Showing papers in "Current Atherosclerosis Reports in 2010"

Saturated fatty acids and risk of coronary heart disease: modulation by replacement nutrients.

Abstract: Despite the well-established observation that substitution of saturated fats for carbohydrates or unsaturated fats increases low-density lipoprotein (LDL) cholesterol in humans and animal models, the relationship of saturated fat intake to risk for atherosclerotic cardiovascular disease in humans remains controversial. A critical question is what macronutrient should be used to replace saturated fat. Substituting polyunsaturated fat for saturated fat reduces LDL cholesterol and the total cholesterol to high-density lipoprotein cholesterol ratio. However, replacement of saturated fat by carbohydrates, particularly refined carbohydrates and added sugars, increases levels of triglyceride and small LDL particles and reduces high-density lipoprotein cholesterol, effects that are of particular concern in the context of the increased prevalence of obesity and insulin resistance. Epidemiologic studies and randomized clinical trials have provided consistent evidence that replacing saturated fat with polyunsaturated fat, but not carbohydrates, is beneficial for coronary heart disease. Therefore, dietary recommendations should emphasize substitution of polyunsaturated fat and minimally processed grains for saturated fat.

Particulate matter air pollution and atherosclerosis.

Abstract: Particulate matter (PM) air pollution less than 2.5 μm in diameter (PM2.5), which is now an all-pervading element of modern-day society, is associated with heightened cardiovascular morbidity and mortality. Not only can short-term PM2.5 exposure trigger acute cardiovascular events, but longer-term exposure over years augments cardiovascular risk to an even greater extent. One biological mechanism capable of explaining this observation is that chronic exposure may promote the progression and vulnerability of atherosclerotic plaques. Indeed, recent epidemiologic studies have demonstrated an association between ambient PM2.5 exposure and the presence or extent of atherosclerosis in humans. Several animal experiments have provided corroborating evidence that chronic exposures in fact do enhance the progression and perhaps vulnerability of atherosclerotic lesions. Due to the billions of people continually exposed to PM2.5, the long-term pro-atherosclerotic effects of this ubiquitous air pollutant are likely to be of enormous and growing global public health importance.

Effects of whole grains on coronary heart disease risk.

Abstract: Characterizing which types of carbohydrates, including whole grains, reduce the risk for coronary heart disease (CHD) is challenging. Whole grains are characterized as being high in resistant carbohydrates as compared with refined grains, meaning they typically are high in fiber, nutrients, and bound antioxidants. Whole grain intake consistently has been associated with improved cardiovascular disease outcomes, but also with healthy lifestyles, in large observational studies. Intervention studies that assess the effects of whole grains on biomarkers for CHD have mixed results. Due to the varying nutrient compositions of different whole grains, each could potentially affect CHD risk via different mechanisms. Whole grains high in viscous fiber (oats, barley) decrease serum low-density lipoprotein cholesterol and blood pressure and improve glucose and insulin responses. Grains high in insoluble fiber (wheat) moderately lower glucose and blood pressure but also have a prebiotic effect. Obesity is inversely related to whole grain intake, but intervention studies with whole grains have not produced weight loss. Visceral fat, however, may be affected favorably. Grain processing improves palatability and can have varying effects on nutrition (e.g., the process of milling and grinding flour increases glucose availability and decreases phytochemical content whereas thermal processing increases available antioxidants). Understanding how individual grains, in both natural and processed states, affect CHD risk can inform nutrition recommendations and policies and ultimately benefit public health.

Nuts and Berries for Heart Health

Abstract: Nuts are nutrient-dense foods with complex matrices rich in unsaturated fatty acids and other bioactive compounds, such as L-arginine, fiber, minerals, tocopherols, phytosterols, and polyphenols. By virtue of their unique composition, nuts are likely to beneficially impact heart health. Epidemiologic studies have associated nut consumption with a reduced incidence of coronary heart disease in both genders and diabetes in women. Limited evidence also suggests beneficial effects on hypertension and inflammation. Interventional studies consistently show that nut intake has a cholesterol-lowering effect and there is emerging evidence of beneficial effects on oxidative stress, inflammation, and vascular reactivity. Blood pressure, visceral adiposity, and glycemic control also appear to be positively influenced by frequent nut consumption without evidence of undue weight gain. Berries are another plant food rich in bioactive phytochemicals, particularly flavonoids, for which there is increasing evidence of benefits on cardiometabolic risk that are linked to their potent antioxidant power.

