Publications by authors named "Mingqiang Fu"

31 Publications

Increased ratio of sST2/LVMI predicted cardiovascular mortality and heart failure rehospitalization in heart failure with reduced ejection fraction patients: a prospective cohort study.

BMC Cardiovasc Disord 2021 08 17;21(1):396. Epub 2021 Aug 17.

Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.

Background: Inflammation is one of the principal triggering mechanisms for left ventricular fibrosis and remodeling in heart failure, leading to adverse clinical outcomes. Soluble suppression of tumorigenicity 2 (sST2), a member of the interleukin-1 receptor family, is assumed to play a significant role in the fibrotic response to inflammation. Left ventricular mass index (LVMI) is a parameter of the prefibrotic inflammatory phase of heart failure preceding remodeling. The present study aimed to investigate the prognostic value of the sST2/LVMI ratio in heart failure with reduced ejection fraction.

Methods: This was a prospective cohort study. A total of 45 consecutive patients with heart failure with reduced ejection fraction, treated between September 2015 and December 2016, were enrolled. The sST2/LVMI ratio was measured at baseline. The primary endpoint was a composite of cardiovascular mortality and readmission for heart failure. The prognostic impact of the sST2/LVMI ratio was evaluated using a multivariable Cox proportional hazards regression model.

Results: Forty-five patients were enrolled in this study. Their average age was 48 ± 14 years, and approximately 20% of them were men. Patients were followed for 9 months, during which the primary outcome occurred in 15 patients. Kaplan-Meier analysis showed that patients with a high sST2/LVMI ratio (≥ 0.39) had shorter event-free survival than those with intermediate (between 0.39 and 0.24) and low ratios (< 0.24) (log-rank, P = 0.022). The fully adjusted multivariable Cox regression analysis showed that the sST2/LVMI ratio was positively associated with the composite outcome in patients with heart failure with reduced ejection fraction after adjusting for confounders (hazard ratio 1.64, 95% confidence interval 1.06 to 2.54). By subgroup analysis, a stronger association was found with age between 40 and 55 years, systolic blood pressure < 115 or ≥ 129 mmHg, diastolic blood pressure < 74 mmHg, hematocrit < 44.5%, and interventricular septum thickness ≥ 8.5 mm.

Conclusion: In patients with heart failure with reduced ejection fraction, the relationship between the sST2/LVMI ratio and the composite outcome was linear. A higher baseline ratio of sST2/LVMI was associated with an increased risk of cardiovascular mortality and heart failure rehospitalization in the short-term follow-up.
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http://dx.doi.org/10.1186/s12872-021-02191-3DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8369618PMC
August 2021

Prediction model of in-hospital mortality in intensive care unit patients with heart failure: machine learning-based, retrospective analysis of the MIMIC-III database.

BMJ Open 2021 07 23;11(7):e044779. Epub 2021 Jul 23.

Department of Cardiology, The Affiliated Hospital of Qingdao University, Qingdao, China

Objective: The predictors of in-hospital mortality for intensive care units (ICUs)-admitted heart failure (HF) patients remain poorly characterised. We aimed to develop and validate a prediction model for all-cause in-hospital mortality among ICU-admitted HF patients.

Design: A retrospective cohort study.

Setting And Participants: Data were extracted from the Medical Information Mart for Intensive Care (MIMIC-III) database. Data on 1177 heart failure patients were analysed.

Methods: Patients meeting the inclusion criteria were identified from the MIMIC-III database and randomly divided into derivation (n=825, 70%) and a validation (n=352, 30%) group. Independent risk factors for in-hospital mortality were screened using the extreme gradient boosting (XGBoost) and the least absolute shrinkage and selection operator (LASSO) regression models in the derivation sample. Multivariate logistic regression analysis was used to build prediction models in derivation group, and then validated in validation cohort. Discrimination, calibration and clinical usefulness of the predicting model were assessed using the C-index, calibration plot and decision curve analysis. After pairwise comparison, the best performing model was chosen to build a nomogram according to the regression coefficients.

Results: Among the 1177 admissions, in-hospital mortality was 13.52%. In both groups, the XGBoost, LASSO regression and Get With the Guidelines-Heart Failure (GWTG-HF) risk score models showed acceptable discrimination. The XGBoost and LASSO regression models also showed good calibration. In pairwise comparison, the prediction effectiveness was higher with the XGBoost and LASSO regression models than with the GWTG-HF risk score model (p<0.05). The XGBoost model was chosen as our final model for its more concise and wider net benefit threshold probability range and was presented as the nomogram.

Conclusions: Our nomogram enabled good prediction of in-hospital mortality in ICU-admitted HF patients, which may help clinical decision-making for such patients.
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http://dx.doi.org/10.1136/bmjopen-2020-044779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8311359PMC
July 2021

Clinical Outcomes of Self-Made Polyurethane-Covered Stent Implantation for the Treatment of Coronary Artery Perforations.

J Interv Cardiol 2021 17;2021:6661763. Epub 2021 May 17.

Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China.

Objectives: The present study aimed to investigate the short- and long-term clinical outcomes of self-made polyurethane-covered stents (PU-CS) in patients for the management of coronary artery perforation (CAP) during percutaneous coronary intervention (PCI).

Background: Coronary artery perforation is reckoned as a serious complication in PCI and associated with considerable morbidity and mortality. Covered stents have been used for treating the life-threatening CAP during PCI. But in some catheterization laboratories, no commercial CS is immediately available when there is an urgent need for CS to rescue the coronary rupture site.

Methods: We retrospectively identified 24 patients who underwent 31 self-made PU-CS implantations due to CAP in Zhongshan Hospital, Fudan University, from June 2015 to January 2020.

Results: The total procedural success rate of CS to seal the perforation was 79.2%. Nine patients (37.5%) developed cardiac tamponade, of which 8 patients (33.3%) underwent pericardiocentesis and 4 patients (16.7%) underwent cardiac surgeries. Except for 4 cardiac death cases (16.7%), none of myocardial infarction (MI), target lesion revascularization (TLR), and stent thrombosis (ST) was reported during hospital stay. Data from 22 patients (91.7%) were available at 610.4 ± 420.9 days of follow-up. Major adverse cardiac events (MACE) occurred in 6 patients (27.3%), including 5 cases of cardiac death and one TLR case.

Conclusions: Self-made PU-CS demonstrates high rates of successful delivery and sealing of severe CAP during PCI. Although the in-hospital mortality remains high after PU-CS implantation, the long-term follow-up shows favorable clinical outcomes, indicating the feasibility of PU-CS in treating CAP.
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http://dx.doi.org/10.1155/2021/6661763DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8143889PMC
July 2021

Reattempt Percutaneous Coronary Intervention of Chronic Total Occlusions after Prior Failures: A Single-Center Analysis of Strategies and Outcomes.

