Klaas J. Bel

Verapamil Reduces Tachycardia-Induced Electrical Remodeling of the Atria

BACKGROUND Prolonged periods of atrial fibrillation or rapid atrial pacing induce shortening of the atrial effective refractory period (AERP), which is thought to be related to the lower success rates of various antifibrillatory treatments when the arrhythmia has lasted for a longer period of time. METHODS AND RESULTS To investigate whether an increase in intracellular calcium could be the stimulus for electrical remodeling, the effects of verapamil on shortening of the AERP in response to 24 hours of rapid atrial pacing (300 bpm) were studied in five chronically instrumented conscious goats during infusion of saline or verapamil. During rapid atrial pacing, the ventricular rate was kept constant by ventricular pacing (150 bpm). The AERP was measured by programmed electrical stimulation at basic cycle lengths of 430, 300, and 200 ms. Verapamil had no effects on the AERP before rapid atrial pacing. However, in the course of 24 hours of rapid atrial pacing, the AERP shortened significantly less (27% to 58%) in the presence of verapamil compared with control (at 430, 300, and 200 ms, P < .001, P < .01, and P < .01, respectively). Also, after cessation of pacing, complete recovery of the AERP during verapamil infusion occurred much sooner than in the control experiments. Despite a significant reduction in electrical remodeling, there was only a minimal reduction in inducibility of atrial fibrillation by verapamil (34% versus 39% in the control experiments, P = .03). CONCLUSIONS Electrical remodeling of the atrium during rapid atrial pacing was significantly attenuated by verapamil. This suggests that electrical remodeling of the atrium is triggered by the high calcium influx during rapid atrial pacing rates.

CONCENTRATION-DEPENDENT PROTECTION BY CAPTOPRIL AGAINST MYOCARDIAL DAMAGE DURING ISCHEMIA AND REPERFUSION IN A CLOSED CHEST PIG MODEL

We previously reported concentration-dependent protection of captopril against ischemia-reperfusion injury in the isolated rat heart. In order to study these effects in vivo, we developed a closed-chest pig model. Reversible occlusion of the left coronary artery was achieved with a PTCA catheter during one hour. Captopril (C) i.v. was given in two different concentrations (0.6 mg/kg/10min + 0.3 mg/kg/2 hr and 6 mg/kg/10 min + 3.0 mg/kg/2 hr) timing the experiments to II and 10 pigs. respectively, versus 12 controls, who received only saline. Due to malignant ventricular arrhythmias, nine pigs died during ischemia. At the end of the reperfusion period of two hours, eight pigs were alive in each group. In the entreated pigs, maximum creatine kinase after two hours of reperfusion was significantly lowered to 6.337 ± 709 U/L in the high dose group versus 8.285 ± 851 U/L in the low dose group and 9.635 ± 1,115 U/L in the saline group. A reduction of local inosine overflow in the coronary sinus was seen. Maximum noradrenaline overtlow after 5 min reperfusion diminished dose-dependently to 695 ± 284 and 3,129 ± 1.728 pg/ml in the C treated groups versus 4.693 ± 2,277 pg/ml in the saline group. Mean arterial blood pressure and cardiac output decreased significantly during ischemia and reperfusion, but no significant differences occurred between the treated and untreated groups. Reperfusion arrhythmias, mainly accelerated idioventricular rhythm disturbances, were comparable among the three groups. We conclude that in vivo administration of C reduces myocardial damage upon reperfusion after one hour of ischemia in a dose-dependent way. It is suggested that direct myocardial effects play an important role in the underlying mechanism.

Digoxin Delays Recovery From Tachycardia-Induced Electrical Remodeling of the Atria

BACKGROUND Atrial fibrillation (AF) induces electrical remodeling, which is thought to be responsible for the low success rate of antiarrhythmic treatment in AF of longer duration. Electrical remodeling seems to be related to tachycardia-induced intracellular calcium overload. Due to its vagomimetic action, digoxin is widely used to control the ventricular rate during AF, but it also increases intracellular calcium. On the basis of these characteristics, we hypothesized that digoxin would aggravate tachycardia-induced electrical remodeling. METHODS AND RESULTS We analyzed the atrial effective refractory period (AERP) at cycle lengths of 430, 300, and 200 ms during 24 hours of rapid atrio/ventricular (300/150 bpm) pacing in 7 chronically instrumented conscious goats treated with digoxin or saline. Digoxin decreased the spontaneous heart rate but had no other effects on baseline electrophysiological characteristics. In addition to a moderate increase in the rate of electrical remodeling during rapid pacing, digoxin significantly delayed the recovery from electrical remodeling after cessation of pacing (at 430, 300, and 200 ms: P=0. 001, P=0.0015, and P=0.007, respectively). This was paralleled by an increased inducibility and duration of AF during digoxin. Multivariate analysis revealed that both a short AERP and treatment with digoxin were independent predictors of inducibility (P=0.001 and P=0.03, respectively) and duration (P=0.001 for both) of AF. CONCLUSIONS Dioxin aggravates tachycardia-induced atrial electrical remodeling and delays recovery from electrical remodeling in the goat, which increases the inducibility and duration of AF.

