Fanglin Lu

Genetic polymorphisms of glutathione S-transferase genes GSTM1, GSTT1 and risk of coronary heart disease

To clarify the role of glutathione S-transferases (GSTs; GSTM1 and GSTT1) status in susceptibility to coronary heart disease (CHD), a meta-analysis of published studies was performed. A total of 19 studies including 8020 cases and 11 501 controls were included in this meta-analysis. In a combined analysis, the relative risks for CHD of the GSTM1 null and GSTT1 null polymorphisms were 1.47 [95% confidence interval (CI): 1.08-2.01] and 1.26 (95% CI: 0.90-1.75), respectively. Three potential sources of heterogeneity including ethnicity, source of control and sample size of study were also assessed. However, no significant association was found in stratified analyses. By pooling data from eight studies (2909 cases and 3745 controls) that considered combinations of GSTT1 and GSTM1 genotypes, a statistically significant increased risk for CHD [odds ratio (OR = 2.38, 95% CI: 1.03-5.48)] was detected for individuals with combined deletion mutations in both genes compared with positive genotypes. Results from the meta-analysis of five studies on GSTs stratified according to smoking status showed an increased risk for individuals with null genotype (OR = 2.21, 95% CI: 1.24-3.92 for GSTM1 and OR = 3.29, 95% CI: 1.49-7.26 for GSTT1) versus non-null genotypes. This meta-analysis suggests that the GSTM1 null genotype may slightly increase the risk of CHD and that interaction between unfavourable GSTs genotypes may exist.

MSCs transfected with hepatocyte growth factor or vascular endothelial growth factor improve cardiac function in the infarcted porcine heart by increasing angiogenesis and reducing fibrosis

BACKGROUND Cell transplantation and gene therapy have been demonstrated to have beneficial effects after a myocardial infarction (MI). Here, we used a large animal model of MI to investigate the beneficial effects of mesenchymal stem cells (MSCs) transfected with hepatocyte growth factor (HGF) or vascular endothelial growth factor (VEGF) genes. METHODS A porcine MI model was created by balloon occlusion of the distal left anterior descending artery for 90 min followed by reperfusion. At 1 week after MI, the pigs were infused via the coronary vein with saline (n=8), MSCs + AdNull(n=8), MSC+VEGF(n=10), or MSC+HGF(n=10). Cardiac function and myocardial perfusion were evaluated by using echocardiography and gated cardiac perfusion imaging before and 4 weeks after transplantation. Morphometric and histological analyses were performed. RESULTS All cell-implanted groups had better cardiac function than the saline control group. There were further functional improvements in the MSC+HGF group, accompanied by smaller infarct sizes, increased cell survival, and less collagen deposition. Blood vessel densities in the damaged area and cardiac perfusion were significantly greater in the MSC+AdNull group than in the saline control group, and further increased in the MSC+VEGF/HGF groups. Tissue fibrosis was significantly less extensive in the MSC and MSC+VEGF groups than in the saline control group and was most reduced in the MSC+HGF group. CONCLUSION MSCs (alone or transfected with VEGF/HGF) delivered into the infarcted porcine heart via the coronary vein improved cardiac function and perfusion, probably by increasing angiogenesis and reducing fibrosis. MSC+HGF was superior to MSC+VEGF, possibly owing to its enhanced antifibrotic effect.

Synergistic effect of fibronectin and hepatocyte growth factor on stable cell-matrix adhesion, re-endothelialization, and reconstitution in developing tissue-engineered heart valves.

Stable cell-matrix adhesion, re-endothelialization, and reconstitution represent important issues in creating autologous living heart valve, a close collaboration between growth factors and the extracellular matrix in these processes appears crucial. To prove this action, porcine decellularized valve constructs were precoated with fibronectin and seeded with hepatocyte growth factor-transferred marrow stromal cells (MSCs) and grown in vitro in a pulsatile-flow bioreactor. Results showed hepatocyte growth factor stimulated adhesion of MSCs to fibronectin in a time-dependent manner with a range of 8–128 ng/ml. Histological observation demonstrated a time course of MSC growth on decellularized valve constructs. A handful of cells, a loose cellular layer, a confluent monolayer coverage, a 2-layer structure and a 3-layer structure were observed at weeks 2, 3, 4, 6, and 8, respectively. Immunohistochemical analysis revealed cellular reconstitution of endothelial cells (von Willebrand factor positive) and myofibroblasts (α-smooth muscle actin and vimentin double-positive) at week 8. Importantly, endothelial cell retention (17.3 ± 2.6/mm) remained high under exposure to high flow and pressure conditions in a bioreactor. These results demonstrated that the combination of fibronectin and hepatocyte growth factor contributed to creating autologous living heart valve.

