Cardiovascular & Haematological Disorders - Drug Targets - Volume 18, Issue 3, 2018

Background: Cardiovascular Disease (CVD) is the leading cause of mortality and morbidity worldwide. Four out of five CVD deaths are due to myocardial infarction or stroke. Despite many initiatives that have been established for CVD prevention and risk management, and new therapies to treat existing CVD, patients continue to die from cardiac events. Clearly, we need to identify new therapeutic targets and strategies. Metabolomics offers a novel solution to this problem, as metabolomics-based biomarkers do not only indicate the presence or absence of a disease, but are also capable of assessing risks of developing the disease and detecting the disease prior to the appearance of overt clinical symptoms. Method: In this review, we describe the analytical techniques and workflow used in untargeted metabolomics. We also identify several case studies that highlight the use of untargeted metabolomics in cardiovascular research. Results: Five case studies that employ untargeted metabolomics approaches to identify biomarkers for cardiovascular risk, myocardial ischemia, transient ischemic attack, incident coronary heart disease, and myocardial infarction risk prediction are described. The use of the untargeted metabolomics is still relatively new in cardiovascular research. As such, there remains a need for future advancement in metabolomic technologies. Conclusion: Early diagnosis of CVDs and identification of patients at high risk of developing adverse events would allow for timely intervention that prevents serious consequences or death. There is a need to establish sensitive and non-invasive CV biomarkers, and novel therapeutic targets for the prevention and treatment of CVDs.

Background and Objective: ADAMTS13 (A Disintegrin-like and Metalloproteases with Thrombospondin type-1 repeats, member-13) plays an important role in vascular hemostasis by cleaving the von Willebrand Factor (vWF). ADAMTS13 and vWF are involved in the development of ischemic heart disease. In this review paper, we examine the effects of Single Nucleotide Polymorphisms (SNPs) and mutations in the vWF and ADAMTS13 genes and their contribution to the development of thrombosis. Methods: Relevant English-language literature was searched and retrieved from PubMed search engine (2001-2017). The following keywords were used: “ADAMTS13”, “vWF”, “Polymorphism”, and Thrombosis”. Results: SNPs in the ADAMTS13 and vWF genes cause genetic variability and affect the plasma levels of these genes. Moreover, environmental (such as age, smoking, hypertension) and genetic factors (like ABO blood groups) play a role in the development of different polymorphisms in ADAMTS13 and vWF genes. Conclusion: The increased or decreased activity of these two genes as a result of genetic changes and the development of thrombosis are a challenging and contradictory matter, and the study of genetic variability in ADAMTS13 and vWF genes may be helpful in the diagnosis of thrombotic disorders.

Introduction: Adult People With Hemophilia (PWH) mainly use Factor VIII/Factor IX (FVIII/FIX) to lessen chronic articular pain, followed in frequency by nonsteroidal antiinflammatory drugs. Analgesics are used by only one-third of adult PWH. Limitations in activities of daily living are encountered in the large majority of PWH, and most describe pain as affecting their state of mind. A review of the literature on their treatment is important because the chronic pain in adult PWH is often undertreated or wrongly treated, causing psychological problems for these patients. Aim: To determine the optimal treatment for chronic articular pain in adult PWH. Methods: A review of the literature has been performed. Results: There are three main strategies to alleviate chronic pain secondary to hemophilic arthropathy: pharmacologic treatment (including intra-articular injections of corticosteroids and hyaluronic acid), physical medicine and rehabilitation. Pharmacologic treatment of chronic articular pain is inadequate in many PWH. The optimal pharmacologic treatment for chronic articular pain in these patients is paracetamol and COX-2 inhibitors (celecoxib and rofecoxib). Intra-articular injections of hyaluronic acid and corticosteroids should be second-line therapy. Conclusion: Most adult PWH experience limitations in activities of daily living, and chronic articular pain affects their mental health. Pharmacologic treatment of pain in adult PWH has frequently proven to be inadequate. The optimal pharmacologic treatment of chronic articular pain in these patients is the use of paracetamol and COX-2 inhibitors. Physical medicine, rehabilitation and intra-articular injections of hyaluronic acid and corticosteroids should be second-line therapy.

