Early Investigational and Experimental Therapeutics for the Treatment of Hypertriglyceridemia.

Hypertriglyceridemia has been identified as a risk factor for cardiovascular disease and acute pancreatitis. To date, there are only few drug classes targeting triglyceride levels such as fibrates and ω-3 fatty acids. These agents are at times insufficient to address very high triglycerides and the residual cardiovascular risk in patients with mixed dyslipidemia. To address this unmet clinical need, novel triglyceride-lowering agents have been in different phases of early clinical development. In this review, the latest and experimental therapies for the management of hypertriglyceridemia are presented. Specifically, ongoing trials evaluating novel apolipoprotein C-III inhibitors, ω-3 fatty acids, as well as fibroblast growth 21 analogues are discussed.

Role of dipeptidyl peptidase 4 inhibitors in the new era of antidiabetic treatment.

The last few years important changes have occurred in the field of diabetes treatment. The priority in the therapy of patients with diabetes is not glycemic control per se rather an overall management of risk factors, while individualization of glycemic target is suggested. Furthermore, regulatory authorities now require evidence of cardiovascular (CV) safety in order to approve new antidiabetic agents. The most novel drug classes, i.e., sodium-glucose transporter 2 inhibitors (SGLT2-i) and some glucagon-like peptide-1 receptor agonists (GLP-1 RA), have been demonstrated to reduce major adverse CV events and, thus, have a prominent position in the therapeutic algorithm of hyperglycemia. In this context, the role of previously used hypoglycemic agents, including dipeptidyl peptidase 4 (DPP-4) inhibitors, has been modified. DPP-4 inhibitors have a favorable safety profile, do not cause hypoglycemia or weight gain and do not require dose uptitration. Furthermore, they can be administered in patients with chronic kidney disease after dose modification and elderly patients with diabetes. Still, though, they have been undermined to a third line therapeutic choice as they have not been shown to reduce CV events as is the case with SGLT2-i and GLP-1 RA. Overall, DPP-4 inhibitors appear to have a place in the management of patients with diabetes as a safe class of oral glucose lowering agents with great experience in their use.

Is there a role of lipid-lowering therapies in the management of fatty liver disease?

Atherogenic dyslipidemia is characterized by increased triglyceride-rich lipoproteins and low high-density lipoprotein cholesterol concentrations. It is highly prevalent in non-alcoholic fatty liver disease (NAFLD) and contributes to the increased cardiovascular risk associated with this condition. Alongside insulin resistance it plays an important pathogenetic role in NAFLD/non-alcoholic steatohepatitis (NASH) development and progression. It has been shown that cholesterol-lowering reduces cardiovascular risk more in NAFLD vs non-NAFLD high-risk individuals. This evidence highlights the importance of effective lipid modulation in NAFLD. In this narrative review the effects of the most commonly used lipid-lowering therapies on liver outcomes alongside their therapeutic implications in NAFLD/NASH are critically discussed. Preclinical and clinical evidence suggests that statins reduce hepatic steatosis, inflammation and fibrosis in patients with NAFLD/NASH. Most data are derived from observational and small prospective clinical studies using changes in liver enzyme activities, steatosis/fibrosis scores, and imaging evidence of steatosis as surrogates. Also, relevant histologic benefits were noted in small biopsy studies. Atorvastatin and rosuvastatin showed greater benefits, whereas data for other statins are scarce and sometimes conflicting. Similar studies to those of statins showed efficacy of ezetimibe against hepatic steatosis. However, no significant anti-inflammatory and anti-fibrotic actions of ezetimibe have been shown. Preclinical studies showed that fibrates through peroxisome proliferator-activated receptor (PPAR)α activation may have a role in NAFLD prevention and management. Nevertheless, no relevant benefits have been noted in human studies. Species-related differences in PPARα expression and its activation responsiveness may help explain this discrepancy. Omega-3 fatty acids reduced hepatic steatosis in numerous heterogeneous studies, but their benefits on hepatic inflammation and fibrosis have not been established. Promising preliminary data for the highly purified eicosapentaenoic acid require further confirmation. Observational studies suggest that proprotein convertase subtilisin/kexin9 inhibitors may also have a role in the management of NAFLD, though this needs to be established by future prospective studies.

