Xinshuitong Capsule extract attenuates doxorubicin-induced myocardial edema via regulation of cardiac aquaporins in the chronic heart failure rats.

Doxorubicin (Dox), an effective antineoplastic drug, was limited use for cardiotoxicity. Xinshuitong Capsule (XST), a patented herbal formula, showed desirable beneficial effects in the treatment of chronic heart failure (CHF) patients. However, the drug on Dox-induced cardiotoxicity remains unclear. Ninety male Sprague-Dawley rats were randomized into two groups: 15 rats were selected as the normal group and 75 rats were injected intraperitoneally with Dox to establish CHF rat models, the success ones were randomly divided into five groups: low XST (LXST), medium XST (MXST) or high XST (HXST) (4.9, 9.8, or 19.6 g/kg d) administrated intragastrically twice a day for 4 weeks, with the captopril-treated group and the model group as comparison. The model group showed the cardiac functions generally impaired, and CHF mortality rate higher (47%) than those in the XST-treated groups (averaged 24%, P < 0.05). Compared with XST-treated groups, myocardial remodeling, inflammation and desarcomerization, and higher water content more severe in the cardiac tissue in the model group (P < 0.05), which was associated with higher expressions of mRNA or protein levels of AQP1, 4 and 7. Dox-impaired cardiac functions, cardiac remodeling and myocardial edema could be dose-dependently reverted by XST treatment. XST could inhibit AQP1, 4 and 7 at mRNA levels or at protein levels, which was associated with the attenuation of myocardial edema and cardiac remodeling, decreasing the ventricular stiffness and improving the cardiac functions and rats' survival. AQPs is involved in cardiac edema composed one of the mechanisms of Dox-induced cardiotoxicity, XSTvia inhibition of AQPs relieved the Dox-induced side effects.

Sodium dehydroacetate induces cardiovascular toxicity associated with Ca2+ imbalance in zebrafish.

The environmental effects of additives have attracted increasing attention. Sodium dehydroacetate (DHA-S), as an approved preservative, is widely added in processed foods, cosmetics and personal care products. However, DHA-S has been recently reported to induce hemorrhage and coagulation aberration in rats. Yet little is known about the ecotoxicological effect and underlying mechanisms of DHA-S. Here, we utilized the advantage of zebrafish model to evaluate such effects. DHA-S induced cerebral hemorrhage, mandibular dysplasia and pericardial edema in zebrafish after 24 h exposure (48-72 hpf) at 50 mg/L. We also observed the defective heart looping and apoptosis in DHA-S-treated zebrafish through o-dianisidine and acridine orange staining. Meanwhile, DHA-S induced the deficiency of Ca2+ and vitamin D3 in zebrafish. We further demonstrated that DHA-S stimulated Ca2+ influx resulting in Ca2+-dependent mitochondrial damage in cardiomyocytes. Additionally, DHA-S inhibited glucose uptake and repressed the biosynthesis of amino acids. Finally, we identified that sodium bicarbonate could rescue zebrafish from DHA-S induced cardiovascular toxicity. Altogether, our results suggest that DHA-S is a potential risk for cardiovascular system.

Blood vessels are primary targets for 2,3,7,8-tetrachlorodibenzo-p-dioxin in pre-cardiac edema formation in larval zebrafish.

2,3,7,8-Tetrachlorodibenzo-p-dioxin (TCDD) has adverse effects on the development and function of the heart in zebrafish eleutheroembryos (embryos and larvae). We previously reported that TCDD reduced blood flow in the mesencephalic vein of zebrafish eleutheroembryos long before inducing pericardial edema. In the present study, we compared early edema (pre-cardiac edema), reduction of deduced cardiac output and reduction of blood flow in the dorsal aorta and cardinal vein caused by TCDD. In the same group of eleutheroembryos, TCDD (1.0 ppb) caused pre-cardiac edema and circulation failure at the cardinal vein in the central trunk region with the similar time courses from 42 to 54 h post fertilization (hpf), while the same concentration of TCDD did not significantly affect aortic circulation in the central trunk region or cardiac output. The dependence of pre-cardiac edema on TCDD concentration (0-2.0 ppb) at 55 hpf correlated well with the dependence of blood flow through the cardinal vein on TCDD concentration. Several treatments that markedly inhibited TCDD-induced pre-cardiac edema such as knockdown of aryl hydrocarbon receptor nuclear translocator-1 (ARNT1) and treatment with ascorbic acid, an antioxidant, did not significantly prevent the reduction of cardiac output at 55 hpf caused by 2.0 ppb TCDD. TCDD caused hemorrhage and extravasation of Evans blue that was intravascularly injected with bovine serum albumin, suggesting an increase in endothelium permeability to serum protein induced by TCDD. The results suggest that the blood vessels are primary targets of TCDD in edema formation in larval zebrafish.

