Acute conduction recurrence of mitral isthmus: Incidence, clinical characteristics, and implications.

BACKGROUND: Data on the incidence, clinical characteristics, and implications of acute conduction recurrence during mitral isthmus (MI) ablation are scarce. METHODS: MI ablation was performed in patients with atrial fibrillation. After confirming bidirectional conduction block, the acute conduction recurrence of MI was systematically evaluated. Clinical and electrophysiological characteristics were analyzed. RESULTS: A total of 66 consecutive patients in whom bidirectional conduction block of MI was achieved were prospectively enrolled in a single center. Acute conduction recurrence of MI developed in 12 (18.2%) patients within 14.2 ± 11.5 minutes after the confirmation of bidirectional conduction block. There were two recurrent conduction breakthrough sites of MI along the course of the great cardiac vein (4.5 ± 3.5 min) in two patients and 11 along the course of the ligament of Marshall (LOM) (16.0 ± 11.6 min, P = .035) in 11 patients. LOM accounted for most (84.6%, 11/13) acute MI conduction recurrence. MI length, total ablation time, and procedure time for MI were greater in patients with acute conduction recurrence than in those without acute conduction recurrence. During follow-up, arrhythmia recurrences were less observed in patients with acute conduction when compared to patients without acute conduction recurrence (0% vs 26.4%, P = .055). CONCLUSION: Acute conduction recurrence, predominantly due to recurrent LOM conduction, was a common phenomenon during MI ablation, and its evaluation should therefore be the focus to improve MI ablation efficacy and durability.

A Practical Method for Ablation Catheter Reintroduction into the Left Atrium via Prior Transseptal Puncture, without Radiation.

BACKGROUND: We evaluated the feasibility and safety of reintroducing an ablation catheter (ABL) into the left atrium (LA) through a previously punctured interatrial septum under guidance of the show-catheter image-track function of the CARTO 3 3-dimensional (3D) electroanatomic mapping system. METHODS: One hundred consecutive paroxysmal or persistent drug-refractory atrial fibrillation (AF) patients (men: 55; mean age, 64.7 ± 12.1 years) who had undergone 2 fluoroscopy-guided transseptal punctures and anatomical LA reconstruction under CARTO 3-guidance, and required ABL reinsertion into the LA during mapping or ablation, were included. They were randomized 1:1 to the show-catheter (reintroduction under the CARTO 3 show-catheter image-track function) or fluoroscopy group (reintroduction under conventional fluoroscopy). RESULTS: Although the reconstructed 3D anatomy map was displaced in 21/100 patients (21.0%), the ABL was successfully reintroduced in all patients. In the show-catheter and fluoroscopy groups, model displacement incidence (18% versus 24%), tachyarrhythmias (46.0% versus 52.0%), complications (2% versus 4%), and number of ABLs reintroduced into the LA (3.3 ± 0.8 versus 3.1 ± 0.9) were similar (all P > .05). The show-catheter group displayed shorter ABL reintroduction time (9.5 ± 5.5 s versus 156.4 ± 35.5 s, P < .01), ABL reintroduction X-ray exposure time (0 s versus 39.3 ± 13.8 s, P < .01), and total X-ray exposure time (4.1 ± 1.4 min versus 4.7 ± 0.8, P < .05). CONCLUSION: During AF ablation, the catheter can be safely reintroduced into the LA, without additional fluoroscopy, under guidance of the CARTO 3 show-catheter image track function.

ITE inhibits growth of human pulmonary artery endothelial cells.

