Antiarrhythmic Efficacy of Neferine Assessed by Programmed Electrical Stimulation in a Canine Model of Electropharmacology

An ishemic ventricular tachyarrhythmias canine model was established in open-chest dogs subjected to programmed electrical stimulation (PES)for 5-8 days after acute myocardial infarction. The electrophysiologic effects of neferine (Nef) and procainamide (PA) were observed in this model. With routine methods of PES,ventricular tachycardia (VT)and ventricular fibrillation (VF) could be reproducibly initiated. Both drugs lengthened the QTc interval (P【0.01) and effective refractory period(ERP)of normal and ischemic ventricular myocardia (NERP and IERP) respectively (P【0.01), decreased the dispersion of ERP in ischemic myocardium and the dispersion of ERP in left ventricle (P【0.01), and increased the diastolic excitability threshold of normal and ischemic ventricular myocardia (P【0.01). The two compounds prevented the PES-induced VT or VF (Nef group P【0.01, PA group P【0.05) and ischemia-induced VF (P【0.05). The results indicated that neferine and procainamide may be effective in preventing the onset of reentrant ventricular tachyarrhythmias after myocardial ischemic damage in dogs.

磷酸羟基喹呱对豚鼠心室肌和家兔窦房结细胞慢反应...

为进一步研究HPQP抗心律失常的机理,本实验采用细胞内固定微电极技术,观察到该药在30μmol/L可降低高钾除极化心肌动作电位APA和V_(max);对V_(max)呈频率依赖性抑制作用;抑制钡诱发的心室肌自发电活动;对家兔窦房结优势起搏细胞的V_(max)和APA均有抑制,延长APD_(50)和APD_(100),降低四相除极斜率。以上结果均表明该药对钙通道有阻滞作用。

Effects of IQ_23 on the Repolarization and Both Components of the Delayed Rectifier Potassium Current in Guinea Pig Ventricular Myocytcs

Using patch clamp whole cell recording techiques, we examined the effects ofIQ_23, a benzyl-isoquinoline derivative with antiarrhythmic activities, on the action potential (AP) andpotassium currents in single guinea pig ventricular myocytes. The results showed that IQ_23 at 10, 30and 100 μmol ·L_-1 slowed the repolarization in AP dose-dependently. The APD_90 were prolonged by15%, 28% and 31% respectively. This effect did not depend on the extracellular Ca^2+. In voltageclamp mode, IQ_23 effectively blocked both the components of the delayed rectifier potassium current(I_k), i.e., I_ks and I_kr. At concentrations of 30 and 100 μmol· L^-1, IQ_23 suppressed I_ks by 21% and 26%and suppressed I_kr by 67% and 86% respectively. But even at 100 μmol·L^-1, IQ_23 had little effect onthe inward rectifier potassium current (I_k1). It is concluded: 1. IQ_23 can dose-dependently prolongAPD in the ventriculas myocytes of guinea pig, the effect does not depend on the extracellular Ca^2+; 2.IQ_23 blocks both I_ks and Ikr in the ventricular myocytes without obvious specificities between them.

Effects of IQ23 on the Repolarization and Both Components of the Delayed Rectifier Potassium Current in Guinea Pig Ventricular Myocytcs

Using patch clamp whole cell recording techiques, we examined the effects ofIQ23, a benzyl-isoquinoline derivative with antiarrhythmic activities, on the action potential （AP） andpotassium currents in single guinea pig ventricular myocytes. The results showed that IQ23 at 10, 30and 100 μmol ·L-1 slowed the repolarization in AP dose-dependently. The APD90 were prolonged by15%, 28% and 31% respectively. This effect did not depend on the extracellular Ca2+. In voltageclamp mode, IQ23 effectively blocked both the components of the delayed rectifier potassium current（Ik）, i.e., Iks and Ikr. At concentrations of 30 and 100 μmol· L-1, IQ23 suppressed Iks by 21% and 26%and suppressed Ikr by 67% and 86% respectively. But even at 100 μmol·L-1, IQ23 had little effect onthe inward rectifier potassium current （Ik1）. It is concluded: 1. IQ23 can dose-dependently prolongAPD in the ventriculas myocytes of guinea pig, the effect does not depend on the extracellular Ca2+; 2.IQ23 blocks both Iks and Ikr in the ventricular myocytes without obvious specificities between them.

