Shorter Basic Cycle Lengths Research Articles

Pharmacological Activation of IKr Impairs Conduction in Guinea Pig Hearts

The hERG (Kv11.1) potassium channel underlies cardiac I(Kr) and is important for cardiac repolarization. Recently, hERG agonists have emerged as potential antiarrhythmic drugs. As modulation of outward potassium currents has been suggested to modulate cardiac conduction, we tested the hypothesis that pharmacological activation of I(Kr) results in impaired cardiac conduction. Cardiac conduction was assessed in Langendorff-perfused guinea pig hearts. Application of the hERG agonist NS3623 (10 microM) prolonged the QRS rate dependently. A significant prolongation (16 +/- 6%) was observed at short basic cycle length (BCL 90 ms) but not at longer cycle lengths (BCL 250 ms). The effect could be reversed by the I(Kr) blocker E4031 (1 microM). While partial I(Na) inhibition with flecainide (1 microM) alone prolonged the QRS (34 +/- 3%, BCL 250 ms), the QRS was further prolonged by 19 +/- 2% when NS3623 was added in the presence of flecainide. These data suggest that the effect of NS3623 was dependent on sodium channel availability. Surprisingly, in the presence of the voltage sensitive dye di-4-ANEPPS a similar potentiation of the effect of NS3623 was observed. With di-4-ANEPPS, NS3623 prolonged the QRS significantly (26 +/- 4%, BCL 250 ms) compared to control with a corresponding decrease in conduction velocity. Pharmacological activation of I(Kr) by the hERG agonist NS3623 impairs cardiac conduction. The effect is dependent on sodium channel availability. These findings suggest a role for I(Kr) in modulating cardiac conduction and may have implications for the use of hERG agonists as antiarrhythmic drugs.

Repolarization gradients and arrhythmogenicity in the murine heart

Repolarization gradients and arrhythmogenicity in the murine heart

Lack of benefit of very short basic drive train cycle length or repetition of extrastimulus coupling intervals for induction of ventricular tachycardia.

There are considerable variations of uncertain importance in basic drive train cycle lengths and degree of repetition of extrastimuli used in programmed ventricular stimulation protocols in different laboratories. We compare prospectively three different stimulation protocols to examine the influence of a short basic drive train cycle length and repetition of extrastimuli on induction of ventricular tachycardia. Thirty consecutive patients who had documented ventricular tachycardia or fibrillation based on underlying coronary artery disease underwent programmed ventricular stimulation with each of the three study protocols. Protocol A used a basic drive train cycle length of 400 msec with each extrastimulus coupling interval delivered only once. Protocol B used the same basic drive train cycle length, but with each extrastimulus coupling interval repeated three times before decrementing. Protocol C used 300 msec as the cycle length of basic drive trains without repetition of extrastimuli. Sixty-three percent, 67%, and 63% of the study patients had ventricular tachycardia inducible with protocols A, B, and C, respectively (P = NS). Ventricular fibrillation was induced in 23% of the 30 patients in all three protocols. There were no significant differences in the mean cycle lengths of induced ventricular tachycardia, the number of extrastimuli used, and the coupling interval of the last extrastimulus inducing ventricular tachycardia among the three protocols. This study showed no clinical benefit for repetition of extrastimuli that have failed to induce a ventricular tachyarrhythmia during programmed ventricular stimulation. A short basic cycle length of 300 msec was not superior to 400 msec for induction of ventricular tachyarrhythmias. We recommend the use of basic cycle length 400 msec with delivery of each extrastimulus interval only once as the initial protocol for programmed ventricular stimulation.

Reentrant arrhythmias in the subacute infarction period. The proarrhythmic effect of flecainide acetate on functional reentrant circuits.