Future Therapeutic Directions in Reverse Cholesterol Transport

Abstract: Despite a robust inverse association between high-density lipoprotein (HDL) cholesterol levels and atherosclerotic cardiovascular disease, the development of new therapies based on pharmacologic enhancement of HDL metabolism has proven challenging. Emerging evidence suggests that static measurement of HDL levels has inherent limitations as a surrogate for overall HDL functionality, particularly with regard to the rate of flux through the macrophage reverse cholesterol transport (RCT) pathway. Recent research has provided important insight into the molecular underpinnings of RCT, the process by which excess cellular cholesterol is effluxed from peripheral tissues and returned to the liver for ultimate intestinal excretion. This review discusses the critical importance and current strategies for quantifying RCT flux. It also highlights therapeutic strategies for augmenting macrophage RCT via three conceptual approaches: 1) improved efflux of cellular cholesterol via targeting the macrophage; 2) enhanced cholesterol efflux acceptor functionality of circulating HDL; and 3) increased hepatic uptake and biliary/intestinal excretion.

Lipidomics: a tool for studies of atherosclerosis

Abstract: Lipids, abundant constituents of both the vascular plaque and lipoproteins, play a pivotal role in atherosclerosis. Mass spectrometry-based analysis of lipids, called lipidomics, presents a number of opportunities not only for understanding the cellular processes in health and disease but also in enabling personalized medicine. Lipidomics in its most advanced form is able to quantify hundreds of different molecular lipid species with various structural and functional roles. Unraveling this complexity will improve our understanding of diseases such as atherosclerosis at a level of detail not attainable with classical analytical methods. Improved patient selection, biomarkers for gauging treatment efficacy and safety, and translational models will be facilitated by the lipidomic deliverables. Importantly, lipid-based biomarkers and targets should lead the way as we progress toward more specialized therapeutics.

The Influence of PCSK9 Polymorphisms on Serum Low-Density Lipoprotein Cholesterol and Risk of Atherosclerosis

Abstract: Pro-protein-convertase-subtilisin-kexin-9 (PCSK9) enhances the degradation of the low-density lipoprotein receptor (LDLR) that plays a major role in cholesterol homeostasis. Recent advances have revealed a large number of genetic variants of PCSK9 that may modulate plasma cholesterol levels either positively or negatively, therefore influencing the risk of atherosclerosis. Recognition of these mutants may have clinical implication in assessing severity of disease, prognosis, or response to drug therapy. PCSK9’s expression, secretion, and plasma levels maybe modulated by the proprotein convertase furin, by natural inhibitors (annexin-A2), or influenced by lipid-altering agents such as statins, fibrates, ezetimibe, and berberine. It is now a prime target for therapy, prompting the development of various approaches to reduce its LDLR degrading activity, including antibody neutralization, anti-sense oligonucleotides such as phosphorothioates, locked nucleic acids, and RNA interference, and eventually small molecule inhibitors. Which one will be clinically applicable will depend on long-term effects, cost, and ease of administration.

Legacy effects from DCCT and UKPDS: what they mean and implications for future diabetes trials.

Abstract: The United Kingdom Prospective Diabetes Study (UKPDS) and the Diabetes Chronic Complications Trial (DCCT) are two landmark trials that convincingly demonstrated that tight glycemic control has beneficial effects on microvascular end points. These studies also revealed a “legacy effect,” which is a sustained benefit with respect to cardiovascular disease outcomes seen long after the conclusion of the trial. We discuss possible molecular mechanisms that could play a role in causing the legacy effect.

Evidence-based management of statin myopathy.

Abstract: Statin-associated muscle symptoms are a relatively common condition that may affect 10% to 15% of statin users. Statin myopathy includes a wide spectrum of clinical conditions, ranging from mild myalgia to rhabdomyolysis. The etiology of myopathy is multifactorial. Recent studies suggest that statins may cause myopathy by depleting isoprenoids and interfering with intracellular calcium signaling. Certain patient and drug characteristics increase risk for statin myopathy, including higher statin doses, statin cytochrome metabolism, and polypharmacy. Genetic risk factors have been identified, including a single nucleotide polymorphism of SLCO1B1. Coenzyme Q10 and vitamin D have been used to prevent and treat statin myopathy; however, clinical trial evidence demonstrating their efficacy is limited. Statin-intolerant patients may be successfully treated with either low-dose statins, alternate-day dosing, or using twice-weekly dosing with longer half-life statins. An algorithm is presented to assist the clinician in managing myopathy in patients with dyslipidemia.

