Fixed Rate Atrial Pacing Research Articles

Reverse electrical and structural remodeling of the left atrium occurs early after pulmonary vein isolation for persistent atrial fibrillation.

Adverse left atrial (LA) remodeling is known to be associated with persistent atrial fibrillation (PeAF). The time course and pattern of reversal of LA remodeling following catheter ablation is poorly understood. We aimed to evaluate LA chamber volumes and dimensions, LA conduction velocities, and LA bipolar voltages at baseline and at 2months after catheter ablation for PeAF. Twenty-three patients with PeAF underwent detailed LA mapping during fixed rate atrial pacing using the CARTO3 navigation system prior to undergoing pulmonary vein isolation. All patients returned for protocol-mandated repeat electrophysiology study at 2months, irrespective of symptoms or arrhythmia recurrence, during which all measurements were repeated using an identical mapping protocol. Patients then underwent daily ECG monitoring for 12months. Nineteen out of twenty-three (83.6%) patients had durable PVI of all veins at repeat electrophysiology study, while 4 (17.4%) patients had late reconnection of a single vein each. In the blinded offline analysis, LA volume at follow-up was significantly lower as compared with baseline (55 ± 14mL/m2 vs. 65 ± 15mL/m2, P < 0.001). LA conduction velocities were significantly greater at 2months (0.90 ± 0.13m/s vs. 0.78 ± 0.13m/s, P = 0.01). There was non-uniform regional LA voltage evolution, with a significant increase in bipolar voltages observed on the LA posterior wall (2.18 ± 0.85mV vs. 1.83 ± 0.49mV, P = 0.04), but not elsewhere. Individual variables of remodeling were not associated with AF recurrence. Significant structural and electrical reverse remodeling of the LA can be seen as early as 2months following successful catheter ablation for PeAF.

Acute Enhancement of Cardiac Function by Phosphodiesterase Type 1 Inhibition.

Phosphodiesterase type-1 (PDE1) hydrolyzes cAMP and cGMP and is constitutively expressed in the heart, although cardiac effects from its acute inhibition in vivo are largely unknown. Existing data are limited to rodents expressing mostly the cGMP-favoring PDE1A isoform. Human heart predominantly expresses PDE1C with balanced selectivity for cAMP and cGMP. Here, we determined the acute effects of PDE1 inhibition in PDE1C-expressing mammals, dogs, and rabbits, in normal and failing hearts, and explored its regulatory pathways. Conscious dogs chronically instrumented for pressure-volume relations were studied before and after tachypacing-induced heart failure (HF). A selective PDE1 inhibitor (ITI-214) was administered orally or intravenously±dobutamine. Pressure-volume analysis in anesthetized rabbits tested the role of β-adrenergic and adenosine receptor signaling on ITI-214 effects. Sarcomere and calcium dynamics were studied in rabbit left ventricular myocytes. In normal and HF dogs, ITI-214 increased load-independent contractility, improved relaxation, and reduced systemic arterial resistance, raising cardiac output without altering systolic blood pressure. Heart rate increased, but less so in HF dogs. ITI-214 effects were additive to β-adrenergic receptor agonism (dobutamine). Dobutamine but not ITI-214 increased plasma cAMP. ITI-214 induced similar cardiovascular effects in rabbits, whereas mice displayed only mild vasodilation and no contractility effects. In rabbits, β-adrenergic receptor blockade (esmolol) prevented ITI-214-mediated chronotropy, but inotropy and vasodilation remained unchanged. By contrast, adenosine A2B-receptor blockade (MRS-1754) suppressed ITI-214 cardiovascular effects. Adding fixed-rate atrial pacing did not alter the findings. ITI-214 alone did not affect sarcomere or whole-cell calcium dynamics, whereas β-adrenergic receptor agonism (isoproterenol) or PDE3 inhibition (cilostamide) increased both. Unlike cilostamide, which further enhanced shortening and peak calcium when combined with isoproterenol, ITI-214 had no impact on these responses. Both PDE1 and PDE3 inhibitors increased shortening and accelerated calcium decay when combined with forskolin, yet only cilostamide increased calcium transients. PDE1 inhibition by ITI-214 in vivo confers acute inotropic, lusitropic, and arterial vasodilatory effects in PDE1C-expressing mammals with and without HF. The effects appear related to cAMP signaling that is different from that provided via β-adrenergic receptors or PDE3 modulation. ITI-214, which has completed phase I trials, may provide a novel therapy for HF.

