Current Vascular Pharmacology - Volume 10, Issue 4, 2012

The low incidence of cardiovascular disease in countries bordering the Mediterranean basin, where olive oil is the main source of dietary fat, and the negative association between this disease with high density lipoproteins has stimulated interest. This review summarizes the current knowledge gathered from human and animal studies regarding olive oil and high density lipoproteins. Cumulative evidence suggests that high density lipoprotein (HDL) cholesterol, and its main apolipoprotein A1, may be increased by consuming olive oil when compared with carbohydrate and low fat diets in humans. Conflicting results have been found in many studies when olive oil diets were compared with other sources of fat. The role of virgin olive oil minor components on its protective effect has been demonstrated by a growing number of studies although its exact mechanism remains to be elucidated. Dietary amount of olive oil, use of virgin olive oil, cholesterol intake, and physiopathological states such as genetic background, sex, age, obesity or fatty liver are variables that may offset those effects. Further studies in this field in humans and in animal models are warranted due to the complexity of HDL particles.

High density lipoprotein (HDL) is recognized as the major negative risk factor of cardiovascular disease and number of anti-atherogenic functions has been ascribed to HDL. HDL is an assembly of a neutral lipid core and an outer shell consisting of polar lipids and proteins. It has been defined many different ways based on various distinct properties including density flotation, protein composition, molecular size, and electrophoretic migration. Overall the studies characterizing HDL clearly demonstrate that it is a complex heterogeneous mixture of particles. Furthermore several studies convincingly demonstrated that certain populations of HDL particles have a distinct functionality suggesting that HDL may serve as a platform for assembly of protein complexes with very specific biological functions. Indeed recent proteomics studies described over 100 proteins associated with HDL. Here we review approaches to isolation and proteomic analysis of HDL and discuss potential problems associated with isolation methods which may confound our understanding of the relation of the HDL composition and its biological function.

Hyperalphalipoproteinemia, as observed in patients who are either homozygous or heterozygous for cholesteryl ester transfer protein (CETP) deficiency, has been shown to be associated with striking changes in apolipoprotein size distribution, namely, of high-density lipoprotein (HDL) and HDL-like particles. We compared the effect of varying degrees of CETP activity on the HDL apolipoprotein profile in Caucasian CETP-deficient subjects and following pharmacological decrease in CETP activity, using Size Exclusion Chromatography followed by Reverse Phase Protein Array (SEC RPA). The main HDL-associated apolipoproteins (Apo), i.e. ApoA-I, ApoA-II, ApoC-I, and ApoC-III, co-eluted with the HDL peak. The presence of a HDL-like peak migrating between the ApoB-LDL and ApoA-I-HDL was identified in a Caucasian patient with homozygosity for a point mutation in exon 2 of the CETP gene (c.109 C > T) resulting in a premature termination codon (R37X) and complete CETP deficiency. This HDL-like peak was not observed either in healthy volunteers treated with the CETP modulator dalcetrapib, patients heterozygous for the same mutation, or in patients heterozygous with G165X mutations. SEC RPA offers the possibility to investigate the distribution of a large number of apolipoproteins simultaneously under non-denaturing separation in normal and dyslipidemic subjects. This is only limited by the availability of antibodies against specific apolipoproteins to be investigated.

Omega-3 polyunsaturated fatty acids (ω-3 PUFAs) from marine origin have been strongly associated with cardiovascular protection, even at low doses (< 1g/d). Despite the research performed in this promising area, basic aspects, such as the ideal doses and the mechanisms by which ω-3 PUFAs act, are not precisely defined. The best known biological property of ω-3 PUFAs is their hypotriglyceridemic effect, but other cardioprotective actions, such as reduction of arrhythmia susceptibility, antithrombotic, antiinflammatory and antioxidant effects, improvement of endothelial function, and delayed atherosclerosis development have received an increased interest in recent years. Some of these actions are also ascribable to high-density lipoproteins (HDL). Abundant epidemiological evidence links increasing HDL-cholesterol concentrations to cardiovascular protection. Recently, the protein cargo (proteome) of HDL particles has been attributed a key role in their functionality. In this review, we summarize the main effects of ω-3 PUFAs on HDL-cholesterol, HDL subfractions, and its main proteins, apolipoproteins (apo) AI and AII. The shared cardioprotective actions of ω-3 PUFAs and HDL are reviewed as well.

