Cardiovascular Toxicology

Cardio- and neurotoxicity of amphetamines play an important role in worsening morbidity, making the initial evaluation of the patient’s status a potentially lifesaving action. The current study hypothesized that the S-100β serum level could predict the severity of acute amphetamine toxicity and the in-hospital outcome. The current study is a prospective cohort study conducted on 77 patients diagnosed with acute amphetamine exposure and referred to Aseer Poison Control Center, Saudi Arabia. The patients admitted to ICU showed significantly higher serum levels of S-100β in comparison to those not admitted (p < 0.05). Moreover, the S-100β level was significantly elevated among patients with prolonged QTc intervals. Receiver-operating characteristic curve of S-100β serum level as an in-hospital outcome predictor showed that at a cutoff value > 0.430 ug/L, the sensitivity of S-100β serum level as severity predictor was 100%, and the specificity was 74.1%. In conclusion, the current study revealed that the S-100β serum level could be used as an outcome predictor in hospital admission cases due to toxic amphetamine exposure and offers an idea about the cardiac and neuronal involvement. This can help select patients who will benefit most from ICU admission and early management and assess the severity of cases in settings where GC–MS is not available.

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.

There has an effective way to prevent intimal hyperplasia on vascular smooth muscle cell (VSMC) proliferation in grafted veins. The activator protein-1 (AP-1) transcription factor plays an important role in cardiovascular generation and angioplasty. Once activated, AP-1 binds its specific DNA sequence to promote the proliferation of VSMC, differentiation, and migration. The objectives of this study were to determine toxicological effects of AP-1 silencing study on proliferation, migration, and dedifferentiation of rat vascular smooth muscle cell. To suppress the expression of AP-1 gene, AP-1 siRNA was used to interfere post-transcription in rat primary VSMCs. To observe the expression of SM α-actin and downstream genes of AP-1, the activity of cell matrix metal proteinases and the migration ability of VSMC was examined by a modified Boyden chamber assay. Effects of AP-1 siRNA on proliferation and differentiation in rat VSMCs were evaluated by cell cycle analysis, DNA synthesis, MTT-test, and immunofluorescence. The results showed that the level of SM α-actin protein expression was increased. AP-1 siRNA also significantly decreased the MTT extinction value, DNA synthesis, PCNA expression, and the cell migration velocity when compared to the control group. AP-1 siRNA also clearly arrested cell cycle of VSM at the G0/G1 phase. Zymographic and Western blotting analyses showed that AP-1 siRNA suppressed serum-induced MMP-2 expression. These data suggest that the AP-1 siRNA was able to effectively inhibit the proliferation, migration, and dedifferentiation of smooth muscle cells. Thus, AP-1 siRNA provides a novel method to prevent intimal hyperplasia in blood vessel angioplasty.

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). 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. 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. 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.

Clinical use of doxorubicin (DOX) in cancer therapy is limited by its dose-dependent cardiotoxicity. But molecular mechanisms underlying this phenomenon have not been well defined. This study was to investigate the effect of DOX on the changes of global genomics in hearts. Acute cardiotoxicity was induced by giving C57BL/6J mice a single intraperitoneal injection of DOX (15 mg/kg). Cardiac function and apoptosis were monitored using echocardiography and TUNEL assay at days 1, 3 and 5. Myocardial glucose and ATP levels were measured. Microarray assays were used to screen gene expression profiles in the hearts at day 5, and the results were confirmed with qPCR analysis. DOX administration caused decreased cardiac function, increased cardiomyocyte apoptosis and decreased glucose and ATP levels. Microarrays showed 747 up-regulated genes and 438 down-regulated genes involved in seven main functional categories. Among them, metabolic pathway was the most affected by DOX. Several key genes, including 2,3-bisphosphoglycerate mutase (Bpgm), hexokinase 2, pyruvate dehydrogenase kinase, isoenzyme 4 and fructose-2,6-bisphosphate 2-phosphatase, are closely related to glucose metabolism. Gene co-expression networks suggested the core role of Bpgm in DOX cardiomyopathy. These results obtained in mice were further confirmed in cultured cardiomyocytes. In conclusion, genes involved in glucose metabolism, especially Bpgm, may play a central role in the pathogenesis of DOX-induced cardiotoxicity.