AIM: Pulmonary arterial hypertension (PAH), a deadly disorder is associated with excessive growth of human pulmonary artery endothelial (HPAECs) and smooth muscle (HPASMCs) cells. Current therapies primarily aim at promoting vasodilation, which only ameliorates clinical symptoms without a cure. 2-(1'H-indole-3'-carbonyl)-thiazole-4-carboxylic acid methyl ester (ITE) is an endogenous aryl hydrocarbon receptor (AhR) ligand, and mediates many cellular function including cell growth. However, the roles of ITE in human lung endothelial cells remain elusive. Herein, we tested a hypothesis that ITE inhibits growth of human pulmonary artery endothelial cells via AhR. MATERIALS AND METHODS: Immunohistochemistry was performed to localize AhR expression in human lung tissues. The crystal violet method and MTT assay were used to determine ITE's effects on growth of HPAECs. The AhR activation in HPAECs was confirmed using Western blotting and RT-qPCR. The role of AhR in ITE-affected proliferation of HPAECs was assessed using siRNA knockdown method followed by the crystal violet method. RESULTS: Immunohistochemistry revealed that AhR was present in human lung tissues, primarily in endothelial and smooth muscle cells of pulmonary veins and arteries, as well as in bronchial and alveolar sac epithelia. We also found that ITE dose- and time-dependently inhibited proliferation of HPAECs with a maximum inhibition of 83% at 20 µM after 6 days of treatment. ITE rapidly decreased AhR protein levels, while it increased mRNA levels of cytochrome P450 (CYP), family 1, member A1 (CYP1A1) and B1 (CYP1B1), indicating activation of the AhR/CYP1A1 and AhR/CYP1B1 pathways in HPAECs. The AhR siRNA significantly suppressed AhR protein expression, whereas it did not significantly alter ITE-inhibited growth of HPAECs. CONCLUSIONS: ITE suppresses growth of HPAECs independent of AhR, suggesting that ITE may play an important role in preventing excessive growth of lung endothelial cells.

[Preliminary study on the efficacy and safety of oral sildenafil in pulmonary arterial hypertension in China].

OBJECTIVE: Sildenafil has been shown to be effective in pulmonary arterial hypertension (PAH). However, the impact of sildenafil on PAH has been under-investigated in China. The aim of the present study was to evaluate the efficacy and safety of oral sildenafil in PAH patients in China. METHODS: In this prospective, open-label and multi-center study, 90 patients were recruited from 14 centers to receive oral sildenafil (75 mg/d) for 12 weeks. They underwent a six-minute walk test (SMWT) and cardiac catheterization at the beginning and the end of 12 weeks. The primary endpoint was the changes in exercise capacity as assessed by SMWT. And the secondary endpoints included assessment of functional class, evaluation of cardiopulmonary hemodynamics and clinical deterioration (defined as death, transplantation and re-hospitalization for PAH). Drug safety and tolerability were also examined. RESULTS: There were 19 males and 71 females with an average age of 32.5 ± 12.1 years old (range: 18 - 61). Their etiologies were idiopathic (n = 15), related with congenital heart disease (n = 60), or related with connective tissue disease (n = 9) and chronic thromboembolic pulmonary hypertension (n = 6). Oral sildenafil significantly increased the SMWT distances [(342 ± 93) m vs. (403 ± 88) m, P < 0.001]. There was also remarkable improvement in Borg dyspnea score (2.9 ± 2.6 vs. 2.4 ± 2.0, P = 0.005). Furthermore, significant improvements in World Healthy Organization (WHO) functional class and cardiopulmonary hemodynamics were also found (mean pulmonary artery pressure, P < 0.001; cardiac index, P < 0.001; pulmonary vascular resistance, P < 0.001). Side effects were mild and consistent with other reports. CONCLUSION: This study confirms and extends previous studies. Oral sildenafil is both safe and effective for the treatment of adult PAH patients in China.

Resting heart rate control and prognosis in coronary artery disease patients with hypertension previously treated with bisoprolol: a sub-group analysis of the BISO-CAD study.

