Mechanoelectrical feedback: independent role of preload and contractility in modulation of canine ventricular excitability.

Mechanoelectrical feedback, defined as changes in mechanical state that precede and alter transmembrane potential, may have potential importance in understanding the role of altered load and contractility in the initiation and modulation of ventricular arrhythmias. To assess the independent effects of preload and contractility on myocardial excitability and action potential duration, we determined the stimulus strength-interval relationship and recorded monophasic action potentials in isolated canine left ventricles contracting isovolumically. The strength-interval relationship was characterized by three parameters: threshold excitability, relative refractory period, and absolute refractory period. The effects of a threefold increase in left ventricular volume or twofold increase in contractility on these parameters were independently assessed. An increase in preload did not change threshold excitability in 11 ventricles but significantly shortened the absolute refractory period from 205 +/- 15 to 191 +/- 14 ms (P less than 0.001) (mean +/- SD). Similarly, the relative refractory period decreased from 220 +/- 18 to 208 +/- 19 ms (P less than 0.002). Comparable results were observed when contractility was increased as a result of dobutamine infusion in 10 ventricles. That is, threshold excitability was unchanged but the absolute refractory period decreased from 206 +/- 14 to 181 +/- 9 ms (P less than 0.003), and the relative refractory period decreased from 225 +/- 17 to 205 +/- 18 ms (P less than 0.003). Similar results were obtained when contractility was increased with CaCl2, indicating that contractility associated changes were independent of beta-adrenergic receptor stimulation. An increase in preload or contractility was associated with shortening of the action potential. A threefold increase in preload and twofold increase in contractility were associated with a decrease in action potential duration of 22 and 24 ms, respectively. There was a significant linear correlation between action potential duration and excitability (absolute refractory period). The similar effects of increased preload and contractility on threshold excitability and refractoriness can be explained by the action these perturbations have on the time course of repolarization. Therefore, excitability of the ventricle is sensitive to and is modulated by alteration of load or inotropic state. The similar effects of either increased preload or contractility on excitability may be mediated by a common cellular mechanism which results in a rise in intracellular free Ca2+ and secondary abbreviation of the action potential.

Cycle length dependence of human action potential duration in vivo. Effects of single extrastimuli, sudden sustained rate acceleration and deceleration, and different steady-state frequencies.

Using a new method for long-term recording of monophasic action potentials from the human heart, we studied in 17 patients the effects on ventricular action potential duration (APD) of three clinically pertinent cycle length perturbations: (1) single extrastimuli, (2) abrupt sustained rate acceleration and deceleration, and (3) different steady-state cycle lengths. Results were: (a) APD after single extrastimuli at progressively longer cycle lengths were related to the extrastimulus cycle length with a biphasic electrical restitution curve which after an initial steep rise and a subsequent transient descent rose again more gradually to a plateau at cycle lengths above 800-1,000 ms. (b) After a sustained step decrease in cycle length, the first APD shortened abruptly while final steady-state adaptation required up to several minutes. The transition between the rapid and slow phase of APD change was characterized by a variable alternans of APD which correlated inversely with the preceding diastolic interval. (c) In the steady state, APD correlated linearly with cycle length, increasing an average of 23 ms per 100 ms cycle length increase (r = 0.995). The divergence between steady-state and non-steady-state APD, and the slowness of steady-state adaptation, are important factors to be considered in clinical electrophysiologic studies and in rate correction algorithms of APD or QT intervals, respectively.

Gadolinium decreases stretch-induced vulnerability to atrial fibrillation.

BACKGROUND: Atrial fibrillation (AF) is frequently associated with atrial dilatation caused by pressure or volume overload. Stretch-activated channels (SACs) have been found in myocardial cells and may promote AF in dilated atria. To prove this hypothesis, we investigated the effect of the SAC blocker gadolinium (Gd(3+)) on AF propensity in the isolated rabbit heart during atrial stretch. METHODS AND RESULTS: In 16 isolated Langendorff-perfused rabbit hearts, the interatrial septum was perforated to equalize biatrial pressures. Caval and pulmonary veins were occluded. Intra-atrial pressure (IAP) was increased in steps of 2 to 3 cm H(2)O by increasing the pulmonary outflow fluid column. Vulnerability to AF was evaluated by 15-second burst pacing at each IAP level. At baseline, IAP needed to be raised to 8.8+/-0.2 cm H(2)O (mean+/-SEM) to induce AF. A dose-dependent decrease in AF vulnerability was observed after Gd(3+) 12.5, 25, and 50 micromol/L was added. AF threshold increased to 19.0+/-0.5 cm H(2)O with Gd(3+) 50 micromol/L (P<0.001 versus baseline). Spontaneous runs of AF occurred in 5 hearts on a rise of IAP to 13.8+/-3.3 cm H(2)O at baseline but never during Gd(3+). Atrial effective refractory period shortened progressively from 78+/-3 ms at 0.5 cm H(2)O to 52+/-3 ms at 20 cm H(2)O (P<0.05). Gd(3+) 50 micromol/L had no significant effect on effective refractory period. CONCLUSIONS: Acute atrial stretch significantly enhances the vulnerability to AF. Gd(3+) reduces the stretch-induced vulnerability to AF in a dose-dependent manner. Block of SAC might represent a novel antiarrhythmic approach to AF under conditions of elevated atrial pressure or volume.

