JournalTOCs

Cardiovascular Toxicology
Journal Prestige (SJR): 0.836

Citation Impact (citeScore): 2
Number of Followers: 6

Hybrid journal (It can contain Open Access articles)
ISSN (Print) 1559-0259 - ISSN (Online) 1530-7905
Published by Springer-Verlag

[2626 journals]

Mechanism of Hydrogen Sulfide Preconditioning-Associated Protection
Against Ischemia–Reperfusion Injury Differs in Diabetic Heart That
Develops Myopathy
- Abstract: Abstract Hydrogen sulfide (H2S) is reported to be effective in the management of the myocardial ischemia–reperfusion (I/R) injury via PI3K/GSK3β pathway in normal rats. However, its efficacy against I/R in the presence of diabetic cardiomyopathy is relatively obscure. Thus, the present work aimed to find out H2S-mediated cardioprotection against I/R in diabetic cardiomyopathy and to evaluate its mode of action using Langendorff isolated heart perfusion system. The present work includes three groups of rat, viz. (i) normal, (ii) diabetes mellitus (DM: streptozotocin: 35 mg/kg; normal diet), and (iii) diabetes + high-fat diet (DCM) (streptozotocin: 35 mg/kg; high-fat diet). The effect of NaHS (an H2S donor; 20 µM) on cardiac function in isolated rat hearts demonstrates that H2S preconditioning (HIPC) significantly attenuated myocardial injury in both DM and DCM hearts, as evidenced by the (i) improvement in hemodynamics, which includes rate pressure product [(in mmHg × 103 × bpm) DM: 40 to 56; DCM: 21 to 58] and left ventricular developed pressure [(in mmHg) DM: 53 to 74; DCM: 28 to 74), (ii) reduction in infarct size (25% to 8%) and attenuated caspase activity, compared to their respective I/R controls. Also, the observed positive recovery of mitochondrial function during HIPC treatment reinforces the cardioprotection by HIPC in DCM heart against I/R injury. However, HIPC could not repair I/R-induced oxidative stress in DCM rat heart. Further, to study the H2S mode of action, the experimental rats were exposed to a PI3K inhibitor (Wortmannin) and GSK3β inhibitor (SB216763) before HIPC protocol, whose results suggest that unlike in normal and DM, HIPC mediates its cardioprotective effect independent of PI3K/GSK3β pathway. To conclude, HIPC ameliorates I/R injury in DCM rat via an alternative pathway other than existing PI3K pathway, which is required to be probed under disease conditions.
  PubDate: 2020-04-01
The Protective Effects of Pharmacologic Postconditioning of Hydroalcoholic
Extract of Nigella sativa on Functional Activities and Oxidative Stress
Injury During Ischemia–Reperfusion in Isolated Rat Heart
- Abstract: Abstract Oxidative stress is known to act as the trigger of cardiac damage during ischemia–reperfusion (I/R) injury. Postconditioning (PoC) is employed to minimize the consequences of ischemia at the onset of reperfusion. Regarding the well-known antioxidant properties of Nigella sativa (Ns), the aim of this study was to investigate whether Nigella sativa postconditioning (Ns-PoC) could reduce IRI by lowering the formation of reactive oxygen species (ROS). Isolated rat hearts were perfused with the Langendorff apparatus, which were subjected to 20 min of preperfusion, 20 min of global ischemia, followed by 40 min of reperfusion. At the onset of reperfusion, based on the type of intervention group, a 10-min period of Krebs flow was developed along with the treatment, and then the reperfusion with Krebs solution was conducted for 30 min. Heart rate (HR) and left ventricular pressure (LVP) were recorded by isometric transducers connected to a data acquisition system. Thiobarbituric acid reactive substances (TBARS), 4-hydroxynonenal (4-HNE) levels, total thiol groups (–SH) levels, superoxide anion dismutase (SOD), and catalase (CAT) activities in myocardial tissues were detected to evaluate the oxidative stress damage degree. Ns-PoC significantly improved cardiodynamic parameters including left ventricular developed pressure (LVDP), rate pressure product (RPP), and the maximum up/down rate of the left ventricular pressure (± dp/dt) as well as SH groups, SOD, and CAT activities. Moreover, it decreased MDA and 4-HNE levels during early reperfusion. The results of this study showed that Ns-PoC ameliorated cardiac functions in isolated rat heart during I/R injuries by improving myocardial oxidative stress states, which may be related to the antioxidant effect of Ns.
