Losartan decreased premature ventricular contractions in patients with hypertension.

Losartan, enalapril and amlodipine reduced the number of premature ventricular contractions (PVCs) in patients with essential hypertension as well as blood pressure. The effect of losartan was the most prominent among the three drugs.

Atrial fibrillation threshold predicted long-term efficacy of pharmacological treatment of patients without structural heart disease.

AIMS: To ascertain if an electrophysiological study could predict long-term efficacy of anti-arrhythmic drugs in the treatment of lone atrial fibrillation. METHODS AND RESULTS: Forty-four patients (36 males, 8 females, age 55.5 +/- 10.6) with paroxysmal atrial fibrillation were enrolled to undergo serial electrophysiological studies at the bedside. Two quadripolar catheters were inserted via the subclavian vein. Disopyramide (D: 2 mg/kg iv), cibenzoline (C: 1.4 mg/kg iv), aprindine (A: 2 mg/kg iv), pilsicainide (P: 2 mg/kg po) and flecainide (F: 3 mg/kg po) were tested. Atrial fibrillation threshold (AFT) was measured as the lowest current amplitude of rapid pacing (50 Hz for 1 s) to induce atrial fibrillation lasting more than 30 s. Before drug treatment, AFT was 3.9 +/- 0.3 mA. Pharmacological treatment raised AFT as follows: D 5.9 +/- 0.9 mA, C 7.6 +/- 1.2 mA, A 8.1 +/-1.1 mA, P 6.0 +/- 0.8 mA, F 7.3 +/- 1.1 mA. Recurrence of atrial fibrillation was observed during 1-year follow-up in 12% of cases when they were treated with a drug that raised AFT by 5 mA or more. On the other hand, the recurrence rate was 87% when patients were treated with a drug that raised AFT by less than 5 mA (P = 0.001). CONCLUSION: AFT was a good predictor of long-term efficacy of pharmacological treatment against atrial fibrillation.

Clinical significance of the atrial fibrillation threshold in patients with paroxysmal atrial fibrillation.

AF threshold and the other electrophysiological parameters were measured to quantify atrial vulnerability in patients with paroxysmal atrial fibrillation (PAF, n = 47), and those without AF (non-PAF, n = 25). Stimulations were delivered at the right atrial appendage with a basic cycle length of 500 ms. The PAF group had a significantly larger percentage of maximum atrial fragmentation (%MAF, non-PAF: mean +/- SD = 149 +/- 19%, PAF: 166 +/- 26%, P = 0.009), fragmented atrial activity zone (FAZ, non-PAF: median 0 ms, interquartile range 0-20 ms, PAF: 20 ms, 10-40 ms, P = 0.008). Atrial fibrillation threshold (AF threshold, non-PAF: median 11 mA, interquartile range 6-21 mA, PAF: 5 mA, 3-6 mA, P < 0.001) was smaller in the PAF group than in the non-PAF group. Sensitivity, specificity, and positive predictive value of electrophysiological parameters were as follows, respectively: %MAF (cut off at 150%, 78%, 52%, 76%), FAZ (cut off at 20 ms, 47%, 84%, 85%), AF threshold (cut off at 10 mA, 94%, 60%, 81%). There were no statistically significant differences between the non-PAF and PAF groups in the other parameters (effective refractory period, interatrial conduction time, maximum conduction delay, conduction delay zone, repetitive atrial firing zone, wavelength index), that were not specific for PAF. In conclusion, the AF threshold could be a useful indicator to evaluate atrial vulnerability in patients with AF.

Transient complete atrioventricular block during catheter ablation of left free wall bypass tract.

Radiofrequency catheter ablation of accessory bypass tracts associated with the Wolff-Parkinson-White (WPW) syndrome has become an accepted and widespread therapy. When bypass tracts are located in the free wall of the left ventricle, complete atrioventricular (AV) block is an unusual complication. Two cases of symptomatic WPW syndrome with transient complete atrioventricular block during catheter ablation are described. The first case was a 14-year-old female with an accessory pathway located in the left posterior wall, and the second was a 72-year-old female with an accessory pathway located in the left lateral wall. Radiofrequency energy application resulted in transient complete AV block with escape rhythm. In the first case, AV conduction with left bundle branch block resumed the next day, whereas in the second case, AV conduction soon resumed with prolongation of atrio-His (AH) interval and no evidence of pre-excitation. This phenomenon could have been due to either trauma to the AV node during catheter entry into the left ventricle or compression of the AV node with a catheter shaft during ablation because both patients' hearts were comparatively small.