Analysis of 12-lead T-wave morphology for risk stratification after myocardial infarction.

BACKGROUND: The stratification of post-myocardial infarction (MI) patients at risk of sudden cardiac death remains important. The aim of the present study was to assess the prognostic value of novel T-wave morphology descriptors derived from resting 12-lead ECGs. METHODS AND RESULTS: In 280 consecutive post-MI patients, a 12-lead ECG was recorded before discharge, optically scanned, and digitized. For the present study, 5 T-wave morphology descriptors were automatically calculated after singular value decomposition of the ECG signal. The total cosine R-to-T (TCRT [describes the global angle between repolarization and depolarization wavefront]) and the T-wave loop dispersion were univariately associated (P:=0.0002 and P:<0.002, respectively, U: test) with 27 prospectively defined clinical events in 261 patients (mean follow-up 32+/-10 months). Kaplan-Meier event probability curves for strata above and below the median confirmed the strong risk discrimination by TCRT and T-wave loop dispersion (P:<0.003 and P:<0.001, respectively, log-rank test). On Cox regression analysis, with the entering of age, left ventricular ejection fraction, heart rate, QRS width, reperfusion therapy, beta-adrenergic-blocker treatment, and standard deviation of R-R intervals on 24-hour Holter monitoring, TCRT (P:<0.03) yielded independent predictive value, whereas T-wave loop dispersion was of borderline independence (P:=0.064). Heart rate (P:<0.02), left ventricular ejection fraction (P:<0.02), and reperfusion therapy (P:<0.02) also remained in the final model. CONCLUSIONS: Computerized T-wave morphology analysis of the 12-lead resting ECG permits independent assessment of post-MI risk and an improved risk stratification when combined with other risk markers.

Electrocardiographic indexes of dispersion of ventricular repolarization: an isolated heart validation study.

OBJECTIVES: This study tested the correlation of QT and JT dispersion and other potentially useful electrocardiographic (ECG) indexes with dispersion of repolarization and recovery time. BACKGROUND: Dispersion of ventricular repolarization is currently being assessed noninvasively from the surface ECG by means of QT and JT dispersion, although their correlation with dispersion of repolarization as measured directly from the myocardium is not well established. METHODS: Multiple monophasic action potentials were recorded simultaneously with a 12-lead ECG from isolated Langendorff-perfused rabbit hearts. The QT and JT dispersion was compared with the dispersion of monophasic action potential duration at 90% repolarization (APD90) and with dispersion of recovery time. As new ECG indexes, total T wave area, T wave area after the peak (late T wave area) and T peak to T end interval were also tested. RESULTS: The QT and JT dispersion showed a significant correlation with the dispersion of APD90 and the dispersion of recovery time (r values between 0.58 and 0.64, respectively, p < 0.001). However, total T wave area showed better correlation, respectively, with dispersion of APD90 and recovery time (r = 0.79 and r = 0.82, p < 0.0001), as did late T wave area (r = 0.81 and r = 0.81, p < 0.0001) and T peak to T end interval (r = 0.81 and r = 0.82, p < 0.0001). CONCLUSIONS: The JT and QT dispersion correlate significantly with dispersion of APD90 and recovery time. The ECG assessment of dispersion of repolarization can be improved by three new ECG dispersion indexes: T peak to T end interval, total T wave area and late T wave area. These new indexes should be tested clinically.

Effects of myocardial ischemia on ventricular fibrillation inducibility and defibrillation efficacy.

