MDMA Induced Cardio-toxicity and Pathological Myocardial Effects: A Systematic Review of Experimental Data and Autopsy Findings Abstract 3,4-Methylenedioxymethamphetamine (MDMA), more commonly known as “ecstasy,” is a semi-synthetic entactogenic phenylethylamine. In recent years it has gained popularity as a recreational drug whose use has registered an upward trend especially among adolescents and young adults. Despite its unwarranted reputation of being a “safe” drug, the actual scientific data denote that it actually leaves a trail of cardio-toxicity, above and beyond its neurotoxicity and other somatic effects. Both experimental and clinical data, in fact, indicate that ecstasy can alter cardiac function leading to rhythm disturbances, myocardial infarction, and even sudden cardiac death. We reviewed and summarized the bio-medical literature on the cardiovascular response to MDMA both in humans and laboratory animals. The aim was to elucidate the various pathophysiological mechanisms involved, as well as the clinical, autoptic, and experimental findings underlying MDMA-induced cardio-toxicity. Finally, an illustrative case report of ecstasy-induced adolescent death due to acute cardio-toxicity was described so as to highlight some key features.

Therapeutic Effects of Liraglutide, Oxytocin and Granulocyte Colony-Stimulating Factor in Doxorubicin-Induced Cardiomyopathy Model: An Experimental Animal Study Abstract Doxorubicin-induced (DXR) cardiomyopathy is a serious health issue in oncology patients. Effective treatment of this clinical situation still remains to be discovered. In this experimental animal study, we aimed to define therapeutic effects of liraglutide, oxytocin and granulocyte colony-stimulating factor in DXR-induced cardiomyopathy model. 40 male Sprague–Dawley rats were included to study. 32 rats were given doxorubicin (DXR) for cardiomyopathy model. DXR was administered intraperitonally (i.p.) at every other day of 2.5 mg/kg/day at six times. Eight rats were taken as normal group and no treatment was performed. 32 rats given doxorubicin were divided into 4 groups. Group 1 rats were assigned to a placebo group and was given with a 0.9% NaCl saline solution at a dose of 1 ml/kg/day i.p. (DXR + saline), Group 2 rats were given with 1.8 mg/kg/day of Liraglutide i.p. (DXR + LIR), Group 3 rats were given with 160 μg/kg/day oxytocin i.p. (DXR + OX), Group 4 rats were given with 100 μg/kg/day filgrastim i.p. (DXR + G-CSF). All medications were given for 15 days. On day 16, under anesthesia, ECG was recorded from derivation I. After that, blood samples were taken by tail vein puncture for biochemical analysis. Finally, the animals were euthanized and the heart removed and prepared for immunohistochemical examination. All three treatments were shown to ameliorate the toxic effect of doxorubicin in cardiac tissue with the best results in DXR + OX group. DXR + OX group had the most preserved tissue integrity examined by light microscopy, least immune expression level of CASPASE-3 (5.3 ± 0.9) (p < 0.001) the highest ECG QRS wave voltage amplitude (0.21 ± 0.008 mV) (p < 0.00001) least plasma MDA (115.3 ± 19.8 nm) (p < 0.001), TNF-alpha (26.6 ± 3.05 pg/ml) (p < 0.001), pentraxin-3 (2.7 ± 0.9 ng/ml) (p < 0.001), Troponin T (1.4 ± 0.08 pg/ml) (p < 0.001), pro-BNP (11.1 ± 3.6 pg/ml) (p < 0.001) levels among all three treatment groups. Consistent with previous literature, we found that OX treatment decreased oxidative, apoptotic and inflammatory activity in DXR-induced cardiomyopathy rat model as well as provided better tissue integrity and better results in clinically relevant measures of ECG assessment, plasma Troponin T and pro-BNP levels. LIR and G-CSF treatment caused similar results with less powerful effects. Our findings suggest that with the best results in OX treatment group, all three agents including LIR and G-CSF attenuates DXR-induced cardiomyopathy in this rat model.

