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Find video protocols related to scientific articles indexed in Pubmed.
Assessment and potential determinants of compliance and persistence to antiosteoporosis therapy in Italy.
Am J Manag Care
PUBLISHED: 10-21-2014
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To analyze adherence to antiosteoporosis drugs (AODs) and to assess the influence of patient-related and drug-related factors.
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Homozygous familial hypercholesterolaemia: new insights and guidance for clinicians to improve detection and clinical management. A position paper from the Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society.
Eur. Heart J.
PUBLISHED: 07-22-2014
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Homozygous familial hypercholesterolaemia (HoFH) is a rare life-threatening condition characterized by markedly elevated circulating levels of low-density lipoprotein cholesterol (LDL-C) and accelerated, premature atherosclerotic cardiovascular disease (ACVD). Given recent insights into the heterogeneity of genetic defects and clinical phenotype of HoFH, and the availability of new therapeutic options, this Consensus Panel on Familial Hypercholesterolaemia of the European Atherosclerosis Society (EAS) critically reviewed available data with the aim of providing clinical guidance for the recognition and management of HoFH.
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Statins and the risk of diabetes: evidence from a large population-based cohort study.
Diabetes Care
PUBLISHED: 06-26-2014
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To investigate the relationship between adherence with statin therapy and the risk of developing diabetes.
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Combination therapy in dyslipidemia: Where are we now?
Atherosclerosis
PUBLISHED: 06-23-2014
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Lowering low-density lipoprotein cholesterol (LDL-C) reduces the risk of cardiovascular disease: each 1.0 mmol/L (38.7 mg/dL) reduction in LDL-C reduces the incidence of major coronary events, coronary revascularizations, and ischemic stroke by approximately 20%. Statins are a well-established treatment option for dyslipidemia, with LDL-C reduction in the range of 27-55%. Several lipid goal-driven guidelines recommend reducing LDL-C to <2.59 mmol/L (100 mg/dL) or <1.81 mmol/L (70 mg/dL) in very high-risk patients. Many patients treated with statins do not reach these goals, and remain at risk of future cardiovascular events. The 2013 American College of Cardiology/American Heart Association guidelines move away from advocating LDL-C treatment targets with focus placed on identifying patients most likely to benefit from high-intensity or moderate-intensity statin therapy. While increasing the statin dose can prove efficacious in some patients, this approach typically offers limited additional LDL-C lowering, and is associated with increased incidence of adverse side effects. Indeed, this has led to the investigation of statins in combination with other lipid-modifying agents for the treatment of dyslipidemia. This review of the evidence for statin use in combination with fibrates, niacin, bile acid sequestrants, and the cholesterol absorption inhibitor, ezetimibe, in dyslipidemic patients at increased risk of cardiovascular disease, explores the impact of such combination therapies on lipids, attainment of lipid targets, inflammatory markers, and on cardiovascular outcomes and pathology. Additionally, new and emerging dyslipidemia treatments are summarized.
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Novel concepts in HDL pharmacology.
Cardiovasc. Res.
PUBLISHED: 06-20-2014
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High-density lipoproteins (HDL) are a target for drug development because of their proposed anti-atherogenic properties. In this review, we will briefly discuss the currently established drugs for increasing HDL-C, namely niacin and fibrates, and some of their limitations. Next, we will focus on novel alternative therapies that are currently being developed for raising HDL-C, such as CETP inhibitors. Finally, we will conclude with a review of novel drugs that are being developed for modulating the function of HDL based on HDL mimetics. Gaps in our knowledge and the challenges that will have to be overcome for these new HDL based therapies will also be discussed.
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HDL in innate and adaptive immunity.
Cardiovasc. Res.
PUBLISHED: 06-15-2014
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During infections or acute conditions high-density lipoproteins cholesterol (HDL-C) levels decrease very rapidly and HDL particles undergo profound changes in their composition and function. These changes are associated with poor prognosis following endotoxemia or sepsis and data from genetically modified animal models support a protective role for HDL. The same is true for some parasitic infections, where the key player appears to be a specific and minor component of HDL, namely apoL-1. The ability of HDL to influence cholesterol availability in lipid rafts in immune cells results in the modulation of toll-like receptors, MHC-II complex, as well as B- and T-cell receptors, while specific molecules shuttled by HDL such as sphingosine-1-phosphate (S1P) contribute to immune cells trafficking. Animal models with defects associated with HDL metabolism and/or influencing cell cholesterol efflux present features related to immune disorders. All these functions point to HDL as a platform integrating innate and adaptive immunity. The aim of this review is to provide an overview of the connection between HDL and immunity in atherosclerosis and beyond.
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HDL: to treat or not to treat?
Curr Atheroscler Rep
PUBLISHED: 06-04-2014
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Several studies have shown an inverse relationship between HDL cholesterol (HDL-C) levels and the risk of cardiovascular disease. Low HDL-C levels are commonly present in subjects with diabetes, metabolic syndrome, or obesity. These observations have suggested that increasing HDL concentrations might help in decreasing the cardiovascular disease risk. However, despite initial positive results, some recent data from clinical trials with HDL-raising therapies failed to confirm this hypothesis; in addition, data from Mendelian randomization analyses showed that nucleotide polymorphisms associated with increased HDL-C levels did not decrease the risk of myocardial infarction, further challenging the concept that higher HDL-C levels will automatically translate into lower cardiovascular disease risk. Differences in the quality and distribution of HDL particles might partly explain these findings, and in agreement with this hypothesis, some observations have suggested that HDL subpopulation levels may be better predictors of cardiovascular disease than simple HDL-C levels. Thus, it is expected that increased HDL-C levels may be beneficial when associated with an improvement in HDL function, suggesting that pharmacological approaches able to correct or increase HDL functions might produce more reliable clinical benefits.
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PCSK9 inhibition for the treatment of hypercholesterolemia: promises and emerging challenges.
Vascul. Pharmacol.
PUBLISHED: 05-30-2014
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Hypercholesterolemia, is a prominent risk factor for cardiovascular disease (CVD). Undestanding of the biochemical mechanisms that regulate the expression of the low density lipoproteins receptor (LDLR) and the hepatic clearance of LDL cholesterol (LDL-C) paved the way to the statin therapy as the gold standard for CVD prevention. The discovery of proteins that regulate - at a post-translational level - the activity of the LDLR has been a major breakthrough in developing new cholesterol-lowering drugs. Proprotein convertase subtilisin/kexin type 9 (PCSK9) is a key modulator of the LDLR degradation in the liver. Genetic studies confirmed that in humans PCSK9 mutations associate with hypercholesterolemia and hypocholesterolemia (gain-of-function or loss-of-function variants respectively). Moreover, PCSK9 is up-regulated by statin treatment and limits the efficacy of these agents. These findings led to the development of PCSK9 inhibitors. Anti-PCSK9 monoclonal antibodies showed encouraging results and are currently being evaluated in phase III clinical trials. The aim of this short review is to describe the new frontier of PCSK9 inhibition in the treatment of hypercholesterolemia. Emphasis here is given to critical emerging issues linked to PCSK9 physiology and pharmacology, which will require future investigation to definitely address the potential of anti-PCSK9 drugs in clinical practice.
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Are generic and brand-name statins clinically equivalent? Evidence from a real data-base.
Eur. J. Intern. Med.
PUBLISHED: 05-26-2014
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Use of generic drugs can help contain drug spending. However, there is concern among patients and physicians that generic drugs may be clinically inferior to brand-name ones. This study aimed to compare patients treated with generic and brand-name statins in terms of therapeutic interruption and cardiovascular (CV) outcomes.
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MiR-143/145 deficiency attenuates the progression of atherosclerosis in Ldlr-/-mice.
Thromb. Haemost.
PUBLISHED: 05-14-2014
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The miR-143/145 cluster regulates VSMC specific gene expression, thus controlling differentiation, plasticity and contractile function, and promoting the VSMC phenotypic switch from a contractile/non-proliferative to a migrating/proliferative state. More recently increased miR-145 expression was observed in human carotid atherosclerotic plaques from symptomatic patients. The goal of this study was to investigate the contribution of miR-143/145 during atherogenesis by generating mice lacking miR-143/145 on an Ldlr-deficient background. Ldlr-/- and Ldlr-/--miR-143/145-/- (DKO) were fed a Western diet (WD) for 16 weeks. At the end of the treatment, the lipid profile and the atherosclerotic lesions were assessed in both groups of mice. Absence of miR-143/145 significantly reduced atherosclerotic plaque size and macrophage infiltration. Plasma total cholesterol levels were lower in DKO and FLPC analysis showed decreased cholesterol content in VLDL and LDL fractions. Interestingly miR-143/145 deficiency per se resulted in increased hepatic and vascular ABCA1 expression. We further confirmed the direct regulation of miR-145 on ABCA1 expression by qRT-PCR, Western blotting and 3'UTR-luciferase reporter assays. In summary, miR-143/145 deficiency significantly reduces atherosclerosis in mice. Therapeutic inhibition of miR-145 might be useful for treating atherosclerotic vascular disease.