OBJECTIVES: This study investigated the effects of acute global ischemia on the vulnerable window, the upper limit of vulnerability and the defibrillation threshold. BACKGROUND: Myocardial ischemia, an important factor for arrhythmogenesis and sudden death, may affect the inducibility of ventricular fibrillation by T wave shocks as well as the defibrillation threshold. However, studies of the effect of ischemia on the defibrillation threshold remain inconclusive, and the effect of ischemia on recently established variables of ventricular fibrillation vulnerability is still unknown. METHODS: Ten isolated, perfused rabbit hearts were immersed in a tissue bath between two shock plate electrodes. Truncated 5-ms biphasic shocks were used to determine the vulnerable window, the upper limit of vulnerability and the defibrillation threshold. Measurements were performed during baseline and at 10 to 15 min of acute ischemia induced by an 80% reduction of coronary flow. The effects of ischemia were monitored by measuring the dispersion of ventricular activation and repolarization using multiple monophasic action potential recordings. RESULTS: Acute ischemia caused an increase in dispersion of activation (baseline vs. ischemia [mean +/- SD]: 22 +/- 6 vs. 34 +/- 10 ms, p < 0.001) and dispersion of repolarization (37 +/- 16 vs. 69 +/- 29 ms, p < 0.01). The width of the vulnerable window increased from 25 +/- 22 ms during baseline to 75 +/- 26 ms during ischemia (p = 0.001). The upper limit of vulnerability (baseline vs. ischemia: 294 +/- 44 vs. 274 +/- 53 V, p = 0.21) and the defibrillation threshold (271 +/- 33 vs. 268 +/- 42 V, p = 0.74) remained unchanged during ischemia. CONCLUSIONS: Acute global ischemia caused a threefold increase in the width of the vulnerable window. This increase was associated with increased heterogeneity of ventricular activation and repolarization. Despite these marked changes, the upper limit of vulnerability and the defibrillation threshold were not affected by acute myocardial ischemia. Thus, the previously reported similarity between both measures was maintained under these adverse conditions.

Relation between repolarization and refractoriness in the human ventricle: cycle length dependence and effect of procainamide.

The cycle length dependence of the action potential duration and the effective refractory period of the right ventricular endocardium were investigated in 24 patients undergoing electrophysiologic studies for suspected ventricular tachycardia. The action potential duration at 90% repolarization and the effective refractory period at twice diastolic threshold strength were measured at the same catheter site at steady state cycle lengths of 350 to 600 ms. Both measurements decreased linearly with decreasing cycle length, maintaining a parallel relation. When the relation between action potential duration and effective refractory period was expressed as the effective refractory period-action potential duration difference, nearly constant values (range -12 to -15 ms) were obtained at all cycle lengths. To determine whether sodium channel blocking drugs influence the effective refractory period-action potential duration relation in humans, measurements of these two variables were obtained in 15 patients before and during the infusion of procainamide. Procainamide prolonged the action potential duration at each cycle length by a near constant amount over baseline values (p less than 0.001). Procainamide also increased the effective refractory period at each cycle length but with a greater incremental increase at the shorter cycle lengths. The rate-dependent increase in the effective refractory period-action potential duration difference became significant at cycle lengths less than or equal to 400 ms; at these high rates, the effective refractory period-action potential duration difference became positive (1.6 ms, p less than 0.01 compared with baseline). Thus, in the human ventricle, the action potential duration and the effective refractory period have a close relation that remains fixed over a wide range of cycle lengths.(ABSTRACT TRUNCATED AT 250 WORDS)

The repolarization-excitability relationship in the human right atrium is unaffected by cycle length, recording site and prior arrhythmias.

OBJECTIVES: The goal of this study was to determine the relationship between repolarization and excitability in the human atrium under various conditions. BACKGROUND: Action potential duration (APD) measurements from monophasic action potential (MAP) recordings provide a surrogate for measuring the effective refractory period (ERP) in human ventricle. The relationship between repolarization and refractoriness in human atrium and the effect of prior atrial fibrillation/flutter on the ERP/APD correlation are unknown. METHODS: Seven patients with sinus rhythm and 15 patients after conversion of atrial flutter or fibrillation were evaluated. Monophasic action potentials were recorded at multiple right atrial sites and during different basic cycle lengths from 300 to 700 ms, while ERPs were determined by extrastimulus technique using the MAP recording-pacing combination catheter. RESULTS: There was a close correlation between ERP and APD at 70% repolarization (APD70, r = 0.97; p < 0.001) and 90% repolarization (APD90, r = 0.98; p < 0.001), respectively. Refractoriness occurred at a repolarization level of 72 +/- 8%. The ERP/APD70 and ERP/APD90 ratios averaged 1.06 +/- 0.10 and 0.86 +/- 0.08, respectively. These ratios were nearly constant over the entire range of basic cycle lengths, between different sites in individual patients and between different patients. Patients cardioverted from atrial fibrillation or flutter exhibited no significant differences in the ERP/APD relationship compared with patients with sinus rhythm. CONCLUSIONS: Effective refractory period and APD are closely related in the human right atrium. Using the MAP recording technique, atrial ERPs can be assessed by measurement of APDs. Effective refractory period is most closely reflected by APD70. Thus, MAP recordings allow investigation of the local activation and repolarization time course beat by beat, visualizing the excitable gap.

