Current Vascular Pharmacology - Volume 4, Issue 3, 2006

We are faced with an alarming epidemic of obesity, diabetes and cardiovascular disease. For this reason, the Metabolic Syndrome (MetS) has been receiving a great deal of attention both from the scientific community and from the general public. A recent statement from the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD) called for the concept of the MetS to be re-evaluated (1). The MetS serves two purposes: it is a concept and it is a diagnosis. As a concept, the MetS highlights the fact that its components tend to cluster together. This has raised awareness of cardiovascular risk among health care workers and the general public. It has also provided a conceptual framework in which that risk can be managed. There is, therefore, no doubt that the concept has been useful. The main controversy which surrounds the concept comes down to one key question: what is required to make a syndrome? In a syndrome, a number of symptoms, signs and/ or physiological traits are related to a single underlying cause. In Cushing's syndrome, the cause is corticosteroid excess. In the Sleep Apnea/ Hypopnea syndrome, the underlying cause is intermittent obstruction of the airway during sleep. Both of these syndromes have a clear definition. Corticosteroid excess or airway obstruction may be caused by a wide range of factors, but there is a clear unifying feature. Furthermore, once the diagnosis of either syndrome is made, that diagnosis influences the subsequent investigation and treatment of the patient. When the existence or usefulness of a syndrome is examined, this is the standard it is expected to meet. The MetS does not measure up to this standard partly because the necessary research is still ongoing, and partly because it is very different in nature from the syndromes against which it is being judged. The MetS is an asymptomatic syndrome; its components are all physiological traits. This immediately makes its existence as an entity harder to grasp and conclusively prove than, for example, Cushing's syndrome. The proposed unifying feature of its components is insulin resistance, which is itself a very heterogeneous and complex physiological trait. Insulin resistance can occur in the context of a far wider neuroendocrine dysfunction, and can be regarded as a cause, a consequence, a sustainer and a marker of this dysfunction. Furthermore, whole body insulin resistance is the collective result of insulin resistance, which occurs at the cell, tissue and organ levels. Finally, there are many mechanisms at every level, by which insulin resistance can occur. Unifying features of all forms of insulin resistance will doubtlessly be found, and several such features are currently being defined. However, when one takes a global look at the intimidatingly large number of factors, which act either to cause insulin resistance or mediate its proposed effects, the emerging picture is one of a highly complex causal network. Within such a network, interrelated physiological traits will be found to cluster. However, there is no simple underlying cause, but rather a causal network. Is this still a syndrome? We believe that it is, because the clustering of risk factors is related to a meaningful underlying cause, albeit one which is less straightforward than the elevated corticosteroid levels in Cushing’s syndrome. The usefulness of the Metabolic Syndrome as a diagnosis requires much further study. There are several proposed definitions of the MetS accompanied by several confouding questions such as; Which should be used and in which situations? Which group of patients should we seek to identify: patients with insulin resistance or patients with increased cardiovascular risk? Does a diagnosis of the MetS influence the clinical management? However, no specific treatment strategy exists at the present time. Should the MetS be treated as a distinct all-or-nothing diagnosis, or simply as a conceptual framework? There has been concern that the use of the MetS as a diagnosis may lead clinicians to ignore individual risk factors in patients who do not meet the criteria for diagnosis. There is, to our knowledge, no evidence that this is the case. Does the use of the MetS as a diagnosis improve patient outcomes? This is a key question which has not been adequately addressed. Does the diagnosis of the MetS change the management of the patient? There is, at present, no specific treatment strategy for the MetS, it is not yet clear what is required over and above the management of the individual risk factors. The aim of this two-part special issue of Current Vascular Pharmacology is to provide a broad overview of the experimental and clinical research, which has sought to answer these important questions. The MetS, both as a concept and a diagnosis, will be re-examined. Future directions for research to elucidate the pathogenesis of the MetS and to determine the clinical utility of the MetS as a diagnosis will be suggested............

The metabolic syndrome is a clustering of risk factors including central obesity, insulin resistance, dyslipidaemia and hypertension. This syndrome is associated with increased risk of cardiovascular disease and is a common early abnormality in the development of type 2 diabetes. The pathogenesis of the syndrome has multiple origins. Obesity and sedentary lifestyle coupled with genetic factors interact to produce the syndrome. Here, we consider two components of the metabolic syndrome, dyslipidaemia and hypercoagulability.

