Current Pharmaceutical Design - Volume 17, Issue 37, 2011

During the last years, it has been well established the crucial role of inflammatory process in the initiation and progression of atherosclerosis. Large scale studies have reported that the majority of the patients with coronary artery disease have one or more traditional/novel risk factors predisposing to atherosclerosis and strongly associated to inflammatory process [1, 2]. Moreover, several studies have reported that most atherosclerotic manifestations could be prevented if the risk factors were eliminated [3]. Inflammatory mediators have been found to participate in crucial steps of atherosclerosis. More mechanistically, endothelial dysfunction is characterized by enhanced expression of adhesion molecules which mediate the attachment of circulating monocytes and lymphocytes. Not only leukocytes, but also endothelial cells are capable to secrete cytokines and growth factors promoting migration and proliferation of smooth muscle cells. Moreover, chemokines including monocyte chemoattractant protein-1 produced by vascular wall cells in response to modified lipoproteins, regulate the transendothelial migration of adherent monocytes [4, 5]. Monocytes in turn interact with endothelial cells and increase matrix metalloproteinases (MMPs) production such as MMP-9. Within the intima, monocytes mature into macrophages which proliferate and amplify the inflammatory response by the secretion of growth factors and cytokines [6]. Cytokines and growth factors provoke smooth muscle cells' mobilization, proliferation and expression of metalloproteinases that degrade elastin and collagen, allowing their penetration into the expanding lesion [6, 7]. Finally, foam cell accumulation leads to metalloproteinase overexpression, which subsequently triggers extracellular matrix destabilization. Apparently, the inflammatory response is involved in many processes related to plaque development. Thus it has become evident that monitoring inflammatory process is crucial. In addition, identification of risk factors strongly associated to inflammation as well as potential therapeutic approaches to modify inflammatory process is of great importance. In the present issue of the journal we have included the most important pathophysiological aspects of inflammation in atherosclerosis focusing on major risk factors and the potential anti-inflammatory therapeutic approaches. The first two papers by Tousoulis et al [8] and Charakida et al [9] discuss thoroughly the role of inflammation in the pathophysiology of atherosclerosis. In addition, they provide the current available data on the main drug categories that have been proved to ameliorate the inflammatory state in atherosclerosis. The following three articles by Androulakis et al [10], Siasos et al [11] and Kampoli et al [12] focus on major risk factors of atherosclerosis that are strongly associated with increased inflammatory process. Hypertension, hyperlipidemia and diabetes mellitus are major risk factors known to promote inflammation within the atherosclerotic plaque. These articles report the associated mechanisms as well as classic and novel therapeutic approaches used in the prevention or the modification of inflammatory process in these specific group of patients Moreover, the articles by Dumitriu et al [13], Della Bona et al [14] and Toutouzas et al [15] focus on a different aspect of the inflammatory response in atheroslcerosis. They provide insights into the role of the immune system and especially the activity of B and T cells. In addition, classic and novel inflammatory markers for monitoring of atherosclerosis as well as novel therapeutic approaches are presented. It is also worth mentioning the contribution of inflammatory process to plaque formation, erosion and rupture which is mainly discussed in the article by Toutouzas et al [15]. Finally, the article by Van-Assche et al [16] discusses the role of the genotypic background in the initiation and progression of atherosclerosis. In addition, it expands on the current attempts to modify atherosclerosis using inflammation-associated gene therapy. Conclusively, I strongly believe that the present issue provides a comprehensive insight into the role of inflammation in atherosclerosis and the respsective therapeutic approaches. Finally, I would like to extend my thanks and appreciation to all the authors and acknowledge the high-quality reviews submitted to the current issue of therapeutic approaches targeting inflammatory process in atherosclerosis, with the expectation to trigger the interest of the scientific community towards this direction.

Atherosclerosis is a disease of arteries and is characterized by endothelial dysfunction, vascular inflammation, and the build-up of lipids, cholesterol, calcium, and cellular debris within the intima of the vessel wall. A number of factors commonly characterized as “risk factors” for atherosclerosis have been identified to facilitate the development of atherosclerosis by decreasing NO bioavailability in the vascular endothelium. The serious clinical manifestations of atherosclerosis (including coronary heart disease, stroke, and peripheral vascular disease) augment the need of performing the appropriate diagnostic methods to the patients. The most important diagnostic methods include the usage of biochemical markers and the invasive and non-invasive imaging techniques assessing endothelial function. The main drug categories that have been proved to ameliorate the inflammatory state in atherosclerosis are angiotensin converting enzyme inhibitors/angiotensin receptors blockers, statins, and antioxidants.

Recent evidence suggests that patients with chronic inflammatory disorders are at increased cardiovascular risk. A number of different mechanisms have been postulated to contribute to atherosclerotic disease progression in these patients including traditional cardiovascular risk factors, cytokine upregulation, immume mediated pathways and increased oxidative stress. Novel treatments target inflammatory pathways and have beneficial effect on rheumatic disease activity however; their impact on cardiovascular risk reduction remains unclear. Further longitudinal studies are required to assess the value of different therapeutic approaches on cardiovascular outcome of these patients.

The role of inflammation as crucial underlying process contributing to the initiation and the progression of atherosclerosis as well as its clinical manifestations is well established. Recent data have demonstrated also a strong association between essential hypertension and inflammatory process. In addition, several studies have shown that tissue expression and plasma concentrations of several inflammatory biomarkers/mediators are related to increased risk of hypertension. The determination of markers such as acute phase proteins (C-reactive protein), adhesion molecules such as vascular cell adhesion molecule-1, intercellular adhesion molecule-1 and chemokines is crucial in determining therapeutic responses and clinical outcomes of hypertensive patients. In addition, several therapeutic approaches targeting blood pressure may have also beneficial effects in terms of inflammation and thus further clinical benefits. Although the available data are encouraging, further large scale studies are required to evaluate the reported anti-inflammatory effects in management and treatment of arterial hypertension.