Fish Oil for Primary and Secondary Prevention of Coronary Heart Disease

Abstract: Fish consumption and fish oils rich in omega-3 fatty acids were reported to be cardioprotective in both retrospective and prospective studies undertaken over the past two to three decades. In the past several years, there is mounting clinical trial data as well as basic science information supporting the use of fish oil supplements in both primary and secondary cardiovascular prevention. In addition, there appear to be additional benefits to the use of fish oil, including lowering significantly elevated triglyceride levels, preventing atrial fibrillation, reducing mortality rates in congestive heart failure patients, and perhaps stabilizing atherosclerotic plaques. These data have led to specific recommendations for use of omega-3 fatty acids in several cardiovascular areas.

Role of C-Reactive Protein in Contributing to Increased Cardiovascular Risk in Metabolic Syndrome

Abstract: Metabolic syndrome is associated with increased propensity for diabetes and cardiovascular disease. Low-grade inflammation is characteristic of metabolic syndrome. C-reactive protein, the best characterized biomarker of inflammation, is also an independent predictor of future cardiovascular events. This review outlines the role of high-sensitivity C-reactive protein in contributing to increased cardiovascular risk in metabolic syndrome by inducing endothelial cell dysfunction and activating monocytes.

Dietary monounsaturated fatty acids appear not to provide cardioprotection

Abstract: Dietary interventions have been consistently proposed as a part of a comprehensive strategy to lower the incidence and severity of coronary heart disease (CHD), in the process providing long-term cardioprotection. Replacement of dietary saturated fatty acids (SFA) with higher intakes of monounsaturated fatty acids (MUFA) and polyunsaturated fatty acids (PUFA) has been reported to be inversely associated with risk of CHD. The observed lower incidence of CHD among populations consuming a Mediterranean-type diet, mainly enriched in MUFA from olive oil, has long supported the belief that MUFA are an optimal substitution for SFA. However, both epidemiologic and interventional studies suggest that although substituting MUFA-rich foods for SFA-rich foods in the diet can potentially lower total plasma cholesterol concentrations, this substitution does not lower the extent of coronary artery atherosclerosis. In addition, although recent evidence suggests that the source of MUFA (animal fat vs vegetable oils) may differentially influence the correlation between MUFA intake and CHD mortality, animal studies suggest that neither source is cardioprotective.

Soluble epoxide hydrolase in atherosclerosis.

Abstract: Like many eicosanoids, epoxyeicosatrienoic acids (EETs) have multiple biological functions, including reduction of blood pressure, inflammation, and atherosclerosis in multiple species. Hydration of EETs by the soluble epoxide hydrolase (sEH) is the major route of their degradation to the less bioactive diols. Inhibition of the sEH stabilizes EETs, thus, enhancing the beneficial effects of EETs. Human data show an association of sEH (Ephx2) gene polymorphisms with increased risk of atherosclerosis and cardiovascular diseases. These data suggest a potential therapeutic effect of sEH inhibitors (sEHI) in the treatment of atherosclerosis. Indeed, two laboratories reported independently that using different sEHIs in apolipoprotein E–deficient mice significantly attenuated atherosclerosis development and aneurysm formation. The antiatherosclerotic effects of sEHI are correlated with elevation in EET levels and associated with reduction of low-density lipoprotein and elevation of high-density lipoprotein cholesterols, as well as attenuation of expression of proinflammatory genes and proteins. In addition, the antihypertensive effects and improvement of endothelial function also contribute to the mechanism of the antiatherosclerotic effects of sEHI. The broad spectrum of biological action of EETs and sEHIs with multiple biological beneficial actions provides a promising new class of therapeutics for atherosclerosis and other cardiovascular diseases.

