Kejiang Cao

Catheter ablation of ventricular tachycardia in 136 patients with coronary artery disease: results and long-term follow-up.

OBJECTIVES This study attempted to determine the feasibility and long-term efficacy of catheter ablation by means of either radiofrequency or direct current energy in a selected group of patients with coronary artery disease. BACKGROUND Catheter ablation of ventricular tachycardia has proved to be highly effective in patients with idiopathic and bundle branch reentrant ventricular tachycardia. In patients with coronary artery disease and recurrent sustained ventricular tachycardia resistant to medical antiarrhythmic management, the value of catheter ablation has not yet been established. METHODS One hundred thirty-six patients with coronary artery disease and one configuration of monomorphic sustained ventricular tachycardia underwent radiofrequency (72 patients) or direct current catheter ablation (64 patients). The mapping procedure to localize an adequate site for ablation included pace mapping during sinus rhythm, endocardial activation mapping, identification of isolated mid-diastolic potentials and pacing interventions during ventricular tachycardia. RESULTS Primary success was achieved in 102 (75%) of 136 patients (74% of 72 undergoing radiofrequency and 77% of 64 with direct current ablation). Complications were noted in 12% of patients. During a mean (+/- SD) follow-up period of 24 +/- 13 months (range 3 to 68), ventricular tachycardia recurred in 16% of patients. CONCLUSIONS Catheter ablation of ventricular tachycardia in coronary artery disease is feasible in patients with one configuration of monomorphic sustained ventricular tachycardia. There is no significant difference with respect to the type of energy applied. The follow-up data show that in a selected group of patients with coronary artery disease, catheter ablation offers a therapy alternative.

Radiofrequency Catheter Ablation of Right Ventricular Tachycardia Late After Repair of Congenital Heart Defects

BACKGROUND Ventricular arrhythmias after repair of congenital heart defects are a common finding and possibly contribute to sudden death in these patients. Optimal antiarrhythmic management has not yet been defined. METHODS AND RESULTS The study population consisted of 16 patients in whom ventricular arrhythmias occurred 11 to 42 years after complete surgical repair of congenital heart defects. Fifteen patients had a history of symptomatic sustained or nonsustained ventricular tachycardia, and 1 had frequent nonsustained ventricular tachycardia. The diagnostic mapping procedure to identify the origin of the arrhythmia included pace mapping during sinus rhythm, activation mapping, and pacing interventions during ventricular tachycardia. Catheter ablation was carried out by means of radiofrequency energy in the temperature-controlled mode. The follow-up period was 6 to 33 months (mean, 16 months). A right ventricular origin of the tachycardia in the surgically corrected area could be determined in all patients. Catheter ablation was carried out without complications. Immediate noninducibility was achieved in 15 of the 16 patients. One patient in whom the tachycardia was again inducible at repeat stimulation 1 week later was successfully treated with amiodarone. Eleven patients were taken off antiarrhythmic drugs. During follow-up, none of them had a recurrence of the tachycardia that had been ablated. CONCLUSIONS In patients with symptomatic or frequent ventricular tachycardia late after complete surgical repair of congenital heart defects, catheter ablation by means of radiofrequency energy is feasible and safe and thus might be taken into consideration for these patients. Short-term follow-up results are promising.

Coexpression of VEGF and angiopoietin-1 promotes angiogenesis and cardiomyocyte proliferation reduces apoptosis in porcine myocardial infarction (MI) heart