J Interv Cardiol 2021 20;2021:8835104. Epub 2021 Apr 20.

Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai, China.

Objective: The initial recanalization rate of coronary chronic total occlusions (CTOs) is >85% when performed by experienced operators, but only 10% of prior failed CTO patients receive reattempted recanalization. This retrospective study analyzed the success rate and strategies used in reattempt percutaneous coronary intervention (PCI) of CTOs after prior failures.

Methods: Overall, 206 patients with 212 CTOs were enrolled. All patients with prior recanalization failures received reattempt PCIs from January 2015 to March 2019 at Zhongshan Hospital, Fudan University. Data on clinical factors (age, sex, comorbidities, left ventricular ejection fraction, history of cigarette usage, and revascularization), angiographic characteristics of CTOs (target lesion, Japanese Chronic Total Occlusion (J-CTO) score, the morphology of CTO lesions, and collateral channel scale), strategies (procedural approach and use of devices), and major adverse events were obtained and analyzed.

Results: The mean age of enrolled patients was 60.96 ± 12.36 years, with a male predominance of 90.3%. Of the patients, 47.1% had a prior myocardial infarction and 70.4% underwent stent implantation previously, while the in-stent occlusion rate was 6.6%. CTOs were primarily localized in the left anterior descending artery (43.9%) and the right coronary artery (43.9%). 80.7% of lesions were classified as very difficult (J-CTO score ≥3), and the overall success rate was 81.1%. In multivariable regression analysis, J-CTO score, collateral channel scale, application of coronary multispiral computed tomography angiography, dual injection, intravascular ultrasound, active greeting technique, parallel wiring, and CTO morphology were predictors of recanalization success. There were no significant differences in rates of procedural complications between the final recanalization success and failure groups.

Conclusions: Recanalization of complex CTOs is associated with high success rate and low complication rates when performed by high-volume CTO operators and after multiple reattempts.
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http://dx.doi.org/10.1155/2021/8835104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8079192PMC
July 2021

Qiliqiangxin alleviates Ang II-induced CMECs apoptosis by downregulating autophagy via the ErbB2-AKT-FoxO3a axis.

Life Sci 2021 May 27;273:119239. Epub 2021 Feb 27.

Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China; Institute of Biomedical Sciences, Fudan University, Shanghai 200032, China. Electronic address:

Our previous work revealed the protective effect of Qiliqiangxin (QLQX) on cardiac microvascular endothelial cells (CMECs), but the underlying mechanisms remain unclear. We aimed to investigate whether QLQX exerts its protective effect against high-concentration angiotensin II (Ang II)-induced CMEC apoptosis through the autophagy machinery. CMECs were cultured in high-concentration Ang II (1 μM) medium in the presence or absence of QLQX for 48 h. We found that QLQX obviously inhibited Ang II-triggered autophagosome synthesis and apoptosis in cultured CMECs. QLQX-mediated protection against Ang II-induced CMEC apoptosis was reversed by the autophagy activator rapamycin. Specifically, deletion of ATG7 in cultured CMECs indicated a detrimental role of autophagy in Ang II-induced CMEC apoptosis. QLQX reversed Ang II-mediated ErbB2 phosphorylation impairment. Furthermore, inhibition of ErbB2 phosphorylation with lapatinib in CMECs revealed that QLQX-induced downregulation of Ang II-activated autophagy and apoptosis was ErbB2 phosphorylation-dependent via the AKT-FoxO3a axis. Activation of ErbB2 phosphorylation by Neuregulin-1β achieved a similar CMEC-protective effect as QLQX in high-concentration Ang II medium, and this effect was also abolished by autophagy activation. These results show that the CMEC-protective effect of QLQX under high-concentration Ang II conditions could be partly attributable to QLQX-mediated ErbB2 phosphorylation-dependent downregulation of autophagy via the AKT-FoxO3a axis.
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http://dx.doi.org/10.1016/j.lfs.2021.119239DOI Listing
May 2021

Prescription Promotes Angiogenesis of Hypoxic Primary Rat Cardiac Microvascular Endothelial Cells via Regulating miR-21 Signaling.

Curr Pharm Des 2021 ;27(26):2966-2974

Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, 200032, Shanghai, China.

Background And Objective: Angiogenesis is the most important repair process of tissues subjected to ischemic injury. The present study aims to investigate whether the pro-angiogenic effect of Qiliqiangxin prescription (QL) is mediated through miR-21 signaling.

Methods: Cardiac microvascular endothelial cells (CMECs) were isolated and cultured from 2-3 weeks old SD rats by the method of planting myocardium tissues. The purity was identified by CD31 immunofluorescence staining. CMECs were then cultured under 1% O2 hypoxia or normoxia condition for 24h in the presence or absence of QL pretreatment (QL, 0.5mg/ml, 24h). The mimics and inhibitors of miR-21 were transfected into CMECs. miR-21, HIF-1α, and VEGF expressions of CMECs were then detected by qRT-PCR and/or Western blot. The proliferation, migration, and tube formation functions of CMECs were assessed using the BrdU assay, wound healing test, and tube formation assay, respectively.

Results: The results showed that compared with the control group, hypoxia significantly upregulated the expression of miR-21 and impaired CMECs proliferation, migration, and tube formation functions. Compared with the hypoxia group, QL further upregulated miR-21, HIF-1α, and VEGF expressions, and improved cell proliferation, migration, and tube formation of hypoxic CMECs. These effects of QL were abolished by a knockdown of miR-21. Conversely, treatment with miR-21 mimics further enhanced QL induced changes in hypoxic CMECs.

Conclusion: Results indicate that the pro-angiogenesis effects of QL on hypoxic CMECs are mediated by activating miR-21 and its downstream HIF-1α/VEGF pathway possibly.
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http://dx.doi.org/10.2174/1381612826666201005152709DOI Listing
January 2021

Procedural and In-hospital Outcomes of Rotational Atherectomy in Retrograde Coronary Chronic Total Occlusion Intervention.

Angiology 2021 01 17;72(1):44-49. Epub 2020 Aug 17.

Department of Cardiology, 92323Zhongshan Hospital, Fudan University, Shanghai, China.