Cytokine-induced nitric oxide production inhibits mitochondrial energy production and impairs contractile function in rat cardiac myocytes.

OBJECTIVES: The present study examined whether nitric oxide (NO) produced by inducible nitric oxide synthase (iNOS) can directly inhibit aerobic energy metabolism and impair cell function in interleukin (IL)-1beta,-stimulated cardiac myocytes. BACKGROUND: Recent reports have indicated that excessive production of NO induced by cytokines can disrupt cellular energy balance through the inhibition of mitochondrial respiration in a variety of cells. However, it is still largely uncertain whether the NO-induced energy depletion affects myocardial contractility. METHODS: Primary cultures of rat neonatal cardiac myocytes were prepared, and NO2-/NO3- (NOx) in the culture media was measured using Griess reagent. RESULTS: Treatment with IL-1beta (10 ng/ml) increased myocyte production of NOx in a time-dependent manner. The myocytes showed a concomitant significant increase in glucose consumption, a marked increase in lactate production, and a significant decrease in cellular ATP (adenosine 5'-triphosphate). These metabolic changes were blocked by co-incubation with N(G)-monomethyl-L-arginine (L-NMMA), an inhibitor of NO synthesis. Sodium nitroprusside (SNP), a NO donor, induced similar metabolic changes in a dose-dependent manner, but 8-bromo-cyclic guanosine 3',5'-monophosphate (8-bromo-cGMP), a cGMP donor, had no effect on these parameters. The activities of the mitochondrial iron-sulfur enzymes, NADH-CoQreductase and succinate-CoQreductase, but not oligomycin-sensitive ATPase, were significantly inhibited in the IL-1beta, or SNP-treated myocytes. Both IL-1beta and SNP significantly elevated maximum diastolic potential, reduced peak calcium current (I(Ca)), and lowered contractility in the myocytes. KT5823, an inhibitor of cGMP-dependent protein kinase, did not block the electrophysiological and contractility effects. CONCLUSIONS: These data suggest that IL-1beta-induced NO production in cardiac myocytes lowers energy production and myocardial contractility through a direct attack on the mitochondria, rather than through cGMP-mediated pathways.

Successful catheter ablation against ventricular tachycardia associated with myotonic dystrophy.

Myotonic dystrophy (MD) is characterized by myotonia and muscular dystrophy and cardiac involvement with tachy-arrhythmia is rarely encountered. We report a case of MD complicated with severe left ventricular hypofunction and incessant ventricular tachycardia (VT) with varying heart rates. The morphology of VT suggested that it originated from the right ventricular outflow tract, and electrophysiological study disclosed that the mechanism of VT was abnormal automaticity. Catheter ablation was performed to treat this VT. The patient had a cardiomyopathy with normal coronary arteries. The specimen of RV biopsy showed moderate hypertrophy, mild fat infiltration and slight fibrosis. These findings are histologically consistent with myotonic dystrophy.

SD3212, a new antiarrhythmic drug, raises atrial fibrillation threshold in isolated rabbit hearts.