  PubDate: 2020-04-01
The Effects of Thiamine Hydrochloride on Cardiac Function, Redox Status
and Morphometric Alterations in Doxorubicin-Treated Rats
- Abstract: Abstract Previous studies have suggested that thiamine has antioxidant activity and could decrease the production of ROS in various disorders. Our study focused on the effect of thiamine hydrochloride in the reversal of DOX-induced cardiotoxicity and compared it with the reversal in the absence of thiamine pre-treatment. Rats were divided into groups as follows: (a) thiamine + doxorubicin (TIA + DOX), (b) doxorubicin (DOX) and c) healthy (CTRL) groups. For 7 days, thiamine hydrochloride was administered at a dose of 25 mg/kg per day intraperitoneally, while a single dose of 15 mg/kg doxorubicin was injected into all groups except the CTRL group. We measured the following parameters: maximum rate of left ventricular development (dp/dt max), minimum rate of left ventricular development (dp/dt min), systolic left ventricular development (SLVP), diastolic left ventricular development (DLVP), heart rate (HR) and coronary flow (CF), pro-oxidative and antioxidative markers, cardiac activity, and histopathological evaluation. In our study, cardiac contractility was significantly altered after DOX treatment and diminished by thiamine pre-treatment. Additionally, pro-oxidant parameters were significantly increased in the DOX group. The levels of O2−, H2O2 and TBARS were significantly increased in the DOX group and decreased in the DOX + T group compared to those in the DOX group. Morphometric analyses showed moderately expressed interstitial fibrosis and degenerately modified cardiac muscle fibres, with signs of interfibrillary congestion, vacuolar degeneration and myocytolysis in the DOX group as visualized by H&E and Masson’s Trichrome staining. Pre-treatment of thiamine hydrochloride before doxorubicin administration could decrease oxidative stress production, increase myocardial contractility and enhance the antioxidant defence system.
  PubDate: 2020-04-01
Proarrhythmic Effect of Acetylcholine-Esterase Inhibitors Used in the
Treatment of Alzheimer’s Disease: Benefit of Rivastigmine in an
Experimental Whole-Heart Model
- Abstract: Abstract Several studies suggest QT prolongation and torsade de pointes with acetylcholine-esterase inhibitors. We therefore examined the electrophysiologic profile of donepezil, rivastigmine, and galantamine in a sensitive whole-heart model of proarrhythmia. 34 rabbit hearts were isolated and retrogradely perfused employing the Langendorff setup. Hearts were treated either with donepezil, rivastigmine, or galantamine in rising concentrations and electrophysiologic studies were performed. In the presence of donepezil and galantamine, spatial dispersion of repolarization was amplified. Cardiac repolarization (QT interval and action potential duration) was prolonged with donepezil but not with galantamine. Remarkably, both drugs induced triggered activity (early afterdepolarizations and torsade de pointes tachycardia). Despite a pronounced prolongation of repolarization with rivastigmine, no increase in spatial dispersion of repolarization and thus no triggered activity was observed. In the present study, donepezil and galantamine provoked triggered activity, whereas rivastigmine did not have proarrhythmic effects. Spatial dispersion of repolarization but not duration of cardiac repolarization was associated with increased risk of drug-induced proarrhythmia with acetylcholine-esterase inhibitors. Consequently, QT interval duration might be insufficient to estimate the risk of proarrhythmia with acetylcholine-esterase inhibitors. Our findings emphasize the need for further electrocardiographic risk predictors.
  PubDate: 2020-04-01
Suppression of LPS-Induced Hepato- and Cardiotoxic Effects by Pulicaria
petiolaris via NF-κB Dependent Mechanism
- Abstract: Abstract Recently, there is an increasing interest in searching for harmless natural products isolated from plant materials that can be used as beneficial dietary supplements and/or therapeutic drug candidates. The present study aimed to test the potential protective role of Pulicaria petiolaris (PP, Asteraceae) against hepatic and cardiotoxic effects associated with lipopolysaccharide (LPS) injection. PP was given orally for 5 days at two different doses before LPS injection. Results have shown that LPS induced remarkable hepatic and cardiac injurious effects in mice. Hepatic damage was evident through increased serum transaminases, lactate dehydrogenase (LDH), alkaline phosphatase (ALP), and activity. Estimation of high levels of serum creatine kinase-MB (CK-MB) and cardiac troponin I indicated cardiac damage. Histopathological examination of liver and heart confirmed the biochemical results. Increase in oxidative stress along with a depressed antioxidant status of liver and heart were observed in LPS-intoxicated animals. Furthermore, LPS induced activation of nuclear factor-κB (NF-κB) and subsequent elevation of inflammatory cytokines (TNF-α, IL-6). On the other hand, PP treatment successfully safeguards both organs against LPS-induced injury as indicated by the improvement of the biochemical and histopathological parameters. These results suggest that PP ameliorates LPS-induced hepatic and cardiac oxidative injurious effects via antioxidant and anti-inflammatory effects.
