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Background— Genetic predisposition is believed to be responsible for most clinically significant arrhythmias; however, suitable genetic animal models to study disease mechanisms and evaluate new treatment strategies are largely lacking. Methods and Results— In search of suitable arrhythmia models, we isolated the zebrafish mutation reggae ( reg ), which displays clinical features of the malignant human short-QT syndrome such as accelerated cardiac repolarization accompanied by cardiac fibrillation. By positional cloning, we identified the reg mutation that resides within the voltage sensor of the zebrafish ether-à-go-go –related gene (zERG) potassium channel. The mutation causes premature zERG channel activation and defective inactivation, which results in shortened action potential duration and accelerated cardiac repolarization. Genetic and pharmacological inhibition of zERG rescues recessive reg mutant embryos, which confirms the gain-of-function effect of the reg mutation on zERG channel function in vivo. Accordingly, QT intervals in ECGs from heterozygous and homozygous reg mutant adult zebrafish are considerably shorter than in wild-type zebrafish. Conclusions— With its molecular and pathophysiological concordance to the human arrhythmia syndrome, zebrafish reg represents the first animal model for human short-QT syndrome.

Background— The origin of 40% of syncope cases remains unknown even after a complete diagnostic workup. Previous studies have suggested that ATP testing has value in selecting successful therapy. This patient-blinded, multicenter, randomized superiority trial tested whether, in patients with syncope of unknown origin, selecting cardiac pacing in those with a positive ATP test leads to fewer recurrences than those who do not receive pacing. Methods and Results— From 2000 to 2005, 80 consenting patients (mean age, 75.9±7.7 years; 81% women; 56% without diagnosed structural heart disease) with syncope of unknown origin and atrioventricular or sinoatrial block lasting >10 seconds (average, 17.9±6.8 seconds) under ATP administration (20-mg IV bolus) were recruited from 10 hospitals, implanted with programmable pacemakers, and randomized to either active pacing (dual-chamber pacing at 70 bpm) or backup pacing (atrial pacing at 30 bpm). Patients were followed up regularly for up to 5 years for any syncope recurrence, the primary outcome. Mean follow-up was 16 months. Syncope recurred in 8 of 39 patients (21%) randomized to active pacing and in 27 of 41 (66%) randomized to backup pacing (control), yielding a hazard ratio of 0.25 (95% confidence interval, 0.12–0.56). After recurrence, the 27 recurrent control patients were reprogrammed to active pacing, and only 1 reported subsequent syncope. Conclusion— This study suggests that, in elderly patients with syncope of unknown origin and positive ATP tests, active dual-chamber pacing reduces syncope recurrence risk by 75% (95% confidence interval, 44–88). Clinical Trial Registration— URL: http://www.controlled-trials.com/ISRCTN00029383 . Unique identifier: ISRCTN00029383.

Background— Homozygous mutant mice with a defect of klotho gene expression ( kl/kl ) show multiple age-related disorders and premature death from unknown causes. Methods and Results— The kl/kl mice subjected to 20-hour restraint stress showed a high rate (20/30) of sudden death, which was associated with sinoatrial node dysfunction (conduction block or arrest). Heart rate and plasma norepinephrine of kl/kl mice, unlike those of wild-type (WT) mice, failed to increase during the stress. Intrinsic heart rate after pharmacological blockade of autonomic nerves in kl/kl mice was significantly lower than that in WT mice (380±33 versus 470±44 bpm; n=7). The sinus node recovery time after an overdrive pacing (600 bpm, 30 seconds) in kl/kl mice was significantly longer than in WT mice (392±37 versus 233±24 ms; n=6). In isolated sinoatrial node preparations, the positive chronotropic effect of isoproterenol was significantly less, whereas the negative chronotropic effect of acetylcholine was significantly greater in kl/kl than in WT mice. There was no degenerative structural change in the sinoatrial node of kl/kl mice. The precise localization of klotho was analyzed in newly prepared klotho -null mice with a reporter gene system ( kl −geo ). Homozygous kl −geo mice showed characteristic age-associated phenotypes that were almost identical to those of kl/kl mice. In the kl −geo mice, klotho expression was recognized exclusively in the sinoatrial node region in the heart in addition to parathyroid, kidney, and choroid plexus. Conclusions— In the heart, klotho is expressed solely at the sinoatrial node. klotho gene expression is essential for the sinoatrial node to function as a dependable pacemaker under conditions of stress.

