Current Vascular Pharmacology - Volume 7, Issue 3, 2009

The recently published Assessment of Survival and Cardiovascular Events (AURORA) trial showed that rosuvastatin (10 mg/d) compared with placebo did not result in a significant reduction in vascular events despite a 43% fall in low density lipoprotein cholesterol (LDL-C) levels in patients with end-stage renal disease (ESRD). The reasons for this and previous negative findings are discussed. In contrast, there is evidence that statins exert a nephroprotective action in less advanced chronic kidney disease (CKD). There is need for further trials to establish if patients at various stages of CKD will benefit from statin treatment in terms of both nephroprotection and reduction in vascular events.

Common to multiple vascular diseases, including atherosclerosis, interventional restenosis, and transplant vasculopathy, is a localized inflammatory reaction. Activated vascular smooth muscle cells (VSMC) respond to local inflammation and migrate from the media into the lumen of the vessel where they proliferate and synthesize cytokines which they respond to in an autocrine fashion, sustaining the progression of the lesion. The deleterious effects of proinflammatory cytokines, particularly immunomodulatory interleukins, on vascular pathophysiology and development of these maladaptive processes have been the subject of intense study. Although a great deal of attention has been given to the negative effects of pro-inflammatory cytokines and interleukins, relatively little has been reported on the potentially beneficial paracrine and autocrine effects of anti-inflammatory interleukins on the vascular response to injury. The vast majority of emphasis on secretion and function of anti-inflammatory mediators has been placed on leukocytes. Consequently, the role of non-immune cells, and direct effects of anti-inflammatory interleukins on vascular cells is poorly understood. We will review the molecular mechanisms whereby anti-inflammatory interleukins inhibit signal transduction and gene expression in inflammatory cells. We will review studies in which beneficial “indirect” effects of antiinflammatory interleukins on progression of vascular disease are achieved by modulation of immune function. We will also present the limited studies in which “direct” effects of these interleukins on VSMC and endothelial cells dampen the vascular response to injury. We propose that expression of immunomodulatory cytokines by activated vasculature may represent an auto-regulatory feed back mechanism to promote resolution of the vascular response to injury.

Atherosclerosis is a leading cause of morbidity and mortality worldwide. Statins are established as first choice drugs for the management of hyperlipidaemia and cardiovascular risk. However, a residual cardiovascular risk, partially attributable to lipids, remains even after statin treatment. This risk appears to be associated with both high-density lipoprotein cholesterol and triglyceride lipid fractions. Several novel therapeutic approaches have been proposed to reduce lipid levels. Microsomal transfer protein (MTP) is involved in the assembly of very-low-density lipoprotein and chylomicron lipoprotein particles in the liver and the gut, respectively. In the preclinical setting, various agents that affect activity of MTP have shown that inhibition can result in profound reductions in blood triglycerides and cholesterol. Similarly, evidence of efficacy using the target has been confirmed in man with small molecule inhibitors and antisense oligonucleotides. Unfortunately, despite their efficacy in reducing lipids, the clinical utility of small molecule inhibitors has been restricted by their potential to induce hepatic steatosis. Continuing attempts to utilise this clinical target (to decrease cholesterol, triglycerides and weight) have involved the use of lower doses or non-systemically absorbed MTP inhibitors.

Recent evidence has shown that after the initial occlusion, a large portion of stroke patients achieve some degree of reperfusion either through collateral circulation or clot dissolution. However, it appears that this reperfusion may lead to increased inflammation-induced damage. Even though the exact mechanism of this secondary injury is unclear, several experimental studies have indicated an intimate connection between complement and this secondary form of damage. We review the available literature and attempt to identify promising clinical therapeutic targets.

