Effect of Preoperative Infusion of Levosimendan on Biomarkers of Myocardial Injury and Haemodynamics After Paediatric Cardiac Surgery: A Randomised Controlled Trial.

OBJECTIVE: The aim was to test the hypothesis that preoperative infusion of levosimendan would decrease patients' cardiac biomarker profiles during the immediate postoperative stage (troponin I and B-type natriuretic peptide levels) more efficiently than placebo after cardiopulmonary bypass. METHODS: In a randomised, placebo-controlled, double-blinded study, 30 paediatric patients were scheduled for congenital heart disease surgery. 15 patients (50%) received prophylactic levosimendan and 15 patients (50%) received placebo from 12 h before cardiopulmonary bypass to 24 h after surgery. RESULTS: Troponin I levels were higher in the placebo group at 0, 12, and 24 h after cardiopulmonary bypass, although the mean differences between the study groups and the 95% confidence intervals (CIs) for troponin I levels did not present statistically significant differences at any of the three time points considered (mean differences [95% CIs] - 3.32 pg/ml [- 19.34 to 12.70], - 2.42 pg/ml [- 19.78 to 13.95], and - 79.94 pg/ml [- 266.99 to 16.39] at 0, 12, and 24 h, respectively). A similar lack of statistically significant difference was observed for B-type natriuretic peptide (mean differences [95% CIs] 36.86 pg/dl [- 134.16 to 225.64], - 350.79 pg/dl [- 1459.67 to 557.45], and - 310.35 pg/dl [- 1505.76 to 509.82]). Lactic acid levels were significantly lower with levosimendan; the mean differences between the study groups and the 95% CIs for lactate levels present statistically significant differences at 0 h (- 1.52 mmol/l [- 3.19 to - 0.25]) and 12 h (- 1.20 mmol/l [- 2.53 to - 0.10]) after cardiopulmonary bypass. Oxygen delivery (DO2) was significantly higher at 12 h and 24 h after surgery (mean difference [95% CI] 627.70 ml/min/m2 [122.34-1162.67] and 832.35 ml/min/m2 [58.15 to 1651.38], respectively). CONCLUSIONS: Levosimendan does not significantly improve patients' postoperative troponin I and B-type natriuretic peptide profiles during the immediate postoperative stage in comparison with placebo, although both were numerically higher with placebo. Levosimendan, however, significantly reduced lactic acid levels and improved patients' DO2 profiles. These results highlight the importance of this new drug and its possible benefit with regard to myocardial injury; however, evaluation in larger, adequately powered trials is needed to determine the efficacy of levosimendan. Trial registry number: EudraCT 2012-005310-19.

Cardioprotective potential of polyphenols rich Thraatchathi Chooranam against isoproterenol induced myocardial necrosis in experimental rats.

BACKGROUND: The present study establishes the cardioprotective role of Thraatchathi Chooranam (TC), a polyherbal traditional Siddha medicine, in terms of membrane stabilizing and antioxidant properties in isoproterenol (ISO) induced myocardial necrosis model in rats. METHODS: Animals were divided into six groups (n = 6), normal (received vehicle 0.5% CMC, p.o.), ISO control (received 0.5% CMC + ISO 120 mg/kg, b.w. s.c. twice at an interval of 48 h), standard control (received Vit-E 100 mg/kg, p.o.) + ISO, TC low and high dose (50 and 100 mg/kg p.o., respectively) + ISO, and drug control (received TC at 100 mg/kg, p.o.). At the end of experimental period, blood samples collected and plasma cardiac troponin-I (CTn-I) was measured by ELISA. Cardiac tissues were isolated, levels of membrane stabilizing enzymes, antioxidants and inflammatory markers were estimated. Gene expression of Bax, Bcl2, Caspase 3, HIF-α, TNF-α, iNOS, TRX1 and TrxR were performed by RT-PCR. Histopathological studies on cardiac tissues were conducted using hematoxylin and eosin (H&E) stain. Statistical analyses were performed by one-way ANOVA followed by Tukey's multiple comparison as post-hoc test. RESULTS: Administration of ISO resulted in a significant increase in plasma CTn-I, decrease in superoxide dismutase, glutathione and glutathione peroxidase; it also significantly altered membrane stabilizing enzymes like Na+/K+-ATPase, Mg2+-ATPase Ca2+-ATPase and Cathepsin D. Pretreatment with TC (50 mg/kg and 100 mg/kg) decreased CTn-I, and improved membrane stabilizing and endogenous antioxidant enzymes and decreased cathespin D level in a dose dependent manner. Histopathological examination revealed that TC improves cellular membrane integrity and decreases inflammatory cell infiltration and necrotic death. CONCLUSION: The present study provided a strong evidence on the protective effects of TC against ISO-induced myocardial necrosis in rats.

