Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents) - Volume 9, Issue 1, 2011

Objective: Aim of the study was to evaluate the influence of the dihydropyridine derivative BW 9798 on intimal hyperplasia in a carotid artery injury model of New Zealand White rabbits on a high cholesterol diet. Methods: In carotid arteries of 50 New Zealand White rabbits atherosclerotic lesions were induced by cholesterol diet and electrostimulation of the artery. In 40 animals the resulting primary lesion was subjected to balloon angioplasty (BA). Three days prior BA animals received BW 9798 or placebo per os until sacrifice three days or 28 days after BA. Results: BW 9798 led to increased cross sectional area by 128.3% and an increased luminal area by 157% after 28 days after BA compared with placebo. However the degree of stenosis did not significantly decrease. The cell count of the different layers of the arteries decreased by 64.5% in the intima and by 62.6% compared with placebo treated animals after BA. Additionally the number of smooth muscle cell (SMC) layers in the neointima was significantly lower in BW 9798 treated animals than in placebo animals (8±3 vs 14±9, p<0.05) although the proliferation was not changed by BW 9798 treatment 3 days after BA. Conclusion: BW 9798 leads to significant changes in vessel wall geometry although the influence on vascular remodelling of this compound is unclear. It can be speculated that the compound affects the homeostasis of extracellular matrix, invasion of inflammatory cells into the vessel wall and the expression of cytokines. However, further investigation needs to clarify the role of BW 9798 on remodelling after BA.

Immunomodulatory agents which include thalidomide and its analogue lenalidomide have recently emerged as an effective treatment option for patients with multiple myeloma. The anti-tumor property of these molecules is probably related to action on tumor microenvironment, anti-angioenesis and several other hitherto less understood mechanisms. Despite promising efficacy, their progress has been complicated by reports of venous thromboembolism in patients receiving these agents. The background rate of thromboembolism is 4-11% in patients with multiple myeloma, which increases to 15-20% in patients who received intensive treatment with thalidomide. The exact mechanism of this phenomenon is not clear but possible explanations include up-regulation of pro-coagulant factors and selective endothelial damage. The development of thromboembolism is also influenced by disease state, performance status, type of chemotherapy and supportive therapy. Multiple treatment strategies for prevention of thromboembolic events in these patients have been proposed including aspirin, heparins and warfarin but there have been no prospective controlled trials comparing the superiority of one prophylactic measure over another. The diagnosis and treatment of thromboses in these patients involves standard guidelines but the optimal duration is not certain. This review discusses incidence, pathogenesis and management of thrombotic events with the use of immunomodulatory agents in the setting of multiple myeloma as well as recent recommendations regarding appropriate prophylaxis and preventive measures.

Platelets play a central role in the regulation of both thrombosis and haemostasis yet tests of platelet function have, until recently, been exclusively used in the diagnosis and management of bleeding disorders. Recent advances have demonstrated the clinical utility of platelet function testing in patients with cardiovascular disease. The ex vivo measurement of response to antiplatelet therapies (aspirin and clopidogrel), by an ever-increasing array of platelet function tests, is, with some assays, predictive of adverse clinical events and thus, represents an emerging area of interest for both the clinician and basic scientist. This review article will describe the advantages and disadvantages of the currently available methods of measuring platelet function and will discuss both the limitations and emerging data supporting the role of platelet function studies in clinical practice.

Atherosclerosis is rapidly gaining recognition as an inflammatory disease showing contribution from innate and adaptive immunity pathways towards disease initiation and progression. Components of adaptive immunity especially T cells, are shown to be involved in atherogenesis and subsets of T cells are known to drive/ dampen inflammatory processes in atherosclerosis. However, the regulatory balance between the T cell subsets remains unclear. In this review, we summarize the role of T helper cells Th1, 2, 3 and 17, and regulatory cells Treg in atherosclerosis by studying the cytokines involved in Th cell functioning. We further examine the diverse roles of T helper cells for regulating the progression of atherosclerosis.

The glycoprotein CD36, also known as glycoprotein IIIb/IV or FAT, is expressed on the surface of platelets, monocytes, microvascular endothelial cells, smooth muscle cells, cardiomyocytes and other cells of the cardiovascular system. In spite of its abundant presence, CD36 has remained for long a mysterious protein with a poorly understood role. In this paper, we review how CD36 can affect cellular responses by interaction with a variety of ligands, in particular thrombospondin-1, oxidized lipoproteins and fatty acids. Furthermore, given the structure of CD36 with two transmembrane domains and short cytoplasmic tails, we consider how this receptor can induce intracellular signaling, likely in junction with other cellular receptors or associated proteins in the membrane. Current literature points to activation of Src-family and mitogen-activated protein kinases, as well as to activation of the NFκB and Rho pathways. The new insights make CD36 attractive as a therapeutic target to suppress platelet and monocyte/macrophage function and thereby atherothrombosis.

Cardiac surgery with cardiopulmonary bypass (CPB) is associated with activation of the complement system, platelets, neutrophils, monocytes, and macrophages which may lead to systemic inflammatory response syndrome in several cases. Despite modification of surgical techniques, biocompatibility of the bypass circuit and intensive care procedures after operation, CPB is still associated with post-operative morbidity including reduced cardiac function, capillary leak or multi-organ dysfunction. Corticosteroids are known for their anti-inflammatory effects and therefore, they are beneficial in selected trauma or septic patients. Prophylaxis with corticosteroids in cardiac surgery has been used since decades. The studies for methylprednisolone and hydrocortisone, the most commonly used corticosteroids, show conflicting results. For hydrocortisone, which is the mainstream of corticosteroid treatment in septic patients, the number of studies is low, but will increase in the next years. This article reviews the data concerning its use in patients undergoing cardiac surgery, its contraindications, adverse effects, risks, and benefits.