  PubDate: 2020-04-01
FOLFIRI-Mediated Toxicity in Human Aortic Smooth Muscle Cells and Possible
Amelioration with Curcumin and Quercetin
- Abstract: Abstract Systemic chemotherapy-mediated cell toxicity is a major risk factor for cardiovascular disease and atherosclerosis. Life-threatening acute events of the FOLFIRI (irinotecan, folinic acid and 5-fluorouracil) regimen are mainly due to DNA damage induced by antimetabolite and topoisomerase inhibition effects. However, the role of human aortic smooth muscle cells (HaVSMCs) in this process and the mechanisms of oxidative stress, DNA and protein damage and apoptosis have not been investigated. Therefore, the effects of curcumin and quercetin on HaVSMC survival in the generation of molecular and cellular toxicity by FOLFIRI treatment and the involvement of vital cellular signalling pathways were investigated. We analysed both FOLFIRI toxicity and the therapeutic potential of quercetin and curcumin in terms of HaVSMC damage using molecular probe and florescence staining, Random Amplified Polymorphic DNA (RAPD), qRT-PCR and Western blot assays. Our study presents two preliminary findings: (a) in HaVSMCs, FOLFIRI treatment significantly induces oxidative damage to both DNA and protein, leading to a dramatic increase in caspase-dependent apoptotic death through P53-mediated Caspase3-dependent mitochondrial apoptosis, and results in TNF-α/Caspase8-mediated necrotic death, and (b) flavonoids not only regulate the expression of genes encoding antioxidant enzymes and increase DNA damage but also limit programmed and necrotic cell death processes in HaVSMCs. Our results clearly indicate the potential for curcumin and, particularly, quercetin as preventative chemotherapeutic interventions for cardiovascular toxicity induced by the FOLFIRI regime in HaVSMCs.
  PubDate: 2020-04-01
Lipocalin-2 Predicts Long-Term Outcome of Normotensive Patients with Acute
Pulmonary Embolism
- Abstract: Abstract Normotensive patients with acute pulmonary embolism (APE) are accompanied by heterogeneously adverse events. Responding to tissue injury, lipocalin-2 (LCN-2) is elevated in experimental APE model and associated with short-term prognosis. However, the prognostic value of LCN-2 in normotensive patients with APE for long-term major adverse events (MAEs) remains unknown. We evaluated the association of plasma LCN-2 levels with the median 467-day outcome in 170 normotensive patients with APE. We also assessed whether LCN-2 could improve risk stratification. MAEs consisted of mortality or recurrence of venous thromboembolism. During follow-up, 17 (10%) patients suffered from MAEs. These patients had higher LCN-2 levels compared with patients without MAEs (median: 13.97 vs. 8.55 ng/ml, P = 0.01). The proportion of MAEs in the intermediate–low-risk group (14.0%) was higher than that in the intermediate–high-risk group (5.3%). LCN-2 levels independently had prognostic value for MAEs in overall (HR = 3.40, 95% CI 1.46–7.90) and intermediate-risk group (HR = 3.88, 95% CI 1.63–9.23). LCN-2 also showed incremental value in overall (ΔC-index: 0.13, 95% CI 0.02–0.24; category-based NRI = 0.25, 95% CI 0.07–0.42) and intermediate-risk patients (ΔC-index: 0.13, 95% CI 0.05–0.31; category-based NRI = 0.44, 95% CI 0.24–0.65). Adding LCN-2 (cut-off value = 11 ng/ml) to the current risk algorithm improved MAEs of intermediate–risk reclassification (intermediate–high vs. intermediate–low = 25.6% vs. 6.0%, P = 0.002). Elevated plasma LCN-2 levels predict long-term MAEs among normotensive patients with APE. LCN-2 might be a useful biomarker for risk stratification in the intermediate-risk group.