Impact of preoperative atrial fibrillation on mortality and cardiovascular outcomes of mechanical mitral valve replacement for rheumatic mitral valve disease

OBJECTIVES The prognostic significance of preoperative atrial fibrillation on mitral valve replacement remains unclear. The aim of this study was to explore the effects of the presence of preoperative atrial fibrillation on mortality and cardiovascular outcomes of mitral valve replacement for rheumatic valve disease. METHODS A retrospective analysis was performed on a total of 793 patients who underwent mitral valve replacement with or without tricuspid valve repair in our hospital. The patients selected were divided into two groups according to preoperative rhythm status. Patients with preoperative atrial fibrillation were assigned to the AF group, while patients in preoperative sinus rhythm were assigned to the SR group. Postoperative follow-up was performed by outpatient visits, as well as by telephone and written correspondence. Data gathered included survivorship, postoperative complications, left ventricular function and tricuspid regurgitation. RESULTS For patients with atrial fibrillation vs those in sinus rhythm, there was no difference in postoperative mortality and morbidity. Follow-up was a mean of 8.6 ± 2.4 years. For patients with preoperative atrial fibrillation, 10-year survival from a Kaplan-Meier curve was 88.7%, compared with 96.6% in patients with preoperative sinus rhythm (P = 0.002). Multivariate analysis identified low left ventricular ejection fraction, older age, large left atrium and preoperative atrial fibrillation as significant adverse predictors for overall survival. Freedom from thromboembolism complications at 13 years was lower for patients with preoperative atrial fibrillation without maze procedure and left atrial appendage ligation, compared with that for patients with preoperative sinus rhythm without maze procedure and left atrial appendage ligation, and patients with concomitant maze procedure and left atrial appendage ligation (76.3 vs 94.8 vs 94.0%, respectively; P = 0.001). On echocardiography, the proportion of patients with significant tricuspid regurgitation was 38.7% (atrial fibrillation patients) vs 25.4% (patients in sinus rhythm; P < 0.001). Left ventricular ejection fraction measured 5 years after surgery increased by an average of 1.2% in the AF group, while it increased by 5.3% in the SR group (P = 0.028). CONCLUSIONS Preoperative atrial fibrillation is a risk factor for long-term mortality, thromboembolism complications and tricuspid regurgitation, and it also has an adverse effect on the degree of improvement when considering left ventricular function.

Surgical treatment of multivalvular endocarditis: Twenty-one–year single center experience

OBJECTIVE Little information is available about surgical outcomes in patients with multivalvular endocarditis. The aim of this article is to review the 21-year experience with surgical treatment of patients with multivalvular endocarditis at our institution and, in particular, to determine the incidence, pathologic status, diagnosis, surgical strategies, and outcomes of patients with this disease. METHODS From January 1986 to December 2006, a total of 48 patients (40 men, 8 women), with a mean age of 42 +/- 12 years, underwent surgery for multivalvular endocarditis. Endocarditis was active in 32 patients and healed in 16. Preoperative transthoracic echocardiographic evaluation was performed in all 48 patients with addition of transesophageal echocardiography in 22 (45.8%). Intraoperative findings showed that the endocarditis involved mostly the mitral and aortic valves (40/48 patients). Triple or quadruple valve involvement was found in 1 and 2 patients, respectively. Preoperative, perioperative, and postoperative data were retrospectively analyzed and risk factors for early and late survival were determined. RESULTS In only 24 (50.0%) patients was multivalvular endocarditis diagnosed by preoperative transthoracic echocardiography; 17 (77.3%) patients had multivalvular endocarditis confirmed by preoperative transesophageal echocardiography. The 30-day hospital mortality was 12.5% (n = 6). Preoperative renal failure, New York Heart Association class IV, and emergency surgery were identified as independent risk factors for hospital mortality. Overall long-term survival was 74% +/- 6% at 5 years and 62% +/- 3% at 10 years. Multivariate analysis revealed that renal failure and recurrent endocarditis were associated with increased late mortality. Ten-year freedom from recurrent endocarditis was 74% +/- 5% and 10-year freedom from reoperation was 73% +/- 6%. CONCLUSIONS In our institution, multivalvular endocarditis was diagnosed by transthoracic echocardiography in only half of the patients. Intraoperative transesophageal echocardiography provided a more effective means to identify this disease. Radical resection of all infected tissues for patients with multivalvular endocarditis and additional intraoperative interventions, depending on the intraoperative pathologic condition, produced satisfactory in-hospital and long-term results, similar to those in patients with a single infected heart valve.