Protective Effects of Captopril against Ischemia/Reperfusion-Induced Ventricular Arrhythmias in Vitro and in Vivo

The effects of the converting enzyme inhibitor captopril on the susceptibility of the heart to ventricular arrhythmias following ischemia, both in vitro and in vivo, were studied. In isolated rat hearts, captopril, administered either before or at the end of ischemia, reduced ventricular fibrillation upon reperfusion after 15 minutes of local ischemia. Reduction of purine overflow, improvement in contractility, and increase in coronary blood flow occurred concomitantly. In vivo, a closed-chest pig model was used to determine the effects of captopril, administered at the end of ischemia and continued orally, on the susceptibility to ventricular arrhythmias during the chronic phase of myocardial infarction. Myocardial ischemia was induced by 60-minute inflation of a balloon catheter in the left anterior descending coronary artery. Upon reperfusion, an accelerated idioventricular rhythm occurred, both in 10 untreated and in 10 captopril-treated animals. Creatine kinase levels during the reperfusion period were significantly lower after captopril treatment. Two weeks after the short-term experiments, monomorphic ventricular tachycardia could be induced with programmed electrical stimulation in six of eight surviving untreated pigs. In contrast, in none of the six surviving captopril-treated animals was ventricular tachycardia inducible. Thus, early intervention with captopril during the development phase of myocardial infarction may have beneficial effects on the subsequent development of ventricular arrhythmias. Salvage of ischemic myocardium, improvement in ventricular function, beneficial effects on coronary flow, and decreased activity of the sympathetic nervous system may all contribute.

Beneficial effects of bradykinin on porcine ischemic myocardium

SummaryExogenous bradykinin was administered to pigs in which an experimental infarction was evoked by ischemia and reperfusion. Ischemia (45 min) was induced in a closed-chest model with a balloon catheter in the left anterior descending artery, reperfusion by deflating and removing the balloon. The pigs were treated with saline (n = 11) or bradykinin (0.1 mg/kg in 30 min) infusion (n = 10) during the last 15 min of the ischemic period and the first 15 min of reperfusion.During ischemia, heart rate increased in the saline group to 120 ± 9 % of the initial value (p < 0.05) and in the bradykinin group to 155 ± 13 % (p < 0.05). After reperfusion, the rate-pressure product was increased in both groups. The increase of arterial creative kinase levels was significantly less in the bradykinin-treated group. However, the catecholamine and purine levels were increased, as was the plasma renin activity when compared with the saline group.Two weeks after the infarction, six pigs had died in each group. In three out of five surviving saline-treated pigs and one out of four surviving bradykinin-treated pigs, a sustained ventricular tachyarrhythmia was inducible after programmed electrical stimulation.In conclusion, although systemically administered bradykinin caused a temporary increase in myocardial ischemia, it did reduce the (enzymatic indices of) infarct size. Therefore, the beneficial effects, previously found for ACE-inhibitors might at least partially be related to the potentiation of endogenous bradykinin.

Atrial natriuretic peptides during experimental atrial tachycardia: Role of developing tachycardiomyopathy

Introduction: Atrial tachycardia and chronic heart failure (CHF) are associated with elevated levels of atrial natriuretic peptide (ANP) and its amino terminal part NT‐ANP. Chronic high atrial rates may cause CHF due to a rapid ventricular response. The aim of this study was to establish the contribution of elevated atrial rate and of high ventricular rate, resulting in CHF, on ANP and NT‐ANP levels during chronic atrial tachycardia.