SD3212 is a new antiarrhythmic drug which has class I, III, and IV effects. The purpose of this study was to elucidate the electrophysiological effects of this compound on a rabbit atrial fibrillation model, and to test a hypothesis that atrial fibrillation threshold is a quantitative indicator of atrial vulnerability. Whole hearts were excised from rabbits, and the aortas cannulated to perfuse the coronary arteries. Atrial fibrillation was induced with a burst stimulation of 50 Hz for 1 s while 3 microM acetylcholine (ACh) was perfused. When the right atrial appendage was paced at 200-ms intervals, SD3212 prolonged interatrial conduction time: control 30 +/- 1.2 ms, ACh 33 +/- 1.4 ms, ACh + SD 1 microM 37 +/- 2.4 ms, ACh + SD 3 microM 52 +/- 8.1 ms. The drug also prolonged the effective refractory period: control 80 +/-3.0 ms, ACh 48 +/- 3.8 ms, ACh + SD 1 microM 65 +/- 4.7 ms, ACh + SD 3 microM 98 +/- 15 ms. The rate of induction of atrial fibrillation by rapid pacing was 26% in Tyrode's solution, 85% in the presence of ACh, and 38% in the presence of ACh + SD 1 microM. The atrial fibrillation threshold decreased from 8.6 +/- 0.8mA (control) to 2.5 +/- 0.7 mA in the presence of ACh. It increased again to 7.8 +/- 1.0 mA in the presence of SD3212 (1 microM). SD3212 prolonged both the conduction time and refractory period. A reversed use-dependency was not prominent. These features caused antifibrillatory effects. Thus, the atrial fibrillation threshold seems to be a good quantitative indicator of atrial vulnerability.

Improved cardiac function after catheter ablation in a patient with type B Wolff-Parkinson-White syndrome with an old myocardial infarction.

A 67-year-old man was admitted to hospital for the treatment of exertional dyspnea. He suffered from congestive heart failure due to an old inferior myocardial infarction with type B Wolff-Parkinson-White syndrome. Asynchronous wall motion caused by pre-excitation through a right-side bypass tract caused his cardiac function to deteriorate. Catheter ablation of the bypass tract increased the ejection fraction, and improved his symptoms, prior to surgical revascularization.

Biphasic effects of intrapipette cyclic guanosine monophosphate on L-type calcium current and contraction of guinea pig ventricular myocytes.

The effects of intracellular cyclic guanosine monophosphate (cGMP) on L-type calcium current (lCa) and contraction of ventricular myocytes enzymatically isolated from guinea pig hearts were investigated to test the hypothesis that cGMP increases contractions along with ICa in these cells. ICa and contractions, elicited every 15 sec, were recorded simultaneously with a whole-cell voltage-clamp method and a video edge-detector, respectively. Cells were superfused with Tyrode's solution (22 degrees C); the pipette solution contained 120 mM potassium aspartate, 30 mM KCl, 4 mM ATP, 5 mM N-(2-hydroxyethyl)piperazine-N-(2-ethanesulfonic acid), 0.01 mM ethylene glycol bis(beta-aminoethyl ether)-N,N,N',N'-tetraacetic acid and various concentrations of cGMP, which entered the cell interior through the patch electrode. In the presence of 3 nM isoproterenol (ISO) in the bath, ICa was increased 3.2-fold. ICa was further increased by 20% with 30 microM cGMP; cell contractions were also increased by 32%. When ICa was maximal in the presence of 30 nM ISO, cGMP no longer increased ICa or contractions, an indication that the effects of cGMP and ISO were additive. When ICa was increased maximally (4.3-fold) by 100 microM isobutylmethylxanthine, a nonselective phosphodiesterase inhibitor, application of 100 microM cGMP in the pipette decreased ICa by 53% and cell shortening by 64%. Cyclic GMP changed contraction in parallel with ICa in the presence of either ISO or isobutylmethylxanthine. 5'-GMP had no significant effect on ICa or contraction in the presence of ISO or isobutyl-methylxanthine. Cyclic GMP alone, at 30 microM, increased ICa by 25%; this effect on basal ICa was reversed by removal of cGMP from the pipette solution. We conclude that intracellular cGMP had two effects on ICa and contraction, namely, 1) an increase caused by an action on cGMP-inhibited phosphodiesterase and 2) a decrease attributed to activation of cGMP-dependent protein kinase.

Effects of disopyramide on the atrial fibrillation threshold in the human atrium.