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Postprandial lipemia as a cardiometabolic risk factor.
Curr Med Res Opin
PUBLISHED: 05-02-2014
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High levels of fasting circulating triglycerides (TG) represent an independent risk factor for cardiovascular disease. In western countries, however, people spend most time in postprandial conditions, with continuous fluctuation of lipemia due to increased levels of TG-rich lipoproteins (TRLs), including chylomicrons (CM), very low density lipoproteins (VLDL), and their remnants. Several factors contribute to postprandial lipid metabolism, including dietary, physiological, pathological and genetic factors. The presence of coronary heart disease, type 2 diabetes, insulin resistance and obesity is associated with higher postprandial TG levels compared with healthy conditions; this association is present also in subjects with normal fasting TG levels. Increasing evidence indicates that impaired metabolism of postprandial lipoproteins contributes to the pathogenesis of coronary artery disease, suggesting that lifestyle modifications as well as pharmacological approaches aimed at reducing postprandial TG levels might help to decrease the cardiovascular risk.
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Statins and skeletal muscles toxicity: from clinical trials to everyday practice.
Pharmacol. Res.
PUBLISHED: 04-23-2014
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The mechanism(s) underlying the occurrence of statin-induced myopathy are ill defined, but the results of observational studies and clinical trials provide compelling evidence that skeletal muscle toxicity is a frequent, dose-dependent, adverse event associated with all statins. It has been suggested that reduced availability of metabolites produced by the mevalonate pathway rather than intracellular cholesterol lowering per se might be the primary trigger of toxicity, however other alternative explanations have gained credibility in recent years. Aim of this review is: (i) to describe the molecular mechanisms associated to statin induced myopathy including defects in isoprenoids synthesis followed by altered prenylation of small GTPase, such as Ras and Rab proteins; (ii) to present the emerging aspects on pharmacogenetics, including CYP3A4, OATP1B1 and glycine amidinotransferase (GATM) polymorphisms impacting either statin bioavailability or creatine synthesis; (iii) to summarize the available epidemiological evidences; and (iii) to discuss the concepts that would be of interest to the clinicians for the daily management of patients with statin induced myopathy. The interplay between drug-environment and drug-drug interaction in the context of different genetic settings contribute to statins and skeletal muscles toxicity. Until specific assays/algorithms able to combine genetic scores with drug-drug-environment interaction to identify patients at risk of myopathies will become available, clinicians should continue to monitor carefully patients on polytherapy which include statins and be ready to reconsider dose, statin or switching to alternative treatments. The beneficial effects of adding agents to provide the muscle with the metabolites, such as CoQ10, affected by statin treatment will also be addressed.
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The polygenic nature of hypertriglyceridaemia: implications for definition, diagnosis, and management.
Lancet Diabetes Endocrinol
PUBLISHED: 04-16-2014
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Plasma triglyceride concentration is a biomarker for circulating triglyceride-rich lipoproteins and their metabolic remnants. Common mild-to-moderate hypertriglyceridaemia is typically multigenic, and results from the cumulative burden of common and rare variants in more than 30 genes, as quantified by genetic risk scores. Rare autosomal recessive monogenic hypertriglyceridaemia can result from large-effect mutations in six different genes. Hypertriglyceridaemia is exacerbated by non-genetic factors. On the basis of recent genetic data, we redefine the disorder into two states: severe (triglyceride concentration >10 mmol/L), which is more likely to have a monogenic cause; and mild-to-moderate (triglyceride concentration 2-10 mmol/L). Because of clustering of susceptibility alleles and secondary factors in families, biochemical screening and counselling for family members is essential, but routine genetic testing is not warranted. Treatment includes management of lifestyle and secondary factors, and pharmacotherapy. In severe hypertriglyceridaemia, intervention is indicated because of pancreatitis risk; in mild-to-moderate hypertriglyceridaemia, intervention can be indicated to prevent cardiovascular disease, dependent on triglyceride concentration, concomitant lipoprotein disturbances, and overall cardiovascular risk.
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Statins decrease thrombin generation in patients with hypercholesterolemia.
Eur. J. Intern. Med.
PUBLISHED: 03-25-2014
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Statins are cholesterol-lowering agents with antithrombotic effect possibly unrelated to their lipid-lowering properties. Traditional global coagulation tests failed, however, to reveal clinically relevant change after treatment. We therefore sought to investigate whether statins were able to modify thrombin generation in hypercholesterolemia.
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The ACC/AHA 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: the good the bad and the uncertain: a comparison with ESC/EAS guidelines for the management of dyslipidaemias 2011.
Eur. Heart J.
PUBLISHED: 03-17-2014
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Atherosclerotic cardiovascular disease is the most important public health problem of our time in both Europe and the rest of the world, accounting for the greatest expenditure in most healthcare budgets. Achieving consistency of clinical care, incorporating new evidence and their synthesis into practical recommendations for clinicians is the task of various guideline committees throughout the world. Any change in a set of guidelines therefore can have far reaching consequences, particularly if they appear to be at variance with the existing guidelines. The present article discusses the recent American College of Cardiology (ACC)/American Heart Association (AHA) guidelines 2013 on the control of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults. When compared with the ESC/EAS guidelines on lipid modification in 2011, the ACC/AHA guidelines of 2013 differ markedly. Specifically, (i) the scope is limited to randomized trials only, which excludes a significant body of data and promotes essentially a statin centric approach only; (ii) the abolition of low-density lipoprotein cholesterol (LDL-C) targets in favour of specific statin regimens that produce a 30-50% reduction in LDL-C we believe will confuse many physicians and miss the opportunity for medication adherence and patient engagement in self-management; (iii) the absence of target LDL-C levels in very high-risk patients with high absolute risk or residual risk factors will discourage clinicians to consider the addition of lipid modification treatments and individualize patient care; (iv) a reduction in the threshold for treatment in primary prevention will result in a greater number of patients being prescribed statin therapy, which is potentially good in young patients with high life time risk, but will result in a very large number of older patients offered therapy; and (v) the mixed pool risk calculator used to asses CVD risk in the guidelines for primary prevention has not been fully evaluated. This article discusses the potential implications of adopting the ACC/AHA guidelines on patient care in Europe and beyond and concludes with the opinion that the ESC/EAS guidelines from 2011 seem to be the most wide ranging, pragmatic and appropriate choice for European countries.
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Medication persistence and the use of generic and brand-name blood pressure-lowering agents.
J. Hypertens.
PUBLISHED: 02-27-2014
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Because of their lower cost, healthcare systems recommend physicians to prefer generic products, rather than brand-name medicaments. There is then considerable interest and debate concerning safety and effectiveness of generic products. Few studies have compared patients treated with brand-name and generic drugs for adherence to treatment, with somewhat inconsistent results. The primary objective of this study was to compare the risk of discontinuing antihypertensive drug therapy in patients treated with generic or brand-name agents.
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High-potency statins increase the risk of acute kidney injury: evidence from a large population-based study.
Atherosclerosis
PUBLISHED: 02-20-2014
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To assess the association between acute kidney injury and exposure to either high-potency statins or low-potency statins.
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15-lipoxygenase-mediated modification of HDL3 impairs eNOS activation in human endothelial cells.
Lipids
PUBLISHED: 02-12-2014
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Caveolae are cholesterol and glycosphingolipids-enriched microdomains of plasma membranes. Caveolin-1 represents the major structural protein of caveolae, that also contain receptors and molecules involved in signal transduction pathways. Caveolae are particularly abundant in endothelial cells, where they play important physiological and pathological roles in regulating endothelial cell functions. Several molecules with relevant functions in endothelial cells are localized in caveolae, including endothelial nitric oxide synthase (eNOS), which regulates the production of nitric oxide, and scavenger receptor class B type I (SR-BI), which plays a key role in the induction of eNOS activity mediated by high density lipoproteins (HDL). HDL have several atheroprotective functions, including a positive effect on endothelial cells, as it is a potent agonist of eNOS through the interaction with SR-BI. However, the oxidative modification of HDL may impair their protective role. In the present study we evaluated the effect of 15-lipoxygenase-mediated modification of HDL3 on the expression and/or activity of some proteins localized in endothelial caveolae and involved in the nitric oxide generation pathway. We found that after modification, HDL3 failed to activate eNOS and to induce NO production, due to both a reduced ability to interact with its own receptor SR-BI and to a reduced expression of SR-BI in cells exposed to modified HDL. These findings suggest that modification of HDL may reduce its endothelial-protective role also by interfering with vasodilatory function of HDL.