  PubDate: 2020-04-01
Association of Genetic Variations in NRF2, NQO1, HMOX1, and MT with
Severity of Coronary Artery Disease and Related Risk Factors
- Abstract: Abstract NRF2 is a transcription factor which, during oxidative stress, activates transcription of its target antioxidant genes. Polymorphisms in NRF2 and its target antioxidant genes: HMOX-1, NQO1, and MT, have been associated with cardiovascular diseases (CVDs) and diabetes in various ethnic groups, however, with variable results. The aim of this study was to investigate the association of NRF2, HMOX-1, NQO1, and MT gene polymorphisms with CVD risk factors in Thais. The study was conducted in two groups: group with high-risk for coronary artery disease (CAD) and health check-up group. Polymorphisms in NRF2 (rs6721961), NQO1 (rs1800566), MT1A (rs11640851), and HMOX-1 (rs2071746) were genotyped. Expressions of NRF2, HMOX-1, and NQO1 were also determined. In high-risk group, NRF2 rs6721961-TT was associated with CAD [OR (95% CI) 5.07 (1.42–18.10)] and severity of coronary atherosclerosis [Gensini score > 32, OR (95% CI) 4.31 (1.67–11.09)]; rs6721961 GT and TT revealed significant association with lower mRNA expression than GG (p = 0.021). NQO1 rs1800566 also revealed association with CAD, only in female. Combined effect of NQO1-rs1800566, HMOX1-rs2071746, and MT1A-rs11640851 was evaluated on the risks of DM and hypertension. With a combination of risk alleles as genetic risk score (GRS), the highest GRS (score 6) increased risk for hypertension, comparing with GRS 0–2 [OR (95% CI) 1.89 (1.02–3.49)]; group with score 5–6 revealed association with risk of DM [OR (95% CI) 1.481 (1.08–2.04)]. In conclusion, NRF2 rs6721961 associated with CAD and severity of coronary atherosclerosis. NQO1 rs1800566 also associated with CAD, only in female. Combined polymorphisms of three NRF2-regulated genes increased risk of DM and hypertension.
  PubDate: 2020-04-01
Puerarin Alleviates Lipopolysaccharide-Induced Myocardial Fibrosis by
- Abstract: Abstract Myocardial fibrosis (MFs) is a crucial pathological process that results in cardiac failure in the development of multiple cardiovascular diseases. Puerarin could reportedly be used to treat a variety of cardiovascular diseases. However, the exact mechanism of puerarin on MFs was not clear enough. The separated primary cardiac fibroblasts (CFs) were induced by lipopolysaccharide (LPS) and treated with puerarin. The levels of TNF-α, IL-6, HMGB1, PARP-1, α-SMA, collagen-1, collagen-3, NF-κB pathways were examined by ELISA, immunofluorescence, RT-qPCR, western blot and immunohistochemistry assays. In addition, MFs rats’ model was established using transverse aortic constriction (TAC), and the degree of fibrosis was certified by masson staining. We successfully separated primary CFs, and certified that LPS induction could upregulate the levels of PARP-1, HMGB1, inflammatory cytokines and fibrosis-related proteins (α-SMA, collagen-1 and collagen-3). In addition, we proved that puerarin could weaken MFs, and PARP-1 and HMGB1 expressions, which were induced by LPS in primary CFs. In terms of mechanism, HMGB1 expression could be promoted by PARP-1, and PARP-1 could attenuate the therapeutic effect of puerarin on LPS-induced MFs. Besides, PARP-1-HMGB1-NF-κB pathway was related to the protective effect of puerarin on MFs. In vivo, we also verified the protective efficacy of puerarin on MFs induced by TAC, and puerarin also regulated HMGB1-mediated TLR4-NF-κB signaling pathway. We demonstrated that puerarin could ameliorate MFs by downregulating PARP-1 to inhibit HMGB1-mediated TLR4-NF-κB signaling pathway in LPS-induced primary CFs and TAC-induced MFs rats’ model.
  PubDate: 2020-03-31
The Cardioprotective Effects of Aminoguanidine on Lipopolysaccharide
Induced Inflammation in Rats
- Abstract: Abstract Myocardial dysfunction, a major component of sepsis-induced multiorgan failure, contributes to the production of massive amounts of pro-inflammatory cytokines. Nitric oxide (NO) is known to act as a precursor of free radicals in inflammation. This research was conducted to assess the effect of aminoguanidine (AG) on lipopolysaccharide (LPS)-induced heart injury. 50 male rats were categorized into five groups (n = 10): (1) control, (2) LPS, (3) LPS-AG50, (4) LPS-AG100, and (5) LPS-AG150. LPS (1 mg/kg) was injected for 5 weeks, and AG (50, 100 and 150 mg/kg) was injected 30 min prior to LPS administration. All drugs were injected intraperitoneally. LPS-evolved cardiovascular toxicity was indicated by the augmentation in the level of nitric oxide (NO) metabolites, interleukin (IL)-6 and malondialdehyde (MDA), as well as reduced contents of total thiol groups, catalase (CAT), and superoxide dismutase (SOD) activity in serum, heart, and aortic tissues. In AG treated groups, noxious effects of LPS were not observed in the serum and harvested tissues. AG reduced MDA, NO metabolites, and IL- 6 and increased total thiol, CAT, and SOD activity in the heart, aorta and serum. As an inhibitor of inducible NO synthase (iNOS), AG further reduced LPS-induced oxidative stress and inflammation, hence considered as cardioprotective.
