Peng-Pai Zhang

Overexpression of Sema3a in myocardial infarction border zone decreases vulnerability of ventricular tachycardia post-myocardial infarction in rats.

The expression of the chemorepellent Sema3a is inversely related to sympathetic innervation. We investigated whether overexpression of Sema3a in the myocardial infarction (MI) border zone could attenuate sympathetic hyper‐innervation and decrease the vulnerability to malignant ventricular tachyarrhythmia (VT) in rats. Survived MI rats were randomized to phosphate buffered saline (PBS, n = 12); mock lentivirus (MLV, n = 13) and lentivirus‐mediated overexpression of Sema3a (SLV, n = 13) groups. Sham‐operated rats served as control group (CON, n = 20). Cardiac function and electrophysiological study (PES) were performed at 1 week later. Blood and tissue samples were collected for histological analysis, epinephrine (EPI), growth‐associated factor 43 (GAP43) and tyrosine hydroxylase (TH) measurements. QTc intervals were significantly shorter in SLV group than in PBS and MLV groups (168.6 ± 7.8 vs. 178.1 ± 9.5 and 180.9 ± 8.2 ms, all P < 0.01). Inducibility of VT by PES was significantly lower in the SLV group [30.8% (4/13)] than in PBS [66.7% (8/12)] and MLV [61.5% (8/13)] groups (P < 0.05). mRNA and protein expressions of Sema3a were significantly higher and the protein expression of GAP43 and TH was significantly lower at 7 days after transduction in SLV group compared with PBS, MLV and CON groups. Myocardial EPI in the border zone was also significantly lower in SLV group than in PBS and MLV group (8.73 ± 1.30 vs. 11.94 ± 1.71 and 12.24 ± 1.54 μg/g protein, P < 0.001). Overexpression of Sema3a in MI border zone could reduce the inducibility of ventricular arrhythmias by reducing sympathetic hyper‐reinnervation after infarction.

Resveratrol protects rabbit ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca2+ overload.

Aim:To investigate whether resveratrol suppressed oxidative stress-induced arrhythmogenic activity and Ca2+ overload in ventricular myocytes and to explore the underlying mechanisms.Methods:Hydrogen peroxide (H2O2, 200 μmol/L)) was used to induce oxidative stress in rabbit ventricular myocytes. Cell shortening and calcium transients were simultaneously recorded to detect arrhythmogenic activity and to measure intracellular Ca2+ ([Ca2+]i). Ca2+/calmodulin-dependent protein kinases II (CaMKII) activity was measured using a CaMKII kit or Western blotting analysis. Voltage-activated Na+ and Ca2+ currents were examined using whole-cell recording in myocytes.Results:H2O2 markedly prolonged Ca2+ transient duration (CaTD), and induced early afterdepolarization (EAD)-like and delayed afterdepolarization (DAD)-like arrhythmogenic activity in myocytes paced at 0.16 Hz or 0.5 Hz. Application of resveratrol (30 or 50 μmol/L) dose-dependently suppressed H2O2-induced EAD-like arrhythmogenic activity and attenuated CaTD prolongation. Co-treatment with resveratrol (50 μmol/L) effectively prevented both EAD-like and DAD-like arrhythmogenic activity induced by H2O2. In addition, resveratrol markedly blunted H2O2-induced diastolic [Ca2+]i accumulation and prevented the myocytes from developing hypercontracture. In whole-cell recording studies, H2O2 significantly enhanced the late Na+ current (INa,L) and L-type Ca2+ current (ICa,L) in myocytes, which were dramatically suppressed or prevented by resveratrol. Furthermore, H2O2-induced ROS production and CaMKII activation were significantly prevented by resveratrol.Conclusion:Resveratrol protects ventricular myocytes against oxidative stress-induced arrhythmogenic activity and Ca2+ overload through inhibition of INa,L/ICa,L, reduction of ROS generation, and prevention of CaMKII activation.