Atrial fibrillation in the elderly

This review discusses atrial fibrillation according to the guidelines of Brazilian Society of Cardiac Arrhythmias and the Brazilian Cardiogeriatrics Guidelines. We stress the thromboembolic burden of atrial fibrillation and discuss how to prevent it as well as the best way to conduct cases of atrial fibrillatios in the elderly, reverting the arrhythmia to sinus rhythm, or the option of heart rate control. The new methods to treat atrial fibrillation, such as radiofrequency ablation, new oral direct thrombin inhibitors and Xa factor inhibitors, as well as new antiarrhythmic drugs, are depicted.

Use of antiarrhythmic drugs in elderly patients

Human aging is a global issue with important implications for current and future incidence and prevalence of health conditions and disability. Cardiac arrhythmias, including atrial fibrillation, sudden cardiac death, and bradycardia requiring pacemaker placement, all increase exponentially after the age of 60. It is important to distinguish between the normal, physiological consequences of aging on cardiac electrophysiology and the abnormal, pathological alterations. The age-related cardiac changes include ventricular hypertrophy, senile amyloidosis, cardiac valvular degenerative changes and annular calcification, fibrous infiltration of the conduction system, and loss of natural pacemaker cells and these changes could have a profound effect on the development of arrhythmias. The age-related cardiac electrophysiological changes include up- and down-regulation of specific ion channel expression and intmcellular Ca2＋ overload which promote the development of cardiac arrhythmias. As ion channels are the substrates of antiarrhythmic drugs, it follows that the pharmacokinetics and pharmacodynamics of these drugs will also change with age. Aging alters the absorption, distribution, metabolism, and elimination of antiarrhythmic drugs, so liver and kidney function must be monitored to avoid potential adverse drug effects, and antiarrhythmic dosing may need to be adjusted for age. Elderly patients are also more susceptible to the side effects of many antiarrhytbanics, including bradycardia, orthostatic hypotension, urinary retention, and falls. Moreover, the choice of antiarrhythmic drugs in the elderly patient is frequently complicated by the presence of co-morbid conditions and by polypharmacy, and the astute physician must pay careful attention to potential drug-drug interactions. Finally, it is important to remember that the use of antiarrhythmic drugs in elderly patients must be individualized and tailored to each patient＇s physiology, disease processes, and medication regimen.

Cell and gene therapy for arrhythmias： Repair of cardiac conduction damage

Action potentials generated in the sinoatrial node （SAN） dominate the rhythm and rate of a healthy human heart. Subsequently, these action potentials propagate to the whole heart via its conduction system. Abnormalities of impulse generation and/or propagation in a heart can cause arrhythmias. For example, SAN dysfunction or conduction block of the atrioventricular node can lead to serious bradycardia which is currently treated with an implanted electronic pacemaker. On the other hand, conduction damage may cause reentrant tachyarrhythmias which are primarily treated pharmacologically or by medical device-based therapies, including defibrillation and tissue ablation. However, drug therapies sometimes may not be effective or are associated with serious side effects. Device-based therapies for cardiac arrhythmias, even with well developed technology, still face inadequacies, limitations, hardware complications, and other challenges. Therefore, scientists are actively seeking other alternatives for antiarrhythmic therapy. In particular, cells and genes used for repairing cardiac conduction damage/defect have been investigated in various studies both in vitro and in vivo. Despite the complexities of the excitation and conduction systems of the heart, cell and gene-based strategies provide novel alternatives for treatment or cure of cardiac arrhythmias. This review summarizes some highlights of recent research progress in this field.

Anticoagulation in elderly patients at high risk of atrial fibrillation without documented arrhythmias

Recent studies have suggested that patients with high CHA2DS2VASc-score [Congestive Heart failure, hyperten- sion, Age ≥ 75 years （doubled）, Diabetes, Stroke （doubled）, Vascular disease, Age 65-74 years, Sex category （female sex）] thromboembolic complications occurred irrespective of the presence of atrial fibrillation （AF） and anticoagulant therapy may be initiated irrespective of documented AF.

