Current Vascular Pharmacology - Volume 14, Issue 3, 2016

The non-vitamin K oral anticoagulants (NOACs) are set to replace vitamin K antagonists (principally warfarin), unfractionated heparin and low molecular weight heparin as the leading antithrombotic prophylaxis in several medical and surgical settings. As a group, NOACs have a better safety profile and at least an equivalent (and sometimes superior) efficacy profile than their comparator. The objective of this review is to provide the practitioner with a comprehensive, balanced and contemporary view of these drugs and their applications. More specifically, it focuses on the evidence base for their licences, use in clinical practice (such as in renal dysfunction, orthopaedic surgery, atrial fibrillation, and venous thromboembolism, and the effects of co-medications), responses to actual or perceived haemorrhage, and the role of the laboratory.

Preeclampsia (PE), gestational diabetes mellitus (GDM), and maternal supraphysiological hypercholesterolaemia (MSPH) are pregnancy-related conditions that cause metabolic disruptions leading to alterations of the mother, fetus and neonate health. These syndromes result in fetoplacental vascular dysfunction, where nitric oxide (NO) plays a crucial role. PE characterizes by abnormal increase in the placental blood pressure and a negative correlation between NO level and fetal weight, suggesting that increased NO level and oxidative stress could be involved. GDM courses with macrosomia along with altered function of the fetal cardiovascular system and fetoplacental vasculature. Even when NO synthesis in the fetoplacental vasculature is increased, NO bioavailability is reduced due to the higher oxidative stress seen in this disease. In MSPH, there is an early development of atherosclerotic lesions in fetal and newborn arteries, altered function of the fetoplacental vasculature, and higher markers of oxidative stress in fetal blood and placenta, thus, vascular alterations related with NO metabolism occur as a consequence of this syndrome. Potential mechanisms of altered NO synthesis and bioavailability result from transcriptional and post-translational NO synthases (NOS) modulation, including phosphorylation/dephosphorylation cycles, coupling/uncoupling of NOS, tetrahydrobiopterin bioavailability, calcium/calmodulin-NOS and caveolin-1-NOS interaction. Additionally, oxidative stress also plays a role in the reduced NO bioavailability. This review summarizes the available information regarding lower NO bioavailability in these pregnancy pathologies. A common NO-dependent mechanism in PE, GDM and MSPH contributing to fetoplacental endothelial dysfunction is described.

Chronic kidney disease (CKD) is associated with the risk of multiple life-threatening complications such as: progression to chronic renal failure and cardiovascular disease including coronary heart disease, heart failure and peripheral arterial disease. Also, atrial fibrillation (AF) is common in this group of patients. Factors contributing to the occurrence of AF in patients undergoing dialysis include: age, presence of coronary heart disease, echocardiographic abnormalities (low ejection fraction, atrial enlargement, valvular calcification, left ventricular hypertrophy), heart failure, chronic obstructive pulmonary disease, hypertension, stroke, malnutrition (low levels of albumin, total cholesterol and high-density lipoprotein (HDL), secondary hyperparathyroidism, low predialysis systolic blood pressure, duration of renal replacement therapy as well as the method of renal replacement therapy (more frequent in haemodialysis patients). The optimal management of thromboprophylaxis in patients with CKD and AF is complex due to the fact that in patients with CKD many physiologic mechanisms are altered which lead to substantial changes in haemostasis and thus this group of patients is characterized by an increased risk of thrombotic and haemorrhagic complications. Recommendations concerning the treatment of patients with AF do not include guidelines on how to manage patients with advanced CKD, due to the lack of large randomized trials assessing the efficacy and benefits of drugs in these patients. Patients with CKD and permanent, persistent, and paroxysmal AF ought to be treated as a group with high risk of bleeding and ischaemic stroke. In case of patients with no or only one moderate risk factors, it seems that anticoagulation with antiplatelet drugs can be considered as efficient therapy, while in patients with ≥2 risk factors an oral anticoagulation therapy may be used. During long-term treatment, the international normalized ratio (INR) must be controlled at least every 14 days and adjusted within a target range of 2.0-2.5. Moreover, renal function should be evaluated before initiation of direct thrombin or factor Xa inhibitors and re-evaluated when clinically indicated and at least annually.