The incidence of myocardial infarction in patients who have the aquired immunodeficiency syndrome (AIDS) is increasing. However, no effective therapeutic agents have been discovered to reduce myocardial ischemia-reperfusion (I/R) injury in pathologies associated with AIDS. The aim of this study was to determine if infarct size is increased in murine AIDS after I/R injury and if I/R injury could be attenuated with vitamin E supplementation. Three groups of mice were studied: control, murine AIDS, and murine AIDS with vitamin E supplementation. Anesthetized mice were subjected to 30 min of left anterior descending coronary artery occlusion and 120 min of reperfusion. The hearts in mice that had murine AIDS had a larger infarct size compared to controls after I/R injury. Vitamin E supplementation significantly reduced infarct size and inhibited polymorphonuclear neutrophil (PMN) CD11b expression (p<0.05). However, vitamin E supplementation did not affect PMN reactive oxygen species (ROS) production and platelet CD62p expression. These results suggest that the reduction of myocardial I/R injury with vitamin E supplementation may be the result of the inhibition of PMN CD11b expression. Vitamin E may be a promising prophylactic agent for the reduction of the severity of myocardial I/R injury in patients who have AIDS.

Vascular smooth muscle cells (VSMCs) shift from a physiological contractile phenotype to an adverse proliferative or synthetic state, which is a major event leading to aortic disease. VSMCs are exposed to multiple mechanical signals from their microenvironment including vascular extracellular matrix (ECM) stiffness and stretch which regulate VSMC contraction. How ECM stiffness regulates the function and phenotype of VSMCs is not well understood. In this study, we introduce in vitro and in vivo models to evaluate the impact of ECM stiffnesses on VSMC function. Through unbiased transcriptome sequencing analysis, we detected upregulation of synthetic phenotype-related genes including osteopontin, matrix metalloproteinases, and inflammatory cytokines in VSMCs cultured using soft matrix hydrogels in vitro, suggesting VSMC dedifferentiation toward a synthetic phenotype upon ECM softening. For the in vivo model, the lysyl oxidase inhibitor β-aminopropionitrile monofumarate (BAPN) was administrated to disrupt the cross-linking of collagen to induce ECM softening. Consistently, decreased ECM stiffnesses promoted VSMC phenotypic switching to a synthetic phenotype as evidenced by upregulation of synthetic phenotype-related genes in the aortas of mice following BAPN treatment. Finally, BAPN-treated mice showed severe expansion and developed aortic dissection. Our study reveals the pivotal role of ECM softening in regulating the VSMC phenotype switch and provides a potential target for treating VSMC dysfunction and aortic dissection disease.

Exposure to nanoparticles has been associated with inflammation-related progression of atherosclerosis. To examine nanoparticle-induced cardiac effects in more detail, we characterized heart gene expression profiles alongside plasma proteins associated with cardiovascular disease in C57BL/6 mice intratracheally instilled with vehicle or 0.162 mg Printex 90 carbon black nanoparticles (CBNPs). Mice were killed 1, 3, and 28 days after the exposure and expression profiles were derived using DNA microarrays. Cardiac gene expression was unperturbed by CBNP exposure in two independent experiments, despite substantive changes in pulmonary and hepatic gene expression. MicroRNAs were not affected. Plasma levels of cell adhesion molecules (sE-selectin, sICAM-1, sVCAM-1) and total PAI-1 were immediately increased up to day 3, whereas Apo-A1 and Apo-E were marginally decreased on day 1. These data suggest that though adverse cardiovascular effects are likely following CBNP exposure, these effects are unlikely to be mediated by major direct effects on cardiac gene expression.