Validation of EuroSCORE II in Chinese Patients Undergoing Heart Valve Surgery

BACKGROUND To assess the performance of the The European System for Cardiac Operative. Risk Evaluation II (EuroSCORE II) in Chinese patients undergoing heart valve surgery at our centre. METHODS From January 2006 to December 2011, 3479 consecutive patients who underwent heart valve surgery at our centre were collected and scored according to the original EuroSCORE and EuroSCORE II models. All patients were divided into single valve surgery and multiple valve surgery subgroups. The entire cohort and each subgroup were analysed. Calibration of the original EuroSCORE and EuroSCORE II models was assessed by the Hosmer-Lemeshow (H-L) test. Discrimination was tested by calculating the area under the receiver operating characteristic (ROC) curve. RESULTS Observed mortality was 3.32% overall, compared to expected mortality 3.84% for the original additive EuroSCORE (H-L: P = 0.013), 3.33% for the original logistic EuroSCORE (H-L: P = 0.08), and 2.52% for the EuroSCORE II (H-L: P < 0.0001). The EuroSCORE II model showed good calibration in predicting in-hospital mortality for patients undergoing single valve surgery (H-L: P = 0.103) and poor calibration for patients undergoing multiple valve surgery (H-L: P < 0.0001). The discriminative power of the original EuroSCORE model (area under the ROC curve of 0.684 and 0.673 for the additive and logistic model, respectively) and EuroSCORE II model (area under the ROC curve of 0.685) for the entire cohort was poor. The discriminative power of the EuroSCORE II model was good for the single valve surgery group (area under the ROC curve of 0.792) and was poor for the multiple valve surgery group (area under the ROC curve of 0.605). CONCLUSION The EuroSCORE II model gives an accurate prediction for individual operative risk in patients undergoing single valve surgery but an imprecise prediction in patients undergoing multiple valve surgery at our centre. Therefore, the use of the EuroSCORE II model for risk evaluation may be suitable in patients undergoing single valve surgery, and the creation of a new model which accurately predicts outcomes in patients undergoing multiple valve surgery is possibly required at our centre in the future.

Meta-analysis of RAGE gene polymorphism and coronary heart disease risk.

Background Recent data from human and animal studies have shown an upregulated expression of advanced glycosylation end product–specific receptor (RAGE) in human atherosclerotic plaques 1 and in retina, messangial, and aortic vessels, suggesting an important role of RAGE in the pathogenesis of atherothrombotic diseases. In the past few years, the relationship between RAGE polymorphisms (−429T/C, −374T/A, and G82S) and coronary heart disease (CHD) has been reported in various ethnic groups; however, these studies have yielded contradictory results. Methods PubMed, ISI web of science, EMBASE and the Chinese National Knowledge Infrastructure databases were systematically searched to identify relevant studies. Data were abstracted independently by two reviewers. A meta-analysis was performed to examine the association between RAGE polymorphisms and susceptibility to CHD. Odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Results A total of 17 studies including 4343 patients and 5402 controls were involved in this meta-analysis. Overall, no significant results were observed for −429T/C (OR  = 1.01, 95% CI: 0.92–1.12, P  = 0.78), −374T/A (OR  = 1.11, 95% CI: 0.98–1.26, P  = 0.09) and G82S (OR  = 1.12, 95% CI: 0.86–1.45, P  = 0.41) polymorphism. In the stratified analyses according to ethnicity, sample size, CHD endpoint and Hardy-Weinberg status, no evidence of any gene-disease association was obtained. Conclusions This meta-analysis demonstrates that there is no association between the RAGE −429T/C, −374T/A and G82S polymorphisms and CHD.