VEGF and angiopoietin-1 (Ang1) are two major angiogenic factors being investigated for the treatment of myocardial infarction (MI). Targeting VEGF and Ang1 expression in the ischemic myocardium can increase their local therapeutic effects and reduce possible adverse effects. Adeno-associated viral vectors (AAVs) expressing cardiac-specific and hypoxia-inducible VEGF [AAV-myosin light chain-2v (MLC)VEGF] and Ang1 (AAV-MLCAng1) were coinjected (VEGF/Ang1 group) into six different sites of the porcine myocardium at the peri-infarct zone immediately after ligating the left descending coronary artery. An identical dose of AAV-Cytomegalovirus (CMV)LacZ or saline was injected into control animals. AAV genomes were detected in the liver in addition to the heart. RT-PCR, Western blotting, and ELISA analyses showed that VEGF and Ang1 were predominantly expressed in the myocardium in the infarct core and border of the infarct heart. Gated single-photon emission computed tomography analyses showed that the VEGF/Ang1 group had better cardiac function and myocardial perfusion at 8 wk than at 2 wk after vector injection. Compared with the saline and LacZ controls, the VEGF/Ang1 group expressed higher phosphorylated Akt and Bcl-xL, less Caspase-3 and Bad, and had higher vascular density, more proliferating cardiomyocytes, and less apoptotic cells in the infarct and peri-infarct zones. Thus, cardiac-specific and hypoxia-induced coexpression of VEGF and Ang1 improves the perfusion and function of porcine MI heart through the induction of angiogenesis and cardiomyocyte proliferation, activation of prosurvival pathways, and reduction of cell apoptosis.

Electrocardiographic algorithm to identify the optimal target ablation site for idiopathic right ventricular outflow tract ventricular premature contraction

AIMS Several electrocardiographic (ECG) algorithms have been developed to identify the site of origin of ventricular premature contractions (VPCs) from right ventricular outflow tract (RVOT) based on pacemapping; however, their accuracy remains unclear. METHODS AND RESULTS We evaluated the accuracy of these algorithms in 52 consecutive patients (31 female, mean age 42.6+/-14.6 years) with successful radiofrequency ablation of RVOT-VPC as guided by 3D electroanatomical non-contact mapping (Ensite, St Jude Medical, USA) and compared with a newly proposed ECG algorithm. As guided by 3D electroanatomical mapping, the successful ablation sites of RVOT-VPC were RVOT septum (n=31), RVOT free wall (n=19), and His region (n=2). Retrospective evaluation in the initial 39 patients shows that the overall positive prediction value to identify a successful ablation site of this newly proposed ECG algorithm is 77.3% and is higher than the 73.3% by Ito et al., 73.3% by Joshi et al., and 53.8% by Dixit et al. (P>0.05). Prospective evaluation in the subsequent 13 patients also demonstrate similar high overall sensitivity (79.0%), specificity (92.7%), and positive prediction value (88.2%) to identify a successful ablation site with this newly proposed ECG algorithm. CONCLUSION On the basis of detail 3D electroanatomical mapping of successful ablation sites, a newly proposed ECG algorithm was developed to improve the sensitivity, specificity, and positive prediction value in identification of targeted ablation sites for RVOT-VPC.

Intramyocardial transplantation of undifferentiated rat induced pluripotent stem cells causes tumorigenesis in the heart.

Background Induced pluripotent stem cells (iPSCs) are a novel candidate for use in cardiac stem cell therapy. However, their intrinsic tumorigenicity requires further investigation prior to use in a clinical setting. In this study we investigated whether undifferentiated iPSCs are tumorigenic after intramyocardial transplantation into immunocompetent allogeneic recipients. Methodology/Principal Findings We transplanted 2×104, 2×105, or 2×106 cells from the established rat iPSC line M13 intramyocardially into intact or infarcted hearts of immunocompetent allogeneic rats. Transplant duration was 2, 4, or 6 weeks. Histological examination with hematoxylin-eosin staining confirmed that undifferentiated rat iPSCs could generate heterogeneous tumors in both intracardiac and extracardiac sites. Furthermore, tumor incidence was independent of cell dose, transplant duration, and the presence or absence of myocardial infarction. Conclusions/Significance Our study demonstrates that allogeneic iPSC transplantation in the heart will likely result in in situ tumorigenesis, and that cells leaked from the beating heart are a potential source of tumor spread, underscoring the importance of evaluating the safety of future iPSC therapy for cardiac disease.

