemic stroke, increasing evidences have suggested that lipid-modifying agents may reduce cerebrovascular events. To determine whether blood lipids are risk factors for ischemic stroke among hypertensive rural adults in China. A cross-sectional survey was conducted during 2004-2006, which underwent cluster multistage sampling to a hypertensive resident group in the countryside of China. A total of 6,412 individuals (2,805 men, 3,607 women) with age>or=35 years were included. At baseline, lifestyle and other factors were obtained and blood lipids were assessed at a central study laboratory. Ischemic stroke was defined according to the criteria established by the National Survey of Stroke and all cases were further classified into lacunar infarction and other ischemic strokes. Univariable and multivariable logistic regression were used. In the univariable logistic regression model, LDL cholesterol (LDLc) in men and total cholesterol (TC), LDLc and TC-to-HDL cholesterol (TC: HDLc ratio) in women were risk factors for other ischemic strokes, with OR 1.42 (95% CI, 1.16-1.75), 1.31 (95% CI, 1.11-1.55), 1.47 (95% CI, 1.16-1.88) and 1.67 (95% CI, 1.28-2.14), respectively. After adjusting for independent variables, an increase in non-HDL cholesterol (non-HDLc) was associated with a significant increased risk of other ischemic strokes in women, with adjusted OR 1.45 (95% CI, 1.08-1.93). LDLc was the common risk factor for ischemic stroke in men and women, whereas Non-HDLc, TC and TC: HDLc ratio levels were related to ischemic stroke as risk factors only in women.

Cholesterol Feeding Increases C-Reactive Protein and Serum Amyloid A Levels in Lean Insulin-Sensitive Subjects

Inflammatory markers associated with elevated cardiovascular risk are increased by cholesterol feeding in animal models. However, whether dietary cholesterol increases inflammatory marker levels in humans is not known. C-reactive protein (CRP), serum amyloid A (SAA), and lipoprotein levels were compared in 201 healthy subjects on an American Heart Association-National Cholesterol Education Program step 1 diet at baseline and after addition of 4 eggs per day for 4 weeks. Subjects were classified a priori into 3 groups based on their body mass index (BMI) and insulin sensitivity index (SI): lean insulin sensitive (LIS), mean+/-SEM BMI, 23.2+/-0.3 kg/m2, and SI, 6.7+/-0.3x10(-4)min(-1)/(microU/mL), n=66; lean insulin resistant (LIR), BMI, 24.5+/-0.2 kg/m2 and SI, 2.9+/-0.1x10(-4)min(-1)/(microU/mL), n=76; or obese insulin resistant (OIR), BMI, 31.4+/-0.5 kg/m2 and SI, 2.1+/-0.1x10(-4)min(-1)/(microU/mL), n=59. Insulin resistance and obesity each were associated with increased baseline levels of both CRP (P for trend, <0.001) and SAA (P for trend=0.015). Egg feeding was associated with significant increases in both CRP and SAA in the LIS group (both P<0.01) but not in the LIR or OIR groups. Egg feeding also was associated with a significant increase in non-HDL cholesterol (P<0.001) in LIS subjects; however, there was no correlation between the change in non-HDL cholesterol or changes in either CRP or SAA in this group. A high-cholesterol diet leads to significant increases in both inflammatory markers and non-HDL cholesterol levels in insulin-sensitive individuals but not in lean or obese insulin-resistant subjects.

Adenoviral-mediated expression of Pcsk9 in mice results in a low-density lipoprotein receptor knockout phenotype.