Ginseng is one of the most widely used herbal medicines and is reported to have a wide range of therapeutic and pharmacological applications. Ginsenosides, the major pharmacologically active ingredients of ginseng, appear to be responsible for most of the activities of ginseng including vasorelaxation, antioxidation, anti-inflammation and anticancer. Approximately 40 ginsenoside compounds have been identified. Researchers now focus on using purified individual ginsenoside to reveal the specific mechanism of functions of ginseng instead of using whole ginseng root extracts. Individual ginsenosides may have different effects in pharmacology and mechanisms due to their different chemical structures. Among them the most commonly studied ginsenosides are Rb1, Rg1, Rg3, Re, Rd and Rh1. The molecular mechanisms and medical applications of ginsenosides have attracted much attention and hundreds of papers have been published in the last few years. The general purpose of this update is to provide information of recently described effects of ginsenosides on antioxidation, vascular system, signal transduction pathways and interaction with receptors. Their therapeutic applications in animal models and humans as well as the pharmacokinetics and toxicity of ginsenosides are also discussed in this review. This review concludes with some thoughts for future directions in the further development of ginseng compounds as effective therapeutic agents.

Varicose veins and the complications of venous disease are thought to affect over a quarter of the adult population and the management of these conditions are a major cause of health service expense. Advances in the understanding of venous pathophysiology have highlighted numerous potential targets for pharmacotherapy. This review considers the evidence for pharmacological agents used for the treatment of chronic venous disease. A literature search using Pubmed, Embase and Cinahl databases was performed. The initial search terms ‘varicose vein’, ‘venous ulcer’ and ‘venous disease’ were used with appropriate search limits to identify prospective studies of pharmacotherapy in venous disease. A wide range of venoactive and non-venoactive drugs have been studied in patients with venous disease. The use of micronized purified flavonoid fraction (Daflon) can reduce symptoms of pain, heaviness and oedema in patients with venous reflux and a recent meta-analysis concluded that Daflon improves healing in patients with venous ulceration treated with compression. Pentoxifylline may be a useful adjunct to compression therapy for patients with venous ulceration. Oxerutins and calcium dobesilate may be of benefit in reducing oedema and rutosides may help to relieve the symptoms of varicose veins in pregnancy. The clinical benefits of other medications remain unproven. Although numerous pharmacological agents have been proposed and studied, Daflon has demonstrated the greatest clinical benefits in patients with venous disease. Further research is needed to define the role of venoactive drugs in clinical care and improve our understanding of the pathophysiology of venous disease to help identify new therapeutic avenues.

Anticoagulation is recommended for prophylaxis and treatment of venous thromboembolism (VTE) (deep vein thrombosis and pulmonary embolism) and/or arterial thromboembolism. The therapeutic arsenal of anticoagulants available to clinicians is mainly composed by unfractionated heparin (UFH), low-molecular-weight heparin (LMWH), fondaparinux and oral vitamin K antagonists (VKA) (i.e. warfarin and acenocumarol). These anticoagulants are effective, but they require parenteral administration (UFH, LMWH, fondaparinux) and/or frequent anticoagulant monitoring (intravenous UFH, oral VKA). Novel anticoagulants in clinical testing include orally active direct factor II inhibitors [dabigatran etexilate (BIBR 1048), AZD0837)], parenteral direct factor II inhibitors (flovagatran sodium), orally active direct factor X inhibitors [rivaroxaban (BAY 59-7939), apixaban, betrixaban, YM150, DU-176b, LY-517717, GW813893, TAK-442, PD 0348292] and new parenteral FXa inhibitors [idraparinux, idrabiotaparinux (biotinilated idraparinux; SSR 126517), ultralow- molecular-weight heparins (ULMWH: AVE5026, RO-14)]. These new compounds have the potential to complement heparins and fondaparinux for short-term anticoagulation and/or to replace VKA for long-term anticoagulation in most patients. Dabigatran and rivaroxaban have been the firsts of the new oral anticoagulants to be licensed for the prevention of VTE after hip and knee replacement surgery. In the present review, we discuss the pharmacology of new anticoagulants, the key points necessary for interpreting the results of studies on VTE prophylaxis and treatment, the results of clinical trials testing these new compounds and their potential advantages and drawbacks over existing therapies.