Reversal of pulmonary vein remodeling after catheter ablation of atrial fibrillation

Background Pulmonary veins （PV） and the atria undergo electrical and structural remodeling in atrial fibrillation （AF）. This study aimed to determine PV and left atrial （LA） reverse remodeling after catheter ablation for AF assessed by chest computed tomography （CT）. Methods PV electrophysiologic studies and catheter ablation were performed in 63 patients （68% male; mean ± SD age： 56 ± 10 years） with symptomatic AF （49% paroxysmal, 51% persistent）. Chest CT was performed before and 3 months after catheter ablation. Results At baseline, patients with persistent AF had a greater LA volume （91 ±29 cm3 vs. 66 ± 27 cm3; P = 0.003） and mean PV ostial area （241 ＋ 43 mm2 vs. 212 ± 47 mm2; P = 0.03） than patients with paroxysmal AF. There was no significant correlation between the effective refractory period and the area of the left superior PV ostium. At 3 months of follow-up after ablation, 48 patients （76%） were AF free on or off antiarrhythmic drugs. There was a significant reduction in LA volume （77 ±31 cm3 to 70 ± 28 cm3; P 〈 0.001） and mean PV ostial area （224 ± 48 mm2 to 182 ± 43 mm2; P 〈 0.001）. Patients with persistent AF had more reduction in LA volume （11.8 ± 12.8 cm3 vs. 4.0 ± 11.2 cm3; P = 0.04） and PV ostial area （62 mm2 vs. 34 mm2; P = 0.04） than those who have paroxysmal AF. The reduction of the averaged PV ostial area was significantly correlated with the reduction of LA volume （r = 0.38, P = 0.03）. Conclusions Catheter ablation of AF improves structural remodeling ofPV ostia and left atrium. This finding is more apparent in patients with persistent AF treated by catheter ablation.

Long-term stroke rates after catheter ablation or antiarrhythmic drug therapy for atrial fibrillation： a meta-analysis of randomized trials

Background Atrial fibrillation （AF） is an independent risk factor for ischemic stroke and is associated with increased risk of death. Randomized studies suggest improved quality of life for patients with AF after successful catheter ablation compared to antiarrhythmic drug therapy. The value of ablation in long-term risk of ischemic stroke, however, has not been assessed. We conducted a meta-analysis to determine whether AF ablation reduces the long-term risk of stroke compared to antiarrhythmic drug therapy in randomized controlled trials. Methods ＆ Results PubMed and the Cochrane Central Register were searched for randomized trials from January 1990 to December 2014 comparing AF catheter ablation to drug therapy. The results are reported as risk differences （RDs） and 95% CI. Thirteen trials were analyzed with 1097 patients treated by catheter ablation and 855 patients received antiarrhythmic drug therapy. Overall, seven patients （0.64%） in the catheter ablation group had ischemic stroke or transient ischemic attacks vs. two patients （0.23%） in the drug therapy group. No difference was shown in the rate of stroke or transient ischemic attack between ablation and drug therapy （RD： 0.003, 95% CI： -0.006 to 0.012, P = 0.470）, and no evidence of heterogeneity was observed （I^2 = 0, P = 0.981）. No potential publication bias was found. There was also no difference in mortality between the two groups （RD： -0.004, 95% CI： -0.014 to 0.006, P = 0.472）. Conclusions This meta-analysis of randomized controlled trials showed similar rates of ischemic stroke or transient ischemic attack and death in AF patients undergoing catheter ablation compared to drug therapy. A larger prospective randomized trial to confirm this finding is warranted.

Effects of allocryptopine on outward potassium current and slow delayed rectifier potassium current in rabbit myocardium

