Cardiovascular & Haematological Disorders - Drug Targets - Volume 7, Issue 3, 2007

Heparin induced thrombocytopenia (HIT) in addition to bleeding complications are the most serious and dangerous side effects of heparin treatment. HIT remains the most common antibody-mediated, drug-induced thrombocytopenic disorder and a leading cause of morbidity and mortality. Two types of HIT are described: Type I is a transitory, slight and asymptomatic reduction of platelet count occurring during 1-2 days of therapy. HIT type II, which has an immunologic origin, is characterized by a thrombocytopenia that generally onset after the fifth day of therapy. Despite thrombocytopenia, haemorrhagic complications are very rare and HIT type II is characterized by thromboembolic complications consisting in venous and arterial thrombosis. The aim of this paper is to review new aspects of epidemiology, pathophysiology, clinical features, diagnosis and therapy of HIT type II. There is increasing evidence that platelet factor 4 (PF4) displaced from endothelial cells, heparan sulphate or directly from the platelets, binds to heparin molecule to form an immunogenic complex. The anti-heparin/PF4 IgG immune-complexes activates platelets through binding with the Fcγ RIIa (CD32) receptor inducing endothelial lesions with thrombocytopenia and thrombosis. Cytokines are generated during this process and inflammation could play an additional role in the pathogenesis of thromboembolic manifestations. The onset of HIT type II is independent from dosage, schedule, and route of administration of heparin. A platelet count must be carried out prior to heparin therapy. Starting from the fourth day, platelet count must be carried out daily or every two days for at least 20 days of any heparin therapy regardless of the route of the drug administration. Patients undergoing orthopaedic or cardiac surgery are at higher risk for HIT type II. The diagnosis of HIT type II should be formulated on basis of clinical criteria and confirmed by in vitro demonstration of heparin-dependent antibodies detected by functional and antigen methods. However, the introduction of sensitive ELISA tests to measure anti-heparin/PF4 antibodies has showed the immuno-conversion in an higher number of patients treated with heparin such as the incidence of anti-heparin/PF4 exceeds the incidence of the disease. If HIT type II is likely, heparin must be immediately discontinued, even in absence of certain diagnosis of HIT type II, and an alternative anticoagulant therapy must be started followed by oral dicumaroids, preferably after resolution of thrombocytopenia. Further studies are required in order to elucidate the pathogenetic mechanism of thrombosis and its relation with inflammation; on the other hand large clinical trials are needed to confirm the best therapeutic strategies for HIT Type II.

Due to its small size and amphiphilic nature, indoleamine melatonin is able to reach all cell compartments quickly. The highest Melatonin concentrations are to be found in the mitochondria, and cytochrome c (cyt c) represents a Melatonin target, since Melatonin is able to oxidise organic molecules in the presence of physiological amounts of hydrogen peroxide (H2O2). The mitochondrial cyt c-mediated oxidation of melatonin depends on oxoferrylheme in two oneelectron steps. The protective effects of Melatonin against cardiac ischemia/reperfusion (I/R)-induced mitochondrial oxidative damage are well documented as an antioxidant agent which prevents and/or modulates the production of reactive oxygen species (ROS) responsible for the reperfusion injury. On the basis of our previous studies on ischemia/reperfusion (I/R) in human cardiomyocytes it has become clear that severe hypoxic and ischemic stimuli evoke a mitochondrial response in terms of the functional adaptation of cyt c oxidase (COX) to oxygen altered availability. Most, if not all, data are compatible with a mechanism of adaptation, in which nitric oxide (NO) generation is now considered as the major player. The NO-induced COX inhibition represents a key point in ischemia-induced, adaptive changes, since a balanced oxidative metabolism between lower O2 concentrations and COX catalytic capacity down-regulation is thus obtained. This mechanism is a limiting factor in the cardiac ischemia-induced ROS mitochondrial generation. In the light of this concept and if we consider melatonin to be strongly active in cyt c up-regulation, it is obvious that the use of this molecule in the course of cardiac ischemia could be deleterious. On the contrary, the prompt restoration of the coronary blood flow is inexorably associated with the so-called “reperfusion syndrome” and/or with a condition of myocardial stunning. These phenomena are strictly linked to the aforementioned ischemia-induced cyt c adaptive changes, for the reason that a primary imbalance is induced between the persistent down-regulated enzymatic oxidative capacity and mitochondrial oxygen gradients are rapidly restored. This leads to a massive ROS neo-generation, which evokes well-known cellular disorders. In this scenario the melatonin treatment could play a pivotal role in terms of a cyt c up-regulating agent, crucial for counteracting most, if not all the biochemical and molecular phenomena, on which the clinical symptoms proper of myocardial reperfusion syndrome are based.