Omega-3 (ω-3) polyunsaturated fatty acids (PUFAs) from fish and fish oils appear to protect against coronary heart disease: their dietary intake is in fact inversely associated with cardiovascular disease morbidity/mortality in population studies. Recent evidence suggests that at least a part of this protective effect is mediated by a relatively small but significant decrease in blood pressure (BP) level. In fact, ω-3 PUFAs exhibit wide-ranging biological actions that include regulating both vasomotor tone and renal sodium excretion, partly competing with ω-6 PUFAs for common metabolic enzymes and thereby decreasing the production of vasoconstrictor rather than vasodilator and anti-inflammatory eicosanoids. PUFAs also reduce angiotensin-converting enzyme (ACE) activity, angiotensin II formation, Tumor Growth Factor- beta (TGF-β) expression, enhance endothelial nitric oxide (NO) generation and activate the parasympathetic nervous system. The final results are improved vasodilation and arterial compliance of both small and large arteries. Preliminary clinical trials involving normotensive and hypertensive dyslipidaemic patients, diabetics and elderly subjects, confirm this working hypothesis: 3 meta-analyses suggest that PUFAs are able to slightly, but significantly improve arterial hypertension. Future research will clarify if PUFA supplementation could improve the antihypertensive action of specific BP lowering drug classes and of statins.

Ultrasound contrast agents, consisting of gas-filled microbubbles, have long been used to enhance ultrasonographic imaging of various organs and in several settings. In echocardiography, after their first use for Doppler signal enhancement, their applications have expanded and several studies, combining a range of stress modalities with myocardial contrast echocardiography have shown the clinical utility of these agents. In experimental isolated heart animal models, the interaction of ultrasound with echo-contrast microbubbles was shown to have significant biologic effects when the acoustic energy of the beam exceeded a threshold, leading them to rupture and causing cavitation phenomena; the observed consequences in the experimental setting included microvascular damage, transient decrease of contractile performance and increased lactate production. From the clinical point of view, the reporting of a number of serious adverse events - whose association with the echo-contrast agents was debated - has led to the addition of warning boxes in the prescribing documentation of these preparations. On the other hand, clinical studies including high numbers of patients have shown good safety and tolerance of contrast use during stress echocardiography, both for left ventricle opacification and myocardial perfusion imaging. The present review aims at presenting a balanced account of the existing data regarding the mechanisms and clinical implications of echo-contrast bioeffects, in order to make an informed assessment of their safety in clinical practice.

Neoangiogenesis, the development of new blood vessels from a pre-existing vasculature involves the migration behavior, proliferation and differentiation of endothelial cells. This process is an important aspect to both the growth and metastasis of solid tumors. In growing tumors, the development of a sufficient vascular supply is a highly complex event, which is controlled by many factors. An interaction between tumor cells, endothelial cells, macrophages, fibroblasts, and the extracellular matrix, all of which are capable of releasing factors influencing the angiogenic mechanisms is necessary for the building of new sufficient vascular structures. The increased understanding of the balance of angiogenesis and mechanisms of vascular control allowed the development of new therapeutic substances that influence that process in different ways. For example, work done over the last decade has elucidated the central role of vascular endothelial growth factor (VEGF) in the regulation of normal and pathological angiogenesis. Therefore, the blockade of VEGF signaling is currently a major part of strategies for the therapy of malignant tumors. Several studies tested neutralizing antibodies against mature VEGF protein or its isoforms, blockade of VEGF receptors by VEGF receptor antibodies, soluble VEGF receptor mutants or fusion-proteins and finally, intracellular interference with VEGF mRNA or signaling in the target cell. In this review, we present strategies and substances for the blockade of neoangiogenesis that are already in clinical use or in pre-clinical trials. Also the combination of these approaches with conventional chemotherapy or radiotherapy will be discussed.

