Cardiovascular & Haematological Disorders - Drug Targets - Volume 21, Issue 1, 2021

Background: Heart failure (HF) is one of the leading public health problems with a substantial burden in the global healthcare system. Although significant efforts are based on prevention, early recognition, and proper management of HF, the worldwide surge of risk factors like hypertension, diabetes, and obesity has further complicated the existing problem. Objective: This study aims to define the role of the sodium-glucose cotransporter 2 (SGLT2) inhibitors in non-diabetic HF. Methods: We performed a comprehensive literature review to examine the available evidence in the clinical implications of SGLT2 inhibitors in non-diabetic HF using the online databases (PubMed and Embase). Results: We identified two RCTs-DAPA-HF and DEFINE-HF, which were conducted to analyze the net clinical benefit of dapagliflozin in non-diabetic HF patients. Although we could not study the composite effects of these studies due to the difference in outcome measures, the individual outcomes look promising. The number needed to treat (NNT) to prevent one primary event was 21 (95% CI: 15 to 38) in the DAPA study. In DEFINE HF study, responder analysis showed a significant proportion of patients in the treatment arm experienced improvements in the functional status with clinically meaningful improvement in KCCQ-OS by 3.7 points and KCCQ-CS by 4.6 points with NNT of 10 and 7, respectively, at 12 weeks. Both studies also showed low safety concerns in patients without T2D. Conclusion: The outcomes of the two RCTs, DAPA-HF and DEFINE-HF, that studied the effects of SGLT2 inhibitors in non-diabetic HF showed promising clinical outcomes. Although we are waiting for other prospective RCTs to reflect similar results and safety profiles, it seems the SGLT2 inhibitors can have broader clinical implications in managing non-diabetic HF with improved cardiovascular outcomes.

Incorrectly expressed or mutated proteins associated with hematologic malignancies have been generally targeted by chemotherapy using small-molecule inhibitors or monoclonal antibodies. But the majority of these intracellular proteins are without active sites and antigens. PROTACs, proteolysis targeting chimeras, are bifunctional molecules designed to polyubiquitinate and degrade specific pathological proteins of interest (POIs) by hijacking the activity of E3-ubiquitin ligases for POI polyubiquitination and subsequent degradation by the proteasome. This strategy utilizes the ubiquitin-proteasome system for the degradation of specific proteins in the cell. In many cases, including hematologic malignancies, inducing protein degradation as a therapeutic strategy offers therapeutic benefits over classical enzyme inhibition connected with resistance to inhibitors. Limitations of small-molecule inhibitors are shown. PROTACs can polyubiquitinate and mark for degradation of “undruggable“proteins, e.g. transcription factor STAT3 and scaffold proteins. Today, this technology is used in preclinical studies in various hematologic malignancies, mainly for targeting drug-resistant bromodomain and extraterminal proteins and Bruton tyrosine kinase. Several mechanisms limiting selectivity and safety of PROTAC molecules function are also discussed.

The coronavirus disease 2019 (COVID-19) caused by severe acute respiratory syndrome coronavirus (SARS- CoV-2) is our latest pandemic and has turned out to be a global public health crisis. One of the special characteristics of this disease is that it may predispose patients to thrombotic disease both in the venous and arterial circulation. We review arterial and venous thromboembolic complications in patients with COVID-19, epidemiology, pathogenesis, hematologic biomarkers, and current antithrombotic strategies. Future perspectives and clinical trials are ongoing to determine the best thromboprophylaxis strategies in the hospitalized patients with severe COVID-19.

Background: The ASPIRE and ENDEAVOUR trials have shown cardiovascular adverse effects in patients treated with carfilzomib-based regimens. Therefore, we conducted this meta- analysis of published clinical trials to identify the cumulative incidence and risk of cardiovascular adverse effects due to carfilzomib. Methods: A systematic search of PubMed, Embase, Web of Science, and Cochrane library was performed, and we identified 45 prospective trials of carfilzomib with data on 5583 patients. Among all patients being treated with carfilzomib (N=5,583), 8.9% sustained all grade cardiotoxicity, while 4.4% sustained high-grade cardiotoxicity. All-grade hypertension was present in 13.2%, while the incidence of high-grade hypertension was 5.3%. Results: The observed incidences of all-grade heart failure, edema, and ischemia were 5.1%, 20.7%, and 4.6%, respectively. Likewise, for high-grade heart failure and edema observed incidence was 3.2%, and 2.7%, respectively. There was no difference in the event rate of all and highgrade cardiotoxicity between newly diagnosed multiple myeloma and relapsed/refractory (p-value 0.42 and 0.86, respectively). Likewise, we did not observe any difference in the event rate of all and high-grade cardiotoxicity when carfilzomib was used as a single agent versus when used in combination therapy with other agents (p-value 0.43 and 0.73, respectively). Conclusion: Carfilzomib is associated with a significant risk of cardiovascular toxicity and hypertension. With the increasing utilization of carfilzomib, it is critical for primary care physicians, oncologists and cardiologists to be aware of the risk of cardiotoxicity associated with the use of carfilzomib to recognize and treat baseline cardiovascular risk factors in such patients.