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Plant sterols and plant stanols in the management of dyslipidaemia and prevention of cardiovascular disease.
Atherosclerosis
PUBLISHED: 01-29-2014
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This EAS Consensus Panel critically appraised evidence relevant to the benefit to risk relationship of functional foods with added plant sterols and/or plant stanols, as components of a healthy lifestyle, to reduce plasma low-density lipoprotein-cholesterol (LDL-C) levels, and thereby lower cardiovascular risk.
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Statins and primary liver cancer: a meta-analysis of observational studies.
Eur. J. Cancer Prev.
PUBLISHED: 12-24-2013
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Statins are among the most commonly prescribed drugs used to manage dyslipidemia. Hepatocellular carcinoma is the third leading cause of cancer mortality and its rates have recently been increasing in central and northern Europe and USA. To quantify the association between statin use and risk for HCC, we performed a meta-analysis of published studies. We conducted a MEDLINE search for observational studies reporting the association between exposure to statins and risk for incident liver cancer until March 2012. Fixed-effect and random-effect models were used to estimate summary relative risks (RR) and the corresponding 95% confidence intervals (CIs). Moreover, between-study heterogeneity and publication bias were assessed using adequate statistical tests. Five observational studies (two case-control and three cohort studies) based on 2574 cases of HCC were included. Statin treatment, compared with no treatment, was inversely related to HCC (summary RR=0.58; 95% CI 0.46-0.74). Between-study heterogeneity was significant (P<0.001) and numerically relevant (I=65%). When only longest statin use was considered, the RR was 0.66 (95% CI 0.55-0.80). Influence analysis on the overall estimate showed that heterogeneity was largely because of one study; when omitting it, the I dropped to 27% (P=0.240), whereas the summary RR was only marginally modified (RR=0.52; 95% CI 0.44-0.62). There was no evidence of publication bias. This meta-analysis suggests a favorable effect of statins on HCC, in the absence, however, of a duration-risk relationship.
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Targeting PCSK9 for Hypercholesterolemia.
Annu. Rev. Pharmacol. Toxicol.
PUBLISHED: 10-16-2013
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Dyslipidemias are a predominant risk factor for cardiovascular disease. Biological and genetic research has led to the identification of several genes and proteins that may be pharmacologically targeted to improve lipoprotein profiles and possibly cardiovascular outcomes in patients with dyslipidemia. The observation that proprotein convertase subtilisin/kexin type 9 (PCSK9) regulates the levels of circulating low-density lipoprotein C (LDL-C) by enhancing the degradation of the hepatic low-density lipoprotein receptor (LDLR) prompted the search for drugs that inhibit PCSK9 activity. Several approaches to inhibiting PCSK9 activity have been proposed; these involve inhibitory antibodies, small molecules, and gene silencing. To date, the most promising and advanced approach relates to monoclonal antibodies, which can decrease LDL cholesterol by 65-70%, even as an add-on therapy to a maximal dose of a statin. Phase III studies and large, event-driven clinical trials are ongoing and will fully address the viability and role of these drugs in clinical practice. Expected final online publication date for the Annual Review of Pharmacology and Toxicology Volume 54 is January 06, 2014. Please see http://www.annualreviews.org/catalog/pubdates.aspx for revised estimates.
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Long-term effect of high dose omega-3 fatty acid supplementation for secondary prevention of cardiovascular outcomes: A meta-analysis of randomized, double blind, placebo controlled trials.
Atheroscler Suppl
PUBLISHED: 08-21-2013
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Although omega-3 fatty acids have well documented properties which would reduce the cardiovascular (CV) disease risk, the evidence from randomized controlled trials (RCTs) remains inconclusive. We performed a meta-analysis of the available RCTs for investigating the CV preventive effect of administrating at least 1 gram/day, and for at least 1 year, omega-3 fatty acid supplements to patients with existing CV disease.
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Omega-3 polyunsaturated fatty acids in the treatment of atherogenic dyslipidemia.
Atheroscler Suppl
PUBLISHED: 08-21-2013
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Epidemiological studies have established an association between high triglycerides (TG) plasma levels and increased cardiovascular risk. Increased TG levels, commonly coupled with low HDL-C levels, are common in high cardiovascular risk subjects including those with dyslipidemia, metabolic syndrome and type 2 diabetes. Management of hypertriglyceridemia (HTG) includes lifestyle modification for mild-to-moderate HTG and pharmacological therapies for the treatment of high and very high TG levels. Among drugs, fibrates, nicotinic acid and omega-3 polyunsaturated fatty acids may be considered. Omega-3 fatty acids reduce plasma TG levels by several mechanisms; beside the effects on TG, omega-3 can also influence the levels of other lipids and lipoproteins including HDL-C and LDL-C. Clinical trials have also shown that omega-3 fatty acid supplementation is effective also when added in combination with other lipid-lowering drugs. These findings suggest that omega-3 fatty acids may be usefully considered for the management of high TG levels.
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Omega-3 polyunsaturated fatty acids in the treatment of hypertriglyceridaemia.
Int. J. Cardiol.
PUBLISHED: 07-12-2013
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Hypertriglyceridaemia (HTG) is an independent risk factor for cardiovascular disease; high-risk patients with HTG, such as those with metabolic syndrome or diabetes, may benefit from hypolipidaemic therapies. Several lipid-lowering drugs act by reducing triglyceride (TG) levels, including fibrates, nicotinic acid and omega-3 fatty acids. The omega-3 polyunsaturated fatty acids eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA) dose-dependently reduce plasma TG levels; the effect tends to be greater in patients with higher TG levels at baseline. Evidence from clinical trials suggests that EPA+DHA doses of ?2g/day are required to achieve significant effects. The optimal TG-lowering doses of EPA+DHA are 3-4g/day, with little evidence to support lipid-altering efficacy of doses of EPA and DHA <1g/day. Predicted changes in fasting serum TG levels at the recommended dietary intakes of EPA and/or DHA of 200-500mg/day are -3.1% to -7.2%. Reductions of plasma TG levels at the optimal doses are from 25-35% up to 45% in the presence of severely elevated TG levels (?500mg/dl; ?5.65mmol/l), along with a reduction in non-high-density lipoprotein-cholesterol (non-HDL-C) and an increase in HDL-C. This observation has also been confirmed in statin-treated patients.
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Soluble lectin-like oxidized low density lipoprotein receptor-1 as a biochemical marker for atherosclerosis-related diseases.
Dis. Markers
PUBLISHED: 06-27-2013
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Lectin-like oxidized low density lipoprotein receptor-1 (LOX-1), the main oxidized low-density lipoprotein (OxLDL) in endothelial cells, is upregulated in atherosclerotic lesions and is involved in several cellular processes that regulate the pathogenesis of atherosclerosis. The LOX-1 expressed on the cell surface can be proteolytically cleaved and released in a soluble form (sLOX-1) in the circulation under pathological conditions. Serum levels of sLOX-1, in fact, are elevated at the early stages of acute coronary syndrome and are associated with coronary plaque vulnerability and with the presence of multiple complex coronary lesions. Moreover, in subjects with stable CAD, levels of serum sLOX-1 are associated with the presence of lesions in the proximal and mid-segments of the left anterior descending artery that are the most prone to rupture; in subjects undergoing percutaneous coronary intervention, baseline preprocedural serum sLOX-1 levels are associated with the incidence of periprocedural myocardial infarction. Altogether, these findings suggest that circulating levels of sLOX-1 might be a diagnostic and prognostic marker for atherosclerotic-related events.
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Abdominal visceral fat measurement using dual-energy X-ray: association with cardiometabolic risk factors.
Obesity (Silver Spring)
PUBLISHED: 05-21-2013
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To examine the association between cardiometabolic risk factors and visceral adipose tissue (VAT) measurements using a dual-energy X-ray absorptiometry (DXA) based approach.
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LOX-1, OxLDL, and atherosclerosis.
Mediators Inflamm.
