Shigeki Yoshida

Clinical effects of long-term administration of pimobendan in patients with moderate congestive heart failure.

SummaryThe long-term efficacy of the positive inotropic and vasodilator drug, pimobendan, was assessed in 21 patients suffering from symptomatic heart failure. Patients were randomized to 16 weeks of double-blind therapy with either 2.5 or 5.0mg/day of pimobendan (n = 10), or a matching placebo (n = 11). Patients were blinded on the study drug if their clinical status had not substantially worsened during the study. Of the placebo-treated patients, 5 patients were withdrawn from the study because of a deterioration of their heart failure, while none of the active treated group was withdrawn because of increased symptoms. Quality of life, assessed by the specific activity scale derived from the metabolic costs of individual physical activity, was 3.45 ± 0.90 (SD) mets in the baseline state and increased significantly after week 16, averaging 5.07 ± 1.40 and 4.67 ± 1.47 mets at weeks 16 and 24, respectively. In the placebo-treated group, the specific activity scale was 3.27 ± 1.21 mets at the baseline and remained unchanged throughout the study period. Patients treated with pimobendan were able to significantly increase their exercise duration. The accompanying increase in peak oxygen uptake was statistically insignificant, due to the limited number of patients enrolled in the study. These results suggest that in contrast to the recent pessimistic view of the long-term efficacy of cardiotonic drugs, pimobendan is beneficial in treating patients with congestive heart failure and may favorably modify their prognosis. Further largescale evaluation of this agent is warranted.

Quantitative Relationship Between Atrial Refractoriness and the Dispersion of Refractoriness in Atrial Vulnerability

We investigated the quantitative relationship between the atrial refractory period and the dispersion of refractoriness with respect to atrial vulnerability in 19 adult mongrel dogs. The atrial effective refractory period (AERP) was measured at the sinus node area (SNA), the low posterior right atrium (LRA), and the distal coronary sinus. The study was performed under the following conditions: (1) control status; (2) hypothermia (30°C); (3) vagus nerve stimulation; and (4) a combination of (2) and (3). The subjects were separated into two groups: atrial fibrillation (AF) (+) group (n = 23), which developed AF by atrial extrastimulus due to increased vulnerability, and AF (−) group (n = 39), which did not develop AF. The mean AERP was 97 ± 23 msec (mean ± SD) in the AF (+) group and 124 ± 23 msec in the AF (−) group, with a significantly shorter refractory period seen in the former (P < 0.001). The dispersion of refractoriness was 59 ± 24 msec in the AF (+) group and 29 ± 18 msec in the AF (−) group, with a significant increase noted in the former (P < 0.001), On X‐Y coordinates (where X denotes the AERP, and Y denotes the dispersion of refractoriness) the data from the AF (+) group were clustered in the upper left region of the graph while the data from the AF (−) group were clustered in the lower right region. These two groups were separated by a linear equation of Y = 0.86X ‐ 57 with a predictability of 90.3%. No difference in the time from SNA stimulation to LRA excitation was found between the groups. On the basis of these results, we suggest that increased atria) vulnerability can be predicted from an analysis of the quantitative relationship between the atrial refractory period and the dispersion of refractoriness.

Quantification of human concealed atrioventricular nodal conduction: Relation to ventricular response during atrial fibrillation

We studied the relation between a new quantitative index of concealed atrioventricular nodal (AVN) conduction and the variability of ventricular response during atrial fibrillation in 12 patients without preexcitation. The second atrial extrastimulus (A3) was introduced following the first extrastimulus (A2), which was fixed at a coupling interval 20 to 40 msec longer than the AVN effective refractory period (ERP) during a basic atrial drive (A1) cycle length of 400 to 750 msec. The AVNERP of conducted A2 defined as the longest A2A3 interval at which A3 was not conducted to the His bundle was determined. This pacing sequence was repeated, whereas A2 was fixed at a coupling interval 20 to 40 msec shorter than the AVNERP, which means A2 was concealed within the AVN. Thus AVNERP of blocked A2, defined as the longest A2A3 interval at which A3 was not conducted to the His bundle, was measured. Concealment index (AVNERP of blocked A2/AVNERP of conducted A2) was developed to quantitate the magnitude of concealed penetration into the AVN by A2. During atrial fibrillation induced by premature or rapid atrial stimulation, the coefficient of variation (SD/mean) of R-R intervals and the maximum R-R/minimum R-R interval were significantly correlated with the concealment index (r = 0.838, p less than 0.001; r = 0.678, p less than 0.05). However, neither of these parameters was correlated with AVNERP. Both the minimum R-R and the mean R-R interval were related to the AVNERP (r = 0.946, r = 0.823, p less than 0.001).(ABSTRACT TRUNCATED AT 250 WORDS)

Efficacy of class ia antiarrhythmic drugs in converting atrial fibrillation unassociated with organic heart disease and their relation to atrial electrophysiologic characteristics

Abstract We speculate that the mechanism of paroxysmal AF may be multifactorial, and may have different responses to class Ia drugs during AF depending on the electrophysiologic factors predisposing to AF.

