[Show abstract][Hide abstract] ABSTRACT: High-density lipoprotein (HDL) provides a pathway for the passage of lipid peroxides and lysophospholipids to the liver via hepatic scavenger receptors. Perhaps more importantly, HDL actually metabolizes lipid hydroperoxides preventing their accumulation on low-density lipoprotein (LDL), thus impeding its atherogenic structural modification. A number of candidates have been suggested to be responsible for HDL's antioxidant function, with paraoxonase-1 (PON1) perhaps the most prominent. Here we review the evidence for HDL anti-oxidative function and the potential contributions of apolipoproteins, lipid transfer proteins, paraoxonases and other enzymes associated with HDL.
Frontiers in Pharmacology 10/2015; 6. DOI:10.3389/fphar.2015.00222 · 3.80 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background:
The aim of this study was to explore the influence of extended-release niacin/laropiprant (ERN/LRP) versus placebo on high-density lipoprotein (HDL) antioxidant function, cholesterol efflux, apolipoprotein B100 (apoB)-containing lipoproteins, and mediators of vascular inflammation associated with 15% increase in high-density lipoprotein cholesterol (HDL-C). Study patients had persistent dyslipidemia despite receiving high-dose statin treatment.
Methods and results:
In a randomized double-blind, placebo-controlled, crossover trial, we compared the effect of ERN/LRP with placebo in 27 statin-treated dyslipidemic patients who had not achieved National Cholesterol Education Program-ATP III targets for low-density lipoprotein cholesterol (LDL-C). We measured fasting lipid profile, apolipoproteins, cholesteryl ester transfer protein (CETP) activity, paraoxonase 1 (PON1) activity, small dense LDL apoB (sdLDL-apoB), oxidized LDL (oxLDL), glycated apoB (glyc-apoB), lipoprotein phospholipase A2 (Lp-PLA2), lysophosphatidyl choline (lyso-PC), macrophage chemoattractant protein (MCP1), serum amyloid A (SAA) and myeloperoxidase (MPO). We also examined the capacity of HDL to protect LDL from in vitro oxidation and the percentage cholesterol efflux mediated by apoB depleted serum. ERN/LRP was associated with an 18% increase in HDL-C levels compared to placebo (1.55 versus 1.31 mmol/L, P<0.0001). There were significant reductions in total cholesterol, triglycerides, LDL cholesterol, total serum apoB, lipoprotein (a), CETP activity, oxLDL, Lp-PLA2, lyso-PC, MCP1, and SAA, but no significant changes in glyc-apoB or sdLDL-apoB concentration. There was a modest increase in cholesterol efflux function of HDL (19.5%, P=0.045), but no change in the antioxidant capacity of HDL in vitro or PON1 activity.
ERN/LRP reduces LDL-associated mediators of vascular inflammation, but has varied effects on HDL functionality and LDL quality, which may counter its HDL-C-raising effect.
Clinical trial registration:
URL: http://www.clinicaltrials.gov. Unique identifier: NCT01054508.
Journal of the American Heart Association 09/2015; 4(9):pii: e001508. DOI:10.1161/JAHA.114.001508. · 4.31 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Dyslipidaemia is an important cardiovascular disease risk factor. Many drugs affect lipid profile and lipoprotein metabolism. We reviewed unintended effects of nonlipid modifying, commonly used medications on lipid profile and lipoprotein metabolism.
Several detrimental effects of many drug classes such as diuretics, antidepressant, anticonvulsant and antiretroviral drugs have been reported, whereas other drug classes such as antiobesity, alpha 1-blockers, oestrogens and thyroid replacement therapy were associated with positive effects.
Dyslipidaemia is a common side-effect of many medications. This should be taken into consideration, especially in patients at high risk of cardiovascular disease. Other drugs demonstrated positive effects on circulating lipids and lipoproteins. The impact of these unintended effects on atherosclerotic disease risk and progression is unclear.
Current opinion in lipidology 06/2015; 26(4). DOI:10.1097/MOL.0000000000000198 · 5.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: To summarize the current evidence about how HDL impedes the oxidative and glycative atherogenic modification of LDL.
Paraoxonase 1 (PON1) is located on HDL. Meta-analysis of clinical epidemiological investigations reveals a substantial association of low serum PON1 activity with coronary heart disease incidence independent of other risk factors including HDL cholesterol and apolipoprotein AI (apoAI). Transgenic animal models also indicate an antiatherosclerotic role for PON1. However, highly purified and recombinant PON1 do not retain their antioxidant properties.
The therapeutic potential of PON1 should be recognized in preventing atherosclerosis and combating infection and organophosphate toxicity. In unleashing this potential, it is important to consider that both highly purified and recombinant PON1 are dissociated from the lipid phase and other components of HDL, such as apoAI and apoM, all of which may be required for HDL (through its PON1 component) to hydrolyze more lipophilic substrates.
