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Contents

Non Peptidic Urotensin II Antagonists: Perspectives for a New Class of Drugs Pp. 80-91
Alessandro Cosenzi
[Abstract]

Pre-Emptive Conditioning of the Ischemic Heart Pp. 92-104
Joseph M. Vitale, Hongyu Qiu and Christophe Depre
[Abstract]

Drug-Eluting Stents: Present and Future Pp.105-115
Lakshmana Pendyala, Refat Jabara, Toshiro Shinke, Nicolas Chronos, Keith Robinson, Jinsheng Li and Dongming Hou
[Abstract]

Pharmacological and Cellular Therapies to Prevent Restenosis after Percutaneous Transluminal Angioplasty and Stenting Pp. 116-124
Thomas J. Kiernan, Bryan P. Yan , Ignacio Cruz-Gonzalez, Roberto J. Cubeddu, Angel Caldera, Gareth D. Kiernan and Vishal Gupta
[Abstract]

Pharmacological Approach of No-Reflow Phenomenon Related with Percutaneous Coronary InterventionsPp. 125-129
S. Jiménez Valero, R. Moreno, R. Martin Reyes, A. Sánchez Recalde, G. Galeote, L. Calvo, A. Villate and J.L. López Sendón
[Abstract]

Antithrombotic Agents for Acute Coronary Syndromes Pp. 130-141
Debabrata Mukherjee
[Abstract]

Depression and Cardiovascular Disease: Role of Nitric Oxide Pp. 142-149
Vivian Liane M. Pinto, Tatiana M.C. Brunini, Marcos R. Ferraz, Anicet Okinga and Antonio Cláudio Mendes-Ribeiro
[Abstract]

IL-1 Cytokines in Cardiovascular Disease: Diagnostic, Prognostic and Therapeutic Implications Pp. 150-158
Stavros Apostolakis, Konstantina Vogiatzi, Elias Krambovitis and Demetrios A. Spandidos
[Abstract]

Abstracts

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Non Peptidic Urotensin II Antagonists: Perspectives for a New Class of Drugs
Alessandro Cosenzi

Urotensin II (U-II) is a cyclic peptide isolated from a fish. Subsequently, human U-II and its receptor were identified. In rat thoracic aorta U-II triggers powerful vasoconstrictor activity. However, the constrictor response to U-II appears to be variable and highly dependent on the vascular bed examined. Vasoconstriction is not its only effect; U-II and its receptor have been demonstrated in the central nervous system, where U-II induces a cardiovascular, behavioural, motor and endocrine response and in the kidney, where it seems to influence renal hemodynamics but also salt and water excretion, in rat pancreas where it inhibits insulin secretion, in the heart where it seems to play a role in cardiac hypertrophy and fibrosis. In humans high plasma or urine levels of U-II have been described in some pathologic conditions. Peptidic and non peptidic UT receptor antagonists have been synthesized and their effects have been evaluated particularly in animal models of diabetes and heart failure. After promising results in animal models, palosuran, a non peptidic U-II antagonist has been administered also in diabetic patients to evaluate its potential nephroprotective activity. This review presents the data available on the U-II system and its role in physiological and pathological conditions, together with data regarding palosuran and other non peptidic and peptidic U-II antagonists.

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Pre-Emptive Conditioning of the Ischemic Heart
Joseph M. Vitale, Hongyu Qiu and Christophe Depre

Ischemic heart disease remains one of the most frequent causes of morbidity and mortality worldwide. Although the prognosis of myocardial ischemia has been dramatically improved by the techniques of early reperfusion, the prevention of irreversible ischemic damage remains a critical aspect of the treatment. An appealing novel therapeutic avenue for the prevention of myocardial ischemia relates to the possibility of a pre-emptive conditioning of the heart, in which an activation of survival pathways could be achieved in patients with ischemicheart disease who are at risk for a subsequent lethal ischemia.These patients would include those with unstable angina, or with severe and repetitive ischemic episodes, and patients scheduled for surgical revascularization. In these situations, the pre-emptive activation of survival signaling mechanisms would confer a prophylactic cardioprotection during the following ischemic stress. During the last twenty years, it became clear that the heart can trigger survival mechanisms when submitte to stress, in such conditions as myocardial stunning, hibernation and preconditioning. The goal of the pre-emptive conditioning is to activate such survival pathways as a prophylactic measure to prevent myocardial cell death when the heart is threatened by potentially lethal ischemia. Based on the experimental data collected at the bench side, we review how this approach could be applied in the clinical setting.