Coronary chronic total occlusions (CTOs) are characterized by a high incidence of severe plaque calcifications, which are associated with a high use of the retrograde approach and a low success rate of percutaneous coronary intervention (PCI). However, the feasibility of rotational atherectomy (RA) in retrograde CTO-PCI remains unknown. The aim of the present study is to examine the safety and efficacy of RA in retrograde CTO-PCI. Consecutive patients (n = 129) who underwent RA during CTO-PCI were categorized into anterograde and retrograde groups according to the CTO crossing approach. The distributions of the baseline characteristics were similar in the 2 groups, but the lesion type was more complex ( = .001), and the starting burr size was smaller ( = .003) in the retrograde group than in the anterograde group. There was a trend of a higher incidence of procedural complications in the retrograde group than in the anterograde group ( = .054). Technical and procedural success and in-hospital outcomes were not significantly different between the 2 groups. In conclusion, RA was feasible in retrograde CTO PCI, but some specific precautions are required before and during the procedure. In addition, further investigation of the long-term outcomes of RA in retrograde CTO PCI is necessary.
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http://dx.doi.org/10.1177/0003319720949312DOI Listing
January 2021

Improves Cardiac Function through Regulating Energy Metabolism via HIF-1-Dependent and Independent Mechanisms in Heart Failure Rats after Acute Myocardial Infarction.

Biomed Res Int 2020 12;2020:1276195. Epub 2020 Jun 12.

Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.

The present study is aimed at investigating whether (QL) could regulate myocardial energy metabolism in heart failure rats after acute myocardial infarction (AMI) and further exploring the underlying mechanisms. AMI was established by ligating the left anterior descending coronary artery in adult male SD rats. AMI rats with ejection fraction (EF) < 50% at two weeks after the operation were chosen as heart failure rats for the main study. Rats were randomized into the sham, MI, MI+QL, and MI+QL+2-MeOE2 groups. The results showed that compared with the MI group, QL significantly improved cardiac function, reduced serum NT-proBNP level, and alleviated myocardial fibrosis. QL also increased myocardial capillary density by upregulated protein expressions of vascular endothelial growth factor (VEGF) and CD31 by regulating the HIF-1/VEGF pathway. Moreover, QL promoted ATP production, glucose uptake, and glycolysis by upregulating HIF-1 and a series of glycolysis-relevant enzymes in a HIF-1-dependent manner. QL also improved myocardial glucose oxidation enzyme expression and free fatty acid uptake by a HIF-1-independent pathway. Our results indicate that QL treatment improves cardiac function through regulating glucose uptake, FFA uptake, and key enzymes of energy metabolism via HIF-1-dependent and independent mechanisms.
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http://dx.doi.org/10.1155/2020/1276195DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7306086PMC
April 2021

Diffuse myocardial fibrosis and the prognosis of heart failure with reduced ejection fraction in Chinese patients: a cohort study.

Int J Cardiovasc Imaging 2020 Apr 1;36(4):671-689. Epub 2020 Jan 1.

Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.

Evidence regarding the relationship between diffuse myocardial fibrosis and the prognosis of heart failure with reduced ejection fraction (HFrEF) was limited. Therefore, this study set out to investigate whether diffuse myocardial fibrosis was independently related to the prognosis of failure with reduced ejection fraction in Chinese patients after adjusting for other covariates. The present study was a cohort study. A total of 45 consecutive HFrEF patients were involved in Zhongshan Hospital of Fudan University in China from 1/9/2015 to 31/12/2016. The target-independent variable was extracellular volume (ECV) quantified by cardiac magnetic resonance T1 mapping using the modified Look-Locker inversion recovery (MOLLI) sequence at baseline. To assess the prognostic impact of MOLLI-ECV, its association with hospitalization for heart failure/cardiac death was tested by multivariable Cox regression analysis. Covariates involved in this study included age, gender, body mass index, heart rate, systolic blood pressure diastolic blood pressure, smoking, hypertension, diabetes mellitus, etiology, NYHA functional class, blood urea nitrogen, creatinine, serum uric acid, total bilirubin, and growth stimulation-expressed gene 2. Ten age- and sex-matched healthy participants with no history of cardiovascular disease served as a control group. Mean MOLLI-ECV was significantly higher in HFrEF patients versus healthy controls (29.55 ± 1.46% vs. 23.17 ± 1.93%, P < 0.001). Patients were followed for 9 months, during which the primary outcome (cardiac death or first heart failure hospitalization) occurred in 15 patients. By Kaplan-Meier analysis, patients with high MOLLI-ECV ≥ 30.10% had shorter event-free survival than the middle (MOLLI-ECV between 30.10 and 28.60) and low (MOLLI-ECV < 28.60) MOLLI-ECV patients (log-rank, P = 0.0035). Result of fully-adjusted multivariable Cox regression analysis showed MOLLI-ECV was positively associated with the composite outcome of HFrEF patients after adjusting confounders hazard ratio (HR) 2.57, 95% CI (1.09, 6.04). By subgroup analysis, a stronger association was seen in patients who with NYHA functional class III-IV, hematocrit < 39.8%, left atrial diameter ≥ 53.5 mm, or without the medical history of MRA or diuretics other than MRA. The P for interaction was < 0.05. In HFrEF patients, the relationship between MOLLI-ECV determined by CMR and the composite outcome is linear. High MOLLI-ECV was associated with a higher rate of cardiac mortality and first HF hospitalization in the short term follow up.
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http://dx.doi.org/10.1007/s10554-019-01752-0DOI Listing
April 2020

Effects of Adiponectin on Diastolic Function in Mice Underwent Transverse Aorta Constriction.

J Cardiovasc Transl Res 2020 04 16;13(2):225-237. Epub 2019 Oct 16.

Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.

Diastolic dysfunction is common in various cardiovascular diseases, which could be affected by adiponectin (APN). Nevertheless, the effects of APN on diastolic dysfunction in pressure overload model induced by transverse aorta constriction (TAC) remain to be further elucidated. Here, we demonstrated that treatment of APN attenuated diastolic dysfunction and cardiac hypertrophy in TAC mice. Notably, APN also improved active relaxation of adult cardiomyocytes, increased N2BA/N2B ratios of titin isoform, and reduced collagen type I to type III ratio and lysyl oxidase (Lox) expressions in the myocardial tissue. Moreover, APN supplementation suppressed TAC-induced oxidative stress. In vitro, inhibition of AMPK by compound C (Cpc) abrogated the effect of APN on modulation of titin isoform shift and the anti-hypertrophic effect of APN on cardiomyocytes induced by AngII. In summary, our findings indicate that APN could attenuate diastolic dysfunction in TAC mice, which are at least partially mediated by AMPK pathway.
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http://dx.doi.org/10.1007/s12265-019-09913-1DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7166206PMC
April 2020

Angiotensin II induces apoptosis of cardiac microvascular endothelial cells via regulating PTP1B/PI3K/Akt pathway.