Current opinion in lipidology 06/2015; 26(4). DOI:10.1097/MOL.0000000000000194 · 5.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We investigated whether atorvastatin 10 mg daily lowered C-reactive protein (CRP) and whether the effects of atorvastatin on cardiovascular disease (CVD) varied by achieved levels of CRP and LDL-cholesterol.
CRP levels were measured at baseline and 1 year after randomisation to atorvastatin in 2,322 patients with type 2 diabetes (40-75 years, 69% males) in a secondary analysis of the Collaborative Atorvastatin Diabetes Study, a randomised placebo-controlled trial. We used Cox regression models to test the effects on subsequent CVD events (n = 147) of CRP and LDL-cholesterol lowering at 1 year.
After 1 year, the atorvastatin arm showed a net CRP lowering of 32% (95% CI -40%, -22%) compared with placebo. The CRP response was highly variable, with 45% of those on atorvastatin having no decrease in CRP (median [interquartile range, IQR] per cent change -9.8% [-57%, 115%]). The LDL-cholesterol response was less variable, with a median (IQR) within-person per cent change of -41% (-51%, -31%). Baseline CRP did not predict CVD over 3.8 years of follow-up (HRper SD log 0.89 [95% CI 0.75, 1.06]), whereas baseline LDL-cholesterol predicted CVD (HRper SD 1.21 [95% CI 1.02, 1.44]), as did on-treatment LDL-cholesterol. There was no significant difference in the reduction in CVD by atorvastatin, with above median (HR 0.57) or below median (HR 0.52) change in CRP or change in LDL-cholesterol (HR 0.61 vs 0.50).
CRP was not a strong predictor of CVD. Statin efficacy did not vary with achieved CRP despite considerable variability in CRP response. The use of CRP as an indicator of efficacy of statin therapy on CVD risk in patients with type 2 diabetes is not supported by these data. Trial registration NCT00327418.
[Show abstract][Hide abstract] ABSTRACT: Paraoxonase 1 (PON1) protects against the development of atherosclerosis by hydrolysing damaging lipid peroxides formed in low-density lipoprotein (LDL) and cell membranes. The effect of migration on PON1 activity is unknown. We have investigated the effect of migration on serum PON1 activity by comparing an Indian Gujarati community who had migrated to Sandwell (West Midlands, UK) with people still living in their villages of origin around the town of Navsari (Gujarat, NorthWest India) and determined biochemical and nutritional parameters which may correlate with PON1 activity. PON1 activity was almost double in men and women living in Sandwell compared to those in Navsari. In the Spearman's Rank correlation analysis, PON1 activity was significantly negatively correlated with fasting glucose and C-reactive protein, and positively with fasting non-esterified fatty acids, homeostasis model assessment (HOMA)-insulin sensitivity, and high-density lipoprotein (HDL) in rural Indian men, positively with HDL and apolipoprotein A1 (apo A1) in migrant Indian men, negatively with HOMA-cell activity and apo A1. It was positively correlated with HDL cholesterol, mean LDL particle diameter, and oxidised-LDL (ox-LDL) in rural Indian women and positively with HDL cholesterol, apo A1, and ox-LDL in migrant Indian women. Multivariate analysis with PON1 as the dependent variable indicated significant relationships with migrant status and HDL cholesterol only (both p<0.001). In conclusion, in the South Asian populations studied here, PON1 activity significantly correlated with measures of insulin sensitivity and the metabolic syndrome; however, by far the strongest determinant of PON1 activity was migration, or at least environmental and dietary changes which accompany migration. We also found an as yet unexplained lack of gender difference in HDL cholesterol, which requires further investigation.
[Show abstract][Hide abstract] ABSTRACT: Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
[Show abstract][Hide abstract] ABSTRACT: Commentary on: Keene D, Price C, Shun-Shin MJ, et al. Effect on cardiovascular risk of high density lipoprotein targeted drug treatments niacin, fibrates, and CETP inhibitors: meta-analysis of randomised controlled trials including 117,411 patients. BMJ 2014;349:g4379. Context Decreasing low-density lipoprotein (LDL) cholesterol with statin treatment reduces cardiovascular disease (CVD) incidence. The National Institute for Health and Care Excellence (NICE) has recently recommended that first-line statin treatment in primary prevention should be atorvastatin 20 mg daily and in secondary prevention atorvastatin 80 mg daily, doses which typically decrease LDL cholesterol by 43% and 55%, respectively.1 In many patients this will leave little scope to reduce residual CVD risk by additional LDL lowering. Attention is therefore drawn to the epidemiological inverse association between HDL cholesterol and CVD risk. This is widely exploited in the …
Evidence-Based Medicine 09/2014; 20(1). DOI:10.1136/ebmed-2014-110084
[Show abstract][Hide abstract] ABSTRACT: Purpose of review:
Guidelines seeking to deploy statin treatment rely heavily on the use of estimates of absolute cardiovascular disease (CVD) risk as an arbiter of who should receive statins. We question whether this is an effective strategy unless the LDL-cholesterol (LDL-C) response is also considered.