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Drug-Eluting Stents: Present and Future
Lakshmana Pendyala, Refat Jabara, Toshiro Shinke, Nicolas Chronos, Keith Robinson, Jinsheng Li and Dongming Hou

In-stent restenosis (ISR) caused by neointimal hyperplasia is the major drawback after percutaneous coronary intervention (PCI) for obstructive coronary disease, occurring in up to 40% of lesions. Recently, one of the most intriguing new therapies developed is drug-eluting stents (DES) that target the central phenomenon of cellular proliferation that causes ISR. The benefits of stent-based drug delivery include maximizing the local tissue levels of therapeutic agents while minimizing systemic toxicity. Numerous DES using different thin-film polymeric drug carrier have been developed and tested, those eluting either antimitotic or antimicrotublar agents such as sirolimus and paclitaxel have been shown ef-fective in clinical trials. Two DES, the J&J Cypher (sirolimus-eluting) and the Boston Scientific Taxus (paclitaxel-eluting) stents, are commercially available in the U.S. after a number of randomized trials demonstrated reductions in late lumen loss, binary restenosis rate, and need for repeat revascularization compared with bare-metal stents (BMS). Because ISR is multifactorial, ideal agents for DES should inhibit thrombus formation, inflammation and cellular proliferation as well as enhance re-endothelialization. The next generation of DES currently undergoing preclinical studies includes new technology, new stent designs and materials, biological polymers,bioabsorbable stents coated with new drugs including stent based gene, as well as cell delivery. The current paper will review and discuss the current and future status of DES.

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Pharmacological and Cellular Therapies to Prevent Restenosis after Percutaneous Transluminal Angioplasty and Stenting
Thomas J. Kiernan, Bryan P. Yan , Ignacio Cruz-Gonzalez,Roberto J. Cubeddu, Angel Caldera, Gareth D. Kiernan and Vishal Gupta

Angioplasty and stenting have become routine practice for the treatment of significant obstructive atherosclerotic vascular disease. This method of revascularization has a longer history concerning coronary artery disease but is becoming an increasingly used modality of revascularization in the peripheral circulation. Neointimal formation is the pathological basis for restenosis after revascularization procedures such as angioplasty, stenting, and bypass grafting. While restenosis is less of a problem in the coronary circulation with the advent of drug-eluting stents, it continues to be a problem however in the peripheral arterial system. Current treatments to prevent restenosis include pharmacologic, mechanical and cellular approaches which we will discuss in this manuscript.

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Pharmacological Approach of No-Reflow Phenomenon Related with Percutaneous Coronary Interventions
S. Jiménez Valero, R. Moreno, R. Martin Reyes, A. Sánchez Recalde, G. Galeote, L. Calvo, A. Villate and J.L. López Sendón

The no-reflow phenomenon (NRP) is characterized by an inadequate myocardial tissue perfusion in the presence of apatent epicardial coronary artery. It generally occurs after temporary occlusion of the artery causing myocardial ischemia and necrosis that persist after relief of the vessel occlusion, without evidence of epicardial mechanical obstruction.Currently, the main scenario of NRP is the setting of percutaneous coronary interventions (PCI), especially in patients with acute myocardial infarction or saphenous vein graft disease, and its occurrence is associated with adverse clinical outcomes. Pathophysiology of NRP is not fully understood but it seems to be related with microvascular damage. Several mechanisms have been involved, such as distal microembolization, interstitial and intracellular edema,coronary spasm and capillary plugging. Diagnosis of NRP is generally based on clinical and angiographic data. Several methods have been proposed for the assessment of NRP, such as electrocardiography, myocardial contrast echocardiography,contrast-enhanced magnetic resonance imaging, nuclear imaging or positron emission tomography, that have demonstrated additional prognostic value over angiography.There are different pharmacological and mechanical approaches for the prevention of NRP but none of them have demonstrated a clear efficacy. The treatment of established NRP is mainly based on the administration of coronary vasodilators, like adenosine, verapamil or nitroprusside, but clinical results are frequently disappointing. The objective of this review is to describe the state of the art of the pathophysiology,diagnosis and pharmacological management of NRP

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Antithrombotic Agents for Acute Coronary Syndromes
Debabrata Mukherjee