Glycoprotein (GP) IIb\IIIa receptor plays a central role on platelets activation and its blockage has been a matter of interest since the beginning of percutaneous revascularization. After first promising trials, GP IIb\IIIa inhibitors (GPI) have been widely used in cath labs for about a decade, significantly improving prognosis for patients with STSegment Elevation Myocardial Infarction (STEMI). However, their utilization isn’t exempt from risks, mainly in form of bleeding disorders, which can negatively affect patients’ outcome. Moreover, routinary administration of thyenopiridines like clopidogrel and the introduction of new anticoagulants like bivalirudin significantly reduced indications for GPI. In this review, a risk/benefit evaluation GP IIb\IIIa inhibitors is presented and their indications for STEMI patients addressed to revascularization are discussed according to recent advances reported in literature.

The glycoprotein (GP) IIb/IIIa receptor is critical to the process of platelet aggregation and thrombus formation as it serves as the final common pathway for platelet aggregation. For this reason, the development of GP IIb/IIIa inhibitors that block fibrinogen binding to the receptor has become an attractive strategy for antiplatelet therapy with an expected strong and specific effect. Presently, there are three commercially available GP IIb/IIIa inhibitors: abciximab, eptifibatide and tirofiban. All three drugs are commonly administered intravenously, and large-scale clinical trials have demonstrated a clear clinical benefit and good safety profile in patients at high risk, especially those undergoing percutaneous coronary interventions (PCI). Recently, several studies tested the intracoronary (IC) route for GP IIb/IIIa inhibitors in order to verify its safety and its possible superiority as compared to the intravenous (IV) route. The majority of the studies testing the IC route were conducted using abciximab and in patients with STEMI with better results in terms of myocardial reperfusion and infarct size and also promising results in terms of clinical outcome. On the IC administration of eptifibatide and tirofiban only some, even if promising, data are available. Larger and randomized studies are warranted to confirm the superiority of the IC route of administration of the GP IIb/IIIa inhibitors to the IV one in patients with coronary artery disease undergoing PCI.

Primary percutaneous coronary intervention (PCI) encompassing stent implantation is a mainstay in the management of acute ST-elevation myocardial infarction (STEMI). Despite refinements in techniques and devices, peri- and post-procedural antithrombotic therapy remains pivotal to prevent early and late thrombotic events, without unduly increasing bleeding risk. Concomitant dual antiplatelet therapy with aspirin and clopidogrel has been considered until recently the standard of care in terms of oral antiplatelet agents. However, most recently a novel and more potent thienopyridine, prasugrel, has been tested in randomized trials including patients with STEMI, and subsequently approved for clinical practice in Europe and North America. Despite its potent antithrombotic effect, prasugrel also carries a statistically significant increase in the risk of bleeding, especially in the elderly, those with low body weight, and previous stroke or transient ischemic attack. Thus, the use of prasugrel, as well as that of clopidogrel or ticagrelor, should best be individualized to maximize clinical benefits and minimize hazards.

Ticagrelor is a new oral antagonist of the platelet P2Y12 receptor that offers several potential advantages compared to clopidogrel including faster and more effective inhibition of platelet aggregation. Ticagrelor has been compared to clopidogrel in the PLATelet inhibition and patient Outcomes (PLATO) trial in a broad population of patients with acute coronary syndrome showing a reduction of the 12-month risk of death from vascular causes, myocardial infarction and stroke without increasing the overall risk of major bleeding. In a subanalysis of the PLATO trial focusing on patients with ST-elevation myocardial infarction, ticagrelor results were consistent with those of the overall trial. Additionally, possible pleiotropic effects of ticagrelor, including an appealing interaction with adenosine, might constitute a specific advantage in this particular subset of patients.