Lipoprotein (a) as a treatment target for cardiovascular disease prevention and related therapeutic strategies: a critical overview.

Advances in several fields of cardiovascular (CV) medicine have produced new treatments (e.g. to treat dyslipidaemia) that have proven efficacy in terms of reducing deaths and providing a better quality of life. However, the burden of CV disease (CVD) remains high. Thus, there is a need to search for new treatment targets. Lipoprotein (a) [Lp(a)] has emerged as a potential novel target since there is evidence that it contributes to CVD events. In this narrative review, we present the current evidence of the potential causal relationship between Lp(a) and CVD and discuss the likely magnitude of Lp(a) lowering required to produce a clinical benefit. We also consider current and investigational treatments targeting Lp(a), along with the potential cost of these interventions.

Recent developments in pharmacotherapy for hypertriglyceridemia: what's the current state of the art?

Introduction: Hypertriglyceridemia is associated with both the development of cardiovascular disease (CVD) when mild-to-moderate and high risk of pancreatitis when more severe. The residual CVD risk after low-density lipoprotein cholesterol (LDL-C) lowering is, in part, attributed to high triglyceride (TG) levels. Therefore, there appears to be a need for effective TG-lowering agents.Areas covered: This review presents the most recent advances in hypertriglyceridemia treatment; specifically, it discusses the results of clinical trials and critically comments on apolipoprotein C-III inhibitors, angiopoietin-like 3 inhibitors, alipogene tiparvovec, pradigastat, pemafibrate and novel formulations of omega-3 fatty acids.Expert opinion: In the era of extreme lowering of LDL-C levels with several agents, there seems to be space for novel therapeutic options to combat parameters responsible for residual CVD risk, among which are elevated TGs. Furthermore, a significant number of individuals have very high TG levels and encounter the risk of acute pancreatitis. The most recently developed TG-lowering drugs appear to have a role in both conditions; the choice is mainly based on baseline TG levels. Dyslipidemia guidelines are likely to change in the near future to include some of these agents. Of course, long-term data regarding their safety and efficacy in terms of CVD outcomes and pancreatitis are warranted.

Investigating the lowest threshold of vascular benefits from LDL cholesterol lowering with a PCSK9 mAb inhibitor (alirocumab) in healthy volunteers - a mechanistic physiological study (INTENSITY-LOW): protocol and study rationale.

Objective: Whether reducing low density lipoprotein cholesterol (LDL-C) is associated with cardiovascular benefits in low risk normocholesterolaemic subjects is unknown. The INTENSITY LOW [Investigating the lowest threshold of vascular benefits from LDL-cholesterol lowering with a PCSK9 mAb inhibitor (alirocumab) in healthy volunteers] study aims to assess whether lowering LDL-C by alirocumab monotherapy can improve endothelial-dependent vascular function compared with placebo (primary objective) in low-risk normocholesterolaemic healthy individuals. Changes in endothelial-dependent or endothelial-independent vascular function, arterial stiffness and biomarkers of systemic inflammation by alirocumab, atorvastatin or their combination are secondary objectives. Study design and methods: This is a single-center, randomized, two-period, single-blind, placebo-controlled clinical trial. The study was registered on clinicaltrials.gov (N03273972). It will include 30 healthy low-risk subjects with LDL-C < 4.1 mmol/l. After passing the screening visit (Visit 1), eligible participants will be randomized 1:1 to either subcutaneous alirocumab 150 mg or placebo. These will be administered as single doses in 2 visits 14 days apart (Visits 2 and 3). Atorvastatin 20 mg once nightly will be prescribed for 14 days at Visit 3 in both groups through to Visit 4. At baseline (Visit 2) and during all post-dose visits (Visits 3-4), endothelial function will be assessed using venous occlusion plethysmography. Specifically, changes in forearm blood flow responses to intra-arterial infusions of acetylcholine, sodium nitroprusside and L-NG-monomethyl-arginine acetate will be assessed as surrogates of endothelial-dependent and -independent vasodilatation. Additionally, arterial stiffness and carotid intima-media thickness will be evaluated at the same timepoints. The above-mentioned changes will be correlated with changes in lipid and systemic inflammation biomarkers.