The effects of disopyramide on the atrial fibrillation threshold (AFT) in the human atrium were investigated. To evaluate atrial vulnerability, the following electrophysiologic parameters were measured before and after the administration of disopyramide (2 mg/kg) in 12 patients with paroxysmal atrial fibrillation: The right atrial effective refractory period (ERP) and percentage maximum atrial fragmentation (%MAF) were measured by atrial premature stimulation based on a cycle length of 500 ms. The inter-atrial conduction time (ACT) was measured by burst pacing (120/min) for 30 s. AFT was measured by applying a high-frequency (50 Hz) stimulation for 1 s given at the right atrial appendage. AFT was defined as the lowest intensity of electrical current that could induce atrial fibrillation lasting for more than 30 s. Disopyramide significantly reduced %MAF, and prolonged ERP and ACT. AFT was measured in all patients and the mean AFT was 3.1 +/- 1.7 mA. After the administration of disopyramide, AFT significantly increased to 6.1 +/- 3.6 mA. There was a positive correlation between ERP and AFT, and a negative correlation between %MAF and AFT. No correlation was detected between ACT and AFT. In conclusion, disopyramide increased AFT in the human atrium.

Kinetics of frequency-dependent conduction delay by class I antiarrhythmic drugs in human atrium.

We investigated use-dependent prolongation of interatrial conduction time (IACT) by class I antiarrhythmic drugs in 16 patients. Changes in IACT at the initiation of atrial pacing were used to evaluate the onset kinetics. We examined recovery kinetics by giving a single extra stimulus with a varying coupling interval after discontinuing train stimulation. Time constants of the onset kinetics were 1.52 +/- 0.15/n(fast) and 0.087 +/- 0.031/n(slow) for mexiletine, 0.075 +/- 0.015/n for aprindine, 0.078 +/- 0.019/n for disopyramide, and 0.050 +/- 0.006/n for pilsicainide. The recovery time constants were 203 +/- 66 ms for mexiletine, 1,021 +/- 162 ms for aprindine, 993 +/- 101 ms for disopyramide, and 2,930 +/- 569 ms for pilsicainide. Class I antiarrhythmic drugs produced use-dependent IACT prolongation in humans, with characteristic kinetics for each agent similar to that of depression of the maximum upstroke velocity of cardiac action potential (Vmax) reported in in vitro studies.

Effects of E-4031 on atrial fibrillation threshold in guinea pig atria: comparative study with class I antiarrhythmic drugs.

The effects of E-4031, a new class III antiarrhythmic agent, on atrial fibrillation threshold (AFT), atrial effective refractory period (ERP), and interatrial conduction time (ACT) were investigated in Langendorff-perfused guinea pig hearts; the results were then compared with those of the class I agents disopyramide, procainamide, lidocaine, and flecainide. Whole guinea pig hearts were perfused with Tyrode's solution containing acetylcholine (ACh 3 x 10(-7) M). The three indexes were measured before and after administration of the test drugs, using right atrial extrastimulus and 50-Hz continuous stimulation. Disopyramide, procainamide, and flecainide (> or = 10(-6) M) significantly increased AFT. Although E-4031 (> or = 3 x 10(-6) M) also increased AFT, this effect was less potent than that observed with the other drugs. E-4031 (> or = 10(-6) M) significantly prolonged ERP, and this prolongation was less pronounced than that observed with disopyramide but similar to that observed with procainamide or flecainide. E-4031 did not affect ACT, and the greatest prolongation of ACT was observed with flecainide. Lidocaine had no effect on any of the indexes. These findings suggest that in guinea pig hearts E-4031 exerts an antifibrillatory effect by prolonging atrial ERP alone, but this effect is less pronounced than that observed with class I drugs, because AFT measured by 50-Hz continuous stimulation is influenced by both ERP and ACT.

Structure and expression of the gene responsible for the triplet repeat disorder, dentatorubral and pallidoluysian atrophy (DRPLA).

Dentatorubral and pallidoluysian atrophy is associated with expansion of an unstable CAG repeat on chromosome 12p. We have determined the nucleotide sequences of overlapping cDNA clones and deduced the gene structure. The gene is ubiquitously expressed to form a single 4.5 kb transcript and encoded by an open reading frame of 1184 amino acids (aa), in which a polyglutamine track with variable length starts at aa 484. Although the predicted amino acid sequence does not reveal any function, it does contain several interesting motifs consisting of a simple repeated amino acid sequence, a homo-proline track, two stretches of arginine-glutamic acid dipeptides and a stretch of alternative histidine residues. These results provide clues toward understanding neurodegenerative diseases associated with triplet repeat expansion.

