Optimal antiarrhythmic drug therapy for electrical storm

Electrical storm, defined as 3 or more separate episodes of ventricular tachycardia or ventricular fibrillation within 24 hours, carries significant morbidity and mortality. These unstable ventricular arrhythmias have been described with a variety of conditions including ischemic heart disease, structural heart disease, and genetic conditions. While implantable cardioverter defibrillator implantation and ablation may be indicated and required, anti- arrhythmic medication remains an important adjunctive therapy for these persons.

Radioimmunoassay of Antiarrhythmic Peptide and Its application

To establish a specific and sensitive radioimmunoassay (RIA) for antiarrhythmic peptide (AAP) and study serum AAP levels in normal Sprague-Dawley rats (NR) and spontaneous hypertension rats (SHR), AAP-bovine serum albumin (BSA) conjugate was prepared by ammonium bicarbonate method. The New Zealand rabbits were immunized by administering intradermally the conjugate. Then the rabbit anti-AAP serum was produced and iodinated AAP was made by Bolton-Hunter method. The RIA for serum AAP was set up and serum AAP levels in NR and SHR were determined. The minimal detectable range of the AAP RIA was (0.45±0.06) μg/L. The affinity constant for antiserum was 1.05×10 9 L/mol, and the rate of cross-reactivity with atrial peptide (AP) and human growth hormone (hGH) were 0.12 % and 0.20 %, respectively. The mean recovery rate of high, medium and low doses was 97.6 %, and the mean coefficients of variation for intra- and interbath-assay were (6.43±0.85) % and (9.62±1.04) %, respectively. The mean levels of AAP in NR with different age (3 months, 8-10 months and 18-20 months) were (1.75±0.13) μg/L, (1.74±0.11) μg/L and (1.79±0.15) μg/L, respectively, while those in SHR with different age (3 months, 8-10 months and 18-20 months) were (2.38±0.35) μg/L, (2.54±0.25) μg/L and (2.83±0.21) μg/L, respectively. The levels of serum AAP showed a positive correlation with blood pressure (r=0.8667, P<0.05). It was indicated that this AAP RIA had high specificity, high accuracy and good reproducibility. The levels of serum AAP had a close relation with blood pressure.

Changes in Phosphorylation of Connexin43 in Rats during Acute Myocardial Hypoxia and Effects of Antiarrhythmic Peptide on the Phosphorylation

In order to confirm the hypothesis that during acute hypoxia, the antiarrhythmic peptide (AAP10) could improve conductance by changing the phosphorylation state of connexin43 (Cx43), isolated perfused rat hearts were randomly divided into three groups: control, hypoxia and AAP10 (n=9 in each group). The change in Cx43 phosphorylation was tested by Western-blot; the distribu- tion of Cx43 was observed by confocal immunofluorescence microscopy. Western-blot analysis re- vealed that the expression of total Cx43 protein was significantly decreased during acute hypoxia, while nonphosphorylated Cx43 (NP-Cx43) was unchanged. AAP10 could increase the expression of total Cx43 protein, but had no effects on the NP-Cx43 protein. Immunofluorescence study showed that during acute hypoxia, both total Cx43 and NP-Cx43 proteins were greatly decreased, while AAP10 only increased the expression of total Cx43 protein, but had no effect of the NP-Cx43 protein expression. These findings suggested that the decrease of intercellular communication may be associ- ated with the reduction of phosphorylated Cx43 (p-Cx43) and translocation of NP-Cx43 from the surface of gap junction into intracellular pools during acute hypoxia. AAP10 can improve intercelluar communication by enhancing phosphorylation of Cx43.

