Slow Pacing Rates Research Articles

Rate dependence of [Na+]i and contractility in nonfailing and failing human myocardium.

In the failing human heart, altered Ca2+ homeostasis causes contractile dysfunction. Because Ca2+ and Na+ homeostasis are intimately linked through the Na+/Ca2+ exchanger, we compared the regulation of [Na+]i in nonfailing (NF) and failing human myocardium. [Na+]i was measured in SBFI-loaded muscle strips. At slow pacing rates (0.25 Hz, 37 degrees C), isometric force was similar in NF (n=6) and failing (n=12) myocardium (6.4+/-1.2 versus 7.2+/-1.9 mN/mm2), but [Na+]i and diastolic force were greater in failing (22.1+/-2.6 mmol/L and 15.6+/-3.2 mN/mm2) than in NF (15.9+/-3.1 mmol/L and 3.50+/-0.55 mN/mm2; P<0.05) myocardium. In NF hearts, increasing stimulation rates resulted in a parallel increase in force and [Na+]i without changes in diastolic tension. At 2.0 Hz, force increased to 136+/-17% of the basal value (P<0.05), and [Na+]i to 20.5+/-4.2 mmol/L (P<0.05). In contrast, in failing myocardium, force declined to 45+/-3%, whereas [Na+]i increased to 27.4+/-3.2 mmol/L (both P<0.05), in association with significant elevations in diastolic tension. [Na+]i was higher in failing than in NF myocardium at every stimulation rate. [Na+]i predicted in myocytes from Na+ (pipette)-contraction relations was 8.0 mmol/L in NF (n=9) and 12.1 mmol/L in failing (n=57; P<0.05) myocardium at 0.25 Hz. Reverse-mode Na+/Ca2+ exchange induced significant Ca2+ influx in failing but not NF myocytes, compatible with higher [Na+]i in failing myocytes. Na+i homeostasis is altered in failing human myocardium. At slow heart rates, the higher [Na+]i in failing myocardium appears to enhance Ca2+ influx through Na+/Ca2+ exchange and maintain sarcoplasmic reticulum Ca(2+) load and force development. At faster rates, failing myocytes with high [Na+]i cannot further increase sarcoplasmic reticulum Ca2+ load and are prone to diastolic Ca2+ overload.

Progress toward the development of a safe and effective agent for treating reentrant cardiac arrhythmias: synthesis and evaluation of ibutilide analogues with enhanced metabolic stability and diminished proarrhythmic potential.

A series of ibutilide analogues with fluorine substituents on the heptyl side chain was prepared and evaluated for class III antiarrhythmic activity, metabolic stability, and proarrhythmic potential. It was found that fluorine substituents stabilized the side chain to metabolic oxidation. Many of the compounds also retained the ability to increase the refractoriness of cardiac tissue at both slow and fast pacing rates. The potential for producing polymorphic ventricular tachycardia in the rabbit model was dependent on the chirality of the benzylic carbon. The S-enantiomers generally had less proarrhythmic activity than the corresponding racemates. One compound from this series (45E, trecetilide fumarate) had excellent antiarrhythmic activity and metabolic stability and was devoid of proarrhythmic activity in the rabbit model. It was chosen for further development.

Effects of EGIS-7229 (S 21407), a novel class III antiarrhythmic drug, on myocardial refractoriness to electrical stimulation in vivo and in vitro.

