Monocyte chemoattractant protein‐1 and CC‐chemokine receptor‐2 in severe hypercholesterolaemia

Objectives: To investigate whether plasma concentrations of monocyte chemoattractant protein‐1 (MCP‐1) and the gene expression of its receptor on the monocyte cell surface CCR‐2 were elevated above normal in subjects with asymptomatic, isolated hypercholesterolaemia and if statin treatment could influence this cytokine. Methods: The investigation was designed as a cross sectional study followed by a single, blind, treatment study of patients receiving pravastatin 80?mg/day for 8 weeks. The study included 23 patients with severe hypercholesterolaemia (LDL>5.2?mmol/L) and 39 normocholesterolaemic controls. Blood samples were obtained from patients and controls at baseline and from patients at end of the study and analysed for lipoproteins and inflammatory mediators: MCP‐1, high‐sensitivity C‐reactive protein (HS‐CRP). Isolated peripheral mononuclear cells were analysed for CCR‐2 gene expression. Results: Mean plasma LDL‐C was significantly higher in patients than in controls. No difference in plasma MCP‐1 levels or CCR‐2 gene expression was seen between the groups at baseline, nor were there any differences in plasma concentrations of CRP. After treatment with pravastatin, LDL‐C decreased by 31%. Treatment did not significantly affect the levels of MCP‐1 or CCR‐2 gene expression, nor was CRP affected by treatment with pravastatin. Conclusions: Our study does not support the view that MCP‐1 plasma levels and CCR‐2 gene expression in circulating monocytes are directly responsible for the monocyte recruitment into the arterial intima in patients with severe asymptomatic hypercholesterolaemia. In addition, the inflammatory response of a high concentration of LDL‐C in isolated asymptomatic hypercholesterolaemia is minute.     

Post-prandial remnant lipoprotein metabolism in autosomal recessive hypercholesterolaemia

Eur J Clin Invest 2012; 42 (10): 1094-1099 ABSTRACT: Background Phenotype of autosomal recessive hypercholesterolaemia (ARH), a rare lipid disorder, is known to be milder than that of homozygous familial hypercholesterolaemia (FH) with LDL receptor gene mutation. However, few data exist regarding the functional differences in ARH and FH particularly in terms of remnant-like particles' (RLP) metabolism. Materials and methods Blood sampling was performed up to 6?h after OFTT cream loading (50?g/body surface area) with 2-h intervals in a single ARH proband, four heterozygous FH patients with LDL receptor gene mutation and four normal controls. Plasma lipoprotein and RLP fraction were determined by HPLC system. The area under curve (AUC) of each lipoprotein including RLP fractions was evaluated. Results The AUC of TG, RLP cholesterol (RLP-C) and RLP triglyceride (RLP-TG) levels of heterozygous FH subjects was significantly higher than those of controls (466?±?71?mg/dL?×?h vs. 303?±?111?mg/dL?×?h, P?相似文献   

PCSK9 inhibitors in clinical practice: Novel directions and new experiences

BackgroundIn randomized clinical trials, proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) effectively reduce low-density lipoprotein-cholesterol (LDL-C) with a favorable tolerability and safety profile. Our purpose is to provide real-world data regarding the indications, efficacy and safety of PCSK9i.MethodsThe cohort comprised 141 patients who attended the lipid clinic of 3 hospitals in Greece and started using PCSK9i. Patients were requested to attend the lipid clinic at 3 months and at 1 year.ResultsNinety percent of patients had heterozygous familial hypercholesterolaemia (heFH) and 75% had cardiovascular disease (CVD). A PCSK9i [evolocumab 140 mg/2 weeks (n = 82), alirocumab 75 mg/2 weeks (n = 46) and alirocumab 150 mg/2 weeks (n = 13)] was prescribed due to failure to achieve LDL-C targets despite maximum lipid-lowering therapy (LLT) in 75% of patients, while in the remaining cases, the indication was statin intolerance. The mean reduction of LDL-C at 3 months was 56.2% and remained constant at 12 months (55.8% reduction from baseline). LDL-C target was achieved by 68.1% of patients at 3 months. “Totally” intolerant to statins patients (unable to tolerate any statin dose, n = 23) showed the lowest LDL-C reduction (47.7%). Side effects attributed to treatment were reported by 14 patients (10%). The total number of patients who stopped PCSK9i at 1 year was 14 (10%) but only 2 (1.4%) discontinued treatment because of side effects (myalgias).ConclusionsOur real-world results of PCSK9i showed comparable efficacy and tolerability to those reported in clinical trials and highlighted the value of treatment with PCSK9i heFH patients not achieving LDL-C targets despite maximum LLT and high or very high risk statin intolerant patients.     