2,3,7,8-Tetrachlorodibenzo- p -dioxin Induces Vascular Dysfunction That is Dependent on Perivascular Adipose and Cytochrome P4501A1 Expression Abstract 2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) is associated with hypertension in humans and animals, and studies suggest that cytochrome P4501A1 (Cyp1a1) induction and vascular dysfunction may contribute. We investigated the role of perivascular adipose tissue (PVAT) and Cyp1a1 in TCDD-induced vascular dysfunction. Cyp1a1 wild-type (WT) and knockout (KO) male mice were fed a dough pill containing 1,4-p-dioxane (TCDD vehicle control) on days 0 and 7, or 1000 ng/kg TCDD on day 0 and 250 ng/kg TCDD on day 7. mRNA expression of Cyp1a1 was assessed on days 3, 7, and 14, and of Cyp1b1, 1a2, angiotensinogen, and phosphodiesterase 5a on day 14. Dose-dependent vasoconstriction to a thromboxane A2 mimetic (U46619), and vasorelaxation to acetylcholine and a nitric oxide donor (S-nitroso-N-acetyl-DL-penicillamine, SNAP), were investigated in the aorta with and without PVAT. Cyp1a1 and 1a2 mRNA was induced in aorta of WT mice only with PVAT, and Cyp1a1 induction was sustained through day 14. TCDD significantly enhanced constriction to U46619 in WT mice and inhibited relaxation to both acetylcholine and SNAP, but only in the presence of PVAT. The effects of TCDD on U46619 constriction and SNAP relaxation were not observed in Cyp1a1 KO mice. Finally, in aorta + PVAT of WT mice TCDD significantly induced expression of angiotensinogen and phosphodiesterase 5a both of which could contribute to the TCDD-induced vascular dysfunction. These data establish PVAT as a TCDD target which is critically involved in mediating vascular dysfunction. Graphical Abstract TCDD enhances vasoconstriction via the thromboxane/prostanoid (TP) receptor and inhibits vasorelaxation via nitric oxide (NO) signaling. This TCDD-induced vascular dysfunction requires perivascular adipose (PVAT) and cytochrome P4501a1 (CYP1a1) induction.

Acylated Ghrelin Protects the Hearts of Rats from Doxorubicin-Induced Fas/FasL Apoptosis by Stimulating SERCA2a Mediated by Activation of PKA and Akt Abstract This study investigated if the cardioprotective effect of acylated ghrelin (AG) against doxorubicin (DOX)-induced cardiac toxicity in rats involves inhibition of Fas/FasL-mediated cell death. It also investigated if such an effect is mediated by restoring Ca+2 homeostasis from the aspect of stimulation of SERCA2a receptors. Adult male Wistar rats were divided into 4 groups (20 rats/each) as control, control + AG, DOX, and DOX + AG. AG was co-administered to all rats consecutively for 35 days. In addition, isolated cardiomyocytes were cultured and treated with AG in the presence or absence of DOX with or without pre-incubation with [d-Lys3]-GHRP-6 (a AG receptor antagonist), VIII (]an Akt inhibitor), or KT-5720 (a PKA inhibitor). AG increased LVSP, dp/dtmax, and dp/dtmin in both control and DOX-treated animals and improved cardiac ultrastructural changes in DOX-treated rats. It also inhibited ROS in control rats and lowered LVEDP, intracellular levels of ROS and Ca2+, and activity of calcineurin in LVs of DOX-treated rats. Concomitantly, it inhibited LV NFAT-4 nuclear translocation and downregulated their protein levels of Fas and FasL. Mechanistically, in control or DOX-treated hearts or cells, AG upregulated the levels of SERCA2a and increased the activities of PKA and Akt, leading to increase phosphorylation of phospholamban at Ser16 and Thr17. All these effects were abolished by d-Lys3-GHRP-6, VIII, or KT-5720 and were independent of food intake or GH/IGF-1. In conclusion, AG cardioprotection against DOX involves inhibition of extrinsic cell death and restoring normal Ca+2 homeostasis.