Background: Since long back, it has been a matter of discussion regarding the role of peripheral blood vessels in the regulation of cardiorespiratory (CVR) system. Objective: The role of 5-HT3 and TRPV1 receptors present on perivascular nerves in elicitation of CVR reflexes was examined after intra-arterial instillation of bradykinin in urethane anesthetized rats. Materials and Methods: Femoral artery was cannulated retrogradely and was utilized for the instillation of saline/agonist/antagonist and recording of blood pressure (BP), using a double ported 24G cannula. BP, respiration and ECG were recorded for 30 min after bradykinin (1 μM) in the absence or presence of antagonists. Results: Instillation of bradykinin produced immediate hypotensive (40%), bradycardiac (17%), tachypnoeic (45%) and hyperventilatory (96%) responses of shorter latencies (5-8 s) favoring the neural mechanisms in producing the responses. In lignocaine (2%) pretreated animals, bradykinin- induced hypotensive (10%), bradycardiac (1.7%), tachypnoeic (13%) and hyperventilatory (13%) responses attenuated significantly. Pretreatment with ondansetron (100 μg/kg), 5-HT3-antagonist attenuated the hypotensive (10%), bradycardiac (1.7%), tachypnoeic (11%) and hyperventilatory (11%) responses significantly. Pretreatment with capsazepine (1 mg/kg), transient receptor potential vanilloid 1- antagonist blocked the hypotensive (5%), bradycardiac (1.2%), tachypnoeic (6%) and hyperventilatory (6%) responses significantly. Conclusion: In conclusion, presence of a nociceptive agent in the local segment of an artery evokes vasosensory reflex responses modulating CVR parameters involving TRPV1 and 5-HT3 receptors present on the perivascular sensory nerve terminals in anesthetized rats.

Background: Congenital heart diseases are the most prevalent congenital abnormalities in the neonates, caused by environmental and genetic factors and contributing to the leading cause of death. This study aims to evaluate the relationship between neonates with large for gestational age and increased risk of congenital heart diseases among non-diabetic mothers. Methods: In this study, 179 neonates with large gestational age in Khorramabad were enrolled where heart abnormalities were evaluated using echocardiography. Results: 87 neonates had more than 4000 g of birth weight with no heart abnormalities and 92 (51%) macrosomic neonates had congenital heart diseases. Statistical analysis revealed a significant relationship between birth weight and increased risk of acquiring congenital heart disease between the two groups. There was no significant relationship between birth weight, maternal age, gender, labor type and blood group between the two groups. The highest incidence of congenital heart anomalies was related to 38% of arterial septal defect (ASD) and 15.2% of ASD and VSD, respectively. Conclusion: The most prevalent abnormality was arterial septal ASD. None of these abnormalities were associated with maternal age, birth weight and neonate gender. Future studies for congenital heart disease and neonatal birth weight are, therefore, recommended.

Aims: Congenital heart disease is among the most common congenital anomalies in pediatrics. The aim of this study was to evaluate the prevalence of congenital heart disease in children in Khorramabad, Iran. Methods: This is a descriptive-cross sectional study where all the children diagnosed with congenital heart disease by echocardiography were enrolled to the Shahid Madani Hospital. Patient information was collected by means of a questionnaire. Of 1600 children who underwent cardiac counseling, 9.75% presented congenital heart disease. These were most prevalent among the children of 0-28 days of the age (14.7%) and least in children aged 1 month-1 year. According to this study, atrial (20.3%) and ventricular septal defect (10.5%) were the most common heart defects, respectively. Among signs and symptoms of cardiac disease, 49.1% of children had cyanosis, 89.7% with increased CT (cardiothoracic)-ratio, and 82.7% of had heart murmur. Congenital heart disease was more prevalent in male infants (58%) and 6.6% patients had heart failure and 1.4% had other congenital conditions, such as Down syndrome. Results: According to our findings, atrial and ventricular septal defects are the most common congenital heart anomalies, respectively, in pediatric patients in Khorramabad.

