Effect of Gestational Age on Maternofetal Vascular Function Following Single Maternal Engineered Nanoparticle Exposure Abstract Normal pregnancy outcome is accomplished, in part, by rapid and expansive physiological adaptations to the systemic circulation, the extent of which is specific to gestational day (GD) and anatomical location. Pregnancy-related hemodynamic changes in uterine placental blood flow stimulate compensatory vascular signaling and remodeling that begins early and continues throughout gestation. Exposure of the maternal environment to engineered nanomaterials (ENM) during pregnancy has been shown to impact health of the dam, fetus, and adult offspring; however, the consequences of specific temporal (gestational age) and spatial (vascular location) considerations are largely undetermined. We exposed pregnant Sprague–Dawley rats to nano-TiO2 aerosols at three critical periods of fetal development (GD 4, 12, and 17) to identify vascular perturbations associated with ENM exposure at these developmental milestones. Vascular reactivity of the maternal thoracic aorta, the uterine artery, the umbilical vein, and the fetal thoracic aorta were evaluated using wire myography on GD 20. While impairments were noted at each level of the maternofetal vascular tree and at each exposure day, our results indicate the greatest effects may be identified within the fetal vasculature (umbilical vein and fetal aorta), wherein effects of a single maternal inhalational exposure to nano-TiO2 on GD 4 modified responses to cholinergic, NO, and α-adrenergic signaling.

Acute and Subacute Effects of Low Versus High Doses of Standardized Panax ginseng Extract on the Heart: An Experimental Study Abstract Panax ginseng is commonly used in Chinese medicine and Western herbal preparations. However, it has also been recently noted to be associated with some cardiac pathologies-including cardiogenic shock due to acute anterior myocardial infarction, trans-ischemic attack, and stent thrombosis. This study was aimed to elucidate acute and subacute effects of the low and high doses of standardized Panax ginseng extract (sPGe) on cardiac functions. Rats were randomly assigned to control group, acute low-dose group (ALD), subacute low-dose group (SALD), acute high-dose group (AHD), and subacute high-dose group (SAHD). The cardiac effects of sPGe were evaluated using hemodynamic, biochemical, echocardiographic, genetic, and immunohistopathologic parameters. Mean blood pressures were significantly lower in all sPGe-treated groups compared with the control group. Troponin I and myoglobin levels were increased in the SALD, AHD, and SAHD groups. Mitral E-wave velocity was reduced after sPGe administration in all the groups. Acidophilic cytoplasm and pyknotic nucleus in myocardial fibers were observed in AHD and SAHD groups. Cu/Zn-SOD1 gene expressions were significantly higher in the sPGe-treated groups whereas caveolin 1 and VEGF-A gene expressions were not changed. According to our results, sPGe may have a potential effect to cause cardiac damage including diastolic dysfunction, heart failure with preserved ejection fraction, and reduction of blood pressure depending on the dose and duration of usage. Healthcare professionals must be aware of adverse reactions stemming from the supplementation use, particularly with cardiac symptoms.

Ischemic Preconditioning Efficacy Following Anabolic Steroid Usage: A Clear Difference Between Sedentary and Exercise-Trained Rat Hearts Abstract Previous studies show that anabolic steroids impair innate cardioprotective mechanisms. Here, we investigated the effect of supraphysiological doses of nandrolone on ischemic preconditioning (IPC) as a potent cardioprotective tool against ischemia reperfusion (IR) injury in rat hearts. Male Wistar rats in two experimental settings of sedentary and exercise-trained (60 min/day swimming, 5 days/week, for 8 weeks) were either pretreated with intramuscular injections of arachis oil (Arach, n = 16) as vehicle or nandrolone decanoate (ND, n = 8), 10 mg/kg/week, for 8 weeks. At the end, the hearts were excised and perfused in a Langendorff system. Then, the vehicle-treated hearts subdivided into the IR (30 min of LAD coronary artery occlusion and 120 min reperfusion, n = 8) and IPC (three cycles of 3-min ischemia and 3-min reperfusion before test ischemia, n = 8) groups and nandrolone-treated hearts served as ND + IPC (nandrolone pretreatment before IR and IPC protocols, n = 8) group. Post-ischemic cardiac function and infarct size were assessed. Reperfusion arrhythmias were analyzed using a standard scoring system. In sedentary hearts, ND slightly increased heart-to-body weight ratio and increased baseline cardiac contractile function. In trained hearts, ND markedly increased heart-to-body weight ratio which was also associated with enhanced baseline cardiac function. ND pretreatment enhanced protective effects of IPC in sedentary group; however, abolished these effects in exercise-trained group. The arrhythmia score was not significantly different between nandrolone-treated groups vs. respective preconditioned groups. Our findings show that ND impairs IPC-induced cardioprotection in exercise-trained rat hearts. Cardiac hypertrophy seems to play a crucial role in this response.