Effects of valsartan on ventricular arrhythmia induced by programmed electrical stimulation in rats with myocardial infarction

The impact of angiotensin II receptor blockers (ARBs) on electrical remodelling after myocardial infarction (MI) remains unclear. The purpose of the present study was to evaluate the effect of valsartan on incidence of ventricular arrhythmia induced by programmed electrical stimulation (PES) and potential link to changes of myocardial connexins (Cx) 43 expression and distribution in MI rats. Fifty‐nine rats were randomly divided into three groups: Sham (n = 20), MI (n = 20) and MI + Val (20 mg/kg/day per gavage, n = 19). After eight weeks, the incidence of PES‐induced ventricular tachycardia (VT) and fibrillation (VF) was compared among groups. mRNA and protein expressions of Cx43, angiotensin II type 1 receptor (AT1R) in the LV border zone (BZ) and non‐infarct zone (NIZ) were determined by real‐time PCR and Western blot, respectively. Connexins 43 protein and collagen distribution were examined by immunohistochemistry in BZ and NIZ sections from MI hearts. Valsartan effectively improved the cardiac function, reduced the prolonged QTc (163.7 ± 3.7 msec. versus 177.8 ± 4.5 msec., P < 0.05) after MI and the incidence of VT or VF evoked by PES (21.1% versus 55%, P < 0.05). Angiotensin II type 1 receptor expression was significantly increased in BZ and NIZ sections after MI, which was down‐regulated by valsartan. The mRNA and protein expressions of Cx43 in BZ were significantly reduced after MI and up‐regulated by valsartan. Increased collagen deposition and reduced Cx43 expression in BZ after MI could be partly attenuated by Valsartan. Valsartan reduced the incidence of PES‐induced ventricular arrhythmia, this effect was possibly through modulating the myocardial AT1R and Cx43 expression.

Pharmacogenetics-based warfarin dosing algorithm decreases time to stable anticoagulation and the risk of major hemorrhage: an updated meta-analysis of randomized controlled trials.

Abstract: Warfarin is yet the most widely used oral anticoagulant for thromboembolic diseases, despite the recently emerged novel anticoagulants. However, difficulty in maintaining stable dose within the therapeutic range and subsequent serious adverse effects markedly limited its use in clinical practice. Pharmacogenetics-based warfarin dosing algorithm is a recently emerged strategy to predict the initial and maintaining dose of warfarin. However, whether this algorithm is superior over conventional clinically guided dosing algorithm remains controversial. We made a comparison of pharmacogenetics-based versus clinically guided dosing algorithm by an updated meta-analysis. We searched OVID MEDLINE, EMBASE, and the Cochrane Library for relevant citations. The primary outcome was the percentage of time in therapeutic range. The secondary outcomes were time to stable therapeutic dose and the risks of adverse events including all-cause mortality, thromboembolic events, total bleedings, and major bleedings. Eleven randomized controlled trials with 2639 participants were included. Our pooled estimates indicated that pharmacogenetics-based dosing algorithm did not improve percentage of time in therapeutic range [weighted mean difference, 4.26; 95% confidence interval (CI), −0.50 to 9.01; P = 0.08], but it significantly shortened the time to stable therapeutic dose (weighted mean difference, −8.67; 95% CI, −11.86 to −5.49; P < 0.00001). Additionally, pharmacogenetics-based algorithm significantly reduced the risk of major bleedings (odds ratio, 0.48; 95% CI, 0.23 to 0.98; P = 0.04), but it did not reduce the risks of all-cause mortality, total bleedings, or thromboembolic events. Our results suggest that pharmacogenetics-based warfarin dosing algorithm significantly improves the efficiency of International Normalized Ratio correction and reduces the risk of major hemorrhage.

Semaphorin 3a transfection into the left stellate ganglion reduces susceptibility to ventricular arrhythmias after myocardial infarction in rats.

AIMS Myocardial infarction (MI) induces neural remodelling of the left stellate ganglion (LSG), which may contribute to ischaemia-induced arrhythmias. The neural chemorepellent Semaphorin 3a (Sema3a) has been identified as a negative regulator of sympathetic innervation in the LSG and heart. We previously reported that overexpression of Sema3a in the border zone could reduce the arrhythmogenic effects of cardiac sympathetic hyperinnervation post-MI. This study investigated whether Sema3a overexpression within the LSG confers an antiarrhythmic effect after MI through decreasing extra- and intra-cardiac neural remodelling. METHODS AND RESULTS Sprague-Dawley rats were subjected to MI, and randomly allocated to intra-LSG microinjection of either phosphate-buffered saline (PBS), adenovirus encoding green fluorescent protein (AdGFP), or adenovirus encoding Sema3a (AdSema3a). Sham-operated rats served as controls. Two weeks after infarction, MI-induced nerve sprouting and sympathetic hyperinnervation in the LSG and myocardium were significantly attenuated by intra-LSG injection with AdSema3a, as assessed by immunohistochemistry and western blot analysis of growth-associated protein 43 and tyrosine hydroxylase. This was also confirmed by sympathetic nerve function changes assessed by cardiac norepinephrine content. Additionally, intra-LSG injection with AdSema3a alleviated MI-induced accumulation of dephosphorylated connexin 43 in the infarct border zone. Furthermore, Sema3a overexpression in the LSG reduced the incidence of inducible ventricular tachyarrhythmia by programmed electrical stimulation post-MI, and arrhythmia scores were significantly lower in the AdSema3a group than in the PBS and AdGFP groups. CONCLUSION Semaphorin 3a overexpression in the LSG ameliorates the inducibility of ventricular arrhythmias after MI, mainly through attenuation of neural remodelling within the cardiac-neuraxis.