Antiarrhythmic peptide AAP10 prevents ventricular arrhythmia in rabbit LQT2 model

Background and Objective Increased transmural dispersion ofrepolarization (TDR) has been shown to contribute to initiation and maintenance of ventricular arrhythmia in long QT syndromes (LQTS).Intercellular uncoupling through gap junctions is an important mechanism for maintaining TDR in both intact and diseased heart.The present study was to test the hypothesis that improving gap junction communication reduces TDR and prevents ventricular arrhythmia in rabbit LQT2 model.Methods An arterially perfused rabbit left ventricular preparation and E4031 (0.5μmol/L) were used to establish a model of LQT2.Preparations were randomly assigned to control (n=10),AAP-100nmol/L(n=10),AAP-500nM(n=10) groups.Transmural ECG as well as action potentials from both endocardium and epicardium was simultaneously recorded.Results In LQT2 model,presence of 500nmol/L AAP 10 reduced endocardial action potential and TDR and prevented ventricular arrhythmia comparing with the control and AAP 100nmol/ L groups (P【0.05).Conclusions The presence of 500 nmol/L AAP10 reduces TDR and prevents ventricular arrhythmia in rabbit ventricular model of LQT2.This study suggests a possible role of GJs in TDR in rabbit LQT2 model and indicates a new clinical approach to the management of LQTS.

Gate-related receptor hypothesis for sodium-channel blocker antiarrhythmic agents

Sodium-channel blocker is an important class of drugs(Class Ⅰ) used in antiarrhythmictherapy. Its antiarrhythmic effects are mainly due to its capability of blocking cardiac sodiumchannels. Several hypotheses have been offered to explain the mechanisms of action of so-dium-channel blocker, in which the modulated receptor hypothesis (MRH) and guarded re-

Antiarrhythmic drug usage and prostate cancer： a population-based cohort study

Even though the relationship between antiarrhythmic drug usage and subsequent prostate cancer （PCa） risk has recently been highlighted, relevant findings in the previous literature are still inconsistent. In addition, very few studies have attempted to investigate the association between sodium channel blockers or potassium channel blockers for arrhythmia and the subsequent PCa risk. Therefore, this cohort study aimed to find the relationship between antiarrhythmic drug usage and the subsequent PCa risk using a population-based dataset. The data used in this study were derived from the Longitudinal Health Insurance Database 2005, Taiwan, China. We respectively identified 9988 sodium channel blocker users, 3663 potassium channel blocker users, 65 966 beta-blocker users, 23 366 calcium channel blockers users, and 7031 digoxin users as the study cohorts. The matched comparison cohorts （one comparison subject for each antiarrhythmic drug user） were selected from the same dataset. Each patient was tracked for a 5-year period to define those who were subsequently diagnosed with PCa. After adjusting for sociodemographic characteristics, comorbidities, and age, Cox proportional hazard regressions found that the hazard ratio （HR） of subsequent PCa for sodium channel blocker users was 1.12 （95% confidence interval [CI]： 0.84-1.50）, for potassium channel blocker users was 0.89 （95% CI. 0.59-1.34）, for beta-blocker users was 1.08 （95% Ch 0.96-1.22）, for calcium channel blocker users was 1.14 （95% Ch 0.95-1.36）, and for digoxin users was 0.89 （95% Ch 0.67-1.18）, compared to their matched nonusers. We concluded that there were no statistical associations between different types of antiarrhvthmic drug usage and subsequent PCa risk.

Flecainide: Current status and perspectives in arrhythmia management

Flecainide acetate is a class IC antiarrhythmic agent and its clinical efficacy has been confirmed by the results of several clinical trials. Nowadays, flecainide is recommended as one of the first line therapies for pharmacological conversion as well as maintenance of sinus rhythm in patients with atrial fibrillation and/or supraventricular tachycardias. Based on the Cardiac Arrhythmia Suppression Trial study results, flecainide is not recommended in patients with structural heart disease due to high proarrhythmic risk. Recent data support the role of flecainide in preventing ventricular tachyarrhythmias in patients with catecholaminergic polymorphic ventricular tachycardia associated both with ryanodine receptor and calsequestrin mutations. We herein review the current clinical data related to flecainide use in clinical practice and some concerns about its role in the management of patients with coronary artery disease.

Acupuncture for paroxysmal and persistent atrial fibrillation:An effective non-pharmacological tool?

