Haoyu Meng

Beneficial effects of schisandrin B on the cardiac function in mice model of myocardial infarction.

The fruit of Schisandra chinensis has been used in the traditional Chinese medicine for thousands of years. Accumulating evidence suggests that Schisandrin B (Sch B) has cardioprotection effect on myocardial ischemia in vitro. However, it is unclear whether Sch B has beneficial effects on continuous myocardial ischemia in vivo. The aim of the present study was to investigate whether Sch B could improve cardiac function and attenuate myocardial remodeling after myocardial infarction (MI) in mice. Mice model of MI was established by permanent ligation of the left anterior descending (LAD) coronary artery. Then the MI mice were randomly treated with Sch B or vehicle alone. After treatment for 3 weeks, Sch B could increase survival rate, improve heart function and decrease infarct size compared with vehicle. Moreover, Sch B could down-regulate some inflammatory cytokines, activate eNOS pathway, inhibit cell apoptosis, and enhance cell proliferation. Further in vitro study on H9c2 cells showed similar effects of Sch B on prevention of hypoxia-induced inflammation and cell apoptosis. Taken together, our results demonstrate that Sch B can reduce inflammation, inhibit apoptosis, and improve cardiac function after ischemic injury. It represents a potential novel therapeutic approach for treatment of ischemic heart disease.

Beneficial effects of muscone on cardiac remodeling in a mouse model of myocardial infarction.

Musk has been traditionally used in East Asia to alleviate the symptoms of angina pectoris. However, it remains unclear as to whether muscone, the main active ingredient of musk, has any beneficial effects on persistent myocardial ischemia in vivo. The aim of the present study was to investigate whether muscone can improve cardiac function and attenuate myocardial remodeling following myocardial infarction (MI) in mice. Mice were subjected to permanent ligation of the left anterior descending coronary artery to induce MI, and then randomly treated with muscone (2 mg/kg/day) or the vehicle (normal saline) for 3 weeks. Sham-operated mice were used as controls and were also administered the vehicle (normal saline). Treatment with muscone significantly improved cardiac function and exercise tolerance, as evidenced by the decrease in the left ventricular end-systolic diameter, left ventricular end-diastolic diameter, as well as an increase in the left ventricular ejection fraction, left ventricular fractional shortening and time to exhaustion during swimming. Pathological and morphological assessments indicated that treatment with muscone alleviated myocardial fibrosis, collagen deposition and improved the heart weight/body weight ratio. Muscone inhibited the inflammatory response by reducing the expression of transforming growth factor (TGF)-β1, tumor necrosis factor (TNF)-α, interleukin (IL)-1β and nuclear factor (NF)-κB. Treatment with muscone also reduced myocardial apoptosis by enhancing Bcl-2 and suppressing Bax expression. Muscone also induced the phosphorylation of protein kinase B (Akt) and endothelial nitric oxide synthase (eNOS). Our results demonstrate that muscone ameliorates cardiac remodeling and dysfunction induced by MI by exerting anti-fibrotic, anti-inflammatory and anti-apoptotic effects in the ischemic myocardium.

Association of admission serum calcium levels and in-hospital mortality in patients with acute ST-elevated myocardial infarction: an eight-year, single-center study in China.

