Juying Qian

Efficacy of emergent transcatheter transplantation of stem cells for treatment of acute myocardial infarction (TCT-STAMI)

Objective: To study whether emergent intracoronary autologous bone marrow cell transplantation (BMT) is applicable for the treatment of acute myocardial infarction (AMI). Methods: 20 patients admitted within 24 h after the onset of a first AMI were randomly allocated to receive intracoronary autologous BMT (n  =  10) or bone marrow supernatant (controls, n  =  10) immediately after primary percutaneous coronary intervention. Left ventricular ejection fraction (LVEF), left ventricular end diastolic internal diameter (LVDd) and myocardial perfusion defect scores were examined respectively by echocardiography and single-photon emission computed tomography at one week and six months after AMI. Results: From one week to six months after AMI, LVEF was enhanced from mean 53.8 (SD 9.2)% to 58.6 (9.9)% (p < 0.05) in the BMT group but was unchanged in the control group (58.2 (7.5)% v 56.3 (3.5)%, p > 0.05); LVDd remained unchanged (52.5 (2.8) v 52.1 (3.2) mm, p > 0.05) in the BMT group but was significantly enlarged in the control group (50.4 (6.0) v 55.2 (7.1) mm, p < 0.05). Additionally, myocardial perfusion defect scores decreased from 21 (11) to 13 (10) (p < 0.01) in the BMT group but were unchanged in the control group (20 (14) v 17 (15), p > 0.05). Conclusion: Emergent intracoronary transplantation of bone marrow mononuclear cells after AMI is practicable, and it improved cardiac function, prevented myocardial remodelling and increased myocardial perfusion at six months’ follow up.

Administration of intracoronary bone marrow mononuclear cells on chronic myocardial infarction improves diastolic function

Background: Regeneration of the myocardium and improved ventricular function have been demonstrated in patients with acute myocardial infarction (MI) treated by intracoronary delivery of autologous bone marrow mononuclear cells (BMC) a few days after successful myocardial reperfusion by percutaneous coronary intervention (PCI); however, the effects of intracoronary cell infusion in chronic MI patients are still unknown. Aims: To investigate whether intracoronary infusion of BMC into the infarct-related artery in patients with healed MI could lead to improvement in left ventricular (LV) function. Methods: Among 47 patients with stable ischaemic heart disease due to a previous MI (13 (SD 8) months previously), 24 were randomised to intracoronary infusion of BMC (BMC group) and 23 to a saline infusion (control group) into the target vessel after successful PCI within 12 hours after chest pain occurred. LV systolic and diastolic function, infarct size and myocardial perfusion defect were assessed with the use of echocardiography, magnetic resonance imaging (MRI) or 201Tl single-photon-emission computed tomography (SPECT) at baseline and repeated at the 6-month follow-up examination. Results: BMC treatment did not result in a significant increase in LV ejection fraction in any of the groups by any of the methods used, and the apparent tendency of an improvement was not statistically different between the two groups. The two groups also did not differ significantly in changes of LV end-diastolic and systolic volume, infarct size or myocardial perfusion. However, there was an overall effect of BMC transfer compared with the control group with respect to early/late (E/A) (p<0.001), early diastolic velocity/late diastolic (Aa) velocity (Ea/Aa) ratio (p = 0.002) and isovolumetric relaxation time (p = 0.038) after 6 months, as evaluated by tissue Doppler echocardiography. We noted no complications associated with BMS transfer. Conclusion: Intracoronary transfer of autologous BMC in patients with healed MI did not lead to significant improvement of cardiac systolic function, infarct size or myocardial perfusion, but did lead to improvement in diastolic function.

High density lipoprotein protects mesenchymal stem cells from oxidative stress-induced apoptosis via activation of the PI3K/Akt pathway and suppression of reactive oxygen species.

