Kang Yao

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.

Impact of Timing on Efficacy and Safetyof Intracoronary Autologous Bone Marrow Stem Cells Transplantation in Acute Myocardial Infarction: A Pooled Subgroup Analysis of Randomized Controlled Trials

Until now there were no clinical studies or systematic reviews to investigate the impact of timing on efficacy and safety of intracoronary bone marrow stem cell (BMSC) transfer in patients with acute myocardial infarction (AMI).

Repeated autologous bone marrow mononuclear cell therapy in patients with large myocardial infarction

We sought to determine whether repeat administration of bone marrow mononuclear cells (BMC) can improve left ventricular function compared with a single infusion in patients with large acute myocardial infarction (AMI).

Intracoronary autologous bone marrow stem cells transfer for patients with acute myocardial infarction: a meta-analysis of randomised controlled trials.

BACKGROUND Conflicting results existed now on the clinical utility of intracoronary bone marrow stem cells (BMSC) transfer for acute myocardial infarction (AMI). This study sought to analyze the efficacy and safety of autologous BMSC transfer in patients with AMI by performing a meta-analysis based on published randomised controlled trials. METHODS A systematic literature search of PubMed, MEDLINE, BIOSIS, EMBASE, and Cochrane EBM databases during the period of 1990-2007 was made, objective being the randomised controlled trials in patients with AMI who underwent primary percutaneous coronary intervention (PCI) and received intracoronary BMSC transfer, and were followed up for at least 3 months. RESULTS A total of 6 trials with 525 patients were available for analysis. The pooled statistics showed the mean increase in left ventricular ejection fraction (LVEF) from baseline was 7.05% in BMSC group (p=0.01), whereas only 2.46% in control group (p=0.02), and the effect on the absolute change in LVEF was an increase of 4.77% compared with the control (95% confidence interval [CI] 1.42% to 8.12%; p=0.005). The similar effect on left ventricular (LV) end-diastolic dimensions was demonstrated in inter-group comparison (standardized mean difference [SMD]=-0.15, 95%CI -0.50 to 0.20; p=0.41). The incidence of major adverse cardiac events was also similar in two groups but in favor of BMSC group (relative risk [RR]=0.85, 95%CI, 0.61 to 1.19; p=0.34). CONCLUSIONS Post PCI BMSC transplantation in patients with AMI significantly increases LVEF but has no effects on LV remodeling, and there is not an incremental effect on the occurrence of major adverse cardiac events in the observed period.

Efficacy and safety of intracoronary autologous bone marrow-derived cell transplantation in patients with acute myocardial infarction: insights from randomized controlled trials with 12 or more months follow-up.

Until now there was no systematic review concerning the chronic effects of intracoronary bone marrow‐derived cell (BMC) transplantation in patients with acute myocardial infarction (MI).

Exosomes derived from dendritic cells improve cardiac function via activation of CD4(+) T lymphocytes after myocardial infarction.

CD4(+) T cell activation plays a key role in facilitating wound healing after myocardial infarction (MI). Exosomes (EXs) secreted from dendritic cells (DCs) can activate T cells in tumor models; however, whether DEXs (DC-EXs) can mediate CD4(+) T cell activation and improve wound healing post-MI remains unknown. This study sought to determine whether DEXs mediate CD4(+) T cell activation and improve cardiac function post-MI in mice. We used supernatants of hypoxic primary or necrotic HL-1 cardiomyocytes to simulate the post-MI cardiomyocyte microenvironment in vitro. Cultured bone marrow-derived DCs (BMDCs) from mice were stimulated with the supernatants of normal (Control group), hypoxic primary or necrotic HL-1 cardiomyocytes (MI group); a subset of BMDCs remained unstimulated (Negative group). DEXs were then isolated from the BMDC supernatants and either incubated with CD4(+) T cells or injected into mice via the tail vein. In this study, we found that the supernatants of both hypoxic primary and necrotic HL-1 cardiomyocytes upregulate DC maturation markers. After the injection of DEXs, a greater number of MI-DEXs are recruited by the mouse spleen and with greater rapidity than control- or negative-DEXs. Confocal imaging and flow cytometry revealed that MI-DEXs exhibited higher uptake by splenic CD4(+) T cells than the control- and negative-DEXs, and this increase was correlated with significantly greater increases in the expression of chemokines and the inflammatory cytokines IFN-γ and TNF by the CD4(+) T cells in vitro and in vivo. In addition, the injection of MI-DEXs improved cardiac function in mice post-MI. These results suggest that DEXs could mediate the activation of CD4(+) T cells through an endocrine mechanism and improve cardiac function post-MI. Our findings provide the basis for a novel strategy for the treatment of MI through the systemic delivery of DEXs.

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.