Electrical remodeling of the human atrium: similar effects in patients with chronic atrial fibrillation and atrial flutter.

OBJECTIVES: This study sought to determine whether chronic atrial fibrillation (AF) and atrial flutter in patients lead to electrical remodeling of the human atrial myocardium, manifested by an abnormal relation between atrial cycle length and action potential duration (APD). BACKGROUND: Experimental studies in goats and isolated human atrial tissue have shown that prolonged AF leads to persistent shortening of atrial refractoriness, a phenomenon referred to as electrical remodeling and which helps to explain why AF begets AF. Direct data on human in situ myocardium are still lacking. METHODS: Using monophasic action potential recordings at two right atrial sites simultaneously, we determined in 7 patients with chronic AF and 13 with chronic atrial flutter (3 weeks to 3 years in duration) the relation between paced cycle length and APD at 90% repolarization (APD90) 15 to 30 min after conversion to sinus rhythm. APD90 was measured during regularly paced cycle lengths (250 to 800 ms) to determine the steady state cycle length relation and during extrastimulus intervals (from 800 ms to refractoriness) at a basic cycle length of 600 ms to determine electrical restitution curves. The same pacing protocols and measurements were performed in nine control patients with sinus rhythm and no overt atrial disease. RESULTS: In control patients, steady state APD90 increased steadily with increases in cycle length from 250 to 800 ms, reaching a maximal value of 325 +/- 41 ms (mean +/- SD) at a cycle length of 800 ms. In patients with cardioversion from atrial flutter or AF, the steady state cycle length-APD90 relation was shifted downward and flattened at cycle lengths >400 ms, reaching only 219 +/- 44 and 245 +/- 39 ms, respectively, at the 800-ms cycle length (p < 0.005 vs. control). The early time course of electrical restitution (200- to 300-ms extrastimulus intervals) was similar between all three groups, but at extrastimulus intervals >350 ms, APD90 was shorter in both the AF and atrial flutter groups than in the control group (p < 0.05). There were no significant differences between patients with cardioversion from atrial flutter and those with cardioversion from AF. APD90 at a steady state cycle length of 600 ms showed no significant correlation with the duration of previous AF or atrial flutter. CONCLUSIONS: AF and atrial flutter lead to marked, quantitatively similar decreases in the right atrial APD during steady state pacing and extrastimulation a considerable time after cardioversion. These data confirm that both AF and atrial flutter lead to electrical remodeling in the human atrium, with a preponderance at longer cycle lengths. It may be prudent to abort both types of arrhythmias early to prevent electrical remodeling.

High dispersion of ventricular repolarization after an implantable defibrillator shock predicts induction of ventricular fibrillation as well as unsuccessful defibrillation.

OBJECTIVES: To test the hypothesis that post-shock dispersion of repolarization (PSDR) is higher in T wave shocks that induce ventricular fibrillation (VF) than in those that do not, as well as in implantable cardioverter defibrillator (ICD) defibrillation shocks which fail to terminate VF when compared with those that are successful. BACKGROUND: Ventricular fibrillation has been linked to the presence of dispersion of repolarization, which facilitates reentry. Most of the studies have been done in animals, and the mechanism underlying the generation and termination of VF in humans is speculative and remains to be determined. METHODS: Monophasic action potentials (MAPs) were recorded simultaneously from the right ventricular outflow tract (RVOT) and the right ventricular apex (RVA) in 27 patients who underwent implantation and testing of an ICD. T wave shocks were used to induce VF while the termination was attempted using internal defibrillator shocks. The post-shock repolarization time (PSRT) was measured in both the RVA and RVOT MAPs, and the difference between the two recordings was defined as the PSDR. The averages of PSDR were compared between the successful and unsuccessful inductions and terminations of VF. RESULTS: T wave shocks that induced VF generated a greater PSDR (93.4 +/- 85.1 ms) than the unsuccessful ones (45.1 +/- 55.9 ms, p < 0.001). On the other hand, shocks that failed to terminate VF were associated with a greater PSDR (59.9 +/- 41.2 ms) than shocks that terminated VF (21.1 +/- 20.1 ms), p < 0.001. CONCLUSIONS: A high PSDR following a T wave shock is associated with induction of VF; while following a defibrillating shock, it is associated with its failure and the continuation of VF. Conversely, a low PSDR is associated with failure of a T wave shock to induce VF and successful termination of VF by a defibrillating shock.