The effect of rutin on cisplatin-induced oxidative cardiac damage in rats.

OBJECTIVE: Cisplatin is an anticancer drug used for treating childhood solid tumors. Symptoms related to cisplatin-induced cardiovascular adverse effects may be mild or severe. Rutin (vitamin P1) has many properties, including as antioxidant, anticancer, antidiabetic, antimicrobial, antiulcer, and tissue renewal properties. Therefore, we aimed to biochemically, histopathologically, and immunohistochemically demonstrate the effect of rutin on cisplatin-induced cardiotoxicity in rats. METHODS: The rats included in our study were divided into four groups: Healthy group (HE), 5-mg/kg cisplatin group (CP), 50 mg/kg rutin+5-mg/kg cisplatin (CR-50), 100-mg/kg rutin+5-mg/kg cisplatin (CR-100) group. RESULTS: CP group administered cisplatin had significantly increased blood, serum, and cardiac tissue malondialdehyde (MDA), interleukin 1 beta (IL-1ß), tumor necrosis factor alpha (TNF-α), troponin I, creatine kinase (CK), and CK-MB levels compared to the HE group, whereas there was a significant decrease in the total glutathione (tGSH) levels. Rutin was observed to prevent the increase in MDA, IL-1ß, TNF-α, troponin I, CK, and CK-MB levels as well as prevent the decrease in tGSH levels more significantly when administered at a 100-mg/kg dose than at a 50-mg/kg dose. Histopathologically, cardiac necrosis, dilated/congested blood vessels, hemorrhage, polymorphonuclear leukocyte, edema, and cells with pyknotic nuclei were observed in the CP group. Rutin was shown to prevent cisplatin-induced cardiac damage more effectively when used at a100-mg/kg dose than at a 50-mg/kg dose. CONCLUSION: These results suggest that rutin is useful for preventing cisplatin-related cardiovascular damage.

Developmental toxicity and inhibition of the fungicide hymexazol to melanin biosynthesis in zebrafish embryos.

Hymexazol is an efficacious and widely used fungicide. However, its environmental toxicological assessment has not been well documented. It had no report of its toxicity to fish embryo. Fish embryo acute toxicity tests are highly predictive of aquatic embryotoxicity outcome. In this study, zebrafish (Danio rerio) embryos were exposed to hymexazol at varying concentrations for the study of the developmental toxicity, melanin biosynthesis, biochemical and transcriptional endpoints. The embryotoxicity tests indicated that the 96h LC50 value of hymexazol was 649mg/L with a 95% confidence interval range of 632-667mg/L. Hymexazol at concentrations of 417-738mg/L decreased the heart rate and increased the voluntary swing. Hymexazol inhibited normal development at concentrations above 554mg/L. the 96h EC50 was 411mg/L. Hymexazol in a concentration range of 417-738mg/L induced cardiac edema and yolk sac edema. Exposure of hymexazol at such concentrations to zebrafish embryos for 48h decreased the pigment area density compared with the no hymexazol control. Tyrosinase activity was inhibited by hymexazol relative to the untreated control. The P53 mRNA expression level in embryos upon exposure to 480mg/L or greater of hymexazol was significantly higher than that of the control. The results indicated that hymexazol has quite low acute toxicity and low embryotoxicity to zebrafish.

Characterization of the Changes in Cardiac Structure and Function in Mice Treated With Anthracyclines Using Serial Cardiac Magnetic Resonance Imaging.