In Traditional Chinese Medicine,stimulation of the Neiguan spot has been utilized to treat palpitations and symptoms related to different cardiovascular diseases.We evaluated whether acupuncture might exert an antiarrhythmic effect on patients with paroxysmal or persistent atrial fibrillation(AF).Two sets of data are reviewed.The first included patients with persistent AF who underwent electrical cardioversion to restore sinus rhythm.The second included patients with symptomatic paroxysmal AF.All subjects had normal ventricular function.Acupuncture treatment consisted of 10 acupuncture sessions on a once a week basis with puncturing of the Neiguan,Shenmen and Xinshu spots.In patients with persistent AF,the recurrence rate after acupuncture treatment was similar to that observed in patients on amiodarone,but significantly smaller than that measured after sham acupuncture treatment or in the absence of any antiarrhythmic drugs.In a small group of patients with paroxysmal AF,acupuncture resulted in a significant reduction in the number and duration of symptomatic AF episodes.In conclusion,we observed that acupuncture of the Neiguan spot was associated with an antiarrhythmic effect,which was evident in patients with both persistent and paroxysmal AF.These preliminary data,observed in 2 small groups of AF patients,need to be validated in a larger population but strongly suggest that acupuncture may be an effective non-invasive and safe antiarrhythmic tool in the management of these patients.

Present concepts in management of atrial fibrillation:From drug therapy to ablation

Atrial fibrillation(AF) management requires knowledge of its pattern of presentation,underlying conditions,and decisions about restoration and maintenance of sinus rhythm,control of the ventricular rate,and antithrombotic therapy.Maintenance of sinus rhythm is a desirable goal in AF patients because the prevention of recurrence may improve cardiac function,relieve symptoms and reduce the likelihood of adverse events.Anti-arrhythmic drug therapy is the first-line treatment for patients with paroxysmal and persistent AF based on current guidelines.However,currently used drugs have limited efficacy and cause cardiac and extracardiac toxicity.Thus,there is a continued need to develop new drugs,device and ablative approaches to rhythm management.Additionally,simpler and safer stroke prevention regimens are needed for AF patients on life-long anticoagulation,including occlusion of the left atrial appendage.The results of the Randomized Evaluation of Long-Term Anticoagulant Therapy study are encouraging in these settings.Knowledge on the pathophysiology of AF is rapidly expanding and identification of focally localized triggers has led to the development of new treatment options for this arrhythmia.Conversely,the clinical decision whether to restore and maintain sinus rhythm or simply control the ventricular rate has remained a matter of intense debate.In the minority of patients in whom AF cannot be adequately managed by pharmacological therapy,the most appropriate type of non-pharmacological therapy must be selected on an individualized basis.Curative treatment of AF with catheter ablation is now a legitimate option for a large number of patients.The evolution of hybrid therapy,in which two or more different strategies are employed in the same patient,may be an effective approach to management of AF.In any case,planning a treatment regimen for AF should include evaluation of the risks inherent in the use of various drugs as well as more invasive strategies.

EFFECTS OF AMIODARONE AND SOME CLASS ⅠAGENTS ON QT DISPERSION

Objective To investigate the elfects of some class Ⅰ antiarrhythmic agents on QT dispersion and compared with those of amiodarone. Methods Group I was composed of 30 cases, they were all treated with class Ⅰ agents. The drugs used include: mexiletine (8 cases), moricizine (9), propafenone (12) and apridine (1). GrouP Ⅱ was composed of other 30 patients, and were all treated with amiodarone. The ddlerences of QT intervals between ECG leads (QTd and QTcd) were measured belore and aler medication. Results Before medication, the QTmax and QTcmax in group Ⅱ were signilicantly longer than those of group Ⅰ, resulting in greater QTd and QTcd in grouP Ⅱ (QTd:66± 14ms vs 31± 16ms, P<0.01; QTcd:71±36ms vs 44± 18ms, P<0.01). Alter medication, QTmax and QTcmax of group Ⅰ were prolonged, leading to the lengthening of QTd (from 31±16ms to 45±17ms, P<0.01) and QTcd (from 44± 18 ms to 58± 21ms, P<0.05), indicating the increase of inhomogeneity of myocardial repolarization after the treatment of class Ⅰ agents. Alter amiodarone treatment, QTmin and QTmax in grouP Ⅱ were both prolonged, with a greater amplitude of QTmin prolongation, resulting in decreased QTd and QTcd in group Ⅱ (QTd /rom 66± 14ms to 36±22ms, P<0.01, QTcd from 71±36ms to 45±27ms, P<0.01). The signifcant dofference of QTd and QTcd between two groups disappeared aler medication. Conclusion The results of the present study may relect the opposite effects of amiodarone and these class Ⅰ agents on myocardial repolarization.