Distal embolization (DE) of atherothrombotic debris into the coronary microcirculation occurs both in stable and unstable coronary syndromes. Despite the well recognized clinical significance of periprocedural myocardial infarction (MI) in stable percutaneous coronary intervention (PCI), the impact of DE has a much higher prognostic impact in the acute setting, and especially in ST-elevation myocardial infarction, where DE is a main determinant of no-reflow phenomenon. The present review aims to describe the pathophysiology of DE and to summarize the currently available pharmacological strategies to prevent and treat DE in the setting of MI, especially focusing on antithrombotic, antiinflammatory and vasodilator agents.

Oral anti-platelet agents targeting the platelet P2Y12 receptor are an integral component of treating patients undergoing percutaneous coronary interventions. Advancements in the design of stents and catheters are pushing the technique towards treatment of high risk lesions whose failure would expose patients to catastrophic events. Success of these complex procedures largely lays on efficacy of anti-platelet drugs and the limitation of stent restenosis and/or thrombosis. Clopidogrel has been the most commonly used agent in this respect worldwide. However, there are certain shortcomings of clopidogrel, the most important of which is the wide response variability of platelet inhibition. Thus, clinicians are facing challenges in treating patients where high inhibition of platelets is necessary and the response to clopidogrel may be insufficient. In the last few years, cilostazol, a phosphodiesterase (PDE) 3 inhibitor, has been tested in the setting of acute coronary syndromes: it exerts not only anti-platelet actions, but also pleiotropic effects, including inhibition on neointimal hyperplasia, therefore preventing both stent restenosis and thrombosis. Therefore, cilostazol may be considered, on top of our current anti-platelet therapy, as a potential candidate to achieve optimal platelet inhibition especially in patients undergoing primary-PCI (p-PCI) or high risk procedures. This review will focus on the pharmacological characteristics of cilostazol and the initial evidences that support the use of this drug in the setting of p-PCI.

Currently available data on drug coated balloon (DCB) angioplasty as a clinical treatment modality for coronary and peripheral artery disease are limited but hold promise. Advantages over standard angioplasty and stent technologies include a homogeneous drug delivery to the vessel wall, an immediate drug release without the use of a polymer, the option of using balloon catheters alone or in combination with a bare metal stent, no foreign object left behind in the body, the potential of reducing anti-platelet therapy, and a lower restenosis rates in some indications. The clinical and angiographic presentation of patients with acute coronary syndromre (ACS) is heterogeneous. Therefore, different clinical scenarios of DCB application in ACS may be discussed. Frequently, thrombosis in the ACS-related lesion plays a major role. Patients in hemodynamic critical situations under catecholamine therapy may present with too small vessel diameters. Another clinically relevant scenario represents in-stent restenosis (ISR) which is frequently associated with ACS.

Thrombin a key modulator of the complex process involved in coronary obstruction during acute ST-segment elevation myocardial is infarction. A correct and complete thrombin inhibition has to be achieved early in this setting and is complementary with fast and potent antiplatelet treatment. Bivalirudin, a direct thrombin inhibitor, has clearly shown to be an effective tool for acute coronary syndromes managed invasively, contemporarily causing fewer hemorragies. However, its efficacy has been questioned, mostly in cases of inadequate platelet inhibition and during primary PCI if compared with therapy with heparin and glycoprotein IIb/IIIa inhibitors due to an increase in acute stent thrombosis. Other modalities of infusion have been shown to improve the antithrombotic properties of bivalirudin, maintaining its safety profile. In this article, we discuss on the most recent studies on this drug in the catheterization laboratory during acute myocardial infarction.

