Flecainide Versus Procainamide in Electrophysiological Study in Patients With Syncope and Wide QRS Duration.

OBJECTIVES: This study sought to compare the differences between procainamide and flecainide to stress the His-Purkinje system during electrophysiological study (EPS) in patients with syncope and bundle branch block (BBB). BACKGROUND: Patients with syncope and BBB are at risk of developing atrioventricular block. EPS is recommended including class I drug challenge to unmask His-Purkinje disease in cases with baseline normal His-ventricular interval. There is little data on differences between different class I drugs. METHODS: This was a prospective study of all consecutive patients undergoing EPS for syncope and BBB at a single center (January 1, 2012 to June 30, 2017). Of those patients with negative baseline EPS, 2 cohorts were compared: group A (historical cohort: procainamide) and group B (flecainide). RESULTS: During the study, 271 patients (age 73.9 ± 12.1 years, 64.9% male, QRS duration: 139.4 ± 13.9 ms) underwent EPS. In 166, baseline EPS was negative and class I drug challenge was performed (90 procainamide, 76 flecainide). The final value and percentage increase in the His-ventricular interval (76 ± 16 ms vs. 64 ± 10 ms and 22.5 ± 6.2% vs. 11.8 ± 5.3%; p < 0.001) and diagnostic yield (14.5% vs. 7.8%, p = 0.04) were higher with flecainide. No differences were found in baseline characteristics. During follow-up (25.8 ± 6.3 months), 39 patients (24.8%) with negative EPS (19.2% with flecainide vs. 30.1% with procainamide: relative risk: 5.1; 95% confidence interval: 2.6 to 10.2; p < 0. 001) received a pacemaker. CONCLUSIONS: Flecainide has a higher diagnostic yield than does procainamide in patients with BBB, syncope, and negative baseline EPS due to a greater increase of the His-ventricular interval. Additionally, there is a lesser need for pacemaker implantation in patients in whom the class I drug test using flecainide was negative.

Therapeutic Effects of Procainamide on Endotoxin-Induced Rhabdomyolysis in Rats.

Overt systemic inflammatory response is a predisposing mechanism for infection-induced skeletal muscle damage and rhabdomyolysis. Aberrant DNA methylation plays a crucial role in the pathophysiology of excessive inflammatory response. The antiarrhythmic drug procainamide is a non-nucleoside inhibitor of DNA methyltransferase 1 (DNMT1) used to alleviate DNA hypermethylation. Therefore, we evaluated the effects of procainamide on the syndromes and complications of rhabdomyolysis rats induced by lipopolysaccharide (LPS). Rhabdomyolysis animal model was established by intravenous infusion of LPS (5 mg/kg) accompanied by procainamide therapy (50 mg/kg). During the experimental period, the changes of hemodynamics, muscle injury index, kidney function, blood gas, blood electrolytes, blood glucose, and plasma interleukin-6 (IL-6) levels were examined. Kidneys and lungs were exercised to analyze superoxide production, neutrophil infiltration, and DNMTs expression. The rats in this model showed similar clinical syndromes and complications of rhabdomyolysis including high levels of plasma creatine kinase, acute kidney injury, hyperkalemia, hypocalcemia, metabolic acidosis, hypotension, tachycardia, and hypoglycemia. The increases of lung DNMT1 expression and plasma IL-6 concentration were also observed in rhabdomyolysis animals induced by LPS. Treatment with procainamide not only inhibited the overexpression of DNMT1 but also diminished the overproduction of IL-6 in rhabdomyolysis rats. In addition, procainamide improved muscle damage, renal dysfunction, electrolytes disturbance, metabolic acidosis, hypotension, and hypoglycemia in the rats with rhabdomyolysis. Moreover, another DNMT inhibitor hydralazine mitigated hypoglycemia, muscle damage, and renal dysfunction in rhabdomyolysis rats. These findings reveal that therapeutic effects of procainamide could be based on the suppression of DNMT1 and pro-inflammatory cytokine in endotoxin-induced rhabdomyolysis.

In vitro electrophysiological drug testing using human embryonic stem cell derived cardiomyocytes.

