Cees D.J. De Langen

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.

On the role of calcium ions in the presynaptic alpha-receptor mediated inhibition of [3H]noradrenaline release from rat brain cortex synaptosomes.

Rat brain cortex synaptosomes, previously labeled by incubation with [3H]noradrenaline ([3H]NA) were continuously superfused with Krebs-Ringer media. Release of [3H]NA was induced by superfusion with medium containing either 15 mM K+, 20 microM veratrine or 1 microM of the calcium-ionophore A 23187 and was strongly dependent on the concentration of Ca2+ in the medium. Noradrenaline (1 microM, in the presence of the uptake inhibitor desipramine) inhibited K+-induced [3H]NA release by activation of presynaptic alpha-receptors. When the Ca2+-concentration in the medium was reduced, or the Mg2+-concentration increased, [3H]NA release appeared to be more susceptible to alpha-receptor mediated inhibition. Noradrenaline (1 microM) inhibited [3H]NA release induced by 15 mM K+, in the presence of 0.075 Ca2+ and 10 mM Mg2+, by 86%. Veratrine-induced release was also inhibited by alpha-receptor activation. However, [3H]NA release induced by the calcium-ionophore was not affected by alpha-receptor agonists. These results strongly support the view that alpha-receptor activation results in a decrease of the availability of Ca2+ for stimulus-secretion coupling processes. Presumably this is effected by an inhibition of voltage-sensitive calcium channels in the neuronal membrane associated with neurotransmitter release.

CAPTOPRIL REDUCES PURINE LOSS AND REPERFUSION ARRHYTHMIAS IN THE RAT-HEART AFTER CORONARY-ARTERY OCCLUSION

Captopril was perfused through isolated rat hearts; its effects after local ischemia and reperfusion were assessed. Upon reperfusion all untreated (10 out of 10) but only 4 (out of 10) captopril-treated (80 micrograms/ml) hearts fibrillated (P less than 0.02). Purine overflow increased upon reperfusion but was reduced by captopril (597 +/- 62 and 333 +/- 41 nmol/min gdwt respectively; P less than 0.05). The pressure-rate index and the apex displacement were severely impaired after 30 min of reperfusion (32 +/- 16 and 10 +/- 5% respectively of initial values) but captopril reduced the injury of mechanical function (60 +/- 8; P less than 0.05 and 61 +/- 11; P less than 0.05 respectively). These results show that captopril reduces ventricular fibrillation and the loss of high energy phosphate nucleotides and thereby partly maintains mechanical function impaired by ischemia and reperfusion.

Presynaptic noradrenergic α-receptros and modulation of 3H-noradrenaline release from rat brain synaptosomes

The depolarization (15 mM K+)-induced release of 3H-NA from superfused rat brain synaptosomes and the effects of alpha-noradrenergic drugs thereon were studied. Noradrenaline (NA; in the presence of the uptake inhibitor desipramine) reduced synaptosomal 3H-NA release. Reduction of the concentration of calcium ions in the medium during K+ stimulation greatly enhanced the sensitivity of 3H-NA release to alpha-receptor-mediated inhibition. Under these conditions NA dose-dependently inhibited 3H-NA release from synaptosomes obtained from cortex or hypothalamus, but did not affect 3H-NA release from striatal (i.e dopaminergic) synaptosomes. Adrenaline, clonidine and oxymetazoline potently inhibited 3H-NA release from cortex synaptosomes at concentrations in the nanomolar range. Phentolamine by itself did not affect synaptosomal 3H-NA release, but antagonized the inhibitory effects of both noradrenaline and adrenaline. The data obtained further substantiate the hypothesis that the alpha-receptors mediating a local negative feedback control of NA release are localized on the varicosities of central noradrenergic neurons, Furthermore, noradrenergic nerve terminals in the hypothalamus appear to be less senstive to alpha-receptor-mediated presynaptic inhibition than those in the cortex.

