Current Vascular Pharmacology - Volume 14, Issue 6, 2016

Background: Non-steroidal anti-inflammatory drugs (NSAIDs) are widely used, having numerous indications. However, despite their therapeutic role, they are associated with serious cardiovascular (CV) adverse events. Objectives-Methods: This review comprising recent observational studies and metaanalyses over the past few years aims at updating the assessment of CV adverse events, namely stroke, myocardial infarction (MI), CV death, atrial fibrillation (AF), serious bleeding and heart failure related to the use of 4 of the most widely prescribed NSAIDs: ibuprofen, naproxen, diclofenac and mefenamic acid. Results: The best safety profile related to MI was found for naproxen, while the worst safety profile, with excessively increased risk for stroke, MI and major bleeding, was for diclofenac. Naproxen showed higher risk for major bleeding than ibuprofen and the risk for stroke was slightly higher than ibuprofen. Regarding heart failure, ibuprofen presented the highest risk while the highest risk for AF was attributed to the current use of diclofenac. There are few data related to mefenamic acid, which showed a strong association with increased risk for stroke and a moderately increased risk for MI. Conclusion: Further research is needed in order to devise new guidelines for safer use of NSAIDs.

Background: Aortic aneurysms (AAs) are without effective pharmacologic therapy, in clinical usage, in part because of the limited understanding of factors leading to AA development. Objective: The objectives of this study were to examine the evidence that cigarette smoking induces AAs through altering matrix metalloproteinases (MMP) and the molecular biology/pharmacology that maybe involved in this effect. Methods: A systematic search was conducted to identify studies that examined the links between cigarette smoke, MMP and AAs. Results: Eleven studies were identified. There was consistency, between studies. They found that cigarette smoke, nicotine or tobacco products increased aortic dimension and the proportion of AAs. Nicotine and tobacco constituents induced MMPs: MMP-1, MMP-2, MMP-8, MMP-9 and MMP-12 but with different levels of consistency. The molecular mechanisms involved in the pathogenesis of cigarette-induced AA formation, ranked according to the consistency of evidence include JNK, AMPK-2, Jak Stat, and mTOR/p70Sk and PTEN pathways. Conclusion: Nicotine and tobacco constituents translate the exposure to cigarette smoke into increased MMP expression through various molecular mechanisms whose interruption can form the basis for pharmacologic management of AAs.

Statins remain the cornerstone of lipid-lowering treatment. They significantly reducing cardiovascular morbidity and mortality in primary and secondary prevention settings. Statin-treated patients may present adverse events (clinical and/or biochemical) that can lead to treatment discontinuation or a reduction in the dose of statins. Statin intolerance may appear at any time during the treatment. In each case, secondary causes should be assessed and treated and lifestyle measures should be implemented. Up to 3 different statins can be tried at a low dose; statin dosing everyother- day or once weekly may be another option. Several non-statin lipid-lowering drugs (ezetimibe, fibrates, colesevelam, niacin or proprotein convertase subtilisin kexin-9 inhibitors) are available as monotherapy or in combination with statins to achieve efficacy and tolerability.

The estimation of risk for atherosclerotic cardiovascular (CV) events based only on the presence of classical risk factors is often insufficient. Therefore, efforts have been made to find markers that indicate the presence of preclinical or clinical disease. Inflammation mediates all stages of the disease, from initiation to the thrombotic complications of atherosclerosis. Raised levels of several circulating markers, particularly inflammatory mediators, have been reported in subjects with atherosclerosis. Increased risk for CV events is associated with increased levels of cytokines, celladhesion molecules, P-selectin and E-selectin, and acute phase reactants, such a highsensitivity C-reactive protein and serum amyloid-A. Elevation of some of these markers predicts the outcomes of patients with acute coronary syndromes. However, because of their non-specificity, these biomarkers represent only a moderate added predicting value after considering conventional CV risk factors. Consequently, recent research has focused on the detection of vulnerable plaque, using vascular bed-specific biomarkers that can help identify individuals at highest risk and help guide how to intervene to prevent CV events. Considerable progress in the understanding of the role of the inflammation in atherogenesis has opened new possibilities for the management of atherosclerosis. Recently new drugs mediating the direct inhibition of circulating markers of inflammation were developed. These drugs could provide a novel therapeutic approach and further enhance the understanding of the role of inflammation in atherosclerosis.

The prevalence of methicillin-resistant Staphylococcus aureus (MRSA) was investigated among infected diabetic foot ulcers in hospitalized and nonhospitalized patients in southern Poland to assess the virulence patterns and antimicrobial resistance among these strains. MRSA was detected in 10.3% of all studied isolates, from the hospitalized patients only. The rest of the isolates was methicillin susceptible. The minimal inhibitory concentration that inhibits 50% of bacterial isolates (MIC50) for vancomycin was 1.0 mg/mL. The mupA gene was detected in six (8.8%) isolates, in one MRSA strain and five methicillin-sensitive S. aureus (MSSA) strains. Among the mupA-positive strains, two were resistant to mupirocin (1 MRSA and 1 MSSA). Such results raise serious concern about the usage of mupirocin in MRSA decolonization. The pvl gene was not detected among the study isolates. The majority of isolates (70.6%) possessed the lukE gene, with no significant difference in prevalence between MRSA and MSSA isolates. An interesting finding was the presence of enterotoxin genes among the study isolates. Diabetic foot may therefore be a reservoir of bacteria, containing genes localized on mobile genetic elements that could be easily transferred to other non-pathogenic strains. The prevalence of MRSA was alarmingly high (as also suggested by others), as evaluated by the presence of the mup gene among strains, highlighting the importance of appropriate clinical management of MRSA infections in patients with diabetic foot ulcers. In this group of patients, screening of ulcer samples before antimicrobial therapy would enable informed choices regarding the selection of antimicrobial agents (e.g. octenidine, authorized for the treatment of chronic wounds) maximizing the chances of positive therapy.