Effect of Loss of Heart Rate Variability on T-Wave Heterogeneity and QT Variability in Heart Failure Patients: Implications in Ventricular Arrhythmogenesis.

Heart rate variability (HRV) modulates dynamics of ventricular repolarization. A diminishing value of HRV is associated with increased vulnerability to life-threatening ventricular arrhythmias, however the causal relationship is not well-defined. We evaluated if fixed-rate atrial pacing that abolishes the effect of physiological HRV, will alter ventricular repolarization wavefronts and is relevant to ventricular arrhythmogenesis. The study was performed in 16 subjects: 8 heart failure patients with spontaneous ventricular tachycardia [HFVT], and 8 subjects with structurally normal hearts (H Norm). The T-wave heterogeneity descriptors [total cosine angle between QRS and T-wave loop vectors (TCRT, negative value corresponds to large difference in the 2 loops), T-wave morphology dispersion, T-wave loop dispersion] and QT intervals were analyzed in a beat-to-beat manner on 3-min records of 12-lead surface ECG at baseline and during atrial pacing at 80 and 100bpm. The global T-wave heterogeneity was expressed as mean values of each of the T-wave morphology descriptors and variability in QT intervals (QTV) as standard deviation of QT intervals. Baseline T-wave morphology dispersion and QTV were higher in HFVT compared to H Norm subjects (p≤0.02). While group differences in T-wave morphology dispersion and T-wave loop dispersion remained unaltered with atrial pacing, TCRT tended to fall more in HFVT patients compared to H Norm subjects (interaction p value=0.086). Atrial pacing failed to reduce QTV in both groups, however group differences were augmented (p<0.0001). Atrial pacing and consequent loss of HRV appears to introduce unfavorable changes in ventricular repolarization in HFVT subjects. It widens the spatial relationship between wavefronts of ventricular depolarization and repolarization. This may partly explain the concerning relation between poorer HRV and the risk of ventricular arrhythmias.

136-02: Effect of Loss of Heart Rate Variability on T-wave Heterogeneity and QT Variability in Heart Failure Patients: Implications in Ventricular Arrhythmogenesis

Background: A diminishing value of heart rate variability (HRV) robustly increases vulnerability to life-threatening ventricular arrhythmias, yet the electrophysiological mechanism of this dynamic relationship is still not well understood. We evaluated if fixed-rate atrial pacing, that abolishes the effect of physiological HRV, will modulate ventricular repolarization wavefronts and is relevant to ventricular arrhythmogenesis. Methods: The study was performed in 16 subjects: 8 heart failure patients with history of spontaneous ventricular tachycardia [HFVT], and 8 subjects with structurally normal hearts (HNorm). The T-wave heterogeneity descriptors [total cosine angle between QRS and T-wave loop vectors (TCRT, negative value corresponds to large difference in the 2 loops), T-wave morphology dispersion, T-wave loop dispersion] and QT intervals were analyzed in a beat-to-beat manner on 3-minutes records of 12-lead surface ECG at baseline and during atrial pacing at physically inert rates of 80 and 100 bpm. The global T-wave heterogeneity was expressed as mean values of each of the T-wave morphology descriptors and variability in QT intervals (QTV) as standard deviation of QT intervals. Results: Baseline T-wave morphology dispersion and QTV were higher in HFVT compared to HNorm subjects (p ≤ 0.02). While group differences in T-wave morphology dispersion and T-wave loop dispersion remained unaltered with atrial pacing, TCRT tended to fall more in HFVT patients compared to HNorm subjects (interaction p value = 0.086). Atrial pacing failed to reduce QTV in both groups, however group differences were augmented (p < 0.0001). Conclusions: Atrial pacing and consequent loss of HRV appears to introduce unfavorable changes in ventricular repolarization in HFVT subjects. It widens the spatial relationship between wavefronts of ventricular depolarization and repolarization (Figure). This may partly explain the concerning relation between poorer HRV and the risk of ventricular arrhythmias.

