Current Vascular Pharmacology - Volume 8, Issue 3, 2010

Peripheral arterial disease (PAD) is a progressive disease most often due to atherosclerosis and characterized by obstruction of arterial blood flow in the lower limbs. The defining symptom of PAD, intermittent claudication, is evident in only a minority of patients, leading to frequent underdiagnosis. Patients with PAD are more likely to suffer from polyvascular disease than patients with other cardiovascular conditions and have an increased risk of cardiovascular death and ischemic events. This review considers current PAD awareness and treatment, including important findings from the REduction of Atherothrombosis for Continued Health (REACH) and PAD Awareness, Risk and Treatment: New Resources for Survival (PARTNERS) registries. Information on simple diagnostic tools to aid early PAD detection and therapeutic options for global atherosclerosis risk factor management are also presented.

Rheumatoid arthritis (RA) associates with excess cardiovascular morbidity and mortality, resulting in significantly shortened lifespan. Traditional risk factors (e.g. dyslipidaemia and hypertension) and novel risk factors (e.g. systemic inflammation) contribute to the development of cardiovascular disease (CVD) in RA. In the general population, dyslipidaemia has been found to be central to the development of CVD, playing an important role in all stages of atherosclerotic plaque formation. In RA, lipid metabolism may be altered by systemic inflammation, environmental lifestyle factors, drug therapy and several genetic factors. This may result in changes in overall lipid levels, as well as modifications of lipid/lipoprotein structure and function. In this review, we discuss lipid abnormalities specifically in the context of RA and highlight the potential impact of inflammation, genetic factors, lifestyle, and anti-rheumatic drugs on lipid metabolism.

Cardiovascular events occurring in type 2 diabetes (T2DM) are a major problem in clinical practice. In particular, the risk of myocardial infarction (MI) presented by patients affected by T2DM without previous cardiac events is similar to that of non-diabetic patients with previous MI. To reduce the elevated cardiovascular risk associated with T2DM, tight glycemic control and aggressive therapy against all known cardiovascular risk factors are strictly required. Despite the role played by hyperglycemia in the pathogenesis of cardiovascular events, studies showing an improvement of cardiovascular outcomes by anti-hyperglycemic or hypoglycemic agents are not conclusive. The United Kingdom Prospective Diabetes Study (UKPDS) demonstrated that in obese type 2 diabetic patients metformin reduces the risk of MI more than sulphonylureas or insulin. This observation identified metformin as the first-line treatment for T2DM. The vasoprotective role of metformin is largely independent of its hypoglycemic action and has been ascribed to pleiotropic effects. The present review considers the putative beneficial action exerted by metformin on arterial vessels by evaluating its effects on lipids, inflammation, hemostasis, endothelial and platelet function and vessel wall abnormalities. Furthermore, the molecular mechanisms of the beneficial metabolic and vascular effects of metformin will be considered, with a particular attention for its ability to activate AMP-activated protein kinase.

Biologic therapy for rheumatoid arthritis (RA) targets specific molecules that mediate and sustain the clinical manifestations of this complex illness. Compared with the general population, patients with RA die prematurely, in part due to associated cardiovascular disease. Even though the mechanisms by which premature atherosclerosis develops in RA is unknown, chronic inflammation may play a major role. This review connects current knowledge of the pathophysiology of RA with data available in the literature related to thrombospondin-1 (TSP1), transforming growth factor beta (TGFβ) and connective tissue growth factor (CTGF) and their relationship with cardiovascular disease in RA. The TSP1/TGFβ/CTGF axis may contribute in the pro-inflammatory and pro-atherogenic state in patients affected with RA. In fact, increased TSP1 plasma levels are found in patients of RA. TGFβ is activated by TSP1 through a non-enzymatic mechanism and is constitutively overexpressed by synovial fibroblasts from RA patients. Activation of TGFβ pathway in synovial fibroblasts and other cells including neutrophils leads to downstream upregulation of CTGF. Overexpression of CTGF is associated with angiogenesis, fibrosis, atherosclerotic blood vessels and erosive arthritis lesions. Recent RA therapies emphasize the need for aggressive control of the activity of the disease to prevent premature atherosclerosis in RA patients. The complexity and heterogeneity of RA as judged by response to a wide spectrum of treatments mandates the elucidation of unknown pro-inflammatory pathways playing a major role in this disease. The TSP1/TGFβ/CTFG axis represents one of these pro-inflammatory pathways that may result in the development of promising therapeutic strategies to prevent chronic inflammation and thus premature atherosclerosis in RA.