SSeCKS/Gravin/AKAP12 Inhibits PKCζ-Mediated Reduction of ERK5 Transactivation to Prevent Endotoxin-Induced Vascular dysfunction Abstract SSeCKS/Gravin/AKAP12 is a protein kinase C (PKC) substrate that inhibits the activity of PKC through binding with it. SSeCKS is expressed in vascular endothelial cells (ECs). The atypical PKC isoform ζ (PKCζ) is a pathologic mediator of endothelial dysfunction. However, the functional significance of SSeCKS/PKCζ dimerization in the vascular endothelium remains poorly understood. Given this background, we investigated the effects of SSeCKS on endothelial dysfunction and elucidated the possible mechanism involved. Vascular endothelial dysfunction and inflammatory changes were induced by treatment with bacterial endotoxin lipopolysaccharide (LPS, a vascular endothelial toxicity inducer). LPS can increase the level of SSeCKS. However, we also found that depletion of SSeCKS aggravated the LPS-induced vascular endothelial dysfunction, upregulated pro-inflammatory proteins and phosphorylation level of PKCζ, increased ROS formation, decreased extracellular-signal-regulated kinase 5 (ERK5) transcriptional activity, and reduced eNOS expression. Further examination revealed that depletion of SSeCKS increased PKCζ/ERK5 dimerization. These findings provide preliminary evidence that the expression of SSeCKS induced by LPS, as a negative feedback mechanism, has the potential to improve endothelium-dependent relaxation in vascular disease conditions by inhibiting PKCζ-mediated reduction of ERK5 transactivation.

Linoleic Acid Metabolite DiHOME Decreases Post-ischemic Cardiac Recovery in Murine Hearts Abstract Cardiac ischemia/reperfusion injury is associated with the formation and action of lipid mediators derived from polyunsaturated fatty acids. Among them, linoleic acid (LA) is metabolized to epoxyoctadecanoic acids (EpOMEs) by cytochrome P450 (CYP) epoxygenases and further to dihydroxyoctadecanoic acids (DiHOMEs) by soluble epoxide hydrolase (sEH). We hypothesized that EpOMEs and/or DiHOMEs may affect cardiac post-ischemic recovery and addressed this question using isolated murine hearts in a Langendorff system. Hearts from C57Bl6 mice were exposed to 12,13-EpOME, 12,13-DiHOME, or vehicle (phosphate buffered sodium; PBS). Effects on basal cardiac function and functional recovery during reperfusion following 20 min of ischemia were investigated. Electrocardiogram (ECG), left ventricular (LV) pressure and coronary flow (CF) were continuously measured. Ischemia reperfusion experiments were repeated after administration of the sEH-inhibitor 12-(3-adamantan-1-yl-ureido)dodecanoic acid (AUDA). At a concentration of 100 nM, both EpOME and DiHOME decreased post-ischemic functional recovery in murine hearts. There was no effect on basal cardiac parameters. The detrimental effects seen with EpOME, but not DiHOME, were averted by sEH inhibition (AUDA). Our results indicate that LA-derived mediators EpOME/DiHOME may play an important role in cardiac ischemic events. Inhibition of sEH could provide a novel treatment option to prevent detrimental DiHOME effects in acute cardiac ischemia.