The crucial role of activin A/ALK4 pathway in the pathogenesis of Ang-II-induced atrial fibrosis and vulnerability to atrial fibrillation

AbstractsAtrial fibrosis, the hallmark of structural remodeling associated with atrial fibrillation (AF), is characterized by abnormal proliferation of atrial fibroblasts and excessive deposition of extracellular matrix. Transforming growth factor-β1 (TGF-β1)/activin receptor-like kinase 5 (ALK5)/Smad2/3/4 pathway has been reported to be involved in the process. Recent studies have implicated both activin A and its specific downstream component activin receptor-like kinase 4 (ALK4) in stimulating fibrosis in non-cardiac organs. We recently reported that ALK4 haplodeficiency attenuated the pressure overload- and myocardial infarction-induced ventricular fibrosis. However, the role of activin A/ALK4 in the pathogenesis of atrial fibrosis and vulnerability to AF remains unknown. Our study provided experimental and clinical evidence for the involvement of activin A and ALK4 in the pathophysiology of atrial fibrosis and AF. Patients with AF had higher activin A and ALK4 expression in atriums as compared to individuals devoid of AF. After angiotensin-II (Ang-II) stimulation which mimicked atrial fibrosis progression, ALK4-deficient mice showed lower expression of ALK4 in atriums, reduced activation of atrial fibroblasts, blunted atrial enlargement and atrial fibrosis, and further reduced AF vulnerability upon right atrial electrophysiological studies as compared to wild-type littermates. Moreover, we found that apart from the well-known TGF-β1/ALK5 pathway, the activation of activin A/ALK4/smad2/3 pathway played an important role in the pathogenesis of Ang-II-mediated atrial fibrosis and inducibility of AF, suggesting that targeting ALK4 might be a potential therapy for atrial fibrosis and AF.

Clinical Features of Post Cardiac Injury Syndrome Following Catheter Ablation of Arrhythmias: Systematic Review and Additional Cases

BACKGROUND Post cardiac injury syndrome (PCIS) is a troublesome but not uncommon complication following catheter ablation of arrhythmias. We aimed to study the clinical features of ablation-associated PCIS. METHODS For this purpose, we conducted a computerised literature search that identified 19 published cases, and we additionally included another 2 new cases from our centres. Twenty-one cases of PCIS following ablation were analysed. RESULTS Among the 21 cases, PCIS most commonly occurred after atrial flutter/fibrillation (AFL/AF) ablation (71.4%), followed by atrioventricular re-entrant tachycardia (AVRT) ablation (9.5%), atrioventricular node (AVN) ablation (9.5%), atrioventricular nodal re-entrant tachycardia (AVNRT) ablation (4.8%) and ventricular tachycardia (VT) ablation (4.8%). Thirty-eight per cent of PCIS was suggested to be secondary to cardiac perforation. Specific symptoms or features include pleuritic chest pain (76.2%), fever (76.2%), elevated markers of inflammation (76.2%), pericardial effusion (90.5%), pleural effusion (71.4%) and pulmonary infiltrates (28.6%). Interestingly, all the six cases with pulmonary infiltrates were following AFL/AF ablation (6/15, 40%). Serious clinical manifestations include cardiac tamponade, massive pleural effusion with hypoalbuminaemia and hyponatraemia, and massive pulmonary infiltrates with hypoxaemia. Notably, empiric antibiotic therapy was used in seven cases including five with pulmonary infiltrates but failed to work. No mortality occurred during a mean follow-up of 4.1±5.3 (1 to 19) months. CONCLUSIONS Catheter ablation of AFL/AF was most commonly involved in ablation-associated PCIS. Pulmonary infiltrate is an important feature of PCIS following AFL/AF ablation and may be misdiagnosed as pneumonia. Although PCIS is troublesome and even dangerous, it does carry a benign prognosis.