Current evidence suggests a central role for antithrombotic agents such as unfractionated heparin (UFH) or low-molecular weight heparin (LMWH) in the management of acute coronary syndromes (ACS). In patients with acute myocardial infarction,several studies have shown that LMWHs may represent an effective alternative to UFH as an adjunct to thrombolytic therapy and are not associated with an increased risk of major bleeding. In patients with unstable angina or non-ST-segment elevation myocardial infarction, trials have shown that the LMWH enoxaparin significantly reduces the risk of cardiovascular events, compared with UFH, while other trials have shown that the combination of enoxaparin and aglycoprotein IIb/IIIa antagonist is not associated with an excess risk of bleeding. However, LMWHs are significantly more expensive that UFH. Recently, newer antithrombotic agents such as fondaparinux and bivalirudin have shown equivalent efficacy to the heparins with less bleeding and appear clinically attractive. This review examines the current evidence for the efficacy and safety of antithrombotic agents in ACS.

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Depression and Cardiovascular Disease: Role of Nitric Oxide
Vivian Liane M. Pinto, Tatiana M.C. Brunini, Marcos R.Ferraz, Anicet Okinga and Antonio Cláudio Mendes-Ribeiro

Both depression and cardiovascular disease are major public health problems. Growing evidence shows that depression is arisk factor for the development of coronary artery disease(CAD). However, the exact mechanisms underlying the interplay between depression and CAD remain to be elucidated. Depression adversely affects autonomic and hormonal homeostasis, resulting in metabolic abnormalities, inflammation,increased platelet aggregation and endothelial dysfunction. All of these pathological features lead to atherothrombosis and cardiovascular events. However, there is no clear evidence that anti-depressant drugs or psychotherapy will reduce the risk or improve the outcome of CAD. Recent studies suggest that the L-arginine-nitric oxide (NO) pathway is involved in the genesis of depression. NO has many physiological functions, including vasodilatation, neurotransmission and platelet aggregation inhibition. It is synthesised from the cationic amino acid Larginine by a family of enzymes: NO synthases (NOS). There are three NOS isoforms: inducible NOS (iNOS), endothelial NOS and neuronal NOS (nNOS). The availability and transport of L-arginine modulate rates of NO biosynthesis in circulating blood cells and vasculature, which provides a protective effect against cardiovascular disease. In depressive patients, the Larginine-nitric oxide pathway seems to be impaired. The present review seeks a better understanding of the mechanisms that could identify depression as a cardiovascular risk factor and introduce new possible therapeutic interventions.

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IL-1 Cytokines in Cardiovascular Disease: Diagnostic, Prognostic and Therapeutic Implications
Stavros Apostolakis, Konstantina Vogiatzi, Elias Krambovitis and Demetrios A. Spandidos

Interleukins (ILs) are key mediators in the chronic vascular inflammatory response underlying several aspects of cardiovascular disease. Due to their powerful pro-inflammatory potential, and the fact that they are highly expressed by almost all cell types actively implicated in atherosclerosis, members of the IL-1 cytokine family were the first to be investigated in the field of vessel wall inflammation. The IL-1 family is comprised of five proteins that share considerable sequence homology: IL 1α , IL-1β , IL-1 receptor antagonist (IL-1Ra), IL-18 (also known as IFN γ -inducing factor), and the newly discovered ligand of the ST2L receptor, IL-33. Expression of IL-1s and their receptors has been demonstrated in atheromatous tissue, and serum levels of IL-1-cytokines have been correlated with various aspects of cardiovascular disease and their outcome. In vitro studies have confirmed pro-atherogenic properties of IL-1α, IL 1β and IL-18 such as, up-regulation of endothelial adhesion molecules, the activation of macrophages and smooth muscle cell proliferation. In contrast with this, IL-1Ra, a natural antagonist of IL-1, possesses anti-inflammatory properties,mainly through the endoge-nous inhibition of IL-1 signaling. IL 33 was identified as a functional ligand of the, till recently,orphan receptor, ST2L. IL-33/ST2L signaling has been reported as a mechanically activated, cardioprotective paracrine system triggered by myocardial overload. As the roles of individual members of the IL-1 family are being revealed, novel therapies aimed at the modulation of interleukin function in severa aspects of cardiovascular disease, are being proposed. Several approaches have produced promising results. However, none of these approaches has yet been applied in clinical practice.

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