BACKGROUND: Resting heart rate (RHR) is considered as a strong predictor of total mortality and hospitalization due to heart failure in hypertension patients. Bisoprolol fumarate, a second-generation beta-adrenoreceptor blockers (ß-blocker) is commonly prescribed drug to manage hypertension. The present study was to retrospectively evaluate changes in the average RHR and its association with cardiovascular outcomes in bisoprolol-treated coronary artery disease (CAD) patients from the CAD treated with bisoprolol (BISO-CAD) study who had comorbid hypertension. METHODS: We performed ad-hoc analysis for hypertension sub-group of the BISO-CAD study (n = 866), which was a phase IV, multination, multi-center, single-arm, observational study carried out from October 2011 to July 2015 across China, South Korea, and Vietnam. Multivariate regression analysis was used to identify factors associated with incidence of composite cardiac clinical outcome (CCCO), the results were presented as adjusted odds ratio (OR) along with 95% confidence interval (CI) and adjusted P value. RESULTS: A total of 681 patients (mean age: 64.77 ± 10.33 years) with hypertension from BISO-CAD study were included in the analysis. Bisoprolol improved CCCOs in CAD patients with comorbid hypertension, with RHR <65 and <70 beats/min compared with RHR ≥65 and ≥75 beats/min, respectively, in the efficacy analysis (EA) set. In addition, it lowered RHR in both intent-to-treat (ITT) and EA groups after 6, 12, and 18 months of treatment. Further, RHR 70 to 74 beats/min resulted in significantly higher risk of CCCOs EA set of patients (adjusted OR: 4.34; 95% CI: 1.19-15.89; P = 0.03). Also, events of hospitalization due to acute coronary syndrome were higher when RHR 69 to 74 beats/min compared to RHR <69 beats/min in ITT patients. CONCLUSION: Bisoprolol can effectively reduce RHR in Asian CAD patients with comorbid hypertension and hence, improve CCCO without affecting their blood pressure.

Occurrence of composite cardiac endpoints with change in resting heart rate among Chinese patients with coronary artery disease: Chinese cohort from the real-world BISO-CAD study.

OBJECTIVE: We evaluated change in resting heart rate (RHR) and its impact on prognosis in Chinese coronary artery disease (CAD) patients treated with bisoprolol, and also assessed drug safety and tolerability. METHODS: This phase IV, single arm observational study was a sub-study of the BISO-CAD study conducted across 20 hospitals in China between October 2011 and July 2015 with follow-up at 6, 12 and 18 months after baseline. The primary endpoint was occurrence of composite cardiac events. RESULTS: A total of 663 CAD patients (baseline RHR 75.47 ± 6.62 bpm) were enrolled in the intent-to-treat (ITT) set, and 513 patients were included in the efficacy analysis (EA) set. In the ITT set, the risk and the number of composite cardiac events in patients with mean RHR 69-74 bpm were significantly higher than in the <65 bpm group (ITT: estimate 1.03 ± 0.47, p = .029). The incidence of the composite cardiac endpoint was not affected by continuous mean RHR (p = .5070). RHR significantly decreased from baseline to 18 months, most obviously in the first 6 months (p < .0001). Ejection fraction and fractional shortening significantly improved in both the ITT and EA sets. An average RHR of 69-74 bpm had a significant effect on admission to hospital for acute coronary syndrome in the ITT (estimate 1.10, HR 3.004, p = .0196) and EA (estimate 1.26, HR 3.526, p = .0132) groups. Seven (1.1%) patients reported drug related adverse events. CONCLUSION: Reduction in RHR with bisoprolol lowered the incidence of composite cardiac events along with an acceptable safety and tolerability profile.

Transfer of human hepatocyte growth factor reduces inflammation and prevents pulmonary arterial remodeling in monocrotaline-induced.

Inflammation and endothelial dysfunction contribute to the pathogenesis and development of pulmonary arterial hypertension (PAH). This study was to investigate the therapeutic effect of human hepatocyte growth factor (HGF) gene transfer on monocrotaline (MCT) induced PAH rat models. PAH was induced by injecting MCT for 4 weeks. The rats were randomly assigned to phosphate buffered saline control group, MCT group, and HGF treatment group. After 2 weeks of induction, measures of mean pulmonary artery pressure (mPAP), weight ratio of the RV to the LV plus septum, percent wall thickness index (TI) and area index (AI) were significantly increased in MCT-group and HGF treatment-group compared with those in control group (P < 0.05). Those measurements in MCT-group were significantly higher than those in HGF treatment-group (P < 0.05). IL-6 significantly decreased in HGF treatment-group compared with MCT-group, but higher than that of control group (all P < 0.05). IL-10 in HGF treatment-group significantly increased compared with MCT-group, but lower than that of control group (all P < 0.05). Endothelial microparticles (EMP) started to decrease in the HGF treatment-group 3 days after treatment and was most significant after 1 and 2 weeks of treatment (all P < 0.05). Our results showed that transfer of human HGF may attenuate the inflammatory cell infiltrate, reduce the expression of inflammatory factors, and those effects are possibly due to the inhibition of EMP production which may decrease pulmonary vascular wall damage in PAH.