Rapid pacing results in changes in atrial but not in ventricular refractoriness

SCHOONDERWOERD, B.A., et al.: Rapid Pacing Results in Changes in Atrial But Not in Ventricular Refractoriness. It is well known that atrial tachycardia causes atrial electrical remodeling, characterized by shortening of atrial effective refractory periods (AERPs) and loss of physiological adaptation of AERP to rate. However, the nature and time course of changes in ventricular effective refractory periods (VERP) caused by rapid rates are to be established. After being instrumented with epicardial electrodes on both atria and both ventricles nine goats were subjected to 1 week of rapid AV pacing with a rate of 240 beats/min and an AV delay of 100 ms. Pacing was only interrupted for measurement of left and right AERPs and VERPs at three basic cycle lengths (BCL) of 400 ms, 300 ms, and 200 ms during sinus rhythm in the conscious animal. Left and right AERPs decreased at all BCLs, reaching minimum values after 3 days (right AERP at BCL of 400 ms, 96 ± 16 ms after 3 days vs 144 ± 16 ms at baseline, P < 0.05). In contrast, both left and right VERPs did not change at any BCL. This study demonstrates a difference between the atria and ventricles with respect to tachycardia induced changes in refractoriness.

Prediction of Lesion Size Through Monitoring the 0°C Isothermic Period Following Transcatheter Cryoablation

A prototype steerable 8.5F bipolar catheter fitted with a feedback thermocouple was tested in 7 anaesthetized pigs (30 kg) guided by the electrocardiogram in order to modify the AV nodal and His-Purkinje system conductive properties. Thermal energy was delivered by a pressurized N2O tank (>650 psi) via a cardiac cryo unit (Spembly, Hampshire, UK) into the catheter wherein gas expands resulting in a tip temperature as low as−70± 2°C within 10 seconds. Cryoablation under fluoroscopic and electrocardiographic guidance was applied at distinct sites in both ventricles for 60 or 120 seconds. After a follow-up period of 6 weeks, the ablation lesions found were well demarcated with small margins of hypertrophy of myocardial cells. With respect to lesion volume variability (8–207 mm3) and geometry, a relationship between the 0°C isothermic period and cryolesion volume was found. Results of an in vitro model corroborated this relationship. Therefore, an isothermic period probably can predict the lesion size and its geometry in terms of lesion depth. This potential therapeutic mode of transcatheter cryoablation deserves further investigation.

Electrophysiological, rate dependent, and autonomic effects of the Class III antiarrhythmic almokalant after myocardial infarction in the pig

Ventricular arrhythmias remain a major problem, in particular in patients with left ventricular dysfunction or heart failure. In this group of patients, Class I drugs were shown to be ineffective, and they even increased mortality during chronic treatment. New antiarrhythmic agents should preferably not only have pure antiarrhythmic effects, but should also be free from adverse autonomic properties. In the present study, the electrophysiological, rate dependent and autonomic effects of intravenously administered almokalant, a new Class III antiarrhythmic drug, were investigated in nine pigs surviving a myocardial infarction. The ventricular effective refractory period (VERP) increased after almokalant (loading dose: 0.05 μmoLkg −1 .min−1, continuous infusion: 0.0025 uμmol/kg−1.min−1) from 292 ± 25 to 308 ± 13 ms (pacing cycle length [PCL] 500 ms + 1 extrasystole [ES]), from 249 ± 19 to 261 ± 16 ms (PCL 400 ms +1ES), and from 209 ± 18 to 219 ± 18ms (PCL 300 ms +1ES). The VERPs increased most after three ES at PCL 400 ms: from 167 ± 27 to 186 ± 29 ms (P < 0.05) and at PCL 300 ms: from 159 ± 29 to 174 ± 27 ms (P < 0.05). The ventricular monophasic action potential durations (MAPD) were similarly prolonged and the ratio VERP/MAPD did not change. Prolongation of MAPD after almokalant remained present at short pacing cycle lengths. Before almokalant infusion, sustained monomorphic ventricular tachycardia (VT) was inducible in two pigs, and nonsustained VT in a third animal. After almokalant, only one pig remained inducible. Two weeks after myocardial infarction, heart rate variability and baroreflex sensitivity were reduced. Furthermore, subsequent electrophysiological testing transiently reduced these parameters of autonomic activity. During almokalant however, no changes in autonomic functions were observed after programmed stimulation. Heart rate variability decreased after myocardial infarction from 6.3 ± 2.5 ms to 5.4 ± 4,2 ms (P = NS}. After programmed stimulation, it further decreased to 2.8 ± 2.0 ms (P = 0.028). Almokalant infusion prevented autonomic deterioration: 3.3 ± 2.2 ms before stimulation and 3.3 ± 1.3 after stimulation (P = NS). In postinfarct pigs, almokalant prolongs VERP and MAPD at shorter pacing cycle lengths. The results indicate absence of reverse rate dependence and of adverse autonomic changes.