Effect of pericardial incision on left ventricular morphology and systolic function in patients during coronary artery bypass grafting.

BACKGROUND: Accurate assessment of left ventricular (LV) systolic function is important after coronary artery bypass grafting (CABG). LV ejection fraction (LVEF) is conventionally used to evaluate LV systolic function; deformation parameters can be used to detect subtle LV systolic dysfunction. It is unclear whether an incised pericardium without sutures during CABG could affect LV morphology and function. We investigated the effect of pericardial incision on LV morphology and systolic function during CABG. METHODS: Intraoperative transesophageal echocardiography was performed in 27 patients during elective off-pump beating heart CABG 5 min before and after pericardial incision. LV longitudinal and mid-cavity transversal diameters, sphericity index, volumes, and LVEF were measured. LV global longitudinal strain (GLS), global circumferential strain (GCS), global radial strain (GRS), and twist obtained by two-dimensional speckle tracking echocardiography were measured simultaneously. RESULTS: LV mid-cavity transversal diameter increased, while the LV sphericity index decreased (P < 0.001) immediately after pericardial incision. The GLS, GCS, and twist significantly decreased, while the GRS notably increased (P < 0.001). The LV volumes and LVEF remained unchanged. CONCLUSIONS: Pericardial incision immediately transformed LV morphology from an ellipsoid to sphere, with decreased longitudinal and circumferential strain and twist, and increased radial strain, while LVEF remained unchanged. This should be considered when evaluating LV systolic function in patients after CABG.

Overexpression of miR-210 promotes the potential of cardiac stem cells against hypoxia.

OBJECTIVE: To evaluate the effects of miR-210 on cardiac stem cells (CSCs) against hypoxia-induced injury. METHODS: CSCs were isolated from rat ventricular wall and cultured until passage 4. After exposure to hypoxia for 6 h, the expression of miR-210 was determined. Thereafter, transfection of miR-210 mimic and inhibitor was carried out. 1 week later, in vitro experiments were performed to measure the expression of caspase-8-associated protein 2 (Casp8ap2), Caspase 8, protein tyrosine phosphatase, non-receptor type 2 (PTPN2) and CXC chemokine receptor 4 (CXCR4), as well as migration and apoptosis of CSCs under hypoxic condition. RESULTS: Hypoxia induced a significant up-regulation of miR-210 expression in CSCs. Notably, the expression of Casp8ap2, Caspase8, PTPN2 was dramatically inhibited by overexpression of miR-210 in CSCsmiR-210 Group (P < .05), but no changes in CXCR4 (P > .05), compared with the control. Additionally, a decreased apoptosis of CSCs was detected in CSCsmiR-210 Group (26.22 ± 1.15%, P < .001), compared with Control Group (34.97 ± 0.63%). Moreover, the migration of CSCs was significantly promoted in CSCsmiR-210 Group (45.73 ± 2.4, P < .001), compared with Control Group (19.6 ± 1.11). Meanwhile, down-regulation of miR-210 reversed these results (P < .05). CONCLUSIONS: miR-210 was a hypoxia responsive element in CSCs, and its up-regulation inhibited apoptosis of CSCs and promoted their migration under hypoxic condition, through regulating its target genes Casp8ap2/Caspase 8 and PTPN2, which may provide a new strategy for cell therapy of ischemic heart disease.

[Effect of implantation of cardiosphere-derived cells combined with rat heart tissue-derived extracellular matrix on acute myocardial infarction in rats].