Distinct roles of HIF1A in endothelial adaptations to physiological and ambient oxygen.

Fetoplacental endothelial cells reside under physiological normoxic conditions (∼2-8% O2) in vivo. Under such conditions, cells are believed to sense O2 changes primarily via hypoxia inducible factor 1 α (HIF1A). However, little is known regarding the role of HIF1A in fetoplacental endothelial function under physiological normoxia. We recently reported that physiological chronic normoxia (PCN; 20-25 day, 3% O2) enhanced FGF2- and VEGFA-stimulated proliferation and migration of human umbilical vein endothelial cells (HUVECs) via the MEK/ERK1/2 and PI3K/AKT1 pathways compared to standard cell culture normoxia (SCN; ambient O2: ∼21% O2). Here, we investigated the action of HIF1A in regulating these cellular responses in HUVECs. HIF1A adenovirus infection in SCN-cells increased HIF1A protein expression, enhanced FGF2- and VEGFA-stimulated cell proliferation by 2.4 and 2.0-fold respectively, and promoted VEGFA-stimulated cell migration by 1.4-fold. HIF1A adenovirus infection in SCN-cells did not affect either basal or FGF2- and VEGFA-induced ERK1/2 activation, but it decreased basal AKT1 phosphorylation. Interestingly, HIF1A knockdown in PCN-cells via specific HIF1A siRNA transfection did not alter FGF2- and VEGFA-stimulated cell proliferation and migration, or ERK1/2 activation; however, it inhibited FGF2-induced AKT1 activation by ∼50%. These data indicate that HIF1A differentially regulates cell proliferation and migration, and ERK1/2 and AKT1 activation in PCN- and SCN-HUVECs. These data also suggest that HIF1A critically regulates cell proliferation and migration in SCN-, but not in PCN-HUVECs.

Quercetin attenuates the progression of monocrotaline-induced pulmonary hypertension in rats.

Pulmonary arterial hypertension (PAH) is a progressive disease associated with increased constriction and remodeling of the pulmonary vasculature. Quercetin is a natural flavonoid and has a variety of pharmacological effects including improvement of endothelial cell function. However, its pharmacological effects on pulmonary hypertension have been rarely reported. We sought to observe the protective effect of quercetin in rats with monocrotaline induced PAH. We divided 30 male Sprague-Dawley rats randomly into three groups with ten rats in each group: the monocrotaline group, the quercetin group and the control group. We found that, compared with the controls, the mean pulmonary artery pressure (mPAP) and the right ventricular hypertrophy index in the monocrotaline group were significantly higher (P < 0.01). Quercetin caused a significant reduction both in the mPAP and right ventricular hypertrophy index compared with the monocrotaline group (P < 0.01) while no difference was found between the quercetin group and the control group (P > 0.05). Monocrotaline induced a marked increase in the wall thickness (WT) in small and mid-sized pulmonary arteries compared with the controls (P < 0.01). Monocrotaline also induced a marked increase in the wall area (WA) in small [(56.38±6.65)% in monocrotaline vs. (19.80±4.63)% in control] and mid-sized [(43.71±5.38)% in monocrotaline vs. (14.24±3.66)% in control] pulmonary arteries (P < 0.01). Quercetin treatment markedly reduced monocrotaline induced increase in both WT and WA (P < 0.01), which, however, still remained significantly elevated compared with those of the controls (P < 0.01). Furthermore, compared with controls, proliferating cell nuclear antigen (PCNA) expression in the pulmonary artery tissues was markedly increased by monocrotaline [(45.59±1.27) in monocrotaline vs. (9.64±0.69) in controls], which was significantly attenuated by quercetin. Our animal experiment indicated that quercetin could have protective effects on monocrotaline-induced PAH.

Oral sildenafil therapy for Chinese patients with pulmonary arterial hypertension: a multicenter study.