Coenzyme Q10 Alleviates Chronic Nucleoside Reverse Transcriptase Inhibitor-Induced Premature Endothelial Senescence Abstract Human immunodeficiency virus (HIV)-infected patients undergoing antiretroviral therapy are afforded an increased lifespan but also exhibit an elevated incidence of cardiovascular disease. HIV therapy uses a combination drug approach, and nucleoside reverse transcriptase inhibitors (NRTI) are a backbone of this therapy. Endothelial dysfunction is an initiating event in cardiovascular disease etiology, and in our prior studies, NRTIs induced an endothelial dysfunction that was dependent upon mitochondrial oxidative stress. Moreover, short-term NRTI administration induced a mitophagy-associated endothelial toxicity and increased reactive oxygen species (ROS) production that was rescued by coenzyme Q10 (Q10) or overexpression of a mitochondrial antioxidant enzyme. Thus, our objective was to examine mitochondrial toxicity in endothelial cells after chronic NRTI treatment and evaluate Q10 as a potential adjunct therapy for preventing NRTI-induced mitochondrial toxicity. Human aortic endothelial cells (HAEC) were exposed to chronic NRTI treatment, with or without Q10. ROS production, cell proliferation rate, levels of senescence, and mitochondrial bioenergetic function were determined. Chronic NRTI increased ROS production but decreased population doubling. In addition, NRTI increased the accumulation of β-galactosidase, indicative of an accelerated rate of senescence. Moreover, ATP-linked respiration was diminished. Co-treatment with Q10 delayed the onset of NRTI-induced senescence, decreased ROS production and rescued the cells’ mitochondrial respiration rate. Thus, our findings may suggest antioxidant enrichment approaches for reducing the cardiovascular side effects of NRTI therapy.

The Use of iPSC-Derived Cardiomyocytes and Optical Mapping for Erythromycin Arrhythmogenicity Testing Abstract Erythromycin is an antibiotic that prolongs the QT-interval and causes Torsade de Pointes (TdP) by blocking the rapid delayed rectifying potassium current (IKr) without affecting either the slow delayed rectifying potassium current (IKs) or inward rectifying potassium current (IK1). Erythromycin exerts this effect in the range of 1.5–100 μM. However, the mechanism of action underlying its cardiotoxic effect and its role in the induction of arrhythmias, especially in multicellular cardiac experimental models, remain unclear. In this study, the re-entry formation, conduction velocity, and maximum capture rate were investigated in a monolayer of human-induced pluripotent stem cell (iPSC)-derived cardiomyocytes from a healthy donor and in a neonatal rat ventricular myocyte (NRVM) monolayer using the optical mapping method under erythromycin concentrations of 15, 30, and 45 μM. In the monolayer of human iPSC-derived cardiomyocytes, the conduction velocity (CV) varied up to 12 ± 9% at concentrations of 15–45 μM as compared with that of the control, whereas the maximum capture rate (MCR) declined substantially up to 28 ± 12% (p < 0.01). In contrast, the tests on the NRVM monolayer showed no significant effect on the MCR. The results of the arrhythmogenicity test provided evidence for a “window” of concentrations of the drug (15–30 μM) at which the probability of re-entry increased.

Role of Speckle Tracking Echocardiography in the Evaluation of Breast Cancer Patients Undergoing Chemotherapy: Review and Meta-analysis of the Literature Abstract Diagnosis and management of Cancer therapeutics-related cardiac dysfunction is of crucial importance in breast cancer (BC) patients. The role of advanced echocardiographic techniques, such as deformation imaging, in the diagnosis and characterization of patients receiving cancer therapy has so far involved relatively small studies in the research setting. Therefore, we conducted a meta-analysis and systematic review of observational studies evaluating myocardial changes during chemotherapy detected through conventional echocardiographic parameters, such as 2D left ventricular ejection fraction (2D LVEF), and 2D Speckle tracking echocardiography (STE). The literature search retrieved 487 research works, articles, of which 17 were found to be pertinent with this topic. After full article review, 16 studies were considered suitable for the present analysis. Two separate analyses, one for the anthracyclines-based therapeutic regimen and one for the trastuzumab based therapeutic regimen, were performed. A significant reduction in 2D LVEF and 2D STE parameters during cancer therapy was found in both the investigations. Peak systolic global longitudinal strain demonstrated to be the most consistent 2D STE parameter in detecting early myocardial changes among all the studies. Thus, we confirmed the role of 2D STE for the early detection of myocardial damage, suggesting its crucial role in monitoring BC patients and eventually driving the introduction of cardioprotective treatment.