Prevalence, Identification, and Scouting for Familial Hypercholesterolaemia Including Registries.

BACKGROUND: Familial Hypercholesterolaemia (FH) is the most common metabolic genetic disorder, with around 13 million people worldwide having the disease. However, FH is globally underdiagnosed and undertreated, while the vast majority of those treated do not achieve treatment goals. OBJECTIVE: This review aims to clarify how to identify patients with FH. METHODS: We performed a comprehensive search of the literature to identify available data. RESULTS: Patients with FH are at high risk for cardiovascular events and death at an early age. Therefore, prompt detection of individuals with FH is of pivotal importance in order to implement appropriate preventive measures at a young age. Patient registries are a powerful tool for recording and monitoring a disease and encouraging clinical practices, subsequently improving outcomes and reducing healthcare costs. National FH registries are successfully applied in several countries (e.g. Spain, Denmark, UK, USA and the Netherlands). Importantly, in the last few years, the European Atherosclerosis Society (EAS) launched a global FH network aiming to collect data from specialized FH centres from different countries and establish a worldwide, standardised registry of patients with FH. CONCLUSION: It appears that the establishment and proper function of such registries will improve FH diagnosis, as well as preventive measures and management of FH patients.

Statins and mortality: the untold story.

Statins are first-line evidence-based drugs for the management of dyslipidaemias and to reduce the risk of cardiovascular events. However, statin clinical trials have shown marginally significant benefits on mortality, especially in the primary prevention setting. A major limitation of those trials is their relatively short follow-up. A reduced number of fatal events within a 5-year follow-up make mortality benefits unlikely to arise. This is particularly relevant for the primary prevention trials, where the risk of cardiovascular death is low. The short follow-up is a limitation for safety assessments too. However, extended major statin trials failed to detect any major safety concerns. Safety and efficacy assessments are even more complicated considering the differences of cardiovascular risk status in primary prevention individuals, and also given some potential ethnic and inter-individual genetic variations in response to statin treatment. Considerable evidence suggests a favourable risk-benefit balance for statin treatment. It can be assumed that statins reduce mortality in the long term by preventing cardiovascular events with complications that reduce lifespan. Unfortunately, this hypothesis cannot be proven as there is no current ethical basis on designing long-term placebo-controlled statin trials. Nevertheless, by effectively reducing disabilities related to cardiovascular events, statins have major benefits for public health. Therefore, clinicians should not withhold statin treatment awaiting proof of mortality benefits, as this may remain an 'untold story'.

Statins and their increased risk of inducing diabetes.

INTRODUCTION: Statins are evidence-based drugs to prevent cardiovascular (CV) disease. However, their benefits have been disputed by a statin-related increased risk of new onset diabetes (NOD) in randomized controlled trials and meta-analyses. AREAS COVERED: This review provides an update based on recent outstanding evidence on the statin effect on the risk of diabetes. It also describes mechanisms potentially explaining adverse effects of statins on glucose homeostasis. PubMed was searched for original articles and reviews published from January 2010 (inclusive) to May 2015 (inclusive), which include the Search terms statins, diabetes, glucose, and insulin. NOD risk seems to be more relevant with high-intensity rather than with low-intensity statin treatment. Also, this risk is particularly increased in patients at risk for the development of diabetes. It appears that statins adversely affect glucose homeostasis in parallel with their 3-hydroxy-3-methylglutaryl-coenzyme A inhibition capacity. It was suggested that lipophilic statins are more diabetogenic than the hydrophilic ones. Mechanisms explaining statin diabetogeneicity include impaired insulin secretion by pancreatic ß cells together with increased insulin resistance of various tissues. EXPERT OPINION: The CV outcome benefits from statin use outweigh the diabetes menace. However, patients at risk for the development of diabetes should be prescribed statins with caution.