The I(Kr) blocker EGIS-7229 (S-21407), displays class Ib and class IV effects that may alter its pharmacologic profile compared with those of pure I(Kr) blockers. Therefore, the concentration- and frequency-dependent effects of EGIS-7229, and of the I(Kr) blockers d,l-sotalol and dofetilide, on the effective refractory period (ERP) were measured in isolated right ventricular papillary muscle of the rabbit in vitro. The effects of these drugs on right ventricular fibrillation threshold (RVFT) at increasing intravenous doses were also determined in anesthetized cats. Dofetilide and d,l-sotalol increased ERP in a concentration-dependent manner (dofetilide: 3-100 nM; d,l-sotalol: 3-100 microM) with strong reverse frequency dependence at high concentrations. EGIS-7229 concentration dependently lengthened ERP at 1-30 microM. Its effect on ERP was clearly reverse frequency dependent at 3 microM, but this feature of the drug diminished at 10 microM and was not apparent at 30 microM. The effect of EGIS-7229 (30 microM) on ERP was devoid of reverse frequency dependence as it was more effective (31%) than dofetilide (16 %) at high-pacing rate (3 Hz), whereas it was less effective (50%) than dofetilide (70%) at slow-pacing rate (1 Hz). Reverse frequency-dependent ERP effect of dofetilide (100 nM) was similarly abolished by the addition of lidocaine (30 microM). EGIS-7229 (1-8 mg/kg iv), d,l-sotalol (1-8 mg/kg iv), and dofetilide (10-80 microg/kg iv) caused a dose-dependent increase in RVFT. The minimum effective dose of d,l-sotalol and EGIS-7229 was 1 and 2 mg/kg, respectively, whereas that of dofetilide was 10 microg/kg. EGIS-7229 induced a smaller peak effect in RVFT than sotalol or dofetilide. In conclusion, EGIS-7229 markedly increased refractoriness to electrical stimulation in vitro and in vivo. Compared with pure I(Kr) blockers, the benefits of EGIS-7229 seem to be a greater lengthening of effective refractory period at rapid stimulation rates, suggesting a strong antiarrhythmic action, and a smaller effect at slow stimulation rates, suggesting low potential to induce early afterdepolarizations.

Clinical evaluation of a pacemaker algorithm that adjusts the pacing rate during sleep using activity variance.

Even though rate responsive pacemakers are able to regulate pacing rates based on sensor activity, they are set with a minimum rate that is not adjusted to provide rate decreases during sleep. The aim of this study was to evaluate the performance of the "Sleep Rate" feature, as compared to patient diaries and a validated method that identifies sleep from wrist actigraphy. In 19 patients (15 men; age 69 +/- 8 years) with Pacesetter Trilogy DR+ pacemakers, the base rate and the sleep rate were set to 80 and 50 ppm, respectively. When the patients returned 2 days later, data recorded by the pacemaker and wrist actigraph were analyzed to find the agreement in corresponding sleep/wake periods. In 17 (89%) patients, the pacemaker went into the sleep mode. The total sleep time derived from actigraphy significantly exceeded the time during which the pacemaker was in sleep mode (1156.8 +/- 83.4 vs 307.3 +/- 77.2 minutes). Frequent reversions out of the sleep mode limited the total sleep time derived from the pacemaker. Cumulative analysis of the pacemaker data showed that the maximum time in the sleep mode was 78 minutes, and exceeded 1 hour in six instances, 30 minutes in 32 instances, and 15 minutes in 83 instances. Epoch by epoch comparisons revealed a good agreement (93.6 +/- 1.8%) during wakefulness between the corresponding actigraph and pacemaker epochs. However, only 24.6 +/- 3.7% of the corresponding epochs during sleep were identical, and the overall agreement was 54.4 +/- 3.7%. Except for one patient who reported palpitations, patients did not suffer from a pacemaker rate change. The Sleep Rate feature provides rate reduction during sleep, while assuring rapid frequency response during physical activity. However, the current algorithm does not allow long periods of slow pacing rate during continuous sleep, possibly due to its conservative design and the presence of movement arousals, which has to be improved in future generation algorithms.

Rate- and site-dependent effects of propafenone, dofetilide, and the new I(Ks)-blocking agent chromanol 293b on individual muscle layers of the intact canine heart.

Recent in vitro studies have demonstrated regional differences in electrophysiological properties of individual left ventricular muscle layers. Controversy exists on the relevance of these findings for the situation in vivo. Thus, this study was designed to determine whether the in vivo canine heart exhibits regional differences in left ventricular refractoriness and in the susceptibility to sodium and potassium channel blockers. In 16 dogs, 36 needle electrodes (12 mm long, 4 bipolar electrodes, interelectrode distance 2.5 mm) were inserted into the left ventricular wall. By use of a computerized multiplexer-mapping system, the spread of activation in epicardial, endocardial, and midmyocardial muscle was reconstructed during ventricular pacing at 300- and 850-ms basic cycle length (BCL). Effective refractory periods (ERPs) were determined at baseline and after application of propafenone (2 mg/kg), dofetilide (30 microg/kg), or chromanol 293b (10 mg/kg) by the extrastimulus technique (BCL 300 and 850 ms). At baseline, activation patterns and ERPs were uniform in all muscle layers. Propafenone homogeneously decreased conduction velocity and moderately prolonged ERPs without any regional differences. Dofetilide and chromanol 293b did not affect the spread of activation. Dofetilide exhibited reverse use-dependent effects on ERP, still preserving transmural homogeneity of refractoriness. Chromanol 293b led to a regionally uniform but more pronounced increase in local ERPs at faster than at slower pacing rates. At the heart rates applied, the in vivo canine heart does not exhibit regional differences in electrophysiological properties. Given the homogeneity of antiarrhythmic drug effects, induction of local gradients of refractoriness is obviously not a common mechanism of proarrhythmia in normal hearts.