Pro-arrhythmia (development of cardiac arrhythmias as a pharmacological side effect) has become the single most common cause of the withdrawal or restrictions of previously marketed drugs. The development of new medications, free from these side effects, is hampered by the lack of an in vitro assay for human cardiac tissue. We hypothesized that human embryonic stem cell-derived cardiomyocytes (hESC-CMs) assessed with a combination of single cell electrophysiology and microelectrode array (MEA) mapping can serve as a novel model for electrophysiological drug screening. Current-clamp studies revealed that E-4031 and Sotalol (IKr blockers) significantly increased hESC-CM's action potential duration and also induced after-depolarizations (the in vitro correlates of increased arrhythmogenic potential). Multicellular aggregates of hESC-CMs were then analyzed with the MEA technique. Application of class I (Quinidine, Procaineamide) and class III (Sotalol) antiarrhythmic agents, E-4031, and Cisapride (a noncardiogenic agent known to lengthen QT) resulted in dose-dependent prolongation of the corrected field potential duration (cFPD). We next utilized the MEA technique to also assess pharmacological effects on conduction. Activation maps demonstrated significant conduction slowing following administration of Na channel blockers (Quinidine and Propafenone) and of the gap junction blocker (1-heptanol). While most attention has been focused on the prospects of using hESC-derived cardiomyocytes for regenerative medicine, this study highlights the possible utilization of these unique cells also for cardiac electrophysiological studies, drug screening, and target validation.

The mechanisms of atrial fibrillation.

In this article we have reviewed the mechanisms of atrial fibrillation (AF) with special emphasis on the thoracic veins. Based on a number of features, the thoracic veins are highly arrhythmogenic. The pulmonary vein (PV)-left atrial (LA) junction has discontinuous myocardial fibers separated by fibrotic tissues. The PV muscle sleeve is highly anisotropic. The vein of Marshall (VOM) in humans has multiple small muscle bundles separated by fibrosis and fat. Insulated muscle fibers can promote reentrant excitation, automaticity, and triggered activity. The PV muscle sleeves contain periodic acid-Schiff (PAS)-positive large pale cells that are morphologically reminiscent of Purkinje cells. These special cells could be the sources of focal discharge. Antiarrhythmic drugs have significant effects on PV muscle sleeves both at baseline and during AF. Both class I and III drugs have effects on wavefront traveling from PV to LA and from LA to PV. Separating the thoracic veins and the LA with ablation techniques also prevents PV-LA interaction. By reducing PV-LA interaction, pharmacological therapy and PV isolation reduce the activation rate in PV, intracellular calcium accumulation, and triggered activity. Therefore, thoracic vein isolation is an important technique in AF control. We conclude that thoracic veins are important in the generation and maintenance of AF.

Amelioration of postischemic reperfusion injury by antiarrhythmic drugs in isolated perfused rat lung.

Antiarrhythmic drugs, such as lidocaine, quinidine, and procainamide, have been shown to be effective against postischemic reperfusion injury in isolated rat lungs. Rat lungs were perfused at a constant flow with Krebs-Henseilet buffer supplemented with 4% bovine serum albumin and ventilated with air containing 5% CO2. The lungs were subjected to ischemia by stopping perfusion and ventilation for 60 min followed by 30 min of reperfusion. Lung injury was determined by measuring the increase in wet-to-dry lung weight ratio, while pulmonary arterial pressure and peak airway pressure were calculated from the pre- and postischemic differences. Lidocaine, quinidine, and procainamide at doses of 5, 10, and 20 mg/kg body weight, respectively, were found to attenuate the postischemic lung injury significantly (p < 0.0001). The formation of cyclooxygenase products, which were elevated during reperfusion, was also significantly (p < 0.0001) inhibited by these drugs. Since these antiarrhythmic agents are found to be powerful scavengers of hydroxyl radicals and can prevent membrane lipid peroxidation, these findings suggest that the antioxidant properties of these drugs may, in part, be responsible for protecting the lungs against reperfusion injury.

Schwartz-Jampel syndrome: II. Na+ channel defect causes myotonia.

Skeletal muscle fibers from a patient with Schwartz-Jampel syndrome were studied in vitro. The fibers had normal resting membrane potentials, but their resting [Ca2+]i was elevated. The resting potentials were unstable and spontaneous depolarizations caused twitching in all fibers. Stimulated contractions were characterized by markedly slowed relaxation which was due to electrical after-activity. Neither curare (0.7 microM), tocainide (50 microM), nor phenytoin (80 microM) had an effect on the myotonic activity. In contrast, procainamide (200 microM) suppressed the hyperexcitability without affecting the twitch amplitude. The steady-state current-voltage relation was normal in 5 fibers, but altered in 3 others. These latter fibers had an increased specific membrane resistance owing to a decreased Cl- conductance. The Na+ channels were investigated in the cell-attached patch clamp mode. In all patches on either type of fiber, depolarizing pulses elicited delayed, synchronized openings of Na+ channels. These abnormal openings occurred even after the surface membrane repolarized. We hypothesize that these altered membrane conductances are responsible for the hyperexcitability and the associated slowed relaxation.