  PubDate: 2020-03-30
Cardioprotective Effect of Paricalcitol on Amitriptyline-Induced
Cardiotoxicity in Rats: Comparison of [ 99m Tc]PYP Cardiac Scintigraphy
with Electrocardiographic and Biochemical Findings
- Abstract: Abstract Taking an overdose of AMT, a commonly prescribed tricyclic antidepressant drug, has an increased risk of sudden cardiac death. The cardiotoxicity of amitriptyline (AMT) is a commonly observed toxicity with high morbidity and mortality rates in emergency departments (ED). Nevertheless, there are still no effective treatment options for AMT-induced cardiotoxicity. The aim of the present study was to evaluate the effects of paricalcitol (PRC), a Vitamin D receptor agonist, using electrocardiographic (ECG), biochemical, and scintigraphic methods. Twenty-eight male Wistar rats were randomly divided into four groups: untreated control (CON), amitriptyline-induced cardiotoxicity (AMT), paricalcitol (PRC), and amitriptyline + paricalcitol (AMT + PRC). Cardiotoxicity was induced by intraperitoneal (i.p) injection of a single-dose AMT (100 mg/kg). PRC was administered as 10 μg/kg (i.p.) after the injection of AMT. We examined ECG, biochemical, and scintigraphic results of PRC administration on AMT-induced changes. Cardiotoxicity of AMT was characterized by conduction abnormalities (increased QRS complex, T wave, and QT interval duration and elevation of ST segment amplitude), elevated 99mTechnetium Pyrophosphate ([99mTc]PYP) uptake, and increased cardiac troponin T (cTnT) levels. Treatment with PRC significantly decreased all AMT-associated conduction abnormalities in ECG (p < 0.001), and decreased [99mTc]PYP uptake (p < 0.001) and serum cTnT level (p < 0.001). The present study indicated that the vitamin D receptor agonist paricalcitol could decrease the AMT-induced cardiotoxicity. This suggests [99mTc]PYP as a non-invasive method for the evaluation of myocardial injury induced by AMT. According to the results of the present study, PRC has beneficial effects on AMT-induced cardiotoxicity.
  PubDate: 2020-03-26
Electropharmacological Characterization of Aciclovir in the
Halothane-Anesthetized Dogs: A Proposal of Evaluation Method for
Cardiovascular Safety Pharmacology of Anti-virus Drugs
- Abstract: Abstract Given limited information regarding the pathophysiology underlying aciclovir-associated, clinically observed cardiovascular adverse events including chest pain, tachycardia, bradycardia, palpitation, arrhythmia, hypertension and hypotension, we investigated its electropharmacological effects using the halothane-anesthetized beagle dogs. Aciclovir in doses of 2 and 20 mg/kg was sequentially infused over 10 min with an interval of 20 min (n = 4), which would achieve sub-therapeutic to supra-therapeutic levels of plasma concentrations. Aciclovir decreased the total peripheral vascular resistance along with the blood pressure in a dose-related manner, which increased the heart rate, ventricular contraction and atrioventricular nodal conduction speed probably via a reflex-mediated increase of sympathetic tone. No significant change was detected in the intra-atrial or intra-ventricular conduction, indicating that aciclovir may not inhibit atrial or ventricular INa. Aciclovir prolonged the repolarization period in a dose-related as well as in a reverse frequency-dependent manners, indicating that aciclovir may inhibit IKr, which was supported by the Tpeak − Tend prolongation. Aciclovir transiently prolonged the J − Tpeakc possibly through a reflex-mediated increase of sympathetic tone, indicating an increase of net inward current in the early repolarization phase. Thus, aciclovir may directly inhibit IKr, and also have the potential to indirectly induce Ca2+ overload leading to early afterdepolarization. These in vivo electropharmacological profile of aciclovir would partly explain the onset mechanism of clinical adverse events.