PUBLISHED: 04-30-2013
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Oxidized low-density lipoprotein (OxLDL) contributes to the atherosclerotic plaque formation and progression by several mechanisms, including the induction of endothelial cell activation and dysfunction, macrophage foam cell formation, and smooth muscle cell migration and proliferation. Vascular wall cells express on their surface several scavenger receptors that mediate the cellular effects of OxLDL. The lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) is the main OxLDL receptor of endothelial cells, and it is expressed also in macrophages and smooth muscle cells. LOX-1 is almost undetectable under physiological conditions, but it is upregulated following the exposure to several proinflammatory and proatherogenic stimuli and can be detected in animal and human atherosclerotic lesions. The key contribution of LOX-1 to the atherogenic process has been confirmed in animal models; LOX-1 knockout mice exhibit reduced intima thickness and inflammation and increased expression of protective factors; on the contrary, LOX-1 overexpressing mice present an accelerated atherosclerotic lesion formation which is associated with increased inflammation. In humans, LOX-1 gene polymorphisms were associated with increased susceptibility to myocardial infarction. Inhibition of the LOX-1 receptor with chemicals or antisense nucleotides is currently being investigated and represents an emerging approach for controlling OxLDL-LOX-1 mediated proatherogenic effects.
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The CD1d-Natural Killer T Cell Axis in Atherosclerosis.
J Innate Immun
PUBLISHED: 03-29-2013
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A key role for lipid-sensing CD1-restricted natural killer T (NKT) cells in the pathogenesis of atherosclerosis has been suggested. However, the biology of NKT cells remains poorly characterized, as in different experimental settings their activation was reported to both stimulate and suppress innate and adaptive immune responses. Most of the data from experimental models suggest that NKT cells are proatherogenic; however, it is debated whether the increase in atherosclerosis observed following NKT cell stimulation is a consequence of the inability to induce functional NKT cells rather than the proatherogenic nature of NKT cells. CD1d-expressing antigen-presenting cells and NKT cells were detected in mouse and human atherosclerotic lesions. Furthermore, several lysophospholipids and glycosphingolipids, known to accumulate in atherosclerotic plaques, are antigenic for human NKT cell clones. Lipid transfer proteins, such as apolipoprotein E and microsomal triglyceride transfer protein, are central to NKT cell responses. All these data suggest a profound relation between lipid metabolism, CD1d-NKT cell axis activation and atherosclerosis. In this review, we summarize the advances and gaps in our knowledge of NKT cell biology in the context of atherosclerosis as well as the possibility of influencing NKT cell polarization toward an atheroprotective phenotype.
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Identification of seven loci affecting mean telomere length and their association with disease.
Veryan Codd, Christopher P Nelson, Eva Albrecht, Massimo Mangino, Joris Deelen, Jessica L Buxton, Jouke Jan Hottenga, Krista Fischer, Tonu Esko, Ida Surakka, Linda Broer, Dale R Nyholt, Irene Mateo Leach, Perttu Salo, Sara Hägg, Mary K Matthews, Jutta Palmen, Giuseppe D Norata, Paul F O'Reilly, Danish Saleheen, Najaf Amin, Anthony J Balmforth, Marian Beekman, Rudolf A de Boer, Stefan Böhringer, Peter S Braund, Paul R Burton, Anton J M de Craen, Matthew Denniff, Yanbin Dong, Konstantinos Douroudis, Elena Dubinina, Johan G Eriksson, Katia Garlaschelli, Dehuang Guo, Anna-Liisa Hartikainen, Anjali K Henders, Jeanine J Houwing-Duistermaat, Laura Kananen, Lennart C Karssen, Johannes Kettunen, Norman Klopp, Vasiliki Lagou, Elisabeth M van Leeuwen, Pamela A Madden, Reedik Mägi, Patrik K E Magnusson, Satu Mannisto, Mark I McCarthy, Sarah E Medland, Evelin Mihailov, Grant W Montgomery, Ben A Oostra, Aarno Palotie, Annette Peters, Helen Pollard, Anneli Pouta, Inga Prokopenko, Samuli Ripatti, Veikko Salomaa, H Eka D Suchiman, Ana M Valdes, Niek Verweij, Ana Viñuela, Xiaoling Wang, H-Erich Wichmann, Elisabeth Widén, Gonneke Willemsen, Margaret J Wright, Kai Xia, Xiangjun Xiao, Dirk J van Veldhuisen, Alberico L Catapano, Martin D Tobin, Alistair S Hall, Alexandra I F Blakemore, Wiek H van Gilst, Haidong Zhu, Cardiogram Consortium, Jeanette Erdmann, Muredach P Reilly, Sekar Kathiresan, Heribert Schunkert, Philippa J Talmud, Nancy L Pedersen, Markus Perola, Willem Ouwehand, Jaakko Kaprio, Nicholas G Martin, Cornelia M van Duijn, Iiris Hovatta, Christian Gieger, Andres Metspalu, Dorret I Boomsma, Marjo-Riitta Järvelin, P Eline Slagboom, John R Thompson, Tim D Spector, Pim van der Harst, Nilesh J Samani.
Nat. Genet.
PUBLISHED: 03-29-2013
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Interindividual variation in mean leukocyte telomere length (LTL) is associated with cancer and several age-associated diseases. We report here a genome-wide meta-analysis of 37,684 individuals with replication of selected variants in an additional 10,739 individuals. We identified seven loci, including five new loci, associated with mean LTL (P < 5 × 10(-8)). Five of the loci contain candidate genes (TERC, TERT, NAF1, OBFC1 and RTEL1) that are known to be involved in telomere biology. Lead SNPs at two loci (TERC and TERT) associate with several cancers and other diseases, including idiopathic pulmonary fibrosis. Moreover, a genetic risk score analysis combining lead variants at all 7 loci in 22,233 coronary artery disease cases and 64,762 controls showed an association of the alleles associated with shorter LTL with increased risk of coronary artery disease (21% (95% confidence interval, 5-35%) per standard deviation in LTL, P = 0.014). Our findings support a causal role of telomere-length variation in some age-related diseases.
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New therapeutic principles in dyslipidaemia: focus on LDL and Lp(a) lowering drugs.
Eur. Heart J.
PUBLISHED: 03-18-2013
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Dyslipidaemias play a key role in determining cardiovascular risk; the discovery of statins has contributed a very effective approach. However, many patients do not achieve, at the maximal tolerated dose, the recommended goals for low-density lipoprotein-cholesterol (LDL-C), non-high-density lipoprotein-cholesterol, and apolipoprotein B (apoB). Available agents combined with statins can provide additional LDL-C reduction, and agents in development will increase therapeutic options impacting also other atherogenic lipoprotein classes. In fact, genetic insights into mechanisms underlying regulation of LDL-C levels has expanded potential targets of drug therapy and led to the development of novel agents. Among them are modulators of apoB containing lipoproteins production and proprotein convertase subtilisin/kexin type-9 inhibitors. Alternative targets such as lipoprotein(a) also require attention; however, until we have a better understanding of these issues, further LDL-C lowering in high and very high-risk patients will represent the most sound clinical approach.
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Long-term use of statins reduces the risk of hospitalization for dementia.
Atherosclerosis
PUBLISHED: 03-12-2013
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Dementia is a major public health problem because of its high prevalence in elderly individuals, particularly in the growing category of subjects aged 80 years or more. There is accumulating evidence that cholesterol may be implicated in the pathogenesis of dementia, and this has led us to assess the relationship between time spent with statins available and the risk of hospitalization for dementia.
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Long pentraxin 3: experimental and clinical relevance in cardiovascular diseases.
Mediators Inflamm.
PUBLISHED: 02-27-2013
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Pentraxin 3 (PTX3) is an essential component of the humoral arm of innate immunity and belongs, together with the C-reactive protein (CRP) and other acute phase proteins, to the pentraxins superfamily: soluble, multifunctional, pattern recognition proteins. Pentraxins share a common C-terminal pentraxin domain, which in the case of PTX3 is coupled to an unrelated long N-terminal domain. PTX3 in humans, like CRP, correlates with surrogate markers of atherosclerosis and is independently associated with the risk of developing vascular events. Studies addressing the potential physiopathological role of CRP in the cardiovascular system were so far inconclusive and have been limited by the fact that the sequence and regulation have not been conserved during evolution between mouse and man. On the contrary, the conservation of sequence, gene organization, and regulation of PTX3 supports the translation of animal model findings in humans. While PTX3 deficiency is associated with increased inflammation, cardiac damage, and atherosclerosis, the overexpression limits carotid restenosis after angioplasty. These observations point to a cardiovascular protective effect of PTX3 potentially associated with the ability of tuning inflammation and favor the hypothesis that the increased levels of PTX3 in subjects with cardiovascular diseases may reflect a protective physiological mechanism, which correlates with the immunoinflammatory response observed in several cardiovascular disorders.
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High-density lipoprotein subfractions--what the clinicians need to know.