BACKGROUND: Anthracyclines are cardiotoxic; however, there are limited data characterizing the serial changes in cardiac structure and function after anthracyclines. The aim of this study was to use cardiac magnetic resonance to characterize anthracycline-induced cardiotoxicity in mice. METHODS AND RESULTS: This was a longitudinal cardiac magnetic resonance and histological study of 45 wild-type male mice randomized to doxorubicin (n=30, 5 mg/kg of doxorubicin/week for 5 weeks) or placebo (n=15). A cardiac magnetic resonance was performed at baseline and at 5, 10, and 20 weeks after randomization. Measures of primary interest included left ventricular ejection fraction, myocardial edema (multiecho short-axis spin-echo acquisition), and myocardial fibrosis (Look-Locker gradient echo). In doxorubicin-treated mice versus placebo, there was an increase in myocardial edema at 5 weeks (T2 values of 32±4 versus 21±3 ms; P<0.05), followed by a reduction in left ventricular ejection fraction (54±6 versus 63±5%; P<0.05) and an increase in myocardial fibrosis (extracellular volume of 0.34±0.03 versus 0.27±0.03; P<0.05) at 10 weeks. There was a strong association between the early (5 weeks) increase in edema and the subacute (10 weeks) increase in fibrosis (r=0.90; P<0.001). Both the increase in edema and fibrosis predicted the late doxorubicin-induced mortality in mice (P<0.001). CONCLUSIONS: Our data suggest that, in mice, anthracycline-induced cardiotoxicity is associated with an early increase in cardiac edema and a subsequent increase in myocardial fibrosis. The early increase in edema and subacute increase in fibrosis are strongly linked and are both predictive of late mortality.

Anthracycline-Associated T1 Mapping Characteristics Are Elevated Independent of the Presence of Cardiovascular Comorbidities in Cancer Survivors.

BACKGROUND: Cardiovascular magnetic resonance T1 mapping characteristics are elevated in adult cancer survivors; however, it remains unknown whether these elevations are related to age or presence of coincident cardiovascular comorbidities. METHODS AND RESULTS: We performed blinded cardiovascular magnetic resonance analyses of left ventricular T1 and extracellular volume (ECV) fraction in 327 individuals (65% women, aged 64±12 years). Thirty-seven individuals had breast cancer or a hematologic malignancy but had not yet initiated their treatment, and 54 cancer survivors who received either anthracycline-based (n=37) or nonanthracycline-based (n=17) chemotherapy 2.8±1.3 years earlier were compared with 236 cancer-free participants. Multivariable analyses were performed to determine the association between T1/ECV measures and variables associated with myocardial fibrosis. Age-adjusted native T1 was elevated pre- (1058±7 ms) and post- (1040±7 ms) receipt of anthracycline chemotherapy versus comparators (965±3 ms; P<0.0001 for both). Age-adjusted ECV, a marker of myocardial fibrosis, was elevated in anthracycline-treated cancer participants (30.4±0.7%) compared with either pretreatment cancer (27.8±0.7%; P<0.01) or cancer-free comparators (26.9±0.2%; P<0.0001). T1 and ECV of nonanthracycline survivors were no different than pretreatment survivors (P=0.17 and P=0.16, respectively). Native T1 and ECV remained elevated in cancer survivors after accounting for demographics (including age), myocardial fibrosis risk factors, and left ventricular ejection fraction or myocardial mass index (P<0.0001 for all). CONCLUSIONS: Three years after anthracycline-based chemotherapy, elevations in myocardial T1 and ECV occur independent of underlying cancer or cardiovascular comorbidities, suggesting that imaging biomarkers of interstitial fibrosis in cancer survivors are related to prior receipt of a potentially cardiotoxic cancer treatment regimen.

Protective effect of prostacyclin against pre-cardiac edema caused by 2,3,7,8-tetrachlorodibenzo-p-dioxin and a thromboxane receptor agonist in developing zebrafish.

The role of prostaglandin pathways has been suggested in some toxicological responses to dioxins. Cyclooxygenase type 2b (COX2b), thromboxane synthase, and the thromboxane receptor (TP) pathway have been implicated in mediating 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD)-induced pre-cardiac edema in developing zebrafish at 55 h post fertilization (hpf). Pre-cardiac edema refers to edema located in a small cavity between the heart and body wall of zebrafish eleutheroembryos. In the present study, we assessed the role of prostacyclin, which counteracts some biological effects of thromboxane, in TCDD-induced pre-cardiac edema. Pre-cardiac edema induced by TCDD exposure (0.5 and 1 ppb) beginning at 24 hpf was markedly inhibited by exposure to beraprost (5 and 10 µM), a prostacyclin receptor (IP) agonist, beginning at 33 hpf. The preventive effect of beraprost was reduced by exposure to CAY10441 (10 µM), an IP antagonist starting at 33 hpf. Knockdowns of the IP receptor (IP-KD) with two different morpholinos caused edema by themselves and enhanced pre-cardiac edema caused by the low concentration of TCDD (0.5 ppb). On the other hand, short exposure beginning at 48 hpf to U46619 (7.5-30 µM), a thromboxane receptor agonist caused pre-cardiac edema, which was inhibited by exposure beginning at 48 hpf to both ICI-192,605 (24 µM), a TP antagonist, and beraprost. Expression of prostacyclin synthase was increased from fertilization, plateaued by 48 hpf, and was maintained until at least 96 hpf. Overall, the results demonstrate a preventive effect of prostacyclin on TCDD-induced pre-cardiac edema in developing zebrafish.