How Do Contrast Agents Affect Cardiac Markers and Coagulation Tests? Experimental Study.

BACKGROUND: The discovery that biotin interferes with results of troponin and Nt-proBNP led some commercial firms to update their measurement methods. In particular, the clinical incompatibility of cardiac test results may affect the risk of morbidity and mortality. OBJECTIVE: The aim of this study is to investigate the interference effects of 7 different contrast agents on cardiac markers (Troponin-I, Nt-proBNP, Mass CK-MB, CK, AST, LDH) and in coagulation tests (PT, APTT). METHODS: Seven different contrast media were added into control materials by using interference protocol. The concentrations of PT, APTT, CK, AST, LDH, Mass CK-MB, Troponin-I, and Nt-proBNP were measured by Sysmex CS-2100, Abbott c16000, Siemens Centaur XP and AFIAS-6 analyzer. The number of deviations from target values was calculated. RESULTS: The 7 different contrast media caused negative interference in troponin levels between 57.43% and 62.87%. It was found that different contrast media produced false negativity in the Nt-proBNP test, ranging from 6.11% to 96.01%. Enzymes and coagulation tests were less affected. CONCLUSION: Different contrast media may cause false negatives in cTnI and Nt-proBNP. The contrast medium that causes the least interference should be preferred. The results of samples taken in the first hour after contrast imaging should be interpreted with care.

Cerebral Perfusion Pressure Directed-Therapy Modulates Cardiac Dysfunction After Traumatic Brain Injury to Influence Cerebral Autoregulation in Pigs.

BACKGROUND: Traumatic brain injury (TBI) is an important contributor to morbidity and mortality. Low cerebral perfusion pressure (CPP, mean arterial pressure [MAP] minus intracranial pressure) after TBI is associated with cerebral ischemia, impaired cerebral autoregulation, and poor outcomes. Normalization of CPP and limitation of cerebral autoregulation impairment is a key therapeutic goal. However, some vasoactive agents used to elevate MAP such as phenylephrine (Phe) improve outcome in females but not male piglets after TBI while dopamine (DA) does so in both sexes. Clinical evidence has implicated neurological injuries as a cause of cardiac dysfunction, and we recently described cardiac dysfunction after TBI. Cardiac dysfunction may, in turn, influence brain health. One mechanism of myocyte injury may involve catecholamine excess. We therefore tested the hypothesis that TBI caused cardiac dysfunction and catecholamine excess which may reciprocally be modulated by vasoactive agent choice to normalize CPP and prevent impairment of cerebral autoregulation after injury. METHODS: TBI was produced in anesthetized pigs equipped with a closed cranial window, and Phe or DA administered to normalize CPP. RESULTS: Plasma cardiac enzymes troponin and creatine kinase and catecholamines epinephrine and norepinephrine were elevated by TBI, such release potentiated by Phe in males but blocked in female piglets and blocked in both sexes after DA. Cerebral autoregulation was impaired after TBI, worsened by Phe in males but protected in females and males treated with DA. Papaverine-induced dilation was unchanged by fluid percussion brain injury, DA, and Phe. CONCLUSIONS: These data indicate that pressor choice in elevation of CPP is important in limiting cardiac dysfunction and suggest that DA protects cerebral autoregulation in both sexes via reduction of cardiac biomarkers of injury and catecholamines released after TBI.

Effects of rotigotine and rotigotine extended-release microsphere therapy on myocardial ischemic injury in mice.