Background: Bupivacaine and Levobupivacaine are frequently used local anesthetic drugs in spinal anesthesia practice. Both agents have arrhythmic effects on the heart. However, there is no clear information about which agent is more arrhythmogenic. Objective: The aim of this article is to investigate the effects of bupivacaine and its S (-)-enantiomer, levobupivacaine, on cardiac arrhythmias in patients. Methods: The study included 40 patients scheduled for inguinal hernia surgery. Patients were randomly divided into the following two groups using a sealed envelope method: Group I, the bupivacaine group (n = 20); and Group II, the levobupivacaine group (n = 20). The QT values were taken preoperatively and during the 10th of the spinal block, the 10th of the surgical incision, and the 10th postoperative minute. Additionally, systolic blood pressure (SBP), diastolic blood pressure (DBP), mean arterial pressure (MAP), oxygen saturation (SO2), and heart rate (HR) values, in addition to motor block (Bromage scale) levels and durations, were recorded for each patient. Results: HR values measured at 10 min after spinal block were significantly higher than the baseline values in the levobupivacaine group (p < 0.05). The corrected QT interval (QTc) values increased significantly at 10 minutes after spinal block and at 10 min postoperatively in the bupivacaine group (p < 0.05). QTd and QTcd measurements were taken at the 10th minute of spinal anesthesia, the 10th minute of the incision, and the 10th minute postoperatively. When compared to the levobupivacaine group, a statistically significant increase was found in the bupivacaine group (p < 0.05). Conclusion: Levobupivacaine allows greater hemodynamic stability, while bupivacaine affects QTc and QTd measurement times more. As such, we believe that levobupivacaine may be a better alternative to bupivacaine during clinical practice, particularly in patients with cardiac problems.

Aims: In the present study, we have investigated the cardioprotective properties of Isosteviol (STV) under conditions of hypoxia-reoxygenation and elucidated the underlying mechanism. Background: In our previous studies, we have determined that STV exhibits neuro- and cardio-protective properties. However, the mechanism underlying STV-induced cardioprotection has not yet been fully understood. Methods: All experiments were performed on rat heart embryonic H9c2 cell line. To induce hypoxia- reoxygenation, cells were exposed to 1% oxygen (in no glucose and no sodium pyruvate DMEM) following by reoxygenation (using fully supplemented MEM). Cells viability was tested by MTT assay, and protein levels were compared by Western blotting. Results: Treatment of heart embryonic H9c2 cells with STV (10 μM) significantly increased the survival of cells exposed to hypoxia-reoxygenation. STV (10 μM) activated ERK1/2 and DRP1 in hypoxia-reoxygenation, but did not have any effects on ERK1/2 or DRP1 in normoxia. STV (10 μM) did not regulate CAMKII, AKT or AMPK signaling pathways. Conclusion: Taken all together, our findings demonstrate that 1) STV protects H9c2 cells against hypoxia-reoxygenation and that 2) this effect is mediated via ERK1/2. The property of STV that selectively activates ERK1/2 in cells exposed to stress, but not in cells under non-stress conditions, makes this compound a promising candidate-drug for therapy against myocardial ischemia-reperfusion in clinical practice.

Introduction: Ventricular interdependence in pulmonary arterial hypertension (PAH) by the use of most recent echocardiographic techniques is still rare. The current case-controlled study aims to assess left ventricular (LV) torsion in patients with PAH. Methods: The study included 42 cases of moderate to severe PAH and 42 age and gender-matched healthy controls between March 2016 and January 2018. All the patients and controls undergo routine practice echocardiography using the Vivid 7-echocardiography (2.5MHz transducer) system. Results: The LV twisting parameters, peak basal rotation, peak apical rotation, and twist were similar among both cases and controls, however, LV torsion was significantly (p=0.04) impacted. Right ventricular (RV) longitudinal deformation was clinically significant in the cases compared to controls: RV systolic strain imaging (p=0.001, 95% CI-9.75 to -2.65), RV systolic strain rate (p=0.01, 95% CI-0.99 to -0.09), and RV late diastolic strain rate (p=0.01, 95% CI-0.64 to -0.85). Although PAH did not impact longitudinal LV deformations significantly. At basal level circumferential strain and strain rate were significantly impacted (p=0.005, 95% CI-4.38 to -0.70; p=0.004, 95% CI-0.35 to -0.07) in the PAH group, while the radial strain was preserved. All RV echocardiographic parameters and LV end-diastolic dimension, LV end-systolic volume in the PAH were affected significantly (p=0.002, 95% CI-19.91 to -4.46; p=0.01, 95% CI-8.44 to -2.77). However, only a weak correlation (p=0.05, r =-0.20) was found between tricuspid annular plane systolic excursion and LV Tei index. Conclusion: RV pressure overload directly affects RV longitudinal systolic deformation further influences the interventricular septal and LV geometry, which impaired LV torsion.