Changfa Guo

Cardioprotective Effect of MicroRNA-21 in Murine Myocardial Infarction

INTRODUCTIONnTo investigate the cardioprotective effect of MicroRNA-21 (miR-21) in murine myocardial infarction (MI).nnnMETHODSnForty C57BL/6 male mice were divided into sham group, MI group, LV-GFP group, and miR-21 group. Mice in the MI group, LV-GFP group, and miR-21 group were subjected to MI by left anterior descending artery (LAD) ligation, while chest was opened/closed without ligation in sham group. In MI group, expression of miR-21 in the MI area and its surrounding areas was detected at 1st, 2nd, and 4th week after experiment. Subsequently, lentivirus expressing miR-21 and lentivirus that did not express miR-21 were transfected into mice left ventricular cavity of miR-21 group and LV-GFP group, respectively. Cardiac function, MI size, miR-21 expression, collagen I level, fibronectin content, number of α-SMA-positive cells, number of apoptotic cells, apoptosis-related factors were compared between the three groups.nnnRESULTSnCompared with sham group, miR-21 levels in MI group were significantly decreased in the 1st week and 2nd week, but were almost the same in the 4th week. Left ventricular fractional shortening (LVFS) and left ventricular ejection fraction (LVEF) in the miR-21 group improved compared to the LV-GFP group. In miR-21 group, myocardial infarct size reduced by 36.9% in comparison with LV-GFP group. Compared to sham group, miR-21 expression in the miR-21 group and LV-GFP group decreased significantly. In the miR-21 group, collagen I level, fibronectin content and number of α-SMA-positive cells of miR-21 decreased significantly compared to the LV-GFP group. The number of apoptotic cells in the MI areas of the miR-21 group was significantly less than the LV-GFP group. Compared with the LV-GFP group, Bcl-2 level and the ratio of Bcl-2 to Bax were significantly increased, and the levels of Bax and Caspase-3 decreased.nnnCONCLUSIONSnOur results suggest miR-21 is an important regulatory molecule in the pathophysiology of MI.

Early Assistance With Left Ventricular Assist Device Limits Left Ventricular Remodeling After Acute Myocardial Infarction in a Swine Model

UNLABELLEDnAlthough left ventricular assist devices (LVADs) have been commonly used for patients with cardiogenic shock after acute myocardial infarction (AMI), their effects on post-AMI prognosis remain to be elucidated. In this study, we aimed to explore the effects of an LVAD on left ventricular (LV) remodeling and function at the postinfarction stage in a swine model. AMI was induced by ligation of the circumflex artery or its branches for 120 min, followed by 120 min of reperfusion. In the assist group (n = 6), LVAD was initiated at 90 min after ischemia and was maintained for support until 120 min after reperfusion, whereas the control group (n = 6) received no support. LV pressure, volume, wall stress, and stroke work were all decreased by LVAD assistance at the ischemia and reperfusion stages, and blood pressure and cardiac output were maintained. All swine were studied 1 month after the procedure, and those in the assist group showed less increased end-diastolic volumes (assist vs.nnnCONTROLn57.9 ± 6.6 vs. 79.0 ± 6.7 mL, P = 0.032) and sphericity (assist vs.nnnCONTROLn1.33 ± 0.16 vs. 1.51 ± 0.12, P = 0.01), as well as improved ejection fractions (assist vs.nnnCONTROLn59.0 ± 7.8 vs. 42.3 ± 6.0%, P = 0.002). Furthermore, despite a presence of a similar initial ischemic area, the percent of infarcted myocardium was reduced by 49.9% in the assist group (assist vs.nnnCONTROLn18.1 ± 4.8 vs. 35.3 ± 6.2%, P < 0.001). These results suggested that early assistance with an LVAD in AMI limited LV remodeling, preserved postinfarction systolic function, and improved the prognosis.

Combination of IGF‑1 gene manipulation and 5‑AZA treatment promotes differentiation of mesenchymal stem cells into cardiomyocyte‑like cells

Mesenchymal stem cell (MSC) transplantation has been proposed as a promising therapeutic strategy for ischemic myocardium repair following myocardial infarction. Differentiation of MSCs into cardiomyocyte-like cells prior to cell transplantation is advantageous in improving their potential clinical benefits for cardiac repair. In the present study, we isolated and cultured porcine MSCs and evaluated the synergistic effect of 5-azacytidine (5-AZA) treatment and insulin-like growth factor-1 (IGF-1) gene manipulation on MSC differentiation into cardiomyocyte-like cells. Our results demonstrated that 5-AZA treatment alone induced a limited cardiomyocyte-like differentiation effect in vitro. Overexpression of the IGF-1 gene in MSCs improved the induction effect of 5-AZA, while knockdown of the IGF-1 gene attenuated the differentiation. These results suggest that IGF-1 is a significant stimulus affecting the cardiomyocyte-like differentiation of porcine MSCs. In addition, the combination of IGF-1 gene manipulation and 5-AZA treatment provides a new strategy to obtain more committed differentiated cardiomyocyte-like cells from porcine MSCs prior to cell transplantation.