Paroxysmal atrial fibrillation with and without primary atrial vulnerability: Clinical and electrophysiological differences

Primary atrial vulnerability defined as induction of repetitive atrial firing by a single atrial extrastimulus cannot always be demonstrated in patients with paroxysmal atrial fibrillation. The authors studied the electrophysiological differences between paroxysmal atrial fibrillation with and without primary atrial vulnerability. In 14 of 31 patients with documented history of atrial fibrillation, single extrastimulation at the high right atrium initiated repetitive atrial firing defined as rapid disorganized atrial activity continuing longer than 1 second. In the 14 patients with vulnerable atrium, the atrial effective and functional refractory were periods significantly shorter and the duration of the local atrial electrogram of the premature beat was longer and was fractionated. The % sinus node recovery time was longer in patients without vulnerability. Nine of the 17 patients without atrial vulnerability had sinus node dysfunction, and 4 of the remaining 8 patients had a repetitive type of atrial automatic tachycardia. In contrast, only 3 (21%) of the 14 patients with vulnerability had sinus node dysfunction, and none showed repetitive atrial tachycardia. The high prevalence of sinus node dysfunction or repetitive type of atrial automatic tachycardia in patients without primary atrial vulnerability suggests that these transient electrophysiological modifications which are not dealt with in the basic conditions may have a role in the enhancement of atrial vulnerability.

Effects of Chronotropic Responsive Cardiac Pacing on Ventilatory Response to Exercise in Patients with Complete AV Block

To identify the effect of chronotropic responsive cardiac pacing on the ventilatory response to exercise, ten selected patients with complete atrioventricular block underwent paired cardiopulmonary exercise tests in fixed rate ventricular (WI) and dual chamber (DDD) or rate responsive ventricular (VVIR) pacing modes. Compared to VVI pacing, DDD or VVIR pacing increased peak oxygen uptake (P < 0.005) and augmented anaerobic threshold (P < 0.001), In eight patients, dyspnea was the major symptom limiting exercise with VAT pacing and this was markedly attenuated with DDD or VVIR pacing. In all patients, ventilation (VE) and the ratio of ventilation to CO2 production (VE/VCO2) were consistently higher with VVI pacing during exercise. To compare the response of the two pacing modes at the same workloads in an aerobic condition, we measured ventilatory variables 1 minute prior to the anaerobic threshold obtained with VVI pacing. When DDD or VVIR pacing was compared with VVI pacing, VE and VE/VCO2 significantly decreased from 20.5 ± 5.3 L/min to 18.3 ± 5.0 L/min (P < 0.005) and from 35.9 ± 5.8 to 31.9 ± 5.0 (P < 0.003), respectively. Respiratory frequency rose significantly more with VVI pacing (P < 0.001) despite an unchanged tidal vohame. Although peak VE did not differ between the two pacing modes, VE/VCO2 at the peak exercise increased significantly more with VVI pacing (P < 0.005). Respiratory frequency also rose more with VVI pacing (P < 0.005) and tidal volume did not change. This study suggests that chronotropic responsive cardiac pacing attenuates the exertional dyspnea by improving the ventilatory response to exercise as well as increasing the cardiac output in patients with complete atrioventricular block.

Intermittent wolff-parkinson-white syndrome due to phase 3 and phase 4 block: Disappearance of rapid ventricular response during atrial fibrillation

A 65-year-old man with Wolff-Parkinson-White syndrome type A had a rapid ventricular response over an accessory pathway during atrial fibrillation. Four months later, electrophysiological study revealed the following properties: 1) The antegrade accessory pathway conduction showed phase 3 and phase 4 block. 2) The retrograde concealed accessory pathway conduction eliminated phase 4 block in the antegrade accessory pathway conduction. 3) Premature ventricular excitation arose from the accessory pathway or from the ventricular muscle close to its distal end. 4) Atrial fibrillation during isoproterenol infusion did not show rapid ventricular response. Spontaneous impairment of accessory pathway conduction due to phase 3 and phase 4 block was suspected.

Fast-slow type of atrioventricular nodal reentrant tachycardia: horizontal dissociation of the AV node during tachycardia.

