Cardiovascular & Hematological Agents in Medicinal Chemistry (Formerly Current Medicinal Chemistry - Cardiovascular & Hematological Agents) - Volume 11, Issue 2, 2013

In a variant proportion of patients presenting with chest pain and electrocardiographic changes characteristic for ST – elevation myocardial infarction, percutaneous coronary intervention achieves epicardial coronary artery reperfusion but not the myocardial reperfusion (ranging from 5% to 50%). Furthermore, prolonged myocardial ischemia often breaks down the coronary microvasculature and the flow to the infarct myocardium may seem to be markedly reduced. This condition is known as no reflow - phenomenon. The no reflow - phenomenon is associated with an increased incidence of malignant ventricular arrhythmias, heart failure and 30-days mortality. In the recent years in literature, several articles (subsequently discussed in the present review) have been published and made relevant to the study of the pathophysiology regarding no reflow - phenomenon. This knowledge has assisted in the development of new treatment strategies, such as prophylactic use of vasodilators, mechanical devices and drugs inhibiting platelet. The review has focused on the current literature about intra – coronary injection of drugs to treat no - reflow and microvascular dysfunction.

Acute coronary syndromes and, in paticular, ST – segment elevation myocardial infarction are the principle causes or mortality and morbidity in the industrialized countries. The manadgement of acute myocadial infarction is much debated in the literature; primary percutaneous coronary intervention is the treatment of choice. In the recent years there has been an increasing interest in the concept of adjunctive pharmacological therapy to improve outcomes in primary percutaneous coronary intervention. In the literature randomized trials of intravenous or more recently intracoronary injection of glycoprotein IIb/IIIa inhibitors have provided conflicting results with no definitive evidence for efficacy. The aim of the report is to review the evidence to our date on the role of intracoronary injection of abciximab during primary percutaneous intervention in the setting of acute myocardial infarction.

Coronary artery diseases continue to be the most common causes of mortality and morbidity in the industrialized world, especially in the setting of acute myocardial infarction. Anticoagulation during primary percutaneous coronary intervention (PCI) for ST-elevation myocardial infarction (STEMI) has traditionally been supported by anticoagulant unfractionated heparin (UFH). Recently, alternative anticoagulants such as low molecular weight heparin (LMWH) were included in the management of STEMI. The aim of the present review is to compare efficacy and safety outcomes among patients receiving low molecular weight heparins (LMWH) or unfractionated heparin (UFH) while undergoing PCI for STEMI.

Platelets play a critical role in the pathogenesis of atherothrombotic processes and inhibition of platelet aggregation by antiplatelet therapy is essential and really important in the acute coronary syndromes or in the setting of percutaneous coronary intervention. The first family of adenosine diphosphate P2Y12 receptors inhibiting drug is represented by thienopyridines and among these ticlopidine was the first approved by Food and Drug Administration; actually its use is discouraged because of its potential side effects (neutropenia, anemia, gastrointestinal distress and thrombotic thrombocytopenic purpura). The second generation of thienopyridines is represented by clopidogrel that has replaced ticlopidine in the clinical practice; clopidogrel has the largest clinical experience. Prasugrel represents the third generation. It inhibits platelet aggregation by irreversibly blocking the adenosine diphosphate P2Y12 receptor. Ticagrelor, Cangrelor and Enilogrel represent the last generation of thienopyridines. This review is focused on the effects of adenosine diphosphate P2Y12 inhibitors.

The direct thrombin inhibitor bivalirudin has gained popularity in cardiovascular medicine over the past decade because, in comparison with unfractionated heparin, it guarantees a predictable dose-related degree of anticoagulation with a low immunogenic profile and, possibly, with reduced rates of major bleeding complications. In the past bivalirudin has been frequently employed in the management of patients with heparin-induced thrombocytopenia. The REPLACE-2, ACUITY and ISAR-REACT4 studies demonstrated bivalirudin non-inferiority in comparison with unfractionated heparin in terms of ischemic end-points with a reduction of the bleeding rate also in patients acute coronary syndrome without ST elevation. Finally the results of the HORIZONS-AMI study positioned this drug as a first choice anticoagulant during percutaneous coronary interventions in patients with ST-elevation myocardial infarction. In fact the bivalirudin alone regimen, compared to unfractionated heparin plus GP2b3a inhibitors, decreased inhospital bleeding rates and short and long term mortality. Given the body of clinical evidence, bivalirudin is likely to contend to GP2b3a inhibitors the leading place among the proposed anticoagulation strategies in the setting of acute coronary syndromes. The duration of the bivalirudin infusion after PCI and the optimal oral antiplatelet regimen associated to bivalirudin are important issues to be solved in future randomized controlled studies.

