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Objective: This study evaluated the efficacy and safety of early vs. late tirofiban administration in the treatment of patients with acute ST-elevation myocardial infarction (STEMI) and diabetes mellitus (DM) undergoing primary percutaneous coronary intervention (pPCI)., Methods: 120 patients with STEMI and DM treated with pPCI were randomly divided into an observation group (n=60) and a control group (n=60). The observation group and the control group were intravenously injected with a bolus of tirofiban preoperatively or intraoperatively, respectively; both groups were then given an intravenous infusion over 24 h at 0.15 μg/kg/min. Thrombolysis in myocardial infarction (TIMI) grade flow, myocardial perfusion index, and functional heart parameters, as well as major adverse cardiovascular events and bleeding, were compared between the two groups., Results: Functional heart parameters, including left ventricular ejection fraction and cardiac output, were significantly improved in the observation group 6 months after discharge. Thrombus aspiration, inflammatory factors, and cardiac troponin I (cTNI) were more significantly decreased in the observation group than in the control group. The sum-ST-segment elevation at 2 h after pPCI treatment in the observation group was better than that in the control group. There was no significant difference in the incidence of adverse reactions and bleeding between the two groups., Conclusion: The administration of tirofiban before reperfusion therapy compared with after reperfusion therapy is more effective in reducing the hyperthrombotic load, thrombus aspiration, inflammatory factors, and cTNI and can effectively improve myocardial perfusion and heart function., (Copyright© Bentham Science Publishers; For any queries, please email at epub@benthamscience.net.)

Cell therapy of the post-infarcted myocardium is still far from clinical use. Poor survival of transplanted cells, insufficient regeneration, and replacement of the damaged tissue limit the potential of currently available cell-based techniques. In this study, we generated a multilayered construct from adipose-derived mesenchymal stromal cells (MSCs) modified to secrete stem cell factor, SCF. In a rat model of myocardium infarction, we show that transplantation of SCF producing cell sheet induced activation of the epicardium and promoted the accumulation of c-kit positive cells in ischemic muscle. Morphometry showed the reduction of infarct size (16%) and a left ventricle expansion index (0.12) in the treatment group compared to controls (24-28%; 0.17-0.32). The ratio of viable myocardium was more than 1.5-fold higher, reaching 49% compared to the control (28%) or unmodified cell sheet group (30%). Finally, by day 30 after myocardium infarction, SCF-producing cell sheet transplantation increased left ventricle ejection fraction from 37% in the control sham-operated group to 53%. Our results suggest that, combining the genetic modification of MSCs and their assembly into a multilayered construct, we can provide prolonged pleiotropic effects to the damaged heart, induce endogenous regenerative processes, and improve cardiac function.

Long noncoding RNAs (lncRNAs) can participate in various biological behaviors, including regulating cell differentiation, proliferation, and apoptosis. The investigators have previously confirmed that highly conserved lncRNA NR_045363 controls cardiomyocyte (CM) proliferation and cardiac repair. The present study investigates the effects of NR_045363 on CM apoptosis. Seven-day-old mice were subjected to permanent left anterior descending coronary artery ligation (LAD), and the NR_045363 expression was analyzed by quantitative real-time polymerase chain reaction (qRT-PCR). The expression of NR_045363 in the MI group significantly exceeded the Sham group during the first week after the operation. The NR_045363 expression was knocked down in primary cultured CMs using an NR_045363-targeting lncRNA Smart silencer, and the apoptosis of CMs was analyzed by terminal-deoxynucleoitidyl transferase mediated nick end labeling and Annexin-V/PI double staining. These present results indicate that the NR_045363 knockdown significantly promoted the apoptosis of CMs. In order to investigate the underlying mechanism, RNA-sequencing (RNA-seq) was performed, and ingenuity pathway analysis (IPA) was used to analyze the RNA-seq results. The RNA-seq data revealed that a total of 2,291 genes were upregulated or downregulated in NR_045363 knockdown CMs, and the IPA analysis indicated that tumor protein 53 (p53) was the upstream regulator. In vivo, the NR_045363 overexpression through the AAV9 system improved the heart function after MI in 7-day-old mice and inhibited the CM apoptosis. These data suggest that NR_045363 is involved in CM apoptosis and that NR_045363 overexpression exerts positive effects on cardiac repair by alleviating CM apoptosis through the inhibition of the p53 pathway., (© 2020 International Federation for Cell Biology.)

Background: Qiliqiangxin (QLQX) is a preparation refined from a traditional Chinese medicine compound. It plays an important role in protecting cardiac function after myocardial infarction (MI). However, the underline mechanism of QLQX action is not clear. The purpose of this study was to detect the effects of QLQX on mitophagy after MI., Methods: Male FVB/NJ mice aged 8-10 weeks were underwent left coronary artery ligation and were orally administered either QLQX (0.25 g/kg/d) or saline. Twenty-eight days after surgical operation, the cardiac function of mice was detected by echocardiography. Electron Microscopy was used to observe the microstructure of cardiomyocytes. Myocardial apoptosis was examined by TdT-mediated dUTP Nick-End Labeling (TUNEL) and western blot. H9c2 cells were cultured in a hypoxic incubator chamber (5% CO 2 , 1% O 2 , 94% N 2 ) for 12 h and pretreated with or without QLQX (0.5 mg/mL). The cell apoptosis, reactive oxygen species (ROS), mitochondrial membrane potential and mitophagy were detected., Results: When compared to sham group, the cardiac function of MI mice decreased significantly, and their cardiomyocyte apoptosis and mitochondrial damage were more serious. These MI-induced cardiac changes could be reversed by QLQX treatment. In vitro experiments also confirmed that QLQX could protect cardiomyocytes from hypoxia-induced apoptosis and mitochondrial damage. Further study indicated that QLQX could increase the expression of Pink1 and Parkin in cardiomyocytes., Conclusion: Qiliqiangxin could reduce cardiomyocytes apotosis and improved heart function in infarcted heart through Pink1-mediated mitochondrial autophagy.