Effects of resveratrol on number and activity of endothelial progenitor cells from human peripheral blood.

1 It has been well established that oestrogens can increase the number of endothelial progenitor cells (EPC) by anti‐apoptotic effects. Resveratrol, a polyphenolic phytoalexin extracted from grapes and wine, has been reported to act as an oestrogen receptor agonist. We hypothesize that putative phyto‐oestrogen may promote EPC proliferation and survival in vitro. 2 Endothelial progenitor cells were isolated from human peripheral blood and identified immunocytochemically. Endothelial progenitor cells were incubated with resveratrol (1, 10, 25 and 50 mmol/L) or control for specified times. Cell proliferation, migration and in vitro vasculogenesis were assayed using the 3‐(4,5‐dimethylthiazol‐2‐yl)‐2,5‐diphenyltetra‐zolium bromide (MTT) assay, modified Boyden chamber assay and in vitro vasculogenesis detection, respectively. 3 Resveratrol increased the number of EPC and promoted EPC proliferation, adhesion and migration in a dose‐ and time‐dependent manner. Cell number peaked at 50 mmol/L resveratrol after incubation for 24 h compared with vehicle control (61.3 ± 5.8 vs 112.8 ± 7.2, respectively; P < 0.01). 4 Furthermore, cell cycle analysis showed that 50 mmol/L resveratrol significantly increased the S phase and decreased the G0/G1 phase of EPC. In addition, resveratrol increased vascular endothelial growth factor production and further induced vasculogenesis in vitro. 5 In conclusion, resveratrol significantly induces EPC proliferation, migration and further promotes angiogenesis in vitro.

Mesenchymal stem cell injection ameliorates the inducibility of ventricular arrhythmias after myocardial infarction in rats.

BACKGROUND Mesenchymal stem cell transplantation is a promising new therapy to improve cardiac function after myocardial infarction (MI). The electrophysiological consequences of MSC implantation has not been systematically studied. METHODS We investigated the electrophysiological and arrhythmogenic effects of mesenchymal stem cells (MSCs) therapy in experimental infarction model. Rats were subjected to MI operation by LAD ligation and randomly allocated to receive intramyocardially injection PBS (MI-PBS) or 5 × 10(5) EGFP labeled MSCs (MI-MSCs). Electrophysiological study, histological examination, and western blotting were performed 2 weeks after cell transplantation. RESULTS Programmed electrical stimulation (PES) showed a significant reduced inducible ventricular tachycardias (VTs), raised ventricular fibrillation threshold (VFT) and prolonged ventricular effective refractory period (VERP) in MSC-treated rats compared to PBS-treated animals. MSC implantation led to markedly longer action potential duration (APD) and shorter activation time (AT) in infarcted border zone (IBZ) of left ventricular epicardium compared with PBS-treated hearts. Histological study revealed that fibrotic area and collagen deposition in infarcted region were significantly lower in MI-MSC group than in MI-PBS group. Abnormal alterations of Connexin 43 including reduction and lateralization were significantly attenuated by MSC treatment. CONCLUSIONS This study provide strong evidence that MSC implantation ameliorates interstitial fibrosis and the remodeling of gap junction, attenuates focal heterogeneity of reporlarization and conduction and reduces vulnerability to VTs. The results suggest that MSC transplantation might emerge as a new preventive strategy against VAs besides improving cardiac performance in ischemic heart disease.