a) Objectives: Investigations of the four synthetic coumarin-related compounds: N' - allylthiouridine-3- carbamoil coumarin (GSH-16), N'- morpholylthiouridine-3-carbamoil coumarin (GSH-17), N'-O-fluor-benzyl-N'-3- carbamoil piperaside coumarin (GSH-10) and 6-nitroallylamide-3-carboxy coumarin (GSH-84), were done for study of their role in the processes of hemocoagulation. b) Design and Methods: Investigations were carried out on 120 white rats (180-200g), which were injected intravenously by 0.5 ml and 1.0 ml of 1 % solution of GSH-17 and decapitated after 10 and 30 min after the injection by use of light chloroform narcosis. Separation of the liver was done by simultaneous washing with cold physiological solution. c) Results: It was shown that the hemostabilization action of GSH-17 is highly dose- and time - dependent, with by the pronounced decrease of rat liver thromboplastic activity after 10 and especially 30 min following intravenous injection. d) Conclusion: One of the possible mechanisms for haemostatic effect of the studied preparations, particularly GSH-17, probably can be accepted their effect on metabolism of arachidonic acid by lipoxygenase and cycloxygenase mechanisms [9, 10].The results of this investigations have not only the academic interest, but they have also a significant importance for definite branches of practical medicine as a very effective blood stabilizing factors.

Hypertrophic cardiomyopathy (HCM) is a complex cardiac disease, relatively common among genetic disorders. The prevalence is about 1:500 in the general population. Obstructive type occurs in about 25% of the cases. The clinical course is heterogeneous due to the large variety of genetic-based phenotypes with different prognostic impact. Primary HCM is one of the most important causes of sudden death in young people and may be a medical problem in athletes with physiologic left ventricular hypertrophy. In the last decade, however, several studies reported normal longevity. Echocardiography has emerged as the most important noninvasive method to make diagnosis and provide classifications of the disease. In this commentary, some out of the most recent and sophisticated applications of this method in HCM are reported. The most common pathophysiologic aspects and a proposal of classification of the obstruction-causing mechanisms, like systolic anterior motion of the mitral valve, papillary hypertrophy and dislocation, chordal slack, mid-cavity obliteration, are described. Some recent studies on coronary blood flow velocity and coronary reserve, performed by sophisticated Doppler echocardiography, have demonstrated important pathophysiological insights on microcirculatory impairment in patients with HCM. At present, advanced echocardiography surely improves the clinical management of these patients, and contributes to optimize the therapeutic strategies. However, the most appropriate framework of tests to be performed in the majority of them still remains a challenging clinical matter.