Diabetes increases the risk of cardiovascular disease; however, this risk is further increased as a result of other factors. This observation is particularly relevant with regard to lipid abnormalities. Although diabetic dyslipidemia is characterized by hypertriglyceridemia, low HDL-cholesterol, and small dense LDL particles, the main determinant of the role of dyslipidemia in the prognosis of diabetics is LDL cholesterol. In recent years, LDL cholesterol targets have become progressively lower, and most current recommendations establish an LDL cholesterol target of <70 mg/dL for diabetics. This target can only be achieved using potent statins at adequate doses. Although it has been suggested that statins may interfere with glycemic metabolism, the benefits of reducing LDL cholesterol by statins are much greater than this possible deleterious effect. Rosuvastatin is one of the most potent statins available. Several studies have shown that it effectively reduces LDL cholesterol to recommended targets in diabetics. Moreover, rosuvastatin modestly increases HDL cholesterol and decreases triglycerides. The risk of side effects is low, as is the risk of interactions with other drugs. In this manuscript, the efficacy and safety profile of rosuvastatin in diabetic population is reviewed.

Hypoxia-inducible factor (HIF) is a dimeric transcription factor identified as the major regulator of hypoxic responses in cells. Its activity is mainly regulated by protein stability. In well-oxygenated tissues prolyl hydroxylases hydroxylate HIF-1α and HIF-2α protein to provoke their proteasomal degradation. Under hypoxia the α-subunits are stabilized and dimerize with ß-subunits to constitute active transcriptional complexes. As the α-subunits are constantly translated and degraded, any interference with cellular translation will alter HIF-α expression and HIF activity. Cytokines such as interleukins or interferons as well as growth factors such as vascular endothelial growth factor or insulin-like growth factor are good examples of hormones that affect transcription, translation, or degradation of HIF-1α. In turn, HIF specific target genes also modulate the expression and/or signaling quality of cytokines or growth factors to create signal amplifying/intercepting cellular networks. We define how these signaling circuits promote or delay the progression of diseases and describe potential outcomes for patients.

Platelets play a key role in the pathogenesis of atherothrombosis, involved in both the development and progression of atherosclerotic heart disease, and the attendant acute thrombotic complications. Antiplatelet therapy constitutes a mainstay therapy for patients with acute coronary syndromes and generally high-risk patients with atherothrombosis. Until recently, dual antiplatelet therapy (DAPT) for the treatment and prevention of the complications of atherothrombotic disease was traditionally limited to aspirin plus clopidogrel. However, a most important pertaining issue emerged, that of the occurrence of drug-resistance or tolerance observed in some patients for both these antithrombotic agents, which limited the efficacy and applicability of this combined therapy.The availability of the newer thienopyridine, prasugrel, and the cyclopentyl-triazolopyrimidine, ticagrelor, represents an important addition to the physician's armamentarium. Dual antiplatelet therapy with aspirin and clopidogrel or one of the newer agents interferes with platelet activation in complementary, but separate pathways. Aspirin irreversibly inhibits cyclooxygenase, thus preventing the production of thromboxane A2, which is a prothrombotic and vasoconstrictive substance. Thienopyridines (clopidogrel/prasugrel) irreversibly and ticagrelor reversibly prevent and inhibit platelet activation by blocking one of the three known adenosine 5'-diphosphate (ADP) receptors (the P2Y12 receptor) on the platelet surface, thus interfering with platelet activation, degranulation and aggregation. Each of these antiplatelet agents has a protective effect against adverse vascular events; classical DAPT with aspirin and clopidogrel has an even stronger antiplatelet effect compared with either agent alone, however DAPT combining aspirin with one of the newer more potent agents translates into superior antithrombotic protection in atherothrobotic vascular disease, albeit at an increased, though not inordinately, risk for bleeding complications. A number of randomized clinical trials have demonstrated and confirmed the incremental benefit and efficacy of DAPT with use of either classical or newer agents, above and beyond that of each antiplatelet agent alone. Data have also been obtained from studies where indications for the use of DAPT continue to expand into other patient groups, rendering and maintaining DAPT a sweeping combination in Cardiology. This article is a comprehensive review of all these data and the landmark trials on the two classical and also the newer antiplatelet agents, the issues involved and the current recommendations for their use in patients with atherosclerotic heart disease and other cardiovascular disorders and procedures.