Current Vascular Pharmacology - Volume 13, Issue 6, 2015

Dyslipidemia plays an important role in the initiation and progression of atherosclerotic coronary artery disease. However, regression of atherosclerotic atheroma by introducing lipid lowering agents is not fully understood but looks promising. More questions still need to be answered in terms of the modality of assessment, time course of changes and its documentation, whether plaque progression or regression assessed by imaging one arterial tree reflects a uniform effect throughout all arterial territories and whether atheroma regression is a therapeutic goal. Physicians need to define the type of statins, the use of statin as monotherapy or in combination with other agents, and the intensity of statin therapy. Furthermore, the impact of factors like age, gender and ethnicity on the regression process should be of consideration. We still need more randomized controlled studies based on evidence-based diagnostic interventional tools. This narrative review considers this debate.

The current view is that systemic inflammation, which is specific to all chronic inflammatory rheumatic diseases (CIRD), accelerates atherogenesis; this hypothesis is supported by the high cardiovascular (CV) morbidity and mortality rates and the high prevalence of all atherosclerosis stages and complications in CIRD patients. The assessment of traditional CV risk factors underestimates the actual risk in patients with CIRD. A comprehensive evaluation and follow-up of both traditional and non-traditional CV risk factors, as well as the correct classification of risk reduction categories are necessary. Imaging techniques (e.g. carotid intima-media thickness and flow-mediated vasodilation) can be used for the early diagnosis of endothelial dysfunction. Immunologic and metabolic markers (anti-cyclic citrullinated peptide (CCP) antibodies, IgM rheumatoid factor, circulating immune complexes, proinflammatory cytokines, TH0/TH1 lymphocytes and homocysteine) may be involved in the atherosclerotic disease development specific to CIRD. A modern therapeutic approach should include the early diagnosis of endothelial dysfunction and atherosclerosis, treatment of CIRD, specific medication designed to control atherosclerosis, changes in patient lifestyle and periodic follow-ups. The assessment and diagnosis of traditional and non-traditional CV risk factors, followed by aggressive prevention and therapy, are necessary to achieve efficient control over the inflammation, immunologic and metabolic disorders specific to CIRD.

Rhabdomyolysis is a syndrome due to a damage of skeletal muscle and the leakage of intracellular contents into the extracellular fluid and the circulation. Several causes may induce rhabdomyolysis and the major one is the crush syndrome. Most cases of non-traumatic rhabdomyolysis are related to drugs. Many molecules are subject to hepatic metabolism and the concomitant use of drugs, as statins, with other medications acting as substrates of the same isoenzymes can interact and increase the risk of myopathy. Subclinical rise of creatine kinase may be the expression of rhabdomyolysis that can present as a medical emergency such as acute kidney injury (AKI), compartment syndrome, cardiac dysrhythmias and disseminated intravascular coagulopathy. The main pathophysiological mechanisms of myoglobinuric-related AKI are renal vasoconstriction, formation of intraluminal casts and direct cytotoxicity promoted by heme-protein. The aim of this review is to analyze the pathophysiology of myolysis, the causes of rhabdomyolysis and especially the link between the liver and the kidney, which can represent the connecting element for the development of the syndrome.

Atrial fibrillation (AF), one of the most prevalent supra-ventricular arrhythmia in adults, is related to a substantial increase in the risk of thromboembolic events requiring tailored preventive strategy. In AF, antithrombotic therapy should be individualized according to a careful decisionmaking process, taking in account the likely concomitant presence of risk factors for stroke and bleeding. Anticoagulation management is particularly challenging in women with AF, to the extent that female sex is incorporated in commonly used stratification schemes for both thromboembolic and bleeding risk evaluation. Nevertheless, gender- based differences on the efficacy and safety of either “old” (i.e. vitamin K antagonist) or “new” oral anticoagulants (i.e. direct thrombin inhibitors and activated factor X inhibitors) are not conclusive and not always reported. This review aims to analyse the literature on sex differences in AF anticoagulation management. We focus on safety data, bleeding complications and specific haemostatic mechanisms currently under investigation, which could account for observed disparities among sexes. Moreover, details on sex difference in response to anticoagulant treatment will be discussed. Comparing old and new antithrombotics, a need clearly emerges for differentiated and integrated strategies for the treatment of AF in female patients.

Endothelial dysfunction (ED) is the initial step in the development of atherosclerosis, leading to cardiovascular disease (CVD). It has been suggested that periodontal disease (PD) could be associated to pathogenesis of atherosclerosis, since it is able to trigger a host response with systemic inflammation. Although a number of epidemiological studies have shown that periodontitis could be associated with ED, it is still unclear whether periodontal treatment could improve ED and therefore cardiovascular outcomes. In this narrative review we analysed the literature in the databases of Medline under ‘‘endothelial function OR dysfunction OR vasodilatation’’, AND ‘‘periodontal disease” OR periodontal treatment” AND “cardiovascular disease” OR atherosclerosis AND “endothelial biomarker”. Research articles, systematic reviews and clinical trials were screened. ED could be related to periodontitis as well as to CVD. Periodontal treatment reduces the risk of teeth loss and may improve ED and the risk of CVD. Since controversial results exist, there is an urgent need for well-designed clinical trials to find and validate novel biomarkers of endothelial function, such as circulating endothelial progenitors, which may be crucial for further investigation of the association of PD with endothelial function and CVD.