Chloroquine được sử dụng để điều trị cho bệnh nhân nhiễm COVID-19, mặc dù chưa có bằng chứng rõ ràng cho thấy nó có tác dụng tích cực. Chloroquine được biết đến là làm kéo dài khoảng QRS và QTc trên điện tâm đồ (ECG). Để đánh giá tác động của chloroquine lên khoảng QRS và QTc ở bệnh nhân COVID-19, chúng tôi đã đưa vào nghiên cứu tất cả bệnh nhân nội trú được điều trị bằng chloroquine cho COVID-19 tại Bệnh viện Spaarne Gasthuis (Haarlem/Hoofddorp, Hà Lan) và có thực hiện ECG cả trong 72 giờ trước và trong hoặc ít nhất 48 giờ sau khi điều trị. Chúng tôi đã phân tích (sự thay đổi của) khoảng QRS và QTc bằng cách sử dụng kiểm định t một mẫu. Trong số 106 bệnh nhân được điều trị bằng chloroquine, 70 người đạt tiêu chí đưa vào nghiên cứu. Thay đổi trung bình của khoảng QRS là 6.0 ms (95% CI 3.3–8.7) và thay đổi trung bình của khoảng QTc là 32.6 ms (95% CI 24.9–40.2) đã được hiệu chỉnh theo công thức Bazett và 38.1 ms (95% CI 30.4–45.9) đã được hiệu chỉnh theo công thức Fridericia. Trong 19 trong số 70 bệnh nhân (27%), khoảng QTc ở trên 500 ms sau khi bắt đầu điều trị chloroquine hoặc thay đổi khoảng QTc vượt quá 60 ms. Nhịp tim trên 90 bpm, suy thận và khoảng QTc dưới 450 ms là các yếu tố nguy cơ kéo dài khoảng QTc. Chloroquine làm kéo dài khoảng QTc ở một số lượng bệnh nhân đáng kể, có khả năng gây ra rối loạn nhịp tim. Do không có bằng chứng rõ ràng về tác dụng tích cực của chloroquine, những kết quả này không khuyến khích việc sử dụng chloroquine ở bệnh nhân COVID-19.

Các tác động lên hệ tim mạch của cisapride được tiêm tĩnh mạch với liều tăng dần, có và không có tiền điều trị bằng erythromycin, đã được đánh giá trên những chú chó được gây mê bằng morphine/chloralose. Những chú chó đã được gắn thiết bị cho phép ghi lại đồng thời điện tâm đồ (ECG), áp lực thất trái (LVP) và áp lực động mạch chủ (AoP), cũng như kích thích điện có lập trình (PES). Liều tiêm tĩnh mạch của cisapride từ 2 đến 8 mg/kg (gấp bốn lần liều điều trị khuyến nghị) làm tăng nhịp tim (HR) và kéo dài khoảng QT đã chỉnh (QTc) (p<0.05) so với nhóm chứng. Tiền điều trị bằng erythromycin không làm tăng cường tác động của cisapride lên HR hoặc QTc. Cisapride, dù có hay không có tiền điều trị bằng erythromycin, không tạo ra tác động lên AoP, nhưng đã làm giảm các chỉ số về khả năng co bóp của thất trái (dP/dt max giảm và PEP/ET tăng) so với nhóm chứng. Không có chú chó nào phát triển rối loạn nhịp tim tự phát và rối loạn nhịp tim không thể được gây ra bởi PES. Cisapride, có hoặc không có tiền điều trị bằng erythromycin, đã thay đổi định hướng của vector sóng T (p<0.05) so với nhóm chứng, cho thấy tác động chính của cisapride lên sự tái phân cực thất. Các thay đổi về QTc và sóng T quan sát được phù hợp với tác động đã biết của cisapride lên các kênh canine lKr.