A low level of high-density lipoprotein cholesterol (HDL-C) is an important risk factor for cardiovascular disease. Epidemiological and clinical studies provide evidence that HDL-C levels are linked ...to rates of coronary events. The cardioprotective effects of HDL-C have been attributed to its role in reverse cholesterol transport, its effects on endothelial cells, and its antioxidant activity. Although some clinical trials suggest a benefit of raising HDL-C to reduce risk, further studies are needed, and HDL-C is still not considered a primary target of therapy in the National Cholesterol Education Program guidelines. However, HDL-C should be considered as part of the patient's overall profile of established risk factors in determining treatment strategies.
Observational studies provide overwhelming evidence that a low high-density
lipoprotein (HDL)-cholesterol level increases the risk of coronary
events, both in healthy subjects and in patients with ...coronary heart disease.
Based on in vitro experiments, several mechanistic explanations for the
atheroprotective function of HDL have been suggested. However, few of these
were verified in vivo in humans or in experiments with transgenic animals. The
HDL functions currently most widely held to account for the antiatherogenic
effect include participation in reverse cholesterol transport, protection
against endothelial dysfunction, and inhibition of oxidative stress. This
review summarizes current views on the molecular mechanism underlying these
atheroprotective effects of HDL.
Despite achieving targets for low-density lipoprotein (LDL) cholesterol, blood pressure, and glycemia in accordance with current standards of care, patients with dyslipidemia remain at high residual ...risk of vascular events. Atherogenic dyslipidemia, characterized by elevated triglycerides and low levels of high-density lipoprotein (HDL) cholesterol, often with elevated apolipoprotein B and non-HDL cholesterol, is common in patients with established cardiovascular disease (CVD), type 2 diabetes mellitus, or metabolic syndrome and contributes to both macrovascular and microvascular residual risk. However, atherogenic dyslipidemia is largely underdiagnosed and undertreated in clinical practice. The Residual Risk Reduction Initiative (R3 i) was established to address this highly relevant clinical issue. The aims of this position paper are (1) to highlight evidence that atherogenic dyslipidemia is associated with residual macrovascular and microvascular risk in patients at high risk for CVD, despite current standards of care for dyslipidemia and diabetes; and (2) to recommend therapeutic intervention for reducing this residual vascular risk supported by evidence and expert consensus. Lifestyle modification with nutrition and exercise is an important, effective, and underutilized first step in reducing residual vascular risk. Therapeutic intervention aimed at achievement of all lipid targets is also often required. Combination lipid-modifying therapy, with the addition of niacin, a fibrate, or omega-3 fatty acids to statin therapy, increases the probability of achieving all lipid goals. Outcomes studies are in progress to evaluate whether these combination treatment strategies translate to a clinical benefit greater than that achieved with statins alone. The R3 i highlights the need to address with lifestyle and/or pharmacotherapy the high level of residual risk of CVD events and microvascular complications among patients with dyslipidemia receiving therapy for high levels of LDL cholesterol and for diabetes in accordance with current standards of care.
The 2 most widely used criteria to diagnose the metabolic syndrome (MS) are those developed by the United States Adult Treatment Panel III of the National Cholesterol Education Program (ATP III) and ...by the International Diabetes Federation (IDF). A major difference between these 2 sets of criteria is that the IDF places more emphasis on waist circumference. We compared the prevalence of MS using the ATP III and the IDF guidelines in 2 American (the Dallas Health Study and National Health and Nutrition Examination Survey) and 1 German (Prospective Cardiovascular Munster study) population samples. When the ATP III criteria were used, the prevalence of MS was higher in the United States than the German samples in both women (37% vs. 18%) and men (30% vs 25%), whereas when the IDF criteria were used, the prevalence of MS was 25% higher in the German than the American sample. Although in the United States both sets of criteria identified mostly the same people (concordance of about 90%), this was less true in Germany (concordance about 80%). To determine which criteria better predicted adverse cardiovascular outcomes, the incidence of coronary events associated with MS, as defined using the ATP III or the IDF criteria, were compared over a 10-year period among the middle-aged men in the German sample (n = 7,152). A total of 3.4% of men without MS developed an event. A much higher percentage of the men with MS defined by the ATP III criteria (10.7%) than the IDF criteria (5.5%) had a cardiovascular event. In conclusion, although the prevalence of MS was higher when the IDF criteria were used in the German sample, the IDF criteria have lower predictive power for coronary events.
High-density lipoprotein (HDL) levels are inversely proportional to the risk of atherosclerosis, but mechanisms of HDL atheroprotection remain unclear. Monocyte chemoatractant protein-1 (MCP-1) ...constitutes an early component of inflammatory response in atherosclerosis. Here we investigated the influence of HDL on MCP-1 production in vascular smooth muscle cells (VSMCs) and rat aortic explants.
HDL inhibited the thrombin-induced production of MCP-1 in a concentration-dependent manner. The HDL-dependent inhibition of MCP-1 production was accompanied by the suppression of reactive oxygen species (ROS), which regulate the MCP-1 production in VSMCs. HDL inhibited NAD(P)H oxidase, the preponderant source of ROS in the vasculature, and prevented the activation of Rac1, which precedes NAD(P)H-oxidase activation. The HDL capacity to inhibit MCP-1 production, ROS generation, and NAD(P)H-oxidase activation was emulated by sphingosine 1-phosphate (S1P) and sphingosylphosphorylcholine (SPC), two lysosphingolipids present in HDL, but not by apolipoprotein A-I. HDL-, S1P-, and SPC-induced inhibition of MCP-1 production was attenuated in VSMCs pretreated with VPC23019, an antagonist of lysosphingolipid receptors S1P(1) and S1P(3), but not by JTE013, an antagonist of S1P(2). In addition, HDL, S1P, and SPC failed to inhibit MCP1 production and ROS generation in aortas from S1P(3)- and SR-B1-deficient mice.