Essential hypertension may be a consequence of structural and functional alterations of the microvascular network growth resulting partly from abnormal regulation of vascular endothelial growth factor (VEGF), one of the most potent known angiogenic factors. As data from clinical trials on anti-VEGF drugs are becoming available, it is increasingly recognized that VEGF, in addition to being a proliferation and migration factor, is also a maintenance and protection factor for endothelial cells, whose altered regulation may cause a disturbance of vascular homeostasis. Elevated VEGF levels in hypertensive patients were shown to correlate with cardiovascular risk, early microvascular and target organ damage; accordingly treatment of hypertension significantly reduced VEGF levels. Recently and in agreement with the theory that impaired angiogenesis can contribute to increased peripheral resistance and raised blood pressure (BP), an involvement of VEGF gene promoter polymorphisms in the pathophysiology of hypertension has been hypothesized. In the last decade, anti-VEGF drugs have been used in clinical practice, especially in the oncology field. This review will summarize the present understanding of the contribution of VEGF to neoangiogenesis in hypertension and its possible role as a marker of vascular damage. Given the well established effects that antihypertensive drugs exert on the vasculature beyond BP lowering (pleiotropic effects), we will also discuss the effects of antihypertensive treatment on circulating VEGF levels. The biological mechanism and clinical impact of hypertensive complications during anti-angiogenic treatments will also be reviewed.

Platelets are key players in arterial thrombosis, and oral antiplatelet therapy is a cornerstone in the treatment and prevention of cardiovascular events. However, although currently approved antiplatelet drugs have proved successful in reducing cardiovascular events, platelet-dependent thrombosis remains an important cause of morbidity and mortality in patients with coronary artery disease. It is well-known that patients with diabetes mellitus (DM) have an increased risk of cardiovascular events and, therefore, understanding the mechanism of action and safety profile of antiplatelet drugs in this high-risk population is of particular interest. There is considerable inter-individual variation in the efficacy of established antiplatelet drugs, and high on-treatment platelet reactivity is associated with an increased risk of cardiovascular events, thus prompting the search for novel drugs against platelet-dependent thrombosis. New antiplatelet treatment strategies include drugs with more efficient and reversible platelet inhibition. This review discusses selective inhibitors of the platelet cyclooxygenase enzyme, thienopyridine and non-thienopyridine inhibitors of the platelet adenosine diphosphate receptor, phosphodiesterase inhibitors, and protease-activated receptor antagonists. An overview of currently available antiplatelet drugs is provided, focusing on benefits and limitations in patients with DM. Furthermore, the rationale for new oral antiplatelet drugs under development is discussed with particular focus on the potential role of these drugs to improve cardiovascular outcomes in patients with DM.

Several lines of evidence show that blood pressure (BP) control in treated hypertensive patients is largely unsatisfactory and that this depends on a variety of factors, such as the poor patient’s compliance, insufficient use of combination drug treatment as well as true difficulties in achieving well controlled BP. This review article will be focused on the main features of BP control by discussing the data obtained in clinical trials as well as the results available in clinical practice. The paper will also discuss the possible factors responsible for these findings as well as the favourable outcome on cardiovascular risk profile of an effective control of elevated BP. The possible approaches for controlling elevated BP values will be highlighted.

The aim of this review is to summarize present knowledge of genetic variation in cytochrome P450 1B1 (CYP1B1) and 2C9 (CYP2C9) genes and risk of tobacco-related cancer, female cancer, chronic obstructive pulmonary disease and ischemic vascular disease. The CYP1B1 and CYP2C9 enzymes metabolize polycyclic aromatic hydrocarbons found in tobacco smoke and thereby generate disease-causing metabolites suggested to be important in tobacco-related diseases. Furthermore, CYP1B1 also metabolizes estrogen while CYP2C9 metabolizes arachidonic acid, both creating metabolites potentially important in risk of female cancer or ischemic vascular disease. Genetic variation in genes coding for CYP1B1 and CYP2C9 enzymes have shown altered enzyme activity affecting levels of metabolites and thus potentially risk of disease. So far, however, findings have been inconsistent. Recently, large studies on the association between genetic variation in CYP1B1 and CYP2C9 and risk of disease with considerable statistical power rebutted the hypotheses that these genetic variants affect risk of tobacco-related cancer, female cancer, chronic obstructive pulmonary disease and ischemic vascular disease.