We present clinical practice guidelines for the diagnosis and treatment of homozygous familial hypercholesterolaemia (HoFH) in the Middle East region. While guidelines are broadly applicable in Europe, in the Middle East we experience a range of confounding factors that complicate disease management to a point whereby the European guidance cannot be applied without significant modification. Specifically, for disease prevalence, the Middle East region has an established epidemic of diabetes and metabolic syndrome that can complicate treatment and mask a clinical diagnosis of HoFH. We have also a high incidence of consanguineous marriages, which increase the risk of transmission of recessive and homozygous genetic disorders. This risk is further augmented in autosomal dominant disorders such as familial hypercholesterolaemia (FH), in which a range of defective genes can be transmitted, all of which contribute to the phenotypic expression of the disease. In terms of treatment, we do not have access to lipoprotein apheresis on the same scale as in Europe, and there remains a significant reliance on statins, ezetimibe and the older plasma exchange methods. Additionally, we do not have widespread access to anti-apolipoprotein B therapies and microsomal transfer protein inhibitors. In order to adapt existing global guidance documents on HoFH to the Middle East region, we convened a panel of experts from Oman, Saudi Arabia, UAE, Iran and Bahrain to draft a regional guidance document for HoFH. We also included selected experts from outside the region. This panel statement will form the foundation of a detailed appraisal of the current FH management in the Middle Eastern population and thereby provide a suitable set of guidelines tailored for the region.

Background: Financial status has been considered as an important health determinant and associated with compliance to healthier lifestyle habits, medical treatment and increased prevalence of mental disorders. The aim of this work was to evaluate the association between financial status, patient adherence to medication, 10-year allcause mortality and risk for Acute Coronary Syndrome (ACS), in a Greek sample of cardiac patients. Methods: From October 2003-September 2004 a sample of 2,172 consecutive ACS patients from 6 hospitals was enrolled. In 2013-14, the 10-year follow-up was performed in 1,918 participants. Adherence to medical treatment was recorded through self-reports and financial status was classified as low (<9,000), moderate (9-18,000), good (19-48,000) and very good (>48,000). Results: The “low”-to-“very” good financial status 10-year all-cause mortality rate was 1.7:1 (p<0.001). Unadjusted analysis revealed no association between financial status and ACS incidence (p=0.22); however, multi-adjusted analysis, after taking into account various clinical and lifestyle factors, revealed that “good/very good” financial status was associated with 23% (95%CI 2%, 40%, p=0.04) lower 10-year risk of ACS as compared with “low/moderate”; a finding that became insignificant when adherence to medication was taken into account. Conclusions: Low financial status seems to play a critical role in the long-term ACS prognosis. Health policies, to tackle non-compliance to medication, are needed to minimize the disease burden in clinical and community settings.

Background and Aims: The protective role of Mediterranean diet on cardiovascular disease (CVD) risk has been extensively discussed in the literature, but its incremental effect over the use of CVD risk reducing agents (such as hypolipidemic treatment) has rarely been evaluated. Methods: The ATTICA study was carried out in the Athens area during 2001-2002 and included 3042 participants free of CVD at baseline (49.8% men, aged 18-89 years). Adherence to Mediterranean diet was assessed using the MedDietScore (range 0-55) and statin use was recorded for all subjects. During 2011-2012, 2583 out of the 3042 baseline participants attended the 10-year follow-up of the ATTICA study (15% lost-to-follow-up) and CVD development was recorded. Results: Adherence to Mediterranean diet (highest tertile) decreased CVD risk by 29.3% (Hazard Ratio (HR): 0.707, 95% Confidence Intervals (CI): 0.537-0.831) as compared with the lowest tertile, independently of statin use. Patients with hyperlipidemia on a statin that adopted unhealthy dietary habits (lowest tertile) had 75% increased CVD risk than normolipidemic subjects with healthy dietary habits (HR=1.75, 95%CI: 1.33-2.29). The addition of Mediterranean diet tertiles in the multivariable model reclassified 46.7% of the participants to CVD risk categories. Conclusion: Adherence to Mediterranean diet confers a considerable reduction in CVD risk, independently of gender, age, family history of CVD, diabetes mellitus, smoking status, hypertension and physical activity status. Therefore, CVD prevention strategies should involve the implementation of a Mediterranean diet in both the general population and patients on a statin.