Objective Allocryptopine （ALL） is an effective alkaloid of Corydalis decumbens （Thunb.） Pers. Papaveraceae and has proved to be an- ti-arrhythmic. The purpose of our study is to investigate the effects of ALL on transmural repolarizing ionic ingredients of outward potassium current （Ito） and slow delayed rectifier potassium current （IKs）. Methods The monophasic action potential （MAP） technique was used to record the MAP duration of the epicardium （Epi）, myocardium （M） and endocardium （Endo） of the rabbit heart and the whole cell patch clamp was used to record/to and IKs in cardiomyocytes of Epi, M and Endo layers that were isolated from rabbit ventricles. Results The effects of ALL on MAP of Epi, M and Endo layers were disequilibrium. ALL could effectively reduce the transmural dispersion of repolarization （TDR） in rabbit transmural ventricular wall. ALL decreased the current densities of/to and IKs in a voltage and concentration dependent way and narrowed the repolarizing differences among three layers. The analysis of gating kinetics showed ALL accelerated the channel activation ofIto in M layers and partly inhibit the channel openings of/to in Epi, M and Endo cells. On the other hand, ALL mainly slowed channel deactivation of IKs channel in Epi and Endo layers without affecting its activation. Conclusions Our study gives partially explanation about the mechanisms of tmnsmural inhibition of/to and IKs channels by ALL in rabbit myocardium. These findings provide novel perspective regarding the anti-arrhythmogenesis application of ALL in clinical settings.

Torsades de Pointes Secondary to Excessive Loperamide Use

Abstract： Loperamide is a common, over-the-counter, antidiarrheal medication that has been implicated in cases of ventricular tachycardia. A 32 year-old female patient with a history of opioid abuse and no prior history of cardiovascular disease experienced Torsades de pointes. An electrocardiogram at the time of hospital presentation revealed a prolonged QT interval at 636 msec. Diagnostic evaluation was unremarkable for any underlying cardiovascular pathology. Further investigation revealed the patient had been taking 30-40 loperamide 2 mg tablets oral daily for 2 weeks prior to the onset of Torsades de pointes. At high doses, loperamide may prolong the QT interval through antagonism of the human ether-a-go-go potassium current, thus increasing the risk of ventricular arrhythmias. Clinicians should be cautious with administration of high doses of loperamide to all patients, especially patients at high risk for QT interval prolongation.

Anticonvulsant and hypnotic effects of amiodarone

Amiodarone hydrochloride is a potent anti-arrhythmic agent, known as a multiple ion-channel blocker in the heart. Although it has been detected in the rat brain, there are no data related to its central nervous system （CNS） effects. In this study, we evaluated anticonvulsant and hypnotic effects of amiodarone. Convulsions were induced by phentylenetetrazole （PTZ） （100 mg/kg） or caffeine （300 mg/kg） in mice. In both models, amiodarone prolonged both latency period and time to death, and acted as an anticonvulsant drug. It was found to be more effective in the PTZ model than in the caffeine model; none of the animals treated with 150 mg/kg dose amiodarone had died in the PTZ model. For hypnotic effect, sleeping was induced with pentobarbital （35 mg/kg） in rats. Amiodarone dose-dependently increased the sleeping time （677.7%-725.9%）. In the sleeping test, all rats in 200 mg/kg amiodarone group died. In conclusion, anticonvulsant and hypnotic effects of amiodarone have shown the depressant effects on CNS. These effects may be dependent on its pharmacological properties.

Effects of Lüfukang Capsules (律复康胶囊) on Coronary Artery Ligation-Induced Arrhythmia in Dogs

Objective: To observe the effects of Lüfukang Capsules (律复康胶囊 LFKC) on arrhythmia induced by ligation of coronary artery in dogs. Methods: Thirty dogs were randomly divided into 5 groups, the model group administrated with equal volume of distilled water, the positive control group administrated with Wenxin Granules (稳心颗粒), and the small, medium and large dosage LFKC groups, 6 dogs in each group. Thirty minutes after medication, electrocardiogram was conducted and the time of arrhythmia occurrence, times of ventricular premature beat (VP), and incidence rates of ventricular tachycardia (VT) and ventricular fibrillation (VF) were recorded in the model dogs with arrhythmia induced by ligation of coronary artery. Results: Compared with the model group, the occurrence time of arrhythmia induced by the coronary artery ligation in the medium and large LFKC groups was significantly delayed (20.45±9.10 and 19.92±3.78, respectively, both P<0.05). The frequency of VP in the medium and large LFKC groups was also significantly decreased (8.17±6.62 and 3.83±2.79, respectively, both P<0.01). Conclusion: LFKC has anti-arrhythmic effects for the experimental arrhythmia induced by the ligation of coronary artery in dogs.