Longitudinal assessment of concurrent changes in left ventricular ejection fraction and left ventricular myocardial tissue characteristics after administration of cardiotoxic chemotherapies using T1-weighted and T2-weighted cardiovascular magnetic resonance.

BACKGROUND: In a murine anthracycline-related cardiotoxicity model, increases in cardiovascular magnetic resonance myocardial contrast-enhanced T1-weighted signal intensity are associated with myocellular injury and decreases with left ventricular ejection fraction. We sought to determine whether T1- and T2-weighted measures of signal intensity associate with decreases in left ventricular ejection fraction in human subjects receiving potentially cardiotoxic chemotherapy. METHODS AND RESULTS: In 65 individuals with breast cancer (n=51) or a hematologic malignancy (n=14), we measured left ventricular volumes, ejection fraction, and contrast-enhanced T1-weighted and T2-weighted signal intensity before and 3 months after initiating potentially cardiotoxic chemotherapy using blinded, unpaired analysis of cardiovascular magnetic resonance images. Participants were aged 51 ± 12 years, of whom 55% received an anthracycline, 38% received a monoclonal antibody, and 6% received an antimicrotubule agent. Overall, left ventricular ejection fraction decreased from 57 ± 6% to 54 ± 7% (P<0.001) because of an increase in end-systolic volume (P<0.05). T1-weighted signal intensities also increased from 14.1 ± 5.1 to 15.9 ± 6.8 (P<0.05), with baseline values trending higher among individuals who received chemotherapy before study enrollment (P=0.06). Changes in T1-weighted signal intensity did not differ within the 17 LV myocardial segments (P=0.97). Myocardial edema quantified from T2-weighted images did not change significantly after 3 months (P=0.70). CONCLUSIONS: Concordant with previous animal studies, cardiovascular magnetic resonance measures of contrast-enhanced T1-weighted signal intensity occur commensurate with small but significant left ventricular ejection fraction declines 3 months after the receipt of potentially cardiotoxic chemotherapy. These data indicate that changes in T1-weighted signal intensity may serve as an early marker of subclinical injury related to the administration of potentially cardiotoxic chemotherapy in human subjects.

Involvement of COX2-thromboxane pathway in TCDD-induced precardiac edema in developing zebrafish.

The cardiovascular system is one of the most characteristic and important targets for developmental toxicity by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) in fish larvae. However, knowledge of the mechanism of TCDD-induced edema after heterodimerization of aryl hydrocarbon receptor type 2 (AHR2) and AHR nuclear translocator type 1 (ARNT1) is still limited. In the present study, microscopic analysis with a high-speed camera revealed that TCDD increased the size of a small cavity between the heart and body wall in early eleutheroembryos, a toxic effect that we designate as precardiac edema. A concentration-response curve for precardiac edema at 2 days post fertilization (dpf) showed close similarity to that for conventional pericardial edema at 3 dpf. Precardiac edema caused by TCDD was reduced by morpholino knockdown of AHR2 and ARNT1, as well as by an antioxidant (ascorbic acid). A selective inhibitor of cyclooxygenase type 2 (COX2), NS398, also markedly inhibited TCDD-induced precardiac edema. A thromboxane receptor (TP) antagonist, ICI-192,605 almost abolished TCDD-induced precardiac edema and this effect was canceled by U46619, a TP agonist, which was not influential in the action of TCDD by itself. Knockdown of COX2b and thromboxane A synthase 1 (TBXS), but not COX2a, strongly reduced TCDD-induced precardiac edema. Knockdown of COX2b was without effect on mesencephalic circulation failure caused by TCDD. The edema by TCDD was also inhibited by knockdown of c-mpl, a thrombopoietin receptor necessary for thromobocyte production. Finally, induction of COX2b, but not COX2a, by TCDD was seen in eleutheroembryos at 3 dpf. These results suggest a role of the COX2b-thromboxane pathway in precardiac edema formation following TCDD exposure in developing zebrafish.