Coronary Heart Disease and Body Fat Distribution

Abstract: Larger waist circumference or waist-hip ratio, as crude indicators of visceral fat mass, are associated with adverse metabolic profile, but their role in predicting future coronary heart disease (CHD) events has been less investigated. Recent epidemiologic findings suggest that these simple and inexpensive measures of abdominal fat distribution predict CHD independently of body mass index, and, to a certain extent, cardiovascular disease risk factors. The magnitude and shape of the association between abdominal adiposity and CHD have been shown to vary with age, gender, and ethnicity. Studies have also suggested that lower body fat is associated with reduced CHD risk, although the clinical relevance for this finding needs further elucidation. Assessing body fat distribution may be useful for improving CHD risk assessment, although more studies are needed to assess consistency in CHD risk predictions across populations. A consensus is also needed to define the clinically relevant cut-off points for waist circumference or waist-hip ratio.

Dysfunctional High-Density Lipoprotein and Atherosclerosis

Abstract: High-density lipoprotein (HDL) is well established as a negative risk factor for the development of atherosclerosis. Epidemiologic, pathologic, and experimental studies have demonstrated a role for HDL in protection from coronary artery disease. HDL has been demonstrated to reduce the risk from atherosclerosis by multiple pathophysiologic mechanisms. Low-density lipoprotein is a metabolic end product that can be recognized and cleared by specific hepatic receptors with excretion into the bile. However, low-density lipoprotein may also be scavenged in the periphery by the monocyte-macrophage system, with subsequent generation of lipid-laden foam cells. HDL may reduce the atherosclerotic burden by multiple potential mechanisms. HDL can interact with the foam cell to remove cholesterol via receptor-mediated binding, passive diffusion, and alteration of intracellular cholesterol trafficking by ATP binding cassettes. The process of reverse cholesterol transport is a major mechanism by which HDL can remove cholesterol from the periphery, allowing it to be cleared by the liver and then excreted into the bile. However, HDL exhibits multiple additional potential beneficial physiologic effects. Endothelial function and repair is potentiated by HDL. Normal HDL has significant anti-inflammatory and antioxidant activity. Prostacyclin production and improvement in fibrinolytic balance is also attributed to normally functioning HDL. HDL is also intimately related to the metabolism of other circulating lipoproteins. However, multiple clinical studies have identified individuals with a significant atherosclerotic burden despite normal or elevated levels of HDL cholesterol. Clinical conditions associated with inflammation and oxidative stress have adversely altered the normal functions of HDL. Clinical assays have been developed to assess the functionality of HDL. Dysfunctional HDL may be returned to normal by diet, exercise, degree of fat intake, and pharmacologic approaches. Orally active mimetic proteins are in development and have shown clinical promise.

Alpha-Linolenic Acid: Is It Essential to Cardiovascular Health?

Abstract: There is a large body of scientific evidence that has been confirmed in randomized controlled trials indicating a cardioprotective effect for omega-3 fatty acids from fish. For alpha-linolenic acid (ALA), which is the omega-3 fatty acid from plants, the relation to cardiovascular health is less clear. We reviewed the recent literature on dietary ALA intake, ALA tissue concentrations, and cardiovascular health in humans. Short-term trials (6–12 weeks) in generally healthy participants mostly showed no or inconsistent effects of ALA intake (1.2–3.6 g/d) on blood lipids, low-density lipoprotein oxidation, lipoprotein(a), and apolipoproteins A-I and B. Studies of ALA in relation to inflammatory markers and glucose metabolism yielded conflicting results. With regard to clinical cardiovascular outcomes, there is observational evidence for a protective effect against nonfatal myocardial infarction. However, no protective associations were observed between ALA status and risk of heart failure, atrial fibrillation, and sudden death. Findings from long-term trials of ALA supplementation are awaited to answer the question whether food-based or higher doses of ALA could be important for cardiovascular health in cardiac patients and the general population.

Revisiting Dietary Cholesterol Recommendations: Does the Evidence Support a Limit of 300 mg/d?

Abstract: The perceived association between dietary cholesterol (DC) and risk for coronary heart disease (CHD) has resulted in recommendations of no more than 300 mg/d for healthy persons in the United States. These dietary recommendations proposed in the 1960s had little scientific evidence other than the known association between saturated fat and cholesterol and animal studies where cholesterol was fed in amounts far exceeding normal intakes. In contrast, European countries, Asian countries, and Canada do not have an upper limit for DC. Further, current epidemiologic data have clearly demonstrated that increasing concentrations of DC are not correlated with increased risk for CHD. Clinical studies have shown that even if DC may increase plasma low-density lipoprotein (LDL) cholesterol in certain individuals (hyper-responders), this is always accompanied by increases in high-density lipoprotein (HDL) cholesterol, so the LDL/HDL cholesterol ratio is maintained. More importantly, DC reduces circulating levels of small, dense LDL particles, a well-defined risk factor for CHD. This article presents recent evidence from human studies documenting the lack of effect of DC on CHD risk, suggesting that guidelines for DC should be revisited.