Recently, meta-analyses of randomized clinical trials of statins have revealed that CVD risk decreases linearly by 22% for each 1 mmol/l reduction in LDL-C. Calculation of the number needed to treat with statins to prevent one CVD event using both the pretreatment absolute CVD risk and the LDL-C response that can be achieved is thus possible. Application of this evidence reveals that many people (including younger ones) with high LDL-C levels can benefit more than people currently receiving statin treatment solely on the basis of their absolute CVD risk, whereas others at higher CVD risk, but with lower LDL-C, will derive little benefit. This does not seem to have been adequately considered in recent clinical guidelines.
A simple additional mathematical step in risk assessment to take account of the LDL-C response to statins and provide knowledge of number needed to treat would greatly improve individual management, cost-effectiveness and the population impact of statins.
Current Opinion in Lipidology 06/2014; 25(4):239. DOI:10.1097/MOL.0000000000000097 · 5.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose of review:
Despite being both the longest known and the most prevalent genetic risk marker for atherosclerotic cardiovascular disease (CVD), little progress has been made in agreeing a role for lipoprotein (a) [Lp(a)] in clinical practice and developing therapies with specific Lp(a)-lowering activity. We review barriers to progress, and discuss areas of controversy which are important to future research.
Epidemiological and genetic studies have supported a causal role for Lp(a) in accelerated atherosclerosis, independent of other risk factors. Progress continues to be made in the understanding of Lp(a) metabolism, and Lp(a) levels, rather than apolipoprotein (a) isoform size, have been shown to be more closely related to CVD risk. Selective Lp(a) apheresis has offered some evidence that Lp(a)-lowering can improve cardiovascular end-points.
We have acquired a great deal of knowledge about Lp(a), but this has not yet led to reductions in CVD. This is at least partially due to disagreement over Lp(a) measurement methodologies, its physiological role and the importance of the elevations seen in renal diseases, diabetes mellitus and familial hypercholesterolaemia. Renewed focus is required to bring assays into clinical practice to accompany new classes of therapeutic agents with Lp(a)-lowering effects.
Current Opinion in Lipidology 06/2014; 25(4). DOI:10.1097/MOL.0000000000000096 · 5.66 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Context: Obstructive sleep apnea (OSA) complicates morbid obesity and is associated with increased cardiovascular disease incidence. An increase in circulating markers of chronic inflammation and dysfunctional high density lipoprotein (HDL) occur in severe obesity. Objective: To establish whether the effects of obesity on inflammation and HDL dysfunction are more marked when complicated by OSA. Design and patients: Morbidly obese patients (n=41) were divided into those whose apnea-hypo-apnea index (AHI) was more or less than the median value and on the presence of OSA ("OSA" and "no OSA (nOSA)" groups). We studied the antioxidant function of HDL and measured serum paraoxonase 1 (PON1) activity, tumor necrosis factor α (TNFα) and intercellular adhesion molecule 1 (ICAM-1) levels in these patients. In a subset of 19 patients, we immunostained gluteal subcutaneous adipose tissue (SAT) for TNFα, macrophages and measured adipocyte size. Results: HDL lipid peroxide (LPO) levels were higher and serum PON1 activity was lower in the high AHI group versus the low AHI group (p<0.05 and p<0.0001, respectively) and in the OSA group versus the "nOSA" group (p=0.005 and p<0.05 respectively). Serum TNFα and ICAM1 levels and TNFα immunostaining in SAT increased with the severity of OSA. Serum PON1 activity was inversely correlated with AHI (r= -0.41, p<0.03) in the OSA group. TNFα expression in SAT directly correlated with AHI (r= 0.53, p<0.03) in the subset of 19 patients from whom biopsy was obtained. Conclusion: Increased serum TNFα, ICAM-1 and TNFα expression in SAT provide a mechanistic basis for enhanced inflammation in patients with OSA. Decreased serum PON1 activity, impaired HDL anti-oxidant function and increased adipose tissue inflammation in these patients could be a mechanism for HDL and endothelial dysfunction.