The metabolic syndrome (MetS) is a cluster of metabolic abnormalities including abdominal obesity, glucose intolerance, hypertension and dyslipidaemia and is associated with an increased risk of vascular events. Since the initial description of the MetS, several expert groups produced different definitions. This variability led to confusion and absence of comparability between studies. Although there is agreement that the MetS is a major public health challenge worldwide and consistent evidence stresses the need for intervention, the definition of the syndrome remains a matter of debate. This review considers the different definitions of the MetS. These include those proposed by the World Health Organisation, the European Group for the Study of Insulin Resistance, the National Cholesterol Education Program Adult Treatment Panel III, the American College of Endocrinology and American Association of Clinical Endocrinologists and the latest International Diabetes Federation definition which includes ethnic-specific waist circumference cut-off points. These definitions share several features but also include important differences; all have limitations. Selected (after a Medline search) studies comparing the different definitions are also considered. There is a need for a standardised definition of the MetS. Furthermore, a definition tailored for children and adolescents is essential. Prospective long-term studies are needed to validate the prognostic power of these definitions. As new information becomes available the definition of the MetS might be further modified.

Exposure to ambient pollutant particle (APP) is associated with increased cardiovascular morbidity and mortality. Recent evidence indicates that APP-induced vasoconstriction may be an important mechanism. APP constricts systemic arteries and increases blood pressure in human. APP decreases the diameter of pulmonary arterioles in animals. Intratracheal instillation of APP increases pulmonary artery resistance in isolated buffer-perfused lungs, and APP constricts isolated arterial rings. APP-induced vasoconstriction may be secondary to the release of inflammatory mediators from lung cells, which then activate vascular endothelial and smooth muscle cells. The vasoconstriction may also be caused by alterations in autonomic nervous system balance. Some soluble metals (e.g., vanadium) can produce acute vasoconstriction in in vitro and in vivo systems, and contribute to the systemic health effects of APP since they can more easily permeate the alveolar-capillary membrane than the whole particle. Both APP and its associated metals have been shown to enhance the release of endothelin 1 and reactive oxygen species, activate epithelial growth factor receptor and mitogenactivated protein kinases, and inhibit nitric oxide vasodilator activity. The vasoactive properties of APP and metals raised the possibility that patients with vascular diseases may be more susceptible to APP-induced adverse health effects, and that people who are regularly exposed to high amount of metals, e.g., vanadium contained in certain dietary and musclebuilding regimens or in the air of boiler making plants, may have increased risk for vascular diseases. Understanding how metals induce vasoconstriction may lead to the development of novel vasodilator therapies for vascular diseases.

Inflammation and immune activation are crucially involved in the pathogenesis of atherosclerosis and cardiovascular disease. Accordingly, markers of inflammation such as fibrinogen, ferritin, C-reactive protein or neopterin are found in patients with vascular diseases, correlating strongly with the extent of disease and predicting disease progression. Neopterin formation by human monocyte-derived macrophages and dendritic cells is induced by the pro-inflammatory cytokine interferon-γ, which is released by activated T-lymphocytes. Human macrophages are centrally involved in plaque formation, and interferon-γ and macrophages are also of importance in the development of oxidative stress for antimicrobial and antitumoural defence within the cell-mediated immune response. Interferon-γ also stimulates the enzyme indoleamine- 2,3-dioxygenase, which degrades tryptophan to kynurenine. Again, macrophages are the most important cell type executing this enzyme reaction, but also other cells like dendritic cells, endothelial cells or fibroblasts can contribute to the depletion of tryptophan. Likewise, enhanced tryptophan degradation was reported in patients with coronary heart disease and was found to correlate with enhanced neopterin formation. In chronic diseases such as in cardiovascular disease, biochemical reactions induced by interferon-γ may have detrimental consequences for host cells. In concert with other pro-inflammatory cytokines, interferon-γ is the most important trigger for the formation and release of reactive oxygen species (ROS). Chronic ROS-production leads to the depletion of antioxidants like vitamin C and E and glutathione, with a consequence that oxidative stress develope. Oxidative stress plays a major role in the atherogenesis and progression of cardiovascular disease, and it may also account for the irreversible oxidation of other oxidation-sensitive substances like B-vitamins (e.g. folic acid and B12). They are essential cofactors in homocysteine-methionine metabolism. Associations between moderate hyperhomocysteinaemia and cellular immune activation are found in several diseases including coronary heart disease, and data indicate that hyperhomocysteinaemia may develop as a consequence of immune activation. Homocysteine accumulation in the blood is established as an independent risk factor for cardiovascular disease. Homocysteine itself has the capacity to further enhance oxidative stress. Interferon-γ appears to be a central player in atherogenesis and in the development and progression of cardiovascular disease. Anti-inflammatory and immunosuppressive treatment (e.g. with non-steroidal anti-inflammatory drugs or statins) may among other consequences, also contribute to a slow-down of the adverse effects of interferon-γ.