Two patients with recurrent supraventricular tachycardia are presented. The tachycardia was initiated and terminated by atrial extrastimulation beyond the atrial relative refractory period and the atrial activation sequence during the tachycardia was low to high. The induction of tachycardia was dependent on a critical AH interval. In patient 1 who had ventriculoatrial conduction, the tachycardia was initiated by the premature ventricular stimulation followed by double atrial response. In patient 2 the ventriculoatrial conduction was not observed. In both patients, the unchanged atrial cycle length during the tachycardia with antegrade Wenckebach AH block was observed. When AH block occurred during tachycardia the first AH interval was shorter than the subsequent HA interval. In patient 2 verapamil (5 mg) prolonged the atrial cycle length during tachycardia and rapid intravenous injection of adenosine triphosphate (10 mg) terminated the tachycardia. Oral diltiazem (280 mg/day) suppressed the tachycardia in patient 1. These findings suggest that the mechanism of tachycardia may be fast‐slow type of AV nodal reentry in the upper portion of the AV node and this type of arrhythmia has tendency to show incessant form.

Electrophysiologic Effects and Efficacy of Cibenzoline in Patients with Supraventricular Tachycardia

Summary: Electrophysiologic effects of intravenous (i.v.) cibenzoline were evaluated in 18 patients with accessory pathways or dual atrioventricular (AV) nodal pathways (12 men and 6 women with a mean age of 44 ± 18 years). Twelve patients had accessory AV pathways, including 6 patients with a manifest accessory pathway. Six patients had AV nodal reentrant tachycardia (AVNRT). Electrophysiologic studies were performed before and after cibenzoline (1.4 mg/kg i.v.) infusion for 5 min. Sinus cycle length did not change significantly after cibenzoline administration. Cibenzoline increased both the AH (85 ± 20 vs. 91 ± 21 ms, p < 0.05) and HV intervals (41 ± 10 ms vs. 53 ± 11 ms, p < 0.001). Neither the atrial nor ventricular effective refractory period (ERP) was altered by cibenzoline. Complete block in the accessory pathway occurred antegradely in 4 patients and retrogradely in 1 patient. Cibenzoline prevented induction of AV reentrant tachycardia (AVRT) in 3 of 8 patients with sustained orthodromic AVRT by abolishing retrograde accessory pathway conduction or prolonging the retrograde accessory pathway ERP. Of 5 patients who continued to have inducible AVRT before and after cibenzoline administration, the tachycardia cycle length was increased in 3, mainly due to the increase in retrograde accessory pathway conduction time. Cibenzoline prevented induction of sustained AVNRT in 4 of 5 patients by prolonging the minimum pacing cycle length, maintaining 1:1 ventriculoatrial (VA) conduction through the retrograde fast AVN pathway or shortening the ante-grade fast AVN pathway ERP equal to the slow AVN pathway. In one patient who had an uncommon type of AVNRT, sustained tachycardia was induced by cibenzoline. We conclude that the effects of i.v. cibenzoline at a dose of 1.4 mg/kg on suppression of initiation of paroxysmal supraventricular tachycardia are due mainly to the effects of class I antiarrhythmic agents and not class IV agents according to the Vaughan Williams classification. Cibenzoline may prevent both AVRT and AVNRT by suppressing retrograde VA conduction in selected patients.

Electrophysiologic mechanisms of adverse effects of class I antiarrhythmic drugs (cibenzoline, pilsicainide, disopyramide, procainamide) in induction of atrioventricular re-entrant tachycardia

SummaryWe evaluated the electrophysiological mechanisms of adverse effects of class I antiarrhythmic drugs (cibenzoline in seven patients, pilsicainide in two, and disopyramide in two, and procainamide in three) in the induction of orthodromic atrioventricular re-entrant tachycardia (AVRT). In 14 patients (10 males, 4 females; mean age 37±18 years) who had inducible AVRT despite the administration of class I drugs, electrophysiological effects of class I antiarrhythmic drugs were evaluated using programmed electrical stimulation techniques. In 4 out of 6 patients with a manifest accessory pathway, class I drugs induced unidirectional conduction block of the accessory pathway (antegrade conduction block associated with preserved retrograde conduction) and enhanced the induction of AVRT with atrial extrastimulation. In eight patients with a concealed accessory pathway, the outward or inward expansion of the tachycardia induction zone was observed in patients who had greater prolongation of the conduction time than the refractory period of the retrograde accessory pathway after class I drugs. During ventricular extrastimulation, the induction of bundle branch reentry after class I drugs initiated the AVRT in patients with either manifest or concealed accessory pathways. We conclude that the adverse effects of class I drugs are mainly due to induction of unidirectional retrograde conduction of the manifest accessory pathway and the greater prolongation of the retrograde conduction time of the concealed accessory pathway than the refractory period, regardless of the subclassification of class I drugs.