OBJECTIVE: To investigate whether heart tissue-derived extracellular matrix (ECM) promotes the differentiation of cardiosphere-derived cells (CDCs) implanted in rat infracted myocardium to improve the cardiac structure and function. METHODS: Rat CDCs were cultured by cardiac explant methods, and ECM was prepared by decelluariztion method. In a Wistar rat model of acute myocardial infarction established by ligating the left anterior descending branch, IMDM solution, ECM suspension, 106 CDCs in IMDM solution, or 106 CDCs in ECM suspension were injected into the infracted rat myocardium (6 rats in each group). The cardiac function of the rats was evaluated by cardiac ultrasonography, and the percentage of positive heart fibrosis area after infarction was determined with Masson staining. The differentiation of implanted CDCs in the infarcted myocardium was detected using immunofluorescence assay for the markers of cardiac muscle cells (α-SA), vascular endothelial cells (vWF) and smooth muscle cells (α-SMA). RESULTS: Three weeks after acute myocardial infarction, the rats with injection of CDCs in ECM showed the highest left ventricular ejection fraction (LVEF) and percentage of fraction shortening with the lowest percentage of positive heart fibrosis area; implantation of CDCs with ECM resulted in significantly higher rates of CDC differentiation into cardiac muscle cells, vascular endothelial cells and smooth muscle cell (P<0.05). CONCLUSION: Heart-tissue derived ECM significantly promotes the differentiation of CDCs implanted in the infracted myocardium into cardiac muscle cells, vascular endothelial cells and smooth muscle cells to improve the cardiac structure and cardiac functions in rats.

Edaravone promotes activation of resident cardiac stem cells by transplanted mesenchymal stem cells in a rat myocardial infarction model.

OBJECTIVE: To explore the effect of edaravone on bone marrow mesenchymal stem cells (BMSCs) transplanted to treat acute myocardial infarction (AMI) and the underlying mechanism. METHODS: After pretreatment or treatment with edaravone under conditions of deep hypoxia and serum deprivation, the rat BMSCs were evaluated for reactive oxygen species (ROS), Akt pathway, apoptosis, migration, and paracrine function mediating cardiac stem cell (CSC) activation. Edaravone-pretreated BMSCs, control-released edaravone, and BMSCs were respectively transplanted into a rat AMI model. Apoptosis and paracrine functions of the BMSCs, resident CSC activation, and myocardial regeneration and function were measured at various time points. RESULTS: Compared with the control and edaravone pretreatment, edaravone treatment showed significantly increased apoptosis inhibition, migration, and cytokine secretion of BMSCs under an in vitro deep hypoxia and serum deprivation condition (P < .05), via inhibiting intracellular accumulation of ROS and prolonging the Akt pathway activation. At 24 hours postoperatively, up-regulated expression of cytokines within the transplanted area, and decreased apoptotic BMSCs, were detected in the BMSC + edaravone group, compared with the BMSCs and edaravone pretreatment BMSC groups (n = 10 for each group, P < .05). Four weeks later, the BMSCs + edaravone group showed more CSCs, CSC-derived cardiomyocytes, new vessels, and myocardial density within the ischemic area, and improved ejection fraction, compared with the other groups (n = 10 in each group, P < .05). CONCLUSIONS: Edaravone can protect the BMSCs against hypoxia and activate their potential to activate CSCs via the Akt pathway. The combined treatment can promote angiogenesis, resident CSC-mediated myocardial regeneration, and cardiac function after AMI, providing a new strategy for cell therapy.

bFGF binding cardiac extracellular matrix promotes the repair potential of bone marrow mesenchymal stem cells in a rabbit model for acute myocardial infarction.

To assess the effect of basic fibroblast growth factor-binding extracellular matrix (bFGF-ECM) combined with bone marrow mesenchymal stem cells (BMSCs) transplantation on acute myocardial infarction (AMI) and explore the underlying mechenisms. Rabbit hearts were processed by decellularization with sodium dodecyl sulfate (SDS) perfusion, heparin immobilization, bFGF-binding and homogenization, for preparation of bFGF-binding cardiac ECM suspension (bFGF-ECM). Thereafter, the characteristics of bFGF release were analyzed in vitro. Following ligation of the mid-third of the left anterior descending artery, the rabbits were divided into a control group (no treatment), BMSCs group (BMSCs transplantation), bFGF-ECM group (bFGF-ECM implantation), and BMSCs + bFGF-ECM group (BMSCs and bFGF-ECM implantation). Apoptosis and differentiation of implanted BMSCs, and the left ventricular (LV) remodeling and function were assessed. The ex vivo proliferation, apoptosis, migration and differentiation of BMSCs were determined after exposure to bFGF and/or ECM. The ECM could sustainably release bFGF. 24 h and 6 weeks after the operation, improved viability and differentiation of the implanted BMSCs, as well as inhibited dilatation and preserved function of the left ventricle (LV), were significant in the BMSCs + bFGF-ECM group compared with other groups (P < 0.05), although BMSCs and ECM-bFGF groups also showed better results than control group (P < 0.05). Additionally, ECM and bFGF showed a synergistic effect on BMSCs proliferation, viability, migration and differentiation. The combination of bFGF-binding ECM and BMSCs implantation may promote myocardial regeneration and LV function, and become a new strategy for the treatment of AMI.