  PubDate: 2020-03-19
Exendin-4 Ameliorates Cardiac Remodeling in Experimentally Induced
Myocardial Infarction in Rats by Inhibiting PARP1/NF-κB Axis in A
SIRT1-Dependent Mechanism
- Abstract: Abstract Sirt1 is a potent inhibitor of both poly(ADP-ribose) polymerases1 (PARP1) and NF-kB. This study investigated the cardioprotective effect of exendin-4 on cardiac function and remodeling in rats after an expreimentally-induced myocardial infarction (MI) and explored if this protection involves SIRT1/PARP1 axis. Rats were divided into five groups (n = 10/each): sham, sham + exendin-4 (25 nmol/kg/day i.p.), MI (induced by LAD occlusion), MI + exendin-4, and sham + exendin-4 + EX527 (5 mg/2×/week) (a SIRT1 inhibitor). All treatments were given for 6 weeks post the induction of MI. In sham-operated and MI-induced rats, exendin-4 significantly upregulated Bcl-2 levels, enhanced activity, mRNA, and levels of SIRT1, inhibited activity, mRNA, and levels of PARP1, and reduced ROS generation and PARP1 acetylation. In MI-treated rats, these effects were associated with improved cardiac architectures and LV function, reduced collagen deposition, and reduced mRNA and total levels of TNF-α and IL-6, as well as, the activation of NF-κB p65. In addition, exendin-4 inhibited the interaction of PARP1 with p300, TGF-β1, Smad3, and NF-κB p65 and signficantly reduced mRNA and protein levels of collagen I/III and protein levels of MMP2/9. In conclusion, exendin-4 is a potent cardioprotective agent that prevents post-MI inflammation and cardiac remodeling by activating SIRT1-induced inhibition of PARP1.
  PubDate: 2020-03-19
Evolution of Electrocardiographic Repolarization Parameters During
Antiandrogen Therapy in Patients with Prostate Cancer and Hypogonadism
- Abstract: Abstract We assessed the effects of antiandrogen therapy on ECG parameters of ventricular repolarization related to arrhythmic risk in 35 patients aged 70.3 ± 7 years with advanced prostate cancer treated with degarelix associated with enzalutamide (group A, 26 patients) or degarelix monotherapy (group B, 9 patients). We analyzed Fridericia corrected Q-T interval (QTc), Q-T dispersion (QTd), J-Tpeak interval (JTp), mean and maximum Tpeak-Tend interval (Tpe) and Tpe/QT ratio, Tpeak-Tend dispersion (Tped), index of cardio-electrophysiological balance (iCEB) from ECG tracings, and occurrence of ventricular premature beats (VPB) recorded by Holter ECG, before initiation of medication (M0) and after 6 months of treatment (M1). The groups had similar demographics except for a higher prevalence of prior myocardial infarction in group B (p = 0.01). All patients had low serum testosterone at M1. Baseline QTc, QTd, maxTpe/QT, meanTpe, maxTpe, Tped values were higher in B compared to A. They had a significant prolongation at M1 only in A. 20 patients in A and 6 in B had a 10% prolongation or decrease of iCEB (p = 0.66). In 5 patients, VPB severity increased from non-complex to complex: 3 in A and 2 in B (p = 0.31), but no sustained ventricular arrhythmia was registered. In conclusion, after 6 months of treatment, patients with hypogonadism on degarelix associated with enzalutamide had significant prolongation of QTc, QTd, maxTpe, meanTpe/QT, maxTpe/QT, Tped compared to patients on degarelix alone. The proportion of patients with 10% iCEB variation was similar between groups. There was no record of severe arrhythmias during the first 6 months of treatment.
  PubDate: 2020-03-09
Mechanisms of the Cardiac Myocyte-Damaging Effects of Dasatinib
- Abstract: Abstract The anticancer drug dasatinib (Sprycel) is a BCR-ABL1-targeted tyrosine kinase inhibitor used in treating chronic myelogenous leukemia that has been shown in clinical trials to display cardiovascular toxicities. While dasatinib potently inhibits BCR-ABL1, it is not a highly selective kinase inhibitor and may have off-target effects. A neonatal rat cardiac myocyte model was used to investigate potential mechanisms by which dasatinib damaged myocytes. The anthracycline cardioprotective drug dexrazoxane was shown to be ineffective in preventing dasatinib-induced myocyte damage. Dasatinib treatment increased doxorubicin accumulation in myocytes and doxorubicin-induced myocyte damage, likely through its ability to bind to one or more ABC-type efflux transporters. Dasatinib induced myocyte damage either after a brief treatment that mimicked the clinical situation, or more potently after continuous treatment. Dasatinib slightly induced apoptosis in myocytes as evidenced by increases in caspase-3/7 activity. Dasatinib treatment reduced pERK levels in myocytes most likely through inhibition of RAF, which dasatinib strongly inhibits. Thus, inhibition of the RAF/MEK/ERK pro-survival pathway in the heart may be, in part, a mechanism by which dasatinib induces cardiovascular toxicity.