Proprotein convertase subtilisin kexin 9 (Pcsk9) is a subtilisin serine protease with a putative role in cholesterol metabolism. Pcsk9 expression is down-regulated by dietary cholesterol, and mutations in Pcsk9 have been associated with a form of autosomal dominant hypercholesterolemia. To study the function of Pcsk9 in mice, an adenovirus constitutively expressing murine Pcsk9 (Pcsk9-Ad) was used. Pcsk9 overexpression in wild-type mice caused a 2-fold increase in plasma total cholesterol and a 5-fold increase in non-high-density lipoprotein (HDL) cholesterol, with no increase in HDL cholesterol, as compared with mice infected with a control adenovirus. Fast protein liquid chromatography analysis showed that the increase in non-HDL cholesterol was due to an increase in low-density lipoprotein (LDL) cholesterol. This effect appeared to depend on the LDL receptor (LDLR) because LDLR knockout mice infected with Pcsk9-Ad had no change in plasma cholesterol levels as compared with knockout mice infected with a control adenovirus. Furthermore, whereas overexpression of Pcsk9 had no effect on LDLR mRNA levels, there was a near absence of LDLR protein in animals overexpressing Pcsk9. These results were confirmed in vitro by the demonstration that transfection of Pcsk9 in McA-RH7777 cells caused a reduction in LDLR protein and LDL binding. In summary, these results indicate that overexpression of Pcsk9 interferes with LDLR-mediated LDL cholesterol uptake. Because Pcsk9 and LDLR are coordinately regulated by cholesterol, Pcsk9 may be involved in a novel mechanism to modulate LDLR function by an alternative pathway than classic cholesterol inhibition of sterol regulatory element binding protein-mediated transcription.

Phenotype interaction of apobec-1 and CETP, LDLR, and apoE gene expression in mice: role of apoB mRNA editing in lipoprotein phenotype expression.

Apolipoprotein (apo) B mRNA editing determines the amount of apoB-100 and apoB-48 produced. Surprisingly, apobec-1 knockout mice, which do not edit apoB, have an essentially normal lipoprotein phenotype. By selected cross-breeding of mice of different genotypes, we show in this report that inactivation of editing produces profound phenotypic effects in cholesteryl ester transfer protein (CETP) transgenic mice and in apoE and low density lipoprotein receptor (LDLR) knockout mice. Compared with mice with an apobec-1+/+ background, CETP expression in apobec-1-/- mice caused a doubling of the plasma apoB-100 concentration (from 3.5+/-0.6 to 8.8+/-1.9 mg/dL, P<.01) and a much greater shift of plasma cholesterol from HDL to IDL/LDL as assayed by fast protein liquid chromatography analysis; the ratio of non-HDL to HDL cholesterol was 0.47, 0.46, 0.76, and 1.43 in apobec-1(+/+)/CETP-/-, apobec-1(-/-)/CETP-/-, apobec-1(+/+)/CETP+/-, and apobec-1(-/-)/CETP+/- animals, respectively. Feeding of a Western-type diet further exaggerated the shift in this ratio. In LDLR-/- mice, inactivation of apobec-1 caused an approximately 200% rise in plasma apoB-100 concentration, an approximately 60% increase in apoE concentration, and a 70% increase in total plasma cholesterol, which resulted exclusively from an increase in non-HDL cholesterol. The exaggerated hypercholesterolemia involving the VLDL+LDL fractions was further enhanced by a Western-type diet. In contrast, in apoE-/- mice, inactivation of apobec-1 caused a massive increase (from <0.5 to 55.5+/-16.4 mg/dL) in plasma apoB-100 concentration but an approximately 55% reduction in hypercholesterolemia due to partial amelioration of the marked VLDL+IDL elevation. However, the difference in lipid profiles between apobec-1(+/+)/apoE-/- and apobec-1(-/-)/apoE-/- mice was abolished in a time-dependent manner as further increases in total plasma cholesterol were induced by a Western-type diet. Whereas apobec-1 inactivation in wild-type mice produced little or no change in lipoprotein phenotype, giving rise to speculation that apoB mRNA editing does not have significant effect on lipoprotein dynamics, we show herein that there is important gene-gene interaction between apobec-1 and the CETP, LDLR, and apoE loci, which is subject to further substantial modulation by environmental factors such as a Western-type diet in mice.