Cardiovascular & Haematological Disorders - Drug Targets - Volume 12, Issue 1, 2012

Atrial fibrillation (AF) is a common arrhythmia in clinical practice. An important component of the management of patients with AF involves prevention of thromboembolism and stroke. Coumarins, such as warfarin had been the only available oral antithrombotic agent for prevention of thromboembolism for many decades. Following intestinal absorption, coumarins inhibit multiple steps of the clotting cascade that leads to inhibition of coagulation factors II, VII, IX and X. In addition to delayed and variable inhibition of coagulation, coumarin therapy has a narrow therapeutic window for optimal balance of risk and benefit, which requires regular assessment of the international normalized ratio (INR) to monitor coagulation. A quest for safer, more effective therapies that do not need monitoring has led to the development of dabigatran, rivaroxaban, and apixaban. In this article, we review these newer antithrombotic agents and discuss role of these drugs in clinical practice.

Primary myelofibrosis is a clonal hematopoietic disorder characterized by ineffective hematopoiesis and progressive bone marrow fibrosis. Patients with high risk myelofibrosis as determined by their advanced age, degree of anemia, leukocytosis, constitutional symptoms and high percentage of circulating blasts have a very short median survival of 2 years. In addition quality of life is significantly compromised due to cytokine induced constitutional symptoms, frequent transfusion for cytopenias and bulky splenomegaly. Progression to myelogenous leukemia occurs in about 20% of patients within 10 years of diagnosis and is often fatal. Allogeneic hematopoietic transplantation is the only curative therapy but is limited by patient eligibility, transplant related mortality and graft versus host disease. Androgens, erythropoietin analogues, hydroxyurea, alkylators and spleen directed therapies have all been used with limited efficacy and no curative potential. The discovery of mutations in the hematopoietic progenitors of patients with myelofibrosis, including the JAK2 V617F mutation and others has greatly improved our understanding of the disease and facilitated development of newer targeted therapies. Our article will review new discoveries in the pathogenesis of myelofibrosis and focus on emerging targeted treatments. These novel therapies including oral JAK2 inhibitors, immunomodulators, as well as inhibitors of HDAC and mTOR, in isolation and in combination are likely to improve outcomes in management of this disease.

Patients can develop malignancies due to various reasons including genetic factors, chemical carcinogens, radiation, and defects in their immune system. The immune system is postulated to carry out routine surveillance for malignancy. Patients who have defective immune responses may be susceptible to malignancies due to complicated underlying mechanisms. These include defective immune response to cancer-causing bacteria, transforming viruses, and concomitant molecular, cellular and immunoregulatory defects. Common variable immune deficiency (CVID) is characterized by hypogammaglobulinemia, impaired antibody responses and an increased susceptibility to infections. A disorderly immune response, or immune dysregulation, may also lead to autoimmune complications and possibly to malignancy. The treatment of CVID involves infusion of replacement doses of immunoglobulin, either intravenously (IGIV) or subcutaneously (SCIG). However, it is unclear whether adequate replacement of immunoglobulins is sufficient to prevent the increased risk of malignancy seen in this disease. We present two cases of unusual solid tumors complicating CVID treated with adequate doses of intravenous immunoglobulins. In this study we review the occurrence of malignancy in patients with CVID and postulate mechanisms that may be involved indigent to this disease. We will also review the role of replacement immunoglobulin and discuss cancer screening in these high risk individuals.

High-density lipoproteins (HDL) are small particles comprised of phospholipids and stabilizing proteins, which carry cholesterol and triglycerides in the blood stream. The incidence of cardiovascular events is high in patients with low level of HDL-cholesterol (HDL-C). In the present study, we defined The PH index [Δcoronary plaque volume/ΔHDL-C] index as a putative clinical index of cholesterol efflux capacity of HDL from atheromatous plaque. The present study investigated the PH index in response to treatment with different types of HMG-CoA reductase inhibitors (statins), in contrast to similar changes in the PL index [Δcoronary plaque volume/Δlow-density lipoprotein-cholesterol (LDL-C)] by the same statins. Using the 2000-2011 PubMed database, the search keywords were “statins” and “intravascular ultrasound (IVUS)” and “plaque volume”. Cross references were checked. PubMed search identified 29 references, and finally 4 published studies were selected for data analysis. The PL index, representing the change in plaque volume induced by 1% reduction in LDL-C, showed no difference among the different statins. On the other hand, the PH index, representing the change in plaque volume induced by 1% increase in HDL-C, showed wide variability among the different statins; 1.4 by atorvastatin, 1.0 by pravastatin, -0.1 by simvastatin, -0.2 or -0.5 by rosuvastatin, and -1.8 by pitavastatin. In conclusion, the best coronary plaque regression index attributed to HDL-cholesterol elevation (PH index) was found in pitavastatin treatment, in comparison with the other 4 statins (atorvastatin, pravastatin, simvastatin, rosuvastatin) investigated in the articles scanned by their search.