In Vitro Cell Dev Biol Anim 2019 Dec 9;55(10):801-811. Epub 2019 Sep 9.

Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.

Endothelial cell apoptosis and renin-angiotensin-aldosterone system (RAAS) activation are the major pathological mechanisms for cardiovascular disease and heart failure; however, the interaction and mechanism between them remain unclear. Investigating the role of PTP1B in angiotensin II (Ang II)-induced apoptosis of primary cardiac microvascular endothelial cells (CMECs) may provide direct evidence of the link between endothelial cell apoptosis and RAAS. Isolated rat CMECs were treated with different concentrations of Ang II to induce apoptosis, and an Ang II concentration of 4 nM was selected as the effective dose for the subsequent studies. The CMECs were cultured for 48 h with or without Ang II (4 nM) in the absence or presence of the PTP1B inhibitor TCS 401 (8 μM) and the PI3K inhibitor LY294002 (10 μM). The level of CMEC apoptosis was assessed by TUNEL staining and caspase-3 activity. The protein expressions of PTP1B, PI3K, Akt, p-Akt, Bcl-2, Bax, caspase-3, and cleaved caspase-3 were determined by Western blot (WB). The results showed that Ang II increased apoptosis of CMECs, upregulated PTP1B expression, and inhibited the PI3K/Akt pathway. Furthermore, cotreatment with PTP1B inhibitor significantly decreased the number of apoptotic CMECs induced by Ang II, along with increased PI3K expression, phosphorylation of Akt and the ratio of Bcl-2/Bax, decreased caspase-3 activity, and a cleaved caspase-3/caspase-3 ratio, while treatment with LY294002 partly inhibited the anti-apoptotic effect of the PTP1B inhibitor. Ang II induces apoptosis of primary rat CMECs via regulating the PTP1B/PI3K/Akt pathway.
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http://dx.doi.org/10.1007/s11626-019-00395-8DOI Listing
December 2019

Short and long-term outcomes of coronary perforation managed by coil embolization: A single-center experience.

Int J Cardiol 2020 01 1;298:18-21. Epub 2019 Aug 1.

Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Disease, NO 180, Fenglin Road, Shanghai 200032, China. Electronic address:

Background: Coronary perforation is a serious complication in percutaneous coronary intervention (PCI). In this article, we reported the short and long-term outcomes of patients with coronary perforation managed by coil embolization in our center.

Methods: We retrospectively analyzed 66 patients who had coronary perforation treated by coil embolization during PCI performed in our center from Oct 2012 to June 2018.

Results: Of sixty-six cases of coronary perforation, twenty-six cases were distal coronary perforation, while 40 cases were collateral perforation. The average coil number used in distal coronary and collateral perforation lesion is 1.8 ± 0.9 and 1.8 ± 1.0, respectively. The maximum number of coils implanted in each patient is 4 in both groups. Two emergency cardiac surgery to seal the perforation was performed after coil embolization in distal coronary perforation and pericardiocentesis. In collateral perforation, one case of CABG was performed due to myocardial ischemia caused by CTO lesion. During a follow-up of 707 ± 476 days, one patient in collateral perforation group had CABG one month later, while no death or myocardial infarction (MI) was detected. Fifty-four (81.2%) cases of perforations occurred while treating chronic total occlusion, and 74.0% of these perforations were located in collateral vessels, mostly epicardial vessels. Thirty-nine CTO cases (72.2%) were revascularized successfully with the aid of coil embolization.

Conclusion: Coil embolization is feasible and effective in treating distal coronary perforation and collateral perforation during PCI procedure. In CTO lesions, coil embolization facilitates the success of revascularization by PCI.
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http://dx.doi.org/10.1016/j.ijcard.2019.07.091DOI Listing
January 2020

Qiliqiangxin attenuates hypoxia-induced injury in primary rat cardiac microvascular endothelial cells via promoting HIF-1α-dependent glycolysis.

J Cell Mol Med 2018 05 4;22(5):2791-2803. Epub 2018 Mar 4.

Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.

Protection of cardiac microvascular endothelial cells (CMECs) against hypoxia injury is an important therapeutic strategy for treating ischaemic cardiovascular disease. In this study, we investigated the effects of qiliqiangxin (QL) on primary rat CMECs exposed to hypoxia and the underlying mechanisms. Rat CMECs were successfully isolated and passaged to the second generation. CMECs that were pre-treated with QL (0.5 mg/mL) and/or HIF-1α siRNA were cultured in a three-gas hypoxic incubator chamber (5% CO , 1% O , 94% N ) for 12 hours. Firstly, we demonstrated that compared with hypoxia group, QL effectively promoted the proliferation while attenuated the apoptosis, improved mitochondrial function and reduced ROS generation in hypoxic CMECs in a HIF-1α-dependent manner. Meanwhile, QL also promoted angiogenesis of CMECs via HIF-1α/VEGF signalling pathway. Moreover, QL improved glucose utilization and metabolism and increased ATP production by up-regulating HIF-1α and a series of glycolysis-relevant enzymes, including glucose transport 1 (GLUT1), hexokinase 2 (HK2), 6-phosphofructokinase 1 (PFK1), pyruvate kinase M2 (PKM2) and lactate dehydrogenase A (LDHA). Our findings indicate that QL can protect CMECs against hypoxia injury via promoting glycolysis in a HIF-1α-dependent manner. Lastly, the results suggested that QL-dependent enhancement of HIF-1α protein expression in hypoxic CMECs was associated with the regulation of AMPK/mTOR/HIF-1α pathway, and we speculated that QL also improved HIF-1α stabilization through down-regulating prolyl hydroxylases 3 (PHD3) expression.
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http://dx.doi.org/10.1111/jcmm.13572DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5908112PMC
May 2018

Cardiomyocyte-Restricted Low Density Lipoprotein Receptor-Related Protein 6 (LRP6) Deletion Leads to Lethal Dilated Cardiomyopathy Partly Through Drp1 Signaling.

Theranostics 2018 1;8(3):627-643. Epub 2018 Jan 1.

Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, and Institutes of Biomedical Sciences, Fudan University, Shanghai 200032, China.