Background: Beta blockers are standard therapy for myocardial infarction (MI). Preclinical studies have shown efficacy and safety of thyroid hormone (TH) treatment of cardiovascular disorders. Since THs interact with the sympathoadrenergic system, this study aimed to compare triiodothyronine (T3) and metoprolol (Met) in the treatment of rats with MI on pathophysiology and TH-adrenergic signaling., Methods: Female Sprague-Dawley rats aged 12 weeks underwent left anterior descending coronary artery ligation (MI) or sham surgeries. T3 (5 μg/kg/day) or Met (100 mg/kg/day) was given in drinking water immediately after surgery for eight weeks. At the terminal of the experiments, the rats were subjected to morphological, functional, and molecular examination., Results: T3 and Met significantly enhanced left ventricular contractility (left ventricular fractional shortening 21.37 ± 2.58% and 21.14 ± 3.71%, respectively) compared to untreated MI (17.88 ± 1.23%), and decreased the incidence of inducible atrial tachyarrhythmia by 87.5% and 62.5%, respectively. Although both treatments showed efficacy, T3 but not Met showed statistically significant improvements compared to MI in arrhythmia duration, left atrial diameter (T3 vs. MI 4.33 ± 0.63 vs. 5.65 ± 1.32 mm; p < 0.05), fibrosis (6.1 ± 0.6%, 6.6 ± 0.6% vs. 8.2 ± 0.7%, T3, Met vs. MI, respectively), and aortic vasorelaxation responsiveness to acetylcholine (pD2 6.97 ± 0.22, 6.83 ± 0.21 vs. 6.66 ± 0.22, T3, Met vs. MI, respectively). Quantitative polymerase chain reaction showed that T3 and Met attenuated expression of genes associated with inflammation and oxidative stress and restored expression of ion channels and contractile proteins., Conclusion: These results support comparable efficacy of T3 and Met treatments, suggesting that T3 may provide a therapeutic alternative to standard β-receptor blockade, especially for patients intolerant to treatment with β-blockers after MI.

Background: Toll-like receptor-4 (TLR4), a receptor of the innate immune system, is suggested to have detrimental effects on cardiac function after myocardial infarction (MI). RP105 (CD180) is a TLR4 homolog lacking the intracellular signaling domain that competitively inhibits TLR4-signaling. Thus, we hypothesized that RP105 deficiency, by amplifying TLR4 signaling, would lead to aggravated cardiac dysfunction after MI., Methods and Results: First, whole blood from RP105-/- and wild-type (WT) male C57Bl/6N mice was stimulated with LPS, which induced a strong inflammatory TNFα response in RP105-/- mice. Then, baseline heart function was assessed by left ventricular pressure-volume relationships which were not different between RP105-/- and WT mice. Permanent ligation of the left anterior descending coronary artery was performed to induce MI. Infarct sizes were analyzed by (immuno)histology and did not differ. Fifteen days post MI heart function was assessed and RP105-/- mice had significantly higher heart rate (+21%, P<0.01), end systolic volume index (+57%, P<0.05), end systolic pressure (+22%, P<0.05) and lower relaxation time constant tau (-12%, P<0.05), and a tendency for increased end diastolic volume index (+42%, P<0.06), compared to WT mice. In the area adjacent to the infarct zone, compared to the healthy myocardium, levels of RP105, TLR4 and the endogenous TLR4 ligand fibronectin-EDA were increased as well as the number of macrophages, however this was not different between both groups., Conclusion: Deficiency of the endogenous TLR4 inhibitor RP105 leads to an enhanced inflammatory status and more pronounced cardiac dilatation after induction of MI, underscoring the role of the TLR4 pathway in post-infarction remodeling., (Copyright © 2014 Elsevier Ireland Ltd. All rights reserved.)

Hydrogel has been used for regenerating myocardial infraction (MI) as a delivery vehicle for cells and growth factors. This study showed that injectable hyaluronic acid (HA)-based hydrogels alone would effectively regenerate the damaged infarcted heart tissue. We found that there are two major factors of regeneration in MI. One is molecular weight of HA and another is the progression of MI; sub-acute and chronic. Rat MI model was prepared by ligating the left anterior descending coronary artery (LAD). Four weeks after injection of hydrogel, functional analysis of the heart and histological analysis was assessed. When different molecular weight HA-based hydrogels with 50 kDa, 130 kDa, and 170 kDa were applied to the infarcted area in the sub-acute model, 50 kDa HA-based hydrogel showed the most significant regeneration of myocardium as well as functional recovery among samples. For the disease progression, 50 kDa HA-based hydrogels were injected to sub-acute and chronic MI models. The regeneration activity was significantly decreased in the chronic models reflecting that injection timing of the therapeutic agents is also major determinants in the regeneration process. These results suggest that injection time and composition of hydrogel are two major points treating MI., (Copyright © 2014 The Society for Biotechnology, Japan. Published by Elsevier B.V. All rights reserved.)