  PubDate: 2020-03-02
Human Amnion Membrane Proteins Prevent Doxorubicin-Induced Oxidative
Stress Injury and Apoptosis in Rat H9c2 Cardiomyocytes
- Abstract: Abstract Doxorubicin (DOX) is widely used as an effective chemotherapy agent in cancer treatment. Cardiac toxicity in cancer treatment with DOX demand urgent attention and no effective treatment has been established for DOX-induced cardiomyopathy. It has been well documented that human amniotic membrane proteins (AMPs), extracted from amnion membrane (AM), have antioxidant, anti-apoptotic, and cytoprotective properties. Therefore, in this study, we aimed to investigate the protective effects of AMPs against cardiotoxicity induced by DOX in cultured rat cardiomyocyte cells (H9c2). DOX-induced cell injury was evaluated using multi-parametric assay including thiazolyl blue tetrazolium bromide (MTT), the release of lactic dehydrogenase (LDH), intracellular Ca2+ , reactive oxygen species (ROS) levels, cellular antioxidant status, mitochondrial membrane potential (ΔΨm), malondialdehyde (MDA), and NF-κB p65 DNA-binding activity. Moreover, expression profiling of apoptosis-related genes (P53, Bcl-2, and Bax) and Annexin V by flow cytometry were used for cell apoptosis detection. It was shown that AMPs pretreatment inhibited the cell toxicity induced by DOX. AMPs effectively attenuated the increased levels of LDH, Ca2+ , ROS, and MDA and also simultaneously elevated the ΔΨm and antioxidant status such as superoxide dismutase (SOD) and Catalase (CAT) in pretreated H9c2 cardiomyocytes. Besides, the activity of NF-kB p65 was reduced and the p53 and Bax protein levels were inhibited in these myocardial cells subjected to DOX. These findings provide the first evidence that AMPs potently suppressed DOX-induced toxicity in cardiomyocytes through inhibition of oxidative stress and apoptosis. Thus, AMPs can be a potential therapeutic agent against DOX cardiotoxicity.
  PubDate: 2020-02-21
The Effect of High Lactate Level on Mortality in Acute Heart Failure
Patients With Reduced Ejection Fraction Without Cardiogenic Shock
- Abstract: Background We aimed to determine the effect of blood lactate levels on cardiovascular (CV) death and hospitalization for heart failure (HF) in acute HF patients with reduced left ventricular ejection fraction (EF). Methods Eighty-five acute HF patients with reduced ejection fraction were divided into two groups according to admission blood lactate levels. 48 of them had low blood lactate levels (< 2 mmol/l) and 37 of them had high blood lactate levels (≥ 2 mmol/l). Patients with acute coronary syndrome, cardiogenic shock, sepsis and low blood pressure at admission were excluded from the study. Primary endpoint is the composite of cardiovascular (CV) death and hospitalization for heart failure (HHF) in 6-month follow-up. Secondary endpoint is the change in NT-proBNP levels from admission to 72 h. Results Baseline characteristics of patients were similar in two groups. On baseline echocardiographic evaluation; patients with high lactate revealed a higher mitral E/A ratio (2.34 [0.43–3.31], p = 0.008) and a lower TAPSE ratio (14 [10–27], p = 0.008) than patients with low lactate levels. Over a median follow-up period of 6 months, the primary end point occurred in 28 (75.7%) of 37 patients assigned to high lactate group and in 20 (41.7%) of 48 patients assigned to low lactate group (p = 0.006). High lactate levels significantly increased the risk of CV death and HHF at 6 months by nearly 5.35-fold in acute HF patients with reduced EF. The change in NT-proBNP levels at 72nd hour after admission were similar between two groups. Conclusion Higher lactate levels at admission related with higher HHF at 6 months and may be related with higher risk of CV death in acute HF patients with reduced EF.