Dentatorubral and pallidoluysian atrophy expansion of an unstable CAG trinucleotide on chromosome 12p.

Dentatorubral and pallidoluysian atrophy (DRPLA) is an autosomal dominant neurodegenerative disorder characterized by combined systemic degeneration of the dentatofugal and pallidofugal pathways. We investigated a candidate gene and found that DRPLA patients had an expanded CAG trinucleotide repeat in a gene on the short arm of chromosome 12. The repeat size varied from 7-23 in normal individuals. In patients one allele was expanded to between 49-75 repeats or occasionally even more. Expansion was usually associated with paternal transmission and only occasionally with maternal transmission. Repeat size showed a close correlation with age of onset of symptoms and disease severity. We conclude that DRPLA is the seventh genetic disorder known to be associated with expansion of an unstable trinucleotide repeat.

Effects of PDE inhibitors and carbachol on the L-type Ca current in guinea pig ventricular myocytes.

The phosphodiesterase inhibitors 3-isobutyl-1-methylxanthine (IBMX; 100 microM) and papaverine (100 microM) increased peak L-type Ca current (ICa) more than fivefold in a way similar to isoproterenol, forskolin, or intracellular adenosine 3',5'-cyclic monophosphate in guinea pig ventricular myocytes studied with the whole cell voltage-clamp technique at 22-24 degrees C. IBMX and papaverine could also induce a chloride current. Both drugs caused an apparent increase of ICa inactivation as revealed by 1) a negative shift of the ICa inactivation curve between -40 and 0 mV and 2) a suppression of the relief from inactivation at potentials positive to 0 mV. In the presence of IBMX or papaverine, the amplitudes of both the rapidly and slowly inactivating components of ICa were increased; the effect on the fast component was more pronounced. The drugs did not accelerate the inactivation time course of either component. Carbachol (CCh; 100 microM) reversed the increase in ICa produced by IBMX or papaverine. However, ICa could not be restored to its original magnitude on washout of CCh in the presence of phosphodiesterase inhibitors. In pertussis toxin-treated cells or in the presence of Ly-83583 (1-100 microM), IBMX retained its effect but CCh was unable to reduce ICa. Dialysis with guanosine 3',5'-cyclic monophosphate (cGMP; 0.1-100 microM) or 8-bromoguanosine 3',5'-cyclic monophosphate (30 microM) suppressed the increase of ICa by IBMX; the inhibition by cGMP was additive with that produced by CCh. We suggest that the major part of IBMX and papaverine effect is mediated by phosphodiesterase inhibition and involves an increase in intracellular adenosine 3',5'-cyclic monophosphate levels. CCh reversal of phosphodiesterase inhibitor action probably involves an elevation of cGMP levels and activation of cGMP-dependent protein kinase.

[Effect of pilsicainide hydrochloride on atrial fibrillation threshold].

To inventigate the electrophysiologic effects of pilsicainide hydrochloride on atrial fibrillation, we compared atrial fibrillation threshold (AFT), right atrial effective refractory period (RAERP), and inter-atrial conduction time (Inter-ACT) before and after the administration of pilsicainide in 12 patients with lone paroxysmal atrial fibrillation. The following electrophysiologic study was performed before and after the administration of the drug as the paced cycle length of 500msec. First, RAERP was measured. Secondly, Inter-ACT from the stimulating artifact to the initial deflection in the elecrocardiograms of the coronary sinus was measured. Thirdly, high-frequency (50Hz) stimulation was given at right atrial appendage continuously for one second just after the eighth basic paced beat. The stimulation current was increased by 1mA in a stepwise fashion from 2mA until atrial fibrillation ensued. AFT was defined as the lowest intensity of the current that induced atrial fibrillation or flutter of more than 30 seconds. Pilsicanide significantly increased AFT and Inter-ACT, but did not change RAERP. In conclusion, it is suggested that pilsicainide might decrease atrial vulnerability mainly by its effect on inter-atrial conduction delay and by the resulting increase in AFT.