Rotigotine is a dopamine receptor agonist that can improve motor function in Parkinson's disease (PD) patients. Rotigotine extended-release microsphere (RoMS) is an extended-release intramuscular formulation that exhibits a sustained release of rotigotine over a 14-day period. The clinical trials of RoMS has been carried out in USA and China. The purpose of this study is to observe the effects of RoMS therapy on myocardial ischemic injury in mice, to know whether RoMS alleviate or deteriorate the myocardial ischemic injury while PD patient has onset of myocardial ischemia concurrent after administered with RoMS. A mouse model of myocardial ischemia was established using isoproterenol, and mice were pretreated with rotigotine or RoMS before inducing myocardial ischemic injury. The effects of rotigotine or RoMS therapy on the degree of myocardial ischemic injury were studied by evaluating troponin I level, creatine kinase-MB (CK-MB) activity, and histopathological changes in cardiomyocytes. The dopamine receptor blocker chlorpromazine was used to further investigate the effects of rotigotine or RoMS on myocardial ischemic injury. Furthermore, serum rotigotine concentrations were also assayed. When myocardial ischemia occurred during rotigotine or RoMS administration, troponin I level and CK-MB activity were decreased, and ischemia-induced histopathological changes in cardiomyocytes were alleviated. The effects of rotigotine were maintained only 12 h and after that no protective effect was observed. RoMS releases continuously into the circulation after intramuscular injection. The cardioprotective effects of RoMS were maintained 14 days after a single RoMS administration. When combined with chlorpromazine, the protective effects of rotigotine on myocardial ischemic injury were eliminated, and the protective effects of RoMS were also partially abolished. In the animal model of myocardial ischemia, pretreatment with rotigotine or RoMS does not deteriorate, but can alleviate cardiomyocyte injury. Furthermore, RoMS pretreatment show long-term and continuous protective effects on cardiomyocyte injury. RoMS therapy in PD patients at high risk for cardiovascular diseases may attenuate the degree of cardiomyocyte injury caused by ischemia.

The effect of telmisartan on the ventricular systolic function in dogs with experimental supraventricular tachyarrhythmia.

Maintaining a good ventricular systolic function is important in the long-term therapy of dogs with supraventricular tachyarrhythmia (SVTA). The objective of this study was to evaluate the inhibitory effect of telmisartan on myocardial injury and the resulting ventricular systolic dysfunction in a canine model of SVTA. A total of 14 dogs were randomly assigned to a Telmisartan (oral telmisartan, 1.0 mg/kg daily, n=7) or a Control (no drug administration, n=7) group; the duration of rapid atrial pacing (RAP) was 3 weeks for both groups. The cardiac troponin I (cTnI) concentration in the Control group was significantly increased after 3 weeks compared to that before RAP initiation (baseline), but no significant difference was observed in the Telmisartan group. Moreover, the cTnI concentration at 3 weeks was significantly lower in the Telmisartan group than in the Control group. The left ventricular fractional shortening was significantly decreased at 3 weeks compared to that at baseline in both groups. However, fractional shortening at 3 weeks was significantly higher in the Telmisartan group than in the Control group. The cardiac output values in the Control group were significantly decreased at 3 weeks compared with those at baseline, but no significant difference was observed in the Telmisartan group. This study demonstrates that telmisartan inhibits the reduction in ventricular systolic function and prevents myocardial injury in a canine model of SVTA. Therefore, telmisartan is suggested as a novel treatment for canine SVTA.

Fisetin, a plant flavonoid ameliorates doxorubicin-induced cardiotoxicity in experimental rats: the decisive role of caspase-3, COX-II, cTn-I, iNOs and TNF-α.

Doxorubicin (DOX) is a widely used anthracycline antibiotic for the management of carcinoma. However, it is associated with cardiotoxicity. Fisetin is a plant flavonoid reported to have anti-inflammatory and antiapoptotic potential. To evaluate the cardioprotective potential of fisetin in DOX-induced cardiotoxicity in experimental rats. Sprague-Dawley rats were pre-treated with either fisetin (10, 20 and 40 mg/kg) or sitagliptin (10 mg/kg, p.o.) for 7 days. Cardiac toxicity was induced in rats (except the normal group) by doxorubicin (15 mg/kg i.p.) on 8th day. Various behavioral, biochemical, molecular and histological parameters were assessed in cardiac tissue. DOX-induced alterations in electrocardiographic, hemodynamic and left ventricular function were significantly (p < 0.05) inhibited by fisetin (20 and 40 mg/kg) treatment. Fisetin significantly decrease (p < 0.05) DOX-induced elevated serum CK-MB, LDH, AST, ALT and ALP levels. DOX-induced elevated cardiac oxido-nitrosative (SOD, GSH, MDA and NO) was significantly inhibited (p < 0.05) by fisetin. Up-regulated cardiac caspase-3, COX-II, cTn-I, iNOs, TNF-α, and IL-1ß mRNA, as well as protein expressions were significantly decreased (p < 0.05) by fisetin treatment. It also significantly (p < 0.05) attenuated DOX-induced histopathological alterations in cardiac tissue. In conclusion, the fisetin exerts its cardioprotective potential against DOX-induced toxicity via inhibition of multiple pathways including oxidative stress (SOD, GSH, MDA and NO), inflammation (COX-II, TNF-α, and IL-1ß), and apoptosis (Caspase-3). Therefore, fisetin can be considered as a potential cardioprotective agent during the management of carcinoma using doxorubicin anthracyclines.