Background: Inhibition of dipeptidyl peptidase-4 (DPP-4) has been proposed as a therapeutic target for type 2 diabetes (T2DM). Arterial stiffness, a predictor of future cardiovascular events and all-cause mortality, is augmented in these patients. However, effects of DPP-4 inhibitors on arterial stiffness remain unknown. In this study, we compared effects of anagliptin, an inhibitor of DPP-4 on arterial stiffness evaluated by cardio-ankle vascular index (CAVI) with those of an equipotent glucose-lowering agent, glimepiride in patients with T2DM. Methods: The study involved 50 consecutive outpatients (33 males and 17 females; mean age of 72.5±9.5 years) who visited our hospitals for a risk-screening test or treatment for T2DM. They underwent complete history and physical examination, and determination of blood chemistry and anthropometric variables, and then were randomized to receive either anagliptin (n=26) or glimepiride (n=24) for 6 months. Results: After 6-months treatment, fasting plasma glucose and HbA1c values were comparably reduced in both groups. Anagliptin, but not glimepiride treatment significantly decreased low-density lipoprotein cholesterol, malondialdehyde-modified LDL, remnant-like particle (RLP) cholesterol, CAVI, alanine transaminase (ALT), γ-glutamyl transferase and visceral fat volume. In multiple regression analysis, absolute changes from baseline of RLP cholesterol and ALT after anagliptin treatment for 6 months (RLP cholesterol and ALT) were independently correlated with ΔCAVI (R2=0.445). Conclusion: The present study suggests that anagliptin may exert a beneficial effect on arterial stiffness in patients with T2DM, which is independent of its blood glucose-lowering property. Anagliptin may ameliorate arterial stiffness partly via reduction of RLP cholesterol and improvement of liver function.

Objectives: A considerable number of patients do not achieve an adequate response to clopidogrel. Our study aimed to evaluate genetic and non-genetic factors as possible risks for clopidogrel high on-treatment platelet reactivity (HTPR) in patients (n=112) with carotid artery stenosis undergoing endarterectomy (CEA). Methods: Using multiple-electrode impedance aggregometry (MEA) the antiplatelet effectiveness of clopidogrel was measured after 24 h, 7 and 30 days of clopidogrel treatment, which was introduced after elective CEA at a dose of 75 mg daily, for at least 30 days. Results: HTPR was observed among 25% patients after clopidogrel therapy for 30 days. Further analysis showed that 53.3% of patients carrying the CYP2C19*2 gene variant had clopidogrel-HTPR, while in the wild type group there were 14.6% (p<0.001). Multivariate logistic regression analysis identified the CYP2C19*2 variant allele (OR 4.384; 95% CI 1.296-14.833, p=0.017) and high total cholesterol level (OR 2.090; 95% CI 1.263-3.459, p=0.004) as the only independent risk factors for clopidogrel-HTPR. Conclusion: The CYP2C19*2 gene variant and high total cholesterol level were major factors for clopidogrel- HTPR in patients with carotid artery stenosis undergoing CEA.

Objective: We evaluated the safety and efficacy of hypertension management with Coveram (perindopril/amlodipine combination) in patients with uncontrolled blood pressure (BP). All patients were on previous angiotensin receptor blocker (ARB) treatment. Methods: This was a 3 country, multi-centre (7 cities), open-label, observational study in the Arabian Gulf. Patients (≥18 years) were recruited between October 2012 and November 2013 and followed-up for 3 months after enrolment. Outcomes included changes in BP from baseline and BP goal attainment rates as per Joint National Committee- 8 (<140/90 mmHg for diabetics and those <60 years of age and <150/90 mmHg for those ≥60 years of age without diabetes). Medication tolerance was also assessed from both patient and physician perspectives. Results: Hypertensive patients (n=760; mean age: 51±10 years; 67% were males) were included. A total of 178 patients (23%) were lost to follow-up. The perindopril/amlodipine combination was associated with an overall reduction in systolic BP (SBP) (31 mmHg; p<0.001) and diastolic BP (DBP) (18 mmHg; p<0.001) from baseline. An overall BP control rate was achieved in 87% (n=507) of the participants. There were significant incremental BP reductions with dose up-titration, especially SBP (p<0.001). Those with high SBP (>180 mmHg) at baseline were associated with a mean reduction of 59 mmHg (p<0.001). The perindopril/amlodipine combination had excellent tolerance levels over the study period from both patient and physician perspectives (at 99% and 98%, respectively; p<0.001). Conclusions: The perindopril/amlodipine combination is an effective and well tolerated anti-hypertensive option in patients on previous ARB treatment.