In the last decade there have been considerable advances in the understanding of the pathophysiology of malignant ventricular tachyarrhythmias (VA) and Sudden Cardiac Death (SCD). Over 80% of SCD occurs in patients with organic heart disease. However, approximately 10-15% of SCD occurs in the presence of structurally normal heart and the majority of those patients are young. In this group of patients, changes in genes encoding cardiac ion channels produce modification of the function of the channel resulting in an electrophysiological substrate of VA and SCD. Collectively these disorders are referred to as Cardiac Ion Channelopathies. The 4 major syndromes in this group are: The Long QT Syndrome (LQTS), the Brugada Syndrome (BrS), the Short QT Syndrome (SQTS), and the Catecholaminergic Polymorphic VT (CPVT). Each of these syndromes includes multiple subtypes with different and sometimes complex genetic abnormalities of cardiac ion channels. Many are associated with other somatic and neurological abnormalities besides the risk of VA and SCD. The current management of cardiac ion channelopathy could be summarized as follows: 1) in symptomatic patients, the implantable cardioverter defibrillator (ICD) is the only viable option; 2) in asymptomatic patients, risk stratification is necessary followed by the ICD, pharmacotherapy, or a combination of both. A genotype-specific approach to pharmacotherapy requires a thorough understanding of the molecular-cellular basis of arrhythmogenesis in cardiac ion channelopathies as well as the specific drug profile.

This review considers the actions of an endogenously produced molecule, melatonin, on heart diseases. Recent research has shown that inflammation plays a key role in coronary heart disease (CHD) and other manifestations of atherosclerosis. Immune cells dominate early atherosclerotic lesions, their effector molecules accelerate progression of the lesions and activation of inflammation can elicit acute coronary syndromes (ACS). Scientific evidence from the last 15 years has suggested that melatonin has positive effects on the cardiovascular system. The presence of vascular melatoninergic receptor binding sites has been demonstrated; these receptors are functionally linked to vasoconstrictor or vasodilatory effects of melatonin. It has been shown that patients with CHD have a low melatonin production rate, especially those with higher risk of cardiac infarction and /or sudden death. Similarly to other organs and systems, the cardiovascular system exhibits diurnal and seasonal rhythms, including those in the heart rate, cardiac output and blood pressure. The suprachiasmatic nuclei of hypothalamus and, possibly, the melatoninergic system modulate the cardiovascular rhythms. The melatonin attenuates molecular and cellular damages resulting from cardiac ischemia/reperfusion in which destructive free radicals are involved. Anti-inflammatory and antioxidative properties of melatonin are also involved in the protection against vascular disease, i.e. atherosclerosis. The current brief summary of the literature provides an overview on the role of melatonin in the ACS.

Chronic Kidney Disease Mineral and Bone Disorder (CKD-MBD) is a systemic disorder of mineral and bone metabolism that occurs in Chronic Kidney Disease (CKD). In addition to abnormalities in serum calcium (Ca) and phosphate (P) profile, CKD-MBD is characterized by abnormalities of bone turnover, mineralization, volume and growth as well as vascular calcification (VC). Indeed, the co-localization of bone markers such as Osteopontin, Alkaline Phosphatase and Osteocalcin along with osteoblast-like cells in the contest of the arterial wall of uremic patients, indicate that VC is an active biological process with peculiar analogies with bone mineralization. Thus, VC represents a plausible link between Ca and P derangements and the increased mortality associated with CKD-MBD. The process of VC starts in early stages of CKD and patients with CKD-3, -4 and -5 not undergoing haemodialysis may present a significant burden of calcification in the coronaries. Considering that presence and extent of VC in CKD portend poor prognosis, many efforts have been made to shed light on this complicated phenomenon to prevent VC deposition and progression. Indeed, careful control of calcium load, serum P and parathyroid hormone along with the use of calcium-free P binders and vitamin D analogs represent our current armamentarium to improve quality of life and reduce mortality in CKD. We herein summarize the current understanding and evidence supporting strategies available for VC treatment.