The therapeutic effect of transplantation of mesenchymal stem cells (MSCs) in myocardial infarction (MI) appears to be limited by poor cell viability in the injured tissue, which is a consequence of oxidative stress and pro-apoptotic factors. High density lipoprotein (HDL) reverses cholesterol transport and has anti-oxidative and anti-apoptotic properties. We, therefore, investigated whether HDL could protect MSCs from oxidative stress-induced apoptosis. MSCs derived from the bone marrow of rats were pre-incubated with or without HDL, and then were exposed to hydrogen peroxide (H2O2) in vitro, or were transplanted into experimentally infarcted hearts of rats in vivo. Pre-incubation of MSCs with HDL increased cell viability, reduced apoptotic indices and resulted in parallel decreases in reactive oxygen species (ROS) in comparison with control MSCs. Each of the beneficial effects of HDL on MSCs was attenuated by inhibiting the PI3K/Akt pathway. Preconditioning with HDL resulted in higher MSC survival rates, improved cardiac remodeling and better myocardial function than in the MSC control group. Collectively, these results suggest that HDL may protect against H2O2-induced apoptosis in MSCs through activation of a PI3K/Akt pathway, and by suppressing the production of ROS.

Myocardial transfection of hypoxia-inducible factor-1α and co-transplantation of mesenchymal stem cells enhance cardiac repair in rats with experimental myocardial infarction

IntroductionMesenchymal stem cells (MSCs) have potential for the treatment of myocardial infarction. However, several meta-analyses revealed that the outcome of stem cell transplantation is dissatisfactory. A series of studies demonstrated that the combination of cell and gene therapy was a promising strategy to enhance therapeutic efficiency. The aim of this research is to investigate whether and how the combination of overexpression of hypoxia-inducible factor-1α (HIF-1α) and co-transplantation of mesenchymal stem cells can enhance cardiac repair in myocardial infarction.MethodsWe investigated the therapeutic effects of myocardial transfection of HIF-1α and co-transplantation of MSCs on cardiac repair in myocardial infarction by using myocardial transfection of HIF-1α via an adenoviral vector. Myocardial infarction was produced by coronary ligation in Sprague-Dawley (SD) rats. Animals were divided randomly into six groups: (1) HIF-1α + MSCs group: Ad-HIF-1α (6 × 109 plate forming unit) and MSCs (1 × 106) were intramyocardially injected into the border zone simultaneously; (2) HIF-1α group: Ad-HIF-1α (6 × 109 plate forming unit) was injected into the border zone; (3) HIF-1α-MSCs group: Ad-HIF-1α transfected MSCs (1 × 106) were injected into the border zone; (4) MSCs group: MSCs (1 × 106) were injected into the border zone; (5) Control group: same volume of DMEM was injected; (6) SHAM group. Cardiac performance was then quantified by echocardiography as well as molecular and pathologic analysis of heart samples in the peri-infarcted region and the infarcted region at serial time points. The survival and engraftment of transplanted MSCs were also assessed.ResultsMyocardial transfection of HIF-1α combined with MSC transplantation in the peri-infarcted region improved cardiac function four weeks after myocardial infarction. Significant increases in vascular endothelial growth factor (VEGF) and stromal cell-derived factor-1α (SDF-1α) expression, angiogenesis and MSC engraftment, as well as decreased cardiomyocyte apoptosis in peri-infarcted regions in the hearts of the HIF-1α + MSCs group were detected compared to the MSCs group and Control group.ConclusionsThese findings suggest that myocardial transfection of HIF-1α and co-transplantation of mesenchymal stem cells enhance cardiac repair in myocardial infarction, indicating the feasibility and preliminary safety of a combination of myocardial transfection of HIF-1α and MSC transplantation to treat myocardial infarction.

Magnetic targeting enhances retrograde cell retention in a rat model of myocardial infarction

IntroductionRetrograde coronary venous infusion is a promising delivery method for cellular cardiomyoplasty. Poor cell retention is the major obstacle to the establishment of this method as the preferred route for cell delivery. Here, we explored whether magnetic targeting could enhance retrograde cell retention in a rat model of myocardial infarction.MethodsRat mesenchymal stem cells were labeled with superparamagnetic oxide nanoparticles. The magnetic responsiveness of MSCs was observed while cells flowed through a tube that served as a model of blood vessels in a 0.6-Tesla magnetic field. In a Sprague–Dawley rat model of acute myocardial infarction, 1 × 106 magnetic mesenchymal stem cells were transjugularly injected into the left cardiac vein while a 0.6-Tesla magnet was placed above the heart. The cardiac retention of transplanted cells was assessed by using quantitative Y chromosome-specific polymerase chain reaction, cardiac magnetic resonance imaging, and optical imaging. Cardiac function was measured by using echocardiography, and histologic analyses of infarct morphology and angiogenesis were obtained.ResultsThe flowing iron oxide-labeled mesenchymal stem cells were effectively attracted to the area where the magnet was positioned. Twenty-four hours after cellular retrocoronary delivery, magnetic targeting significantly increased the cardiac retention of transplanted cells by 2.73- to 2.87-fold. Histologic analyses showed that more transplanted cells were distributed in the anterior wall of the left ventricle. The enhanced cell engraftment persisted for at least 3 weeks, at which time, left ventricular remodeling was attenuated, and cardiac function benefit was improved.ConclusionsThese results suggest that magnetic targeting offers new perspectives for retrograde coronary venous delivery to enhance cell retention and subsequent functional benefit in heart diseases.