Cellular Basis of Biventricular Hypertrophy and Arrhythmogenesis in Dogs With Chronic Complete Atrioventricular Block and Acquired Torsade de Pointes

In the dog with chronic complete atrioventricular block (AVB), torsade de pointes arrhythmias (TdP) can be induced reproducibly by class III antiarrhythmic agents. In vivo studies reveal important electrophysiological alterations of the heart at 5 weeks of AVB, resulting in increased proarrhythmia. Autopsy studies indicate the presence of biventricular hypertrophy. In this study, the cellular basis of proarrhythmia and hypertrophy in chronic AVB was investigated. From chronic-AVB dogs with increased heart weights and TdP, left midmyocardial and right ventricular myocytes were isolated by enzymatic dispersion. These myocytes were significantly larger than sinus rhythm (SR) controls. In chronic AVB, the action potential spike-and-dome configuration was preserved. However, the action potential duration (APD) at 95% and 50% of repolarization of the left midmyocardium was significantly larger in chronic AVB than in SR, with little change in the right ventricle, causing enhanced interventricular dispersion of repolarization at slow pacing rates. Treatment with the class III agent almokalant increased the APD to a much larger extent in chronic-AVB than in SR myocytes and resulted in a higher incidence of early afterdepolarizations (EADs). EADs had their takeoff potential between -35 and 0 mV. There was no evidence that spontaneous sarcoplasmic reticulum Ca2+ release underlies these EADs. In the dog, chronic AVB leads to hypertrophy of both right and left ventricular myocytes. The repolarization abnormalities predisposing for class III-dependent TdP in vivo are the results of cellular electrophysiological remodeling.

Modulation of atrioventricular nodal function by metabolic and allosteric regulators of endogenous adenosine in guinea pig heart.

There has been increasing interest in the development of agents that utilize endogenous adenosine to exert their actions. We tested the hypothesis that substances that either potentiate the activity (allosteric enhancers) or increase the interstitial concentration (inhibitors of metabolism) of endogenous adenosine may cause event (tachycardia)-specific depression of AV nodal conduction. The frequency-dependent effects of iodotubercidin (ITU, an inhibitor of adenosine kinase), erythro-9-(2-hydroxy-3-nonyl)adenine (EHNA, an inhibitor of adenosine deaminase), draflazine (a nucleoside transport blocker), and PD81,723 (an allosteric enhancer of the A1 adenosine receptor binding) on the stimulus-to-His bundle (SH) interval, a measure of AV nodal conduction, were determined in guinea pig hearts and compared with those of adenosine and diltiazem. All drugs depressed AV nodal conduction in a frequency-dependent manner. The ratios of SH interval prolongations at fast to slow pacing rates for draflazine, ITU + EHNA, PD81,723, adenosine, and diltiazem were 17.5 +/- 3.4, 11.1 +/- 5.0, 3.5 +/- 0.9, 10.1 +/- 2.8, and 8.3 +/- 3.5, respectively. Coincident with the prolongation of the SH interval at rapid pacing rates, draflazine and ITU + EHNA increased the epicardial fluid adenosine concentrations by 2.2- and 2.6-fold, respectively. In contrast, epicardial transudate levels of adenosine do not change in the presence of PD81,723. The AV nodal effects of draflazine, ITU, EHNA, and PD81,723 were reversed by the A1 adenosine receptor antagonist 8-cyclopentyltheophylline and adenosine deaminase, implicating endogenous adenosine acting at the A1 adenosine receptor. Adenosine-regulating agents that act in an event- and site-specific manner represent a novel drug design strategy that may potentially be valuable for the long-term treatment of supraventricular arrhythmias and control of ventricular rate during atrial fibrillation or flutter.

