Cardiovascular & Hematological Agents in Medicinal Chemistry - Volume 8, Issue 4, 2010

Apart from nitric oxide (NO) and carbon monoxide (CO), hydrogen sulfide (H2S) is the third gaseous mediator in mammals. H2S is synthesized from L-cysteine by cystathionine β -synthase (CBS), cystathionine γ -lyase (CSE), or by sequential action of alanine aminotransferase and 3-mercaptopyruvate sulfurtransferase. In the cardiovascular system, H2S is involved in the regulation of vascular tone and blood pressure, inhibits atherogenesis, and protects myocardium from ischemia-reperfusion injury. Recently, the first organic, water-soluble H2S donor, GYY4137, has been synthesized. In addition, H2S-releasing derivatives of several currently used drugs such as sildenafil, diclofenac, aspirin and mesalamine were obtained. Such compounds may be used in the future treatment of cardiovascular diseases. In this article, we describe the role of H2S in the regulation of blood pressure and in the pathogenesis of arterial hypertension and atherosclerosis which are two most common cardiovascular disorders.

Myelodysplastic syndromes (MDS) are acquired hematopoietic stem cell disorders characterized by ineffective hematopoiesis, cellular dysfunction and increased risks of transformation into acute myeloid leukemia.The natural history of the disease remains variable and depends upon multiple prognostic factors at the time of initial diagnosis. The current prognostic models are helpful to determine the outcome of individual patients but they remain imperfect. Earlier, the most frequent treatment given for patients with MDS was supportive with transfusion of blood products and administration of erythropoietic stimulating agents and iron chelation therapy. Now, there is an arsenal of therapies available and the landscape for the treatment of MDS is rapidly evolving. There are several FDA approved therapies available for this disorder that makes this review particularly timely and relevant.

Bivalirudin, a DTI, has evolved from relative obscurity as an anticoagulation option in patients resistant to or allergic to either LMWH or UFH to a commonly used, safe alternative. Most of the early studies comparing bivalirudin to UFH with or without a GP IIb/IIIa agent had composite endpoints (death, MI, bleeding) whose statistical significance were driven exclusively by a significant reduction in bleeding. Newer studies now demonstrate reductions in mortality, which has led to a paradigm shift in anticoagulant choice both in elective and emergent coronary procedures. We present the major studies that have brought bivalirudin to the forefront of coronary artery disease, specifically coronary interventional procedures.

Normal pregnancy is associated with significant hemodynamic changes and vasodilation of the uterine and systemic circulation in order to meet the metabolic demands of the mother and developing fetus. Preeclampsia (PE) is one of the foremost complications of pregnancy and a major cause of maternal and fetal mortality. The pathophysiological mechanisms of PE have been elusive, but some parts of the puzzle have begun to unravel. Genetic factors such as leptin gene polymorphism, environmental and dietary factors such as Ca2+ and vitamin D deficiency, and co-morbidities such as obesity and diabetes may increase the susceptibility of pregnant women to develop PE. An altered maternal immune response may also play a role in the development of PE. Although the pathophysiology of PE is unclear, most studies have implicated inadequate invasion of cytotrophoblasts into the uterine artery, leading to reduced uteroplacental perfusion pressure (RUPP) and placental ischemia/hypoxia. Placental ischemia induces the release of biologically active factors such as growth factor inhibitors, anti-angiogenic factors, inflammatory cytokines, reactive oxygen species, hypoxiainducible factors, and antibodies to vascular angiotensin II (AngII) receptor. These bioactive factors could cause vascular endotheliosis and consequent increase in vascular resistance and blood pressure, as well as glomerular endotheliosis with consequent proteinuria. The PE-associated vascular endotheliosis could be manifested as decreased vasodilator mediators such as nitric oxide, prostacyclin and hyperpolarizing factor and increased vasoconstrictor mediators such as endothelin-1, AngII and thromboxane A2. PE could also involve enhanced mechanisms of vascular smooth muscle contraction including intracellular Ca2+, and Ca2+ sensitization pathways such as protein kinase C and Rho-kinase. PE-associated changes in the extracellular matrix composition and matrix metalloproteinases activity also promote vascular remodeling and further vasoconstriction in the uterine and systemic circulation. Some of these biologically active factors and vascular mediators have been proposed as biomarkers for early prediction or diagnosis of PE, and as potential targets for prevention or treatment of the disease.

In the last decade several attempts have been made to achieve the goal of cardiac regeneration after myocardial infarction. To date, two cell types have completed phase-III clinical trials: Skeletal Myoblasts and Bone-Marrow Mononuclear Cells (BM-MNCs). In the first case, all benefits have been limited by an increased risk of arrhythmia. In the case of BM-cells, most studies showed a significant, although limited, advantage in the cell-treated group. This may be due to the choice of the wrong BM cell type: other candidates would be e.g. CD34+ HSCs, or non-hematopoietic Mesenchymal Stem Cells. After positive results from the experimental studies, phase I/II clinical trials are currently on-going for both. Ideally, the best cell to use to regenerate the heart would be a precursor of all cardiac lineages; until the isolation and expansion of Cardiac Stem Cells (CSCs), such a cell was thought to exist only during embryogenesis. Using CSCs researchers managed to generate electrically-coupled contractile tissue within the infarct of animal models. Still, some doubts persist over the possibility to translate such results in real-life patients. Another approach, therefore, involves the use of induced Pluripotent Stem Cells (iPS) obtained from fibroblasts after genetic reprogramming. This new type of cell would combine the pluripotency of embryonal stem cells with the advantages of an autologous use. Nevertheless, iPS cells form teratomas, and their effective differentiation in vivo is largely unknown. This review will critically compare the data from the Literature concerning cell therapy after myocardial infarction. Can we name the best cell?