Subclinical hypothyroidism (SH) is characterized by a mildly elevated concentration of thyroid stimulating hormone (TSH) despite free thyroxine (FT4) and triiodothyronine (FT3) levels within the reference range. Numerous studies revealed SH to be an independent risk factor for cardiovascular disease (CVD), including atherosclerosis, congestive heart failure, coronary heart disease, ischemic heart disease and the associated mortality. The relationship between SH and CVD is well documented, but the molecular mechanism underlying this correlation remain unknown. Endothelial dysfunction has been recognized as an initial step leading to CVD in patients with SH. Changes in lipid profile, inflammation and/or oxidative stress contribute to the endothelial dysfunction in SH. Moreover, the progression of SH is characterized by significantly decreased nitrite and nitrate levels. Recent animal and clinical studies discussed in this review suggest that nitric oxide (NO) levels could be a reliable biomarker for cardiovascular risk in SH. Understanding the regulation of NO production by thyroid hormone may provide novel and useful knowledge regarding how endothelial dysfunction in SH is linked with CVD and help us to uncover new treatments for SH. We suggest that serum NO level may be an indicator for the introduction and dosage of levothyroxine (LT4) replacement therapy in SH patients. Future studies should focus on understanding the molecular mechanisms underlying the effects of NO in physiological as well as in pathophysiological conditions such as hypothyroidism and their clinical relevance.

Psoriasis is a chronic skin disease of unknown aetiology but increasing evidence suggests that cutaneous angiogenesis plays an important role. Vascular endothelial growth factor (VEGF) is one of the pro-angiogenic cytokines which is related to the pathogenesis of psoriasis. Our study evaluated the influence of imiquimod (IMQ) on VEGF in IMQ-induced mouse model. Balb/c female mice (n=16) 8-12 weeks of age were randomly divided into an experimental group (5% IMQ cream) and the control group (Vaseline cream). Serum levels of circulating VEGF-A were quantified by enzyme-linked immunosorbent assay. VEGF protein expression in tested skin was measured by western blotting and immunohistochemical staining. The tested skin in the experimental group expressed higher levels of VEGF protein than in the control group (p=0.012); immunohistochemical staining revealed that the cells over-expressing VEGF localized predominantly in the epidermis and vascular endothelium. Circulating VEGF-A levels showed no significant difference between the experimental and control groups (p=0.445). The IMQ-induced mouse psoriatic model showed an upregulation of VEGF in the skin lesions mimicking human psoriasis but the circulating VEGF-A levels showed no difference. This model may be useful to investigate the role of angiogenesis in psoriasis.

Background: The use of combination antiretroviral therapy (cART) has significantly decreased the morbidity and mortality associated with human immunodeficiency virus (HIV) infection. Lipid disorders, including lipodystrophy, hypertriglyceridemia, and hypercholesterolemia, remain the most commonly reported metabolic disorders among those treated with long-term cART. Mounting evidence suggests an association between drug abuse and poor glycemic control and diabetes complications. Substance related disorders (SRD) may increase the risk of metabolic syndrome. Materials and Methods: The aim of this retrospective cohort study was to examine the relationship between SRD, cART, and lipid-lowering agent use in an HIV infected population. Patients received efavirenz or protease inhibitor-based cART for at least 6 months. Prescription information was retrieved from the medical records. The primary outcome was the use of lipid-lowering agents including statins, fibrates and fish oil. The impact of SRD and cART was assessed on the lipidlowering agent use. Results: A total of 276 subjects with HIV infection were included, 90 (33%) received lipid-lowering agents, and 31 (34%) had SRD. Smoking was prevalent among subjects with SRD (84 vs 15%, p<0.001). Statins were the mainstay for the management of dyslipidemia (66%), followed by the fibrates (24%), omega-3 fatty acids (5%), nicotinic acid (3%) and the cholesterol absorption inhibitors (3%). Use of statins or fibrates was significantly higher among subjects without SRD than those with (40 vs 23%, p=0.005). The type of cART, including efavirenz and protease inhibitors, appeared to have no significant impact on the use pattern of lipid-lowering agents. Lopinavir/ritonavir (lopinavir/r) was mostly prescribed for subjects with SRD (25 vs 8%, p=0.02). Conclusion: Among HIV-infected patients, statins remain the mainstay for the management of dyslipidemia in routine clinical care, followed by fibrates. A significant high risk of metabolic disorders among patients with SRD is implicated by heavy tobacco use and prevalent lopinavir/r-based treatment. Significantly low rate of lipid-lowering agent use in this population underscores the importance of lipid disorder scrutiny and cART treatment optimization for HIV-infected patients with SRD.