The impact of sildenafil on pulmonary arterial hypertension (PAH) in Chinese patients has been less investigated. A prospective, open-label, uncontrolled and multicenter study, therefore, was carried out to address this issue. Ninety patients with multicause-induced PAH received oral sildenafil (75 mg/day) for 12 weeks. The 6-minute walk test (SMWT) and cardiac catheterization were performed at the beginning and the end of the 12 weeks. The primary endpoint was the changes in exercise capacity assessed by the SMWT; the secondary endpoint included assessment of functional class, evaluation of cardiopulmonary hemodynamics, and clinical worsening. Drug safety and tolerability were also examined. The results showed that there was a significant improvement in SMWT distances (342 ± 93 m vs 403 ± 88 m, P < .0001), Borg dyspnea score (2.9 ± 2.6 vs 2.4 ± 2.0, P = .0046), World Health Organization functional class, and cardiopulmonary hemodynamics (mean pulmonary artery pressure, P < .0001; cardiac index, P < .0001; pulmonary vascular resistance, P < .0001) after 12 weeks of oral sidenafil therapy. Almost all enrolled patients did not experience significant clinical worsening. This study confirms and extends the findings of previous studies relating to effects of sildenafil on PAH, suggesting that oral sildenafil is safe and effective for the treatment of adult patients with PAH in the Chinese population.

Impact of sildenafil therapy on pulmonary arterial hypertension in adults with congenital heart disease.

BACKGROUND: It has been demonstrated that sildenafil is effective in patients with pulmonary arterial hypertension (PAH). However, the impact of sildenafil on PAH in adults with congenital heart disease (CHD) has been less investigated. OBJECTIVE: In this prospective, open-label, uncontrolled and multicenter study, 60 patients with PAH related to CHD received oral sildenafil (75 mg/day) for 12 weeks. The enrolled patients underwent six-minute walk test (SMWT) and cardiac catheterization at the beginning and the end of the 12 weeks. The primary end point was the changes in exercise capacity assessed by SMWT; the secondary end point included assessment of functional class, evaluation of cardiopulmonary hemodynamics, and clinical worsening (defined as death, transplantation, and rehospitalization for PAH). Drug safety and tolerability were also examined. RESULTS: Oral sidenafil significantly increased SMWT distances (422.94 ± 76.95 m vs. 371.99 ± 78.73 m, P < 0.0001). There was also remarkable improvement in Borg dyspnea score (2.1 ± 1.32 vs. 2.57 ± 1.42, P = 0.0307). Moreover, significant improvements in World Healthy Organization (WHO) functional class and cardiopulmonary hemodynamics were also discovered (mean pulmonary artery pressure, P = 0.0002; cardiac index, P < 0.0001; pulmonary vascular resistance, P < 0.0001). Side effects in this study were mild and consistent with reported studies. None of the enrolled patients experienced significant clinical worsening. CONCLUSIONS: This study confirmed and extended previous studies. It suggested that oral sildenafil was safe and effective for the treatment of adult patients with CHD-related PAH.

[Tanshinone IIA down-regulates the expression of MMP-12 and TF in RAW 264.7 cells].

OBJECTIVE: To investigate the effect of tanshinone IIA (TanIIA) on the expression of tissue factor (TF) and matrix metalloproteinase-12 (MMP-12) in RAW264.7 cells and explore the possible mechanism. METHODS: RAW 264.7 cells were incubated with ox-LDL in the presence or absence of different concentrations of tanshinone IIA. At the end of the incubation, the cell proliferation was assessed by MTT assay, and superoxide dismutase (SOD) activity and malondialdehyde (MDA) and TF concentrations in the supernatant were detected by xanthine oxidase method, thiobarbituric acid method and ELISA, respectively. Western blotting was employed to determine MMP-12 expression in the cells. RESULTS: The cell proliferation was dose-dependently inhibited by TanIIA. SOD activity in the supernatant was increased significantly, while the MDA and TF concentration and MMP-12 expression in cells decreased after treatment of the cells with different concentrations of TanIIA. CONCLUSION: TanIIA inhibits the cell proliferation and TF and MMP-12 expressions in RAW264.7 cells stimulated by ox-LDL, and these effects may be related with the anti-oxidation property of TanIIA.