Pleiotropic Effects of Transforming Growth Factor-β1 on Pericardial Interstitial Cells: Implications for Fibrosis and Calcification in Idiopathic Constrictive Pericarditis

To the Editor: Chronic and permanent constrictive pericarditis represents a serious hemodynamic syndrome that can lead to heart failure unless surgically treated ([1][1]). Although a number of factors may cause constriction, idiopathic constrictive pericarditis (ICP) is becoming increasingly

Treatment of fusiform ascending aortic aneurysms: A comparative study with 2 options

OBJECTIVE Ascending aortic replacement and reinforced reduction aortoplasty are 2 optional procedures for the treatment of fusiform ascending aneurysms. This study was designed to compare the early and late results of these 2 options. METHODS Between January 2000 and January 2008, 71 patients with fusiform ascending aortic aneurysms and aortic valve disease underwent reinforced reduction aortoplasty associated with aortic valve replacement (RRA group, n = 32) or ascending aortic replacement combined with aortic valve replacement (AAR group, n = 39). Patients requiring other concomitant cardiac procedures were excluded. Perioperative events and late results were compared. RESULTS The variables of the 2 groups were similar, except age and preoperative diameter of the ascending aorta. Despite the nearly identical perioperative morbidity in the 2 groups, mean cardiopulmonary bypass time and aortic crossclamping time were shorter in the RRA group. The follow-up period was between 1 and 8 years (mean, 3 years and 4 months). The 5-year survival rate was 90.7% ± 6.4% versus 87.0% ± 6.3%, respectively. Although there was a significant increase in aortic sinus diameters in the AAR group, all aortic sinus diameters were within the acceptable range. There was no increase in proximal aortic arch diameters in the 2 groups. CONCLUSIONS For the treatment of fusiform ascending aortic aneurysms, both procedures can result in favorable and comparable late results in appropriate patients. Furthermore, reinforced reduction aortoplasty should be encouraged more because of its significant operative simplicity and safety if only the quality of the aortic wall is acceptable.

Characteristics of pericardial interstitial cells and their implications in pericardial fibrocalcification

Pericardial fibrocalcification (PF) is a prominent feature of human pericardial pathology, including constrictive pericarditis and, to a lesser extent, degenerated autologous pericardial substitutes. However, the role of pericardial interstitial cells (PICs) in the pathogenesis of PF has yet to be established. Using a combination of histology and immunohistochemistry, we showed that the critical cellular event in PF in situ was the transdifferentiation of PICs into myofibroblasts/osteoblasts and that the percentage of myofibroblasts/osteoblasts correlated positively with the severity of PF. In vitro studies demonstrated that PICs, similar to mesenchymal stem cells, had the potential to differentiate along adipogenic, osteogenic, chondrogenic or myogenic lineages. However, PICs exhibited a more limited self-renewal capacity and a lower expression of Oct4 (POU5F1) and Kruppel-like transcription factor Klf4, underwent earlier senescence and spontaneously transdifferentiated into myofibroblasts/osteoblasts. Quantitative-real-time reverse transcriptase-polymerase chain reaction (qRT-PCR) confirmed that the mRNA levels of α-smooth muscle actin (α-SMA), alkaline phosphatase (ALP), core-binding factor α1/runt-related transcription factor2 (Cbfa1/Runx2), transforming growth factor (TGF)-β1 and bone morphogenetic protein (BMP)-2 were upregulated as the passage number increased. The mRNA level of platelet-derived growth factor (PDGF)-AA was also significantly upregulated with higher levels at passage 3. Ectopic expression of Oct4 and Klf4 enhanced the colony formation of PICs and selectively impaired induction of genes involved in transdifferentiation into myofibroblasts/osteoblasts (α-SMA, ALP, Cbfa1/Runx2, PDGF-AA and BMP-2). These data, while offering new insights into the biology of PICs, reinforce the central role of these cells in cell-mediated PF and may assist in future strategies to treat fibrocalcific pericardial diseases.