Successful retrieval of a broken circular mapping catheter after entrapment in the tricuspid valve apparatus

Introduction Invasive electrophysiology study and catheter ablation are relatively safe procedures with only rare complications. A circular mapping catheter is commonly used to localize abnormal foci within the atria and thoracic vein. Entrapment of the circular mapping catheter in the mitral valve (MV) apparatus has been reported previously by Wu et al, who noted serious complications following the catheter retrieval procedure. In the present case, the circular catheter was inadvertently mispositioned into the right ventricle, entrapped, and broken in the tricuspid valve (TV) apparatus during the mapping of premature atrial complexes (PACs) from the right atrium (RA) in a patient with frequent episodes of palpitation who underwent a cardiac electrophysiology study (EPS) and eventually catheter ablation. In the present case report, we describe the successful retrieval of the fragment by a percutaneous transfemoral venous approach.

Adenosine Sensitivity is Associated with Ablation Success Rate and Recurrence Rate with Nonirrigated Catheters in Patients with Ventricular Premature Contractions/Tachycardia from the Ventricular Outflow Tract

Background: A high ablation success rate for ventricular arrhythmia (VA) from outflow tract has been achieved, but some of them cannot be eliminated from endocardium. We investigated the association between adenosine sensitivity and ablation success/recurrence rates with a nonirrigated or an irrigated catheter. Methods: According to adenosine test, all patients were divided into a sensitive group (S group) or an insensitive group (I group). The patients of each group were randomized into a nonirrigated catheter (NA) subgroup or an irrigated catheter (IA) subgroup with a 2:1 ratio. Results: In S group of 122 patients (84 in NA subgroup), the ablation success rate was similar between two subgroups (94.7% vs. 90.5%, P > 0.05), but in I group of 94 patients (60 in NA subgroup), it was higher in IA subgroup (94.1%) than that in NA subgroup (73.3%, P < 0.05). The success rate using nonirrigated catheter was significantly higher in S group (90.5%) than that in I group (73.3%, P < 0.01), and the recurrence rate was lower in S group than that in I group (1.3%, vs. 13.6%, P < 0.05). On the contrary, the success rate and the recurrence rate using irrigated catheter were similar between S group and I group (94.7%, 94.1%, P > 0.05, vs. 2.8%, 6.3%, P > 0.05). Conclusions: Adenosine insensitivity is associated with a lower success rate and a higher recurrence rate for VA patients undergoing nonirrigated catheter ablation. Thus, irrigated catheters should be the first choice for VA ablation in adenosine insensitive patients.

Acute impact of pacing at different cardiac sites on left ventricular rotation and twist in dogs.

Objectives We evaluated the acute impact of different cardiac pacing sites on two-dimensional speckle-tracking echocardiography (STE) derived left ventricular (LV) rotation and twist in healthy dogs. Methods Twelve dogs were used in this study. The steerable pacing electrodes were positioned into right heart through the superior or inferior vena cava, into LV through aorta across the aortic valve. The steerable pacing electrodes were positioned individually in the right atrium (RA), right ventricular apex (RVA), RV outflow tract (RVOT), His bundle (HB), LV apex (LVA) and LV high septum (LVS), individual pacing mode was applied at 10 minutes interval for at least 5 minutes from each position under fluoroscopy and ultrasound guidance and at stabilized hemodynamic conditions. LV short-axis images at the apical and basal levels were obtained during sinus rhythm and pacing. Offline STE analysis was performed. Rotation, twist, time to peak rotation (TPR), time to peak twist (TPT), and apical-basal rotation delay (rotational synchronization index, RSI) values were compared at various conditions. LV pressure was monitored simultaneously. Results Anesthetic death occurred in 1 dog, and another dog was excluded because of bad imaging quality. Data from 10 dogs were analyzed. RVA, RVOT, HB, LVA, LVS, RARV (RA+RVA) pacing resulted in significantly reduced apical and basal rotation and twist, significantly prolonged apical TPR, TPT and RSI compared to pre-pacing and RA pacing (all P<0.05). The apical and basal rotation and twist values were significantly higher during HB pacing than during pacing at ventricular sites (all P<0.05, except basal rotation at RVA pacing). The apical TPR during HB pacing was significantly shorter than during RVOT and RVA pacing (both P<0.05). The LV end systolic pressure (LVESP) was significantly lower during ventricular pacing than during pre-pacing and RA pacing. Conclusions Our results show that RA and HB pacing results in less acute reduction on LV twist, rotation and LVESP compared to ventricular pacing.