Objective: Animal models for myocardial injuries represent important cornerstones in cardiovascular research to monitor the pathological processes and therapeutic approaches. We investigated the association of 18F-FDG derived left ventricular metabolic volume (LVMV), defect area and cardiac function in mice after permanent or transient ligation of the left anterior descending artery (LAD).Methods: Serial non-invasive ECG-gated 2-deoxy-2-[18F]fluoro-D-glucose positron emission tomography (18F-FDG PET) after permanent or transient LAD ligation enabled a longitudinal in vivo correlation of 18F-FDG derived left ventricular metabolic volume to functional parameters and myocardial defect.Results: The LVMV shows a more prominent drop after permanent than transient LAD ligation and recovers after 30 days. The loss of LVMV correlates with the defect area assessed by QPS software. Cardiac function parameters (e.g., EDV, ESV, SV) by the QGS software positively correlate with LVMV after permanent and transient LAD ligation.Conclusions: This study provides novel insight into 18F-FDG derived LVMV after permanent and transient LAD ligation by longitudinal in 18F-FDG PET imaging and underlines the associations of the FDG derived parameter and cardiac function. [ABSTRACT FROM AUTHOR]

Background: This study was conducted with the aim to investigate the effectiveness of a psychological bioenergy economy intervention on the cardiac function and inflammatory factors in patients with myocardial infarction (Ml). Methods: This randomized controlled trial (RCT) was performed on 60 post-MI patients who referred to the Cardiovascular Research Institute, Isfahan, Iran, in 2019. The intervention group received an energy-based bioenergetics intervention that consisted of rehabilitation training and nutrition patterns training. In the control group, only rehabilitation training and nutrition pattern training was provided in 8 sessions. Quantitative data were expressed as mean ± standard deviation (SD). Between-group differences of data departing from normal distribution were analyzed using the Mann-Whitney U test. All statistical analyses were performed in SPSS software. Results: The enrolled patients included 60 post-MI patients (27.3% women in the intervention group, and 18.2% in the control group). We lost 16 patients during the study. Fasting blood sugar was higher in the control group before the intervention (106.7 ± 14.1 vs. 96.3 ± 11.0; P < 0.001). Systolic blood pressure was significantly higher in the control group before the intervention (P = 0.04). There was no significant difference in total cholesterol, TG, HDL, and LDL after the intervention compared to before the intervention in either groups. Intercellular adhesion molecule 1 (ICAM-1) and vascular cell adhesion molecule 1 (VCAM-1) did not change during the intervention in either groups (P < 0.05). Conclusion: Our results displayed that the psychological intervention based on bioenergy economy has no significant effect on cardiac function and inflammatory factors in patients with Ml. However, it is suggested that this study be repeated on a larger population. [ABSTRACT FROM AUTHOR]

Abstract Background Qiliqiangxin (QLQX) is a preparation refined from a traditional Chinese medicine compound. It plays an important role in protecting cardiac function after myocardial infarction (MI). However, the underline mechanism of QLQX action is not clear. The purpose of this study was to detect the effects of QLQX on mitophagy after MI. Methods Male FVB/NJ mice aged 8–10 weeks were underwent left coronary artery ligation and were orally administered either QLQX (0.25 g/kg/d) or saline. Twenty-eight days after surgical operation, the cardiac function of mice was detected by echocardiography. Electron Microscopy was used to observe the microstructure of cardiomyocytes. Myocardial apoptosis was examined by TdT-mediated dUTP Nick-End Labeling (TUNEL) and western blot. H9c2 cells were cultured in a hypoxic incubator chamber (5% CO2, 1% O2, 94% N2) for 12 h and pretreated with or without QLQX (0.5 mg/mL). The cell apoptosis, reactive oxygen species (ROS), mitochondrial membrane potential and mitophagy were detected. Results When compared to sham group, the cardiac function of MI mice decreased significantly, and their cardiomyocyte apoptosis and mitochondrial damage were more serious. These MI-induced cardiac changes could be reversed by QLQX treatment. In vitro experiments also confirmed that QLQX could protect cardiomyocytes from hypoxia-induced apoptosis and mitochondrial damage. Further study indicated that QLQX could increase the expression of Pink1 and Parkin in cardiomyocytes. Conclusion Qiliqiangxin could reduce cardiomyocytes apotosis and improved heart function in infarcted heart through Pink1-mediated mitochondrial autophagy.

To analyze the effect of resveratrol on myocardial remodeling and cardiac function after myocardial infarction by inhibiting myocardial cell apoptosis through regulating silent information regulator 1/protein kinase R-like endoplasmic reticulum kinase pathway. 32 healthy male sprague dawley rats were divided into control group (without any treatment), model group (ligation of left anterior descending branch to establish a model), sham operation group (ligation of left anterior descending branch without ligation) and resveratrol group (ligation of left anterior descending branch+resveratrol 8 mg/kg/d), 8 rats each. The changes of cardiac function, myocardial remodeling, myocardial apoptosis and silent information regulator 1/protein kinase R-like endoplasmic reticulum kinase pathway related proteins were observed 4 w after modeling. Left ventricular end-diastolic diameter and left ventricular end-systolic dimension levels in the model group were significantly higher than those in the control group, left ventricular ejection fraction and left ventricular short axis shortening rate levels were significantly lower than those in the control group (p<0.01), left ventricular end-diastolic diameter and left ventricular end-systolic dimension levels in the resveratrol group were significantly lower than those in the model group and left ventricular ejection fraction and left ventricular short axis shortening rate levels were significantly higher than those in the model group (p<0.01). In the model group, the myocardial cells were arranged in a disordered manner and fibrogenic hyperplasia occurred, while the pathological changes of the myocardial cells in the resveratrol group were reduced compared with the model group. The collagen volume fraction of myocardial tissue in the model group was significantly higher than that in the control group (p<0.05) and the collagen volume fraction in the resveratrol group was significantly lower than that in the model group (p<0.05). The apoptosis rate of myocardial cells in the model group was significantly higher than that in the control group (p<0.01) and the apoptosis rate of myocardial cells in the resveratrol group was significantly lower than that in the model group (p<0.01). The expression levels of Phosphate-protein kinase R like endoplasmic reticulum kinase, Phosphate eukaryotic initiation factor 2 and Activating transcription factor 4 in the model group were significantly higher than those of the control group and the expression levels of Silent Information Regulator 1 were significantly lower than those of the control group (p<0.01). The expression levels of Phosphate-protein kinase R like endoplasmic reticulum kinase, Phosphate eukaryotic initiation factor 2 and Activating transcription factor 4 in the resveratrol group were significantly lower than those of the model group and the expression levels of silent information regulator 1 were significantly higher than those of the model group (p<0.01). Resveratrol can reduce apoptosis of myocardial cells after myocardial infarction by regulating the silent information regulator 1/protein kinase R-like endoplasmic reticulum kinase pathway endoplasmic reticulum stress pathway and improve myocardial remodeling and cardiac function in rats, providing a new target for clinical treatment of myocardial infarction. [ABSTRACT FROM AUTHOR]

