Cardiovascular & Haematological Disorders - Drug Targets - Volume 19, Issue 3, 2019

Background: Curcumin is the one of the main phenolic ingredients in curcuma species rhizome. Curcuma species have traditionally been used for the treatment of diabetes, cardiovascular, and renal diseases. Methods: The present study was designed to review the scientific literature on the protective effects of curcumin against nephrotoxic agents. Results: Studies have shown the protective effects of curcumin against nephrotoxic agents such as gallic acid, glucose, tartrazine, streptozotocin, lead, cadmium, fluoride, maleate, malathion, nicotine, cisplatin, gentamicin, and methotrexate. However, further investigations are needed to determine the efficacy of curcumin as an antidote agent due to the lack of clinical trial studies. Therefore, it is recommended to conduct clinical trials in humans to confirm these effects. Conclusion: The current review indicated that curcumin may be effective against nephrotoxicity by modulating oxidative stress and inflammatory responses.

Atrial fibrillation (AF) is the most frequent arrhythmogenic disease in humans, ranging from 2% in the general population and rising up to 10-12% in 80+ years. Genetic analyses of AF familiar cases have identified a series of point mutations in distinct ion channels, supporting a causative link. However, these genetic defects only explain a minority of AF patients. Genomewide association studies identified single nucleotide polymorphisms (SNPs), close to PITX2 on 4q25 chromosome, that are highly associated to AF. Subsequent GWAS studies have identified several new loci, involving additional transcription and growth factors. Furthermore, these risk 4q25 SNPs serve as surrogate biomarkers to identify AF recurrence in distinct surgical and pharmacological interventions. Experimental studies have demonstrated an intricate signalling pathway supporting a key role of the homeobox transcription factor PITX2 as a transcriptional regulator. Furthermore, cardiovascular risk factors such as hyperthyroidism, hypertension and redox homeostasis have been identified to modulate PITX2 driven gene regulatory networks. We provide herein a state-of-the-art review of the genetic bases of atrial fibrillation, our current understanding of the genetic regulatory networks involved in AF and its plausible usage for searching novel therapeutic targets.

Leukemia is a group of progressive hematologic malignancies derived from stem cells in bone marrow which causes a large number of cancer deaths. Even with treatment such as traditional chemotherapy, targeted therapy, and allogeneic stem cell transplantation (allo-HSCT), many patients suffer from relapse/refractory disease, and the overall survival is dismal. Leukemic stem cells (LSCs) are induced by gene mutations and undergo an aberrant and poorly regulated proliferation process which is involved in the evolution, relapse, and drug-resistance of leukemia. Emerging studies demonstrate that CD123, the interleukin 3 receptor alpha (IL-3Rα), is highly expressed in LSCs, while not normal hematopoietic stem cells (HSCs), and associates with treatment response, minimal residual disease (MRD) detection and prognosis. Furthermore, CD123 is an important marker for the identification and targeting of LSCs for refractory or relapsed leukemia. Anti-CD123 target-therapies in pre-clinical studies and clinical trials confirm the utility of anti-CD123 neutralizing antibody-drugs, CD3×CD123 bispecific antibodies, dual-affinity retargeting (DART), and anti-CD123 chimeric antigen receptor-modified T-cell (CAR-T) therapies in progress. This review summarizes the most recent progress on the study of CD123 biology and the development of novel CD123-targeted therapies.

In patients having undergone the Fontan operation, besides the well discussed changes in the cardiac, pulmonary and gastrointestinal system, alterations of further organ systems including the hematologic, immunologic, endocrinological and metabolic are reported. As a medical adjunct to Fontan surgery, the systematic study of the central role of the liver as a metabolizing and synthesizing organ should allow for a better understanding of the pathomechanism underlying the typical problems in Fontan patients, and in this context, the profiling of endocrinological and metabolic patterns might offer a tool for the optimization of Fontan follow-up, targeted monitoring and specific adjunct treatment.