The Journal of Clinical Endocrinology and Metabolism 05/2014; 99(9):jc20133939. DOI:10.1210/jc.2013-3939 · 6.21 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: OBJECTIVE
Diabetes-associated autoantibodies can be detected in adult-onset diabetes, even when initially non-insulin requiring, i.e., with latent autoimmune diabetes. We aimed to identify adult-onset autoimmune diabetes in patients with established "type 2 diabetes" participating in the Collaborative Atorvastatin Diabetes Study (CARDS) to characterize their phenotype and clinical outcome.RESEARCH DESIGN AND METHODS
We prospectively studied 2,425 European patients with presumed type 2 diabetes (mean age 62 years, diabetes duration 7.9 years) for outcomes at 3.9 years after randomization to either atorvastatin or placebo. Subjects were screened for autoantibodies to GAD (GADA), insulinoma-associated antigen-2 (IA-2A), and zinc-transporter 8 (ZnT8A).RESULTSA total of 173 patients (7.1%) had GADA, of whom 11 (0.5%) and 5 (0.2%) were also positive for IA-2A and ZnT8A, respectively. At baseline, 44% of GADA-positive patients were not on insulin. Fewer autoantibody-positive than autoantibody-negative patients had metabolic syndrome (64 vs. 80%), and more were on insulin (56 vs. 17%) (P < 0.0001 for each) without lower HbA1c (69 mmol/mol [8.5%] vs. 62 mmol/mol [7.8%]). The frequency of microvascular and macrovascular events was similar in both cohorts, independent of atorvastatin.CONCLUSIONS
Adult-onset autoimmune diabetes was prevalent, even in patients with established diabetes presumed to have type 2 diabetes. After 11.8 years' diabetes duration, nearly half the patients with autoimmune diabetes were not on insulin treatment and almost two-thirds had metabolic syndrome. The type of diabetes, whether autoimmune diabetes or type 2 diabetes, did not impact the risk of microvascular disease.
Diabetes care 04/2014; 37(6). DOI:10.2337/dc13-2383 · 8.42 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Background Patients with rheumatoid arthritis (RA) have premature mortality and increased risk of cardiovascular morbidity and mortality. Dyslipidemia is a known risk factor for increased risk of cardiovascular diseases in the general population. The association between lipids and RA is complex. A paradoxical association between dyslipidemia and cardiovascular disease in patients with RA has been noted recently.
Objectives The aim of this study was to examine the association between lipids and overall/cardiovascular mortality in patients with early inflammatory polyarthritis (IP).
Methods Patients aged ≥18 years, who had 2 or more swollen joints for more than 4 weeks were recruited by the Norfolk Arthritis Register (NOAR) a primary inception cohort. The patients were recruited from January 2000-December 2010. Patients were followed up untill event (death) or untill the end of the study (total number of person year follow up 7607.8). The cause of death was coded on death certificates according to the ICD-10. A detailed baseline assessment of patients including joint counts (swollen, tender) was performed. Symptom duration, current and previous therapies were recorded. Fasting blood samples were collected and stored for routine assessment of CRP, rheumatoid factor (RF), anti-CCP antibodies (ACPA) and lipid profiles including total and HDL cholesterol, apolipoprotein (Apo-) A1 and B and triglyceride (TG) levels. Cox-proportional hazard survival analysis was used to determine the association between lipid-subtypes and overall/CVD mortality.
Results We recruited 1266 patients with IP. The median (IQR) age and symptom duration at the time of assessment was 58 (47, 68) years and 8 (4.5, 15) months respectively. The cohort included 848 (67%) women, 538 (42.7%) were RF-positive, and 394 (34.5%) were ACPA-positive. The median (IQR) CRP and DAS-28crp were 11 (5.4, 20.8) and 3.68 (2.82, 4.62) respectively. Overall 568 (41.3%) patients fulfilled 1987 ACR criteria for RA. During the period of follow up 100 (7%) patients died (all causes) of which 30% (27) deaths were attributed to CVD. On univariate analysis all cause mortality was associated with; increasing age HR (95%CI); 1.09 (1.07-1.11) per year, hypertension 2.21 (1.47-3.31), RF+ve 1.54 (1.03-2.29), and ACPA+ve 1.81 (1.15-2.86) respectively. Female gender HR (95%CI) 0.52 (0.35-0.77), BMI 0.93 (0.89-0.97) per kg/m2, TC 0.79 (0.68-0.93) per mmol, LDL 0.73 (0.59-0.89) per mmol, HDL 0.47 (0.27-0.81) per mmol were associated with reduced risk of overall mortality. This remained significant after adjusting for age and gender. Both ApoA-1 and ApoB were associated with reduced risk but did not reach significant level. A similar trend was also observed in association with CVD mortality. Forward stepwise regression analysis indicated that only increasing age and low level of TC were independently associated with increased risk of both all cause and CVD mortality.
Conclusions In patients with IP, lower lipids at baseline were associated with all cause mortality and CVD deaths. Lower cholesterol levels may reflect a higher inflammatory burden but may also be associated with lipid subsets more prone to oxidation.
Disclosure of Interest None Declared
Annals of the Rheumatic Diseases 01/2014; 71(Suppl 3):93-93. DOI:10.1136/annrheumdis-2012-eular.1801 · 10.38 Impact Factor