Introduction: Full-length osteopontin (OPN-FL), whose levels are elevated in association with atherosclerosis, is cleaved by thrombin, resulting in the formation of a putatively biologically-active N-terminal cleavage product (OPNN). This study addresses the hypothesis that statin and antiplatelet therapy in hypertensive patients specifically reduces OPN-N, rather than OPN-FL, in carotid plaques. Methods: Seventy-four carotid plaques were collected from patients who underwent carotid endarterectomy (CEA). Plaque tissue was used to measure OPN proteins and for histological and immunohistochemical characterization. Results: There were 22 statin-negative and 52 statin-treated patients. In the carotid plaque, immunohistochemical staining for macrophages was higher in statin-negative vs. statin-treated patients (high CD68 immunostaining was in 61.9 vs. 28.6%, p=.03, respectively). OPN-FL staining had a similar trend, but without statistical significance (78.7 vs. 47.8%, p=.08, respectively). Western blot analysis of plaque OPN-FL showed that statin treatment was not associated with significant alteration of its abundance, but with a significantly lower plaque content of OPN-N [median 0.08 (IQR 0.05-1.01) vs. 0.81 (IQR 0.27-2.86), respectively, p=.015]. Comparable pattern of association between OPN proteins and antiplatelet therapy was found: the abundance of OPN-FL was not different in plaques from untreated or treated patients, while the abundance of OPN-N was significantly reduced in antiplatelet treated vs. non-treated patients [0.08, (IQR 0.05-0.66) vs. 0.89, (IQR 0.13-1.94), p=0.004]. Conclusion: The effect of anti-atherosclerotic treatment on carotid plaques of hypertensive patients more readily associates with OPN-N than with OPN-FL expression, suggesting that anti-atherosclerotic treatment including statins and antiplatelet drugs modulates the "OPN system".

Although hypertension, hypercholesterolemia and diabetes mellitus (DM) are recognized as major cardio-metabolic risk factors in primary Acute Coronary Syndrome (ACS) prevention, studies focusing on secondary ACS incidence are scarce. In the present study, the association between the aforementioned factors and 10-year ACS prognosis was evaluated. From October 2003 to September 2004 2,172 consecutive patients with ACS diagnosis, from 6 Greek hospitals, were enrolled. During 2013-14, the 10-year follow-up was performed in 1,918 participants. Baseline clinical factors were assessed through physical examination, medical records and pharmacological management. All-cause mortality and the development of fatal or non-fatal ACS events were recorded through medical records or hospital registries. Logistic regression models were applied to evaluate the impact of baseline clinical status on the ACS prognosis. The 10-year all cause and ACS mortality rate was 32.6 and 17.8%, respectively. Multi-adjusted analysis highlighted that, after taking into account various potential confounders, DM was the sole clinical factor associated with adverse effect on the 10-year ACS fatal incidence [Odds Ratio (OR)=1.35, 95% Confidence Interval (95% CI) 1.01, 1.80, p=0.04]. DM was the only clinical factor that aggravated ACS prognosis, whereas abnormal lipids profile and blood pressure did not seem to determine prognosis. Thus, glycaemic control may play a critical role in the secondary CVD prevention management of ACS patients.