A Long-Term and Slow-Releasing Hydrogen Sulfide Donor Protects against Myocardial Ischemia/Reperfusion Injury

Hydrogen sulfide (H2S) has been recognized as an important gasotransmitter exerting various physiological effects, especially in the cardiovascular system. Herein we investigated the cardioprotective effects of a novel long-term and slow-releasing H2S donor, DATS-MSN, using in vivo myocardial ischemia/reperfusion (I/R) models and in vitro hypoxia/reoxygenation cardiomyocyte models. Unlike the instant-releasing pattern of sodium hydrosulphide (NaHS), the release of H2S from DATS-MSN was quite slow and continuous both in the cell culture medium and in rat plasma (elevated H2S concentrations during 24u2009h and 72u2009h reperfusion). Correspondingly, DATS-MSN demonstrated superior cardioprotective effects over NaHS in I/R models, which were associated with greater survival rates, reduced CK-MB and troponin I levels, decreased cardiomyocyte apoptosis index, increased antioxidant enzyme activities, inhibited myocardial inflammation, greater reduction in the infarct area and preserved cardiac ejection fraction. Some of these effects of DATS-MSN were also found to be superior to classic slow-releasing H2S donor, GYY4137. In in vitro experiments, cardiomyocytes injury was also found to be relived with the use of DATS-MSN compared to NaHS after the hypoxia/reoxygenation processes. The present work provides a novel long-term and slow-releasing H2S donor and an insight into how the release patterns of H2S donors affect its physiological functionality.

Intramyocardial Autologous Bone Marrow-derived Stem Cells Injection for Ischemic Heart Disease Ineligible for Revascularization: A Systematic Review and Meta-analysis

BACKGROUND AND AIMSnIntramyocardial autologous bone marrow-derived stem cells injection (IM-BMCs) has been used in patients with ischemic heart disease (IHD) who are ineligible for revascularization; however, the procedure has yielded mixed results. The objective of this meta-analysis was to evaluate the safety and therapeutic benefits of this treatment on a relatively large scale.nnnMETHODSnPubMed, EMBASE, and Cochrane Library databases through September 2014 were searched for randomized clinical trials (RCTs) of IM-BMCs to treat IHD. Outcome measures were defined as mortality after treatment, change in left ventricular ejection fraction (LVEF), left ventricular end-systolic volume (LVESV) and left ventricular end-diastolic volume (LVEDV). Weighted mean differences for the changes were estimated with a random-effects model.nnnRESULTSnNine RCTs were eligible for inclusion. IM-BMCs significantly reduced the risk of mortality (RR, 0.33; 95% CI, 0.17-0.65; p = 0.001). IM-BMCs significantly improved LVEF by 2.57% (95% CI, 0.34-4.80%; p = 0.02) and reduced LVESV by 9.67 mL (95% CI, -16.43 mL to -2.91 mL; p = 0.005). No significant improvement in LVEDV (WMD = 4.73 mL; 95% CI, -7.22 mL to 16.68 mL; p = 0.44) was detected in patients who received IM-BMC therapy.nnnCONCLUSIONSnIM-BMC therapy showed clinical safety while being used as stand-alone treatment in IHD with no option of revascularization. The therapeutic efficacy requires further confirmation in large well-powered trials with long-term follow-up.

A biomimic reconstituted high density lipoprotein nanosystem for enhanced VEGF gene therapy of myocardial ischemia

A biomimic reconstituted high density lipoprotein (rHDL) based system, rHDL/Stearic-PEI/VEGF complexes, was fabricated as an advanced nanovector for delivering VEGF plasmid. Here, Stearic-PEI was utilized to effectively condense VEGF plasmid and to incorporate the plasmid into rHDL. The rHDL/Stearic-PEI/VEGF complexes with diameter under 100 nm and neutral surface charge demonstrated enhanced stability under the presence of bovine serum albumin. Moreover, in vitro cytotoxicity and transfection assays on H9C2 cells further revealed their superiority, as they displayed lower cytotoxicity with much higher transfection efficiency when compared to PEI 10K/VEGF and Lipos/Stearic-PEI/VEGF complexes. In addition, in vivo investigation on ischemia/reperfusion ratmodel implied that rHDL/Stearic-PEI/VEGF complexes possessed high transgene capacity and strong therapeutic activity. These findings indicated that rHDL/Stearic-PEI/VEGF complexes could be an ideal gene delivery system for enhanced VEGF gene therapy of myocardial ischemia, which might be a new promising strategy for effective myocardial ischemia treatment.