Objective: Arterial hypertension is an important risk factor for the development and progression of cardiovascular disease (CVD). The renin angiotensin aldosterone system (RAAS) plays a crucial role in the pathophysiology of hypertension and associated complications. Direct renin inhibitors (DRIs) are novel antihypertensive drugs which inhibit the first step of RAAS. Aliskiren is the first orally active DRI approved as monotherapy or in combination with other antihypertensive agents for the treatment of hypertension. Scope: This article reviews the efficacy and safety of aliskiren as monotherapy and in combination with other antihypertensive agents and comments on its potential role in clinical practice. Methods: Relevant articles were identified through a PubMed search (up to 17 August 2009). Findings: Aliskiren, used alone or in combination with other antihypertensive agents, has a favourable effect on blood pressure (BP). Specifically, aliskiren is equally effective with other RAAS inhibitors and probably superior to hydrochlorothiazide in the reduction of systolic and diastolic BP. The combination of aliskiren with other antihypertensive drugs seems to be an effective and safe therapeutic option. In addition, aliskiren may have favourable effects in terms of ameliorating several microvascular and macrovascular complications of hypertension and diabetes. Conclusions: Aliskiren appears to be an effective and safe antihypertensive drug. Whether the BP lowering effect of aliskiren is associated with improvements in cardiovascular outcomes remains to be elucidated.

The burden of atherosclerosis is particularly high in western countries in terms of mortality and disability. The cerebral arteries (stroke or transient ischemic attack [TIA]), coronary arteries (myocardial infarction [MI]) and peripheral arteries (intermittent claudication [IC], ischemic limb) can be affected. Atherosclerosis may involve different mechanisms such as inflammation, platelet activation, endothelial damage, balance between proliferation and apoptosis of smooth muscle cells and oxidative stress. Research is focused to counteract each of these aspects. Many antithrombotic drugs are currently available and most of them act as inhibitors of platelet function. Aspirin, ticlopidine, clopidogrel and the combination of aspirin plus dipyridamole are widely used for primary (in high-risk patients) and secondary prevention of atherosclerotic diseases. Research of new pharmacological strategies is driven by the need to reduce the risk of bleeding associated with the use of antiplatelet drugs. In this context cilostazol, a type III phosphodiesterase inhibitor, has demonstrated antiplatelet and vasodilator effects with low rate of bleeding complications. This review will focus on the pharmacological properties of cilostazol and its use in the management of atherothrombotic vascular diseases.

Venous thromboembolism (VTE) is a major public health issue, with a high incidence in hospitalised patients. Furthermore, many VTE events are preventable with appropriate thromboprophylaxis. Medical thromboprophylaxis usually comprises heparins, while warfarin has been the mainstay of long term anticoagulation for many years. Both drugs are limited by their narrow therapeutic index and the need for regular monitoring. The introduction of low molecular weight heparins and fondaparinux has overcome some of these shortfalls but their use remains restricted by requisite parenteral administration. There is a clear need for new anticoagulants with predictable pharmacokinetics and anticoagulant effect. To this end, 2 new agents; dabigatran and rivaroxaban, have recently been licensed for use in orthopaedic thromboprophylaxis. This review discusses the limitations of traditional anticoagulants, and summarises the development and clinical studies pertaining to the use of 3 new targeted anticoagulants: idraparinux, rivaroxaban and dabigatran in VTE, in addition to the limitations of these novel agents.