HDL-associated lysosphingolipids inhibit NAD(P)H oxidase-dependent ROS generation and MCP-1 production in a process that requires coordinate signaling through S1P(3) and SR-B1 receptors.
The inverse correlation between serum levels of high density lipoprotein (HDL) cholesterol and the risk of coronary heart disease, the protection of susceptible animals from atherosclerosis by ...transgenic manipulation of HDL metabolism, and several potentially anti-atherogenic in vitro-properties have made HDL metabolism an interesting target for pharmacological intervention in atheroslcerosis. We have previously reviewed the concept of reverse cholesterol transport, which describes both the metabolism and the classic anti-atherogenic function of HDL (Arterioscler. Thromb. Vasc. Biol. 20 2001 13). We here summarize the current understanding of additional biological, potentially anti-atherogenic properties of HDL. HDL inhibits the chemotaxis of monocytes, the adhesion of leukocytes to the endothelium, endothelial dysfunction and apoptosis, LDL oxidation, complement activation, platelet activation and factor X activation but also stimulates the proliferation of endothelial cells and smooth muscle cells, the synthesis of prostacyclin and natriuretic peptide C in endothelial cells, and the activation of proteins C and S. These anti-inflammatory, anti-oxidative, anti-aggregatory, anti-coagulant, and pro-fibrinolytic activities are exerted by different components of HDL, namley apolipoproteins, enzymes, and even specific phospholipids. This complexity further emphasizes that changes in the functionality of HDL rather than changes of plasma HDL-cholesterol levels determine the anti-atherogenicity of therapeutic alterations of HDL metabolism.
Aims To investigate pulse pressure (PP) as an independent predictor of coronary heart disease (CHD) risk. Methods and results On the basis of a 10-year follow-up of 5389 men aged 35–65 at recruitment ...into PROCAM, we used a proportional hazards model to calculate the effect of systolic blood pressure (SBP), diastolic blood pressure (DBP), and PP on CHD risk after correcting for age, high-density lipoprotein cholesterol, LDL cholesterol, triglycerides, smoking, diabetes, and family history of premature CHD. Increases of 10 mmHg in DBP, SBP, and PP were associated with an increased CHD hazard ratio (HR) of ∼10%. When the group was divided into the age groups <50, 50–59, and >59 years, this relationship was seen in the age group 50–59 years for DBP, SBP, and PP and in men aged ≥60 for PP only (25% increase in HR). Overall, CHD risk in men with PP ≥70 mmHg was more three times that of men with PP <50 mmHg. This increased risk was not apparent at age <50 years, was greatest at age >60 years, and was also present in men who were normotensive at recruitment (SBP ≤160 mmHg, DBP ≤95 mmHg). Conclusion In older European men, increased PP is an important independent determinant of coronary risk, even among those initially considered normotensive.
Despite current standards of care aimed at achieving targets for low-density lipoprotein (LDL) cholesterol, blood pressure and glycaemia, dyslipidaemic patients remain at high residual risk of ...vascular events. Atherogenic dyslipidaemia, specifically elevated triglycerides and low levels of high-density lipoprotein (HDL) cholesterol, often with elevated apolipoprotein B and non-HDL cholesterol, is common in patients with established cardiovascular disease, type 2 diabetes, obesity or metabolic syndrome and is associated with macrovascular and microvascular residual risk. The Residual Risk Reduction Initiative (R3I) was established to address this important issue.
This position paper aims to highlight evidence that atherogenic dyslipidaemia contributes to residual macrovascular risk and microvascular complications despite current standards of care for dyslipidaemia and diabetes, and to recommend therapeutic intervention for reducing this, supported by evidence and expert consensus. Lifestyle modification is an important first step. Additionally, pharmacotherapy is often required. Adding niacin, a fibrate or omega-3 fatty acids to statin therapy improves achievement of all lipid risk factors. Outcomes studies are evaluating whether these strategies translate to greater clinical benefit than statin therapy alone. In conclusion, the R3i highlights the need to address with lifestyle and/or pharmacotherapy the high level of residual vascular risk among dyslipidaemic patients who are treated in accordance with current standards of care.
Apoptotic cell death following injury of vascular endothelium is assumed to play an important role in the pathogenesis of atherosclerosis. In this report, we demonstrate that high density ...lipoproteins (HDL), a major anti-atherogenic lipoprotein fraction, protect endothelial cells against growth factor deprivation-induced apoptosis. HDL blocked the mitochondrial pathway of apoptosis by inhibiting dissipation of mitochondrial potential (Δψm), generation of reactive oxygen species, and release of cytochrome c into the cytoplasm. As a consequence, HDL prevented activation of caspases 9 and 3 and apoptotic alterations of the plasma membrane such as increase of permeability and translocation of phosphatidylserine. Treatment of endothelial cells with HDL induced activation of the protein kinase Akt, an ubiquitous transducer of anti-apoptotic signals, and led to phosphorylation of BAD, a major Akt substrate. Suppression of Akt activity both by wortmannin and LY-294002 or by a dominant negative Akt mutant abolished the anti-apoptotic effect of HDL. Two bioactive lysosphingolipids present in HDL particles, sphingosylphosphorylcholine and lysosulfatide, fully mimicked the survival effect of HDL by blocking the mitochondrial pathway of apoptosis and potently activating Akt. In conclusion, the present study identifies HDL as a carrier of endogenous endothelial survival factors and suggests that inhibition of endothelial apoptosis by HDL-associated lysosphingolipids may represent an important and novel aspect of the anti-atherogenic activity of HDL.
PDF