Total flavones of Rhododendron simsii Planch flower protect isolated rat heart from ischaemia-reperfusion injury and its mechanism of UTR-RhoA-ROCK pathway inhibition.

OBJECTIVES: Total flavones of Rhododendron simsii Planch flower (TFR) are an effective part extracted from the flower. The present study was designed to investigate the protective effect of TFR in isolated rat heart following global ischaemia-reperfusion and the possible underlying mechanisms. METHODS: Langendorff perfusion apparatus was used to perfuse isolated rat heart which was subjected to global ischaemia-reperfusion. The hemodynamic parameters were continuously monitored. Coronary flow as well as lactate dehydrogenase (LDH), creatine phosphokinase-MB (CK-MB) and cardiac troponin I (cTnI) in coronary effluents was measured. RhoA activity and urotensin receptor (UTR) and Rho-related coiled-coil-forming protein kinase (ROCK) protein expressions in rat myocardium were examined, respectively. Cardiac dysfunction was indicated by the alterations of hemodynamic parameters and the reduced coronary flow. KEY FINDINGS: Total flavones of Rhododendron simsii Planch flower significantly improved ischaemia-reperfusion-induced cardiac dysfunction and leakages of LDH, CK-MB and cTnI, and inhibited myocardial ischaemia-reperfusion-increased RhoA activity and UTR, ROCK1 and ROCK2 protein expressions. The improvement of TFR in the cardiac dysfunction and the leakage of LDH, CK-MB and cTnI were markedly attenuated under the UTR blockade and ROCK inhibition. TFR-inhibited RhoA activity was decreased under the UTR blockade. CONCLUSIONS: Total flavones of Rhododendron simsii Planch flower had a protective effect on ischaemia-reperfusion injury in isolated rat heart, which may be attributed to the blocking of UTR and subsequent inhibition of the RhoA-ROCK pathway.

Correlations of inhaled NO with the cTnI levels and the plasma clotting factor in rabbits with acute massive pulmonary embolism.

PURPOSE: To investigate the correlation of inhaled nitric oxide (NO) on plasma levels of cardiac troponin I (cTnI) and von Willebrand factor (vWF), glycoprotein (GP) IIb/IIIa, granule membrane protein 140 (GMP-140) in rabbits with acute massive pulmonary embolism (PE). METHODS: Thirty apanese white rabbits were divided into 3 groups, thrombus were injected in model group (n = 10), NO were inhalated for 24 h after massive PE in NO group (n = 10), saline were injected in control group (n = 10). The concentrations of vWF, GP IIb/IIIa, GMP-140 and cTnI were tested at 4, 8, 12, 16, 20, and 24 h, Correlation analyses were conducted between cTnI and vWF, GP IIb/IIIa, and GMP-140 by Pearson's correlation. RESULTS: The concentration of cTnI and vWF, GP IIb/IIIa, and GMP-140 was increased in the model group, compared to control group. In the inhaled group, the concentrations of cTnI, vWF, GP IIb/IIIa, and GMP-140 were reduced compared to model group. There was a positive correlation between cTnI and vWF, GP IIb/IIIa, and GMP-140. CONCLUSION: Inhaled nitric oxide can lead to a decrease in levels of cardiac troponin I, von Willebrand factor, glycoprotein, and granule membrane protein 140, after an established myocardial damage, provoked by acute massive pulmonary embolism.

Correlations of inhaled NO with the cTnI levels and the plasma clotting factor in rabbits with acute massive pulmonary embolism

Abstract Purpose: To investigate the correlation of inhaled nitric oxide (NO) on plasma levels of cardiac troponin I (cTnI) and von Willebrand factor (vWF), glycoprotein (GP) IIb/IIIa, granule membrane protein 140 (GMP-140) in rabbits with acute massive pulmonary embolism (PE). Methods: Thirty apanese white rabbits were divided into 3 groups, thrombus were injected in model group (n = 10), NO were inhalated for 24 h after massive PE in NO group (n = 10), saline were injected in control group (n = 10). The concentrations of vWF, GP IIb/IIIa, GMP-140 and cTnI were tested at 4, 8, 12, 16, 20, and 24 h, Correlation analyses were conducted between cTnI and vWF, GP IIb/IIIa, and GMP-140 by Pearson's correlation. Results: The concentration of cTnI and vWF, GP IIb/IIIa, and GMP-140 was increased in the model group, compared to control group. In the inhaled group, the concentrations of cTnI, vWF, GP IIb/IIIa, and GMP-140 were reduced compared to model group. There was a positive correlation between cTnI and vWF, GP IIb/IIIa, and GMP-140. Conclusion: Inhaled nitric oxide can lead to a decrease in levels of cardiac troponin I, von Willebrand factor, glycoprotein, and granule membrane protein 140, after an established myocardial damage, provoked by acute massive pulmonary embolism.