Objective: To compare the effect of primary PCI and delayed PCI on the heart function of patients with ST-segment elevation myocardial infarction(STEMI) by thoracic impedance method for testing cardiac output. Methods: 114 patients with STEMI were selected in the No 1 Hospital of Naval Force of Southern Theater Command of PLA from January 2016 to June 2018, they were divided into the primary PCI group(n=48), delayed PCI group(n=40) and control group without receiving any coronary artery reperfusion(n=26). The stroke volume(SV), cardiac index(CI), cardiac contractility index(CTI), ejection fraction(EF) were measured at 3 days and 6 months after therapy were detected by using thoracic impedance method, and the rehospitalization due to heart failure events in each group in 6 months were evaluated. Results: At 6 months after therapy, the SV, CI, CTI, EF were higher in the primary PCI group and delayed PCI groupthan these in control group, and SV, CTI, EF in primary PCI group were higher than these in delayed PCI group(P<0.05). The rehospitalization rate due to heart failure in primary PCI group and delayed PCI group were remarkably lower than these of control group(P<0.05). Conclusions: Both primary and delayed PCI can improve the heart function in medium and long term in patiens of STEMI, and the primary PCI is more effective. [ABSTRACT FROM AUTHOR]

Reduced regenerative capacity of aged stem cells hampers the benefits of autologous cell therapy for cardiac regeneration. This study investigated whether neuron-derived neurotrophic factor (NDNF) could rejuvenate aged human bone marrow (hBM)- multipotent mesenchymal stromal cells (MSCs) and whether the rejuvenated hBM-MSCs could improve cardiac repair after ischemic injury. Over-expression of NDNF in old hBM-MSCs decreased cell senescence and apoptosis. Engraftment of NDNF over-expressing old hBM-MSCs into the ischemic area of mouse hearts resulted in improved cardiac function after myocardial infarction, while promoting implanted stem cell survival. Our findings suggest NDNF could be a new factor to rejuvenate aged stem cells and improve their capability to repair the aged heart after injury.

This study aimed to investigate the therapeutic effect of traditional Chinese medicine-Buxin Yishen decoction (BXYS) on type 2 cardiorenal syndrome (CRS) caused by myocardial infarction and explore the possible mechanism BXYS works. A chronic heart failure (CHF) rat model induced by left anterior descending coronary artery ligation was used and five groups were created that included a sham group, a CHF model group, a fosinopril group, a BXYS (0.4 g/kg) group and a BXYS (0.8 g/kg) group. Heart function, renal hemodynamics, neuroendocrine factors, serum, and urine concentration of soluble form connective tissue growth factor (sCTGF), expression of CTGF mRNA, CTGF, α-smooth muscle actin (α-SMA), and low-density lipoprotein receptor-related protein (LRP) in renal tissues were evaluated after 28 days and 60 days of drug administration. Histological analysis of kidney tissues was also performed. In vitro experiments were designed to verify the results of in vivo experiments by detecting factors including CTGF, α-SMA, in NRK-52E cells. Rats with CHF showed obvious pathophysiological changes including: altered renal hemodynamic parameters; dysregulated heart function; changes to serum concentrations of angiotensin II (AngII), cyclic guanosine monophosphate (cGMP), serum creatinine (Scr), blood urea nitrogen (BUN), C-reactive protein (CRP), brain natriuretic peptide (BNP); high serum and urine sCTGF concentration; high CTGF mRNA, CTGF, α-SMA and LRP expression in renal tissues; increased extracellular matrix (ECM) deposition and fibrosis in renal tissues. Treatment of BXYS was correlated with a restoration of heart function and improvement of renal hemodynamics, lower serum and urine sCTGF, lower CTGF mRNA, CTGF, α-SMA and LRP expression in renal tissues and lower ECM deposition. In addition, in vitro experiments showed that treatment with BXYS reduced the α-SMA and LRP concentration in NRK-52E cells, which were similar in vivo experiments. In conclusion, the current study provided evidences that BXYS played a role in improving heart function and delaying the progress of renal fibrosis. Meanwhile, the CTGF-LRP pathway might be one of the therapeutic targets for myocardial infarction caused type 2 CRS which showed a positive change after BXYS treatment and is worthy of further exploration. [ABSTRACT FROM AUTHOR]