EFFECTS OF FLECAINIDE ON THE ATRIAL DEFIBRILLATION THRESHOLD

Abstract Little is known about the effects of antiarrhythmic drugs on the atrial defibrillation threshold in humans. An early study with quinidine 1 showed a significant reduction in number of shocks and a decreased energy requirement to restore sinus rhythm in patients with chronic atrial fibrillation (AF). Quinidine was administered as a loading dose of 1,200 mg in 24 hours before direct current electrical cardioversion. In contrast, Sodermark et al 2 could not show any difference in the atrial defibrillation threshold between patients with chronic AF or atrial flutter treated with quinidine (600 to 800 mg twice daily during 2.5 days) and patients not so treated before direct current electrical cardioversion. Flecainide, a class Ic antiarrhythmic drug, is being used more and more for the treatment of supraventricular tachycardias. Compared with quinidine, flecainide is less effective in the chemical cardioversion of chronic AF or atrial flutter to sinus rhythm. 3 Another difference might stem from the energy required for successful direct current electrical cardioversion in patients using flecainide. Because of the absence of data about the effects of flecainide on the atrial defibrillation threshold, we compared the energy required in patients undergoing direct current electrical cardioversion for chronic AF or atrial flutter with or without intravenously administered flecainide.

Tachycardia induced electrical remodeling of the atria and the autonomic nervous system in goats.

Atrial fibrillation (AF) shortens the atrial effective refractory period (AERP). To investigate the role of the autonomic nervous system during this so‐called electrical remodeling of the atria (ERA) and during recovery from ERA we analyzed heart rate variability (HRV). In 12 goats atrioventricular (300:150 beats/min) pacing was performed for 24 hours, interrupted at 4, 8, 16, and 24 hours for recording of 500 atrial (AA) intervals during sinus rhythm and measurement of the AERP430 ms at 7.4 ± 0.6 sites. After 24 hours, pacing was stopped and the electrophysiological study and recording of the AA intervals was repeated at 4, 8, 16, and 24 hours after cessation of pacing. Time‐ and frequency‐domain parameters were computed from each 500 AA interval recording. After 24 hours of rapid pacing the AERP had shortened significantly (147 ± 5.6 to 102 ± 6.4 ms, P < 0.0001). No significant changes in HRV and dispersion of refractoriness (ΔAERP) (47 ± 7.1 to 44 ± 4.2 ms) were observed. After cessation of pacing, the AERP prolonged again (102 ± 6.4 to 135 ± 8.8 ms, P < 0.0001) and was paralleled by a significant increase in ΔAERP (44 ± 4.2 to 63 ± 7.1 ms, P = 0.01). Furthermore, HRV increased significantly. At each time point an inverse relation between the logarithmically transformed vagal parameter HF (InHF) and AERP was observed. We calculated the mean InHF for each goat using all time points and used the median value to divide the 12 goats into high and low vagal tone groups. We compared the degree of ERA and recovery from ERA for both groups. The AERP shortened 47.4 ± 6.5 versus 43.0 ± 5.0 ms (NS) for goats with high and low vagal tone, respectively. During recovery from ERA the AERP lengthened 23.6 ± 4.0 versus 42.5 ± 1.7 ms (P = 0.001) for goats with high and low vagal tone, respectively. Multivariate regression analysis indicated a short AERP as the single independent determinant of the inducibility of AF during ERA and recovery from ERA (P < 0.0001). During recovery from ERA, the AERP prolonged and vagal tone and ΔAERP increased. A high vagal tone during recovery from ERA was associated with a short AERP and an attenuated recovery of ERA.

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.