Metabolomics and Atherosclerosis

Abstract: Metabolites reflect the dynamic processes underlying cellular homeostasis. Recent advances in analytical chemistry and molecular biology have set the stage for metabolite profiling to help us understand complex molecular processes and physiology. Metabolomics is the comparative analysis of metabolite flux and how it relates to biological phenotypes. As an intermediate phenotype, metabolite signatures capture a unique aspect of cellular dynamics that is not typically interrogated, providing a distinct perspective on cellular homeostasis. To date, there have been only a few metabolomics studies investigating cardiovascular diseases. In this review, we explore the principles of metabolomics and how it can provide further insight into the mechanisms of cardiovascular physiology and ultimately lead to improved diagnostic and therapeutic options for patients with cardiovascular disease.

Lipidomics as a tool for the study of lipoprotein metabolism.

Abstract: Although technologies for lipidomic and proteomic investigations have developed very recently, lipidomic and proteomic studies of plasma lipoproteins have already provided several impressive examples of detailed characterization of distinct metabolic pathways potentially involved in lipoprotein metabolism in both health and disease states (obesity, insulin resistance, fatty liver disease) as well as under lifestyle and dietary modification (fish consumption, carbohydrates, probiotics) and lipid-modifying treatments (statins, low-density lipoprotein apheresis). Available lipidomic methodologies have facilitated detailed characterization of lipid classes and molecular species present in plasma as well as in lipoprotein fractions. Together with emerging proteomic techniques, lipidomics of plasma lipoproteins will soon provide molecular details of lipoprotein composition, which will ultimately be translated into integrated knowledge of the structure, metabolism, and function of lipoproteins in health and disease.

Omega-3 fatty acids, mercury, and selenium in fish and the risk of cardiovascular diseases.

Abstract: Fish consumption is associated with lower risk of cardiovascular disease. Some fish species also contain methylmercury, which may increase cardiovascular risk, as well as selenium, a trace element that could counter the effects of methylmercury or have beneficial effects itself. These potentially conflicting effects have created public confusion about the risks and benefits of fish consumption in adults. We examined the evidence for cardiovascular effects of fish consumption, particularly effects of marine omega-3 fatty acids, methylmercury, and selenium. Compelling evidence indicates that modest fish consumption substantially reduces cardiovascular risk, in particular cardiac mortality, related at least partly to benefits of omega-3 fatty acids. In contrast, observational studies and (for selenium) clinical trials demonstrate mixed and inconclusive results for cardiovascular effects of methylmercury and selenium. Net health benefits of overall fish consumption in adults are clear. Quantitative risk-benefit analyses of cardiovascular effects of consuming specific fish species, based on joint contents of fatty acids, methylmercury, and selenium, cannot currently be performed until the cardiovascular effects of methylmercury and selenium are established.

Red Yeast Rice for Dyslipidemia in Statin-Intolerant Patients

Abstract: Statin-associated myalgias represent a significant health concern as they often limit the ability of patients to receive the mortality benefits associated with statin therapy. Randomized controlled trials show rates of statin-associated myalgias ranging between 1% and 5%, with some rates as high as 15%, although not significantly different from placebo-treated patients [1, 2]. Although not often associated with creatinine phosphokinase (CPK) level elevations or progression to rhabdomyolysis, the symptoms can be disconcerting to patients and are a frequent cause of statin discontinuation. A variety of strategies have been attempted to manage this challenge, including decreasing the statin dose, trying alternative statins or other lipid-lowering agents, and intensifying therapeutic lifestyle changes [3]. An additional tool used by many patients and physicians has been red yeast rice (Monascus purpureus). The mechanism of action is not completely understood, although the active agent is thought to be monacolin K, a 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitor produced as the pharmaceutical lovastatin. However, red yeast rice also contains other monacolins that may have similar or different effects, making red yeast rice not a “true” statin medication. Thus far, widespread use of red yeast has been limited by the variety of preparations (as it is a dietary supplement rather than a pharmaceutical) and the relative paucity of data on its safety and efficacy relative to statin drugs. Many clinicians do use red yeast rice as an alternative for their statinintolerant patients; however, no randomized controlled trial has examined using red yeast rice to treat patients with statin-associated myalgias.