Cell therapy of the post-infarcted myocardium is still far from clinical use. Poor survival of transplanted cells, insufficient regeneration, and replacement of the damaged tissue limit the potential of currently available cell-based techniques. In this study, we generated a multilayered construct from adipose-derived mesenchymal stromal cells (MSCs) modified to secrete stem cell factor, SCF. In a rat model of myocardium infarction, we show that transplantation of SCF producing cell sheet induced activation of the epicardium and promoted the accumulation of c-kit positive cells in ischemic muscle. Morphometry showed the reduction of infarct size (16%) and a left ventricle expansion index (0.12) in the treatment group compared to controls (24–28%; 0.17–0.32). The ratio of viable myocardium was more than 1.5-fold higher, reaching 49% compared to the control (28%) or unmodified cell sheet group (30%). Finally, by day 30 after myocardium infarction, SCF-producing cell sheet transplantation increased left ventricle ejection fraction from 37% in the control sham-operated group to 53%. Our results suggest that, combining the genetic modification of MSCs and their assembly into a multilayered construct, we can provide prolonged pleiotropic effects to the damaged heart, induce endogenous regenerative processes, and improve cardiac function.

Background: The aim of this research was to study whether transplantation of mesenchymal stem cells (MSCs) overexpressing microRNA-1 into mouse infarcted myocardium can enhance cardiac myocyte differentiation and improve cardiac function efficiently. Methods: Eight-week-old female C57BL/6 mice underwent ligation of the left coronary artery to produce models of myocardial infarction. The ligated animals were randomly divided into 4 groups (20 in each). One week later, they were intramyocardially injected at the heart infarcted zone with microRNA-1-transduced MSCs (MSCmiR-1 group), mock-vector-transduced MSCs (MSCnull group), MSCs (MSC group) or medium (PBS group). At 4 weeks post-transplantation, transthoracic echocardiographic assessment, histological evaluation and Western blot were performed. Results: The transplanted MSCs were able to differentiate into cardiomyocytes in the infarcted zone. Cardiac function in the MSC, MSCnull and MSCmiR-1 groups was significantly improved compared to the PBS group (p < 0.01 or p < 0.001). However, treatment of MSCs expressing microRNA-1 was more effective for cardiac repair and improved cardiac function more efficiently by enhancing cell survival and cardiac myocyte differentiation compared to the MSC group or the MSCnull groups (p < 0.05 or p < 0.01, respectively). Conclusions: Transplantation of microRNA-1-transfected MSCs was more conducive to repair of infarct injury and improved heart function by enhancing transplanted cells survival and cardiomyogenic differentiation. Copyright © 2013 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: Ethnopharmacological relevance: The decoction of combined Panax notoginseng (Burk) F.H. Chen and Carthamus tinctorius L. has a history of use in traditional medicine for the prevention and treatment of cardiovascular diseases such as angina pectoris and myocardial infarction. Aim of the study: In this study, we investigated the effects of individual herbal extracts and combined extracts on anti-myocardial ischemia injuries in vivo, and determined the proper dosage of Panax notoginseng (EPN) combined with Carthamus tinctorius (ECT) that could strengthen their cardio-protective effects. Meanwhile, their potential anti-oxidative stress and anti-inflammation effect were assessed. Material and Methods: SD rats were orally given individual EPN 50, 100mg/kg, ECT 100, 200mg/kg, and different combinations between them. Myocardial infarction was produced by occlusion of the left anterior descending coronary artery for 24h. Infarct area was determined with 2,3,5-triphenyltetrazolium chloride (TTC) staining. The biomarkers related to myocardial ischemia injury were determined. Simultaneously, hemodynamic parameters were monitored as left ventricular systolic pressure (LVSP), LV end-diastolic pressure (LVEDP) and maximal rate of increase and decrease of left ventricular pressure (dP/dt max). The oxidative stress indicators and inflammatory factors were also evaluated. Results: The results showed EPN or ECT significantly reduced infarct size, improved cardiac function, decreased levels of creatine kinase (CK) and lactate dehydrogenase (LDH) (all P<0.05 vs. control ). EPN or ECT alone also restrained the oxidative stress related to myocardial ischemia injury as evidenced by decreased malondialdehyde (MDA) and elevated superoxide dismutase (SOD) activity (all P<0.05 vs. control). However, this cardio-protective effect was further strengthened by their combinations. Among all the combinations, EPN 50mg/kg plus ECT 200mg/kg showed predominant potential to reduce infarct size (22.21±1.72%, P<0.05 vs. each single, respectively), preserve cardiac function (P<0.05 vs. ECT 200mg/kg for LVEDP and −dP/dt max) after myocardial ischemia injury in rats. This heart protection was confirmed with the lowered cardiac troponin I (cTnI) (P<0.05 vs. ECT 200mg/kg and EPN 50mg/kg, respectively). Oxidative stress and inflammation are the two key factors in the pathogenesis of myocardial ischemia injury. In the present study, EPN 50mg/kg plus ECT 200mg/kg markedly increased SOD and GSH-Px activity (475.30±23.60U/ml, P<0.05 vs. each single, respectively), while elevated MDA level was significantly depressed. Meanwhile, the inflammatory cascade was inhibited as evidenced by decreased cytokines such as tumor necrosis factor-α (TNF-α), C-reactive protein (CRP) and interleukin-1β (IL-1β). Conclusion: These results demonstrated EPN, ECT and their combinations exhibited significant cardio-protective effects. The findings suggest EPN combined with ECT may be therapeutically more useful for ameliorating anti-myocardial ischemia injuries than individual herbal extract, and EPN 50mg/kg plus ECT 200mg/kg is the appropriate combination in the present research. The cardio-protective effect of this combination was achieved partially by decreasing oxidative stress and repressing inflammatory cascade. [Copyright &y& Elsevier]