Contemporary therapy of atrial fibrillation

Atrial fibrillation (AF) is estimated that by 2010, approximately 2.6 million people will be affected in USA;by 2050, that number may increase to 10 million patients. Generally, rate control alone is reasonable in some AF patients, especially asymptomatic patients. Restoration and maintenance of sinus rhythm (SR) may be achieved by means of cardioversion, drugs or/ and catheter ablation. Pharmacological therapy can be useful to maintain SR and prevent tachycardia-induced cardiomyopathy. All patients with AF regardless of whether a rhythm or rate control strategy recommend anticoagulant, antiplatelet or both combined therapy for prevention of thromboembolism, except those with lone AF or contraindications. Drug selection should be based upon the absolute risk of stroke, bleeding, the relative risk and benefit for a given patient. Biventricular pacing may overcome many of the adverse hemodynamic effects associated with RV pacing alone. A target individual ectopic foci ablation within the pulmonary vein (PV) has evolved to circumferential electrical isolation of the entire PV musculature. Cavotricuspid isthmus should be considered as first-line therapy for patients with typical atrial flutter. Completely non-fluoroscopic ablation guided by Real-Time Magnetic Resonance Imaging (RTMRI) using a steerable and non-ferromagnetic catheter is a promising novel technology in interventional electrophysiology.

Structural characterization,in vivo toxicity and biological activity of two new pyro-type diterpenoid alkaloids derived from 3-acetylaconitine

Objective:The transformations that occur in diterpenoid alkaloids during the process of sand frying for Chinese herbal medicine preparation have yet to be clarified.This study investigated the structural changes that take place in 3-acetylaconitine during a simulation of heat-processing and evaluated the toxicity and biological activity of the pyrolysis products.Methods:The diterpenoid alkaloid 3-acetylaconitine was heated at 180°C for 15 min to simulate the process of sand frying.The pyrolysis products were separated using column chromatography,and their structures were investigated using high-resolution electrospray ionization mass spectroscopy and nuclear magnetic resonance spectroscopy.Further,in vivo cardiotoxicity and acute toxicity of 3-acetylaconitine and its pyrolysis products were compared,and the aconitine-induced arrhythmia model was employed to evaluate the antiarrhythmic effect of the pyrolysis products.Results:Two new diterpenoid alkaloids,pyroacetylaconitine and 16-epi-pyroacetylaconitine,a pair of epimers at C-16,were isolated.After comparing the structures of these compounds,possible transformation pathways were proposed.Compared with the prototype compound,3-acetylaconitine,the cardiotoxicity and acute toxicity of the heat-transformed products were significantly decreased.In the biological activity assay,the two pyrolysis products exhibited an effective increase in ventricular premature beat latency,a reduction in the occurrence of ventricular tachycardia,as well as an increase in the rate of arrhythmia inhibition,implying strong antiarrhythmic activity.Conclusion:Compared with 3-acetylaconitine,its pyrolysis products displayed lower toxicity and good antiarrhythmic effects;thus,they have potential for being developed into antiarrhythmic medicines.