The effects of hypoxia on the human organism has been considered doubly fascinating by the scientific community. The knowledge of the discrete mechanisms allowing the acclimatization both at genetic level or through the cell mediators production in addition to the macroscopic responses of the cardio-circulatory and ventilatory systems to a hypoxic environment has been progressively developed since the last century; moreover granting a safer stay in hypoxic conditions not only for the residents but also for the different cathegories of workers, sportsmen and tourists has been considered a worthy aim of the medical activity. The effects of hypoxia were simulated in laboratory by means of an induced low pressure environment (normobaric hypoxia) or tested on the subjects at different levels of altitude (hypobaric hypoxia). Far from describing all the physiological and pathological responses of the organism, in this review, the authors expose the state of the art in the knowledge of the responsiveness of the pulmonary circle to the acute or chronic hypoxic condition, its possible progression to the pulmonary arterial hypertension, the latter being more appropriately named High-Altitude Pulmonary Hypertension. The currently available therapeutic options in the treatment of High-Altitude Pulmonary Hypertension are also reviewed.

Background & Objective: Acute Myeloid Leukemia (AML) is characterized by the accumulation of ≥20% myeloid premature blast cells in the bone marrow and they are most often found in the peripheral blood. AML is generally classified based on either French-American-British (FAB) or World Health Organization (WHO) systems. For better clinical management, cytogenetic finding in AML is necessary and in patients with normal karyotypes - molecular, epigenetic and proteomic biomarkers are very important in choosing which drugs to prescribe. Mutations of certain genes like NPM1, FLT3, CEBPA, RUNX1 and MLL play a crucial role in the risk management and clinical stratification of AML patients. We reviewed the literature for the current trends of clinical practice based on laboratory based diagnostic tests in AML. Outcome and Result: We listed in AML chromosomal aberrations (translocations, fusions or RUNX1, CBFB, MYHI1, MLL, EVI1, PML-RARA), genes and mutations (NPM1, FLT3, CEPBA, MLL) epigenetic factors (DNMT34, TET2) and proteomic biomarkers (PTP, PTK, PIP) and analysed how on the basis of these factors medical risk was stratified and accordingly managed. Conclusion: AML is genetically and functionally a heterogenous malignant disease. In the western world, leukemia is one of the most common among all cancers. India is ranked 3rd in cancer disease after United States of America and China. Cytogenetic analysis, molecular/proteomic biomarkers and epigenetic factors assist in determining the management strategies and prognosis of the disease. A number of targeted drugs in pre-clinical and clinical trials based on molecular factors and epigenetic mechanisms have been reported to have promising results in AML patients.

Introduction: In coronary bypass surgery, after cardiopulmonary bypass is initiated by arterial cannulation in the ascending aorta and venous cannulation through a single vein generally in the right atrium, the process of cooling the patient is started. Objective: There is a relation between cooling the patient and irisin, which is responsible for releasing heat. Therefore, the main objective of the present study is to explore how irisin concentrations and some other panel of myocardium injury in patients undergoing coronary artery bypass surgery. Methods: The blood samples collected before induction (T1), before bypass (T2), before (T3) and after (T4) removing the cross-clamp, upon admission to intensive care (T5), and at the postoperative 24 (T6) and 72 (T7) hours, and whether these concentrations are correlated with lactate levels classically used in monitoring this surgery. A total of biological samples, 23 from control individuals and 105 from bypass patients (14-16 samples for each timeframe) were analyzed to determine irisin, CK-MB, TnT and BNP levels by ELISA and lactate levels by lactate assay kit. Both lactate and irisin were seen to increase gradually from the time of induction to the removal of the cross-clamp. After the cross-clamp was removed and the patient was started to be warmed, both parameters began to decrease gradually and were restored to normal levels on the second and third post-operative days. The increase and decrease in irisin were found correlated with lactate levels. CK-MB, TnT and BNP alteration were similar to each other. Results: Based on these results, it is estimated that measurement of irisin along with lactate may prove to be a useful parameter in monitoring the coronary bypass surgery and irisin may be a significant marker of hypothermia. Beside CK-MB, TnT and BNP, measurements of irisin concentration in open heart surgery may also be useful parameters for the panel of myocardium injury.

Background: Transient Receptor Potential Vanilloid 1 (TRPV1) channels in sensory nerves have anti-oxidative properties and counteract obesity and diabetes that are associated with diastolic dysfunction with preserved ejection fraction. We tested the hypothesis that TRPV1 knockout exacerbates high-fat diet (HFD)-induced glucose intolerance and diastolic dysfunction. Method: Trpv1-/- and wild-type (WT) mice were fed chow diet or HFD for 20 weeks. Then, we performed the intraperitoneal glucose tolerance test, measured the heart function through transthoracic echocardiography and Langendorff heart perfusion system, analyzed cardiac histology, and measured the myocardial superoxide production and the expression of nicotinamide adenine dinucleotide phosphate (NADPH) oxidases. Results: HFD increased body weight, heart weight, and levels of fasting glucose, insulin, and leptin in both strains, with no differences between two strains. HFD impaired glucose tolerance in both strains with a more profound effect on Trpv1-/- than WT mice. HFD increased left ventricular (LV) internal diameter in diastole in both strains, while increased LV posterior wall thickness in diastole in Trpv1-/- but not in WT mice. HFD increased LV end-diastolic pressure in both strains with a further increase in Trpv1-/- mice, while decreased -dP/dt in Trpv1-/- but not in WT mice. HFDinduced cardiac collagen deposition and superoxide production were enhanced in Trpv1-/- mice. HFD upregulated cardiac p22phox in both strains, while increased p47phox in Trpv1-/- but not in WT mice. Conclusion: In summary, TRPV1 knockout exacerbates HFD-induced glucose intolerance, cardiac oxidative stress and collagen deposition, leading to aggravated LV diastolic dysfunction.