The Na+/Ca2+ exchanger (NCX) is a bidirectional transporter that normally extrudes Ca2+ from the cell (forward mode), but also brings Ca2+ into the cell (reverse mode) under special conditions such as intracellular Na+ (Na+ i) accumulation or membrane depolarization. There are three mammalian NCX isoforms: NCX1 is widely expressed in the heart, kidney, brain, blood vessels, and so on; whereas the expression of NCX2 and NCX3 is limited mainly to the brain and skeletal muscle. The pharmacology of NCX inhibitors has been studied extensively since the development of KB-R7943, a prototype benzyloxyphenyl NCX inhibitor, in 1996. Currently, experiments are actively progressing with more selective inhibitors: SEA0400, SN-6, and YM-244769. Intriguingly, the inhibitory potency of benzyloxyphenyl NCX inhibitors is directly coupled to the rate of Na+ i-dependent inactivation. Therefore, the benzyloxyphenyl inhibitors are apparently dormant during the forward mode under normal conditions (low Na+ i), but become effective during the reverse mode under pathological conditions (high Na+ i). This should be an ideal profile for calcium regulators against Na+ i-related diseases, such as ischemia/reperfusion injuries, salt-dependent hypertension, and digitalis arrhythmia. Existing ion channel blockers, such as amiodarone, dronedarone, bepridil, aprindine, and cibenzoline, have been found to have an NCX inhibitory action. It is possible that this property is partly responsible for their antiarrhythmic and cardioprotective effects. This article presents the characteristics of selective and non-selective NCX inhibitors and their therapeutic potential as a new calcium regulator.

Human cases due to Salmonella enterica subsp. arizonae are especially rare, but it may affect immunocompromised patients and infants. We present a case of endocarditis in a patient with sickle cell disease and a review of earlier cases caused by this rare human pathogen. The patient was successfully treated with ceftriaxone and ciprofloxacin. There are only few cases of salmonella endocarditis reported in the last six decades and it is the first case of Salmonella enterica subsp. arizonae endocarditis in the literature to the best of our knowledge.

The endoplasmic reticulum (ER) is a multifunctional organelle responsible for the synthesis and folding of proteins as well as calcium storage and signaling. Perturbations of ER function cause ER stress leading to the unfolded protein response (UPR), which includes inhibition of protein synthesis, protein refolding and clearance of misfolded proteins. The UPR aims at restoring cellular homeostasis, however, prolonged ER stress can trigger apoptosis. ER stress-induced apoptosis has been implicated in the pathogenesis of various diseases such as brain ischemia/reperfusion, neurodegeneration, diabetes and, most recently, myocardial infarction and heart failure. Initial events leading to UPR and apoptosis in the heart include protein oxidation and disturbed calcium handling upon ischemia/reperfusion, and forced protein synthesis during cardiac hypertrophy. While XBP-1 and ATF6-mediated induction of ER chaperones seems to protect the heart from ischemia/reperfusion injury, the PERK/ATF4/CHOP branch of the UPR might transmit proapoptotic signals. The precise mechanism of ER stress-induced cardiomyocyte apoptosis remains elusive, however, recent data suggest that the mitochondrial apoptotic machinery is recruited through the upregulation of Puma, a proapoptotic member of the Bcl-2 family. Importantly, suppression of Puma activity prevented both ER stress and ischemia/reperfusion-induced cardiomyocyte loss, highlighting the ER stress pathways as potential therapeutic targets in cardiovascular diseases.

Primary chronic cold agglutinin disease (CAD) is an autoimmune hemolytic anemia induced by cold reactive autoantibodies (cold agglutinins) against erythrocyte surface antigens. Corticosteroids or alkylating agents have been used in the treatment of CAD, but the results have been disappointing. The cold agglutinins in CAD patients are monoclonal immunoglobulins, usually of the IgMκ type encoded by the VH4-34 gene segment. Flowcytometric assessment of lymphocytes from bone marrow aspirates and immunohistochemical assessment of biopsy samples have revealed a monoclonal CD20+κ+ B lymphocyte population in 90% of the patients. These pathogenetic features have provided a basis for novel therapies in primary CAD. Infusions of rituximab, a chimeric human-murine anti-CD20 antibody known to be effective in B-cell lymphoma, produced partial response rates of approximately 50% and occasional complete responses. Median response duration, however, was only 11 months. Complement C3 and C4 depletion in many CAD patients, as well as Fcγ-RIIIa receptor polymorphism, have been proposed as explanations for the inconstant efficacy of rituximab therapy. In order to increase response rates and response duration, we are undertaking a phase 2 study of rituximab and fludarabine combination therapy. The preliminary results are encouraging, but further studies are required in order to allow firm conclusions.