HGF and IGF-1 promote protective effects of allogeneic BMSC transplantation in rabbit model of acute myocardial infarction.

OBJECTIVES: To explore effects of hepatocyte growth factor (HGF) combined with insulin-like growth factor 1 (IGF-1) on transplanted bone marrow mesenchymal stem cells (BMSCs), for treatment of acute myocardial ischaemia. MATERIALS AND METHODS: After ligation of the left anterior descending artery, rabbits were divided into a Control group, a Factors group (HGF+IGF-1), a BMSC group and a Factors+BMSCs group. Allogenous BMSCs (1 × 10(7)) and/or control-released microspheres of 2 µg HGF+2 µg IGF-1 were intramyocardially injected into infarcted regions. Apoptosis and differentiation of implanted BMSCs, histological and morphological results, and cardiac remodelling and function were evaluated at different time points. In vitro, BMSCs were exposed to HGF, IGF-1 and both (50 ng/ml) and subsequently proliferation, migration, myocardial differentiation and apoptosis induced by hypoxia, were analysed. RESULTS: Four weeks post-operatively, the above indices were significantly improved in Factors+BMSCs group compared to the others (P < 0.01), although Factors and BMSCs group also showed better results than Control group (P < 0.05). In vitro, HGF promoted BMSC migration and differentiation into cardiomyocytes, but inhibited proliferation (P < 0.05), while IGF-1 increased proliferation and migration, and inhibited apoptosis induced by hypoxia (P < 0.05), but did not induce myocardial differentiation. Combination of HGF and IGF-1 significantly promoted BMSCs capacity for migration, differentiation and lack of apoptosis (P < 0.05). CONCLUSIONS: Combination of HGF and IGF-1 activated BMSCs complementarily, and controlled release of the two factors promoted protective potential of transplanted BMSCs to repair infarcted myocardium. This suggests a new strategy for cell therapies to overcome acute ischemic myocardial injury.

Delayed enrichment for c-kit and inducing cardiac differentiation attenuated protective effects of BMSCs' transplantation in pig model of acute myocardial ischemia.

OBJECTIVE: To investigate the effects of immature cardiomyocytes differentiated from c-kit(+) bone marrow mesenchymal stem cells (BMSCs) against acute myocardial infarction (AMI). METHODS: Miniswine passage 8 BMSCs were enriched for c-kit and induced by 5 µM 5-azacytidine (AZA) for 14 days, and a second enrichment for the dihydropyridine receptor subunit α2δ1 was performed (enriched BMSCs). Thereafter, enriched BMSCs were analyzed by determining cardiac differentiation, secretion function, and the effects of these secreted factors on cardiac stem cells (CSCs). Miniswine with AMI were divided into control, primary BMSCs' (PB), and enriched BMSCs' (EB) groups. Autologous BMSCs were intramyocardially injected into the ischemic regions in PB and EB groups. The following indices were evaluated at different time points, including paracrine of implanted BMSCs, histological and morphological analysis, myocardial perfusion, and cardiac function. RESULTS: As shown by in vitro study, enrichment + AZA significantly promoted BMSCs to express cardiac-specific markers and format action potential, but down-regulated the expression of VEGF and bFGF, consequently attenuated BMSCs-inducing CSCs proliferation, migration, and differentiation. The in vivo experiments revealed similar results like the in vitro 6 weeks postoperatively. And in EB group, there were decreased angiogenesis and myocardial perfusion, attenuated resident CSCs-mediated myocardial regeneration, and consequently impaired cardiac function compared with PB group. CONCLUSIONS: This pretreatment promoted BMSCs to differentiate into myocardiocytes both in vitro and in vivo, but impaired their paracrine function and effects on resident CSCs, suggesting that inducing cardiac differentiation alone may not improve protective effects of BMSCs transplantation on AMI.