The Role of Smoking Cessation in the Prevention of Coronary Artery Disease

Abstract: Smoking (tobacco addiction) is the most significant of the modifiable cardiovascular risk factors. Mistakenly described as a “habit” or “behavioral choice,” the onset of tobacco addiction quickly follows the acquisition of an ability to inhale cigarette smoke and is reflected in a transformation of neurophysiologic function and nicotine-receptor density. Thereafter, comfort and a degree of neurophysiologic “equanimity” require the regular administration of nicotine. Smokers inhale thousands of other chemicals, many of which play critical roles in the initiation and accentuation of atherosclerosis by influencing vasomotor activity, vascular dysfunction, oxidation of lipids, atheroma development, and thrombosis. Smoking cessation is a priority in the management of any patient with cardiovascular disease. The benefits of cessation accrue rapidly in such patients and have a pronounced effect on the likelihood of disease progression, hospital readmission, and mortality. All physicians must be familiar with the principles of cessation practice and be able to initiate smoking cessation attempts.

Novel genetic mechanisms for aortic aneurysms.

Abstract: Aortic aneurysms occur in the thoracic and abdominal sections of the aorta and are a deadly late-age-at-onset disease with complex pathobiology. Currently, the number of published genome-wide analyses including microarray-based expression profiling, DNA linkage studies, and genetic association studies is still limited and it is difficult to make generalizations about the disease pathogenesis or genetic risk factors contributing to aortic aneurysms, but it appears that thoracic aortic aneurysms differ in many ways from abdominal aortic aneurysms. Characterization of diseases at the molecular level is likely to lead to more accurate diagnoses and the use of “genomic nosology” of disease. The biggest future challenge will be to translate the genomic information to the clinic and improve our understanding of the disease processes, help us to develop better diagnostic tools, and lead to the design of new ways to manage aortic aneurysms in the era of personalized medicine.

Management of the patient with statin intolerance.

Abstract: Current guidelines recommend statins as first-line therapy for reducing low-density lipoprotein cholesterol (LDL-C) and preventing cardiovascular events. Patients taking statins frequently experience adverse effects during therapy. The first step is to determine whether the adverse effects are indeed related to statin therapy by statin dechallenge and rechallenge. Strategies for managing statin intolerance include changing statins, intermittent dosing, intensification of lifestyle modifications, and using other LDL-C-lowering agents such as ezetimibe, bile acid sequestrants, and LDL apheresis in suitable patients. More controversial approaches include red yeast rice, coenzyme Q10, and vitamin D supplementation. New therapies for LDL-C lowering are in development.

Coenzyme Q(10) and statin myalgia: what is the evidence?

Abstract: Statins lower cholesterol by inhibiting 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase, the rate-limiting enzyme in the biosynthesis of cholesterol. However, severe adverse events, including myalgias and rhabdomyolysis, have been reported with statin treatment. Different mechanisms have been proposed to explain statin-induced myopathy, including reduction of mevalonate pathway products, induction of apoptosis, mitochondrial dysfunction, and genetic predisposition. A decrease in coenzyme Q10 (CoQ), a product of the mevalonate pathway, could contribute to statin induced myopathy. This article reviews the clinical and biochemical features of statin-induced myopathy, the inter-relationship between statins and the concentration of CoQ in plasma and tissues, and whether there is a role for supplementation with CoQ to attenuate statin-induced myopathy.