Background: Previous studies have shown that metabolism of adenosine 5'-triphosphate (ATP) in systemic blood is a potential surrogate biomarker for cardiovascular toxicity. Objective: To investigate the acute effect of high dose of doxorubicin (DOX) on adenosine and ATP catabolism in systemic blood in vivo. Method: Sprague Dawley (SD) rats were each given either 10 mg/kg of DOX (n = 8) or normal saline (1 mL/kg, n = 11) twice daily for 4 doses by subcutaneous (sc) injection. Blood samples were collected sequentially for up to 6 hours for measuring circulating concentrations of ATP, adenosine and their metabolites. Hemodynmic recording was obtained continuously after the last injection. The difference in response between groups was considered significant at p < 0.05 (t-test). Results: Diastolic blood pressure (DBP) was significantly lower in the DOX treated rats than in the control before the final injection (87 ± 12 vs. 104 ± 11 mmHg, p < 0.05). Blood pressure fell gradually after the last injection and the decrease was significantly greater in the DOX treated group (p < 0.05). Plasma concentration of adenosine was significantly lower in the DOX treated group. In contrast, plasma concentrations of uric acid and hypoxanthine, as well as Red Blood Cell (RBC) concentrations of AMP, were significantly higher (p < 0.05). Conclusion: Acute cardiotoxicity induced by DOX may be measured by the increased breakdown of ATP to AMP in the RBC and also breakdown of adenosine to hypoxanthine and uric acid in plasma.

Background: In exploring the cause of Imatinib Mesylate (IM) resistance among Chronic Myeloid Leukemia (CML) patients who do not harbor BCR-ABL dependent mechanism, BCR-ABL independent pathways are the most probable pathways that should be explored. In BCR-ABL independent pathway, SOCS1 plays an important role as it helps in regulating optimal JAK/STAT activity. Objective: To identify the association of SOCS1 gene hypermethylation in mediating IM Resistance. Method: The SOCS1 promoter methylation level of 92 BCR-ABL non mutated IM resistant CML patients, 83 IM good response CML patients and 5 normal samples from healthy individuals were measured using Methylation Specific-High Resolution Melt (MS-HRM) analysis. Results: Both primers used to amplify promoter region from -333 to -223 and from -332 to -188 showed less than 10% methylation in all CML and normal samples. Consequently, there was no significant difference in SOCS1 promoter methylation level between IM resistant and IM good response patients. Conclusion: SOCS1 promoter methylation level is not suitable to be used as one of the biomarkers for predicting the possibility of acquiring resistance among CML patients treated with IM.

Introduction: Buxus sempervirens L. is used in Morocco as a plant with some medicinal properties including treatment of diabetes and cardiovascular diseases. Methods: The objective of the study was to assess the effect of the aqueous extract of Buxus sempervirens L. (Boxwood) leaves on the blood lipid parameters including total cholesterol, triglycerides, High-Density Lipoprotein Cholesterol (HDL-C), Low-Density Lipoprotein Cholesterol (LDL-C) and Very Low-Density Lipoprotein Cholesterol (VLDL-C) in normal and streptozotocininduced diabetic rats. In addition, antioxidant activity of aqueous Buxus sempervirens extract was evaluated by DPPH and FRAP assays. Results: The results indicated a significant decrease in serum total cholesterol and LDL-C levels, while, no change was observed on triglycerides and VLDL-C values in diabetic rats. Lipid profile of normal animals did not reveal any modification. In addition the aqueous extract of Buxus sempervirens exerted a significant antioxidant activity. Therefore, the results suggest that the aqueous extract of Buxus sempervirens exhibits lipid lowering activity which could be due partially to its antioxidant ability. Conclusion: In conclusion, Buxus sempervirens leaf extract may be helpful in controlling the development of hyperlipidemia as well as atherosclerosis in diabetic animals.