Infarcted myocardium-like stiffness contributes to endothelial progenitor lineage commitment of bone marrow mononuclear cells

Optimal timing of cell therapy for myocardial infarction (MI) appears during 5 to 14 days after the infarction. However, the potential mechanism requires further investigation. This work aimed to verify the hypothesis that myocardial stiffness within a propitious time frame might provide a most beneficial physical condition for cell lineage specification in favour of cardiac repair. Serum vascular endothelial growth factor (VEGF) levels and myocardial stiffness of MI mice were consecutively detected. Isolated bone marrow mononuclear cells (BMMNCs) were injected into infarction zone at distinct time‐points and cardiac function were measured 2 months after infarction. Polyacrylamide gel substrates with varied stiffness were used to mechanically mimic the infarcted myocardium. BMMNCs were plated on the flexible culture substrates under different concentrations of VEGF. Endothelial progenitor lineage commitment of BMMNCs was verified by immunofluorescent technique and flow cytometry. Our results demonstrated that the optimal timing in terms of improvement of cardiac function occurred during 7 to 14 days after MI, which was consistent with maximized capillary density at this time domains, but not with peak VEGF concentration. Percentage of double‐positive cells for DiI‐labelled acetylated low‐density lipoprotein uptake and fluorescein isothiocyanate (FITC)‐UEA‐1 (ulex europaeus agglutinin I lectin) binding had no significant differences among the tissue‐like stiffness in high concentration VEGF. With the decrease of VEGF concentration, the benefit of 42 kPa stiffness, corresponding to infarcted myocardium at days 7 to 14, gradually occurred and peaked when it was removed from culture medium. Likewise, combined expressions of VEGFR2+, CD133+ and CD45– remained the highest level on 42 kPa substrate in conditions of lower concentration VEGF. In conclusion, the optimal efficacy of BMMNCs therapy at 7 to 14 days after MI might result from non‐VEGF dependent angiogenesis, and myocardial stiffness at this time domains was more suitable for endothelial progenitor lineage specification of BMMNCs. The results here highlight the need for greater attention to mechanical microenvironments in cell culture and cell therapy.

Ischemic Postconditioning-Regulated miR-499 Protects the Rat Heart Against Ischemia/Reperfusion Injury by Inhibiting Apoptosis through PDCD4

Background: Here, we determined miR-499 involvement in the protective effect of ischemic postconditioning (IPC) against myocardial ischemia/reperfusion (I/R) injury and identified the underlying mechanisms. Methods: To investigate the cardioprotective effect of IPC-induced miR-499, rats were divided into the following five groups: sham, I/R, IPC, IPC + scramble, and IPC + antagomiR-499. Hemodynamic indexes were measured by carotid-artery intubation to assess left ventricular function . Ischemia and infarction areas of rat hearts were determined by Evans blue and triphenyltetrazolium chloride staining, and cardiomyocyte apoptosis was detected by terminal deoxynucleotidyl transferase dUTP nick-end-labeling assay. Results: IPC attenuated I/R-induced infarct size of the left ventricle (45.28 ± 5.40% vs. 23.56 ± 6.20%, P < 0.05), myocardial apoptosis, and decreased creatine kinase (1867.31 ± 242.41% vs. 990.21 ± 172.39%, P < 0.05), lactate dehydrogenase (2257.50 ± 305.11% vs. 1289.11 ± 347.28%, P < 0.05), and malondialdehyde levels (7.18 ± 1.63% vs. 4.85 ± 1.52%, P < 0.05). Additionally, left ventricular systolic pressure, +dp/dtmax, and -dp/dtmax were elevated, and left ventricular end diastolic pressure was significantly reduced in the IPC group. Furthermore, IPC-mediated cardiac protection against I/R injury was inhibited in vivo and in vitro by knockdown of cardiac miR-499, suggesting that miR-499 may participate in the protective function of IPC against I/R injury through targeting programmed cell death 4 (PDCD4). Conclusion: Our data revealed that IPC-regulated miR-499 plays an important role in IPC-mediated cardiac protection against I/R injury by targeting PDCD4.

Meta-Analysis of Early Versus Deferred Revascularization for Non–ST-Segment Elevation Acute Coronary Syndrome

The impact of a coronary revascularization strategy (early or deferred) on clinical outcomes of non-ST-segment elevation acute coronary syndrome (NSTE-ACS) has not been well established. The goal of this study was to systematically review randomized trials comparing early to deferred revascularization for NSTE-ACS. A systematic literature search of MEDLINE, ISI Web of Science, and Cochrane databases was conducted. Two reviewers independently determined the eligibility of clinical trials. Five trials with 4,155 patients were included for analysis. Meta-analysis showed that early revascularization produced no significant differences in the incidence of death (risk ratio [RR] 0.88, p = 0.47), recurrent myocardial infarction (RR 0.92, p = 0.58), and repeat revascularization compared to a deferred intervention. However, a significant decrease in refractory ischemia was observed in the early intervention group (RR 0.47, p <0.01), and the procedure also showed a tendency toward decreasing major bleeding events (RR 0.77, p = 0.08). According to stratification based on intervention era, extent of revascularization, and time of revascularization, subgroup analysis did not show between-group differences in all-cause mortality, recurrent myocardial infarction, and major bleeding events. Also, sensitivity analysis by alternatively using a random-effects model did not find any relevant influence on overall results in direction and magnitude. In conclusion, meta-analysis demonstrated that early coronary revascularization is feasible and safe for patients with NSTE-ACS, might markedly decrease the incidence of refractory ischemia, and appears to produce less bleeding.