Background: Blood biomarkers are a cost-effective and valid method to diagnose ischemic stroke and differentiate its subtypes in countries with poor resources. Objective: To perform a systematic review of published literature evaluating the diagnostic utility of blood-based biomarkers to diagnose and differentiate the etiology of ischemic stroke. Methods: A comprehensive literature search was carried out till December 2017 in major scientific and medical databases including PubMed, Cochrane, OVID and Google Scholar. Modified Quality Assessment of Diagnostic Accuracy Studies questionnaire was used to assess the methodological quality of each study. Results: Twenty-six studies were identified relevant to our systematic review. Various biomarkers have been studied, though only a few biomarkers such as a B-type natriuretic peptide (BNP) and Ddimer have proved their clinical utility. None of the other tested biomarkers appeared to have consistent results to diagnose ischemic stroke subtypes. Most of the studies had limitations in the classification of ischemic stroke, sample size, sample collection time, methods, biomarker selection and data analysis. Conclusion: Our systematic review does not recommend the use of any blood biomarker for clinical purposes based on the studies conducted to date. BNP and D-dimer may present optimal biomarker for diagnosis and differentiation of ischemic stroke. However, large well-designed clinical studies are required to validate utility of these biomarkers to differentiate subtypes of ischemic stroke.

Background: About one-fourth of patients with hemophilia A (HA) develop alloantibodies against factor (F) VIII, as the main treatment challenge. Here, we assessed the relationship between interleukin-10 (IL-10), tumor necrosis factor alpha (TNF-α), FII and FV polymorphisms and risk of inhibitor formation in patients with severe HA. Methods: We divided 39 patients with severe HA in two groups of case (n: 19) and control (n: 20). Genotyping was performed by multiplex amplification tetra arms refractory mutation systempolymerase chain reaction (ARMS-PCR) and PCR-restriction fragment-length polymorphism (PCR-RFLP). Results: TNFα rs1800629 G>A polymorphism decreased the risk of inhibitor development in codominant and dominant inheritance pattern. Moreover, TNFα rs1800629 A allele, decrease the risk of inhibitor formation, while IL10 rs1800896 A>G, FV rs6025 G>A, and FII rs1799963 G>A polymorphisms were not associated with risk of inhibitor development. Conclusion: It seems that TNFα rs1800629 G>A polymorphism decreased the risk of inhibitor formation in Iranian patients with HA.

Objective: To investigate the prevalence of thrombotic events among patients with proven or highly probable homozygosis for the Arg304Gln (Factor VII Padua) defect or compound heterozygosis containing the Arg304Gln mutation. Methods: Homozygotes and compound heterozygotes proven by molecular studies to have the Arg304Gln mutation were gathered from personal files and from two PubMed searches. In addition, patients with probable homozygosis on the basis of clotting tests (discrepancies among Factor VII activity levels according to the tissue thromboplastin used) were also gathered. Results: 30 proven homozygotes and 17 probable ones were gathered together with 8 compound heterozygotes. In the latter use, the associated mutation was Cys135Arg (twice), Gly180Arg, Arg304Trp, Arg315Trp, His348Gln, Gly365Cys. The prevalence of venous thrombotic events was 16.6, 11.8 and 11.1 percent, respectively for the three groups of patients. Heterozygotes showed no thrombotic event. The difference for proven homozygotes was statistically significant, while for the other groups only a trend was present. Conclusion: proven homozygous or compound heterozygous patients with the Arg304Gln mutation showed a higher than expected incidence of thrombotic events. The same is true for probable cases gathered only on the basis of clotting tests. These patients, because of their frequent lack of bleeding and for their relatively high prevalence of thrombosis should probably receive only limited replacement therapy in case of surgical procedures.