Autonomic modulation of repolarization instability in patients with heart failure prone to ventricular tachycardia

QT variability (QTV) signifies repolarization lability, and increased QTV is a risk predictor for sudden cardiac death. The aim of the present study was to investigate the role of autonomic nervous system activity on QTV. This study was performed in 29 subjects: 10 heart failure (HF) patients with spontaneous ventricular tachycardia [HFVT(+)], 10 HF patients without spontaneous VT [HFVT(-)], and 9 subjects with structurally normal hearts (HNorm). The beat-to-beat QT interval was measured on 3-min records of surface ECGs at baseline and during interventions (atrial pacing and esmolol, isoprenaline, and atropine infusion). Variability in QT intervals was expressed as the SD of all QT intervals (SDQT). The ratio of the SDQT to SD of RR intervals (SDRR) was calculated as an index of QTV normalized to heart rate variability. There was a trend toward a higher baseline SDQT-to-SDRR ratio in the HFVT(+) group compared with the HFVT(-) and HNorm groups (P = 0.09). SDQT increased significantly in the HFVT(+) and HFVT(-) groups compared with the HNorm group during fixed-rate atrial pacing (P = 0.008). Compared with baseline, isoprenaline infusion increased SDQT in HNorm subjects (P = 0.02) but not in HF patients. SDQT remained elevated in the HFVT(+) group relative to the HNorm group despite acute β-adrenoceptor blockade with esmolol (P = 0.02). In conclusion, patients with HF and spontaneous VT have larger fluctuations in beat-to-beat QT intervals. This appears to be a genuine effect that is not solely a consequence of heart rate variation. The effect of acute autonomic nervous system modulation on QTV appears to be limited in HF patients.

Point:Counterpoint: Respiratory sinus arrhythmia is due to a central mechanism vs. respiratory sinus arrhythmia is due to the baroreflex mechanism

Blood pressure and heart periods fluctuate at respiratory frequencies in healthy humans. Some researchers ([8][1], [23][2]) explain this as a cause-and-effect relation: blood pressure changes trigger baroreflex-mediated R-R interval changes. Here I make the case that respiratory sinus arrhythmia is

Modulation of the myocardial redox state by vagal nerve stimulation after experimental myocardial infarction

Redox alteration plays a major role in the pathogenesis of heart failure (HF). Since vagal nerve stimulation (VNS) is known to improve survival and attenuate cardiac remodelling, we hypothesized that VNS may modulate the myocardial redox state. Using a chronic HF mouse model, we applied VNS for 15 min and measured myocardial redox status using in vivo electron spin resonance spectroscopy. Signal decay rate of the nitroxyl probe, an index of redox status, was enhanced in HF compared with sham (0.16 +/- 0.01 vs. 0.13 +/- 0.01 min(-1), P < 0.05; n = 6), and VNS normalized this enhancement (0.13 +/- 0.01 min(-1), P < 0.05). Atropine sulphate abolished the VNS effects, indicating that the VNS modulates myocardial redox state via muscarinic receptors. N(omega)-Nitro-L-arginine methyl ester treatment and fixed-rate atrial pacing showed a trend to suppress the VNS effects, suggesting the involvement of nitric oxide-based signalling and myocardial oxygen consumption. Moreover, VNS decreased the myocardial norepinephrine (NE) level (0.25 +/- 0.07 vs. 0.60 +/- 0.12 ng/mL, P < 0.05; n = 6). Reactive oxygen species production from cultured cardiomyocytes was enhanced by beta-adrenergic activation, which was partially antagonized by 10 micromol/L acetylcholine (ACh) (relative value compared with control: NE 3.7 +/- 0.5, NE + ACh 2.5 +/- 0.3, P < 0.05; n = 12). The present study suggests that VNS modulates the cardiac redox status and adrenergic drive, and thereby suppresses free radical generation in the failing heart.