Electrophysiological effects of flecainide acetate on stretched guinea pig left atrial muscle fibers.

The electrophysiological effects of flecainide acetate (3 x 10(-6) M) on stretched atrial tissue were investigated using guinea-pig left atrial muscle fibers. Before stretching, the resting membrane potential was not affected by flecainide at 1 Hz, although the overshoot potential (Eov) and the action potential duration at 50% repolarization (APD50) were slightly but significantly decreased by 2 +/- 1 mV and 2 +/- 1 msec, respectively. The effective refractory period (ERP) was increased by 3 +/- 1 msec. The reduction of Vmax was 20.6 +/- 1.2%. The half-maximum potential (Vh) of the relationship between Vmax and the resting potential was shifted to become more negative by flecainide (from -60.6 +/- 2.1 mV to -63.2 +/- 1.7 mV). After 90-120 min of washout with drug-free Tyrode's solution, the tissue was mechanically stretched to 150% of its slack length. Stretching significantly decreased the Vmax by 16.9 +/- 3.1%, along with a slight but significant increase in ERP (3 +/- 1 msec) and shifted Vh to become more negative (from -60.6 +/- 2.1 to -63.1 +/- 1.8 mV). In the presence of flecainide, Vmax further decreased by 20.2 +/- 2.6%, and Vh shifted from -63.1 +/- 1.8 to -65.0 +/- 1.5 mV. Comparison with the control unstretched fibers showed that flecainide significantly decreased Vmax by 34.0 +/- 2.7%, reduced the resting membrane potential by 3 +/- 1 mV, decreased Eov by 4 +/- 1 mV, and shifted Vh from -60.6 +/- 2.1 to -65.0 +/- 1.5 mV, while the APD50 and ERP did not change. In conclusion, the reduction of Vmax in the presence of flecainide was much greater in the stretched atrial muscle fibers than in the unstretched fibers, because the Vmax-resting potential relationship was shifted towards more negative potentials by both flecainide and stretching. These results suggest that flecainide exerts a stronger antiarrhythmic action on stretched atrial muscle fibers than on normal fibers.

Carbachol-induced sodium current in guinea pig ventricular myocytes is not regulated by guanine nucleotides.

Muscarinic (M2) receptor occupancy by carbachol induces a tetrodotoxin- and pertussis toxin-resistant Na+ current which underlies its positive inotropic effect in guinea pig ventricular cells. We tested the effect of activating [GTP gamma S, Gpp(NH)p] and inactivating (GDP beta S) guanine nucleotides on this carbachol-induced current because guanine nucleotide binding proteins are reported to transduce the effect of muscarinic agonist. A whole-cell voltage clamp method was used. The carbachol (300 microM)-induced current was not significantly changed at any membrane voltage in the absence and the presence of 10 microM GTP gamma S, 100 microM Gpp(NH)p or 500 microM GDP beta S in the patch pipette (inward current amplitude at -80 mV: -21 +/- 1.5 pA, control; -22 +/- 1.3 pA, GTP gamma S; -20, -16 pA, Gpp(NH)p; -20 +/- 2.3 pA, GDP beta S; n = 31, 11, 2 and 14, respectively). The current amplitude was not affected by prolonged dialysis (120 min) of the cell with Gpp(NH)p and/or by the presence of greater concentrations of guanine nucleotides. On the other hand, 10 microM GTP gamma S directly activated the muscarinic K+ channel current within 60 sec after patch rupture in atrial myocytes; either GTP gamma S or GDP beta S (500 microM) occluded activation of this current by carbachol. When isoproterenol had increased L-type Ca++ current in ventricular myocytes, carbachol-induced inhibition of this current was suppressed when GTP gamma S (10 microM) was present in the pipette solution. Therefore, myocytes were dialyzed with effective concentrations of guanine nucleotides.(ABSTRACT TRUNCATED AT 250 WORDS)