Diabetes represents a serious risk factor for the development of cardiovascular problems such as coronary heart disease, peripheral arterial disease, hypertension, stroke, cardiomyopathy, nephropathy and retinopathy. Identifying the pathogenesis of this increased risk provides a basis for secondary intervention to reduce morbidity and mortality in diabetic patients. Hyperglycemia and protein glycation, increased inflammation, a prothrombotic state and endothelial dysfunction have all been implicated as possible mechanisms for such complications. A linking element between many of these phenomena could possibly be, among other factors, increased production of reactive oxygen species. Vascular endothelial cells have several physiological actions that are essential for the normal function of the cardiovascular system. These include the production of nitric oxide (NO), which regulates vasodilatation, anticoagulation, leukocyte adhesion, smooth muscle proliferation and the antioxidative capacity of endothelial cells. However, under conditions of hyperglycemia, excessive amounts of superoxide radicals are produced inside vascular cells and this can interfere with NO production leading to the possible complications. This article aims at reviewing the links between reactive oxygen species, diabetes and vascular disease and whether or not antioxidants can alter the course of vascular complications in diabetic patients and animal models. A possible beneficial effect of antioxidants might present a new addition to the range of secondary preventive measures used in diabetic patients.

Recent updates in the field of echocardiography have resulted in improvements in both image quality and techniques allowing echocardiography to maintain its position as the primary non-invasive imaging modality. In particular, the development of new ultrasound contrast agents and imaging techniques have now made possible the assessment of myocardial perfusion. Myocardial contrast echocardiography utilises acoustically active gas filled microspheres (microbubbles), which have rheology similar to that of red blood cells. The detection of myocardial perfusion during echocardiographic examinations permits simultaneous assessment of global and regional myocardial structure, function, and perfusion, enabling the optimal non-invasive assessment of coronary artery disease. Myocardial contrast echocardiography is equally adept in assessing chronic coronary artery disease as well as acute coronary syndromes. Furthermore, its use is not limited solely to diagnostic assessment. Preliminary evidence suggests that targeted microbubbles may be useful in enhancing delivery of genes / drugs and in clot lysis.

Elevated plasma levels of homocysteine (Hcy) are a risk factor for systemic vascular diseases, stroke and vascular dementia. In recent years, increasing Hcy levels have been detected in neurological disorders that are not vascular in origin including Alzheimer's Disease and movement disorders (MD) such as idiopathic Parkinson's Disease (PD), Huntington's Disease (HD) and primary dystonia. Hyperhomocysteinemia (HHcy) in PD results from L-Dopa administration and its O-methylation dependent from catechol-O-methyltransferase and may be implicated in the development of motor complications and non-motor symptoms, such as dementia. In a recent study, HHcy has been evidenced in HD patients, compared to controls. Because mutated Huntington protein influences Hcy metabolism by modulating cystathionine- β-synthase activity, Hcy could represent a biological marker of neurodegeneration and could explain the leading role of cardiovascular and cerebrovascular diseases as causes of death in HD. Finally, several cases of homocystinuria associated with dystonia, and some recent reports of elevated Hcy in patients with primary adult onset dystonia have been published. Increased Hcy plasma levels may have important implications in patients affected by these basal ganglia disturbances, by exerting neurotoxic effects, contributing to neurotransmitter imbalance in motor circuits, and increasing the risk for vascular insults and cognitive dysfunctions.