Background —Recently, it has been reported that connexin40 (Cx40) deficiency in targeted mouse mutants is associated with a prolongation of P-wave and QRS complex duration on surface electrograms. The specific effects of Cx40 deficiency on sinus node function, sinoatrial, and atrioventricular conduction properties as well as on atrial vulnerability have not yet been investigated systematically by electrophysiological analysis. Methods and Results —Fifty-two mice (18 Cx40 +/+ , 15 Cx40 +/− , and 19 Cx40 −/− mice) were subjected to rapid atrial transesophageal stimulation after anesthesia with avertin. A significant prolongation of sinus node recovery time was noticed in Cx40 −/− mice compared with Cx40 +/− and Cx40 +/+ mice (287.8±109.0 vs 211.1±61.8 vs 204.4±60.9 ms; P −/− mice than in Cx40 +/− or Cx40 +/+ mice (93.3±11.8 vs 83.9±9.7 vs 82.8±8.0 ms, P −/− mice showed a significant increase in intra-atrial conduction time and atrioventricular conduction time compared with 52 Cx40 +/− and 31 wild-type (Cx40 +/+ ) mice. Furthermore, in Cx40 −/− mice, atrial tachyarrhythmias could be induced frequently by atrial burst pacing, whereas no atrial arrhythmias were inducible in heterozygous or wild-type mice. Conclusions —This study demonstrates that Cx40 deficiency is associated with sinoatrial, intra-atrial, and atrioventricular conduction disturbances. In atrial myocardium of the mouse, Cx40 deficiency results in increased atrial vulnerability and might contribute to arrhythmogenesis.

Exercise or isoproterenol infusion may evoke ventricular arrhythmias in patients with the long QT syndrome. We examined the electrocardiographic effects of the Valsalva maneuver in eight patients with the long QT syndrome and nine healthy subjects. The Valsalva maneuver lengthened the QTc interval in both groups, but the lengthening was greater in the patients. In the patients who were having frequent attacks of ventricular tachycardia, the Valsalva-induced prolongation of the QTc interval was particularly remarkable and was associated with the development of T-wave alternans and short runs of ventricular tachycardia. Propranolol effectively suppressed the lengthening of the QTc interval during Valsalva strain and prevented Valsalva-induced ventricular arrhythmia. These results suggest that the Valsalva maneuver may be useful in evaluating the risk of ventricular tachyarrhythmias and the efficacy of drug treatment in patients with the long QT syndrome.

The electrophysiologic effects of intravenously administered disopyramide (2 mg/kg) on three parameters of sinus node function were examined in 16 symptomatic patients with sinus node dysfunction. Based on their ECG data before study, patients were subdivided into group A (n = 8), those with sinus pauses and/or sinoatrial (SA) exit block; and group B (n = 8), those with sinus bradycardia. Disopyramide shortened spontaneous cycle length in 10 of 16 patients and lengthened it in six--markedly so (91%) in one patient. Estimated SA conduction time decreased in seven of 14 patients and increased in seven. Two patients developed second degree SA exit block after disopyramide. Maximum sinus node recovery time was prolonged by disopyramide in 11 of 16 patients and markedly so in four. For the group as a whole there was no significant difference in spontaneous cycle length, maximum sinus node recovery time or estimated SA conduction time. P-wave and QRS durations and H-V intervals were significantly lengthened by disopyramide. Marked depression of the three parameters of sinus node function occurred in three group A patients and in one group B patient who had persistent severe sinus bradycardia. These four patients also had secondary pauses after termination of rapid atrial pacing under control conditions. Disopyramide should be administered cautiously to patients with sinus node dysfunction, particularly those with sinus pauses, SA exit block or secondary pauses.

Diltiazem, verapamil and nifedipine suppress sinoatrial (SA) nodal function in the excised rabbit heart. Clinically, however, their suppressive effect on the SA node is modified considerably by the reflex increase in sympathetic tone as a result of the fall in blood pressure caused by the vasodilating action of the calcium antagonists. Diltiazem, verapamil and nifedipine suppress atrioventricular (AV) nodal conduction and prolong refractory periods in the excised rabbit AV node. Clinically, diltiazem and verapamil exert a similar suppressive effect on the AV node and are useful for treating and preventing AV nodal reentrant tachycardia. Nifedipine, in clinically practical doses, has no antiarrhythmic properties, probably because of reflex activation of the sympathetic system secondary to its hypotensive effect, which is greater than that of the other two calcium antagonists. Diltiazem and verapamil may sometimes worsen AV conduction, especially in patients with conduction disturbances. Nifedipine, on the other hand, can be used as a coronary vasodilator with the least untoward effect on AV conduction.