Resveratrol protects against lipopolysaccharide-induced cardiac dysfunction by enhancing SERCA2a activity through promoting the phospholamban oligomerization.

The bacterial endotoxin lipopolysaccharide (LPS) is a main culprit responsible for cardiac dysfunction in sepsis. This study examined whether resveratrol could protect against LPS-induced cardiac dysfunction by improving the sarcoplasmic endoplasmic reticulum Ca2+-ATPase (SERCA2a) activity. Echocardiographic parameters, cardiomyocyte contractile and Ca2+ transient properties, markers for cardiac inflammation, cell death, and oxidative stress, SERCA2a activity, and the ratios of phospholamban (PLB) monomer to oligomer were measured. Cardiac function was decreased >50% after LPS challenge (6 mg/kg for 6 h), which was improved by resveratrol. There was neither difference in plasma tumor necrosis factor-α and troponin I levels nor in infiltration of CD45+ cells in cardiac tissue between resveratrol-treated and untreated groups. In cardiomyocytes, LPS significantly decreased contractile amplitude, elongated relengthening time, diminished Ca2+ transient, reduced SERCA2a activity, and increased superoxide generation. These pathological alterations were attenuated by resveratrol treatment. Immunoblot analysis showed that LPS-treated mice had increased levels of malondialdehyde (MDA), 4-hydroxynonenal (4-HNE), and the monomer form of PLB, along with decreases in the levels of SERCA2a, the oligomer form of PLB and nuclear factor erythroid 2-related factor (Nrf-2). Resveratrol treatment upregulated SERCA2a, the oligomer form of PLB, and Nrf-2 expression and function, and downregulated MDA, 4-HNE, and the monomer form of PLB. Our data suggest that the activity of SERCA2a in endotoxemia is inhibited, possibly due to increases in the monomer form of PLB. Resveratrol protects the heart from LPS-induced injuries at least in part through promoting the oligomerization of PLB that leads to enhanced SERCA2a activity.

Effects of isoxsuprine hydrochloride on electrocardiographic and trace element status in sheeps.

OBJECTIVE: To study the effect of isoxsuprine hydrochloride on the ischaemic electrocardiographic change and trace element status in sheep. METHODS: This study was conducted from March 16 to 23, 2012, at Istanbul University, Turkey, and comprised sheep aged 6 months. The animals were divided into two equal groups. The control group was fed a standard diet and had free access to water. In the experimental group, isoxsuprine hydrochloride was injected at a dose of 0.6 mg/kg through the intramuscular route. Electrocardiographic changes, including creatine kinase and cardiac troponin-I, and serum levels of selenium, copper, calcium, magnesium, iron and zinc were investigated in healthy sheep. SPSS 15 was used for statistical analysis. RESULTS: The 14 sheep were divided into two groups of 7(50%) each. The overall mean weight of the study population was 35±10kg. Selenium, calcium, iron and zinc concentrations did not show any difference in serum samples (p>0.05). However, copper and magnesium concentrations decreased in serum after the administration of the drug (p<0.05). In the experimental group, ST segment depression and abnormal T-wave was found in 6(86%) animals within 60min. CONCLUSIONS: Isoxsuprine hydrochloride increased cardiotoxicity risk in sheep.

Zofenopril Protects Against Myocardial Ischemia-Reperfusion Injury by Increasing Nitric Oxide and Hydrogen Sulfide Bioavailability.