Restenosis is a pathophysiological phenomenon that can occur in patients submitted to revascularization procedures (bypass, endarterectomy, angioplasty), possibly resulting in new narrowing of injured vessels. Vascular restenosis remains a pressing clinical problem, despite the therapeutic strategies and devices developed so far. Stem cells hold a great potential for the regeneration of damaged tissues in cardiovascular diseases. Recent studies clearly indicated that different stem cell populations contribute to vascular remodeling after injury. Nevertheless, the exact role of vascular cell precursors in restenosis pathophysiology is not yet well defined, as heterogeneous and contrasting data are currently available. Mesenchymal stromal/stem cells (MSCs) are non-hematopoietic multi-potent stem-like cells able of differentiating into both mesenchymal and non-mesenchymal lineages. MSCs offer a series of advantages: a) they can be isolated from a small aspirate of bone marrow; b) extensively proliferate in vitro while preserving a normal karyotype and telomerase activity on several passages; c) express low immunogenicity and hence their use should not require a pharmacological immunosuppression. MSCs have an intrinsic ability to differentiate into functional cell types able to repair the diseased or injured tissue in which they are localised. For this reason, MSCs are currently under scrutiny for treatment of different cardiovascular diseases. Nevertheless, it has not yet been clearly determined whether MSCs can substantially contribute to a positive resolution of restenosis after vascular injury. This review will provide information about the mechanisms at the basis of vascular restenosis and the current knowledge of the role, positive or negative, played by MSCs in restenosis progression as highlighted by recent experimental protocols.

Lower extremity peripheral arterial disease (PAD) is a manifestation of atherosclerosis, with a prevalence ranging from 4% to 12% in the adult population and increasing up to 20% in older individuals. Intermittent claudication (IC) may markedly impair walking ability, overall functional status and quality of life. PAD is a marker of systemic atherosclerosis and is associated with increased cardiovascular morbidity and mortality. However, leg disease usually runs a rather benign course in claudicant patients, with only about 1% to 3% of them ever requiring a major amputation over a 5-year period. The goals of treatment for claudication are to relieve exertional symptoms, and improve walking capacity and quality of life. Therapeutic strategies aimed at reducing systemic cardiovascular risk burden and prolonging survival, including intensive risk factor modification and antiplatelet therapy, should be implemented in all patients with PAD. Supervised exercise training has proven the most effective conservative treatment for symptomatic relief of IC. Current evidence for drug therapy of IC supports the use of cilostazol as a first-line drug. Other drugs with more limited evidence of benefit for claudication include pentoxifylline and naftidrofuryl. Endovascular or surgical revascularization is indicated for selected patients with vocation- or lifestyle-limiting claudication who are unresponsive to exercise and pharmacotherapy. New drug candidates for managing claudication symptoms include propionyl-L-carnitine and statins. Preliminary studies suggest that therapeutic angiogenesis holds promise for future treatment of IC.

Cardiovascular disease (CVD) is a major cause of morbidity and mortality worldwide. Recently vitamin D deficiency has been identified as a potential risk factor for many diseases not traditionally associated with vitamin D, such as cancer and CVD. This review discusses the evidence suggesting an association between low 25-hydroxyvitamin D levels and CVD and the possible mechanisms mediating it. Vitamin D deficiency has been associated with CVD risk factors such as hypertension and diabetes mellitus, with markers of subclinical atherosclerosis such as intima-media thickness and coronary calcification as well as with cardiovascular events such as myocardial infarction and stroke as well as congestive heart failure. It could be suggested that vitamin D deficiency contributes to the development of CVD through its association with risk factors, such as diabetes and hypertension. However, direct effects of vitamin D on the cardiovascular system may also be involved. Vitamin D receptors are expressed in a variety of tissues, including cardiomyocytes, vascular smooth muscle cells and endothelial cells and vitamin D has been shown to affect inflammation and cell proliferation and differentiation. While much evidence supports a potential antiatherosclerotic effect of vitamin D, prospective, placebo-controlled randomized as well as mechanistic studies are needed to confirm this association. Since vitamin D deficiency is easy to screen for and treat, the confirmation of such an association could have important implications for both, patient care and health policy.