Statins are relevant drugs involved in the reduction of cardiovascular events both in primary and secondary prevention. Related muscular side-effects are the most common cause of withdrawal and statins discontinuation could induce a negative rebound effect in terms of vascular events. Among factors in association with statins side-effects the combination with other drugs and the female sex are established conditions. However recent data suggest a specific genetic influence in intolerance development, at least for some statins. Indeed a genome-wide study in patients treated with simvastatin found an impressive association between single-nucleotide polymorphisms (SNPs) located within SLCO1B1 gene on chromosome 12 and established myopathy. Furthermore, the association between the SLCO1B1*5 variant and side-effects was found also in patients treated with atorvastatin but not, apparently, with pravastatin and categorized as carriers of mild-myopathy. Recently a similar evidence has been suggested in type 2 diabetic patients treated mainly with simvastatin. However another relevant issue is that, apart from genetic influence in liver transporters influencing drug levels, the complexity of mechanisms involved in the muscular side effects of statins has been addressed by the evidence of other influencing pathways such as the variant within the COQ2 gene involved in Coenzyme Q10 mildasymptomatic deficiency and skeletal muscle drug transporters expression. In conclusion, the picture of putative pharmacogenetic modulation of statins safety is reaching a growing body of evidence for translation into clinical practice but more specific studies for each single statin, in different clinical settings, both from genome-wide or competitive candidate genes evaluation, are needed before describing a definitive class-risk profile.

Background: Although treatment of prehypertensives is feasible and effective, it is unclear how to define those who may benefit. We hypothesized that ambulatory blood pressure monitoring (ABPM) might be a tool for selecting prehypertensive subjects, classified according to the JNC 7, who later develop drug-treated hypertension. Methods: Prehypertensives (n=107; 62 M, 45 F; age 50±14 years) with or without cardiovascular risk factors were assessed for drug-treated hypertension development. They underwent ABPM at entry examination and were clinically followed-up for an average of 99±42 months. Thereafter, subjects were divided into 2 groups according to the development of drug-treated hypertension. Stepwise logistic regression (LR) analysis was performed to assess the role of factors contributing independent prediction of outcome (i.e. drug-treated hypertension onset). Results: In LR analysis body mass index [odds ratio (OR)=1.29, confidence intervals (CI)95% 1.03-1.62], female gender (OR=11.10, CI95% 2.66-46.30), total cholesterol (OR=1.03, CI95% 1.01-1.05), smoking (OR=3.90, CI95% 0.94-16.20), daytime SBP (OR=1.10, CI95% 1.01-1.19) and 24h DBP (OR=1.23, CI95% 1.08-1.41) predicted the development of hypertension. The criteria combining BP and clinical variables were superior to BP or clinical criteria alone in the correct classification of true positives and true negatives. Altogether there was an improvement of 14.02% (p<0.01) in comparison to only clinical criteria. Conclusions: In the setting of global cardiovascular risk assessment, ABPM, in the early diagnosis of hypertension in prehypertensive individuals, appears as a useful tool, both diagnostically and prognostically, to index subjects who are suspected to be masked hypertensives.

Increased myocardial collagen accumulation is present in almost every cardiac disease and plays an important role in the reduced heart function. N-terminal and C-terminal propeptides of collagen type I and III, the two major collagen types in the heart, can be assayed in serum.These propeptides (PINP, PIIINP, PICP, ICTP) reflect collagen synthesis and degradation. The use of these serum collagen biomarkers as prognostic or diagnostic tools is an area of active investigation. In this review article these studies will be discussed as well as the limitations of these serum biomarkers as indicators of cardiac fibrosis.

The purpose of this study was to evaluate the efficacy and safety of Cilnidipine tablets to treat Chinese patients with mild to moderate essential hypertension, and to examine the ability of Cilnidipine to lower blood pressure without eliciting unfavorable side effects. Medical databases and review articles were screened for randomized controlled trials that reported the effects of and adverse reactions to Cilnidipine and Amlodipine in treating Chinese patients with mild to moderate essential hypertension. The quality of the included studies was critically evaluated. A total of 547 articles were found, from which 11 articles met the inclusion criteria. The heterogeneity test, the efficacy analysis (Q statistic = 4.62, p = 0.91, I2 = 0%) and safety analysis (Q statistic = 3.73, p = 0.93, I2 = 0%) showed that Cilnidipine was equally effective and safe compared to Amlodipine. The funnel-plot displayed a symmetrical figure, indicating there was no publication bias, and all articles included described high quality trials. In conclusion, Cilnidipine is a useful agent to treat mild to moderate essential hypertension in China.