BACKGROUND: Zofenopril, a sulfhydrylated angiotensin-converting enzyme inhibitor (ACEI), reduces mortality and morbidity in infarcted patients to a greater extent than do other ACEIs. Zofenopril is a unique ACEI that has been shown to increase hydrogen sulfide (H2S) bioavailability and nitric oxide (NO) levels via bradykinin-dependent signaling. Both H2S and NO exert cytoprotective and antioxidant effects. We examined zofenopril effects on H2S and NO bioavailability and cardiac damage in murine and swine models of myocardial ischemia/reperfusion (I/R) injury. METHODS AND RESULTS: Zofenopril (10 mg/kg PO) was administered for 1, 8, and 24 hours to establish optimal dosing in mice. Myocardial and plasma H2S and NO levels were measured along with the levels of H2S and NO enzymes (cystathionine ß-synthase, cystathionine γ-lyase, 3-mercaptopyruvate sulfur transferase, and endothelial nitric oxide synthase). Mice received 8 hours of zofenopril or vehicle pretreatment followed by 45 minutes of ischemia and 24 hours of reperfusion. Pigs received placebo or zofenopril (30 mg/daily orally) 7 days before 75 minutes of ischemia and 48 hours of reperfusion. Zofenopril significantly augmented both plasma and myocardial H2S and NO levels in mice and plasma H2S (sulfane sulfur) in pigs. Cystathionine ß-synthase, cystathionine γ-lyase, 3-mercaptopyruvate sulfur transferase, and total endothelial nitric oxide synthase levels were unaltered, while phospho-endothelial nitric oxide synthase(1177) was significantly increased in mice. Pretreatment with zofenopril significantly reduced myocardial infarct size and cardiac troponin I levels after I/R injury in both mice and swine. Zofenopril also significantly preserved ischemic zone endocardial blood flow at reperfusion in pigs after I/R. CONCLUSIONS: Zofenopril-mediated cardioprotection during I/R is associated with an increase in H2S and NO signaling.

Effect of rosuvastatin therapy on troponin I release following percutaneous coronary intervention in nonemergency patients (from the TIP 3 study).

Several randomized studies have suggested that pretreatment with statins may reduce a periprocedural biomarker release in patients who underwent percutaneous coronary intervention (PCI); however, results remain controversial. The purpose of this study was to investigate the effect of a 1-day rosuvastatin therapy on troponin I release in patients who underwent nonemergency PCI. A total of 445 patients with angina pectoris were randomly assigned to therapy with rosuvastatin (20 mg 12 hours before coronary angiography + 20 mg immediately before PCI; rosuvastatin group, 220 patients) or PCI without statin therapy (control group, 225 patients). In patients taking statins (73%), rosuvastatin was added to their long-term statin therapy. The primary end point was the incidence of TnI microleak defined as TnI elevation >1.5× upper limit of normal, and the secondary end point was the incidence of post-PCI TnI elevation >3× upper limit of normal. The incidence of primary and secondary end point in the rosuvastatin versus control group was 13.6% versus 12% (p = 0.61) and 8.2% versus 7.1% (p = 0.67), respectively. Patients with C-reactive protein ≥2.0 mg/L had a decreased release of post-PCI TnI in the rosuvastatin group (0.032 [0.010 to 0.143] µg/L vs 0.056 [0.018 to 0.241] µg/L; p = 0.04). In conclusion, 1-day rosuvastatin therapy (20 mg twice a day) did not influence post-PCI TnI release in patients with angina. However, these results suggest that, in patients with an advanced inflammatory status, rosuvastatin loading therapy might have a cardioprotective effect.

Regulatory T cells contribute to rosuvastatin-induced cardioprotection against ischemia-reperfusion injury.

OBJECTIVES: CD4CD25 regulatory T cells (Tregs) play a key role in the prevention of various inflammatory and autoimmune disorders by suppressing immune responses. The beneficial effect of statins on myocardial ischemia-reperfusion injury (IRI) depends in part on their immunomodulatory and anti-inflammatory mechanisms. We aimed to determine whether Tregs contribute to statin-induced cardioprotection against myocardial IRI. METHODS: Thirty-two rats were divided into four groups: sham, ischemia-reperfusion (IR), rosuvastatin (RSV)/IR, and mevalonic acid (MVA)+RSV/IR. Myocardial IR was induced by a 30-min coronary occlusion, followed by a 48-h reperfusion. RSV (5 mg/kg) was administered intravenously 18 h before IR. The rats were killed after 48-h reperfusion. Serum cardiac troponin I (cTnI) was measured by ELISA, infiltration of inflammatory cells in myocardium by hematoxylin and eosin staining, expression of FoxP3 protein by western blotting, accumulation of Tregs in myocardium by immunohistochemical examination, and infarct size by TTC staining. RESULTS: Significant elevation in serum cTnI, enlarged infarct size, and marked infiltration of inflammatory cells in myocardium were observed in the IR group. The administration of RSV significantly reduced the serum cTnI level, attenuated the accumulation of inflammatory cells, decreased infarct size, and increased the FoxP3 expression and Treg accumulation in myocardium compared with the IR group. The combination of RSV and MVA pretreatment partially abolished the anti-inflammatory and infarct size-limiting effects and completely reversed Treg accumulation in myocardium induced by RSV. The accumulation of inflammatory cells was negatively correlated with FoxP3 expression and Treg accumulation in the ischemic myocardium. CONCLUSION: RSV pretreatment was associated with more Treg accumulation, less inflammatory response, and myocardial injury, suggesting that such cardioprotection against IRI was partially mediated by Treg-negative modulation of inflammation response, probably through the HMG-CoA reductase pathway.