Effects of Chinese herbs on multiple ion channels in isolated ventricular myocytes

Background Shensong Yangxin （SSYX） is one of the compound recipe of Chinese materia medica. This study was conducted to investigate the effects of SSYX on sodium current （/Na）, L-type calcium current （/Ca.L）, transient outward potassium current （/to）, delayed rectifier current （/K）, and inward rectifier potassium currents （/K1） in isolated ventricular myocytes. Methods Whole cell patch-clamp technique was used to study ion channel currents in enzymatically isolated guinea pig or rat ventricular myocytes. Results SSYX decreased peak Na by （44.84±7.65）% from 27.21±5.35 to 14.88±2..75 pA/pF （n=-5, P〈0.05）. The medicine significantly inhibited the /Ca,L. At concentrations of 0.25, 0.50, and 1.00 g/100 ml, the peak/Ca,L was reduced by （19.22±1.10）%, （44.82±6.50）% and （50.69±5.64）%, respectively （n=5, all P〈0.05）. SSYX lifted the I-V curve of both /Na and /Ca,L without changing the threshold, peak and reversal potentials. At the concentration of 0.5%, the drug blocked the transient component of /to by 50.60% at membrane voltage of 60 mV and negatively shifted the inactive curve and delayed the recovery from channel inactivation. The tail current density of /K was decreased by （30.77±1.11）% （n=5, P〈0.05） at membrane voltage of 50 mV after exposure to the medicine and the time-dependent activity of /K was also inhibited. Similar to the effect on /K, the SSYX inhibited /K1 by 33.10% at the test potential of -100 mV with little effect on reversal potential and the rectification property. Conclusions The experiments revealed that SSYX could block multiple ion channels such as /Na /Ca,L, /k, /to and /K1, which may change the action potential duration and contribute to some of its antiarrhythmic effects.

The effects of paeoniflorin monomer of a Chinese herb on cardiac ion channels

Background Because of the potential proarrhythmic effect of current antiarrhythmic drugs, it is still desirable to find safer antiarrhythmic drugs worldwide. Paeoniflorin is one of the Chinese herb monomers that have different effects on many ion channels. The present study aimed to determine the effects of paeoniflorin on cardiac ion channels.Methods Whole-cell patch-clamp technique was used to record ion channel currents. L-type calcium current （/Ca-L）,inward rectifier potassium current （/K1）, and transient outward potassium current （/to1） were studied in rat ventricular myocytes and sodium current （/Na）, slow delayed rectifier current （/Ks）, and HERG current （/Kr） were investigated in transfected human embryonic kidney 293 cells.Results One hundred μmol/L paeoniflorin reduced the peak /ca-L by 40.29% at the test potential of ±10 mV （from （-9.78±0.52） pA/pF to （-5.84±0.89） pA/pF, n=5, P=0.028）. The steady-state activation curve was shifted to more positive potential in the presence of the drug. The half activation potentials were （-11.22±0.27） mV vs. （-5.95±0.84） mV （n=5,P=0.007）, respectively. However, the steady-state inactivation and the time course of recovery from inactivation were not changed. One hundred μmol/L paeoniflorin completely inhibited the peak /Na and the effect was reversible. Moreover,paeoniflorin inhibited the /K1 by 30.13% at the test potential of -100 mV （from （-25.26±8.21） pA/pF to （-17.65±6.52）pA/pF, n=6, F=0.015） without effects on the reversal potential and the rectification property. By contrast, 100 μmol/L paeoniflorin had no effects on/to1, /Ks or /Kr channels.Conclusions The study demonstrated that paeoniflorin blocked /Ca-L, /Na, and /Kf without affecting /to1, /Ks, or /Kr. The multi-channel block effect may account for its antiarrhythmic effects with less proarrhythmic potential.

Atrial fibrillation in China： a brief review

Atrial fibrillation （AF） is the most common heart .rhythm disturbance encountered in clinical practice.It affects at least ten million Chinese, constituting a major public health epidemic. For the shortness of resource in the initial stage of new China and the chaos during the culture revolution, there was a scarcity of AF data on the Chinese population. However, Chinese physicians had never stopped exploring in this field, which has provided a solid foundation for today＇s flourishing development in the research of AF. This paper aims to review the major achievements in dealing with AF in the past 60 years in China, especially in the latest 15 years.