Delivery of alginate-chitosan hydrogel promotes endogenous repair and preserves cardiac function in rats with myocardial infarction.

The regenerative potential of alginate-chitosan composite in bone and cartilage tissue has been well documented, but its potential utility in cardiac tissue engineering has remained unknown. This study sought to determine whether early intramyocardial injection of alginate-chitosan could prevent left ventricular (LV) remodeling after myocardial infarction (MI), leading to a more favorable course of tissue restoration. In a rat model of acute MI, local injection of alginate-chitosan hydrogel into the peri-infarct zone preserved scar thickness, attenuated infarct expansion, and reduced scar fibrosis after 8 weeks, concomitantly with promoting increased angiogenesis and greater recruitment of endogenous repair at the infarct zone. Furthermore, this treatment prevented cell apoptosis, induced cardiomyocyte cell cycle re-entry. The cardiac function of the control-injected animals deteriorated over the 8-week course, while that of the hydrogel-injected animals did not.In addition, the hydrogel did not exacerbate inflammation in the heart. Intramyocardial injection of alginate-chitosan hydrogel represents a useful strategy to treat MI. It demonstrated marked therapeutic efficacies on various tissue levels after extensive MI, as well as potential to induce endogenous cardiomyocyte proliferation and recruit cardiac stem cells.

High density lipoprotein cholesterol promotes the proliferation of bone-derived mesenchymal stem cells via binding scavenger receptor-B type I and activation of PI3K/Akt, MAPK/ERK1/2 pathways

High-density lipoprotein (HDL) possesses protective properties in cardiovascular diseases. However, the effect of HDL on the mesenchymal stem cells (MSCs), which could be mobilized to the damaged myocardial tissue, has not been well elucidated yet. In the current study, we investigated the effect of HDL on the proliferation of MSCs so as to reveal its molecular mechanisms. MSCs derived from rats were treated with HDL in different concentrations and for different periods. The proliferation of MSCs was measured with MTT and BrdU cell proliferation assay. The phosphorylation of Akt, ERK1/2 and the expression of p21 were evaluated by Western blotting. After the activity of respective pathways was down-regulated by the specific inhibitor and the gene of scavenger receptor-B type I (SR-BI) was knocked down by RNA interference, BrdU assay was performed to examine this effect of HDL on MSCs. We found that the proliferation of MSCs induced by HDL, in a time- and concentration-dependent manner, was the phosphorylation of Akt- and ERK1/2-dependent, which was significantly attenuated by the specific inhibitor to respective pathways. Moreover, MAPK/ERK1/2 pathway exerted a more dominating effect on this process. SR-BI contributed to HDL-induced proliferation of MSCs, which was effectively abolished by the silencing of SR-BI. The results suggested that HDL was capable of improving MSCs proliferation, in which MAPK/ERK1/2 and PI3K/Akt pathways involved and SR-BI played a critical role as well.

miR-210 over-expression enhances mesenchymal stem cell survival in an oxidative stress environment through antioxidation and c-Met pathway activation

AbstractmicroRNA-210 (miR-210) has generally been reported to be associated with cell survival under hypoxia. However, there are few data regarding the role of miR-210 in the survival of mesenchymal stem cells (MSCs) under oxidative stress conditions. Thus, we sought to investigate whether miR-210 over-expression could protect MSCs against oxidative stress injury and what the primary mechanisms involved are. The results showed that over-expression of miR-210 significantly reduced the apoptosis of MSCs under oxidative stress, accompanied by obvious increases in cell viability and superoxide dismutase activity and remarkable decreases in malonaldehyde content and reactive oxygen species production, resulting in a noticeable reduction of apoptotic indices when compared with the control. Moreover, the above beneficial effects of miR-210 could be significantly reduced by c-Met pathway repression. Collectively, these results showed that miR-210 over-expression improved MSC survival under oxidative stress through antioxidation and c-Met pathway activation, indicating the potential development of a novel approach to enhance the efficacy of MSC-based therapy for injured myocardium.