A new single catheter technique for simultaneous measurement of action potential duration and refractory period in vivo.

In vivo correlations of action potential duration measured by a monophasic action potential catheter and effective refractory period measured by a separate pacing catheter have been poor, probably because of the known variability of both action potential duration and effective refractory period between different ventricular sites. In this study, a new quadripolar contact electrode catheter designed for simultaneous pacing and monophasic action potential recording at closely adjacent sites (2 mm separation between recording electrodes and pacing electrodes) was tested in five closed chest dogs and four patients. Dog studies: Pacing thresholds were extremely low, ranging from 0.02 to 0.25 mA (mean +/- SD 0.099 +/- 0.051, n = 36) and were stable over time (less than 20% increase during 1 h of continuous pacing). Because of the close proximity of pacing and recording electrodes, the pacing artifact nearly coincided with the monophasic action potential upstroke. Because of the low pacing threshold, however, pacing artifacts were small (33 +/- 17% of the monophasic action potential amplitude at twice diastolic threshold strength) and did not affect the duration or configuration of the simultaneously recorded monophasic action potential. The short stimulus response time and the undisturbed monophasic action potential signal fidelity during pacing allowed precise simultaneous measurements of action potential duration and effective refractory period at the same endocardial site.(ABSTRACT TRUNCATED AT 250 WORDS)

Rate-dependence of QT dispersion and the QT interval: comparison of atrial pacing and exercise testing.

OBJECTIVES: The study was done to determine whether variables of QT dispersion from the 12-lead electrocardiogram (ECG) are dependent on heart rate. BACKGROUND: The dispersion of the QT interval is under evaluation as a risk marker in patients at risk for ventricular arrhythmias. Assuming that a similar rate correction is necessary as for the QT interval itself, investigators have frequently reported QTc-dispersion values utilizing the Bazett formula. It is not known whether there is a physiologic basis for such a rate correction in the human heart. METHODS: In 35 patients referred for evaluation of ventricular arrhythmias, digital 12-lead ECGs recorded at various heart rates during submaximal exercise testing and again during atrial pacing upon electrophysiologic testing were submitted to computerized interactive analysis of several ECG dispersion variables. RESULTS: Data from 11 patients were excluded due to incomplete high-quality analysis possible at all heart rates. From the remaining 24 patients, a total of 193 ECG recordings at various heart rates (ranging from 76 +/- 17 beats/min to 117 +/- 14 beats/min during atrial pacing and from 78 +/- 18 beats/min to 110 +/- 14 beats/min during exercise testing) were available. A highly significant linear relationship with heart rate was found for both the QT interval and the Q-to-T-peak interval. By contrast, standard QT interval dispersion (QTmax - QTmin), the T-peak-to-T-end interval, and the average area under the T wave did not change with increasing heart rates. CONCLUSIONS: Dispersion of the QT interval and other ECG variables of dispersion of ventricular repolarization are independent of heart rate. Therefore, it is not necessary to rate-correct these measurements.

Mechanically induced action potential changes and arrhythmia in isolated and in situ canine hearts.

Stretch of excised myocardial tissue causes electrophysiological and potentially arrhythmogenic changes in transmembrane action potentials but corresponding data of the intact mammalian heart are lacking. The effects of increases in ventricular volume and pressure on epicardial monophasic action potentials were therefore investigated in isolated, cross circulated and in situ canine hearts. In seven isolated hearts, increases in ventricular volume and pressure resulted in (1) a linearly related decrease in action potential amplitude (r = 0.988; slope = 0.41% amplitude.ml-1; volume intercept = 17.6 ml), mainly due to a decrease in maximum diastolic potential; (2) a decrease in action potential plateau duration (at 20% repolarisation) by 19 (SD 8)%; and (3) appearance of early afterdepolarizations, reaching up to 18% of total action potential amplitude. Afterdepolarizations occurred only when ventricular outflow was obstructed at end diastole but not at end systole. In eight in situ hearts, increase in left intraventricular pressure produced by transient occlusions of the ascending aorta was also accompanied by decrease in maximum diastolic potential and action potential plateau duration, and by appearance of early afterdepolarizations. In both isolated and in situ intact ventricles, the loading induced electrophysiological changes were associated with occurrence of ectopic ventricular beats. These data show that mechanical overload produces significant electrophysiological changes in the intact canine ventricle which may lead to arrhythmia.