Development of Apolipoprotein B Antisense Molecules as a Therapy for Hyperlipidemia

Abstract: As new studies demonstrate that lower levels of low-density lipoprotein cholesterol (LDL-C) reduce cardiovascular disease, and as goals for LDL-C in high-risk individuals are reduced further and further, reaching those goals becomes more difficult for a significant percentage of the population. New therapeutic approaches to lower LDL-C would, therefore, be advantageous, particularly in those who are most likely to suffer cardiovascular disease—associated morbidity and mortality. Mouse and human genetic models suggest that decreasing hepatic apolipoprotein B (apoB) production may be a therapeutic approach for the treatment of dyslipidemia. Because antisense oligonucleotides naturally distribute to the liver and can specifically inhibit synthesis of proteins from their messenger RNAs, antisense oligonucleotides represent a potential approach for decreasing the biosynthesis of apoB, and thereby, the production of both very low density lipoprotein (VLDL) and LDL. Newly developed apoB antisense approaches have produced results in animal models and humans, providing proof of concept regarding reductions in LDL-C concentrations. Surprisingly, despite prior experience with inhibitors of microsomal triglyceride transfer protein, which also inhibits the secretion of VLDL, apoB antisense-mediated reduction in VLDL secretion does not appear to cause marked steatosis. The mechanisms whereby two different approaches for inhibiting apoB and triglyceride secretion have different effects on hepatic triglycerides are currently being examined.

The Spectrum of Atherosclerotic Coronary Artery Disease in HIV Patients

Abstract: The incidence of HIV is on the rise. With the advent of antiretroviral therapy, the average life expectancy of HIV patients has increased by several decades, but the increasing life expectancy has shifted the spectrum of HIV-associated morbidity and mortality away from opportunistic infections and toward chronic medical conditions. In fact, coronary artery disease has become the leading cause of mortality in patients with HIV. The pathophysiology of atherosclerosis in patients with HIV is very complex, including direct endothelial damage from viremia, a heightened overall state of inflammation from immune activation, higher prevalence and contribution from traditional atherosclerotic risk factors, and direct effects from antiretroviral therapy itself. This review focuses on the patterns, predictors, and pathophysiology of atherosclerotic disease in patients with HIV. In addition, the risks and benefits of evidence-based highly active antiretroviral therapy are critically evaluated.

Biological Properties of Apolipoprotein A-I Mimetic Peptides

Abstract: Apolipoprotein A-I (apoA-I) mimetic peptides resemble the physiochemical properties of the helices of apoA-I and show promise for the treatment of atherosclerotic vascular diseases and other chronic inflammatory disorders. These peptides have numerous properties, such as the ability to remodel high-density lipoprotein, sequester oxidized lipids, promote cholesterol efflux, and activate an anti-inflammatory process in macrophages, any or all of which may contribute to their antiatherogenic properties. In murine models, the 4F peptide attenuates early atherosclerosis but seems to require the addition of statins to influence more mature lesions. A recently developed method for the oral delivery of the peptides that protects them from proteolysis will facilitate further research on the mechanism of action of these peptides. This review focuses on the properties of the 4F peptide, although numerous apoA-I mimetics are under investigation and a single “best” peptide that mimics all of the properties of the antiatherogenic protein apoA-I has not been identified.

Hypercholesterolemia in Youth: Opportunities and Obstacles to Prevent Premature Atherosclerotic Cardiovascular Disease

Abstract: Treatment of hypercholesterolemia in youth is predicated on the knowledge that we can identify those youth with this atherosclerotic risk factor most likely to develop premature cardiovascular disease. Unfortunately, this is not the case. Before we can adequately address appropriate lipid-lowering therapies in this special population, we must address and resolve current barriers related to screening and diagnosis. In this article, we describe some of the opportunities and obstacles that clinicians and policy makers confront when applying the current pediatric guidelines focused on screening and treating hypercholesterolemia in the pediatric population.

Proteomic and Metabolomic Profiles in Atherothrombotic Vascular Disease

Abstract: Atherothrombosis remains a major cause of morbidity and mortality in the western world. The underlying processes associated with clinical expression of atherothrombosis include oxidative stress and proteolysis in relation to neovascularisation and intraplaque hemorrhages, leading to immuno-inflammatory response, cell death, and extracellular matrix breakdown. The complex biological multifactorial nature of atherothrombosis requires the development of novel technologies that allow the analysis of cellular and molecular processes responsible for the transition to disease phenotypes and the discovery of new diagnostic and prognostic biomarkers. In the present article, we have reviewed recent advances in the application of proteomic and metabolomic techniques to the study of atherothrombosis. We have focused on recent studies analyzing cells involved in hemo-thrombus formation (platelets, red blood cells, and polymorphonuclear cells), as well as tissues, tissue-conditioned media, and plasma of atherothrombotic patients. In the future, the application of these high-throughput technologies, along with imaging techniques, in systems biology approaches will help to individualize medicine.