Troponin I release after intravenous treatment with high furosemide doses plus hypertonic saline solution in decompensated heart failure trial (Tra-HSS-Fur).

BACKGROUND: High values of cardiac troponin in acute decompensated congestive heart failure (ADHF) identify patients at higher risk and worsened prognosis. A cardiac troponin increase during therapy indicates the need for more appropriate intervention, aimed at compensating cardiac disease and effectively minimizing myocardial wall stress and subsequent cytolysis. This study evaluated the effects of an intravenous high dose of furosemide with (group A) or without small volume hypertonic saline solution (HSS) (group B) on myocardial cytolysis in patients with ADHF. METHODS: A total of 248 consecutive patients with ADHF (148 men, mean age 74.9 ± 10.9 years) were randomly assigned to group A or B. Plasma levels of cardiac troponin-I, brain natriuretic peptide, glomerular filtration rate by Modification of Diet in Renal Disease formula, bioelectrical impedance analysis measurements, and delta pressure/delta time (dP/dt) rate were observed on admission and discharge for all patients. RESULTS: We observed a significant reduction of cardiac troponin in both groups and a significant improvement in renal function, hydration state, pulmonary capillary wedge pressure (P < .0001), end diastolic volume (P < .01), ejection fraction (P < .01), and dP/dt (P < .004) in group A. We also observed a significant reduction in body weight (64.4 vs 75.8 kg) (P < .001), cardiac troponin I (0.02 vs 0.31 ng/mL) (P < .0001) and brain natriuretic peptide (542 vs 1,284 pg/mL) (P < .0001), and hospitalization time (6.25 vs 10.2 days) (P < .0001) in the HSS group. CONCLUSIONS: These data demonstrate that intravenous high doses of furosemide do not increase myocardial injury and, in addition, when associated to HSS, significantly reduce cardiac troponin I release. This behavior is mirrored by the achievement of improved hemodynamic compensation at echocardiography and body hydration normalization.

Cardiovascular effect of nifedipine in morphine dependent rats: hemodynamic, histopathological, and biochemical evidence.

AIM: To investigate whether administration of nifedipine has considerable therapeutic effect in morphine-dependent rats. METHODS: Sixty animals were randomized into control, morphine, morphine plus nifedipine, and morphine plus dimethyl sulfoxide (DMSO, as nifedipine soluble) groups. Each group consisted of two subgroups, with and without heart injury. The groups were treated with incremental doses of morphine or morphine plus nifedipine daily for 7 days. Myocardial injury was induced by isoproterenol (50 mg/kg i.p.) on the day 7. On the day 8, the heart rate (HR), blood pressure (BP), rate-pressure product (RPP), and the plasma level of cardiac troponin I were measured and the hearts were histopathologically examined. RESULTS: In morphine-dependent rats, nifedipine administration was associated with a significantly higher decrease in the plasma level of cardiac troponin I than the administration of morphine alone. This finding was also significant in dependent animals that received only DMSO. HR, BP, RPP, and histopathological indices did not show significant changes in the presence of nifedipine. CONCLUSION: Administration of nifedipine failed to show a significant therapeutic effect in morphine-dependent rats, especially in the group with myocardial injury.

Adiponectin elevation by telmisartan ameliorates ischaemic myocardium in Zucker diabetic fatty rats with metabolic syndrome.