Characterization of return cycle responses predictive of successful pacing-mediated termination of ventricular tachycardia

Objectives. The purpose of this study was to characterize response patterns during overdrive pacing that predict successful termination of ventricular tachycardia.Background. Overdrive pacing during ventricular tachycardia typically results in entrainment at slow pacing rates and in termination or acceleration at faster rates. The factors that determine the critical paced cycle length that results in tachycardia termination have not been extensively studied.Methods. Ventricular tachycardias in 14 patients with coronary artery disease were studied with overdrive pacing at several cycle lengths. Return cycles were measured after each additional paced beat at each paced cycle length. The return cycle responses during pacing trials that resulted in tachycardia termination and those that resulted in entrainment were compared.Results. Three return cycle responses were identified: flat, plateau and increasing. Twenty trials of overdrive pacing resulted in tachycardia termination; all were characterized by an increase in the return cycle with the delivery of each successive beat in the pacing drive until the tachycardia terminated (increasing response). Thirty-four pacing trials resulted in entrainment and not termination; these were characterized either by a constant return cycle (flat response) or an initial increase in return cycle followed by a longer, constant return cycle (plateau response) with the delivery of additional paced beats. The longest paced cycle length that resulted in tachycardia termination correlated with the relative refractory period of the circuit, defined as the tachycardia cycle length minus the fully excitable gap (r2= 0.764, p = 0.0001). Tachycardia termination was not observed unless the paced cycle length was shorter than the relative refractory period of the circuit.Conclusions. The critical paced cycle length that causes termination of ventricular tachycardia depends on the relative refractory period of the circuit because this factor determines whether the nth + 1 beat of the pacing drive will encounter partially recovered tissue. These data provide insights into the mechanism of pacing-mediated tachycardia termination and entrainment and are applicable to the development of improved antitachycardia pacing algorithms.

Rate dependence of sotalol-induced prolongation of ventricular repolarization during exercise in humans.

Studies in animals have shown that drug-induced action potential prolongation with class III antiarrhythmic agents increases with slow pacing rates. We studied the physiological rate dependence of sotalol effects on ventricular repolarization, measured as QT interval duration on the surface electrocardiogram at rest and during a maximal exercise test, in 10 normal volunteers. In a randomized, crossover study, three dosages of sotalol (160 mg/24 hr, 320 mg/24 hr, and 640 mg/24 hr) were administered during 4 days to each subject. In a control period, no drug was administered. During each period, 50-100 QT intervals were measured over a wide range of RR intervals recorded at rest and during the course of a maximal exercise test. Plasma sotalol concentration and beta-adrenoceptor blockade (percent reduction in peak exercise heart rate from control) were also measured. The QT-versus-RR relation was fitted to several formulas, and the overall best fit was used to calculate QT interval duration normalized for a heart rate of 60 beats/min (QTc) and to analyze the rate dependence of QT prolongation with sotalol. Sotalol-induced beta-adrenoceptor blockade and QTc prolongation were dose and concentration dependent. Sotalol reduced peak exercise heart rate by 13.8 +/- 7% at the dosage of 320 mg/24 hr and by 25.4 +/- 8% at the dosage of 640 mg/24 hr (both p less than 0.01). Sotalol prolonged QTc interval by 5.8 +/- 3.7% and 11.8 +/- 3% at these respective dosages (both p less than 0.01). The concentration of sotalol required to produce minimal (mean QTc prolongation, 5.6%; confidence interval, 0-11.2%) QTc prolongation (680 ng/ml) tended to be lower than that required for minimal (mean percent reduction in maximal exercise heart rate, 13.9%; confidence interval, 0-27.8%) beta-blockade (840 ng/ml). QT prolongation with sotalol increased with increasing RR intervals (i.e., decreasing heart rate) at all dosages. QT prolongation became statistically significant for RR of 800 msec or more at all dosages and for RR intervals of 600 msec or more at the dosage of 640 mg/24 hr. This rate dependence altered the relation between QT interval duration and sotalol plasma concentrations. These results suggest that sotalol prolongs QTc interval in humans at dosages and concentrations similar to those required to produce beta-adrenoceptor blockade, QT prolongation with sotalol is more pronounced when heart rate decreases and is not apparent during exercise-induced tachycardia, and the relation between QT prolongation with sotalol and plasma concentrations of the drug depends on the heart rate at which measurements are made.