Modelling hypercholesterolaemia in rats using high cholesterol diet

Hypercholesterolaemia is a complex condition with multiple causes, including both lifestyle and genetic aspects. It is also a risk factor for cardiovascular diseases (CVDs), which are responsible for 172 million deaths/year. Although the reasons for hypercholesterolaemia are known, there are many critical questions that remain to be answered so that new therapeutics can be developed. In order to elucidate the pathobiology of this condition, animal models can mimic the pathology of human hypercholesterolaemia. One example of an animal model is induced by the hypercholesterolaemic diet in Wistar rats. The present review first summarizes the current understanding of the metabolic profile involved in hypercholesterolaemia in humans. Next it comments about the lack of consensus as to which hypercholesterolaemia induction protocol should be used. The present work aimed to review experimental studies that induced hypercholesterolaemia in Wistar rats it was not intended to judge the “best” model, since they all achieved the goal of inducing an increase in serum cholesterol.     

Prevention of cardiac disease: lifestyle modification or pharmacotherapy?

Cardiovascular disease is still the leading cause of death in Australia. There have recently been significant advances in the management of acute coronary syndromes, as well as secondary prevention strategies; however, much of our resources are still directed towards treatment rather than prevention. Prevention of cardiovascular disease involves first, identifying patients at greatest risk of cardiovascular events and second, managing modifiable risk factors. Both pharmacotherapy and lifestyle modification are useful in modifying risk factors; however, the relative importance of each is often dictated by the risk factor profile of the individual. Although there is growing evidence that those at all levels of risk may benefit from lifestyle modification, pharmacotherapy is likely to be most useful in those at higher risk.     

Type 1 diabetes and hypercholesterolaemia reveal the contribution of endothelium-derived hyperpolarizing factor to endothelium-dependent relaxation of the rat aorta

1. The present study evaluated the effect of diabetes, hypercholesterolaemia and their combination on the contribution of nitric oxide (NO) and endothelium-derived hyperpolarizing factor (EDHF) to relaxation of rat isolated aortic rings and the potential contribution of oxidant stress to the disturbance of endothelial function. 2. Thoracic aortic rings from control, diabetic, hypercholesterolaemic and diabetic plus hypercholesterolaemic rats were suspended in organ baths for tension recording. Generation of superoxide by the aorta was measured using lucigenin-enhanced chemiluminescence. 3. The maximal response to acetylcholine (ACh) was significantly reduced in diabetic or hypercholesterolaemic rats compared with control rats. In rats with diabetes plus hypercholesterolaemia, both the sensitivity and maximal response to ACh was impaired. In control rats, the response to ACh was abolished by the NO synthase inhibitor N(G)-nitro-L-arginine (L-NNA) or inhibition of soluble guanylate cyclase with 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ). In contrast, in rats with diabetes, hypercholesterolaemia or both, relaxation to ACh was resistant to inhibition by L-NNA or ODQ, but abolished by additional inhibition of K(Ca) channels with charybdotoxin plus apamin. 4. The generation of superoxide was not significantly enhanced in aortic rings from either diabetic or hypercholesterolaemic rats, but was significantly increased in aortic rings from rats with diabetes plus hypercholesterolaemia. 5. These results suggest that when diabetes and hypercholesterolaemia impair endothelium-dependent relaxation, due to a diminished contribution from NO, a compensatory contribution of EDHF to endothelium-dependent relaxation of the aorta is revealed. The attenuation of NO-mediated relaxation, at least in the presence of both diabetes and hypercholesterolaemia, is associated with enhanced superoxide generation.     

CEPHEUS SA: a South African survey on the undertreatment of hypercholesterolaemia

Aim

The aim of the CEntralised Pan-South African survey on tHE Under-treatment of hypercholeSterolaemia (CEPHEUS SA) was to evaluate the current use and efficacy of lipid-lowering drugs (LLDs), and to identify possible patient and physician characteristics associated with failure, if any, to achieve low-density lipoprotein cholesterol (LDL-C) targets.

Methods

The survey was conducted in 69 study centres in South Africa and recruited consecutive consenting patients who had been prescribed LLDs for at least three months. One visit was scheduled for data collection, including fasting plasma lipid and glucose levels. Physicians and patients completed questionnaires regarding their knowledge, awareness and perceptions of hypercholesterolaemia and the treatment thereof.

Results

Of the 3 001 patients recruited, 2 996 were included in the final analyses. The mean age was 59.4 years, and 47.5% were female. Only 60.5 and 52.3% of patients on LLDs for at least three months achieved the LDL-C target recommended by the NCEP ATP III/2004 updated NCEP ATP III and the Fourth JETF/South African guidelines, respectively. Being male, older than 40 years, falling into the lower-risk categories, compliance with the medication regimen, and patient knowledge that the LDL-C goal had been reached, were associated with the highest probability of attaining LDL-C goals.

Conclusion

The results of this survey highlight the sub-optimal lipid control achieved in many South African patients taking lipid-lowering therapy.