Carnitine Supplementation Attenuates Sunitinib-Induced Inhibition of AMP-Activated Protein Kinase Downstream Signals in Cardiac Tissues Abstract This study has been initiated to investigate whether sunitinib (SUN) alters the expression of key genes engaged in mitochondrial transport and oxidation of long chain fatty acids (LCFA), and if so, whether these alterations should be viewed as a mechanism of SUN-induced cardiotoxicity, and to explore the molecular mechanisms whereby carnitine supplementation could attenuate SUN-induced cardiotoxicity. Adult male Wister albino rats were assigned to one of the four treatment groups: Rats in group 1 received no treatment but free access to tap water for 28 days. Rats in group 2 received l-carnitine (200 mg/kg/day) in drinking water for 28 days. Rats in group 3 received SUN (25 mg/kg/day) in drinking water for 28 days. Rats in group 4 received the same doses of l-carnitine and SUN in drinking water for 28 days. Treatment with SUN significantly increased heart weight, cardiac index, and cardiotoxicity enzymatic indices, as well as severe histopathological changes. Moreover, SUN significantly decreased level of adenosine monophosphate-activated protein kinase (AMPKα2), total carnitine, adenosine triphosphate (ATP) and carnitine palmitoyltransferase I (CPT I) expression and significantly increased acetyl-CoA carboxylase-2 (ACC2) expression and malonyl-CoA level in cardiac tissues. Interestingly, carnitine supplementation resulted in a complete reversal of all the biochemical, gene expression and histopathological changes-induced by SUN to the control values. In conclusion, data from this study suggest that SUN inhibits AMPK downstream signaling with the consequent inhibition of mitochondrial transport of LCFA and energy production in cardiac tissues. Carnitine supplementation attenuates SUN-induced cardiotoxicity.

Measurement of J–T peak c along with QT-Interval Prolongation May Increase the Assay Sensitivity and Specificity for Predicting the Onset of Drug-Induced Torsade de Pointes: Experimental Evidences Based on Proarrhythmia Model Animals Abstract dl-Sotalol which can block both K+ channel and ß-adrenoceptor has been shown to prolong the J–Tpeakc of electrocardiogram in beagle dogs but tended to shorten it in microminipigs, although the drug prolonged the QT interval in both animals under physiologically maintained experimental condition. In order to estimate how the changes in the J–Tpeakc in the normal hearts would be reflected in the pathologic hearts, we compared proarrhythmic effects of dl-sotalol by using proarrhythmia models of beagle dogs and microminipigs, of which atrioventricular node had been ablated > 2 months and 8–9 weeks before, respectively (n = 4 for each species). dl-Sotalol in an oral dose of 10 mg/kg induced torsade de pointes in three out of four beagle dogs, which degenerated into ventricular fibrillation. In microminipigs, the same dose did not trigger torsade de pointes at all, whereas intermittent ventricular pauses were observed in each animal after the drug treatment. These results indicate that assessment of the J–Tpeakc along with the QT-interval prolongation in healthy subjects may provide reliable information of risk prediction for patients susceptible to the drug-induced torsade de pointes.

Micheliolide Protects Against Doxorubicin-Induced Cardiotoxicity in Mice by Regulating PI3K/Akt/NF-kB Signaling Pathway Abstract Micheliolide (MCL) is a naturally derived anti-inflammatory agent. In the present investigation, we examined the protective potential of MCL against doxorubicin (DOX)-induced cardiotoxicity in mice. Mice were injected with a single 15-mg/kg intraperitoneal dose of DOX at day 1 and the study groups received daily 12.5, 25, and 50 mg/kg doses of MCL for 7 days. Cardiac histopathology, cardiac function, serum markers of cardiac injury, and tissue markers of inflammation, and oxidative stress were examined. MCL decreased serum levels of creatinine kinase MB (CK-MB) and cardiac troponin I (cTnI) levels, ameliorated cardiac tissue architecture, and improved cardiac stroke volume. Apart from reducing the activities of NF-kB p65 subunit, MCL attenuated the cardiac levels of PI3K, phosphorylated (p)-Akt, p-Bad, and caspase-3 levels and simultaneously elevated p-PTEN levels. While the gene expressions of tumor necrosis factor alpha (TNF-α) and interleukin 1 beta (IL-1β) were decreased, the tissue activities of superoxide dismutase (SOD) as well as gene expressions of heme oxygenase-1 (HO-1) and NAD(P)H quinone dehydrogenase-1 (NQO1) were increased after treatment with MCL. Furthermore, tissue levels of malondialdehyde (MDA) were also decreased. Collectively, these findings point to the protective effects of MCL against DOX-induced cardiotoxicity by regulating PI3K/Akt/NF-kB signaling pathway in mice.