Late potentials in a bradycardia-dependent long QT syndrome associated with sudden death during sleep

The purpose of this study was to determine the incidence of late potentials and their relation to QT prolongation in a family with a high incidence of sudden death during sleep at a young age and bradycardia-dependent QT prolongation (n = 9) and to compare the findings with those in consanguineous family members without QT prolongation (n = 13). Six (67%) of the 9 family members with QT prolongation had late potentials on the signal-averaged electrocardiogram (ECG) compared with 1 of the 13 normal subjects (p less than 0.007). Positive predictive accuracy of the signal-averaged ECG for the detection of subjects with QT prolongation was 86%; negative predictive accuracy was 80%. During exercise testing, the QT interval normalized, whereas late potentials did not change significantly. Exercise testing did not reveal the presence of coronary artery disease as a possible cause of late potentials. It is concluded that 1) compared with family members with a normal QT interval, patients with this type of bradycardia-dependent QT prolongation have a high incidence of late potentials; 2) late potentials persist despite normalization of the QT interval at high heart rates, indicating that there is no direct relation between late potentials and QT prolongation; and 3) late potentials are not caused by coronary artery disease in these subjects. Therefore, the detection of late potentials might be a new aid in the detection and risk stratification of patients with the long QT syndrome. Late potentials possibly indicate a substrate for ventricular tachyarrhythmias in this type of bradycardia-dependent QT prolongation.

Effects of streptokinase during acute myocardial infarction on the signal-averaged electrocardiogram and on the frequency of late arrhythmias

Although a number of studies have shown that the incidence of late potentials is lower after thrombolytic therapy, it is not known whether this is paralleled by fewer arrhythmic events during long-term follow-up. In patients with first acute myocardial infarction, filtered QRS duration was significantly shorter when treated with streptokinase (95 +/- 11 ms, n = 53) than when treated with conventional therapy (99 +/- 12 ms, n = 77, p < 0.05). The low-amplitude signal (D40) was shorter after thrombolysis (28 +/- 11 vs 33 +/- 12 ms, p < 0.02). Terminal root-mean-square voltage did not differ significantly (41 +/- 24 vs 35 +/- 23 microV). Irrespective of treatment, late potentials were predictive in the complete group (n = 171) for arrhythmic events during follow-up (13 +/- 6 months, range 6 to 24) (hazard ratio 7.7, p < 0.02, Cox proportional-hazards survival analysis), but treatment (streptokinase vs conventional) did not significantly affect outcome when added to the model. It is concluded that thrombolysis prevents the development of late potentials. However, this study does not confirm the hypothesis that prevention of late potentials leads to a decrease in arrhythmic events.

Effects of psychotropic drugs on the distribution of 3H-dopamine into compartments of rat striatal synaptosomes and on subsequent depolarization-induced 3H-dopamine release

SummaryThe effects of various drugs on the distribution of 3H-dopamine in rat striatal synaptosomes were studied after superfusion with this radiolabelled neurotransmitter. By compartmental analysis of the efflux of radioactivity, drug effects on the total accumulation of 3H-dopamine, on the “bound fraction” and on the rate constant of the efflux of radioactivity from the tissue were determined. Subsequently, the synaptosomes were exposed to 40 mM K+, in order to assess also the effects of these drugs on depolarization-induced 3H-dopamine release.The results show that:1.Reserpine strongly diminished K+-induced 3H-dopamine release and prevented the retention of 3H-dopamine as a bound fraction, confirming that this compartment represents vesicular storage of 3H-dopamine.2.Just like cocaine, the uptake inhibitors nomifensine and benztropine did not affect the distribution of accumulated 3H-dopamine into synaptosomal compartments and had no effect on the fraction of 3H-dopamine released upon K+-depolarization. At relatively high concentrations, in the micromolar range these drugs displayed efflux-enhancing properties.3.Both tyramine and (+)-amphetamine strongly affected the intrasynaptosomal distribution of 3H-dopamine and increased the efflux rate constant of radioactivity. However, in contrast to tyramine, (+)-amphetamine affected the K+-induced 3H-dopamine release to a greater extent than the bound fraction, which suggests a preferential effect of this drug on the releasable 3H-dopamine pool.4.In micromolar concentrations, neuroleptic drugs only weakly inhibited the 3H-dopamine accumulation, but enhanced the rate constant of the efflux of radioactivity, presumably by interfering with vesicular 3H-dopamine storage. It is concluded that with the approach used in the present study, a relable distinction between uptake-inhibiting and releasing effects of drugs can be made.