Ambulatory ECG monitoring of T-Wave alternans for arrhythmia risk assessment

Experimental and clinical studies indicate a basic linkage between T-wave alternans (TWA) and susceptibility to malignant arrhythmias. In a variety of clinical populations with elevated risk of ventricular tachyarrhythmias, Fast Fourier Transform (FFT)-based assessment of TWA during fixed-rate atrial pacing or bicycle ergometry has shown predictive ability for arrhythmic events. However, after more than a decade since the introduction of TWA testing in human subjects, few studies have explored its utility in ambulatory ECG (AECG) recordings. This gap probably relates to major technical obstacles associated with monitoring of ambulatory subjects, including motion artifact and the requirement of data stationarity, which mandates fixing heart rate. To cicumvent these difficulties, we devised a time-domain method, “Modified Moving Average Beat Analysis” (MMA) to determine TWA level accurately in freely moving subjects. Recently, MMA analysis was employed to analyze ambulatory ECG (AECG) records of post-myocardial infarction patients who were were at low risk of arrhythmic death. An increased risk of arrhythmic death was predicted by TWA level above the 75 th percentile of controls ( p <.05). Thus, the predictive power of TWA obtained with MMA analysis from AECG records obtained appears promising.

Analysis of complex T-wave oscillations for prediction of ventricular fibrillation

Increased attention has been focused on oscillatory behavior of the T wave as a manifestation of heightened electrical instability and risk for ventricular fibrillation (VF). This interest has stemmed from an increasing number of experimental and clinical studies indicating that the relatively simple ABAB oscillation of T-wave alternans (TWA) can be quantified to assess risk for arrhythmias. However, an important unanswered question is whether TWA represents the initial phase of a stepwise progression to higher-order oscillations that culminate in sudden arrhythmic death. Signals were analyzed from epicardial and endocardial ECGs from anesthetized dogs subjected to LAD coronary artery occlusion during fixed-rate atrial pacing. Our study was the first to demonstrate a stepwise increase in complexity of T-wave oscillations from TWA to T-wave tripling and quadrupling and to more complex forms just prior to onset of VF ( Circ Res 2002;91:727–732). Discordant T-wave episodes, when T waves alternated out-of-phase, were found to be associated with increases in T-wave complexity and VF. None of the animals that failed to fibrillate exhibited discordant TWA. In these observations, complexity of T-wave oscillations points to a fundamental mechanistic link underlying the ability of TWA to predict lethal arrhythmias.

Heart rate-independent vagal effect on end-systolic elastance of the canine left ventricle under various levels of sympathetic tone.

Although we have shown that in rabbits the direct (heart rate [HR]-independent) vagal effect on left ventricular end-systolic elastance (E(es)) was negligible under minimal sympathetic tone, how underlying sympathetic tone modulates the inotropic response to vagal stimulation remains unknown. We used an isolated canine heart preparation with functioning autonomic nerves. We examined the direct vagal inotropic effect by measuring E(es) under fixed-rate atrial pacing with or without concomitant sympathetic nerve stimulation. Right and left vagal stimulation at 20 Hz decreased HR by 27+/-3% and 14+/-2%, respectively, and decreased E(es) by 11+/-2% and 6+/-2%, respectively. When we fixed HR by atrial pacing, right and left vagal stimulation at 20 Hz did not decrease E(es) (0.01+/-0.3% and 0.3+/-0.4%; NS). Concomitant left sympathetic nerve stimulation at 4 Hz enhanced direct vagal negative inotropism to -19+/-3% and -34+/-5% for 20-Hz right and left vagal stimulation (interaction, P<0.01). Direct vagal negative inotropism was unobservable with minimal sympathetic tone in dogs but was enhanced with concomitant sympathetic stimulation.