Effects of benchmarking on the quality of type 2 diabetes care: results of the OPTIMISE (Optimal Type 2 Diabetes Management Including Benchmarking and Standard Treatment) study in Greece.

OBJECTIVES: To investigate the effect of benchmarking on the quality of type 2 diabetes (T2DM) care in Greece. METHODS: The OPTIMISE (Optimal Type 2 Diabetes Management Including Benchmarking and Standard Treatment) study [ClinicalTrials.gov identifier: NCT00681850] was an international multicenter, prospective cohort study. It included physicians randomized 3:1 to either receive benchmarking for glycated hemoglobin (HbA1c), systolic blood pressure (SBP) and low-density lipoprotein cholesterol (LDL-C) treatment targets (benchmarking group) or not (control group). The proportions of patients achieving the targets of the above-mentioned parameters were compared between groups after 12 months of treatment. Also, the proportions of patients achieving those targets at 12 months were compared with baseline in the benchmarking group. RESULTS: In the Greek region, the OPTIMISE study included 797 adults with T2DM (570 in the benchmarking group). At month 12 the proportion of patients within the predefined targets for SBP and LDL-C was greater in the benchmarking compared with the control group (50.6 versus 35.8%, and 45.3 versus 36.1%, respectively). However, these differences were not statistically significant. No difference between groups was noted in the percentage of patients achieving the predefined target for HbA1c. At month 12 the increase in the percentage of patients achieving all three targets was greater in the benchmarking (5.9-15.0%) than in the control group (2.7-8.1%). In the benchmarking group more patients were on target regarding SBP (50.6% versus 29.8%), LDL-C (45.3% versus 31.3%) and HbA1c (63.8% versus 51.2%) at 12 months compared with baseline (p < 0.001 for all comparisons). CONCLUSION: Benchmarking may comprise a promising tool for improving the quality of T2DM care. Nevertheless, target achievement rates of each, and of all three, quality indicators were suboptimal, indicating there are still unmet needs in the management of T2DM.

How effective are the ESC/EAS and 2013 ACC/AHA guidelines in treating dyslipidemia? Lessons from a lipid clinic.

OBJECTIVE: There is a paucity of data regarding the attainment of lipid-lowering treatment goals according to the recent American College of Cardiology/American Heart Association (ACC/AHA) guidelines. The aim of the present study was to assess how applicable these 2013 recommendations are in the setting of an Outpatient University Hospital Lipid Clinic. METHODS: This was a retrospective (from 1999 to 2013) observational study including 1000 consecutive adults treated for hyperlipidemia and followed up for ≥3 years. Comparisons for the applicability of current European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) and recent ACC/AHA guidelines were performed. RESULTS: Achievement rates of low density lipoprotein cholesterol (LDL-C) targets set by ESC/EAS were 21%, 44% and 62% among patients at very high, high and moderate cardiovascular risk, respectively, receiving statin monotherapy. Among individuals on high-intensity statins only 47% achieved the anticipated ≥50% LDL-C reduction, i.e. the ACC/AHA target. The corresponding rate was significantly greater among those on statin + ezetimibe (76%, p < 0.05). Likewise, higher rates of LDL-C target attainment according to ESC/EAS guidelines were observed in patients on statin + ezetimibe compared with statin monotherapy (37, 50 and 71% for the three risk groups, p < 0.05 for the very high risk group). CONCLUSION: The application of the ACC/AHA guidelines may be associated with undertreatment of high risk patients due to suboptimal LDL-C response to high-intensity statins in clinical practice. Adding ezetimibe substantially increases the rate of the ESC/EAS LDL-C target achievement together with the rate of LDL-C lowering response suggested by the ACC/AHA.