Low density lipoprotein receptor-related protein 6 LRP6), a wnt co-receptor, regulates multiple functions in various organs. However, the roles of LRP6 in the adult heart are not well understood. We observed LRP6 expression in heart with end-stage dilated cardiomyopathy (DCM) by western blot. Tamoxifen-inducible cardiac-specific LRP6 knockout mouse was constructed. Hemodynamic and echocardiographic analyses were performed to these mice. Cardiac LRP6 expression was dramatically decreased in patients with end-stage dilated cardiomyopathy (DCM) compared to control group. Tamoxifen-inducible cardiac-specific LRP6 knockout mice developed acute heart failure and mitochondrial dysfunction with reduced survival. Proteomic analysis suggests the fatty acid metabolism disorder involving peroxisome proliferator-activated receptors (PPARs) signaling in the LRP6 deficient heart. Accumulation of mitochondrial targeting to autophagosomes and lipid droplet were observed in LRP6 deletion hearts. Further analysis revealed cardiac LRP6 deletion suppressed autophagic degradation and fatty acid utilization, coinciding with activation of dynamin-related protein 1 (Drp1) and downregulation of nuclear TFEB (Transcription factor EB). Injection of Mdivi-1, a Drp1 inhibitor, not only promoted nuclear translocation of TFEB, but also partially rescued autophagic degradation, improved PPARs signaling, and attenuated cardiac dysfunction induced by cardiac specific LRP6 deletion. Cardiac LRP6 deficiency greatly suppressed autophagic degradation and fatty acid utilization, and subsequently leads to lethal dilated cardiomyopathy and cardiac dysfunction through activation of Drp1 signaling. It suggests that heart failure progression may be attenuated by therapeutic modulation of LRP6 expression.
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http://dx.doi.org/10.7150/thno.22177DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5771081PMC
December 2018

Enhances Cardiac Glucose Metabolism and Improves Diastolic Function in Spontaneously Hypertensive Rats.

Evid Based Complement Alternat Med 2017 19;2017:3197320. Epub 2017 Jun 19.

Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.

Cardiac diastolic dysfunction has emerged as a growing type of heart failure. The present study aims to explore whether (QL) can benefit cardiac diastolic function in spontaneously hypertensive rat (SHR) through enhancement of cardiac glucose metabolism. Fifteen 12-month-old male SHRs were randomly divided into QL-treated, olmesartan-treated, and saline-treated groups. Age-matched WKY rats served as normal controls. Echocardiography and histological analysis were performed. Myocardial glucose uptake was determined by F-FDG using small-animal PET imaging. Expressions of several crucial proteins and key enzymes related to glucose metabolism were also evaluated. As a result, QL improved cardiac diastolic function in SHRs, as evidenced by increased '/'and decreased /' ( < 0.01). Meanwhile, QL alleviated myocardial hypertrophy, collagen deposits, and apoptosis ( < 0.01). An even higher myocardial glucose uptake was illustrated in QL-treated SHR group ( < 0.01). Moreover, an increased CS activity and ATP production was observed in QL-treated SHRs ( < 0.05). QL enhanced cardiac glucose utilization and oxidative phosphorylation in SHRs by upregulating AMPK/PGC-1 axis, promoting GLUT-4 expression, and regulating key enzymes related to glucose aerobic oxidation such as HK2, PDK4, and CS ( < 0.01). Our data suggests that QL improves cardiac diastolic function in SHRs, which may be associated with enhancement of myocardial glucose metabolism.
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http://dx.doi.org/10.1155/2017/3197320DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5494577PMC
June 2017

LCZ696 improves cardiac function via alleviating Drp1-mediated mitochondrial dysfunction in mice with doxorubicin-induced dilated cardiomyopathy.

J Mol Cell Cardiol 2017 07 15;108:138-148. Epub 2017 Jun 15.

Department of Cardiology, Shanghai Institute of Cardiovascular Diseases,Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai 200032, China. Electronic address:

Aims: LCZ696, a novel angiotensin receptor neprilysin inhibitor, is effective in treating heart failure patients. Doxorubicin (DOX) is an effective antitumor medication but the cardiotoxicity limited its clinical use. In this study, we aimed to determine the effect of LCZ696 on DOX-induced cardiomyopathy in mice and in vitro and to explore related mechanisms focusing on fission protein dynamin-related protein 1 (Drp1).

Methods And Results: In human study, we found that myocardial fission protein Drp1 expression and its ser 616 phosphorylation were significantly increased in dilated cardiomyopathy (DCM) patients. Male Balb/c mice and H9c2 cardiomyocytes were randomized into three groups: saline, DOX, DOX plus LCZ696. Reduced cardiac function, mitochondrial morphology disturbance, reduced activity of mitochondrial respiration complex I and lowered adenosine triphosphate (ATP) content were detected post DOX stimulation in mice, which could be significantly improved by LCZ696. Fission protein Drp1 and its ser 616 phosphorylation were also increased post DOX and which could be reduced by LCZ696. In vitro, increased cardiomyocyte apoptosis, Drp1 ser 616 phosphorylation post DOX stimulation could be significantly attenuated by LCZ696 or Drp1 specific inhibitor Midivi-1. Furthermore, over-expression of Drp1 abrogated the protection effect of LCZ696 against DOX-induced cardiotoxicity in H9c2 cells.

Conclusion: The protective effect of LCZ696 against DOX-induced cardiac dysfunction is at least partly associated with alleviating Drp1-mediated mitochondrial dysfunction.
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http://dx.doi.org/10.1016/j.yjmcc.2017.06.003DOI Listing
July 2017

Qiliqiangxin protects against anoxic injury in cardiac microvascular endothelial cells via NRG-1/ErbB-PI3K/Akt/mTOR pathway.

J Cell Mol Med 2017 09 8;21(9):1905-1914. Epub 2017 Mar 8.

Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.

Cardiac microvascular endothelial cells (CMECs) are important angiogenic components and are injured rapidly after cardiac ischaemia and anoxia. Cardioprotective effects of Qiliqiangxin (QL), a traditional Chinese medicine, have been displayed recently. This study aims to investigate whether QL could protect CMECs against anoxic injury and to explore related signalling mechanisms. CMECs were successfully cultured from Sprague-Dawley rats and exposed to anoxia for 12 hrs in the absence and presence of QL. Cell migration assay and capillary-like tube formation assay on Matrigel were performed, and cell apoptosis was determined by TUNEL assay and caspase-3 activity. Neuregulin-1 (NRG-1) siRNA and LY294002 were administrated to block NRG-1/ErbB and PI3K/Akt signalling, respectively. As a result, anoxia inhibited cell migration, capillary-like tube formation and angiogenesis, and increased cell apoptosis. QL significantly reversed these anoxia-induced injuries and up-regulated expressions of NRG-1, phospho-ErbB2, phospho-ErbB4, phospho-Akt, phospho-mammalian target of rapamycin (mTOR), hypoxia-inducible factor-1α (HIF-1α) and vascular endothelial growth factor (VEGF) in CMECs, while NRG-1 knockdown abolished the protective effects of QL with suppressed NRG-1, phospho-ErbB2, phospho-ErbB4, phospho-Akt, phospho-mTOR, HIF-1α and VEGF expressions. Similarly, LY294002 interrupted the beneficial effects of QL with down-regulated phospho-Akt, phospho-mTOR, HIF-1α and VEGF expressions. However, it had no impact on NRG-1/ErbB signalling. Our data indicated that QL could attenuate anoxia-induced injuries in CMECs via NRG-1/ErbB signalling which was most probably dependent on PI3K/Akt/mTOR pathway.
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http://dx.doi.org/10.1111/jcmm.13111DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC5571527PMC
September 2017