AIM: This study investigated whether telmisartan, a selective angiotensin type 1 (AT1) receptor antagonist and gamma peroxisome proliferator-activated receptor (PPAR-γ) partial agonist, reduces myocardial ischaemia/reperfusion (I/R) injury in an experimental model of metabolic syndrome. METHODS: Zucker Diabetic Fatty (ZDF) rats were treated for 3 weeks with telmisartan at doses of 2, 7 and 12 mg/kg/day. After treatment, rats were subjected to a 25-min occlusion of the left descending coronary artery followed by 2-h reperfusion (I/R). RESULTS: Telmisartan reduced the extension of the infarct size in a dose-dependent fashion and decreased the levels of plasma troponin I, a specific marker of myocardial damage. Telmisartan also caused a dose-dependent increase in adiponectin both in plasma and cardiac tissue of infarcted ZDF rats. These levels were minimally increased (p < 0.05 vs. vehicle) by telmisartan 7 mg/kg/day and reached the maximum values with the highest dose of 12 mg/kg/day (p < 0.01 vs. vehicle). In contrast, within the infarcted tissue telmisartan decreased the expression of markers of inflammation such as the transcription factor NF-κB, the toll-like receptors TLR2 and TLR4 as well as TNF-α cytokine. Nitrosative stress was maximal in vehicle-treated infarcted hearts as evidenced by increased expression of iNOS, which was almost abolished after treatement with telmisartan. CONCLUSIONS: Treatment of ZDF rats for 3 weeks with telmisartan, a dual angiotensin II receptor antagonist and partial PPAR-γ receptor agonist, resulted in a significant reduction of myocardial damage induced by I/R and was associated with increased adiponectin and a decrease in inflammatory markers.

[In vitro study on the mechanism of myocardial injury induced by Formoterol and the protective effect of Budesonide in rats].

AIM: To investigate the mechanism of myocardial injury induced by Formoterol (FORM) in vitro and the protective effect of Budesonide (BUD) against such cardiac damage in rats. METHODS: FORM was added in the media of isolated rat myocardial tissues in a concentration gradients of 0 µmol/L, 0.01 µmol/L, 0.05 µmol/L, 0.1 µmol/L, 0.5 µmol/L, 1 µmol/L, 5 µmol/L, respectively, or combined with BUD in a concentration of 10 µmol/L, for 72 hours in vitro. The cardiac troponin I (cTnI) and heart-type fatty acid-binding protein (H-FABP) in supernatant were detected with ELISA method. The mRNA level of glycogen synthase kinase-3ß (GSK-3ß) was detected with RT-PCR. Sarco(endo) plasmic reticulum Ca(2+);-ATPase (SERCA2) and GSK-3ß protein expression were detected with Western blot. RESULTS: (1) The values of cTnI and H-FABP were significantly higher in FORM groups, compared with the control group(P<0.05), and there was a difference between different FORM concentration gradients (P<0.05) except 1 µmol/L and 5 µmol/L groups. In FORM and BUD combined groups, the values of cTnI and H-FABP were significantly lower than FORM groups(P<0.05). (2) With the increase of FORM concentration, there were lower expression of SERCA2 (P<0.05) and higher expression of GSK-3ß protein (P<0.05). But there was no significant statistic difference of GSK-3ß mRNA between FORM treated groups (P>0.05). CONCLUSION: (1) FORM can induce injury in rat's isolated myocardial tissues and the injury is concentration depended. BUD shows protective effect against FORM induced myocardial injury. (2) The mechanism of FORM induced myocardial injury may be associated with the lower expression of SERCA2, which is mediated by GSK-3ß.

The cardioprotective effects of a combination of quercetin and α-tocopherol on isoproterenol-induced myocardial infarcted rats.

The present study aims to evaluate the combined protective effects of quercetin and α-tocopherol on isoproterenol-treated myocardial infarcted rats. Male albino Wistar rats were pretreated with a combination of quercetin (10 mg/kg) and α-tocopherol (10 mg/kg) daily for 14 days. After the pretreatment, rats were injected isoproterenol (100 mg/kg) to induce myocardial infarction. Isoproterenol-treated rats showed increased levels of serum troponins and increased intensities of serum lactate dehydrogenase-1 and -2 isoenzyme bands. Isoproterenol treatment also showed significant decreased levels of antioxidant system and significant increased levels of plasma lipid peroxidation, plasma uric acid, and the heart calcium. Furthermore, isoproterenol-treated rat's electrocardiogram showed elevated ST segments. Combined pretreatment with quercetin and α-tocopherol normalized all the biochemical parameters and minimized the alterations in electrocardiogram. Histopathology of myocardium also confirmed the cardioprotective effects of quercetin and α-tocopherol. In vitro studies confirmed the mechanism of action of quercetin and α-tocopherol. Thus, quercetin and α-tocopherol exhibited cardioprotective effects against isoproterenol-induced cardiotoxicity due to their scavenging free radicals, improving antioxidants and maintaining Ca(2+) levels. Our study also showed that combined pretreatment (quercetin and α-tocopherol) was highly effective than single pretreatment (quercetin or α-tocopherol).