Objective The relationship between admission serum calcium levels and in-hospital mortality in patients with acute ST-segment elevation myocardial infarction (STEMI) has not been well definitively explored. The objective was to assess the predictive value of serum calcium levels on in-hospital mortality in STEMI patients. Methods From 2003 to 2010, 1431 consecutive STEMI patients admitted to the First Affiliated Hospital of Nanjing Medical University were enrolled in the present study. Patients were stratified according to quartiles of serum calcium from the blood samples collected in the emergency room after admission. Between the aforementioned groups,the baseline characteristics, in-hospital management, and in-hospital mortality were analyzed. The association of serum calcium level with in-hospital mortality was calculated by a multivariable Cox regression analysis. Results Among 1431 included patients, 79% were male and the median age was 65 years (range, 55–74). Patients in the lower quartiles of serum calcium, as compared to the upper quartiles of serum calcium, were older, had more cardiovascular risk factors, lower rate of emergency revascularization,and higher in-hospital mortality. According to univariate Cox proportional analysis, patients with lower serum calcium level (hazard ratio 0.267, 95% confidence interval 0.164–0.433, p<0.001) was associated with higher in-hospital mortality. The result of multivariable Cox proportional hazard regression analyses showed that the Killips class≥3 (HR = 2.192, p = 0.026), aspartate aminotransferase (HR = 1.001, p<0.001), neutrophil count (HR = 1.123, p<0.001), serum calcium level (HR = 0.255, p = 0.001), and emergency revascularization (HR = 0.122, p<0.001) were significantly and independently associated with in-hospital mortality in STEMI patients. Conclusions Serum calcium was an independent predictor for in-hospital mortality in patients with STEMI. This widely available serum biochemical index may be incorporated into the current established risk stratification model of STEMI patients. Further studies are required to determine the actual mechanism and whether patients with hypocalcaemia could benefit from calcium supplement.

p27 kip1 haplo-insufficiency improves cardiac function in early-stages of myocardial infarction by protecting myocardium and increasing angiogenesis by promoting IKK activation

p27kip1 (p27) is widely known as a potent cell cycle inhibitor in several organs, especially in the heart. However, its role has not been fully defined during the early phase of myocardial infarction (MI). In this study, we investigated the relationships between p27, vascular endothelial growth factor/hepatocyte growth factor (VEGF/HGF) and NF-κB in post-MI cardiac function repair both in vivo and in the hypoxia/ischemia-induced rat myocardiocyte model. In vivo, haplo-insufficiency of p27 improved cardiac function, diminished the infarct zone, protected myocardiocytes and increased angiogenesis by enhancing the production of VEGF/HGF. In vitro, the presence of conditioned medium from hypoxia/ischemia-induced p27 knockdown myocardiocytes reduced the injury caused by hypoxia/ischemia in myocardiocytes, and this effect was reversed by VEGF/HGF neutralizing antibodies, consistent with the cardioprotection being due to VEGF/HGF secretion. We also observed that p27 bound to IKK and that p27 haplo-insufficiency promoted IKK/p65 activation both in vivo and in vitro, thereby inducing the NF-κB downstream regulator, VEGF/HGF. Furthermore, IKKi and IKK inhibitor negated the effect of VEGF/HGF. Therefore, we conclude that p27 haplo-insufficiency protects against heart injury by VEGF/HGF mediated cardioprotection and increased angiogenesis through promoting IKK activation.

Long Noncoding RNA Kcna2 Antisense RNA Contributes to Ventricular Arrhythmias via Silencing Kcna2 in Rats With Congestive Heart Failure

Background Congestive heart failure (CHF) is a common cardiovascular disease that is often accompanied by ventricular arrhythmias. The decrease of the slow component of the delayed rectifier potassium current (IK s) in CHF leads to action potential (AP) prolongation, and the IK s is an important contributor to the development of ventricular arrhythmias. However, the molecular mechanisms underlying ventricular arrhythmias are still unknown. Methods and Results Kcna2 and Kcna2 antisense RNA (Kcna2 AS) transcript expression was measured in rat cardiac tissues using quantitative real‐time reverse transcription–polymerase chain reaction and Western blotting. There was a 43% reduction in Kcna2 mRNA in the left ventricular myocardium of rats with CHF. Kcna2 knockdown in the heart decreased the IKs and prolonged APs in cardiomyocytes, consistent with the changes observed in heart failure. Conversely, Kcna2 overexpression in the heart significantly attenuated the CHF‐induced decreases in the IKs, AP prolongation, and ventricular arrhythmias. Kcna2 AS was upregulated ≈1.7‐fold in rats with CHF and with phenylephrine‐induced cardiomyocyte hypertrophy. Kcna2 AS inhibition increased the CHF‐induced downregulation of Kcna2. Consequently, Kcna2 AS mitigated the decrease in the IKs and the prolongation of APs in vivo and in vitro and reduced ventricular arrhythmias, as detected using electrocardiography. Conclusions Ventricular Kcna2 AS expression increases in rats with CHF and contributes to reduced IK s, prolonged APs, and the occurrence of ventricular arrhythmias by silencing Kcna2. Thus, Kcna2 AS may be a new target for the prevention and treatment of ventricular arrhythmias in patients with CHF.