The vulnerable period for low and high energy T-wave shocks: role of dispersion of repolarisation and effect of d-sotalol.

INTRODUCTION: The induction of ventricular fibrillation (VF) by T-wave shocks has been related to dispersion of repolarisation, but only indirect evidence of this hypothesis exists. The effects of drugs prolonging repolarisation like d-sotalol on the vulnerability to T-wave shocks remain unknown. METHODS: In 9 isolated rabbit heart, 7 monophasic action potentials (MAPs) and an ECG were recorded simultaneously. Vulnerable periods were determined using two different shock strengths, one close to the fibrillation threshold and the other close to the upper limit of vulnerability, at baseline and after action potential prolongation by d-sotalol. RESULTS: The vulnerable period had a duration of 30 +/- 14 ms for the lower and 34 +/- 12 ms for the higher shock strength (P = NS). Coupling intervals of the vulnerable periods were 13 +/- 10 ms shorter for higher shock strengths as compared to lower shock strengths (P < 0.005). The vulnerable period for low shock strengths coincided with dispersion of MAPs at 90% repolarisation (r = 0.87-0.92, P < 0.005), and the vulnerable period for high shock strengths coincided with dispersion at 70% repolarisation (r = 0.82-0.93, P < 0.005). ECG parameters predicted the vulnerable periods less precisely than MAP repolarisation (r < or = 0.72). d-Sotalol prolonged MAP durations by an average of 33 ms at 70% and 39 ms at 90% repolarisation but did not alter the described relations, nor did it reduce dispersion of repolarisation or duration of the vulnerable periods. CONCLUSIONS: Dispersion of repolarisation determines vulnerable periods and might be part of the arrhythmogenic substrate promoting induction of VF by T-wave shocks. The coupling intervals of the vulnerable periods depend on the applied shock strength as well as repolarisation, with shock strengths close to the fibrillation threshold inducing VF during dispersion at 90% repolarisation and shock strengths close to the upper limit of vulnerability inducing VF during dispersion at 70% repolarisation. d-Sotalol reduces neither vulnerability to T-wave shocks nor dispersion of repolarisation in this isolated heart model.

Stretch-induced voltage changes in the isolated beating heart: importance of the timing of stretch and implications for stretch-activated ion channels.

OBJECTIVES: It is now well recognized that myocardial stretch can cause arrhythmias due to stretch-induced depolarizations. The effects of transient stretch applied during the various phases of the cardiac action potential have not been investigated. This study (1) examined the effects of short stretch pulses and sustained stretch on the monophasic action potential (MPA) repolarization time course and diastolic potential, (2) examined the arrhythmic response to differently timed stretch pulses, and (3) tested by comparison with computer simulations whether these effects are compatible with stretch-activated channel characteristics known from patch-clamp studies. METHODS: We studied the MAP changes elicited by short transient stretch pulses applied at different times during the cardiac cycle to 8 isolated Langendorff-perfused rabbit hearts. The left ventricle (LV) was instrumented with a fluid-filled balloon, the volume of which was altered rapidly and precisely by means of a computer-controlled linear motor-driven piston. MAPs were recorded simultaneously from one right ventricular (RV) and two LV sites while short volume pulses of increasing amplitude were applied to the LV at variable delays after the last of 8 regular electrical pacing stimuli. The effect of pulsatile volume pulses applied at different phases of electrical systole and diastole was compared to the effect of sustained stretch pulses (60 s duration) of the same amplitude. The experimental results were compared with computer simulations of stretch-induced effects on the action potential to further validate the experimentally measured effects with theoretical predictions based on the Oxford Heart model with added stretch channel terms. RESULTS: Stretch pulses applied during early systole caused a brief transient repolarization during the LV MAP plateau phase, with a maximal amplitude of 24 +/- 10% of the total MAP amplitude. Stretch pulses at the end of the MAP caused a transient depolarization, with a maximal amplitude of 13 +/- 5%. These oppositely polarized stretch effects crossed over during a transitional range of repolarization (mean 65 +/- 9% of repolarization) when stretch produced neither transient repolarizations nor depolarizations. Only stretch pulses applied at a mean repolarization level of 77 +/- 5% or later led to arrhythmias, preceded by transient depolarizations. No corresponding de- or repolarizations were seen in MAPs recorded simultaneously from the unstretched RV. The effects of long pulses on the MAP waveform were nearly identical to an overlay plot of the effects of many differently timed short transient pulses. When the stretch-induced voltage changes in the MAP were plotted against the repolarization level at which they were produced, a linear relationship was found (mean correlation coefficient r = 0.97; P < 0.0001) with a reversal at approximately half the total MAP amplitude. The computer simulations of the influence of stretch-activated channels reproduced both the effects of short and sustained stretch seen in the MAP recordings. CONCLUSIONS: We demonstrated in the isolated beating heart that the electrophysiologic effects of sudden myocardial stretch depend on the timing of the stretch relative to electrical systole or diastole. These findings are in agreement with patch clamp studies on stretch-activated ion channels which showed a linear current/voltage relation with a reversal potential between -20 and -30 mV. Only stretch pulses applied at the end of the action potential or during diastole elicit ectopic beats as a result of transient depolarizations, while stretch pulses applied during phase 2 and 3 cause transient repolarizations or no effect, respectively.