Losartan affects the substrate for atrial fibrillation maintenance in a rabbit model.

BACKGROUND: Atrial fibrosis causes abnormal conduction through the atria, creating a substrate for atrial fibrillation (AF). In a rabbit model, rapid atrial pacing produces significant atrial fibrosis and the substrate for AF maintenance. This atrial remodeling is a potential therapeutic target. OBJECTIVE: To evaluate the effects of the losartan on atrial fibrosis. METHODS: Thirty rabbit AF models were produced by rapid atrial stimulation. They were randomly divided into three groups: sham group, rapid atrial pacing group, and rapid atrial pacing with losartan group. We performed AF vulnerability studies, atrial histologic, and molecular analyses after 4 weeks. RESULTS: Only rabbits in the rapid atrial pacing group developed sustained AF (30 min, 4of 10 rabbits). Treatment with losartan resulted in a significant reduction in left atrial fibrosis and AF duration (P<.01). real-time polymerase chain reaction analyses demonstrated the drug's effects on the expression of Collagen I, Collagen III, and TGF-ß/Smads signaling pathway. CONCLUSIONS: The treatment of losartan results in significantly reduced atrial fibrosis and AF vulnerability. Pharmacological therapy targeted at the fibrotic substrate itself may play an important role in the management of AF.

[Effects of mild hypothermia on low cardiac output after cardiac surgery].

OBJECTIVE: To evaluate the effectiveness of mild hypothermia on low cardiac output in patients after cardiac surgery. METHODS: Twelve patients manifesting low cardiac output after cardiac surgery despite of the use of massive doses of catecholamine and intra-aortic balloon pump (IABP) underwent mild hypothermia during May 2009 to February 2011. Changes in hemodynamic parameters of the patients were measured, including cardiac index (CI),mixed venous oxygen saturation [SvO(2)] and urine volume. RESULTS: In the process of mild hypothermia treatment, bladder temperature of patients was lowered to 33-35 centigrade in order to reduce the body oxygen demand. The CI [ml·s(-1)·m(-2)]of patients after mild hypothermia treatment was increased obviously (38.34 ± 5.00 vs. 30.01 ± 5.00), the same as SvO(2) (0.64 ± 0.07 vs. 0.54 ± 0.08) and urine output [ml·kg(-1)·h(-1): 3.0 ± 2.1 vs. 1.5 ± 1.1, all P < 0.05]. However, there was no significant change in heart rate, mean arterial pressure and blood oxygen pressure. CONCLUSION: Mild hypothermia is an effective and simple procedure to improve the cardiac function in patients after cardiac surgery complicated with low cardiac output.

Optimal timing algorithms of para-aortic counterpulsation device: an animal study.

Para-aortic counterpulsation device (PACD) is a promising therapy for severe heart failure (HF). However, the lack of knowledge about mechanisms has limited its clinical application. The aim of this study was to investigate the optimal timing algorithms. At the following four triggering algorithms, pre-R-wave-deflation and dicrotic notch-inflation (PD), pre-R-wave-deflation and postdicrotic notch-inflation (PP), R-wave-deflation and dicrotic notch-inflation (RD), and R-wave-deflation and postdicrotic notch-inflation (RP), hemodynamic effects of PACD were assessed in vivo. There was more significant promotion of left mean coronary artery flow (Q(LM)), carotid artery flow (Q(CA)), cardiac output (CO), pulmonary artery flow/LA pressure ratio (Q(PA)/LAP), left ventricular myocardial oxygen consumption (LVVO(2)), external LV work (ELVW), and cardiac mechanical efficiency (CME) at RD and RP models than PD and PP models. R-wave-deflation and postdicrotic notch-inflation model provided further benefits. There was significant correlation between LV functional parameters and carotid arterial reflux, but aortic pressure-related parameters. Filling at beginning of LV systolic phase and ejection at the end of isovolumic relaxation phase were the optimal triggering algorithms of PACD. It is suggested that carotid artery reflows and ventricular pressure-related parameters should be used as reference standard to adjust the timing of balloon inflation or deflation.