Cardiology
PUBLISHED: 02-20-2013
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Although the inverse relationship between plasma levels of high-density lipoprotein (HDL) and cardiovascular disease has been largely demonstrated, many observations have suggested that the assessment of HDL functionality might be more informative than a simple measurement of HDL-cholesterol plasma levels. HDLs are a class of structurally and functionally heterogeneous particles; in atherosclerosis-related diseases, changes in HDL subfraction levels and functions are frequently observed. Circulating levels of large HDL particles are decreased in dyslipidaemic conditions, while levels of small dense HDL particles are increased in patients with coronary heart disease. Furthermore, specific genetic defects in proteins involved in HDL metabolism significantly impact the distribution of HDL subpopulations. Finally, many drugs used for dyslipidaemia induce changes in HDL subfractions strictly related to cardiovascular disease. Although several methods exist to evaluate HDL subclass levels, most of them are not easily applicable in clinical practice, due to the costs and high variability. However, the possibility to measure the levels of specific HDL subfractions in patients with atherosclerosis-related diseases might help to better define their cardiovascular risk.
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Gene silencing approaches for the management of dyslipidaemia.
Trends Pharmacol. Sci.
PUBLISHED: 01-29-2013
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The key role of dyslipidaemias in determining cardiovascular risk has been well established, and statins often provide effective therapeutic management. However, many patients do not achieve recommended lipid levels despite maximal therapy, and some cannot tolerate high-dose statin therapy. Recently, genetic insights into mechanisms underlying regulation of lipoprotein metabolism have expanded the potential targets of drug therapy and led to the development of novel agents, including development of gene silencing approaches. These therapeutic options include the modulation of synthesis in the liver, maturation in the circulation, and catabolism of lipoproteins. In this review, we discuss the pharmacological consequences of silencing apolipoprotein B, apolipoprotein (a), microRNA 33, proprotein convertase subtilisin/kexin type 9, and apolipoprotein C-III. New potential targets such as other microRNAs, diacylglycerol acyl transferase-1, and angiopoietin-like protein 3 are also presented. The pharmacological consequences of gene silencing and the advancement of these therapeutic approaches in clinical development will be examined.
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Class II phosphoinositide 3-kinases contribute to endothelial cells morphogenesis.
PLoS ONE
PUBLISHED: 01-08-2013
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The question of whether the distinct isoforms of the family of enzymes phosphoinositide 3-kinases (PI3Ks) play redundant roles within a cell or whether they control distinct cellular processes or distinct steps within the same cellular process has gained considerable importance in the recent years due to the development of inhibitors able to selectively target individual isoforms. It is important to understand whether inhibition of one PI3K can result in compensatory effect from other isoform(s) and therefore whether strategies aimed at simultaneously blocking more than one PI3K may be needed. In this study we investigated the relative contribution of distinct PI3K isoforms to endothelial cells (EC) functions specifically regulated by the sphingolipid sphingosine-1-phosphate (S1P) and by high density lipoproteins (HDL), the major carrier of S1P in human plasma. Here we show that a co-ordinated action of different PI3Ks is required to tightly regulate remodelling of EC on Matrigel, a process dependent on cell proliferation, apoptosis and migration. The contribution of each isoform to this process appears to be distinct, with the class II enzyme PI3K-C2? and the class IB isoform p110? mainly regulating the S1P- and HDL-dependent EC migration and PI3K-C2? primarily controlling EC survival. Data further indicate that PI3K-C2? and p110? control distinct steps involved in cell migration supporting the hypothesis that different PI3Ks regulate distinct cellular processes.
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Treating high density lipoprotein cholesterol (HDL-C): quantity versus quality.
Curr. Pharm. Des.
PUBLISHED: 01-05-2013
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Low density lipoproteins (LDL) and high density lipoproteins (HDL) are independent risk factors for coronary heart disease (CHD); decreasing LDL-cholesterol (LDL-C) levels with statin therapy represents the primary goal in the management of cardiovascular disease. However, despite the efficacy of statins in reducing cardiovascular morbidity and mortality, a significant residual risk has been observed even after reaching the LDL-C target, suggesting that other risk factors beyond LDL-C should be addressed, including low levels of HDL-cholesterol (HDL-C). Several clinical trials have shown an inverse relationship between HDL-C levels and cardiovascular risk, and 1 mg/dl increment in HDL-C is associated in epidemiological studies with a 2-3% decrease in cardiovascular risk, suggesting that raising HDL-C levels might have beneficial effects to reduce cardiovascular disease. However, several lines of evidence indicate that the functional properties of HDL may be relevant as well. In patient with CAD and normal HDL-C levels, HDL exhibit significantly reduced protective functions, and rather appear to be pro-atherogenic; on the other hand some genetic mutations causing low levels of HDL-C are not associated with increased atherosclerosis. Furthermore, although niacin significantly increased HDL-C levels, no further clinical benefit was observed from the addition of niacin to statin therapy, suggesting that increasing HDL-C levels is not sufficient and perhaps functional properties of HDL must be considered when choosing a therapeutic strategy to reduce the residual cardiovascular risk.
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Lower rate of cardiovascular complications in patients on bolus insulin analogues: a retrospective population-based cohort study.
PLoS ONE
PUBLISHED: 01-01-2013
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Few studies are available evaluating the impact of rapid-acting insulin analogues on long-term diabetes outcomes. Our aim was to compare the use of rapid-acting insulin analogues versus human regular insulin in relation to the occurrence of diabetic complications in a cohort of diabetic patients through the analysis of administrative databases.
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Prevalence of the prescription of potentially interacting drugs.
PLoS ONE
PUBLISHED: 01-01-2013
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The use of multiple medications is becoming more common, with a correspondingly increased risk of untoward effects and drug-related morbidity and mortality. We aimed at estimating the prevalence of prescription of relevant potentially interacting drugs and at evaluating possible predictors of potentially interacting drug exposure. We retrospectively analyzed data on prescriptions dispensed from January 2004 to August 2005 to individuals of two Italian regions with a population of almost 2.1 million individuals. We identified 27 pairs of potentially interacting drugs by examining clinical relevance, documentation, and volume of use in Italy. Subjects who received at least one prescription of both drugs were selected. Co-prescribing denotes "two prescriptions in the same day", and concomitant medication "the prescription of two drugs with overlapping coverage". A logistic regression analysis was conducted to examine the predictors of potential Drug-Drug Interaction (pDDIs). 957,553 subjects (45.3% of study population) were exposed to at least one of the drugs/classes of the 27 pairs. Overall, pDDIs occurred 2,465,819 times. The highest rates of concomitant prescription and of co-prescription were for ACE inhibitors+NSAIDs (6,253 and 4,621/100,000 plan participants). Considering concomitance, the male/female ratio was <1 in 17/27 pairs (from 0.31 for NSAIDs-ASA+SSRI to 0.74 for omeprazole+clopidogrel). The mean age was lowest for methotrexate pairs (+omeprazole, 59.9 years; +NSAIDs-ASA, 59.1 years) and highest for digoxin+verapamil (75.4 years). In 13/27 pairs, the mean ages were ?70 years. On average, subjects involved in pDDIs received ?10 drugs. The odds of exposure were more frequently higher for age ?65 years, males, and those taking a large number of drugs. A substantial number of clinically important pDDIs were observed, particularly among warfarin users. Awareness of the most prevalent pDDIs could help practitioners in preventing concomitant use, resulting in a better quality of drug prescription and potentially avoiding unwanted side effects.
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-374 T/A RAGE polymorphism is associated with chronic kidney disease progression in subjects affected by nephrocardiovascular disease.
PLoS ONE
PUBLISHED: 01-01-2013
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Chronic kidney disease (CKD) patients present elevated advanced glycation end products (AGEs) blood levels. AGEs promote inflammation through binding to their receptor (RAGE), located on the membrane of mesangial cells, endothelial cells and macrophages. Several genetic polymorphisms influence RAGE transcription, expression and activity, including the substitution of a thymine with an adenine (T/A) in the position -374 of the gene promoter of RAGE. Our study investigates the role of -374 T/A RAGE polymorphism in CKD progression in subjects affected by nephrocardiovascular disease.
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HDLs, immunity, and atherosclerosis.
Curr. Opin. Lipidol.
PUBLISHED: 09-02-2011
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HDLs possess several physiological activities that may explain their antiatherosclerotic properties. Among them, the most relevant is the ability of HDL to promote the efflux of excess cholesterol from peripheral tissues to the liver for excretion.
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ESC/EAS Guidelines for the management of dyslipidaemias: the Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).
Eur. Heart J.