The effect of rosuvastatin on low-density lipoprotein subfractions in patients with impaired fasting glucose.

BACKGROUND: Prediabetes substantially increases cardiovascular risk. We examined the effect of rosuvastatin on the quantity and quality of low-density lipoprotein cholesterol (LDL-C) in patients with dyslipidemia having impaired fasting glucose (IFG) compared to normoglycemic patients with dyslipidemia. METHODS: This was a prospective observational study including patients with dyslipidemia and IFG (IFG group, n = 49) matched with normoglycemic patients with dyslipidemia (control group, n = 64). Study participants, following dietary intervention, were prescribed rosuvastatin 10 or 20 mg/d to achieve LDL-C goals. Baseline as well as 24 weeks posttreatment changes in the serum lipid profile were evaluated. Moreover, analysis of the LDL subfraction profile was conducted using a polyacrylamide tube gel electrophoresis method. RESULTS: Similar effects were observed in lipid profile in both treatment groups. Patients with IFG experienced a greater decrease in the cholesterol concentration of small dense LDL particles (-65.7%, P < .001 vs baseline) compared to controls (-38.5%, P < .001 vs baseline; P = .018 vs patients with IFG). There was no significant difference in the changes of cholesterol concentration of large and buoyant LDL particles in the IFG group when compared to the control group. A greater increase in the mean LDL particle size (+1.5%, P < .001 vs baseline) was noted in the IFG group compared to the control group at 24 weeks (+0.4%, P = .028 vs baseline; P = .008 vs IFG group). CONCLUSION: Targeting dyslipidemia with rosuvastatin was associated with more favorable changes in the LDL subfraction profile in patients with IFG compared to normoglycemic ones.

Lipid target achievement among patients with very high and high cardiovascular risk in a lipid clinic.

This was a retrospective study that assessed achievement of lipid-lowering treatment targets in the setting of a University Hospital Lipid Clinic. Low-density lipoprotein cholesterol (LDL-C) goal attainment according to National Cholesterol Education Program-Adult Treatment Panel III (NCEP ATP III) and European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines was recorded in 1000 consecutive adult patients followed for ≥3 years (mean 8 years). The LDL-C targets according to the NCEP ATP III were attained by 66% and 86% of patients with "very high" (n = 477) and "high" (n = 408) cardiovascular risk, respectively. Fewer patients were within LDL-C goals according to the ESC/EAS guidelines: 25% and 42%. Overall, 92% of the patients were on statins: 67% were on statin monotherapy, while 33% were on combinations with ezetimibe (25%), ω-3 fatty acids (5%), fibrates (4%), or colesevelam (2%). Even in a specialist lipid clinic, a large proportion of patients are not at goal according to the recent ESC/EAS guidelines.

Emerging drugs for hyperlipidaemia: an update.

INTRODUCTION: Hypercholesterolaemia is a significant risk factor for cardiovascular disease (CVD), a major cause of morbidity and mortality. Up to now, the appropriate management has been aggressive hypolipidaemic therapy, particularly with statins, aiming at certain low-density lipoprotein cholesterol (LDL-C) levels for each patient population. This strategy has reduced CVD-related morbidity and mortality. However, many cardiovascular events still occur, probably as a consequence of lipid disorders other than high LDL-C concentration or other risk factors. Because statins do not eliminate the residual CVD risk, there seems to be place for novel lipid modifying drugs with different mechanisms of action. AREAS COVERED: This review is an update since 2010 regarding lipid-modifying drugs in development and their potent role in clinical practice. It focuses on cholesterol ester transfer protein inhibitors, mainly anacetrapib and evacetrapib, microsomal triglyceride transfer protein inhibitors, antisense oligonucleotides, pre-protein convertase subtilisin kexin-9 inhibitors and high-density lipoprotein mimetics. EXPERT OPINION: Several novel lipid-modifying drugs may be beneficial for certain patient populations. However, ongoing and future studies with clinical outcomes will clarify their actual role in clinical practice.