Impaired cardiovascular function caused by different stressors elicits a common pathological and transcriptional response in zebrafish embryos.

Zebrafish embryos have been widely used to study the genes and processes needed for normal vertebrate heart development. We recently observed that exposure to 2,3,7,8-tetra-chlorodibenzo-p-dioxin (TCDD) or retinoic acid (RA) produces very similar signs of heart failure in developing zebrafish via divergent molecular pathways. The fact that diverse stressors and mutations cause severe pericardial edema and circulatory collapse in developing zebrafish has been largely unexplored. We hypothesized that unrelated chemicals can trigger a common pathological response leading to the same end-stage heart failure. To test this hypothesis, we compared the effects of TCDD, RA, carbaryl, valproic acid, and morpholino oligonucleotide (MO) knockdown of TBX5 on the developing heart in zebrafish embryos. These model stressors have all been previously reported to affect zebrafish heart development, and elicited very similar signs of embryonic heart failure. Microarray analysis showed that one cluster of 92 transcripts affected by these different treatments was significantly downregulated by all treatments. This gene cluster is composed of transcripts required for chromosome assembly, DNA replication, and cell cycle progression. We refer to this cluster as the cell cycle gene cluster (CCGC). Immunohistochemistry revealed that downregulation of the CCGC precedes a halt in cardiomyocyte proliferation in the hearts of zebrafish exposed to any of the treatments. Previous work has shown that the initial response to TCDD is a decrease in cardiac output. Since this precedes the signs of edema, heart failure, and fall in CCGC expression, we postulated that any factor that decreases cardiac output will produce the same syndrome of heart failure responses. To test this, we used MO knockdown of cardiac troponin T2 (TNNT2) to specifically block contractility. The TNNT2-MO produced exactly the same signs of cardiotoxicity as the other treatments, including downregulation of the signature CCGC. Our results indicate that agents altering cardiac output can have amplified consequences during specific periods in development.

A small molecule inhibitor of redox-regulated protein translocation into mitochondria.

The mitochondrial disulfide relay system of Mia40 and Erv1/ALR facilitates import of the small translocase of the inner membrane (Tim) proteins and cysteine-rich proteins. A chemical screen identified small molecules that inhibit Erv1 oxidase activity, thereby facilitating dissection of the disulfide relay system in yeast and vertebrate mitochondria. One molecule, mitochondrial protein import blockers from the Carla Koehler laboratory (MitoBloCK-6), attenuated the import of Erv1 substrates into yeast mitochondria and inhibited oxidation of Tim13 and Cmc1 in in vitro reconstitution assays. In addition, MitoBloCK-6 revealed an unexpected role for Erv1 in the carrier import pathway, namely transferring substrates from the translocase of the outer membrane complex onto the small Tim complexes. Cardiac development was impaired in MitoBloCK-6-exposed zebrafish embryos. Finally, MitoBloCK-6 induced apoptosis via cytochrome c release in human embryonic stem cells (hESCs) but not in differentiated cells, suggesting an important role for ALR in hESC homeostasis.

Developmental toxicity of dextromethorphan in zebrafish embryos/larvae.

Dextromethorphan is widely used in over-the-counter cough and cold medications. Its efficacy and safety for infants and young children remains to be clarified. The present study was designed to use zebrafish as a model to investigate the potential toxicity of dextromethorphan during embryonic and larval development. Three sets of zebrafish embryos/larvae were exposed to dextromethorphan at 24, 48 and 72 h post fertilization (hpf), respectively, during the embryonic/larval development. Compared with the 48 and 72 hpf exposure sets, the embryos/larvae in the 24 hpf exposure set showed much higher mortality rates which increased in a dose-dependent manner. Bradycardia and reduced blood flow were observed for the embryos/larvae treated with increasing concentrations of dextromethorphan. Morphological effects of dextromethorphan exposure, including yolk sac and cardiac edema, craniofacial malformation, lordosis, non-inflated swim bladder and missing gill, were also more frequent and severe among zebrafish embryos/larvae exposed to dextromethorphan at 24 hpf. Whether the more frequent and severe developmental toxicity of dextromethorphan observed among the embryos/larvae in the 24 hpf exposure set, as compared with the 48 and 72 hpf exposure sets, is due to the developmental expression of the phase I and phase II enzymes involved in the metabolism of dextromethorphan remains to be clarified. A reverse transcription-polymerase chain reaction analysis, nevertheless, revealed developmental stage-dependent expression of mRNAs encoding SULT3 ST1 and SULT3 ST3, two enzymes previously shown to be capable of sulfating dextrorphan, an active metabolite of dextromethorphan.