PUBLISHED: 06-28-2011
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Cardiovascular disease (CVD) due to atherosclerosis of the arterial vessel wall and to thrombosis is the foremost cause of premature mortality and of disability-adjusted life years (DALYs) in Europe, and is also increasingly common in developing countries.1 In the European Union, the economic cost of CVD represents annually E192 billion1 in direct and indirect healthcare costs. The main clinical entities are coronary artery disease (CAD), ischaemic stroke, and peripheral arterial disease (PAD). The causes of these CVDs are multifactorial. Some of these factors relate to lifestyles, such as tobacco smoking, lack of physical activity, and dietary habits, and are thus modifiable. Other risk factors are also modifiable, such as elevated blood pressure, type 2 diabetes, and dyslipidaemias, or non-modifiable, such as age and male gender. These guidelines deal with the management of dyslipidaemias as an essential and integral part of CVD prevention. Prevention and treatment of dyslipidaemias should always be considered within the broader framework of CVD prevention, which is addressed in guidelines of the Joint European Societies’ Task forces on CVD prevention in clinical practice.2 – 5 The latest version of these guidelines was published in 20075; an update will become available in 2012. These Joint ESC/European Atherosclerosis Society (EAS) guidelines on the management of dyslipidaemias are complementary to the guidelines on CVD prevention in clinical practice and address not only physicians [e.g. general practitioners (GPs) and cardiologists] interested in CVD prevention, but also specialists from lipid clinics or metabolic units who are dealing with dyslipidaemias that are more difficult to classify and treat.
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Reaching LDL-c targets in high-risk patients requires high-efficacy cholesterol-lowering drugs in more than 50% of cases. The results of the CHECK study.
Pharmacol. Res.
PUBLISHED: 06-21-2011
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We estimated the need to use low-efficacy statins or high-efficacy statins or drug combinations to bring high- or very-high cardiovascular risk subjects to their LDL-c target, in a sample representative of the Italian adult population and according to the principles of reimbursement of hypercholesterolemic drugs currently used in Italy. The results allow us concluding that among high or very high cardiovascular risk patients about three patients out of five should be prescribed high-efficacy statins or drug combinations. The other two prescriptions might take into account lower-efficacy statins. If we also compute the values of HDL-c in these subjects--the large majority of which stands below the optimal values as suggested by International guidelines--we bring forward the need either to select specific statins able to increase the levels of these protective lipoproteins or to consider combination therapies of statins with fibrates or nicotinic acid. Our data might conceivably be applied to other low-cardiovascular risk countries and should be taken into account when defining the proportion of drugs with different efficacy and cost in the everyday clinical practice.
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Proprotein convertase subtilisin kexin type 9 (PCSK9) secreted by cultured smooth muscle cells reduces macrophages LDLR levels.
Atherosclerosis
PUBLISHED: 06-15-2011
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Proprotein convertase subtilisin kexin type 9 (PCSK9) is an important regulator of hepatic low-density lipoprotein (LDL)-cholesterol levels. Although PCSK9 is mainly of hepatic origin, extra-hepatic tissues significantly contribute to PCSK9 production and, potentially, local regulation of LDL receptor expression.
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Triglyceride-rich lipoproteins and high-density lipoprotein cholesterol in patients at high risk of cardiovascular disease: evidence and guidance for management.
Eur. Heart J.
PUBLISHED: 04-29-2011
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Even at low-density lipoprotein cholesterol (LDL-C) goal, patients with cardiometabolic abnormalities remain at high risk of cardiovascular events. This paper aims (i) to critically appraise evidence for elevated levels of triglyceride-rich lipoproteins (TRLs) and low levels of high-density lipoprotein cholesterol (HDL-C) as cardiovascular risk factors, and (ii) to advise on therapeutic strategies for management. Current evidence supports a causal association between elevated TRL and their remnants, low HDL-C, and cardiovascular risk. This interpretation is based on mechanistic and genetic studies for TRL and remnants, together with the epidemiological data suggestive of the association for circulating triglycerides and cardiovascular disease. For HDL, epidemiological, mechanistic, and clinical intervention data are consistent with the view that low HDL-C contributes to elevated cardiovascular risk; genetic evidence is unclear however, potentially reflecting the complexity of HDL metabolism. The Panel believes that therapeutic targeting of elevated triglycerides (? 1.7 mmol/L or 150 mg/dL), a marker of TRL and their remnants, and/or low HDL-C (<1.0 mmol/L or 40 mg/dL) may provide further benefit. The first step should be lifestyle interventions together with consideration of compliance with pharmacotherapy and secondary causes of dyslipidaemia. If inadequately corrected, adding niacin or a fibrate, or intensifying LDL-C lowering therapy may be considered. Treatment decisions regarding statin combination therapy should take into account relevant safety concerns, i.e. the risk of elevation of blood glucose, uric acid or liver enzymes with niacin, and myopathy, increased serum creatinine and cholelithiasis with fibrates. These recommendations will facilitate reduction in the substantial cardiovascular risk that persists in patients with cardiometabolic abnormalities at LDL-C goal.
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Emerging role of high density lipoproteins as a player in the immune system.
Atherosclerosis
PUBLISHED: 04-11-2011
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High density lipoproteins (HDL) possess a number of physiological activities. The most studied and, perhaps, better understood is the ability of HDL to promote excess cholesterol efflux from peripheral tissues and transport to the liver for excretion, a mechanism believed to confer protection against atherosclerotic cardiovascular disease. The ability of HDL to modulate cholesterol bioavailability in the lipid rafts, membrane microdomains enriched in glycosphingolipids and cholesterol, is evolutionary conserved and affects the properties of cells involved in the innate and adaptive immune response, tuning inflammatory response and antigen presentation functions in macrophages as well as B and T cell activation. Also sphingosine-1 phosphate (S1P), a major active sphingolipid carried by HDL, is of relevance in the pathogenesis of several immuno-inflammatory disorders through the modulation of macrophage and lymphocyte functions. Furthermore, HDL influence the humoral innate immunity by modulating the activation of the complement system and the expression of pentraxin 3 (PTX3). Finally, in humans, HDL levels and functions are altered in several immune-mediated disorders, such as rheumatoid arthritis, systemic lupus eritematosus, Crohns disease and multiple sclerosis as well as during inflammatory responses. Altogether these observations suggest that the effects of HDL in immunity could be related, to either the ability of HDL to modulate cholesterol content in immune cell lipid rafts and to their role as reservoir for several biologically active substances that may impact the immune system.
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Novel biotinylated bile acid amphiphiles: micellar aggregates formation and interaction with hepatocytes.
Org. Biomol. Chem.
PUBLISHED: 03-03-2011
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Amphiphilic bile acids linked through an oligoethylene glycol to a biotin moiety were synthesized and shown to create micellar structures in aqueous environment, interact with avidin and be efficiently incorporated into hepatocyte cells, suggesting their potential as a drug delivery system against liver diseases.
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Endothelin-1 does not impair insulin-induced angiogenesis in vitro.
Int. J. Mol. Med.
PUBLISHED: 02-21-2011
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Endothelin-1 (ET-1) modulates several vascular functions and plays an important role in the pathogenesis of insulin resistance. However, its role in the pathogenesis of impaired angiogenesis observed under insulin resistance conditions is not known. In the present study, we addressed this issue by analyzing the effect of ET-1 in human umbilical vein endothelial cells (HUVEC) on i) insulin-induced phosphorylation of two protein kinases involved in angiogenesis, Akt and ERK1/2, and on ii) insulin-induced angiogenesis in two in vitro models, those of Matrigel and of fibroblast/endothelial co-culture. Both insulin (100 ng/ml) and ET-1 (10 nmol/l) dose-dependently increased the phosphorylation of Akt and ERK1/2. Pre-treatment with ET-1 did not suppress the insulin-induced Akt and ERK1/2 phosphorylation. In the two in vitro models of angiogenesis, ET-1 did not inhibit insulin-induced angiogenesis. From these data we conclude that in vitro, at the times and at the concentrations examined, ET-1 does not impair insulin-induced angiogenesis.
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Dual effect of hypochlorite in the modification of high density lipoproteins.
Biochem. Biophys. Res. Commun.