Qiliqiangxin improves cardiac function and attenuates cardiac remodeling in rats with experimental myocardial infarction.

Int J Clin Exp Pathol 2015 1;8(6):6596-606. Epub 2015 Jun 1.

Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University Shanghai, China.

Objective: It has been reported that Qiliqiangxin (QL), a traditional Chinese medicine compound, could inhibit cardiac hypertrophy and remodeling, and improve cardiac function. However, whether and how it reverses cardiac remodeling in rats post myocardial infarction (MI) remains unknown. This study aims to explore related mechanisms linked with cardiac function improvement and attenuation of cardiac remodeling by QL in rats with experimental MI.

Methods: MI was induced by ligation of left anterior descending coronary artery (LAD) in male Sprague-Dawley rats. Rats with LVEF < 50% at four weeks after procedure were treated for another 6 weeks with placebo, QL and captopril. Echocardiography and plasma NT-proBNP were measured at the end of study, and histological studies were performed. Protein expressions of Neuregulin-1 (NRG-1), total-Akt, phospho-Akt (Ser473), hydroxy-HIF-1α (Pro564), VEGF, Bax, Bcl-2 and Caspase 3 were examined by Western blot. mRNA expression of NRG-1 and p53 was detected by real-time PCR.

Results: Compared with the placebo group, QL improved cardiac function, reduced left ventricular dimension, inhibited interstitial inflammation and fibrosis, increased neovascularization, and attenuated cardiomyocyte apoptosis. Meanwhile QL significantly upregulated the expression of HIF-1α, VEGF, enhanced phosphorylation of Akt, decreased the ratio of Bax/Bcl-2 and Caspase 3 expression. Furthermore, we observed upregulation of NRG-1 and downregulation of p53 after QL treatment.

Conclusion: Our data suggest that the beneficial effects of QL on improving cardiac function and attenuating cardiac remodeling post MI are associated with angiogenesis enhancement and apoptosis inhibition, which may be mediated via activation of NRG-1/Akt signaling and suppression of p53 pathway.
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http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4525875PMC
June 2016

Qiliqiangxin inhibits angiotensin II-induced transdifferentiation of rat cardiac fibroblasts through suppressing interleukin-6.

J Cell Mol Med 2015 May 6;19(5):1114-21. Epub 2015 Mar 6.

Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.

Qiliqiangxin (QL), a traditional Chinese medicine, had long been used to treat chronic heart failure. Recent studies revealed that differentiation of cardiac fibroblasts (CFs) into myofibroblasts played an important role in cardiac remodelling and development of heart failure, however, little was known about the underlying mechanism and whether QL treatment being involved. This study aimed to investigate the effects of QL on angiotensin II (AngII)-induced CFs transdifferentiation. Study was performed on in vitro cultured CFs from Sprague-Dawley rats. CFs differentiation was induced by AngII, which was attenuated by QL through reducing transforming growth factor-β1 (TGF-β1 ) and α-smooth muscle actin (α-SMA). Our data showed that AngII-induced IL-6 mRNA as well as typeI and typeIII collagens were reduced by QL. IL-6 deficiency could suppress TGF-β1 and α-SMA, and both IL-6 siRNA and QL-mediated such effect was reversed by foresed expression of recombined IL-6. Increase in actin stress fibres reflected the process of CFs differentiation, we found stress fibres were enhanced after AngII stimulation, which was attenuated by pre-treating CFs with QL or IL-6 siRNA, and re-enhanced after rIL-6 treatment. Importantly, we showed that calcineurin-dependent NFAT3 nuclear translocation was essential to AngII-mediated IL-6 transcription, QL mimicked the effect of FK506, the calcineurin inhibitor, on suppression of IL-6 expression and stress fibres formation. Collectively, our data demonstrated the negative regulation of CFs differentiation by QL through an IL-6 transcriptional mechanism that depends on inhibition of calcineurin/NFAT3 signalling.
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http://dx.doi.org/10.1111/jcmm.12512DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4420613PMC
May 2015

[MicroRNA-210 mediates the protective effect of rosuvastatin on human mesenchymal stem cells apoptosis induced by tumor necrosis factor-α].

Zhonghua Xin Xue Guan Bing Za Zhi 2014 Nov;42(11):932-7

Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital Affiliated to Fudan University, Shanghai 200032, China.

Objective: To explore the effect and mechanism of rosuvastatin on tumor necrosis factor-α induced human mesenchymal stem cells (MSCs) apoptosis.

Method: Human MSCs were treated as follows: (1) culture medium; (2) TNF-α (20 µg/ml) for 6 h; (3) rosuvastatin (20 µmol/L) for 24 h; (4) rosuvastatin (20 µmol/L) for 24 h followed by TNF-α (20 µg/ml) for 6 h; (5) TNF-α+rosuvastatin+50 nmol/L antago-miRNA; (6) TNF-α+rosuvastatin+100 nmol/L antago-miRNA. Cell survival and apoptosis were determined by MTT, TUNEL and caspase-3 activity assay. The changes of miRNA-210 in each group were detected with quantitative PCR.

Result: TNF-α significantly induced human MSCs apoptosis in a concentration-dependent manner, and pretreatment with rosuvastatin significantly reduced MSCs apoptosis (caspase-3 assay: TNF-α+Statin group vs. TNF-α group: (1.63 ± 0.25) vs. (2.05 ± 0.36), P < 0.05). Meanwhile, TNF-α progressively reduced the expression of miRNA-210 in human MSCs in a dose-dependent manner, while the miRNA-210 expression was significantly upregulated in TNF-α+Statin group (P < 0.05). The protective effect of rosuvastatin on TNF-α induced MSCs apoptosis was largely abolished by co-treatment with 100 nmol/L antago-miRNA (TUNEL:TNF-α + Statin + antago-miR group vs. TNF-α + Statin group: (42.58 ± 6.71) % vs. (16.87 ± 9.27) %, P < 0.05).