AhR2-mediated, CYP1A-independent cardiovascular toxicity in zebrafish (Danio rerio) embryos exposed to retene.

In the embryo-larval stages of fish, alkylphenanthrenes such as retene (7-isopropyl-1-methylphenanthrene) produce a suite of developmental abnormalities typical of exposure to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), including pericardial and yolk sac edema, cardiovascular dysfunction, and skeletal deformities. To investigate the mechanism and target tissue of retene toxicity, we used observational, histological, and protein knockdown techniques in zebrafish (Danio rerio) embryos. The primary overt signs of toxicity are pericardial edema and reduced blood flow, first observed at 36 h post-fertilization (hpf). The most pronounced effects at this stage are a reduced layer of cardiac jelly in the atrium and reduced diastolic filling. Conversely, an increased layer of cardiac jelly is observed at 72 hpf in retene-exposed embryos. Induction of cytochrome P4501A (CYP1A) is apparent in a subset of cardiomyocytes by 48 hpf suggesting that early cardiac effects may be due to AhR activation in the myocardium. Myocardial CYP1A induction is transient, with only endocardial induction observed at 72 hpf. Knockdown of cyp1a by morpholino oligonucleotides does not affect retene toxicity; however, ahr2 knockdown prevents toxicity. Thus, the mechanism of retene cardiotoxicity is AhR2-mediated and CYP1A-independent, similar to TCDD; however, the onset and proximate signs of retene toxicity differ from those of TCDD. Retene cardiotoxicity also differs mechanistically from the cardiac effects of non-alkylated phenanthrane, illustrating that alkyl groups can alter toxic action. These findings have implications for understanding the toxicity of complex mixtures containing alkylated and non-alkylated polycyclic aromatic hydrocarbons.

Evaluation of adverse cardiac effects induced by arsenic trioxide, a potent anti-APL drug.

Arsenic trioxide (ATO/As2O3) is a promising drug for patients with a relapse of acute promyelocytic leukemia (APL); however, it frequently causes fatal arrhythmias. This study aims to investigate the various cellular and molecular mechanisms of adverse cardiac effects and the electrophysi-ological alterations caused by As2O3. We show the dose-dependent effect of ATO (0.2, 0.4, 0.8, 1.6, 3.2, 6.4 mum) on electrically driven cardiac action potential from the papillary muscle of the guinea pig. ATO causes a significant prolongation of action potential duration (APD) at various levels of repolarization, conduction delay, and increased triangulation, which is a novel marker for the proarrhythmic potential of a compound. Electrolyte imbalance (hypomagnesemia and hypokalemia) has also been found to cause amplification of ATO toxicity. Since ion channels play a very important role in the generation of cardiac action potential, we used various ion channel modulators such as choline, minoxidil, nifedipine, and verapamil to determine whether these agents could antagonize electrophysiological alterations caused by ATO. In in vivo experiments, ATO administration to animals for 10 days caused myocardial disorganization, interstitial edema and infiltration of inflammatory cells in the heart. Efforts were also made to screen the efficacy of vitamin C against ATO toxicity. ATO also caused a significant increase in the activity of certain clinically relevant enzymes for cardiac function and antioxidant mechanismssuch as serum creatine kinase isoenzyme, lactate dehydrogenase, glutathione peroxidase and reduced glutathione. In conclusion, ATO causes significant adverse cardiac effects and we suggest that cardiac function to be monitored during treatment with ATO. Our results also indicate that the status of the body's main electrolyte content (such as magnesium and potassium) is also an influencing factor on the magnitude of toxicity of arsenic trioxide.

The effects of simultaneous antegrade/retrograde cardioplegia on cellular volumes and energy metabolism.