  PubDate: 2020-02-11
Action Potential Triangulation Explains Acute Proarrhythmic Effect of
Aliskiren in a Whole-Heart Model of Atrial Fibrillation
- Abstract: Abstract Recent experimental studies showed a protective effect of the renin inhibitor aliskiren regarding atrial structural remodeling. Purpose of this study was to assess acute electrophysiologic effects of aliskiren in a whole-heart model of atrial fibrillation (AF) and to investigate its impact on the ventricle. Twelve rabbit hearts were excised, retrogradely perfused, and paced at different cycle lengths. To enhance atrial vulnerability, a combination of acetylcholine (ACh) and isoproterenol (Iso) was infused and significantly reduced atrial action potential duration (aAPD90) and atrial effective refractory period (aERP). Additional infusion of aliskiren prolonged aAPD90 but did not alter aERP. A triangulation of action potential with ACh/Iso and a further triangulation after treatment with aliskiren were noted. Vulnerability to AF was tested by employing trains of burst pacing. Administration of ACh/Iso provoked more episodes of AF (baseline: 26 episodes, Iso/Ach: 48 episodes). Additional treatment with aliskiren induced AF significantly more often (108 episodes). Another nine hearts were perfused with aliskiren to examine its ventricular effects. Infusion with aliskiren abbreviated ventricular APD90 and ERP. Utilizing programmed ventricular stimulation, a trend towards more ventricular arrhythmias in aliskiren-treated hearts was observed. Though aliskiren did not reduce aAPD90 or aERP, acute treatment with aliskiren promoted AF. Triangulation of atrial action potentials, which is an established risk factor for ventricular proarrhythmia, may contribute to the increased atrial vulnerability. This effect may interfere with its recently demonstrated beneficial properties in atrial remodeling. Of note, aliskiren might have a proarrhythmic effect on the ventricular level.
  PubDate: 2020-02-01
Dasatinib can Impair Left Ventricular Mechanical Function But May Lack
Proarrhythmic Effect: A Proposal of Non-clinical Guidance for Predicting
Clinical Cardiovascular Adverse Events of Tyrosine Kinase Inhibitors
- Abstract: Abstract Tyrosine kinase inhibitors are known to clinically induce various types of cardiovascular adverse events; however, it is still difficult to predict them at preclinical stage. In order to explore how to better predict such drug-induced cardiovascular adverse events, we tried to develop a new protocol by assessing acute electrophysiological, cardiohemodynamic, and cytotoxic effects of dasatinib in vivo and in vitro. Dasatinib at 0.03 and 0.3 mg/kg was intravenously administered to the halothane-anesthetized dogs for 10 min with an interval of 20 min between the dosing (n = 4). Meanwhile, that at 0.1, 0.3, and 1 μM was cumulatively applied to the human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs) (n = 7). In the dogs, the low and high doses provided peak plasma concentrations of 40 ± 5 (0.08) and 615 ± 38 ng/mL (1.26 μM), respectively. The low dose decreased the heart rate, impaired the left ventricular mechanical function, and prolonged the ventricular effective refractory period. The high dose prolonged the repolarization period, induced hemorrhagic tendency, and increased plasma cardiac troponin I level in addition to enhancement of the changes observed after the low dose, whereas it neither affected the cardiac conduction nor induced ventricular arrhythmias. In the hiPSC-CMs, dasatinib prolonged the repolarization and refractory periods like in dogs, while it did not induce apoptotic or necrotic process, but that it increased the conduction speed. Clinically observed major cardiovascular adverse events of dasatinib were observed qualitatively by currently proposed assay protocol, which may become a useful guide for predicting the cardiotoxicity of new tyrosine kinase inhibitors.
  PubDate: 2020-02-01
Myocardial Repolarization Parameters and Neutrophil-to-Lymphocyte Ratio
are Associated with Cardiotoxicity in Carbon Monoxide Poisoning
- Abstract: Abstract The present study aims to examine the clinical values of complete blood count (CBC) bioindicators and corrected QT (QTc), Tpeak − Tend interval (Tp−e), Tpeak dispersion (Tp disp), and Tp−e/QT ratio that are the parameters of myocardial repolarization (M-rep) for cardiotoxicity, which develops due to acute carbon monoxide (CO) intoxication in patients admitted to the emergency service. This retrospective, cross-sectional, observational, and single-center study was conducted between April and June 2019. Statistical analysis was performed using the SPSS 23.0 software. Data of 234 participants were analyzed. Of these, 54.9% (n = 129) were female. Neutrophil-to-lymphocyte ratio (NLR), QTc, Tp–e values were significantly high in the CO intoxication group (p < 0.001, p < 0.001, and p < 0.001, respectively), whereas Tp−e/QTc ratio was significantly lower in the CO intoxication group than that in the control group (p < 0.001). NLR, Tp−e, Tp disp values were significantly high in the myocardial injury (M-inj) group (p < 0.001, p = 0.003, and p = 0.018, respectively). Furthermore, Tp−e/QTc ratio was significantly low in the M-inj group (p = 0.002). M-rep parameters and NLR are associated with CO intoxication and the development of M-inj. Moreover, these bioindicators and can provide clinicians an early indication of M-inj.
  PubDate: 2019-12-20