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.

The trend of change in catheter ablation versus antiarrhythmic drugs for the management of atrial fibrillation over time： a meta-analysis and meta-regression

Objective To evaluate the trend of change in the efficacy and safety of catheter ablation compared with antiarrhythmic drug therapy （ADT） for rhythm control in patients with atrial fibrillation （AF） over time. Methods The online databases PubMed and EMBASE were searched for relevant studies. STATA software （version 12.0） was used to perform the meta-analysis and meta-regression. Results Fifteen randomized controlled trials including 2249 patients with AF were identified. The pooled results showed that catheter ablation was associated with a 52% reduction in the risk of AF recurrence compared with ADT [risk ratio （RR） = 0.48, 95% confidence interval （CI）： 0.40-0.57, I2 = 70.7%）. Subgroup analyses showed that catheter ablation exhibited less efficacy in studies after 2011 compared to studies before 2011 （RR = 0.61, 95% CI： 0.54-0.68, I2 = 9.3% and RR = 0.34, 95% CI： 0.24-0.47, I2 = 69.9%, respectively）, and the safety outcome showed a 1.08-fold higher incidence of adverse events （14.2% vs. 7.3%; RR = 1.08, 95% CI： 1.04-1.13） in studies after 2011. Conclusions Catheter ablation appears to be superior to ADT for rhythm control. However, less efficacy and a higher rate of adverse events were observed in studies after 2011 compared to studies before 2011.

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.

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.

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.

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.