BACKGROUND AND AIM OF THE STUDY: Simultaneous antegrade/retrograde cardioplegia (SARC) has been employed frequently during cardiac surgery to preserve the jeopardized myocardium. However, retrograde perfusion of SARC may interfere with myocardial drainage and disrupt myocardial fluid homeostasis, which may affect the myocardial energy metabolism and contractile function. The study was, therefore, designed to assess the effects of SARC on myocardial fluid homeostasis, cellular volumes, and energy metabolism. METHODS: Eight isolated pig hearts were subjected to a protocol consisting of a 20-minute control perfusion, 120-minute SARC, and 20-minute reperfusion. The myocardial water content was monitored using near-infrared spectroscopy. Phosphorus-31 magnetic resonance ((31)P MR) spectroscopy was used to monitor the volumes of both intracellular and extracellular compartments and assess myocardial energy metabolism. RESULTS: The near-infrared spectra showed that the 120-min SARC resulted in a 60 +/- 12% increase in the myocardial water content. (31)P MR spectra showed a 36 +/- 4% increase in the intracellular compartment and a 54 +/- 8% increase in the extracellular compartment during SARC relative to their initial volumes measured during control perfusion (100%). However, the myocardial energy metabolites (adenosine triphosphate [ATP] and phosphocreatine [PCr]) remained unchanged during the 120-minute SARC. Moreover, during reperfusion, the hearts showed an almost complete recovery in the left ventricular-developed pressure. CONCLUSIONS: A prolonged SARC resulted in water accumulation in both extracellular and intracellular compartments in the normal myocardium. Although its detrimental effect on tissue fluid homeostasis did not jeopardize the myocardial energy metabolism, a prolonged use of SARC should be avoided, particularly in the diseased hearts.

[Cardiac toxicity and edema].

Anticancerdrug-induced cardiac toxicity has been recognized since the introduction and widespread use of the anthracycline derivative doxorubicin in the 1970's. Risk factors for cardiac toxicity have increased along with the development of multidisciplinary therapy, high-dose combination chemotherapy, and molecular-targeted therapy. Cardiac toxicity is now recognized as a common adverse effect. Cardiac toxicity as an adverse event caused by molecular targeted agents such as trastuzumab may lead to irreversible cardiac dysfunction. The developmental mechanism of cardiac toxicity has not been fully defined for any agent. At present, practical strategies include the evaluation of cardiac function before treatment and the monitoring of cardiac function during treatment to determine whether chemotherapy should be administered or withdrawn. Edema caused by molecular-targeted agents such as imatinib is considered a relatively new adverse event. Prompt and accurate differential diagnosis of edema is essential, followed by appropriate action. Currently, however, only symptomatic treatment is available. Future studies should attempt to elucidate the mechanisms of cardiac toxicity and edema associated with molecular-targeted agents, as well as develop new treatment strategies.

The acute proinflammatory and prothrombotic effects of pulmonary exposure to rutile TiO2 nanorods in rats.

Nanotechnology is extensively used in industry and is widely explored for possible applications in medicine. However, its potential respiratory and systemic adverse effects remain unknown. Here pure titanium dioxide (TiO2) nanorods with rutile structure were prepared at room temperature by using a soft chemistry technique. The structure of the TiO2 rutile nanorods was confirmed by powder X-ray diffraction, and the size was revealed by transmission electron microscopy. Thereafter, we investigated, in Wistar rats, the acute (24-hr) effects of intratracheal instillation of these rutile TiO2 nanorods (1 and 5 mg/kg) on lung inflammation (assessed by bronchoalveolar lavage), systemic inflammation, and platelet aggregation in whole blood. Compared with vehicle-exposed rats, rats that underwent intratracheal instillation of TiO2 nanorods experienced a dose-dependent increase in macrophage numbers at 1 (+50%) and 5 mg/kg (+81%; P < 0.05) and an influx of neutrophils at 1 (+294%) and 5 mg/kg (+4117%; P < 0.01) in their bronchoalveolar lavage fluid. Both doses of rutile TiO2 nanorods caused pulmonary and cardiac edema, assessed by analysis of the wet weight-to-dry weight ratios. Similarly, the numbers of monocytes and granulocytes in the blood were increased in a dose-dependent manner after exposure to rutile TiO2 nanorods. In contrast, the number of platelets was significantly reduced after pulmonary exposure to 5 mg/kg TiO2 nanorods; this result indicated the occurrence of platelet aggregation in vivo. The direct addition of TiO2 nanorods (0.4-10 microg/ml) to untreated rat blood significantly induced platelet aggregation in a dose-dependent fashion in vitro. It is concluded that the intratracheal instillation of rutile TiO2 nanorods caused upregulation of lung inflammation, pulmonary and cardiac edema, and systemic inflammation. Rutile TiO2 nanorods also triggered platelet aggregation in vivo and in vitro.