钾通道开放剂与钙拮抗剂对长QT综合征LQT2模型的跨壁复极离散的作用

采用标准玻璃微电极技术 ,以d 索他洛尔 (Ikr阻断剂 )模拟长QT 2型 (LQT2 )模型观察其对犬心室肌细胞动作电位复极 90 %时程 (APD90 )及跨壁复极离散 (TDR)的作用 ,及钾通道开放剂 (吡那地尔 )和钙通道阻断剂 (硝苯地平 )对d 索他洛尔诱发的电生理变化的影响 ,为临床治疗LQT2的药物选择提供理论基础。结果 :d 索他洛尔 (10 0μmol/L)使三层心肌细胞APD90 均增加 ,但以中层心肌 (M)细胞APD90 增加最为显著 ,结果使TDR增加。d 索他洛尔作用于M细胞 ,诱发早期后除极 (EADs)和APD交替变异 ,而心内膜、外膜细胞则未见。吡那地尔 (2～ 6 μmol/L)和硝苯地平 (2～ 10 μmol/L)均呈浓度依赖性地缩短受d 索他洛尔而延长的三层细胞的APD ,以M细胞最为显著 ,因此明显降低TDR ,并且消除d 索他洛尔所产生的EADs及APD交替变异。结论 :对于Ikr缺陷所致的长QT综合征 ,钾通道开放剂和钙通道阻断剂可能有治疗作用。     

Insights into Mechanisms of Antiarrhythmic Drug Action From Experimental Models of Atrial Fibrillation

Antiarrhythmic Drugs in AF. Atrial fibrillation (AF) remains a challenge to medical therapy. Over the past several years, a variety of experimental models of AF have been developed. These have provided insights into mechanisms underlying AF and antiarrhythmic drug action against the arrhythmia. A variety of drugs effective against clinical AK, including flecainide. propafenone, procainamide, and sotalol, have been found to terminate experimental AF, All of these agents appear to act by prolonging the wavelength for atrial reentry at rapid rates, thereby increasing the size and decreasing the number of functional circuits maintaining the arrhythmia. While the ability to terminate AF is determined by refractoriness prolongation at rapid rates, refractoriness prolongation at slow rates (e.g., sinus rhythm) can prevent AF induction by premature beats. Thus, drugs with strong reverse use-dependence (like sotalol) may be much more effective in preventing than in terminating AF. Spacial heterogeneity in refractoriness is an important contributor to AF occurrence in some models, particularly vagal AF, and is reduced by some (but not all) drugs that terminate AF, New insights are being gained into mechanisms of electrical remodeling, which promotes AF maintenance when rapid atrial rates are maintained, such as during AF, This electrical remodeling may be an interesting novel target for therapy of AF, Insights into AF mechanisms obtained in experimental models of AF should help in the development of new and improved therapeutic approaches.     

Sodium pentobarbital reduces transmural dispersion of repolarization and prevents torsades de Pointes in models of acquired and congenital long QT syndrome

INTRODUCTION: Sodium pentobarbital is widely used for anesthesia in experimental studies as well as in clinics, and it is known to prevent the development of torsades de pointes (TdP) in in vivo models of the long QT syndrome (LQTS). METHODS AND RESULTS: This study examines the effects of pentobarbital on transmural dispersion of repolarization (TDR) and induction of TdP in arterially perfused canine left ventricular wedge preparations in which transmembrane action potentials were simultaneously recorded from epicardial, M, and endocardial regions using floating glass microelectrodes together with a transmural ECG. d-Sotalol and ATX-II were used to mimic the LQT2 and LQT3 forms of congenital LQTS. Both d-sotalol (100 micromol/L, n = 6) and ATX-II (20 nmol/L, n = 6) preferentially prolonged the action potential duration (APD90) of the M cell, thus increasing in the QT interval and TDR, and leading to the development of spontaneous and stimulation-induced TdP. In the absence and presence of d-sotalol, pentobarbital (10, 20, and 50 microg/mL) prolonged the APD90 of epicardial and endocardial cells, and, to a lesser extent, that of the M cell, thus prolonging the QT interval but reducing TDR. In the ATX-II model, the effects of pentobarbital on the QT interval and APD90 were biphasic: 10 microg/mL pentobarbital further prolonged APD90 of epicardial and endocardial cells more than that of the M cell; 20 to 50 microg/mL pentobarbital abbreviated the APD90 of epicardial and endocardial cells less than that of the M cell, thus abbreviating the QT interval and markedly reducing TDR. Twenty to 50 microg/mL pentobarbital totally suppressed spontaneous as well as stimulation-induced TdP in both models CONCLUSION: Our data indicate that pentobarbital reduces TDR in control and under conditions of congenital and acquired LQTS, and suggest that this mechanism may contribute to the ability of the anesthetic to prevent the development of spontaneous as well as stimulation-induced TdP under conditions mimicking LQT2, LQT3, and acquired (drug-induced) forms of the LQTS. The data also serve to illustrate that there are circumstances under which QT prolongation may not be arrhythmogenic.     