REstoration of COronary flow in patients with no-reflow after primary coronary interVEntion of acute myocaRdial infarction (RECOVER)

BACKGROUND No randomized trial has been conducted to compare different vasodilators for treating no-reflow during primary percutaneous coronary intervention (PCI) for ST-segment elevation acute myocardial infarction. METHODS The prospective, randomized, 2-center trial was designed to compare the effect of 3 different vasodilators on coronary no-reflow. A total of 102 patients with no-reflow in primary PCI were randomized to receive intracoronary infusion of diltiazem, verapamil, or nitroglycerin (n = 34 in each group) through selective microcatheter. The primary end point was coronary flow improvement in corrected thrombolysis in myocardial infarction frame count (CTFC) after administration of the drug. RESULTS Compared with that of the nitroglycerin group, there was a significant improvement of CTFC after drug infusion in the diltiazem and verapamil groups (42.4 frames vs 28.1 and 28.4 frames, P < .001). The improvement in CTFC was similar between the diltiazem and verapamil groups (P = .9). Compared with the nitroglycerin group, the diltiazem and verapamil groups had more complete ST-segment resolution at 3 hours after PCI, lower peak troponin T level, and lower N-terminal pro-B-type natriuretic peptide levels at 1 and 30 days after PCI. After drug infusion, the drop of heart rate and systolic blood pressure in the verapamil group was greater than that in the diltiazem and nitroglycerin groups. CONCLUSION Intracoronary infusion of diltiazem or verapamil can reverse no-reflow more effectively than nitroglycerin during primary PCI for acute myocardial infarction. The efficacy of diltiazem and verapamil is similar, and diltiazem seems safer.

TNF-α-induced cardiomyocyte apoptosis contributes to cardiac dysfunction after coronary microembolization in mini-pigs.

This experimental study was designed to clarify the relationship between cardiomyocyte apoptosis and tumour necrosis factor‐alpha (TNF‐α) expression, and confirm the effect of TNF‐α on cardiac dysfunction after coronary microembolization (CME) in mini‐pigs. Nineteen mini‐pigs were divided into three groups: sham‐operation group (n = 5), CME group (n = 7) and adalimumab pre‐treatment group (n = 7; TNF‐α antibody, 2 mg/kg intracoronary injection before CME). Magnetic resonance imaging (3.0‐T) was performed at baseline, 6th hour and 1 week after procedure. Cardiomyocyte apoptosis was detected by cardiac‐TUNEL staining, and caspase‐3 and caspase‐8 were detected by RT‐PCR and immunohistochemistry. Furthermore, serum TNF‐α, IL‐6 and troponin T were analysed, while myocardial expressions of TNF‐α and IL‐6 were detected. Both TNF‐α expression (serum level and myocardial expression) and average number of apoptotic cardiomyocyte nuclei were significantly increased in CME group compared with the sham‐operation group. Six hours after CME, left ventricular end‐systolic volume (LVESV) was increased and the left ventricular ejection fraction (LVEF) was decreased in CME group. Pre‐treatment with adalimumab not only significantly improved LVEF after CME (6th hour: 54.9 ± 2.3% versus 50.4 ± 3.9%, P = 0.036; 1 week: 56.7 ± 4.2% versus 52.7 ± 2.9%, P = 0.041), but also suppressed cardiomyocyte apoptosis and the expression of caspase‐3 and caspase‐8. Meanwhile, the average number of apoptotic cardiomyocytes nuclei was inversely correlated with LVEF (r = −0.535, P = 0.022). TNF‐α‐induced cardiomyocyte apoptosis is likely involved in cardiac dysfunction after CME. TNF‐α antibody therapy suppresses cardiomyocyte apoptosis and improves early cardiac function after CME.