Cardiovascular & Hematological Agents in Medicinal Chemistry - Volume 9, Issue 3, 2011

The metabolic syndrome (MS) has become the new epidemic of this century. Although its associated pathologies may vary, the most common are hypertension, central obesity, dyslipidemia, low High Density Lipoproteins (HDL), high Low Density Lipoproteins (LDL), and type-2 diabetes. Several others can be present, such as hypertriglyceridemia, cardiopathies, atherosclerosis, altered levels of sex hormones, hypogonadism in men and nephropathy. Several factors such as gender, age, race, lifestyle and diet may contribute to modify its prevalence: men develop cardiovascular diseases at an earlier age than pre-menopausal women, who seem to be protected by the antioxidant properties of estrogens. The present review offers information, mostly from 2008 to the present, as well as our own work on a rat model of MS, which was developed by the administration of sucrose in drinking water. Sex steroid hormones play an important role in the appearance and development of the MS and of cardiovascular diseases. Variations in the levels of sex hormones, whether normal or pathological, may have significant influence in the onset of several diseases, metabolic syndrome components included, as well as in the behavior of tissues and organs. These are just some of the non-reproductive actions of sex hormones.

Tirofiban is a nonpeptide tyrosine derivative that together with eptifibatide (both small molecules) and abciximam belongs to the group of glycoprotein IIb/IIIa inhibitors. Though similar to abciximab in that it has a high affinity for the GP IIbIIIa inhibitor receptor, tirofiban dissociates from it much faster tan abciximab, what makes its action reversible in a few hours. Initially used upstream for treatment of patients with non ST-elevation acute coronary síndromes, recent evidence has shown its role as adjuntive therapy in patients with ST-elevation acute myocardial infarction treated with primary angioplasty when used at a higher dose. In this article, we performed a thorough and systematic review of randomized trials comparing tirofiban versus pacebo and tirofiban versus abciximab when used in this subset of patients. All these studies showed tirofiban to be a well tolerated and effective IIbIIIa inhibitor. When compared with placebo, tirofiban was associated with a significant reduction in mortality and myocardial infarction at one month, with a higher risk of minor bleeding in the follow-up. When compared with abciximab, tirofiban showed no difference in mortality and a tendency to higher rate of the composite of death and myocardial infarction in the short term follow-up that disappeared when only studies with high-dose tirofiban were considered. On the basis of the high-dose regimen, tirofiban may be considered useful in the management of patients with ST-elevation myocardial infarction who undergo primary angioplasty.

Platelets play an essential role in the regulation of hemostasis and thrombosis and controlling their level of activation is central to prevention of occlusive clot formation and stroke. Although a number of anti-platelet targets have been identified to address this issue including COX-1, the P2Y12 receptor, the integrin αIIbβ3, and more recently the protease-activated receptor-1, these targets often result in a significant increased risk of bleeding which may lead to pathologies as serious as the thrombosis they were meant to treat including intracranial hemorrhage and gastrointestinal bleeding. Therefore, alternative approaches to treat uncontrolled platelet activation are warranted. Platelet-type 12-lipoxygenase is an enzyme which oxidizes the free fatty acid in the platelet resulting in the production of the stable metabolite 12-hydroxyeicosatetraenoic acid (12-HETE). The role of 12-HETE in the platelet has been controversial with reports associating its function as being both anti- and pro-thrombotic. In this review, the role of 12-lipoxygenase and its bioactive metabolites in regulation of platelet reactivity, clot formation, and hemostasis is described. Understanding the mechanisms by which 12-lipoxygenase and its metabolites modulate platelet function may lead to the development of a novel class of anti-platelet therapies targeting the enzyme in order to attenuate injury-induced clot formation, vessel occlusion and pathophysiological shifts in hemostasis.

Pulmonary hypertension (PH) is a sequel of a variety of cardiovascular and systemic diseases. Heterozygous mutation of BMPRII, a member of the TGFβ superfamily is the commonest genetic defect so far identified in PH. Recent advances have contributed a great deal to the understanding of the disease; however, the actual mechanism/s is not yet clear. Endothelial damage is the key underlying feature of PH. The main effects are loss of vascular relaxation response, increased cell proliferation and impaired apoptosis, matrix deposition, obstruction in the small pulmonary arteries, right ventricular hypertrophy; and eventually leading to right heart failure and death. The diagnosis of PH is often made late because of the insidious onset of symptoms, therefore the treatment poses a daunting challenge. Furthermore, depending on the underlying pathology, not all patients respond equally to same therapeutic agents. Current therapy includes a group of drugs mainly involved in improving vascular relaxation (cAMP and cGMP mechanisms) and endothelin receptor blockers alone or in combination. Newer drugs such as guanylate cyclase activators, PDGF blocker, RhoA/Rho kinase blockers have shown encouraging results in animal studies and in a few clinical cases of PH. Other drugs and signaling pathways such as nitrite, PPARγ, ACE2, ghrelin etc. are under investigation. Studies with gene therapy are being actively pursued. This review summarizes the available therapy and the future prospects.

Portal vein thrombosis (PVT) is a relatively common event in patients with advanced-stage liver cirrhosis, even in patients with a compensated disease. Because of the protean clinical manifestation of PVT, ranging from massive variceal bleeding and mesenteric infarction to the complete absence of any symptom, it is mandatory to provide an early diagnosis and a prompt management. However, even if various treatments have been tested in clinical studies, most of them can be suitable only for a limited number of patients and anticoagulants are recognized as the gold standard, even if the debate about their use in PVT management in cirrhotic patients is still opened. In particular, “old” and “new” generations of anticoagulants have always been used carefully and, sometimes, with skepticism or diffidence in cirrhotic patients. In this review, we report the rationale of anticoagulants use in PVT cirrhotic patients management, analyzing the most accepted controversies and certainties, with a particular attention to their possible role as preemptive therapy.

Chronic pressure overload and atherosclerosis are primary etiologic factors for cardiac hypertrophy and failure. However, mechanisms underlying the transition from hypertrophy to heart failure are incompletely understood. We analyzed the development of heart failure in mice with chronic pressure overload induced by aortic constriction and compared the results with aged apolipoprotein E-deficient mice suffering from advanced atherosclerosis. We combined cardiac function analysis by echocardiography and invasive hemodynamics with a comprehensive microarray gene expression study (GSE25765-8). The microarray data showed that the onset of heart failure induced by pressure overload or advanced atherosclerosis was accompanied by a strong up-regulation of key lipid metabolizing enzymes involved in fat synthesis, storage and oxidation. Cardiac lipid overload may be involved in the progression of heart failure by enhancing cardiomyocyte death. Up-regulation of the cardiac lipid metabolism was related to oxygen and ATP depletion of failing hearts because anti-ischemic treatment with ranolazine normalized the cardiac lipid metabolism and improved cardiac function. Vice versa, inhibition of cellular respiration and ATP generation by mild thiol-blocking with cystamine triggered the cardiac lipid metabolism and caused signs of heart failure. Cardiac tissue specimens of patients with heart failure also showed high protein levels of key fat metabolizing enzymes as well as lipid accumulation. Taken together, our data strongly indicate that up-regulation of the cardiac lipid metabolism and myocardial lipid overload are underlying the development of heart failure.