T wave alternans after sotalol: evidence for increased sensitivity to sotalol after conversion from atrial fibrillation to sinus rhythm

A 64 year old woman with an 11 year history of paroxysmal atrial fibrillation presented to the emergency room because of palpitations that had started two weeks previously. She had used sotalol 80 mg once daily for three years without any episodes of proarrhythmia or other adverse effects. However, she developed pronounced T wave alternans with giant inverted T waves and excessive QT prolongation following sotalol administration one day after conversion from atrial fibrillation to sinus rhythm. This case demonstrates bizarre T wave changes, T wave alternans, and extreme QT prolongation following sotalol administration shortly after conversion from atrial fibrillation to sinus rhythm. In this situation, sotalol administration may be proarrhythmic, because it enhances repolarisation inhomogeneities based on a spatially inhomogeneous distribution of repolarisation controlling ion channels to induce repolarisation abnormalities that may lead to torsade de pointes.

Keywords: T wave alternans; long QT syndrome; torsade de pointes; sotalol; atrial fibrillation     

Effects of intravenous sotalol, aprindine and the combination of sotalol and aprindine on chronic high frequency ventricular arrhythmias in man

The comparative aniiarrhythmic efficacy of three different intravenousdrug regimens was evaluated in 12 symptomatic patients (meanage: 72 years) with chronic high frequency ventricular arrhythmias(mean: 834 PVCs h^–1). In a cross-over study with latinsquare distribution the following drug regimens were administeredintravenously to all patients (a) aprindine 2 mg kg^–1,(b) sotalol 1.5 mg kg^–1, (c) aprindine 1 mg kg^–1& sotalol 0.75 mg kg^–1. The mean percentage of PVCreduction was 41% (P <0.05) for aprindine 2 mg kg^–1;51% (P <0.05) for sotalol 1.5 mg kg^–1 and 72% (P <0.01)for the combined drug therapy (aprindine 1 mg kg^–1 andsotalol 0.75 mg kg^–1). The mean plasma concentration was1371 ng ml^–1 after administration of aprindine 2 mg kg^–1and 1730 ng ml^–1 after infusion of sotalol 1.5 mg kg^–1.After combined drug therapy, mean plasma levels were 942 ngml^–1 for aprindine and 992 ng ml^–1 for sotalol.The different drug regimens were well tolerated in all patientsand no side-effects occurred. Combination therapy consistingof a drug that prolongs action potential duration with an antiarrhythmicagent that has a high affinity for the inactivated channelsmay thus achieve an antiarrhythmic efficacy comparable to singleagent therapy, permitting the use of lower dosages.     

Implementation of an intravenous sotalol initiation protocol: Implications for feasibility,safety, and length of stay

Introduction

Oral sotalol initiation requires a multiple-day, inpatient admission to monitor for QT prolongation during loading. A 1-day intravenous (IV) sotalol loading protocol was approved by the United States Food and Drug Administration in March 2020, but limited data on clinical use and administration currently exists. This study describes implementation of an IV sotalol protocol within an integrated health system, provides initial efficacy and safety outcomes, and examines length of stay (LOS) compared with oral sotalol initiation.

Methods

IV sotalol was administered according to a prespecified initiation protocol to adult patients with refractory atrial or ventricular arrhythmias. Baseline characteristics, safety and feasibility outcomes, and LOS were compared with patients receiving oral sotalol over a similar time period.

Results

From January 2021 to June 2022, a total of 29 patients (average age 66.0 ± 8.6 years, 27.6% women) underwent IV sotalol load and 20 patients (average age 60.4 ± 13.9 years, 65.0% women) underwent oral sotalol load. The load was successfully completed in 22/29 (75.9%) patients receiving IV sotalol and 20/20 (100%) of patients receiving oral sotalol, although 7/20 of the oral sotalol patients (35.0%) required dose reduction. Adverse events interrupting IV sotalol infusion included bradycardia (seven patients, 24.1%) and QT prolongation (three patients, 10.3%). No patients receiving IV or oral sotalol developed sustained ventricular arrhythmias before discharge. LOS for patients completing IV load was 2.6 days shorter (mean 1.0 vs. 3.6, p < .001) compared with LOS with oral load.

Conclusion

IV sotalol loading has a safety profile that is similar to oral sotalol. It significantly shortens hospital LOS, potentially leading to large cost savings.