Long-term recording of monophasic action potentials from human endocardium.

In 36 patients undergoing routine cardiac catheterization, a new "contact electrode" catheter technique was used to record monophasic action potentials (MAPs) from right atrial and right and left ventricular endocardial sites without the application of suction. Although of smaller amplitude, typically ranging from 15 to 40 mV, and of different reversal ratio (33 +/- 3%), MAP recordings closely resembled transmembrane action potentials in configuration and duration. Continuous MAP recordings of stable amplitude and, during regular pacing, of constant duration (+/- 1% at 90% repolarization) could be made from the same endocardial site for test periods of 1 hour (n = 4), permitting direct evaluation of the effect of cycle length alterations on local myocardial repolarization. A linear relation was found between MAP duration and basic cycle length varying from 350 to 700 ms. These rate-dependent changes in MAP duration were caused by a change in the slow phase of repolarization (phase 2), whereas the slope of rapid repolarization (phase 3) was unaltered. Single premature MAPs or MAPs after a pause showed changes in both phases. No MAPs could be recorded in areas of infarcted, aneurysmal myocardium, indicating that local viable myocardium is a prerequisite for the generation of the monophasic signal. Thus, in human subjects this catheter permits safe, long-term recording of MAPs which, although of smaller amplitude than transmembrane action potentials, bear appropriate and predictable phase relations. Such recordings may be useful in evaluating changes in local myocardial electrical activity induced by pacing or resulting from myocardial disease, or both.

Immediate quantitation of antiarrhythmic drug effect by monophasic action potential recording in coronary artery disease.

A contact electrode catheter, which permits clinical recording of cardiac monophasic action potentials (MAPs), was used as a means of quantifying the electrophysiologic effect of 2 antiarrhythmic drugs, procainamide and quinidine. MAP recordings were made in continuous fashion from the right ventricle in 16 patients, before and after the intravenous administration of procainamide (11 patients) or quinidine (5). Increases in the MAP duration at 90% repolarization (MAPD90) were used as indexes of drug effect and related to plasma drug level. Surface electrocardiographic (QRS duration, corrected QT interval [QTC]) and electrophysiologic (ventricular effective refractory period) measurements, in addition to MAPD90, were made at the same time as blood sampling for plasma drug level determination. Dose response curves, plotting change in MAPD90 versus plasma drug level, showed strong linear correlation for both procainamide (p less than 0.0001) and quinidine (p less than 0.0001). The variance (error of estimation) of the predictive relation, change in MAPD90 versus plasma drug level, was significantly lower than that of change in QTC (p less than 0.001), QRS duration (p less than 0.0001) or ventricular effective refractory period (p less than 0.0001) versus plasma drug level for both procainamide and quinidine. Changes in MAP duration closely correlate with plasma drug level, and as such, may serve as an immediate, quantitative indicator of myocardial drug effect during the administration of antiarrhythmic agents.

Electropharmacology of flestolol for supraventricular tachycardia without associated structural heart disease.