HF (heart failure) after MI (myocardial infarction) is a major cause of morbidity and mortality worldwide. Recent studies have shown that hydrogen sulfide (H2S) has cardioprotective effects. Hence, we aimed to elucidate the potential effects of H2S on HF after MI in rats. The HF model after MI was made by ligating the left anterior descending coronary artery. HF groups and sham-operated groups of rats were treated with vehicle, sodium hydrosulfide (NaHS) or PAG (propagylglycine). Equal volumes of saline, 3.136 mg . kg-1 . day-1 NaHS or 37.5 mg . kg-1 . day-1 PAG, were intraperitoneally injected into rats for 6 weeks after operation. Survival, lung-to-body weight ratio and left ventricular haemodynamic parameters were measured. The protein and gene expression of Bcl-2, Bax, caspase 3 and cytochrome c were analysed by Western blotting and RT-PCR (reverse transcription-PCR). TUNEL (terminal deoxynucleotidyl transferase-mediated dUTP nick-end labelling) and EM (electron microscopy) were used to examine apoptosis of heart tissues. NaHS was found to improve the survival and lower the lung-to-body weight ratio. It increased the LVSP (left ventricular systolic pressure) and the maximum rate of pressure and decreased LVEDP (left ventricular end-diastolic pressure). Furthermore, NaHS promoted Bcl-2 protein and mRNA expression and demoted Bax, caspase 3 protein and mRNA expression in HF rats. We also showed that NaHS decreased the leakage of cytochrome c protein from the mitochondria to the cytoplasm. Histological observation by TUNEL and EM proved that NaHS inhibited cardiac apoptosis in HF hearts and improved mitochondrial derangements, but that PAG aggravated those indices. Hence, H2S has protective effects in HF rats. [ABSTRACT FROM AUTHOR]

Abstract: Curcumin has extensive cardioprotective effects against diabetic cardiovascular complications, cardiac hypertrophy and myocardial infarction (MI), but the molecular mechanism behind such cardioprotective effects remains still unclear. To explore the mechanism of MI, a rat model of coronary artery ligation was used to assess the cardioprotective effects of curcumin. Microarray technology was employed to detect the gene expression in the heart of MI rats treated with curcumin. Semiquantitative RT-PCR was then performed to verify the microarray result. Our results showed that curcumin could improve heart function, diminish infarct size and reverse the abnormal changes in the activities of serum lactate dehydrogenase and creatine kinase MB in rats after MI. A total of 179 genes were found to be significantly differentially expressed between sham-operated rats and coronary artery-ligated rats. Cytokine-cytokine receptor interaction, ECM-receptor interaction, focal adhesions and colorectal cancer pathway may be involved in the cardioprotective effects of curcumin. [Copyright &y& Elsevier]

Abstract: Objectives: Coronary occlusion and revascularization leads to myocardial damage and heart function deterioration. Statins can regress atherosclerosis and modulate platelet function, but their effect on post-acute myocardial infarction (AMI) injury remains to be fully determined. We sought to examine whether rosuvastatin (R) exerts any effect on the RISK/apoptosis pathway when administered early after coronary reperfusion. Methods: Pigs were fed 10 days a hypercholesterolemic diet before AMI induction and thereafter for 7 days randomly distributed to receive R or placebo (C) with the same diet. At sacrifice, hearts were sliced and alternatively collected for MI size and molecular analysis (gene and protein expression) in the peri-infarcted and remote myocardium. The RISK components (PKC, Erk2, and Akt/PKB) and downstream targets (HIF-1α and VEGF), and cell survival/apoptosis markers (Bcl-2, Bax, and Caspase-3) were analyzed. Annexin-V, Mito-Tracker staining, and inflammatory infiltration were also evaluated. Results: R enhanced PKC, Erk2, Akt/PKB and its downstream effectors, and attenuated inflammation and cardiomyocyte apoptosis in the peri-infarcted zone (p <0.05). No changes were detected in the remote myocardium. Infarct size was smaller in R than in C pigs (7% absolute reduction; 36% relative reduction; p <0.05) and was associated with an absolute 12% recovery of LVEF (24% relative restoration; p <0.05 vs. post-AMI). Conclusions: HMG-CoA inhibition early after reperfusion activates RISK kinases, reduces the extent of damaged myocardium, and improves heart function. [Copyright &y& Elsevier]

Objective: In this study the effect of ribose on heart function and infarct-size was analyzed 6 h after myocardial infarction (MI) in rats. Methods: Continuous i.v.-infusion of NaCl or ribose (200 mg/kg/h) was started one day prior to induction of MI in female Sprague-Dawley rats which was done by ligation of the left coronary artery. Six hours after MI heart function was measured with 3F tip catheter, cardiac output by thermodilution method. Thereafter the ischemic area was delineated by Evans Blue infusion, and the infarct area was visualized by triphenyltetrazolium chloride staining. The mRNA expression of interleukin (IL)-1β, IL-6, matrix-metalloproteinase (MMP)-8, and -9 was measured by ribonuclease protection assay. Results: Heart function was severely depressed 6 hours after coronary artery occlusion, but recovered significantly under the influence of ribose. Left ventricular (LV) systolic pressure (LVSP) and contractility (LVdP/dtmax) were restored to the normal levels of sham-operated animals, while parameters of LV relaxation (LVdP/dtmin and time constant of relaxation τ) were impaired compared to sham-operated animals, but significantly improved by ribose treatment compared to sham-treated MI-rats. Moreover, the infarct size was significantly smaller in the ribose treated animals despite a comparable ischemic area at risk in all MI-rats. The cytokine mRNA expression after MI was significantly reduced after ribose treatment, while there were no differences regarding MMP expression. Conclusion: MI size was significantly reduced and LV function significantly improved by ribose treatment at 6 h after MI. This seemed to be based on slowing the velocity of the necrotic wave front across the LV wall after MI resulting in smaller infarcts. Copyright © 2009 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