Comparative Time Delays of QT Interval Adjustement to Heart Rate During Autonomic Blockade and After Fixed Rate Atrial Pacing in Young Normal Subjects

Comparative Time Delays of QT Interval Adjustement to Heart Rate During Autonomic Blockade and After Fixed Rate Atrial Pacing in Young Normal Subjects

Comparative time delays of QT interval adjustement to heart rate during autonomic blockade and after fixed rate atrial pacing in young normal subjects

Comparative time delays of QT interval adjustement to heart rate during autonomic blockade and after fixed rate atrial pacing in young normal subjects

Vagal stimulation decreases left ventricular contractility mainly through negative chronotropic effect.

Although an increase in vagal tone is known to slow heart rate (HR), whether it also depresses left ventricular contractility through mechanisms independent of the bradycardic effect remains unknown. The chief aim of this investigation, therefore, was the separation of the observed vagally mediated depression of ventricular contractility into direct and indirect vagal effects, the latter resulting via negative chronotropism. In 12 anesthetized, sympathectomized open-chest rabbits, we measured left ventricular contractility through determination of the end-systolic elastance (Ees). We found that tonic vagal stimulation administered at 0, 5, and 10 Hz decreased both HR (226.9 +/- 39.7, 201.9 +/- 25.7, and 171.3 +/- 18.5 beats/min, respectively; P = 0.0003) and Ees (109.5 +/- 25.7, 85.1 +/- 34.1, and 71.9 +/- 33.1 mmHg/ml, respectively; P = 5 x 10(-6)) in a frequency-dependent fashion. However, we observed that as long as HR was kept constant through fixed-rate atrial pacing, vagal stimulation resulted in little or no change in Ees. Thus we conclude that the negative inotropic effect of vagal stimulation is attributable primarily to its negative chronotropic effect when sympathetic tone is minimal.

Fundamental Relations Between Short-term RR Interval and Arterial Pressure Oscillations in Humans

One of the principal explanations for respiratory sinus arrhythmia is that it reflects arterial baroreflex buffering of respiration-induced arterial pressure fluctuations. If this explanation is correct, then elimination of RR interval fluctuations should increase respiratory arterial pressure fluctuations. We measured RR interval and arterial pressure fluctuations during normal sinus rhythm and fixed-rate atrial pacing at 17.2+/-1.8 (SEM) beats per minute greater than the sinus rate in 16 healthy men and 4 healthy women, 20 to 34 years of age. Measurements were made during controlled-frequency breathing (15 breaths per minute or 0.25 Hz) with subjects in the supine and 40 degree head-up tilt positions. We characterized RR interval and arterial pressure variabilities in low-frequency (0.05 to 0.15 Hz) and respiratory-frequency (0.20 to 0.30 Hz) ranges with fast Fourier transform power spectra and used cross-spectral analysis to determine the phase relation between the two signals. As expected, cardiac pacing eliminated beat-to-beat RR interval variability. Against expectations, however, cardiac pacing in the supine position significantly reduced arterial pressure oscillations in the respiratory frequency (systolic, 6.8+/-1.8 to 2.9 +/-0.6 mm Hg2/Hz, P=.017). In contrast, cardiac pacing in the 40 degree tilt position increased arterial pressure variability (systolic, 8.0+/-1.8 to 10.8 +/-2.6, P=.027). Cross-spectral analysis showed that 40 degree tilt shifted the phase relation between systolic pressure and RR interval at the respiratory frequency from positive to negative (9 +/-7 degrees versus -17+/-11 degrees, P=.04); that is, in the supine position, RR interval changes appeared to lead arterial pressure changes, and in the upright position, RR interval changes appeared to follow arterial pressure changes. These results demonstrate that respiratory sinus arrhythmia can actually contribute to respiratory arterial pressure fluctuations. Therefore, respiratory sinus arrhythmia does not represent simple baroreflex buffering of arterial pressure.