The Cardiac Arrhythmia Suppression Trial has shown that flecainide was associated with an increased incidence of sudden cardiac death in postinfarction patients. The exact mechanism(s) of the proarrhythmic effects of flecainide remain unclear. We performed a detailed analysis of the electrophysiological and proarrhythmic effects of flecainide in a well-characterized model of reentrant arrhythmias in the subacute phase of myocardial infarction. Sixteen dogs were studied 4 days after ligation of the left anterior descending coronary artery. Isochronal mapping of ventricular activation showed that flecainide facilitated both the induction and sustenance of ventricular tachycardia, especially at shorter basic cycle lengths. Flecainide had negligible effect on the length of the arc of functional conduction block but markedly depressed conduction of the common reentrant wave front that was usually oriented parallel to fiber axis. Whole heart mapping was analyzed in combination with basic measurements of the effects of flecainide on conduction and refractory properties of both normal and ischemic myocardia using a high-resolution cross electrode consisting of four orthogonal arms, each comprised of 16 poles with an interelectrode spacing of 500 microns. The electrode was especially designed to study the effects of the drug on anisotropic conduction as determined by a linear regression of activation time and distance in each direction. Flecainide resulted preferentially in more marked rate-dependent depression of conduction in ischemic compared with normal myocardium. On the other hand, the effect of flecainide on refractoriness in both normal and ischemic myocardia was negligible. Because flecainide caused no significant change in refractoriness in both normal and ischemic myocardia, there was no difference in the dimension of the potential reentrant pathway, that is, the continuous line of functional conduction block, around which the reentrant wave fronts circulate. Yet, flecainide resulted in significant rate-dependent slowing of conduction preferentially in ischemic myocardium. The additional slowing of conduction of the common reentrant wave front coupled with minimal changes in the length of the reentrant pathway allowed additional time for the wave front to reexcite normal myocardium on the proximal side of the arc of block. After flecainide, reentry could be induced in hearts in which reentry could not be induced during control. The same proarrhythmic mechanism explains the propensity of nonsustained figure-8 reentrant tachycardias to become sustained after flecainide.

Induced ventricular arrhythmias in regionally dernervated porcine heart with healed myocardial infarction

The aim was to test the hypothesis that chronic sympathetic denervation of the boundaries of a healed myocardial infarction may modify the arrhythmogenic response to programmed electrical stimulation. Electrical induction of ventricular arrhythmias and infarct size were evaluated in a control group of pigs with a one month old myocardial infarction induced by ligature of the left anterior descending coronary artery below the first diagonal branch. These were compared with a group of similarly infarcted pigs subjected to regional denervation of the peri-infarction area induced by topical pericoronary application of phenol. Denervation was verified by the absence of adrenergic histofluorescent reaction to glyoxylic acid in myocardial samples. 24 pigs (weight 15-20 kg) with myocardial infarction were studied, 13 of which were subjected to regional peri-infarction denervation, and 11 acted as controls. Programmed ventricular stimulation with one to four extrastimuli at 500 and 400 ms basic cycle length at the left and right ventricles induced fewer episodes of ventricular fibrillation in the denervated than in the non-denervated group (five episodes in three pigs v 14 in nine pigs, p less than 0.005), but more episodes of sustained ventricular tachycardia (79 in eight pigs v 23 in two, p less than 0.001). Unlike fibrillation, induction of ventricular tachycardia increased with multiple extrastimuli and with short basic cycle length. The denervated preparations tended to develop smaller infarcts but this difference was not statistically significant: infarct weight (g) relative to total ventricular mass (g) = 7.2 (SD 2.4)% v 10.5(4.5)%. Neural integrity of the non-ischaemic myocardium bordering a healed infarction modulates inducibility of ventricular tachycardia and fibrillation during programmed ventricular stimulation.

Electrical Restitution and Conduction Intervals of Ventricular Premature Beats in Man: Influence of Heart Rate

Monophasic action potentials (MAP) were obtained from the outflow tract of the right ventricle during apical pacing in 20 patients with coronary artery disease. The electrical restitution was studied by interpolation of extrasystoles with various coupling intervals to the preceding steady-state beat at basic paced cycle lengths (CL) of 700, 600, and 500 msec. At higher frequencies the ventricular effective refractory periods (V-ERP) and duration of MAPs became shorter and the electrical restitution curves were displaced downwards (P less than 0.001). With increasing diastolic intervals preceding the extrasystole up to a maximum of 100 msec, the duration of premature MAPs increased at all frequencies. An obvious hump of the electrical restitution curve was observed at coupling intervals of 100 msec due to a later transient decrease (P less than 0.01) in duration of MAPs at the basic CL of 500 msec. No significant hump was observed at lower heart rates. Thus, a different time course of the electrical restitution was observed at various CLs. The intraventricular conduction intervals were shorter at the shorter basic CLs when compared to the 700 msec cycles (P less than 0.05). The conduction intervals were also modified by the coupling interval between the interpolated stimulus and the preceding steady-state action potential (AP). The premature beats elicited 30 msec or earlier after refractoriness were conducted more slowly at all basic cycle lengths (P less than 0.005), and those between 60 and 150 msec after the V-ERP more rapidly (P less than 0.01) than the steady-state beats. These observations have implications for the protocols used for introducing two or more frequencies during programmed stimulation in man. Furthermore, the conduction pattern in vivo cannot be interpreted from single cell studies.