Reentrant Tachycardia in a Thin Layer of Ventricular Subepicardium: Effects of d-Sotalol and Lidocaine

Ventricular tachycardia (VT) was induced by premature stimulation or fast pacing in 14 Langendorff-perfused rabbit hearts whose left ventricular endocardial and intramural cells had been selectively killed by freezing. VTs were caused by apparent reentrant excitation in the surviving thin (1 mm thick) subepicardial layer of anisotropically oriented cells having ostensibly normal membrane characteristics. During VT, 100 microM d-sotalol (seven hearts) or 30 microM lidocaine (seven hearts) was added to the perfusate. Electrophysiological variables were measured before and during drug exposure at both slow (S1 = 300 ms) and fast (S1 = 150-180 ms) pacing rates. Sotalol prevented VT reinduction in six of seven preparations, compared to only two of seven with lidocaine. Lidocaine prolonged the functional refractory period (FRP) and slowed conduction velocity (CV). Lidocaine prolonged the wavelength of the cardiac impulse (= FRP x CV) by 18% at slow rates but reduced it by 21% at fast rates. Sotalol, however, since it increased the FRP without reducing CV, caused wavelength prolongation at both rates (43% at slow rates, 26% at fast rates). Thus, this VT model may provide an important contrast of class I and class III drug action, with the drug effects on wavelength predicting susceptibility to VT induction.

The combined electrophysiological effects of lignocaine and sotalol in canine isolated cardiac Purkinje fibres are rate‐dependent

1. The frequency-dependent electrophysiological effects of lignocaine, sotalol, and their combination were studied in dog isolated cardiac Purkinje fibres, both at various constant rates of stimulation and following abrupt changes in pacing cycle length. 2. The combined effect of 18 microM lignocaine and 30 microM sotalol selectively lengthened duration of premature action potentials evoked at a diastolic interval of 40 ms (from 172.2 +/- 5.4 to 201.7 +/- 4.9 ms, n = 6, P less than 0.01) without significantly changing the durations of action potentials evoked at the basic cycle length of 500 ms (259.1 +/- 7.7 vs 251.9 +/- 3.9 ms, n = 11). 3. The combination of lignocaine with sotalol, like lignocaine alone, displayed a use-dependent depression of Vmax and revealed a slow component for a recovery of Vmax (tau = 173.5 +/- 16.0 ms, n = 5). 4. The kinetics for restitution of action potential duration were also slowed by the combination of the two dwo drugs (tau f = 173.6 +/- 16.7, before, vs 268.5 +/- 8.5 ms, after; n = 5, P less than 0.01), while the maximum action potential duration attained in this relation was not increased as it was by sotalol alone. 5. Lignocaine, therefore, appeared to inhibit the sotalol-induced lengthening of action potential duration at slow pacing rates and at long diastolic intervals. The combination of lignocaine with sotalol also completely abolished the occurrence of sotalol-induced early after depolarizations. 6. Finally, sotalol alone moderately increased the range of premature action potential durations, while the combination of the two drugs significantly decreased this parameter. 7. These findings indicate that the combination of lignocaine with sotalol may provide important, and unique, beneficial electrophysiological alterations that might be expected to provide enhanced antiarrhythmic efficacy in patients.

The effect of heart rate on the termination of electrically induced ventricular fibrillation in the isolated perfused rat heart.

Ventricular fibrillation (VF) which is normally sustained in large animals and humans, is transient in small animals. The purpose of the present study was to evaluate the possible effect of changing cardiac rate on spontaneous ventricular defibrillation. In isolated perfused rat heart, VF was electrically induced during normal spontaneous rhythm of the heart at normal rate and at various ventricular pacing rates. It was found that: 1) Electrically induced VF in isolated perfused, non-ischemic rat heart spontaneously terminated in 88% of the hearts; 2) Ventricular pacing rhythm of spontaneous rate plus 10% caused VF to be sustained in 26% of the hearts (which defibrillated spontaneously during normal rates); 3) Ventricular pacing at 200% of the basic rate led to sustained VF in about half the VF episodes (14 out of 33, p less than 0.005). In the remainder, which defibrillated spontaneously, a sustained VF could be achieved by further increase in ventricular pacing rate; 4) Slow pacing rate, as a result of the surgical production of atrioventricular (A-V) block, enhanced the probability of spontaneous defibrillation (21 of 21 episodes after slow pacing vs 24 of 34 episodes following pacing at previous normal sinus rhythm, p less than 0.05). Selective modulation of conduction velocity, refractory period or both, achieved by changes in ventricular pacing rate was assumed to play an important role in determining whether electrically-induced VF would be transient or sustained.

The electrophysiologic effects of propafenone hydrochloride in the neonatal canine.