Intermittent Exposure to Chlorpyrifos Differentially Impacts Neuroreflex Control of Cardiorespiratory Function in Rats Abstract Previous studies showed that chlorpyrifos (CPF) acute exposure impaired cardiorespiratory reflexes. Evidence also indicates that continuous exposure to organophosphorus compounds impairs cardiovascular function. However, the effect of intermittent exposure to CPF, as may be experienced in the real world, on tonic and reflex cardiorespiratory function remains unexplored. Wistar rats were injected with saline or CPF for 4 weeks (3 times/week) or 12 weeks (once/week) at the doses of 7 mg/kg and 10 mg/kg. After exposure, blood pressure (BP), heart rate (HR), respiratory rate (fR), tidal volume (VT), and minute volume (VE) were recorded. Systolic BP and pulse interval (PI) variability, HR spectrum, spontaneous baroreflex and chemoreflex function were also evaluated. Plasma butyrylcholinesterase and brainstem acetylcholinesterase activities were quantified. Enzymatic activity of the CPF animals was reduced after both treatment periods. Baseline BP, HR, and fR, as well as systolic BP and PI variability indices, did not change, after CPF treatment. VT and VE were elevated in CPF animals. CPF exposure increased the very low-frequency component of the HR spectrum. Baroreflex gain was reduced after CPF 4-week exposure. Chemoreflex bradycardia was reduced in the CPF-treated rats. These data show that intermittent exposure to CPF impairs cardiorespiratory function in rats. These results may have important clinical implications for workers seasonally exposed to these compounds.

Direct and Indirect Effect of Air Particles Exposure Induce Nrf2-Dependent Cardiomyocyte Cellular Response In Vitro Abstract Air particulate matter has been associated with adverse effects in the cardiorespiratory system leading to cytotoxic and pro-inflammatory effects. Particulate matter-associated cardiac effects may be direct or indirect. While direct interactions may occur when inhaled ultrafine particles and/or particle components cross the air–blood barrier reaching the cardiac tissue, indirect interactions may occur as the result of pulmonary inflammation and consequently the release of inflammatory and oxidative mediators into the blood circulation. The aim of the study is to investigate the direct or indirectly the effect of Urban Air particles from downtown Buenos Aires (UAP-BA) and residual oil fly ash (ROFA), a surrogate of ambient air pollution, on cardiomyocytes (HL-1 cells). HL-1 cultured cells were directly exposed to particulate matter [UAP-BA (10–200 µg/ml), ROFA (1–100 µg/ml)] or indirectly exposed to conditioned media (CM) from particle-exposed alveolar macrophages (AM). Metabolic activity, reactive oxygen species (ROS), and Nrf2 expression were assessed by MTT, DHR 123, and immunocytochemistry techniques, respectively. We found that direct exposure of cardiomyocytes to UAP-BA or ROFA increased ROS generation but the oxidative damage did not alter metabolic activity likely by a concomitant increase in the cytoplasmic and nuclear Nrf2 expression. However, indirect exposure through CM caused a marked reduction on cardiac metabolic activity probably due to the rise in ROS generation without Nrf2 translocation into the cell nuclei. In this in vitro model, our results indicate both direct and indirect PM effects on cardiomyocytes cells in culture. Our findings employing lung and cardiomyocytes cells provide support to the hypothesis that particle-induced cardiac alteration may possibly involve lung-derived mediators.

Slow-Release Doxorubicin Pellets Generate Myocardial Cardiotoxic Changes in Mice Without Significant Systemic Toxicity Abstract An increasing volume of pre-clinical and clinical-translational research is attempting to identify novel biomarkers for improved diagnosis and risk-stratification of chemotherapy-induced cardiotoxicity. Most published animal models have employed weekly intraperitoneal injections of doxorubicin to reach a desired cumulative dose. This approach can be associated with severe systemic toxicity which limits the animal model usefulness, particularly for advanced imaging. In the current study, slow-release subcutaneous doxorubicin pellets demonstrated histopathologic evidence of cardiotoxicity at doses similar to standard human dose-equivalents without limiting animal survival or ability to participate in advanced imaging studies. This approach may provide a more robust cardiotoxicity animal model.