Conclusion: Pretreatment with rosuvastatin can significantly improve the viability of human MSCs after TNF-α injury, the protective mechanism of rosuvastatin is partly mediated through miRNA-210 up-regulation.
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November 2014

miRNA-130b is required for the ERK/FOXM1 pathway activation-mediated protective effects of isosorbide dinitrate against mesenchymal stem cell senescence induced by high glucose.

Int J Mol Med 2015 Jan 29;35(1):59-71. Epub 2014 Oct 29.

Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.

The present study was carried out to investigate the hypothesis that organic nitrates can attenuate the senescence of mesenchymal stem cells (MSCs), a superior cell source involved in the regeneration and repair of damaged tissue. MSCs were treated with high glucose (HG) in order to induce senescence, which was markedly attenuated by pre-treatment with isosorbide dinitrate (ISDN), a commonly used nitrate, as indicated by senescence-associated galactosidase (SA-β-gal) activity, p21 expression, as well as by the mRNA levels of DNA methyltransferase 1 (DNMT1) and differentiated embryo chondrocyte expressed gene 1 (DEC1), which are senescence-related biomarkers. It was also found that the senescent MSCs (induced by HG glucose) exhibited a marked downregulation in ERK activity and forkhead box M1 (FOXM1) expression, which was reversed by ISDN preconditioning. Of note, the inhibition of ERK phosphorylation or the downregulation of FOXM1 statistically abolished the favourable effects of ISDN. In addition, the investigation of the senescence-associated miR-130 family suggested that miR-130b mediates the beneficial effects of ISDN; it was found that the protective effects of ISDN against the senescence of MSCs were prominently reversed by the knockdown of miR-130b. Furthermore, the downregulation of ERK phosphorylation or FOXM1 expression decreased the miR-130b expression level; however, the suppression of miR-130b demonstrated no significant impact on ERK phosphorylation or FOXM1 expression. Taken together, to the best of our knowledge, the present study is the first to demonstrate the favourable effects of ISDN against HG-induced MSC senescence, which are mediated through the activation of the ERK/FOXM1 pathway and the upregulation of miR-130b.
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http://dx.doi.org/10.3892/ijmm.2014.1985DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4249746PMC
January 2015

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

Sci China Life Sci 2014 Oct 29;57(10):989-97. Epub 2014 Aug 29.

Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, 200032, China.

microRNA-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.
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http://dx.doi.org/10.1007/s11427-014-4725-zDOI Listing
October 2014

Olmesartan attenuates cardiac hypertrophy and improves cardiac diastolic function in spontaneously hypertensive rats through inhibition of calcineurin pathway.

J Cardiovasc Pharmacol 2014 Mar;63(3):218-26

*Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China; †Department of Medicine, Sahlgrenska University Hospital/Sahlgrenska, Gothenburg, Sweden; and ‡Institutes of Biomedical Sciences, Fudan University, Shanghai, China.

Objective: To test whether olmesartan ameliorates cardiac diastolic dysfunction in spontaneously hypertensive rats (SHRs) through calcineurin pathway.

Methods: Twenty-four male SHRs of 6 months were divided into saline- (n = 12) and olmesartan-treated (n = 12) groups. Age-matched WKY (n = 12) rats served as controls. Saline (10 mL·kg·d) or the same volume of olmesartan liquor (2.5 mg·kg·d) was administered by gavage for 3 months. Heart rate, systolic blood pressure, cardiac structure, and function and histological studies were determined. Expression of calcineurin and downstream NFAT3 were also detected.

Results: Compared with age-matched Wistar Kyoto rats, SHRs of 6 months exhibited evident cardiac hypertrophy and diastolic dysfunction as demonstrated by elevated systolic blood pressure and E/E', decreased E/A and E'/A', while F, left ventricular ejection fraction and fractional shortening remained unimpaired. Treatment with olmesartan significantly decreased systolic blood pressure and ventricular hypertrophy, attenuated fibrosis, and improved diastolic function (all P < 0.05). Meanwhile, both calcineurin and NFAT3 expressions were downregulated in olmesartan group compared with the other 2 groups (both P < 0.05).

Conclusions: These data suggest the beneficial effect of olmesartan on cardiac structure and diastolic dysfunction, and it may be mediated through calcineurin pathway. This indicates a new therapeutic target for diastolic dysfunction.
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http://dx.doi.org/10.1097/FJC.0000000000000038DOI Listing
March 2014

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.

Int J Mol Sci 2012 Dec 13;13(12):17104-20. Epub 2012 Dec 13.

Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai Institute of Cardiovascular Diseases, Shanghai 200032, China.

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 (H(2)O(2)) 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 H(2)O(2)-induced apoptosis in MSCs through activation of a PI3K/Akt pathway, and by suppressing the production of ROS.
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http://dx.doi.org/10.3390/ijms131217104DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3546741PMC
December 2012

Adiponectin through its biphasic serum level is a useful biomarker during transition from diastolic dysfunction to systolic dysfunction - an experimental study.

Lipids Health Dis 2012 Aug 30;11:106. Epub 2012 Aug 30.

Shanghai Institute of Cardiovascular Diseases, Department of Cardiology, Zhongshan Hospital, Fudan University, Shanghai, China.

Background: Adiponectin is reported to relate with cardiovascular diseases, we sought to examine whether adiponectin is associated with disease progression of heart failure from hypertension in rats in comparison with other known biomarkers and echocardiographic parameters. Spontaneously hypertensive rats (SHR, n = 35), aged 1 month, were used and followed up to 18 months. High frequency echocardiography was performed both at baseline and every 3 months thereafter. Moreover, serum levels of N-terminal pro-natriuretic peptide (NT-proBNP) and interleukin-6 (IL-6) as well as serum level and tissue expression of adiponectin were determined at the same time as echocardiography.

Results: The results clearly demonstrated time-dependent progression of hypertension and heart dysfunction as evidenced by gradually increased left ventricular mass index, NT-proBNP, IL-6 as well as gradually decreased cardiac function as assessed by echocardiography. Meanwhile, tissue and serum adiponectin decreased from 3 months and reached plateau until 12 months in parallel with decreasing of cardiac diastolic function. Thereafter, adiponectin levels increased prior to occurrence of systolic dysfunction. Adiponectin concentration is inversely related with NT-proBNP, IL-6 and E/E' (correlation coefficient (r) = -0.756 for NT-proBNP, p < 0.001, -0.635 for IL-6, p = 0.002, and -0.626 for E/E', p = 0.002, respectively) while positively correlated with E/A and E'/A' (r = 0.683 for E/A, p = 0.001, 0.671 for E'/A', p = 0.001, respectively). No difference for adiponectin distribution among visceral adipose tissues was found.