High density lipoproteins and type 2 diabetes: Emerging concepts in their relationship.

Patients with type 2 diabetes mellitus (T2DM) frequently exhibit macrovascular complications of atherosclerotic cardiovascular (CV) disease. High density lipoproteins (HDL) are protective against atherosclerosis. Low levels of HDL cholesterol (HDL-C) independently contribute to CV risk. Patients with T2DM not only exhibit low HDL-C, but also dysfunctional HDL. Furthermore, low concentration of HDL may increase the risk for the development of T2DM through a decreased ß cell survival and secretory function. In this paper, we discuss emerging concepts in the relationship of T2DM with HDL.

Benefit-risk assessment of rosuvastatin in the treatment of atherosclerosis and related diseases.

Rosuvastatin has been marketed for approximately a decade. In this review we critically discuss available evidence on the benefits and risks from its use. In clinical trials using rosuvastatin, 'lowest is best' was relevant for on-treatment low-density lipoprotein cholesterol levels. Targeting levels <50 mg/dl was associated with the greatest decrease in vascular morbidity/mortality in the primary prevention setting. Also, such reduction can induce atherosclerosis regression without increasing the risk of adverse effects. Pooled data suggest that the safety profile of rosuvastatin is not different from that of other statins. It was estimated that rosuvastatin-associated absolute hazards of muscle-, liver- and renal-related adverse effects are lower than the corresponding vascular benefits in moderate vascular risk individuals. However, these data are subject to biases and need confirmation on a prospective basis. Significant liver enzyme elevations are rare. These often imply underlying non-alcoholic fatty liver disease (NAFLD), which is associated with increased vascular risk. Rosuvastatin can improve biochemical biomarkers and histological score of NAFLD. Whether this benefit is associated with vascular risk reduction should be assessed by prospective studies. Both chronic kidney disease and albuminuria independently predict vascular morbidity and mortality. Rosuvastatin improved the estimated glomerular filtration rate and decreased albuminuria in patients with moderately impaired kidney function. Also, vascular morbidity and mortality might be reduced in these patients. The same was not relevant in end-stage renal disease. Rosuvastatin-induced proteinuria appears to be of tubular origin, not relating to kidney injury. Rosuvastatin increases the risk of new-onset diabetes by dose-dependently impairing insulin sensitivity. Obese individuals with prediabetes appear to be predominantly affected. However, absolute vascular benefits of rosuvastatin may counterbalance this risk. Rosuvastatin is effective for the prevention and management of atherosclerotic vascular disease. Individualization of its use can maximize benefits and reduce the risk of adverse effects.

Rationale, design and baseline patient characteristics of the optimal type 2 diabetes management including benchmarking and standard treatment study in Greece.

AIM: To describe baseline data of the optimal type 2 diabetes management including benchmarking and standard treatment (OPTIMISE) study in Greece. METHODS: "Benchmarking" is the process of receiving feedback comparing one's performance with that of others. The OPTIMISE (NCT00681850) study is a multinational, multicenter study assessing, at a primary care level, whether using "benchmarking" can help to improve the quality of patient care, compared with a set of guideline-based reference values ("non-benchmarking"). In the Greek region, 797 outpatients (457 men, mean age 63.8 years) with type 2 diabetes were enrolled by 84 office-based physicians. Baseline characteristics of this population are presented. RESULTS: Hypertension was the most prevalent concomitant disorder (77.3%) and coronary heart disease was the most frequent macrovascular complication of diabetes (23.8%). Most patients were overweight or obese (body mass index 29.6 ± 5 kg/m(2)), exhibiting mostly abdominal obesity (waist circumference 102.6 ± 13.6 cm). Biguanides were the most prevalent prescribed drugs for the management of diabetes (70.1% of all prescriptions), whereas statins (93.5% of all prescriptions) and angiotensin receptor blockers (55.8% of all prescriptions) were the most prevalent prescribed drugs for hyperlipidemia and hypertension, respectively. Only 37.4% of patients were on aspirin. Despite treatment, pre-defined targets for fasting plasma glucose (< 110 mg/dL), glycated hemoglobin (< 7%), systolic blood pressure (< 130 mmHg and < 125 mmHg for patients with proteinuria) and low density lipoprotein cholesterol levels (< 100 mg/dL and < 70 mg/dL for patients with coronary heart disease) were reached in a relatively small proportion of patients (29%, 53%, 27% and 31%, respectively). In a Greek population with type 2 diabetes, the control of glycemia or concomitant disorders which increase cardiovascular risk remains poor. CONCLUSION: Despite relevant treatment, there is a poor control of diabetes, hypertension and hyperlipidemia in Greek outpatients with type 2 diabetes.