The administration of therapeutic cell types, such as stem and progenitor cells, has gained much interest for the limitation or repair of tissue damage caused by a variety of insults. However, it is still uncertain whether the morphological and functional benefits are mediated predominantly via cell differentiation or paracrine mechanisms. Here, we assessed the extent and mechanisms of adipose-derived stromal/stem cells (ASC)-dependent tissue repair in the context of acute myocardial infarction. Human ASCs in saline or saline alone was injected into the peri-infarct region in athymic rats following left anterior descending (LAD) coronary artery ligation. Cardiac function and structure were evaluated by serial echocardiography and histology. ASCtreated rats consistently exhibited better cardiac function, by all measures, than control rats 1 month following LAD occlusion. Left ventricular (LV) ejection fraction and fractional shortening were improved in the ASC group, whereas LV remodeling and dilation were limited in the ASC group compared with the saline control group. Anterior wall thinning was also attenuated by ASC treatment, and post-mortem histological analysis demonstrated reduced fibrosis in ASC-treated hearts, as well as increased peri-infarct density of both arterioles and nerve sprouts. Human ASCs were persistent at 1 month in the peri-infarct region, but they were not observed to exhibit significant cardiomyocyte differentiation. Human ASCs preserve heart function and augment local angiogenesis and cardiac nerve sprouting following myocardial infarction predominantly by the provision of beneficial trophic factors. [ABSTRACT FROM AUTHOR]

Objective: In this study the ability of unrestricted somatic stem cells (USSC) and mononuclear cord blood cells (MN-CBC) was tested to improve heart function and left ventricular (LV) remodeling after myocardial infarction (MI). Methods: The cells were delivered by i.v. or intramyocardial injections in rat models of MI by permanent coronary artery occlusion and by ischemia/reperfusion (I/R) injury. Heart function and remodeling was followed by recurrent echocardiography over 8 or 12 weeks after which catheterization was performed. Results: Although injected labeled cells could be observed within the myocardium for up to 6 d, there was no sign of cardiac regeneration 8 or 12 weeks after MI. However, the mRNA expression of components of the extracellular matrix was attenuated in the infarct scar 12 weeks after MI and cell injection. Additionally, the expression of interleukin (IL)-6 but not of IL-1β increased at the site of injury and the adjacent border-zone 12 weeks after I/R and USSC-injection. However, these effects did not translate into improved heart function or attenuated LV dilatation. Conclusion: These data indicate that cord blood cell implantation after MI acts through paracrine mechanisms to modify remodeling rather than myocyte regeneration. The role of myofibroblasts and the optimal conditions of cell application need to be determined to translate these mechanisms into functional improvement. Copyright © 2008 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]

Abstract: The activity of TIMP-3, a natural tissue inhibitor of matrix metalloproteinases (MMPs), is decreased in the failing heart. This study evaluated the response to coronary ligation of cardiac structure, function, and matrix remodeling in wild-type (WT) mice, and those deficient in TIMP-3 (timp-3 −/− ). The coronary artery was ligated in timp-3 −/− and age-matched WT mice. At various time points over the following 28-day period, left ventricular structure and function (by echocardiography, pressure–volume measurements and morphometry), MMP levels and activity, blood vessel density, cell proliferation, apoptosis, matrix structure, and inflammatory cytokine levels were assessed in both groups. After ligation, mortality was significantly greater in timp-3 −/− than in WT mice. Morphometry and echocardiography demonstrated no difference in heart size or function prior to ligation; however, the progression of left ventricular systolic dysfunction was accelerated in timp-3 −/− mice at 7, 14 and 28 days after infarction compared to WT controls. Left ventricular dilatation, gelatinase MMP activity, and TNF-α levels were significantly greater in timp-3 −/− than in WT mice at different times after ligation. By histological evaluation, timp-3 −/− mice exhibited significantly increased blood vessel density, cell proliferation, and apoptosis in the infarct area, and reduced collagen content in the viable remote myocardium compared to WT mice at 7 and 14 days after ligation. TIMP-3 deficiency accelerated maladaptive cardiac remodeling after a myocardial infarction by promoting matrix degradation and inflammatory cytokine expression. This study supports further investigations to determine whether such remodeling could be reduced by augmenting TIMP-3 expression in the infarcted myocardium. [Copyright &y& Elsevier]

Abstract: Echocardiography is a reliable and commonly used method to examine cardiac diseases. Recent employment of modern technologies provides new opportunities to study left ventricular (LV) remodeling after myocardial infarction (MI) also in small rodents. LV volumes as most important prognostic parameters can be estimated by noncontrast enhanced echocardiography in rats from M-mode or single cross sections only. In this study, contrast enhanced echocardiography and volume measurements by the biplane method of discs (Simpson’s rule) were applied in rats to monitor remodeling and function after MI. MI was induced in female Sprague-Dawley rats (n = 26 for MI, and n = 16 for sham). LV remodeling and heart function were serially studied by contrast enhanced echocardiography for 12 to 16 wk. At the end of the observation periods hemodynamic data were additionally measured by left and right heart catheterization. LV end systolic volume (LVESV) measured by biplane method of discs correlated best with LV developed pressure as indicator for severely impaired heart function. Interestingly, LV end systolic area (LVESA) from native short axis view correlated well with LVESV (R2 = 0.93) and was the second best predictor for depressed heart function. Moreover, left atrial size was a powerful indicator of severely impaired heart function whereas ejection fraction or fractional area change were primarily related to infarct size. In conclusion, contrast enhanced echocardiography in rats is feasible and an economical method to study time-dependent LV remodeling and deterioration of contractile function after MI. (E-mail: Alexander.Deten@vetphys.unizh.ch) [Copyright &y& Elsevier]