Flestolol is an ultrashort-acting beta-blocking drug with a half-life of 6.9 minutes. Its antiarrhythmic efficacy was studied in 21 patients with spontaneous and inducible supraventricular tachycardia: atrioventricular (AV) nodal tachycardia in 6 patients and orthodromic AV reciprocating tachycardia in 15. It increased the effective refractory period of the AV node in all patients with AV nodal tachycardia (fast pathway, p less than 0.02; slow pathway, p less than 0.01), but did not alter the anterograde (n = 8) or retrograde (n = 9) refractory periods of accessory pathways. Flestolol prevented initiation of tachycardia by causing block in anterograde AV nodal conduction. It was more effective in patients with AV nodal tachycardia (5 of 6) than in those with AV reciprocating tachycardia (4 of 15, p less than 0.03). In patients in whom it was ineffective, the mean tachycardia cycle length increased by 54 ms because of an increase in AH interval (p less than 0.0001, n = 11). The cycle length of tachycardia induced 30 minutes after infusion was similar to the cycle length in the control state (354 vs 355 ms, n = 16). Flestolol's kinetics permitted clinically indicated electropharmacologic testing of a second antiarrhythmic drug in 8 patients and control of ventricular rate until arrhythmia surgery in 1 patient with incessant tachycardia. No hypotension or toxicity occurred. Our findings indicate that flestolol's principal antiarrhythmic effects are on the AV node, similar to the effects of other beta-blocking drugs. Its ultrashort duration of action is an advantage during electropharmacologic testing.

Effects of amiodarone on the circadian pattern of sudden cardiac death (Department of Veterans Affairs Congestive Heart Failure-Survival Trial of Antiarrhythmic Therapy).

Some antiarrhythmic drugs have been shown to influence the circadian pattern of sudden cardiac death (SCD). The effect of chronic amiodarone therapy on this pattern is unknown. This study determines the circadian pattern of deaths in the Congestive Heart Failure-Survival Trial of Antiarrhythmic Therapy (CHF-STAT) and compares the distribution of SCD between the amiodarone and the placebo arms of the trial. CHF-STAT was a multicenter trial that determined whether amiodarone reduces mortality in patients with heart failure and asymptomatic ventricular arrhythmias. The time of death was retrospectively analyzed in patients who died from pump failure and SCD. In patients who died suddenly, the circadian pattern of deaths was compared between patients receiving amiodarone and those receiving placebo. In CHF-STAT, 274 patients died during follow-up. The time of death was available in 65 of the 74 patients who died from pump failure, and in 96 of the 139 patients who died suddenly. There was a circadian variation of all SCDs compared with other deaths with a distinct peak during the morning (p = 0.04). A similar morning peak of sudden cardiac death was found in both the amiodarone (n = 42) and the placebo (n = 54) groups, and the overall circadian pattern did not differ between them (p = 0.16). In contrast, death from pump failure occurred equally distributed over time. Thus, SCD occurs predominantly during the morning, whereas death from heart failure does not exhibit a morning peak. Amiodarone does not influence the circadian pattern of SCD.

Sudden cardiac death and polymorphous ventricular tachycardia in patients with normal QT intervals and normal systolic cardiac function.

This study delineates the clinical spectrum of 15 patients with polymorphic ventricular tachycardia and normal QT intervals in the absence of apparent structural heart disease, adverse drug effects, or electrolyte disturbances. Patients presented with either palpitations (n = 2), presyncope (n = 5), syncope (n = 4), no symptoms (n = 1), or aborted sudden death (n = 3). Mean age was 41 years (range 20 to 64), and mean follow-up 38 months (range 4 to 109). Left ventricular function was normal as determined by either echocardiogram (n = 9) or left ventriculography (n = 9). Episodes of polymorphic ventricular tachycardia (VT) were analyzed in terms of the preceding interval, and the relation of the initiating coupling interval to the QT interval (coupling interval/QT interval = polymorphic VT index). The mean QT for the group as a whole was 0.41 +/- 0.02 second. Patients could be separated into 3 distinct groups. Four patients had polymorphic VT reproducibly induced by exercise and initiated by late-coupled beats (mean polymorphic VT index 1.27 +/- 0.21). Isoproterenol induced polymorphic VT in 3 of 4 patients, and all 4 responded to chronic beta blockade. Two patients had polymorphic VT during episodes of coronary artery spasm, and both responded to calcium channel blockade. Polymorphic VT unrelated to exertion or coronary vasospasm occurred in 9 patients. Tachycardia onset was initiated by closely coupled beats (mean polymorphic VT index 0.95 +/- 0.16), and was preceded by a pause in 4 patients, and no pause in 5 patients. Sudden death occurred in 5 of 9 patients with the shortest polymorphic VT indexes.(ABSTRACT TRUNCATED AT 250 WORDS)