Aim: To assess the potential differences in the metabolic and cardiovascular disease (CVD) risk between the distinct phenotypes of the Polycystic Ovary Syndrome (PCOS) according to the Rotterdam definition regardless of body mass index (BMI). Patients-Methods: The study included 300 women; 240 women with PCOS, according to the Rotterdam criteria and 60 controls without PCOS. All women were further subdivided, according to their BMI, into normal-weight and overweight/obese and PCOS women were furthermore subdivided to the 4 phenotypes of the syndrome. A complete hormonal and metabolic profile as well as the levels of high sensitivity C reactive protein (hsCRP) and lipoprotein-associated phospholipase A2 (Lp-PLA2) were measured. Outcomes: Levels of surrogate markers of subclinical atherosclerosis (hsCRP and Lp-PLA2), levels of evaluated CVD risk score using risk engines, and several correlations of CVD risk factors. Results: hsCRP levels were higher but not significantly so in PCOS women compared with controls. In lean PCOS patients, Lp-PLA2 levels were significantly higher, compared with lean controls, mainly in the 2 classic phenotypes. Overweight/obese patients in all 4 phenotypes had significantly higher Lp-PLA2 levels compared with overweight/obese controls. Evaluated CVD risk according to 4 risk engines was not different among phenotypes and between PCOS patients and controls. There were several correlations of risk factors with metabolic syndrome and non-alcoholic fatty liver disease requiring appropriate treatment. Conclusions: Only 2 of 4 Rotterdam phenotypes, identical with those of the classic PCOS definition, have excess cardiometabolic risk. These need to be treated to prevent CVD events

Objective The aetiology of varicose veins involves various factors and pathomechanisms including endothelial cell activation or dysfunction, venous hypertension, vein wall hypoxia, shear stress disturbances, inflammatory reaction activation or free radical production. To improve our understanding of the mechanisms of potential pharmacological interventions for chronic venous disease, we evaluated the influence of micronized purified flavonoid fraction (MPFF) on the relationship between antioxidant enzyme balance, endothelin-1 (ET-1) and tumour necrosis factor-α (TNF-α) levels. Material and Methods Blood samples were obtained from 89 women with primary varicose veins; 34 were treated with MPFF and 55 did not receive any phlebotropic drug treatment. For the evaluation of the blood antioxidant enzyme balance, catalase (CAT) and superoxide dismutase (SOD) activity was assessed and the CAT/SOD ratio was calculated. Results Patients taking MPFF had significantly lower ET-1 levels than those not taking MPFF [median (25-75th quartile): 24.2 (22.30-27.87) vs 37.62 (24.9-44.58) pg.ml-1; p <0.05]. In those taking MPFF, a higher CAT/SOD ratio [39.8 (24.7-72.6) vs 28.8 (16.3-57.7); p<0.05] and a lower TNF-α concentration [6.82 (4.42-13.39) vs 12.94 (6.01-27.33) pg.ml-1; p<0.05] was also observed. In women not taking MPFF, ET-1 levels increased with the CAT/SOD ratio. In those taking MPFF, the ET-1 level was stable at approximately 25.0 pg.ml-1¬ up to a CAT/SOD ratio of 100. TNF-α level increased continuously with an increasing CAT/SOD ratio; however, the highest levels of TNF-α were observed in women not taking MPFF. Conclusion We demonstrate the ability of MPFF to effectively lower the levels of ET-1 and TNF-α in patients with chronic venous disease. Further investigations are needed to define the therapeutic potential of MPFF including the potential effect on chronic subclinical inflammation, antioxidant imbalance and vascular dysfunction during the development of chronic venous disease.

Background: The aim of the present interim analysis was to compare the clinical efficacy and safety of the generic clopidogrel besylate (CB) with the innovator clopidogrel hydrogen sulphate (CHS) salt in patient groups eligible to receive clopidogrel. Methods: A 2-arm, multicenter, open-label, phase 4 clinical trial. Consecutive patients (n=1,864) were screened and 1,800 were enrolled in the trial and randomized to CHS (n=759) or CB (n=798). Primary efficacy end point was the composite of myocardial infarction, stroke or death from vascular causes, and primary safety end point was rate of bleeding events as defined by Bleeding Academic Research Consortium (BARC) criteria. Results: At 6-months follow-up no differences were observed between CB and CHS in primary efficacy end point (OR, 0.80; 95% CI, 0.37 to 1.71; p=0.57). Rates of BARC-1,-2,-3a and -5b bleeding were similar between the two study groups whereas no bleeding events according to BARC-3b, -3c, -4 and -5a were observed in either CHS or CB group. Conclusion: The clinical efficacy and safety of the generic CB is similar to that of the innovator CHS salt, thus, it can be routinely used in the secondary prevention of atherothrombotic events for a period of at least 6 months. (Salts of Clopidogrel: Investigation to ENsure Clinical Equivalence, SCIENCE study Clinical Trials.gov Identifier: NCT02126982).