PUBLISHED: 11-04-2010
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HDL-cholesterol levels are inversely correlated to the risk of cardiovascular disease. In recent years the concept that not only the quantity, but also the quality of HDL is related to their atheroprotective function has gained momentum. In fact several studies have showed that HDL can shift their properties from anti-atherogenic to pro-atherogenic upon chemical or enzymatic "modification". However, not all kind of modifications affect the antiatherogenic properties of HDL. For example, tyrosylation of HDL improves its ability to remove cholesterol from cultured cells and inhibits mice atherosclerotic lesion formation; oxidation of HDL(3) with 15-lipoxygenase or with copper ions for short time induce the formation of pre-?-migrating particles that are highly effective as cholesterol acceptors from lipid laden cells. Myeloperoxidase modifies HDL and apoA-I and reduces their ability to promote ABCA1-mediated cholesterol efflux. In the present study we show that modification with low concentration HOCl (a myeloperoxidase product) induces the formation of pre-?-migrating particles, thus improving the function of HDL in the reverse cholesterol transport, without affecting the anti-inflammatory activity. At higher HOCl concentration, pre-?-migrating particles were not detectable and the anti-inflammatory properties of HDL were lost. These findings suggest that during early phases of inflammation, when a low HOCl concentration is generated, changes in HDL occur that increase their ability to remove cholesterol and sparing anti-inflammatory properties; later during acute inflammation, when higher HOCl concentration are present changes in HDL occur that severely decrease their ability to remove cholesterol from macrophages and to protect endothelial cells from pro-inflammatory stimuli.
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Lipoprotein(a) as a cardiovascular risk factor: current status.
Eur. Heart J.
PUBLISHED: 10-21-2010
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The aims of the study were, first, to critically evaluate lipoprotein(a) [Lp(a)] as a cardiovascular risk factor and, second, to advise on screening for elevated plasma Lp(a), on desirable levels, and on therapeutic strategies.
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Severe hypercholesterolaemia: therapeutic goals and eligibility criteria for LDL apheresis in Europe.
Curr. Opin. Lipidol.
PUBLISHED: 10-12-2010
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Despite the use of currently available lipid-lowering therapies, a significant proportion of patients with severe hypercholesterolaemia do not reach treatment goals and consequently remain at increased risk for cardiovascular disease (CVD). On the basis of clinical experience, these patients tend to have the most severe forms of familial hypercholesterolaemia or markedly elevated LDL cholesterol (LDL-C) levels but are unable to tolerate statin therapy.
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Pitavastatin - pharmacological profile from early phase studies.
Atheroscler Suppl
PUBLISHED: 08-05-2010
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Pitavastatin has been designed as a synthetic 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor with a novel cyclopropyl moiety that results in several differences compared to other statins. These include effective inhibition of cholesterol synthesis and increased lipoprotein lipase expression at lower doses than other statins, and significant high-density lipoprotein-cholesterol and apolipoprotein A1-elevating activity that persists with time. The safety, tolerability and pharmacokinetics of pitavastatin and its major metabolite, pitavastatin lactone, have been investigated in a variety of patient groups with similar results, which suggests dosage adjustments are not required for gender, age or race. In healthy subjects, pitavastatin is well tolerated at the approved doses with no serious adverse events. The bioavailability of pitavastatin is, at 60%, higher than that of any other statin and the majority of the bioavailable fraction of an oral dose is excreted unchanged in the bile. The entero-hepatic circulation of unchanged drug contributes to the prolonged duration of action and allows once-daily, any-time dosing. Pitavastatin is only slightly metabolised by cytochrome P450 (CYP) 2C9 and not at all by CYP3A4. Neither pitavastatin nor its lactone form, have inhibitory effects on CYP, and CYP3A4 inhibitors have no effect on pitavastatin concentrations. Moreover, P-glycoprotein-mediated transport does not play a major role in the drugs disposition and pitavastatin does not inhibit P-glycoprotein activity. Pitavastatin is transported into the liver by several hepatic transporters but OATP1B1 inhibitors have relatively little effect on plasma concentrations compared with other statins. In general, interactions, except with multi-transporter inhibitors like ciclosporin, are not clinically significant. Consequently, pitavastatin has minimal drug-food and drug-drug interactions making it a treatment option in the large group of dyslipidaemic people that require multidrug therapy.
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The long pentraxin PTX3: a modulator of the immunoinflammatory response in atherosclerosis and cardiovascular diseases.
Trends Cardiovasc. Med.
PUBLISHED: 07-27-2010
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Innate and adaptive immune responses participate in atherosclerosis. Pentraxins, an essential component of the humoral arm of innate immunity, are a superfamily of acute phase proteins highly conserved during evolution and can be classified as short pentraxins such as C-reactive protein (CRP) and long pentraxins such as PTX3. The latter has an unrelated, long N-terminal domain coupled to the C-terminal pentraxin domain and differs from CRP in gene organization, cellular source, and recognized ligands. PTX3 in humans, like CRP, is a marker of atherosclerosis and correlates with the risk of developing vascular events. Although CRP sequence and regulation have not been conserved during evolution between mouse and man, the conservation of sequence, gene organization, and regulation of PTX3 in evolution enables one to address the question regarding its pathophysiologic roles in genetically modified mice. Deficiency of PTX3 is associated with increased heart damage with a greater no-reflow area and increased inflammatory response in a model of acute myocardial infarction (MI) caused by coronary artery ligation. More recently, deficiency of PTX3 on an apolipoprotein E knockout background was associated with increased atherosclerosis, macrophage accumulation within the plaque, and a more pronounced inflammatory profile in the vascular wall. Although these observations point to a cardiovascular protective effect of PTX3, they also suggest the possibility that the increased levels of PTX3 in subjects with cardiovascular disease (CVD) may reflect a protective physiologic response that correlates with the severity of the disease. In summary, data that are accumulating suggest that the increase of pentraxins in atherosclerosis could not be regarded as a harmful response but rather a further attempt to protection of our body.
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Upregulation of lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) by 15-lipoxygenase-modified LDL in endothelial cells.
Atherosclerosis
PUBLISHED: 06-18-2010
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Lectin-like oxidized LDL receptor-1 (LOX-1), the endothelial receptor for OxLDL, is believed to be responsible for a number of OxLDL-induced effects in the endothelium.
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Circulating CD4+CD25hiCD127lo regulatory T-Cell levels do not reflect the extent or severity of carotid and coronary atherosclerosis.
Arterioscler. Thromb. Vasc. Biol.
PUBLISHED: 06-10-2010
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Regulatory T (Treg) cells play a protective role in experimental atherosclerosis. In the present study, we investigated whether the levels of circulating Treg cells relate to the degree of atherosclerosis in carotid and coronary arteries.
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The androgen derivative 5alpha-androstane-3beta,17beta-diol inhibits tumor necrosis factor alpha and lipopolysaccharide induced inflammatory response in human endothelial cells and in mice aorta.
Atherosclerosis
PUBLISHED: 05-10-2010
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An increasing body of evidence suggests that testosterone may exert beneficial effects against the development of atherosclerosis. These effects are thought to be the consequence of its conversion into estradiol and the activation of the estrogen receptors; however a direct role of androgens, such as dihydrotestosterone, has also been proposed. More recently, it has been shown that the transformation of the dihydrotestosterone to 5alpha-androstane-3alpha,17beta-diol (3alpha-diol) and 5alpha-androstane-3beta,17beta-diol (3beta-Adiol), generates two molecules unable to bind the androgen receptor, but with a high affinity for the estrogen receptors (ERs) in particular the beta isoform. As the actions of testosterone may result from the balance between androgenic and estrogenic molecules originating from its catabolism, we investigated the effects of the 3beta-Adiol on inflammatory responses in vitro in human endothelial cells and ex vivo in mice aortas.
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Blood pressure and antihypertensive therapy according to the global cardiovascular risk level in Italy: the CHECK Study.
Eur J Cardiovasc Prev Rehabil
PUBLISHED: 03-24-2010
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Elevated blood pressure (BP) is one of the most important modifiable risk factors for cardiovascular diseases. In this study we assessed the excess of cardiovascular risk attributable to high BP and antihypertensive treatment in a sample of Italian patients enrolled by the Cholesterol and Health: Education, Control and Knowledge (CHECK) study.
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Individual progression of carotid intima media thickness as a surrogate for vascular risk (PROG-IMT): Rationale and design of a meta-analysis project.
Am. Heart J.
PUBLISHED: 02-02-2010
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Carotid intima media thickness (IMT) progression is increasingly used as a surrogate for vascular risk. This use is supported by data from a few clinical trials investigating statins, but established criteria of surrogacy are only partially fulfilled. To provide a valid basis for the use of IMT progression as a study end point, we are performing a 3-step meta-analysis project based on individual participant data. Objectives of the 3 successive stages are to investigate (1) whether IMT progression prospectively predicts myocardial infarction, stroke, or death in population-based samples; (2) whether it does so in prevalent disease cohorts; and (3) whether interventions affecting IMT progression predict a therapeutic effect on clinical end points. Recruitment strategies, inclusion criteria, and estimates of the expected numbers of eligible studies are presented along with a detailed analysis plan.
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Results of a retrospective database analysis of adherence to statin therapy and risk of nonfatal ischemic heart disease in daily clinical practice in Italy.