Microalbuminuria in patients with preserved renal function as a risk factor for contrast-Induced acute kidney injury following invasive coronary angiography

OBJECTIVES To investigate the association between pre-existing microalbuminuria among patients with preserved renal function and contrast- induced acute kidney injury (AKI) following coronary angiography. MATERIAL AND METHODS 612 consecutive patients with preserved renal function (eGFR≥60ml/min and without macroalbuminuria) undergoing scheduled coronary angiography were stratified into microalbuminuria group (107 patients) and normal-albuminuria group (505 patients) according to the urine albumin to creatinine ratio (ACR) levels. Microalbuminuria was defined as ACR in the range of 30-300mg/g and normal-albuminuria was defined as ACR<30mg/g. Contrast-induced AKI was defined as a relative increase in serum creatinine (SCr) concentration of at least 25% or an absolute increase in SCr of 44.2μmol/L within 72h after the procedure. RESULTS The peak increases of SCr in microalbuminuria group were larger than those in normal-albuminuria group (10.6±12.4μmol/L vs. 4.8±8.9μmol/L，P<0.001). The incidence of AKI was higher in patients with microalbuminuria than those with normal-albuminuria (12.1% vs. 5.0%, P=0.005). Multivariate analysis revealed that there was an association between microalbuminuria and contrast-induced AKI risk after adjusting for confounders. CONCLUSION Pre-existing microalbuminuria is associated with greater risk for AKI in patients with a preserved renal function who undergo scheduled coronary angiography.

Comparison of high-sensitivity C-reactive protein level between systemic and coronary circulation in patients with acute myocardial infarction