The role of inflammation in the development and progression of cardiovascular diseases is well established. Systemic inflammation and immune system play a central role in atherogenesis. The strong dependence of the atherosclerotic process on both a state of continuous low grade inflammation and the presence of lipid abnormalities gave impetus to research the association between hyperlipidemia and inflammatory status. In experimental and clinical studies, several inflammatory markers such as C-reactive protein, tumor necrosis factor-alpha, interleukin 6, nuclear factor kappa-β, adhesion molecules, serum amyloid-α, lipoprotein-associated phospholipase A2, fibrinogen and sCD40 ligand are associated with lipids level. Although, cholesterol lowering treatment has several important beneficial effects, there is still little clinical experience or data from clinical trials, in order to treat patients with hyperlipidemia and impaired inflammatory status.

Insulin resistance and the vascular complications of diabetes include activation of the inflammation cascade, endothelial dysfunction, and oxidative stress. The comorbidities of diabetes, namely obesity, insulin resistance, hyperglycemia, hypertension and dyslipidemia collectively aggravate these processes while antihyperglycemic interventions tend to correct them. Increased C-reactive protein, interleukin 6, tumor necrosis factor alpha and especially interstitial cellular adhesion molecule-1, vascular cellular adhesion molecule-1, and E-selectin are associated with cardiovascular and non-cardiovascular complications of both type 1 and type 2 diabetes. We sought to review the clinical implications of the inflammation theory, including the relevance of inflammation markers as predictors of type 2 diabetes in clinical studies, and the potential treatments of diabetes, inferred from the pathophysiology.

The chronic inflammation process that characterises atherosclerosis involves both the innate and adaptive arms of the immune system. Several lines of evidence have recently highlighted pivotal roles for T and B lymphocytes - cells that belong to the adaptive immune system - in the development and progression of atherosclerosis. In this review, we summarise the current knowledge on the roles of adaptive immune responses in atherosclerosis and present our views on how a better understanding of these immune mechanisms could shape future therapies to slow down or even prevent this disease.

The past decade has seen a steady growth in the treatment options available for Acute Coronary Syndromes (ACS), as a consequence of our better understanding of ACS pathophysiology. Administration of fibrinolytics in ST-elevation myocardial infarction, and of potent antiplatelet and anticoagulant drugs in all ACS, has allowed us to considerably improve their outcome. Yet, the rate of adverse cardiac events at early follow-up ranges from 15% to 20%. Thus, to further improve the outcome of ACS or to prevent their occurrence, it is important to identify new therapeutic target. A number of experimental and clinical studies have highlighted the key role of inflammation in all phases of atherosclerosis, from fatty streaks to disrupted plaques and raised levels of inflammatory markers have been associated to a poor outcome despite optimal treatment, including myocardial revascularization. In this review, we will focus on inflammation as a possible new therapeutic target of ACS, discussing the anti-inflammatory treatments in four sections: 1) non specific anti-inflammatory drugs; 2) specific antagonists of key cytokines; 3) immunomodulatory therapies; 4) immunization as promising therapeutic modality against atherosclerosis.

Although enormous progress has been made in the prevention and treatment of cardiovascular disease, it still remains the leading cause of death worldwide. During the last decades, advances in the understanding of the pathophysiology of vulnerable plaque progression, coupled with novel diagnostic and therapeutic approaches, created a new opportunity for progress against cardiovascular disease. It has been demonstrated that inflammation, implicated in all stages of atherosclerosis, is an integral part of vulnerable plaque development and progression, leading eventually to plaque instability. Thus, new diagnostic modalities have been proposed for the detection of local plaque inflammation. Moreover, treatments such as stenting, photodynamic therapy, and novel pharmaceutical agents are under consideration as methods to stabilize the vulnerable plaques by inhibiting inflammation. This review provides an overview of the inflammatory process leading to atherosclerotic cardiovascular disease and the potential clinical strategies that may substantially decrease the incidence of events. We will mention the major impact of local and systemic inflammation on plaque advancing and destabilization, the imaging techniques for early detection of vulnerable plaques and the potential therapeutic strategies.

The extensive cross-talk between the immune system and vasculature leading to the infiltration of immune cells into the vascular wall is a major step in atherogenesis. In this process, reactive oxygen species play a crucial role, by inducing the oxidation of LDL and the formation of foam cells, and by activating a number of redox-sensitive transcriptional factors such as nuclear factor kappa B (NFkappa B) or activating protein 1 (AP1), that regulate the expression of multiple pro/anti inflammatory genes involved in atherogenesis. Delivery of genes encoding antioxidant defense enzymes (e.g. superoxide dismutase, catalase, glutathione peroxidase or heme oxygenase- 1) or endothelial nitric oxide synthase (eNOS), suppress atherogenesis in animal models. Similarly, delivery of genes encoding regulators of redox sensitive transcriptional factors (e.g. NF-kappa B, AP-1, Nrf2 etc) or reactive oxygen species scavengers have been successfully used in experimental studies. Despite the promising results from basic science, the clinical applicability of these strategies has proven to be particularly challenging. Issues regarding the vectors used to deliver the genes (and the development of immune responses or other side effects) and the inability of sufficient and sustained local expression of these genes at the target-tissue are some of the main reasons preventing optimism regarding the use of these strategies at a clinical level. Therefore, although premature to discuss about effective “gene therapy” in atherosclerosis at a clinical level, gene delivery techniques opened new horizons in cardiovascular research, and the development of new vectors may allow their extensive use in clinical trials in the future.