Background: Gender differences exist in the myocardial response to acute ischemia/reperfusion (I/R) injury and may be attributed to the effects of the sex hormones estrogen and testosterone. The role of estrogen in myocardial injury has been extensively studied but little information exists regarding the myocardial involvement of testosterone. Based on the deleterious effects of chronic endogenous and acute testosterone exposure observed in our previous studies, we postulated that chronic exogenous testosterone administration would also exhibit deleterious effects on myocardial function following I/R. Methods: Langendorff perfused rat hearts were subjected to 25 min ischemia, 40 min reperfusion, and left ventricular developed pressure (LVDP) was recorded. Control and 5α-dihydrotestosterone (DHT) treated groups each consisted of normal males, castrated males, ovariectomized (OVX) females, and senescent females. P < 0.05 = significant. Results: Chronic DHT replacement therapy showed no difference in functional ischemic recovery as measured by LVDP after 40 min reperfusion in castrated males (65.1 ± 8.13% versus 66.3 ± 4.54%), OVX females (64.5 ± 10.6% versus 50.2 ± 5.97%), and senescent females (42.1 ± 0.04% versus 41 ± 0.05%). Interestingly, LVDP was greater in DHT treated males than control males after I/R (65.2 ± 8.20% versus 47.6 ± 5.19%). Also, DHT treatment resulted in significantly increased recovery of LVDP after only 10 min reperfusion in castrated males, OVX females, and senescent females compared with their untreated counterparts (54.8 ± 11.9% versus 32.9 ± 5.75%, 66.7 ± 11.5% versus 43.1 ± 8.15%, 53.4 ± 10.1% versus 32.9 ± 5.75%, respectively). Conclusion: Contrary to the adverse effects we observed in earlier studies with both endogenous and brief exogenous testosterone in myocardium injured by I/R, the present study revealed that chronic exogenous testosterone neither improved nor worsened myocardial functional recovery following 25 min ischemia and 40 min reperfusion. [Copyright &y& Elsevier]

Angiotensin-converting enzyme 2 (ACE2) is the first human homologue of ACE to be described. ACE2 is a type I integral membrane protein that functions as a carboxypeptidase, cleaving a single hydrophobic/basic residue from the COOH-terminus of its substrates. Because ACE2 efficiently hydrolyzes the potent vasoconstrictor angiotensin II to angiotensin (1-7), this has changed our overall perspective about the classical view of the renin angiotensin system in the regulation of hypertension and heart and renal function, because it represents the first example of a feedforward mechanism directed toward mitigation of the actions of angiotensin II. This paper reviews the new data regarding the biochemistry of angiotensin-(1-7)-forming enzymes and discusses key findings such as the elucidation of the regulatory mechanisms participating in the expression of ACE2 and angiotensin-(1-7) in the control of the circulation. [ABSTRACT FROM AUTHOR]

A new dynamic model of left ventricular (LV) pressure-volume relationships in beating heart was developed by mathematically linking chamber pressure-volume dynamics with cardiac muscle force length dynamics. The dynamic LV model accounted for >80% of the measured variation in pressure caused by small-amplitude volume perturbation in an otherwise isovolumically beating, isolated rat heart. The dynamic LV model produced good fits to pressure responses to volume perturbations, but there existed some systematic features in the residual errors of the fits. The issue was whether these residual errors would be damaging to an application where the dynamic LV model was used with LV pressure and volume measurements to estimate myocardial contractile parameters. Good agreement among myocardial parameters responsible for response magnitude was found between those derived by geometric transformations of parameters of the dynamic LV model estimated in beating heart and those found by direct measurement in constantly activated, isolated muscle fibers. Good agreement was also found among myocardial kinetic parameters estimated in each of the two preparations. Thus the small systematic residual errors from fitting the LV model to the dynamic pressure-volume measurements do not interfere with use of the dynamic LV model to estimate contractile parameters of myocardium. Dynamic contractile behavior of cardiac muscle can now be obtained from a beating heart by judicious application of the dynamic LV model to information rich pressure and volume signals. This provides for the first time a bridge between the dynamics of cardiac muscle function and the dynamics of heart function and allows a beating heart to be used in studies where the relevance of myofilament contractile behavior to cardiovascular system function may be investigated. [ABSTRACT FROM AUTHOR]

Abstract: Systemic inflammatory response to acute myocardial infarction (AMI) is detrimental to heart function. In this study, we proved that poly(ADP-ribose) polymerase (PARP) activity of circulating mononuclear cell (MNC) increased significantly in post-AMI patients. MNC PARP activity was correlated positively with plasma tumor necrosis factor-α (TNF-α) level, interleukin-10 (IL-10) level and the ratio of plasma TNF-α/IL-10 respectively. On the contrary, MNC PARP activity was correlated negatively with left ventricular ejection fraction and left ventricular fractional shortening which were measured with echocardiography in the same day when blood sample was collected. These results implicated that activation of PARP in MNC contributes to the increases in plasma TNF-α and IL-10 and is associated with systolic dysfunction of heart after AMI. [Copyright &y& Elsevier]