Polymorphisms of matrix metalloproteinases in myocardial infarction: a meta-analysis

Context The literature provides no clear answer as to whether matrix metalloproteinases (MMPs) polymorphisms increases risk of myocardial infarction (MI). Objective Our purpose was to help clarify the inconsistent findings of MMPs polymorphisms and MI susceptibility and identify which MMP polymorphism might play an active role in the occurrence of MI. Data Sources Articles were identified by a Medline search and citation tracking. Study Selection Eligible articles were case–control studies of MMPs polymorphisms and MI which met our prespecified criteria. Data extraction Data were independently extracted by two authors according to a predefined protocol. Incongruities were settled by consensus decision. Results and Conclusions 18 potentially eligible articles were identified. In a combined analysis, the 5A allele of the MMP-3 5A/6A polymorphism was associated with MI (OR 1.21, 95% CI 1.01 to 1.46, p=0.04), suggesting its role in plaque rupture. In the subgroup analysis by ethnicity, significantly increased risk was found among East Asians (OR 1.39, 95% CI 1.01 to 1.91, p=0.04), whereas no significant association was detected in Caucasian populations. In addition, there were significant associations of the MMP-9 -1562C→T polymorphism with MI (OR 1.14, 95% CI 1.02 to 1.27, p=0.02), whereas the heterogeneity of the studies showed no significance (I2=13.7%, p=0.32). This meta-analysis demonstrated that the MMP-3 5A/6A and MMP-9 -1562 C→T polymorphisms are risk factors associated with increased MI susceptibility, but these associations vary in different ethnic populations.

Connexin43 promotes survival of mesenchymal stem cells in ischaemic heart

The involvement of connexins in regulating cell growth and death has recently been reported. We have investigated whether Cx43 (connexin43) contributes to MSC (mesenchymal stem cell) survival and improves therapeutic efficacy in MI (myocardial infarction). Genetically modified Cx43 MSCs were exposed to hypoxic conditions or injected intramyocardially into a rat MI model. MSCs overexpressing Cx43, with more Bcl-2 and phosphorylated Akt, but less Bax, were relatively tolerant to hypoxic injury. After transplantation, this Cx43 overexpression enhanced cell survival and reduced infarct size, improving contractile performance. Cx43 inhibition by SiRNA reversed the effects of Cx43 overexpression. Therefore, Cx43 may act as a potential target for improving the therapeutic efficacy of MSCs in ischaemic heart disease.

Erythropoietin enhances the angiogenic potency of autologous bone marrow stromal cells in a rat model of myocardial infarction.

Background: Transplantation of marrow stromal cells (MSC) has been shown to improve heart perfusion and cardiac function after ischemia. Erythropoietin (EPO) is capable of inducing angiogenesis and inhibiting cell apoptosis. The aim of this study was to investigate the effect of EPO on the therapeutic potency of MSC transplantation in a rat model of myocardial infarction. Methods: MSC viability was detected by MTT andflow cytometry following culture in serum-free medium for 24 h with or without EPO. Release of vascular endothelial growth factor (VEGF) by MSC incubated with different doses of EPO was assayed using ELISA. Immediately after coronary ligation, autologous MSC (3 × 106 cells) were injected into the ischemic myocardium (MSC and MSC-EPO groups). EPO (3,000 U/kg body weight) was injected daily for 3 consecutive days starting 1 day prior to ligation. The same EPO dose was also injected for consecutive 3 days starting 15 days after surgery (EPO and MSC-EPO groups). Control animals were injected saline solution for the same time period. Cardiac function was assessed by echocardiography 2 and 21 days after surgery, respectively. Western blot and immunohistological assessments were performed to examine the effects of treatments. Results: In vitro, EPO inhibited MSC apoptosis induced by serum-free medium and increased vascular endothelial growth factor (VEGF) release by MSC. In vivo, cardiac infarct size was significantly smaller, cardiac function significantly improved, and capillary density obviously higher in the MSC and EPO groups than in the control group. Combined treatment with EPO infusion and MSC transplantation demonstrated a further decrease in infarct size, a further improvement in cardiac function, and a further increase in capillary density compared with MSC or EPO alone. Furthermore, a higher ratio of phosphorylated Akt to total Akt was measured by Western blot; Bcl-2 was upregulated and Bax was downregulated by immunohistochemistry in the MSC-EPO group compared to the other three groups. Conclusion: Transplantation of MSC combined with EPO infusion is superior to MSC monotherapy for angiogenesis and cardiac function recovery.