Inflammation plays an important role not only in the initiation and progression of atherosclerosis but also in plaque rupture of coronary artery disease (CAD) [1–3], which leads to acute coronary syndrome (ACS) or even acute myocardial infarction (AMI). It is well known that C-reactive protein (CRP) is one of the most important inflammation markers and has been proved to be an independent risk factor for CAD [4–7]. High level of CRP predicts poor clinical outcomes in patients with both stable CAD and ACS [6–9]. Compared with CRP, high-sensitivity CRP (hs-CRP) is more sensitive that can be examined in serum. However, the source of CRP or hs-CRP in CAD or ACS has not been definitively explored. One hypothesis suggested that elevated hs-CRP, which can be measured in systemic circulation, is released from unstable or ruptured plaque in coronary circulation, and then transported to systemic circulation [10]. Another hypothesis suggested that elevated hs-CRP is released from noncoronary circulation tissue (liver cells and fatty tissues) and then transported to coronary circulation, which transforms stable plaque into an unstable or ruptured one, and finally induces ACS or AMI [11,12]. Whether hs-CRP originates from systemic or coronary circulation is still a controversial issue [10–12]. Besides, monocyte is an important chronic inflammatory factor and secretes cytokines such as interleukin-1, interleukin-6, and tumor necrosis factor-a, which stimulates the production of CRP [1–4]. Large amount of monocytes may induce high level of hs-CRP, which predicates high risk of ACS or AMI for patients with CAD. Here, we compared the level of hs-CRP between systemic and coronary circulation in patients with AMI and stable CAD, as well as the difference of monocyte between patients with AMI and stable CAD. The study included 80 patients (60 patients with AMI and 20 patients with single-vessel stable CAD) hospitalized in the Department of Cardiology, the First Afflicted Hospital of Nanjing Medical University from July 2012 to April 2013. All procedures were in accordance with the ethical standards of the responsible committee on human experimentation and with the Helsinki Declaration of 1975, as revised in 2000 [5]. Informed consent was obtained from all the included patients. In the AMI group, coronary angiography was immediately performed after admission, and the time window from the onset of chest pain to the balloon dilatation ranged from 2 to 12 h. In the stable CAD group, patients received coronary angiography 1–2 days after admission. Blood sample was collected from both systemic and coronary circulation. Blood sample of systemic circulation was taken from peripheral arterial puncture, while intracoronary blood sample was taken by using a ‘Diver’ catheter over the wire to the distal site of plaque in the culprit vessel. Fasting blood sample from each site was collected in the coagulation-promoting tubes, and centrifuged at 2100 g for 10 min. Serum was separated and immediately analyzed. Serum level of hs-CRP (mg/l) was measured by the method of rate nephelometry, using Siemens BN-II Special Protein Analyzer (Bonn, Germany). Meanwhile, the level of monocytes (10/l) from systemic circulation was measured. To explore the source of hs-CRP, the difference of hs-CRP level between systemic and coronary circulation was evaluated in each patient. Paired Student’s t-test revealed that the level of hs-CRP was higher in blood sample from systemic circulation than that from coronary circulation in the AMI group (mean difference (MD): 0.67, n 1⁄4 60, 95% confidence interval (CI): 0.08–1.26, P 1⁄4 0.0266); there was no significant difference between systemic and coronary circulation in the stable CAD group (MD: 0.18, n 1⁄4 20, 95% CI: 20.03 to 0.39, P 1⁄4 0.09) (Fig. 1). There was a trend towards higher MD of hs-CRP between systemic and coronary circulation in the AMI group than that in the stable CAD Acta Biochim Biophys Sin 2014, 46: 161–162 |a The Author 2013. Published by ABBS Editorial Office in association with Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. DOI: 10.1093/abbs/gmt129. Advance Access Publication 2 December 2013

A correlation between acute kidney injury and myonecrosis after scheduled percutaneous coronary intervention

Slight elevations in cardiac troponin I and T are frequently observed after percutaneous coronary intervention (PCI). Contrast-induced acute kidney injury (CI-AKI) is a complex syndrome induced by exposure to intravascular contrast media (CM). Currently, the relationships between the CM, pre-existing kidney insufficiency, CI-AKI, and myonecrosis after elective PCI are unclear. To investigate the relationship between CI-AKI and post-procedural myonecrosis (PMN) after PCI, we analyzed 327 non-ST-segment elevation acute coronary syndrome subjects undertaking elective PCI. The levels of cardiac troponins (cTns), cTnI and cTnT, at baseline and on at least one occasion 18–24 h after PCI were measured. We also recorded serum levels of creatinine (SCr) and the urine albumin:creatinine ratio (ACR) before coronary angiography, and 24–48 h and 48–72 h after contrast administration. A post-procedure increase in cTns was detected in 16.21% (53/327) of subjects with cTns levels >99th to 599th percentile upper reference limit (URL). Twenty-seven patients (8.26%) developed CI-AKI. CI-AKI occurred more often in subjects with PMN than in those without PMN (20.8% versus 5.8%, respectively, P=0.001). Multiple logistic regression analysis revealed that pre-existing microalbuminuria (MA) was an important independent predictor of PMN (OR: 3.31; 95% CI: 1.26–8.65, P=0.01). However, there was no correlation between the incidence of CI-AKI and PMN (OR: 2.38; 95% CI: 0.88–6.46, P=0.09). We conclude that pre-existing MA was not only an important independent predictor of CI-AKI but also of PMN.