The electrophysiologic effects of the new antiarrhythmic agent, propafenone, were investigated in 10 mongrel canine neonates, ages 5 to 11 days. Utilizing standard His bundle recording and stimulation techniques, assessments of sinus and atrioventricular (AV) node function and atrial, AV nodal, and ventricular refractory periods were performed prior to (control) and after cumulative intravenous doses of 1, 2, and 4 mg/kg of propafenone. Propafenone depressed the spontaneous heart rate and prolonged the postatrial pacing recovery times. AV nodal function was depressed as manifested by Wenckebach periodicity occurring at slower pacing rates, increases in AV nodal conduction time, and increases in AV nodal refractoriness. Atrial and ventricular refractory periods were prolonged significantly in a dose-dependent fashion. Prolongation of the His-Purkinje conduction time occurred at the highest dose. Thus, propafenone exerts a generalized depressant effect on neonatal myocardial conduction and refractoriness which suggests that this agent may be useful in the therapy of atrial and ventricular dysrhythmias in the immature heart.

Sinus node recovery time related to paced cycle length in normals and patients with sinoatrial dysfunction

Depressed conduction in the sinoatrial junction, common in the sick sinus syndrome (SSS), should decrease the maximum pacing rate at which 1:1 capture of the SA node occurs. This may result in shorter than expected sinus recovery times (SRT) and maximal prolongation of SRT at relatively slow pacing rates. To test this hypothesis we evaluated the range of pacing rates necessary to demonstrate maximal SRT in 34 patients with and 20 patients without sinus node dysfunction. Atrial pacing was performed at multiple paced cycle lengths (PCL) between 400 and ≥ 1000 msec, four times at each. A mean corrected SRT ( CSRT) was determined at each PCL, and the PCL of the longest CSRT was determined (PCL p). PCL p varied linearly with sinus cycle length, was dependent on sinoatrial conduction time, and was longer in patients with SSS than in normal persons. Only 2 of 20 normal persons, but 21 of 34 patients with SSS, had a PCL p > 600 msec. A long PCL p (> 600 msec) suggests the possibility of recovery times that have been limited by A-S entrance block and appears to be indicative of sinus node dysfunction.

Digitalis and the sick sinus syndrome. Clinical and electrophysiologic documentation of severe toxic effect on sinus node function.

Digoxin, in a common clinical dose and at a low serum level, brought out severe manifestations of sinus node dysfunction in a patient who had previously undergone successful mitral valve replacement. This report presents the results of extensive clinical and electrophysiologic studies of this patient before and after a digoxin challenge. In the absence of cardiac glycoside, the only demonstrable abnormalities of sinus node function were mild resting sinus bradycardia and failure to respond to atropine administration. Responses to isoproterenol administration, programmed premature atrial stimulation, and overdrive pacing at several cycle lengths were normal. Following the administration of intravenous digoxin, 1.025 mg/24 hrs, the resting sinus cycle length increased and the response to overdrive pacing became markedly abnormal. The latter was followed by sinus pauses in excess of six seconds, even at relatively slow overdrive pacing rates. The electrophysiologic and clinical implications of these data are discussed. It is suggested that despite previous reports that digitalis preparations are relatively well tolerated by patients with sick sinus syndrome, caution should be used when administering these drugs to this group of patients.

Sinus node recovery time in the elderly.

Measurement of the sinus node recovery time has been proposed as a diagnostic tool for recognition of the sick sinus syndrome. The latter is most frequently encountered in elderly patients with hypertension, coronary heart disease, and atherosclerosis. In order to provide normal values for the sinus node recovery time in this particular population group, atrial pacing studies were carried out in 30 subjects over 50 years of age, all with peripheral vascular disease and some with angina pectoris (10), residua of infarction (6), or hypertension (7). On stimulation, 7 patients maintained a I:I atrioventricular conduction up to the rate of 180/min. Second degree atrioventricular block developed in all other cases. On six occasions, Wenckebach's periods appeared at the relatively slow pacing rate of 120/min. The maximum postoverdrive pause ranged from 680 to 1600 ms with an average of 1100 ms plus or minus 190 (10). For each pacing speed, a correlation was found between the duration of the pause and the control intrinsic cardiac rate, longer pauses being associated with longer resting PP intervals. Beyond 120/min, the duration of the pause was seen to shorten progressively as the driving rate was increased. Finally, the behavior of the sinus node pacemaker following interruption of pacing showed individual variations. After pacing at relatively slow rates, a prompt return to near control values was consistently observed, whereas, after fast rates of driving, a phase of secondary depression developed in about one-half of the studied cases.