Transmyocardial drilling revascularization combined with heparinized bFGF-incorporating stent activates resident cardiac stem cells via SDF-1/CXCR4 axis.

OBJECTIVE: To investigate whether transmyocardial drilling revascularization combined with heparinized basic fibroblast growth factor (bFGF)-incorporating degradable stent implantation (TMDRSI) can promote myocardial regeneration after acute myocardial infarction (AMI). METHODS: A model of AMI was generated by ligating the mid-third of left anterior descending artery (LAD) of miniswine. After 6 h, the animals were divided into none-treatment (control) group (n=6) and TMDRSI group (n=6). For TMDRSI group, two channels with 3.5 mm in diameter were established by a self-made drill in the AMI region, into which a stent was implanted. Expression of stromal cell-derived factor-1(α) (SDF-1(α)) and CXC chemokine receptor 4 (CXCR4), cardiac stem cell (CSC)-mediated myocardial regeneration, myocardial apoptosis, myocardial viability, and cardiac function were assessed at various time-points. RESULTS: Six weeks after the operation, CSCs were found to have differentiated into cardiomyocytes to repair the infarcted myocardium, and all above indices showed much improvement in the TMDRSI group compared with the control group (P<0.001). CONCLUSIONS: The new method has shown to be capable of promoting CSCs proliferation and differentiation into cardiomyocytes through activating the SDF-1/CXCR4 axis, while inhibiting myocardial apoptosis, thereby enhancing myocardial regeneration following AMI and improving cardiac function. This may provide a new strategy for myocardial regeneration following AMI.

Endothelial factors after selective retrograde coronary venous bypass under different pressures.

BACKGROUND: Selective retrograde coronary venous bypass (SRCVB) may be a promising treatment for patients with advanced coronary artery disease (CAD). The aim of this study is to investigate the effect of SRCVB on plasma endothelial factor levels in dog myocardial ischemic model, and explore the possible mechanisms. METHODS: 24 crossbreed dogs were randomly divided into three groups: (1) control group; (2) SRCVB group with 60 mmHg perfusion pressure; (3) SRCVB group with 90 mmHg perfusion pressure. The posterior descending coronary artery (PDA) was ligated in all groups, and SRCVB was performed in the last two groups. The levels of plasma nitric oxide (NO) and endothelin (ET) at different time points were determined in each group. In SRCVB groups, ink and imaging agent were injected to the heart through SVG graft for assessment of vein perfusion. RESULTS: At the acute period, there were significant increase in the plasma levels of NO and decrease in ET in SRCVB 90 mmHg group compared with the control (P < 0. 01), and a further improvement were found in SRCVB 60 mmHg group (P < 0. 01). The ink or imaging agent was found in the myocardial tissue and flowed back to right atrium through contralateral coronary vein. CONCLUSIONS: SRCVB with low level of perfusion pressure could provide effective perfusion for ischemic myocardium and alleviate the myocardial endothelial cell injury. It may be a new therapeutic strategy for severe CAD.

Exogenous basic fibroblast growth factor promotes cardiac stem cell-mediated myocardial regeneration after miniswine acute myocardial infarction.