Diagnostic Value of Parameters Related to White Blood Cell Counts for Troponin I Elevation in CO Poisoning Abstract To assess myocardial injury related to acute carbon monoxide (CO) poisoning, serial troponin I is measured in patients not presenting with troponin I elevation. This retrospective study investigated whether parameters related to white blood cell (WBC) counts (total and differential WBC counts, neutrophil-to-lymphocyte ratio (NLR), monocyte-to-lymphocyte ratio) improved predictive accuracy for troponin I elevation (> 0.04 ng/ml) in patients not presenting with evidence of myocardial injury. Serial parameters, troponin I values, and clinical courses were collected in 241 patients. Troponin I was elevated in 33 (13.7%) patients after hospitalization. The median lag times to troponin I elevation in patients with undetectable and detectable troponin I (0.015 ng/ml ≤ troponin I ≤ 0.04 ng/ml) at presentation were 5.9 h and 3.0 h, respectively. Patients with troponin I elevation after presentation had higher total WBC and neutrophil counts and NLRs and a lower lymphocyte count during the first 4 h after presentation than patients without troponin I elevation during hospitalization. Total WBC count, neutrophil count, and log NLR at presentation were selected as independent predictive factors for troponin I elevation after presentation. However, only the neutrophil count and log NLR at presentation improved the predictive accuracy in combination with clinical parameters compared with that achieved with a predictive model including only clinical parameters. The optimal cut-off neutrophil count and NLR were 5.21 × 103 /uL and 4.02, respectively. The total neutrophil count and NLR, which are widely available and inexpensive parameters obtained in the emergency department (ED), are promising screening tools for predicting the risk of troponin I elevation in patients without evidence of myocardial injury-related acute CO poisoning at presentation.

Fulminant Vascular and Cardiac Toxicity Associated with Tyrosine Kinase Inhibitor Sorafenib Abstract The use of vascular endothelial growth factor inhibitors such as sorafenib is limited by a risk of severe cardiovascular toxicity. A 28-year-old man with acute myeloid leukemia treated with prednisone, tacrolimus, and sorafenib following stem cell transplantation presented with severe bilateral lower extremity claudication. The patient was discharged against medical advice prior to finalizing a cardiovascular evaluation, but returned 1 week later with signs suggestive of septic shock. Laboratory tests revealed troponin I of 12.63 ng/mL, BNP of 1690 pg/mL, and negative infectious workup. Electrocardiogram showed sinus tachycardia and new pathologic Q waves in the anterior leads. Coronary angiography revealed severe multivessel coronary artery disease. Peripheral angiography revealed severely diseased left anterior and posterior tibial arteries, tibioperoneal trunk, and peroneal artery, and subtotal occlusion of the right posterior tibial artery. Multiple coronary and peripheral drug-eluting stents were implanted. An intra-aortic balloon pump was placed. Cardiac magnetic resonance imaging revealed chronic left ventricular infarction with some viability, 17% ejection fraction, and left ventricular mural thrombi. The patient opted for medical management. Persistent symptoms 9 months later led to repeat angiography, showing total occlusion of the second obtuse marginal artery due to in-stent restenosis with proximal stent fracture, and chronic total occlusion of the right internal iliac artery extending to the pudendal branch. Cardiac positron emission tomography/computed tomography viability study demonstrated viable myocardium, deeming revascularization appropriate. Symptom resolution was obtained with no recurrences. Sorafenib-associated vasculopathy may follow a fulminant course. Multimodality cardiovascular imaging is essential for optimal management.