Autonomic Effects on the QT Interval

Background: This study was designed to evaluate the effects of autonomic tone on the QT interval, using conventional and heart rate independent analysis. Effects of autonomic tone on the QT interval have been studied either using rate correction formulae or during fixed rate atrial pacing, both of which have been associated with problems. Since most autonomic interventions are associated with heart rate changes, separation of “true” autonomic effects from rate related effects on the QT interval is essential.Methods: Electrocardiographic recordings were performed in 14 healthy volunteers during: (1) sympathetic stimulation (tilt, epinephrine infusion, isoproterenol infusion, and exercise); (2) β‐adrenergic blockade; (3) parasympathetic blockade; (4) autonomic blockade; (5) tilt following autonomic blockade; (6) parasympathetic stimulation (phenylephrine infusion); and (7) isolated α‐adrenergic stimulation (phenylephrine infusion following atropine). The QT interval was adjusted for heart rate using Bazett's formula. Heart rate independent analysis was performed between conditions with similar cycle lengths.Results: QT interval measurements were reproducible and exhibited the typical QT‐RR relationship. Sympathetic stimulation decreased the RR interval and prolonged the QTc interval. Parasympathetic blockade also increased the QTc. Heart rate independent analysis of the effects of β‐blockade showed a shortening of the QT (from 368.5 ± 20.5 ms to 355.9 ± 17.9 ms; n = 8). Alpha‐adrenergic stimulation also decreased the QT interval from 302.4 ± 16.8 ms to 294.3 ± 17.7 ms (n = 7).Conclusion: Sympathetic stimulation prolongs the QT interval, while β‐blockade shortens it. Alpha‐adrenergic stimulation also shortens the QT interval. Autonomic effects on the QT interval as assessed by heart rate independent analysis may help separate the true autonomic effects from rate related effects.

Atrioventricular nodal reverse alternating wenckebach periods during fixed-rate atrial pacing

Atrioventricular nodal reverse alternating wenckebach periods during fixed-rate atrial pacing

Acute electrophysiologic effects of an HT2-serotonin antagonist, ketanserin, in humans

The acute electrophysiologic effects of an intravenous bolus of ketanserin, a 5HT2 serotonin blocker, were studied in ten patients (four females, six males) during invasive electrophysiology. Following baseline electrophysiologic measurements during sinus rhythm and fixed-rate atrial pacing at 600 ms, a bolus of 0.2 mg/kg ketanserin was given over a 3-minute period. After 30 minutes all measurements were repeated. Systemic blood pressure was measured at regular intervals throughout. During sinus rhythm, there was no significant change in the basic cycle length or in the PA, AH, HV, QRS, QT, and QTc intervals. During atrial pacing there was a nonsignificant increase in the QT interval, from 342 +/- 13 ms to 366 +/- 16 ms, and a significant increase in the QTc interval, from 422 +/- 27 ms to 449 +/- 29 ms (p less than 0.05). There was no reduction in blood pressure. Thus ketanserin produced a significant prolongation of the QTc interval, in the absence of hypokalemia, in humans.

EFFECTS OF NEUROPEPTIDE Y ON BAROREFLEX CONTROL OF HEART RATE AND MYOCARDIAL CONTRACTILITY IN CONSCIOUS RABBITS

1. The effects of intravenous (i.v.) neuropeptide Y (NPY, 10 micrograms/kg bolus) on the stimulus-response curves relating changes in heart period (HP) and in peak left ventricular (LV) dP/dt to acute changes in mean arterial pressure (MAP) were determined in conscious, normotensive rabbits. 2. The relationship between increases and decreases in MAP and the subsequent changes in HP were represented by a sigmoid-shaped curve described by a logistic function. Following NPY administration there was a baroreflex-dependent increase in the maximum slope (sensitivity) at the midpoint of this MAP-HP curve from 7.0 +/- 0.5 to 10.6 +/- 1.3 ms/mmHg (P less than 0.05). NPY caused an upward shift in the whole curve which reflected the NPY-induced bradycardia and was independent of baroreflexes. 3. The relationship between increases in MAP and decreases in peak LV dP/dt was determined during fixed-rate atrial pacing to prevent the effects of the accompanying bradycardia. Increases in MAP and the corresponding reductions in peak LV dP/dt were represented by an exponential function. The slope of the curve, measured at its origin 5-15 min after NPY administration, was reduced from -0.9 +/- 0.2 to -0.4 +/- 0.1 units (P less than 0.05). 4. The effects of NPY are consistent with an action on efferent connections of the arterial baroreceptor reflex, mediated through a reduction in cardiac beta-adrenergic tone. They would also be explained through actions on the afferent or central neural connections of the baroreflex.