The prevalence of diabetes mellitus (DM), particularly Type 2 DM, has rapidly increased in industrialized and many developing countries. The predominant cause of death in diabetic patients is vascular complications. Dyslipidemia and hypercholesterolemia are common in diabetic patients. 3-Hydroxy-3-methylglutaryl-CoA reductase inhibitors (statins) were designed for lowering cholesterol synthesis. Landmark clinical trials indicated that statins effectively reduced cardiac death and events in patients with coronary artery disease or DM. The benefits of statins on the prevention of vascular events were independent from age, sex or baseline lipid levels in diabetic patients. Statins not only prevent atherosclerotic macrovascular complications, but also postpone the development of microvascular complications of DM, such as nephropathy and retinopathy. The non-cholesterol lowering or pleiotropic effects of statins have attracted vast attention. Results from experimental and clinical studies suggest that statins may attenuate inflammation, oxidative stress, coagulation, platelet aggregation, and improve insulin resistance, fibrinolysis and endothelial functions and help to prevent thrombosis, restenosis or organ transplantation rejection. Statins may affect the intracellular prenylation of proteins, which modulate the activity of small-GTP binding proteins. This may be an underlying mechanism for some pleiotropic effects of statins. Statins have an excellent safety profile and seldom cause adverse effects. Increasing evidence suggests that statins are the current treatment of choice to prevent vascular complications in diabetic patients with hypercholesterolemia.

Cardiovascular diseases are the major cause of death and a significant cause of disability in the Western world and more recently threaten to pose an increasing health burden on developing nations. People with pre-existent vascular disease are those at highest risk for adverse cardiovascular outcomes and require aggressive secondary preventive therapies. Large strides have been made in the development of pharmacologic agents that intervene on various pathways implicated in atherogenesis, thus offering the ability to greatly impact on disease progression and to prevent events. Compelling data derived primarily from randomized controlled trials have shown the benefits of aspirin (or antiplatelet agents) and angiotensin converting enzyme (ACE) inhibitors (A), beta-blockers and blood pressure (B) and cholesterol-lowering drugs (C), particularly statins, in preventing recurrent events and improving survival. Taken together these data are the foundation for the simple, but important advice for secondary prevention - the ABCs. In addition, the evidence for the central role of lifestyle factors as determinants of risk has lead to increased efforts towards developing interventions aimed at modifying lifestyle patterns. Today, the biggest challenge remains in the implementation of proven effective therapies. Our focus should turn to educating physicians and patients alike regarding available therapies and their indications. In addition systematic, sustainable and globally applicable approaches to the secondary prevention of cardiovascular diseases need to be developed to truly realize the vast potential benefits of existing therapies.

Many patients with coronary heart disease undergo percutaneous transluminal coronary angioplasty (PTCA) to improve myocardial tissue perfusion. However, a major complication after revascularisation procedures is restenosis of the injured artery. The molecular mechanism involved is not fully elucidated and no successful treatment is currently available. Animal models are preliminary tools that can help improve our understanding of the pathogenesis and treatment of restenosis in humans. Attracted by well-defined genetic systems, a number of investigators began to use the mouse as an experimental system for restenosis research. They demonstrated that several stages involved in this process include thrombus formation, inflammatory cell infiltration and smooth muscle cell (SMC) accumulation to form neointimal lesions. By using transgenic and knockout mice a number of genes related to these processes have been found to play a major role in mediating lesion formation, e.g. the plasminogen system, matrix metalloproteinases (MMP), adhesion molecules, cytokines and signal transducers. This review will not attempt to cover all aspects of related genes or molecules, but will rather focus on several groups of genes, by which the major progress in understanding the mechanisms of the disease has been made. The information obtained by using animal models could be essential for a better understanding of the pathogenesis of restenosis in humans and to provide a basis for therapeutic intervention.

Evidence indicates that oxidative stress refers to a condition where cells are subjected to excessive levels of reactive oxygen species (ROS). Overall vascular function is dependent upon a fine balance between oxidant and antioxidant mechanisms which is required, at least in part, for proper functioning of the endothelium. Considerable experimental and clinical data indicate that the intracellular oxidant milieu is also involved in several redox-sensitive cellular signaling pathways, such as ion transport systems, protein phosphorylation, and gene expression and thus also plays important roles as modulator of vascular cell function, such as cell growth, apoptosis, migration, angiogenesis and cell adhesion. Overproduction of ROS under pathophysiologic conditions is integral in the development of vascular disease. This fact stimulated an intensive search of new pharmacological approaches to improve vascular hemeostasis and, particularly those intended to decrease oxidative stress or augment the antioxidant defense mechanisms.