OBJECTIVE: To investigate the effects of exogenous basic fibroblast growth factor (bFGF) on myocardial regeneration after acute myocardial infarction (AMI). METHODS: AMI models were established by ligating the mid-third of left anterior descending artery, thereafter, miniswines were randomly divided into control (none treatment, n = 6) and bFGF groups (n = 6). For the bFGF group, bFGF (100 µg) was injected with a sterile microinjection at five sites within the ischemic region. 5-Bromo-2-deoxyuridine (250 mg) was administrated intravenously twice a week after the operation, to label cells undergoing DNA replication. The expression of stromal cell-derived factor-1α (SDF-1α) and CXC chemokine receptor 4 (CXCR4), cardiac stem cell-mediated myocardial regeneration, myocardial apoptosis, histological and immunohistochemical analyses, and cardiac function were evaluated at different time points. RESULTS: Four weeks after bFGF therapy, it showed an increased vessel density and myocardial perfusion (P < 0.001), upregulative expression of SDF-1α and CXCR4 (P < 0.001), increased c-kit and 5-bromo-2-deoxyuridine-positive cells (P < 0.001), enhanced myocardial viability (P < 0.001), and improved left ventricular ejection fraction (P = 0.007), compared with the control. CONCLUSION: Exogenous bFGF was shown to have increased angiogenesis and myocardial perfusion, promoted myocardial regeneration by activating the SDF-1α/CXCR4 axis, and thereby improved the cardiac function, which may provide a new therapeutic strategy for AMI.

[Prognosis of different operative procedures of coronary artery bypass grafting in the senile patients].

OBJECTIVE: To investigate myocardial protection and prognosis of the different operative procedures of coronary artery bypass grafting (CABG) for the senile patients with coronary artery disease. METHODS: From July 2008 to June 2009, 125 cases (age ≥ 65 years old) underwent CABG were divided into 3 groups.Group A (70 cases) undertook off-pump CABG, group B (33 cases) undertook on-pump beating heart CABG. group C (22 cases) undertook on-pump CABG with cardiac arrest. Serum level of cardiac troponin I (cTnI) and creatine kinase MB isoenzyme (CK-MB) activity were examined right before operation and 0, 24, 72 and 168 h after operation. The complications during perioperative period and the mortality were investigated. RESULTS: No significant difference was found in the right before operation and 168 h after operation of the serum level of cTnI and CK-MB in the 3 groups (P > 0.05). The serum level of cTnI and CK-MB activity of group A was the lowest and group B was lower than group C. Group A was the best concerning the complications during perioperative period. The mortality of group A was lower than group B but no significant difference was found in the mortality between group A and C. No significant difference was found in the complications during perioperative period and the mortality between group B and C. CONCLUSION: Off-pump CABG could reduce myocardial injury and the complications during perioperative period in the senile patients.

Effect and mechanism of panaxoside Rg1 on neovascularization in myocardial infarction rats.

OBJECTIVE: To investigate the effects and mechanisms of panaxoside Rg1 on the new vessel formation in acute myocardial infarction (AMI) rats. METHODS: The AMI model of male Sprague-Dawley (SD) rats was established, and rats were randomly divided into the AMI model group, the treatment group of panaxoside Rg1, the placebo group and the treatment group of panaxoside Rg1 plus rapamycin. Cardiac creatases were determined with 1 mL blood drawn from vena caudalis of the rats 48 h after the model was successfully made. After 4 weeks, Evans blue was injected into the aorta roots of the rats, and then, red tetrazoline was dyed again and the myocardial infarction area was evaluated. The microvessel density (MVD) of infarction area was determined by the immunohistochemistry of CD31; enzyme-linked immunosorbent assay (ELISA) was used to detect the protein content of CD31 and hypoxia inducible factor-1alpha (HIF-1alpha) of the infarction area. RESULTS: The MVD in the infarction area and the contents of CD31 and HIF-1alpha in the Rg1 treatment group were higher than those in the AMI model group significantly (P<0.05). The cardiac creatase and infarction area were lower in the Rg1 treatment group than those in the AMI model group significantly (P<0.05). The above effects, however, disappeared when rapamycin, the antagonist of mammalian target of rapamycin (mTOR), was administered simultaneously. CONCLUSIONS: Panaxoside Rg1 could increase the expression of HIF-1alpha and CD31 of myocardium and stimulate the angiogenesis. The above mentioned role of panaxoside Rg1 might be related to the excitation of mTOR receptor.