[A new anti-arrhythmia drug. II. Comparative studies of the effects of a new acyl derivative of procainamide, procainamide and N-acetylprocainamide on blood pressure and the electrocardiogram in rabbits]. / Nowy lek antyarytmiczny. II. Wplyw nowej N-acylowej pochodnej prokainamidu na cisnienie tetnicze krwi i elektrokardiogram królika w porównaniu z prokainamidem i N-acetyloprokainamidem.

In the recent years a remarkable number of new antiarrhythmic drugs have been introduced, but their side effects limit the application. Procainamide (PA) and N-acetylprocainamide (Acekainide, NAPA) display many undesired side effects, too. It was assumed that N-propionyl-procainamide, having antiarrhythmic activity, might display less unfavourable effects on arterial blood pressure, heart rate and heart conduction system in rabbits, because of blockade of the primary aromatic amine group. The obtained results were subjected to statistical analysis. It has been stated that N-propionylprocainamide decreases the arterial blood pressure in rabbits to a lesser extent than procainamide. Moreover, in contrast with the latter compound, N-propionylprocainamide accelerates the heart rate, but does not influence the atrio-ventricular conduction, and does not prolong the ventricular refraction time. Antiarrhythmic activity of N-propionylprocainamide, not being inferior to that of procainamide and N-acetylprocainamide, and lesser side effects of N-propionylprocainamide indicate for advisability of further studies of this compound.

Comparison of the effects of calcium channel blockers and antiarrhythmic drugs on digitalis-induced oscillatory afterpotentials on canine Purkinje fiber.

We studied the effects of Ca channel blockers and 3 antiarrhythmic drugs on the digitalis-induced oscillatory afterpotential (OAP). The OAP was observed in Purkinje fibers stimulated by pulse trains, with cycle lengths ranging from 1,000 to 300 msec. The Ca channel blockers verapamil, diltiazem and nifedipine (2.0 x 10(-6) M) depressed OAP significantly and abolished triggered activity. Verapamil was more effective than diltiazem. However, nicardipine and nitrendipine (2.0 x 10(-6) M) had no depressant effects on OAP or triggered activity. The antiarrhythmic drugs procainamide (1.0 x 10(-4) M), mexiletine (1.0 x 10(-5) M) and propranolol (1.0 x 10(-4) M) depressed both OAP and triggered activity. There were no significant differences in the depressant effects between the Ca2+ antagonists (except for nitrendipine and nicardipine) and the other antiarrhythmic drugs. The OAP coupling interval was prolonged by verapamil, diltiazem, propranolol, procainamide and mexiletine. Although the APD50 was shortened by verapamil, diltiazem and nifedipine, it was prolonged by propranolol. It is concluded that nifedipine, verapamil, diltiazem, procainamide, mexiletine and propranolol may be effective for digitalis-related arrhythmia.

Relationship between use-dependent effects of antiarrhythmic drugs on conduction and Vmax in canine cardiac Purkinje fibers.

The purpose of these experiments was to evaluate the relationship between interval dependent effects of antiarrhythmic drugs on conduction time and Vmax in canine cardiac Purkinje fibers. Standard microelectrode techniques were used to monitor action potential characteristics at two sites along a canine cardiac false tendon and to measure interelectrode conduction time. The maximum rate of voltage rise during phase 0 (Vmax) and conduction time were independent of diastolic interval under control conditions. In the presence of local anesthetic drugs, recovery from drug-induced depression of Vmax and conduction were first order processes with recovery time constants (mean +/- S.D. in seconds) of 0.14 +/- 0.02 (for Vmax) and 0.15 +/- 0.04 (for conduction time) for lidocaine; 0.17 +/- 0.04 and 0.18 +/- 0.05, respectively, for mexiletine; 0.26 +/- 0.05 and 0.27 +/- 0.07 for amitriptyline; and 1.01 +/- 0.31 and 1.00 +/- 0.32 for procainamide. The kinetics of onset of block were studied using a 30-sec pause, followed by a pacing cycle length of 300 msec (for procainamide) or 1 sec (for quinidine). The onset time constants averaged 2.66 +/- 0.53 pulses (for Vmax) and 2.49 +/- 0.42 pulses (for conduction time) in the presence of procainamide; and 4.02 +/- 1.33 pulses (for Vmax) and 3.86 +/- 1.22 pulses (for conduction time) in the presence of quinidine. These experiments show that local anesthetic drugs produce use dependent changes in conduction time in vitro with time constants comparable to simultaneously measured time constants for effects on Vmax. They imply that the use dependence of drug effects on cardiac conduction can be studied quantitatively in vivo by studying the response to changes in activation frequency.