Introduction: Acute kidney injury (AKI) is a serious complication of cardiac surgery. The current ‘gold standard’ for determining AKI is change in serum creatinine and urine output, however, this change occurs relatively late after the actual injury occurs. Identification of new biomarkers that detect early AKI is required. Recently, new biomarkers, such as the NephroCheck® Test and AKIRisk have also been tested and found to be good indicators of AKI. Neutrophil gelatinase-associated lipocalin (NGAL) has shown promise in paediatric patients but has displayed varied results in adult populations, particularly post cardiac surgery. The aim of this study was to assess the value of urinary NGAL as a biomarker of AKI in patients with pre-existing renal impairment (eGFR >15ml/min to eGFR<60ml/min). Methods: A post-hoc analysis of urinary NGAL concentrations from 125 patients with pre-existing kidney impairment, who participated in a randomised trial of haemofiltration during cardiac surgery, was undertaken. Urinary NGAL was measured using ELISA at baseline, post-operatively and 24 and 48 hours after surgery, and serum creatinine was measured pre and postoperatively and then at 24, 48, 72 and 96 hours as routine patient care. NGAL concentrations were compared in patients with and without AKI determined by changes in serum creatinine concentrations. A Kaplan-Meier plot compared survival for patients with or without AKI and a Cox proportional hazards analysis was performed to identify factors with the greatest influence on survival. Results: Following surgery, 43% of patients developed AKI (based on KDIGO definition). Baseline urinary NGAL was not found to be significantly different between patients that did and did not develop AKI. Urinary NGAL concentration was increased in all patients following surgery, regardless of whether they developed AKI and was also significant between groups at 24 (p=0.003) and 48 hours (p<0.0001). Urinary NGAL concentrations at 48 hours correlated with serum creatinine concentrations at 48 hours (r=0.477, p<0.0001), 72 hours (r=0.488, p<0.0001) and 96 hours (r=0.463, p<0.0001). Urinary NGAL at 48 hours after surgery strongly predicted AKI (AUC=0.76; P=0.0001). A Kaplan- Meier plot showed that patients with postoperative AKI had a significantly lower 7-year survival compared with those without AKI. Postoperative urinary NGAL at 48 hours >156ng/mL also strongly predicted 7-year survival. However, additive EuroSCORE, age, current smoking and post-operative antibiotics usage were distinctly significantly more predictive of 7-year survival as compared with postoperative urinary NGAL at 48 hours >156ng/mL. Conclusions: Our study demonstrated that postoperative urinary NGAL levels at 48 hours postsurgery strongly predicts the onset or severity of postoperative AKI based on KDIGO classification in patients with preoperative kidney impairment and were also strongly related to 7-year survival.

Background: Cryptogenic stroke (CS) represents 25% of ischemic strokes. Especially after CS, the detection of atrial fibrillation (AF) is important because it provides clues to the mechanism of stroke. However, the relationship between AF and stroke appears more complex than a simple cause-effect mechanism, suggesting that the association between AF and stroke may be due to other systemic and atrial factors including systemic inflammation that may lead to atrial remodeling and subsequent atrial cardiopathy. Objective: The aim of this study was to evaluate the relationship among different electrocardiographic parameters, inflammatory markers and in-hospital AF occurrence after acute CS. Methods: 222 patients with CS underwent 12-lead resting ECG at admission and 7-day in-hospital ECG monitoring. The following indices were evaluated: P-wave dispersion (PWD), P-wave index, P-wave axis, atrial size and high-sensitivity-C reactive protein (CRP). Results: AF was detected in 44 patients. AF-group had significantly higher PWD, P-wave index, PR interval, CRP and greater frequency of abnormal P-wave axis in comparison with no-AF group. There was a significant correlation between CRP and PWD (r=0.28). By using the mediation analysis, performed according to the “bootstrapping” method, we found that PWD is a significant mediator variable of the relationship between CRP and AF occurrence, accounting for 40% of the association. Conclusions: In cryptogenic stroke, high PWD is partly due to systemic inflammation that increases AF risk possibly via atrial electric remodeling. These findings could also suggest inflammation as a possible therapeutic target in order to prevent atrial electrical alterations and finally AF occurrence in CS.

Background: Carfilzomib, a proteasome inhibitor, known as a therapeutical option for people who have already received one or more previous treatments for multiple myeloma, has well known cardiac and systemic adverse effects. Objective: There is evidence supporting that adverse effects are dose dependent, yet there is no known patient phenotype characterized by worse associated consequences, nor are there widely accepted monitoring protocols. Results: In this article we describe two patients with cardiovascular adverse events related to carfilzomib treatment and their clinical course. Our goal was to present two cases of daily practice, which highlighted the complexity of their management and led to underline how baseline evaluation and close follow-up with echocardiography and cardiac biomarkers, including natriuretic peptides, remain an important tool for the cardiotoxicity surveillance. Conclusion: These reflections should lead to further studies in order to identify high risk patients for cardiovascular adverse event and clarify the real incidence of cardiotoxicity of this drug and adequate follow-up timing. Finally further research is needed to evaluate strategies for prevention and attenuation of cardiovascular complications of cancer therapy.