Clin Ther
PUBLISHED: 01-29-2010
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Previous studies have reported that statin use was associated with reductions in cardiovascular morbidity and mortality among patients with dyslipidemia, even without established cardiovascular disease. However, inadequate adherence may reduce statins protective effects.
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Low-density lipoprotein cholesterol reduction and goal achievement with ezetimibe/simvastatin versus atorvastatin or rosuvastatin in patients with diabetes, metabolic syndrome, or neither disease, stratified by National Cholesterol Education Program risk
Metab Syndr Relat Disord
PUBLISHED: 11-26-2009
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Patients with diabetes mellitus (DM) and metabolic syndrome are at increased risk of coronary heart disease (CHD). Studies have shown differential statin efficacy on low-density lipid cholesterol (LDL-C) by CHD risk strata.
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Deficiency of the long pentraxin PTX3 promotes vascular inflammation and atherosclerosis.
Circulation
PUBLISHED: 08-10-2009
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Immune responses participate in several phases of atherosclerosis; there is, in fact, increasing evidence that both adaptive immunity and innate immunity tightly regulate atherogenesis. Pentraxins are a superfamily of acute-phase proteins that includes short pentraxins such as C-reactive protein or long pentraxins such as PTX3, a molecule acting as the humoral arm of innate immunity. To address the potential role of PTX3 in atherogenesis, we first investigated the expression of PTX3 during atherogenesis, generated double-knockout mice lacking PTX3 and apolipoprotein E, and then studied the effect of murine PTX3 deficiency on plasma lipids, atherosclerosis development, and gene expression pattern in the vascular wall.
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Circulating soluble receptor for advanced glycation end products is inversely associated with body mass index and waist/hip ratio in the general population.
Nutr Metab Cardiovasc Dis
PUBLISHED: 05-01-2009
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Advanced glycation end products, AGEs, and its specific receptor, RAGE, are involved in vascular complications. A role for the soluble form of RAGE (sRAGE), which acts as a decoy for AGE, has been documented in patients with diabetes but no information is available in non-diabetic subjects. The aim of this study was to investigate the association of plasma levels of sRAGE with cardiometabolic risk factors in the general population. In addition we evaluated the relation of the common -374A/T polymorphism of RAGE with plasma levels of sRAGE. One hundred and seventy-six healthy subjects free of diabetes or coronary artery disease untreated for hypertension, dyslipidemia or cardiometabolic related diseases were randomly selected for this study from the general population. Plasma sRAGE were negatively and significantly correlated with BMI, waist/hip circumference ratio and fasting glycemia, while a positive correlation was observed with apolipoprotein A-I. These correlations were observed mainly in women who showed significantly higher sRAGE levels (1744+/-660 pg/mL vs 1414+/-649 pg/mL; P<0.05). In a stepwise regression analysis waist circumference was independently associated with sRAGE and, when waist circumference was excluded, BMI was independently associated with sRAGE. Finally in overweight subjects (BMI>25 kg/m(2)) plasma sRAGE was significantly lower compared to lean subjects (1460+/-640 pg/mL vs 1710+/-693 pg/mL; P<0.05). In healthy subjects plasma levels of sRAGE were negatively correlated with BMI and waist/hip ratio supporting a possible protective role for these proteins before any evidence of diabetic or vascular complications.
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Oral L-arginine supplementation improves endothelial function and ameliorates insulin sensitivity and inflammation in cardiopathic nondiabetic patients after an aortocoronary bypass.
Metab. Clin. Exp.
PUBLISHED: 03-26-2009
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It is known that L-arginine treatment can ameliorate endothelial dysfunction and insulin sensitivity in type 2 diabetes mellitus patients, but little is known on L-arginine effects on these variables in nondiabetic patients with stable cardiovascular disease (coronary artery disease). We evaluated the effects of long-term oral L-arginine treatment on endothelial dysfunction, inflammation, adipokine levels, glucose tolerance, and insulin sensitivity in these patients. Sixty-four patients with cardiovascular disease previously submitted to an aortocoronary bypass and not known for type 2 diabetes mellitus had an oral glucose load to define their glucose tolerance. Thirty-two patients with nondiabetic response were eligible to receive, in a double-blind randomized parallel order, L-arginine (6.4 g/d) or placebo for 6 months. An evaluation of insulin sensitivity index during the oral glucose load, markers of systemic nitric oxide bioavailability and inflammation, and blood flow was performed before and at the end of the treatment in both groups. Compared with placebo, L-arginine decreased asymmetric dimethylarginine levels (P < .01), indices of endothelial dysfunction, and increased cyclic guanosine monophosphate (P < .01), L-arginine to asymmetric dimethylarginine ratio (P < .0001), and reactive hyperemia (P < .05). Finally, L-arginine increased insulin sensitivity index (P < .05) and adiponectin (P < .01) and decreased interleukin-6 and monocyte chemoattractant protein-1 levels. In conclusion, insulin resistance, endothelial dysfunction, and inflammation are important cardiovascular risk factors in coronary artery disease patients; and L-arginine seems to have anti-inflammatory and metabolic advantages in these patients.
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Small dense LDL and VLDL predict common carotid artery IMT and elicit an inflammatory response in peripheral blood mononuclear and endothelial cells.
Atherosclerosis
PUBLISHED: 02-16-2009
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The presence of small dense LDL has been associated with increased cardiovascular risk and with the progression of coronary and carotid atherosclerosis in case-control and prospective studies. The aim of this study was to investigate the relation between different lipoprotein subfractions with intima-media thickness of the common carotid artery in a free-living, healthy population, and to evaluate whether in patients with comparable LDL-C, the different lipoprotein subclasses differently affected the expression of chemokines, cytokines and adhesion molecules in peripheral blood mononuclear and endothelial cells.
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Perspectives on low-density lipoprotein cholesterol goal achievement.
Curr Med Res Opin
PUBLISHED: 02-06-2009
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Elevated levels of low-density lipoprotein cholesterol (LDL-C) are associated with an increased risk of coronary heart disease (CHD). European and US guidelines now recommend lower LDL-C levels, particularly in high-risk patients. Although LDL-C treatment goals to reduce the risk of CHD are clear, many patients do not reach their LDL-C goals.
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High density lipoproteins and atherosclerosis: emerging aspects.
J Geriatr Cardiol
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High density lipoproteins (HDL) promote the efflux of excess cholesterol from peripheral tissues to the liver for excretion. This ability is responsible for the most relevant anti-atherogenic effect of HDL. The ability of HDL to promote cholesterol efflux results also in the modulation of a series of responses in the immune cells involved in atherosclerosis, including monocyte-macrophages, B and T lymphocytes. Furthermore, during inflammation, the composition of this class of lipoproteins varies to a large extent, thus promoting the formation of dysfunctional HDL. The aim of this review is to discuss the emerging role of HDL in modulating the activity of immune cells and immune-inflammatory mediators during atherogenesis.
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MicroRNAs and lipoproteins: a connection beyond atherosclerosis?
Atherosclerosis
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MicroRNAs (miRNAs) are short non-coding RNAs involved in the regulation of gene expression at the post-transcriptional level that have been involved in the pathogenesis of a number of cardiovascular diseases. Several miRNAs have been described to finely regulate lipid metabolism and the progression and regression of atherosclerosis including, miR-33, miR-122. Of note miR-33a and -33b, represent one of the most interesting and attractive targets for metabolic-related disorders and anti-miR-33 approaches are under intensive investigation. More recently miRNAs were shown to exert their activities in a paracrine manner and also systemically. The latter is possible because lipid-carriers, including lipoproteins, transport and protect miRNAs from degradation in the circulation. This review will present the complex mechanism by which miRNAs regulate lipid metabolism, illustrate how their therapeutical modulation may lead to new treatments for cardiometabolic diseases, and discuss how lipoproteins and other lipid-carriers transport miRNAs in the circulation. The emerging strong connection between miRNAs, lipoproteins and lipid metabolism indicates the existence of a reciprocal modulation that might go beyond atherosclerosis.
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What is Visualize?

JoVE Visualize is a tool created to match the last 5 years of PubMed publications to methods in JoVE's video library.

How does it work?

We use abstracts found on PubMed and match them to JoVE videos to create a list of 10 to 30 related methods videos.

Video X seems to be unrelated to Abstract Y...

In developing our video relationships, we compare around 5 million PubMed articles to our library of over 4,500 methods videos. In some cases the language used in the PubMed abstracts makes matching that content to a JoVE video difficult. In other cases, there happens not to be any content in our video library that is relevant to the topic of a given abstract. In these cases, our algorithms are trying their best to display videos with relevant content, which can sometimes result in matched videos with only a slight relation.