The effect of nicotine on membrane alterations and fluidity changes in very young models remains unclear. The aim of this study was to evaluate the effect of nicotine on total ATPase, H2O2 and calcium in brain of young rats in the presence of oligoelements. Male Wistar rats (weight 80g) received intraperitoneally either a single dose or repeated doses for 4 days as follows: Group 1 (control) NaCl 0.9%; group 2 nicotine (1mg/kg); group 3 oligoelements (50μl); and group 4 nicotine (1mg/kg) + oligoelements (50μl). The brain regions (cortex, hemispheres and cerebellum + medulla oblongata) of each rat were then obtained to measure the concentrations of total ATPase, H2O2 and calcium using spectrophotometric methods. Results: Total ATPase increased significantly (p<0.05) in groups treated with oligoelements in repeated doses in hemisphere region, and in groups that received oligoelements + nicotine in single or repeated doses in medulla oblongata. Catalase showed significant decreased in cerebellum/medulla oblongata. Results suggest that nicotine induces changes in membrane fluidity in brain of young rats, and that ATPase could be a biomarker of nicotine consumption in young subjects.

Vascular restenosis is affecting 30-40% of patients treated by percutaneous coronary angioplasty (PTCA). The advent of stenting reduced but not abolished restenosis. The introduction of drug eluting stent (DES) further reduced restenosis, but impaired endothelization exposed to intracoronary thrombosis as late adverse event. It is widely accepted that the endothelial denudation and coronary wall damages expose Vascular Smooth Muscle Cells (VSMC) to multiple growth factors and plasma circulating agents thus activating migration and proliferative pathways leading to restenosis. Among the major players of this processes, phosphorylated Elk-1, forming the Elk-1/SRF transcription complex, controls the expression of a different set of genes responsible for cell proliferation. Therefore, it is feasible that gene-specific oligonucleotide therapy targeting VSMC migration and proliferation genes can be a promising therapeutic approach. While a plethora of vehicles is suitably working in static in vitro cultures, methods for in vivo delivery of oligonucleotides are still under investigation. Recently, we have patented a novel erythrocyte-based drug delivery system with high capability to fuse with targeted cells thus improving drug bioavailability at the site of action. Here, the potential of these engineered porcine erythrocytes to deliver a synthetic DNA Elk-1 decoy inside syngenic porcine VSMC was tested. The results of this study indicate that Elk-1 decoy is actually able to inhibit cell proliferation and migration of VSMC. Our data also suggest that erythrocyte-based carriers are more efficient in delivering these oligonucleotides in comparison to conventional vehicles. As a consequence, a lower dose of Elk-1 decoy, delivered by engineered erythrocytes, was sufficient to inhibit cell growth and migration. This approach represents the translational step to reach in vivo experiments in pigs after PTCA and/or stent implantation where oligonucleotide drugs will be site-specific administered by using erythrocyte-based carriers to prevent restenosis.

We reviewed this subject in 2009, pointing out that, to the process of atherothrombosis, glycocalyx dysfunction and damage must be added to the previous known causitive factors. Glycocalyx dysfunction is possibly the very first step in the process of atherothrombosis, being a protective layer between the endothelial cells and the blood. We emphasise the unique feature of glycocalyx mediated vasodilatation in that it is initiated purely by mechanical changes, i.e., changes in vascular wall shear stress, allowing conduit arteries to adjust diameter to demanded blood flow rate. The predeliction of atheroma to sites of low shear stress, the inhibition of the shear response by lumenal hyperglycaemia, and the fact that the response is mediated by nitric oxide (NO), an anti-atheromatous agent has led to the hypothesis that impairment of this pathway is pro-atherogenic. In the microcirculation it has been shown that the glycocalyx must be added to the factors involved in the Starling hypothesis of tissue fluid generation and exchange. As a consequence glycoalyx dysfunction in hyperglycaemia has been postulated to cause oedema and microalbinuria. We suggested that perhaps the arterial glycocalyx will become the most important for future early prevention of people at risk of cardiovascular disease. The advances in this subject since 2009 are the subject of the present review. What has struck us when searching the literature is that research into the glycocalyx has increased very much and now comes from many disciplines; e.g., diabetes, hypertension, bioengineering, physiology, critical care, cardiology, shock. This update is by no means exhaustive, but hopes, again, to bring to the attention of the pharmaceutical industry, the need for grants in the appropriate experimental models.