Conclusion: Adiponectin through its biphasic serum level is a useful biomarker during transition from diastolic dysfunction to systolic dysfunction.
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http://dx.doi.org/10.1186/1476-511X-11-106DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3492043PMC
August 2012

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.

Mol Cell Biochem 2012 Dec 14;371(1-2):55-64. Epub 2012 Aug 14.

Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai 200032, China.

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.
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http://dx.doi.org/10.1007/s11010-012-1422-8DOI Listing
December 2012

Panax quinquefolium saponins inhibited immune maturation of human monocyte-derived dendritic cells via blocking nuclear factor-κB pathway.

J Ethnopharmacol 2012 Jun 26;141(3):982-8. Epub 2012 Mar 26.

Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, PR China.

Ethnopharmacological Relevance: Panax quinquefolium saponins (PQS), a water-soluble antioxidant extracted from a natural herb, radix panacis quinquefolii (American Ginseng), has yielded encouraging results in the treatment of atherosclerotic diseases. However, the underlying mechanisms remain unclear. Here, we tested the hypothesis that the anti-atherosclerotic effect of PQS might be mediated by suppressing human monocyte-derived dendritic cells (DCs) maturation.

Materials And Methods: DCs were derived by incubating purified human monocytes with granulocyte macrophage colony stimulating factor (GM-CSF) and IL-4. DCs were pre-incubated with or without PQS and stimulated by oxidized low density lipoprotein (ox-LDL). Expression of DCs membrane molecules (CD40, CD86, CD1a, HLA-DR) and endocytotic ability were analyzed by FACS, cytokines (IL-12 and TNF-α) were measured by ELISA. Nuclear factor (NF)-κB signaling pathway was determined by Western blotting, and RT-PCR. NF-κB activation was quantified by ELISA.

Results: PQS reduced ox-LDL induced immunophenotypic expressions (CD40, CD1a, CD86, and HLA-DR) and cytokine secretions (IL-12 and TNF-α), and improved endocytotic ability of DCs. These above phenomena were accompanied by decreased protein expression and binding activity of nuclear localized c-Rel subunit.

Conclusions: Our study suggested that PQS inhibited ox-LDL induced immune maturation of DCs in vitro, which might be in part mediated by NF-κB signal transduction pathway.
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http://dx.doi.org/10.1016/j.jep.2012.03.029DOI Listing
June 2012

Efficacy of ACE inhibitors in chronic heart failure with preserved ejection fraction--a meta analysis of 7 prospective clinical studies.

Int J Cardiol 2012 Feb 11;155(1):33-8. Epub 2011 Apr 11.

Department of Cardiology, Shanghai Cardiovascular Institute, Zhongshan Hospital, Fudan University, Shanghai 200032, China.

Background: The effect of ACE inhibitors on the prognosis of chronic heart failure patients with preserved left ventricular ejection fraction remains controversial.

Aims: To assess the impact of ACE inhibitors on the prognosis of chronic heart failure patients with preserved left ventricular ejection fraction.

Methods And Results: Seven prospective studies evaluating the effect of ACE inhibitors compared to placebo or other classes of drugs, such as monotherapy or first-line therapy, on the prognosis of chronic heart failure patients with preserved left ventricular ejection fraction were included. A total of 2554 patients (mean age: 75.1 years, female: 58%) were recruited with an average follow up of 20.9 months. The primary etiology of heart failure with preserved ejection fraction was ischemic heart disease (33.7%), hypertension (69.1%) and diabetes mellitus (25.8%). Our results demonstrated that ACE inhibitors significantly reduced all-cause mortality (odds ratio, OR = 0.52; 95% Confidence Interval (CI), 0.41 to 0.64; P<0.01). Furthermore, ACE inhibitors were able to reduce heart failure related rehospitalization or treatment over 20.9 months (p<0.05) in a subgroup of patients aged over 75 years. However, death due to worsening of heart failure, heart failure related rehospitalization and any-cause readmission were not affected (OR = 0.88; 95% CI: 0.66 to 1.17; P = 0.37 for death due to worsening of heart failure; OR = 0.81; 95% CI: 0.63 to 1.05; P = 0.11 for heart failure related rehospitalization and OR = 0.88; 95% CI: 0.68 to 1.14; P = 0.33 for any-cause readmission, respectively).

Conclusions: In patients with chronic heart failure with preserved ejection fraction, ACE inhibitors reduced all-cause mortality without affecting mortality due to heart failure and any-cause rehospitalization.
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http://dx.doi.org/10.1016/j.ijcard.2011.01.081DOI Listing
February 2012

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.

Clin Cardiol 2010 Jun;33(6):353-60

Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, Shanghai, China.

Background: 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).

Hypothesis: Improvement of cardiac function in patients with acute MI post BMC transplantation might last longer than 12 months.

Methods: We searched MEDLINE, EMBASE, and the Cochrane database through June 2009. Eligible studies were randomized controlled trials of intracoronary BMC transfer in acute MI patients with follow-up duration equal to or longer than 12 months.

Results: A total of 8 trials involving 725 participants were identified. Compared with controls, BMC transplantation significantly improved left ventricular ejection fraction (LVEF) by 4.37% (95% confidence interval [CI]: 2.66%-6.08%; P < 0.00001), reduced left ventricular end-diastolic volume (LVEDV) by 5.71 mL (95% CI: 2.03-9.40 mL; P = 0.002), left ventricular end-systolic volume (LVESV) by 8.94 mL (95% CI: 4.22-13.66 mL; P = 0.0002), and infarct size by 2.42% (95% CI: 1.33%-3.51%, P < 0.00001). Bone marrow-derived cell treatment also significantly reduced the risk of death (relative risk [RR]: 0.33, 95% CI: 0.13-0.89; P = 0.03), while the risk of reinfarction was similar between the 2 groups (RR: 0.62, 95% CI: 0.09-4.12; P = 0.62). Subgroup analysis showed that the BMC transplantation-induced LVEF increase was more significant in patients age < 55 and with cells transferred 6 or 7 days after MI.

Conclusion: Beneficial effects of intracoronary BMC transplantation could last more than 12 months in acute MI patients.
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http://dx.doi.org/10.1002/clc.20745DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6653268PMC
June 2010
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