Safety and Efficacy of Adenovirus Carrying Hepatocyte Growth Factor Gene by Percutaneous Endocardial Injection for Treating Post-infarct Heart Failure: A Phase IIa Clinical Trial

OBJECTIVE Our previous phase I clinical trial has confirmed the safety of Adenovirus carrying Hepatocyte Growth Factor gene (Ad-HGF) by intracoronary administration for treating severe coronary artery disease. This study was performed to evaluate the safety and efficacy of Ad-HGF by percutaneous endocardial injection for treating post-infarct heart failure. METHODS A total of 30 patients (15 in the experimental group and 15 in the control group) with postinfarct heart failure who were not indicated to revascularization and had received the optimal standardized medication therapy were included in the study. Percutaneous endocardial Ad-HGF gene transfer was injected with a catheter-based intramyocardial delivery system in the experimental group. Safety parameters were measured and compared between baseline and follow-ups in the experimental group. The Mean Difference (MD) of efficacy parameters from baseline to 6-month follow-up was measured in both groups and compared with each other. RESULTS No one suffered from serious adverse events in the experimental group during the 6-month follow-up. The experimental group revealed significant lower left ventricular end-diastolic dimension (LVDd) (68.5 vs. 65.8 MD: -2.69±1.08, P=0.03) and higher LVEF of both echocardiograph (35.2 vs. 39.3, MD: 4.05±0.86, P=0.0005) and single photon emission computed tomography (27.7 vs. 30.6, MD: 2.9±0.8, P=0.003) in the 6-month follow-up than that in the baseline, but the control group did not (P>0.05). Compared to the control group, the experimental group showed significant improvement ranges of lower LVDd (2.6 vs. -2.69, MD: -5.3±1.4, P=0.0009) and higher echocardiographic LVEF (-2 vs. 4.05, MD: 6.1±1.6, P=0.0008) from baseline to 6-month follow-up. CONCLUSION Percutaneous endocardial administration of Ad-HGF is safe and potentially efficient in improving LVEF and lowering LVDd of patients with post-infarct heart failure.

Safety and Efficacy of Intracoronary Ad-HGF Administration for TreatingSevere Coronary Disease: Results From Long-Term Follow-Up of a Phase IClinical Trial

Objective: This study is a long-term follow-up of our previous phase I clinical trial and aims at evaluating the long-term safety and efficacy of intracoronary Ad-HGF administration for treating coronary disease. Methods: This study includes 22 patients (11 in the experiment group and 11 in the control group) with diffused and severe coronary disease who had received the optimal standardized medication therapy and was not amenable to revascularization. Intracoronary Ad-HGF gene transfer was administered to the distal part of the accessible artery by over-the wire balloon or at the ostium of the target vessels by diagnostic coronary catheter in the experiment group. Safety parameters were measured and compared between baseline and follow-ups (5-week; 12-month; 36- month) only in the experiment group. The changes of efficacy parameters (ejection fraction, EF) from baseline to 36- month follow-up (δEF) were measured in both groups and compared with each other. Results: This study confirmed the long-term safety of intracoronary Ad-HGF administration for treating severe diffuse coronary disease. All the eleven patients of the experiment group were alive after 36-months follow-up. During the follow-up, no new-onset arrhythmia was recorded; no malignant tumor was diagnosed; no paroxysmal or long-term fever was recorded; no retinal vascular anomaly was diagnosed. There were no statistically significant differences between the follow-ups and baseline in regard to blood parameters, including WBC, Hb, ALT, AST, BUN, Cr, CEA and AFP. In addition, intracoronary Ad-HGF efficiently improved echocardiographic EF at the 36-month follow-up compared to baseline (F=4.4, p=0.024) and with the control group (δEF: 3.5 ± 1.1 vs. -4.5 ± 1.3, MD: 8, p=0.0001). The medium-high dose subgroup also showed higher ECT-EF at the 36-month follow-up than baseline (MD: 4.8, p=0.017, n=8) and higher improvement of ECT-EF than the control group (δEF: 4.8 ± 1.5 vs. 0.3 ± 1.7, MD: 4.5, p=0.08). Conclusion: Intracoronary Ad-HGF administration is safe and potentially efficient in improving EF of patients with severe diffuse coronary disease in 3-year follow-up.