Demonstration of hysteresis in refractoriness of canine ventricular myocardium.

The properties and determinants of hysteresis during ventricular effective refractory period (VERP) measurements by an extrastimulus technique were determined in 15 anesthetized open-chest dogs as well as in isolated ventricular muscle (n = 6). VERP was determined both by decreasing the S1-S2 interval and also by increasing S1S2. Hysteresis was then calculated by subtracting the VERP obtained with the decreasing S1S2 from the VERP obtained with the increasing S1S2. The effects of basic cycle length, pulse width, stimulation intensity, and the number of basic drives on VERP and hysteresis were evaluated. VERP was shorter for long pulse width, high stimulation intensities, and shorter basic cycle lengths. These modifications were not associated with significant changes of hysteresis. VERP was shorter during decreasing S1S2 than during increasing S1S2. Hysteresis was greater with 6 basic drive cycles than with 12 (P less than 0.001) in both in vivo and in vitro preparations. The data suggest that 1) hysteresis occurs during VERP measurements; 2) hysteresis is independent of stimulation modality; and 3) hysteresis decreases with the number of basic drive cycles.

Electrophysiological effects of tocainide on canine subendocardial purkinje fibers surviving infarction

The effects of 10 and 20 mg/l of tocainide on transmembrane action potential characteristics were examined in Purkinje fibers surviving infraction. Infracted tissue was obtained from canine hearts 24 h after coronary artery ligation. The preparation was stimulated at basic cycle lengths (BCL) of 1000−300 ms. Tocainide reduced the overshoot and amplitude of Purkinje fibers surviving infarction. The maximum upstroke velocity (V̇ max) was decreased by tocainine in a dose dependent manner. This effect was more prominent at the shorter BCL. Statistical analysis revealed a significant interaction of the BCL with the drug effect on overshoot, amplitude, V̇ max and action potential durations (APD 50% and APD 90%). Tocainide reduced the effective refractory period (ERP) at the BCL of 1000 ms, but had no significant effect at the BCL of 300 ms. Membrane responsiveness and steady state characteristics of V̇ max were shifted significantly to more negative membrane potentials by tocainide. Investigation of the recovery kinetics of V̇ max in the presence of tocainide showed an exponential recovery of V̇ max with a time constant of 514 ms. These results support the finding that the effect of tocainide on V̇ max and conduction is enhanced at faster rates of stimulation. Thus tocainide may be able to depress conduction to produce bidirectional block in the termination of ventricular tachycardia caused by reentry, while having minimal effect on conduction at normal heart rates.

Incidence and clinical significance of repetitive ventricular response in patients without identifiable organic heart disease

We determined the incidence of repetitive ventricular response (RVR) after programmed electrical stimulation and the incidence of spontaneous ventricular arrhythmias during 24 hr Holter monitoring in 38 patients in whom extensive non-invasive and invasive diagnostic tests had excluded abnormalities suggestive of organic heart disease. A standardized stimulation protocol with single (S 1S 2) and double (S 1S 2S 3) extrastimuli during ventricular drive at cycle lengths of 600, 500 and 430 msec with a current strength below 5 mA at the right ventricular apex was employed. RVR occurred in 20 patients (58%) after S 1S 2 and in 30 patients (79%) after S 1S 2S 3 stimulation. Eighteen patients (47%) showed RVR with 2 echo beats and 1 patient had 3 echo beats. RVR was due to bundle branch reentry (BBR) in 20 patients independent of the mode of stimulation. RVR due to intraventricular reentry (IVR) was found in 17 patients (47%) only after S 1S 2S 3 stimulation. The incidence of both BBR and IVR was influenced by the basic ventricular driving rate, decreasing with shorter basic cycle lengths. 17 patients had no ventricular premature depolarizations (VPDs), 12 patients had uniform, 4 multiform (Lown III), 2 consecutive (Lown IVA) VPDs, and 1 patient had parasystolic rhythm. There was no relation to the incidence of repetitive ventricular response. We conclude that in patients without identifiable organic heart disease RVR with more than 2 consecutive beats is rarely found if single and double extrastimuli are employed during ventricular drive. Both bundle branch and intraventricular reentry with one or two echo beats are a common finding in this population without relation to the incidence of spontaneous ventricular arrhythmias.