Several oral “vasoactive” drugs claim to increase walking capacity in patients with intermittent claudication (IC). Naftidrofuryl, cilostazol, buflomedil, and pentoxifylline are the most studied molecules. Although spanning several decades, several studies underlying these claims were not properly designed, underpowered or showed clinically doubtful outcomes. The evidence for these “vasoactive” drugs has always been received with scepticism, creating the need for systematic reviews and meta-analyses. This brief review discusses the benefit-risk assessment of vasoactive drugs, by applying a systematic review to evaluate randomized, placebo-controlled trials. Oral naftidrofuryl and cilostazol have an acceptable safety profile as well as sustained evidence (documented by Cochrane analyses) of increased walking capacity. Subsequently, these drugs entered recommendations for peripheral arterial disease (PAD). In contrast, buflomedil and pentoxifylline have limited and/or doubtful evidence to increase walking capacity. Moreover, there were safety concerns about the narrow therapeutic range of buflomedil. Most other “vasoactive” drugs were either inappropriately or insufficiently tested or showed no significant if not negative effects on IC. “Vasoactive” drugs are no substitutes for lifestyle or exercise therapy but are adjuvant treatment to the well-appreciated triad of cardiovascular prevention (antiplatelet agents, statins and ACE-inhibitors), of which statins in their own right have documented claims to significantly increase walking capacity. “Vasoactive” drugs may have a place in the pharmacological management of symptomatic PAD in addition to the basic cardiovascular pharmacotherapy, when revascularization is not indicated, when exercise therapy is not feasible or when there is still insufficient benefit.

Early recognition is indispensable for the optimal management of Acute Coronary Syndrome (ACS); moreover, early prognostic stratification of patients with established ACS is useful to improve strategies for these patients. The paper focuses attention on troponins (I and T), the most validated biomarker for early diagnosis of ACS and on B-type natriuretic peptide (BNP) and N-terminal proB-type natriuretic peptide (NT-proBNP), the most powerful cardiac marker after troponin to be used as prognostic indicator in patients with ACS. We pay particular attention to the troponin story in ACS, including discussions about high sensitivity methods and on the most recent techniques (e.g. Point Of Care) available to shorten times from the blood sampling to the validated report [Turn around time (TAT) arm-to-report]. We report the differences between BNP and NT-proBNP, both from an analytical and a clinical point of view and discuss the use of cardiac natriuretic peptides for early recognition of cardiac insufficiency and early management of patients presenting to Emergency Departments with dyspnoea. Finally, we briefly discuss the most promising new cardiac markers actually used only in preclinical studies.

Calcitonin gene related peptide (CGRP) is a vasodilator. Its plasma levels are altered in several human diseases, including migraine, hypertension and diabetes. CGRP is locally released by motor neurons, and is overexpressed in response to surgical or pharmacological blockage of neuromuscular transmission. Additionally to a brief discussion with regard to the clinical relevance of CGRP, this review focuses on the effects of CGRP on skeletal muscle excitation-contraction (EC) coupling, as well as the corresponding pathohysiological consequences. EC coupling involves activation of 2 different types of calcium channels: dihydropyridine receptors (DHPRs) located at the sarcolemma, and ryanodine receptors (RyR1s) located at the sarcoplasmic reticulum (SR). In response to electrical depolarization, DHPRs activate nearby and physically bound RyR1s, allowing Ca2+ from the SR to move into the cytosol (termed voltage-gated Ca2+ release, or VGCR). We recently found that CGRP stimulates VGCR by 350 % in as short as 1h. This effect, which lasts for at least 48 h, is due to activation of the CGRP receptor, and requires activation of the cAMP/PKA signaling pathway. CGRP also increases the amplitude of caffeine-induced Ca2+ release (400 %); suggesting increased SR Ca2+ content underlies stimulation of VGCR. Interestingly, in the long-term CGRP also increases the density of sarcolemmal DHPRs (up to 30%, within 24-48 h). We propose that these CGRP effects may contribute to prevent and/or restore symptoms in central core disease (CCD); a congenital myopathy that is linked to mutations in the gene encoding RyR1.