Association between mediterranean diet and non-fatal cardiovascular events, in the context of anxiety and depression disorders: a case/case-control study.

INTRODUCTION: The aim of this study was to investigate the effect of the Mediterranean diet on the likelihood of having a non-fatal cardiovascular outcome, taking into account anxiety and depression status. METHODS: This was a case-control study with individual matching by age and sex. During 2009-2010, 1000 participants were enrolled; 250 were consecutive patients with a first acute coronary syndrome (ACS), 250 were consecutive patients with a first ischemic stroke, and 500 were population-based control subjects, one-for-one matched to the patients by age and sex. Among other characteristics, adherence to the Mediterranean diet was assessed by the MedDietScore, anxiety was assessed with the Spielberger State-Trait Anxiety Inventory form Y-2, while depressive symptomatology was evaluated by the Zung Depression Rating Scale. RESULTS: Higher adherence to the Mediterranean diet was associated with a lower likelihood of ACS and ischemic stroke, even after adjusting for anxiety or depression (ACS: OR=0.92, 95%CI 0.87-0.98 and 0.93, 0.88-0.98, respectively; ischemic stroke: 0.91, 0.84-0.98 and 0.90, 0.83-0.97, respectively). For both ACS and stroke patients, anxiety and depression were associated with a higher likelihood of ACS and stroke. When stratifying for depression or anxiety status, the Mediterranean diet remained a significantly protective factor only for people with low levels of depression and anxiety for ACS, and only for people with low levels of anxiety, as far as stroke was concerned. CONCLUSION: Anxiety and depression seem to play a mediating role in the protective relationship between adherence to the Mediterranean diet and the likelihood of developing cardiovascular events.

Hemostatic factors and the metabolic syndrome.

Metabolic syndrome (MetS) is associated with increased risk of both atherothrombotic cardiovascular events and venous thromboembolism. The pro-thrombotic potential of MetS, may explain this association. In this review we discuss the relationship of MetS with hemostasis focusing on endothelial function, platelet activity, coagulation, fibrinolysis and hemorheologic markers. Endothelial-dependent vasodilatation is impaired in MetS. This is mostly mediated by a reduced expression of vasodilators (nitric oxide and prostacyclin) with a concomitant increase of vasoconstrictors (endothelin- 1, angiotensin II and thromboxane A2). Platelet activity is enhanced in MetS. A cross-talk between activated endothelium and platelets results in a pro-thrombotic vicious cycle. Enhanced coagulation together with impaired fibrinolysis is also present in MetS. This is mirrored by high fibrinogen and plasminogen activator inhibitor-1 levels. Endothelial dysfunction, expressed by high von Willebrand factor and tissue plasminogen factor levels, also contributes to this abnormality. Whole blood and plasma viscosity is increased in MetS. Lifestyle intervention can improve the MetS-related pro-thrombotic state. These measures include weight reduction and improved composition of the diet. A Mediterranean-style diet rich in olive oil, as a source of monounsaturated fat, and low saturated fat consumption may also be beneficial.