Clinical cardiac electrophysiologic evaluation of the positive inotropic agent, DPI 201-106.

DPI201-106 is a new positive inotropic agent. The cardiac electrophysiology of 16 patients was studied before and during DPI 201-106 administration (loading dose of intravenous DPI 201-106, 1.8 mg kg-1 h-1 administered over 10 min, followed by a maintenance dose of 0.2 mg kg-1 h-1). DPI 201-106 had no effect on the sinus node. The AH interval during fixed-rate atrial pacing became prolonged during DPI 201-106 infusion. There was a significant prolongation of the QT interval [QT (corrected), 417 +/- 22 to 502 +/- 35 ms, P less than 0.05; QT (atrial pacing at 600 ms), 374 +/- 17 to 419 +/- 23 ms, P less than 0.05; QT (ventricular pacing at 600 ms), 409 +/- 37 to 449 +/- 30 ms, P less than 0.05]. The ventricular effective refractory period significantly prolonged during DPI 201-106 administration (242 +/- 21 to 287 +/- 56 ms, P less than 0.05), but the supernormal-period duration decreased. The atrial effective refractory period was shortened in four patients and prolonged in one (261 +/- 67 to 240 +/- 53 ms, NS). The corrected atrial repolarization time (PTac) shortened significantly during DPI 210-106 infusion (479 +/- 26 to 445 +/- 22 ms at 20 min of the maintenance dose, P less than 0.05). Atrial fibrillation was initiated in five patients during DPI infusion, but no ventricular arrhythmia was provoked. These findings suggest that DPI 201-106 has novel differential electrophysiological effects on atria and ventricles.

Electropharmacology of sotalol in patients with Wolff-Parkinson-White syndrome.

The beta-adrenoceptor-blocking and class III effects of sotalol were assessed in 11 patients with inducible orthodromic reciprocating tachycardia. Serum sotalol concentration, maximum exercise heart rate, and electrophysiologic study data were obtained at control, at the beta-adrenoceptor-blocking dosage (407 +/- 149 mg/day, 1.4 +/- 0.5 micrograms/ml), and at the maximum well-tolerated dosage (924 +/- 337 mg/day, 3.2 +/- 1.3 micrograms/ml). Class III effects (increases in anterograde and retrograde accessory connection effective refractory periods, ventricular effective refractory period, and the QT interval during fixed-rate atrial pacing) were evident at the beta-adrenoceptor-blocking dosage of sotalol and became more marked at the maximum well-tolerated dosage. For example, the mean anterograde accessory connection effective refractory period was significantly increased over control (272 +/- 41 msec) by the beta-adrenoceptor blocker (324 +/- 52 msec) and was further significantly increased by the maximum well-tolerated dose (364 +/- 37 msec). Similarly, the minimum preexcited RR interval during atrial fibrillation was increased in all patients at each dosage tested. Antiarrhythmic efficacy, defined by the absence of inducible, sustained, orthodromic reciprocating tachycardia and a minimum preexcited RR interval during atrial fibrillation of 300 msec or greater, was achieved in four patients at the beta-adrenoceptor-blocking dosage and in another four patients at the maximum well-tolerated dosage. These eight patients received long-term sotalol therapy and none has had recurrent, sustained reciprocating tachycardia during 15 +/- 12 months of follow-up.(ABSTRACT TRUNCATED AT 250 WORDS)