Recently, a new view into the molecular mechanisms of phosphate homeostasis and secondary hyperparathyroidism pathogenesis has been proposed, with Fibroblast Growth Factor 23 (FGF-23) as a novel player in the field. Enhanced serum FGF-23 levels cause a reduction in serum phosphate, together with calcitriol suppression and consequent hyperparathyroidism. In contrast, reduced serum FGF-23 levels are associated with hyperphosphatemia, higher calcitriol levels and parathyroid hormone (PTH) suppression. In addition, there are different FGF-23 actions that need investigation. In clinical practice, increased knowledge of mineral metabolism disorders alterations in chronic kidney disease (CKD) may be used to improve diagnostics and select future treatments. The discovery of FGF23 represents a novel factor in the pathogenesis of phosphate handling and secondary hyperparathyroidism in cardiovascular, bone and renal disease.

The last 10 years have seen significant advances in the understanding of the pathophysiology and treatment of pulmonary arterial hypertension (PAH). This has included new insights into the genetics, cell-signalling pathways and pathological changes seen in the small pulmonary arteries as well as the introduction of new treatments which have improved prognosis. The classification of pulmonary hypertension (PH) has also been changed several times, most recently in 2003. It now divides forms of PH into 5 broad groups according to their pathophysiology and response to treatment. This review focuses primarily on the advances that have been made in the comprehension and treatment of Group 1 (PAH); however reference is also made to other groups within the classification. Pharmacologic treatment now includes calcium-channel blockers, endothelin antagonists, prostanoids, phosphodiesterase type 5 inhibitors, anticoagulants and diuretics. There are 2 recent sets of guidelines directing treatment, one published by the American College of Chest Physicians in 2007 and the most recent published by the National Pulmonary Hypertension Centres of the UK and Ireland in 2008. The recent advances in understanding of the underlying cellular mechanisms have also opened the doorway to new potential therapies such as stem cell transplantation and the targeting of platelet-derived factors and apoptosis.

Members of the ErbB receptor tyrosine kinase family are central regulators of several normal as well as tumor cell functions. A number of therapeutic compounds such as small molecular weight tyrosine kinase inhibitors and monoclonal antibodies have been developed to inhibit ErbB signaling in cancer. Drugs that target epidermal growth factor receptor (EGFR = ErbB1) and/or ErbB2 have demonstrated effect against breast, colorectal, lung, pancreatic and head and neck carcinomas, and are currently in clinical use. Part of the anti-tumor effect of the ErbB inhibitor drugs has been suggested to derive from inhibition of tumor angiogenesis. There are several proposed mechanisms by which the ErbB inhibiting agents may regulate tumor neovascularization although most of them are currently not fully characterized. This review addresses the role of ErbB signaling in angiogenesis, as well as the anti-angiogenic mechanisms of ErbB targeted cancer drugs.

Personalized medicine is a new treatment modality where patients are the center of interest. Thus, 1 drug does not fit all; rather we look for a drug which fits the individual patients' disease. Treatment is moving towards molecular medicine driven by the growing knowledge and understanding of pharmacogenetics. Psoriasis is a common dermatological disease characterized by genetic polymorphism. The association of biomarkers and psoriasis is helpful to evaluate susceptibility to the disease, its severity and its progression. Additionally, the response to treatment will be anticipated. The growing expenses of health care systems worldwide are primarily due to increasing costs of chronic disease management. Hence, activation of preventive medicine will minimize treatment costs. A revolution in treatment modalities is expected to start at the level of pharmaceutical companies, as personalization of medicine will decrease the cost of clinical trials by minimizing the number of subjects required. In turn, this will decrease the cost of developing new medications. My vision for the future is that personalized medicine will mandate special physicians capable of understanding molecular medicine and using genetics and biomarkers for diagnosis, evaluation of the effect of drugs and overall prognosis. This new therapeutic modality will need special training.