Myoblast Transplantation for Cardiac Repair: From Automyoblast to Allomyoblast Transplantation

BACKGROUNDnWe sought to compare host immune cell kinetics, survival profile of donor skeletal myoblasts, and skeletal myoblast graft efficacy after autologous and allogeneic skeletal myoblast transplantation into a rat model of myocardial infarction.nnnMETHODSnOne week after myocardial infarction, 128 animals were divided into four groups: group 1 (n = 24, receiving medium only), group 2 (n = 24, receiving medium and cyclosporine), group 3 (n = 40, autologous skeletal myoblast transplantation), and group 4 (n = 40, allogeneic skeletal myoblast transplantation with cyclosporine treatment). Rats were euthanized 10 minutes, 1 day, and 4, 7, and 28 days later. Host immune cell kinetics were assessed by immunohistochemical studies for macrophages, and CD4+ and CD8+ lymphocytes. Donor skeletal myoblast survival was confirmed by tracking prelabeled signals, and quantified by beta-gal assay. Heart function was evaluated by echocardiography.nnnRESULTSnA transient immune cell infiltration was demonstrated in group 3, with macrophage infiltration on day 1 and day 4, CD8+ cell infiltration on day 4 and day 7, and CD4+ cell infiltration on day 4. In group 4, immunocyte infiltration was slightly more severe than that in group 3. Automyoblasts and allomyoblasts showed no significant difference of survival from day 1 to day 7 (p > 0.10); however, on day 28, automyoblasts showed better survival than allomyoblasts (p < 0.05). Transplantation of allomyoblasts increased systolic heart function and limited heart dilation after myocardial injury to a similar degree as automyoblasts (p > 0.10).nnnCONCLUSIONSnThe use of allomyoblasts is feasible and effective for cardiac repair with immunosuppressive treatment as compared with automyoblasts.

Fibrin patch-based insulin-like growth factor-1 gene-modified stem cell transplantation repairs ischemic myocardium:

Bone marrow mesenchymal stem cells (BMSCs), tissue-engineered cardiac patch, and therapeutic gene have all been proposed as promising therapy strategies for cardiac repair after myocardial infarction. In our study, BMSCs were modified with insulin-like growth factor-1 (IGF-1) gene, loaded into a fibrin patch, and then transplanted into a porcine model of ischemia/reperfusion (I/R) myocardium injury. The results demonstrated that IGF-1 gene overexpression could promote proliferation of endothelial cells and cardiomyocyte-like differentiation of BMSCs in vitro. Four weeks after transplantation of fibrin patch loaded with gene-modified BMSCs, IGF-1 overexpression could successfully promote angiogenesis, inhibit remodeling, increase grafted cell survival and reduce apoptosis. In conclusion, the integrated strategy, which combined fibrin patch with IGF-1 gene modified BMSCs, could promote the histological cardiac repair for a clinically relevant porcine model of I/R myocardium injury.

Patch Repair of Anomalous Origin of the Left Main Coronary Artery From the Anterior Aortic Sinus

Anomalous origin of the left main coronary artery from the anterior aortic sinus is a rare but potentially lethal congenital disease. We report two adolescent patients with this anomaly who underwent surgical plasty using a saphenous vein patch, rather than unroofing or fenestration technique, as was typically done. This report suggests that surgical angioplasty can be performed safely and effectively to treat this anomaly.

Sinus of Valsalva aneurysms with concomitant aortic insufficiency: how should the aortic valve be managed?

OBJECTIVESnSinus of Valsalva aneurysms (SVAs) are rare and are often complicated by aortic insufficiency (AI). Treating AI is important for achieving good long-term results in patients with SVA. Here, we have summarized our experience with the surgical management of patients with SVA with concomitant AI.nnnMETHODSnPatients who were diagnosed with SVA and underwent surgical treatment between January 2008 and May 2016 were included. Clinical characteristics, including age, gender, SVA anatomy and concurrent anomalies, were analysed. The surgical strategies, intraoperative results and early and late outcomes were evaluated.nnnRESULTSnA total of 178 patients (age 37.4u2009±u200913.1u2009years, 114 men) were identified. Eighty-seven (48.9%) patients had at least 2+ AI preoperatively. Patients with AI had a significant higher incidence of right coronary SVA with concomitant ventricular septal defects (80.5% vs 54.9%, Pu2009<u20090.001). Concurrent aortic valve surgery was performed in 70 patients with 63 valve replacements and 7 valve repairs. The other 17 patients underwent SVA repair only. The mean follow-up time was 44.4u2009±u200933.8u2009months. During the follow-up, no patients who underwent valve replacement experienced perivalvular leakage, whereas 7 patients who underwent aortic valve repair had trivial-to-mild AI and 3 of the 17 patients who underwent SVA repair only presented with moderate AI.nnnCONCLUSIONSnVarious surgical techniques can be utilized to manage concomitant AI without compromising short-term outcomes. Valve replacement yields good long-term results. According to our experience, valve repair, especially valve-sparing procedures performed by experienced surgeons, could be an acceptable option when managing concomitant AI in young patients.