Two hundred and forty-three patients were evaluated following total correction of tetralogy of Fallot with special emphasis on postoperative conduction disturbances and on the occurrence of sudden death. The average follow-up period was 12 years with a range of 6 1/2 to 16 1/2 years. Sudden death occurred in seven patients. Four deaths were among those with right bundle branch block pattern (RBBB) and three of the four had premature ventricular contractions (PVC) for more than one month postoperatively. PVCs were documented in ten of the 158 patients with RBBB; sudden death occurred in three (30%). Three of the ten (30%) patients with trifascicular block pattern (TB) died suddenly, while no deaths occurred in 24 patients with bifascicular block pattern (BB). Progression of RBBB to BB and TB occurred in 18 patients from one month to seven years postoperatively (58% of BB and 40% of TB). The risk of sudden death in patients with RBBB and PVCs following tetralogy repair is high and warrants consideration of suppressive therapy. TB also carries a high risk. The finding that RBBB may progress to BB or TB mandates long-term careful follow-up of all tetralogy patients with postoperative conduction disturbances.

The electrophysiologic effects of intravenously administered propranolol (0.1 mg/kg) on three parameters of sinus node function were examined in ten symptomatic patients with sinus node dysfunction. The patients ranged in age from 26 to 79 years. Symptoms ranged from fatigue to frank syncope. Sinoatrial (SA) block and sinus pauses were observed in one patient; sinus pauses alone were observed in three patients. Five (5/10) patients had intraatrial block; three (3/10) patients had atrioventricular block; four (4/10) patients had an intraventricular conduction disturbance. At the time of electrophysiologic study, two patients had a control spontaneous sinus cycle length that exceeded 1000 msec. Following propranolol, the mean spontaneous cycle length increased by 17.4% (924 to 1085 msec, P less than 0.005) and spontaneous second degree SA block reappeared in the one patient. The maximum escape cycle ranged from 116% to 229% of the prepacing spontaneous cycle length and was considered to be prolonged in two of ten patients. Propranolol had no significant effect on the maximum escape cycle/prepacing cycle length X 100 (%). The estimated sinoatrial conduction time (SACT) was determined in seven patients and ranged in value from 120 to 238 mes. Propranolol increased the mean value of the estimated SACT from 179 to 213 msec, P less than 0.025. Propranolol may cause marked bradyarrhythmias in some patients with sinus node dysfunction, and should be used with caution in these patients.

This study describes a new method (NM) for estimation of sinoatrial conduction time (SACT), which utilizes constant atrial pacing (AP) instead of the premature atrial beats (PABs) used in the method reported in 1973 by Strauss et al. The SACTs were obtained by both methods in 20 patients. The SACT by the Strauss method (SM) was calculated as A2A3 minus A1A1. The NM consists of high right AP for a train of eight consecutive beats at rates less than or equal to 10 beats/min faster than the sinus rhythm. The interval between the last paced atrial electrogram (Ap) and the first escape atrial electrogram (A) of sinus origin (Ap-A) was measured along with several post pacing sinus cycles. The SACT by the NM was calculated as follows: SACT = Ap-A minus A1A1. The effect of AP at higher rates was also analyzed. In two patients, the SACT with the SM could not be defined, as all the A2A3 intervals were fully compensatory; with the NM the SACT was 217 and 320 msec. In the remaining 18 patients the SACT was obtainable by both methods. With SM, the SACT ranged 105--452 msec (mean 219 +/- 102 SD) and with the NM it was 85--492 msec (mean 201 +/- 112 SD), and the difference was statistically significant (P = 0.0162). The coefficient of correlation between the two methods was r = 0.97. During AP at faster rates, a rate related increment in Ap-A intervals and also post pacing sinus cycles was noted. This study describes a new and simple method for measurement of SACT in man.

Embolization of the sinus node artery was accomplished in dogs by injecting rapidly hardening vinyl latex into the sinus node artery. Embolization immediately shifted the pacemaker to a junctional focus; however, with time postoperatively, the pacemaker shifted to an atrial site. Variable episodes of pacemaker failure, sinoatrial block, junctional rhythm, wandering atrial pacemaker and idioventricular escape rhythms were commonly observed on Holter monitor in isolation but only rarely when the dog was in the laboratory. Severe bradycardia (38.9 +/- 3.7 beats/min) was the predominant rhythm by 3-6 months postoperatively. In addition, these same dogs had a greater overall increase in heart rate after atropine than normal dogs (17.5 +/- 13.5 vs 116.6 +/- 15.9 beats/min above control; p less than 0.02). Responses to vagal stimulation in this group were abnormal, as long periods of asystole and bradycardia were observed after stimulation was terminated. These data suggest an alteration in parasympathetic pacemaker control after chronic embolization of the sinus node artery.

Twenty patients of mean age 66.2 years, with suspected sinus node dysfunction, underwent extensive electrophysiologic study. Sinus bradycardia (18), sinus pauses (3), and sinoatrial block (1) were identified in their ECGs prior to study. Also 11 patients had some abnormality of atrioventricular nodal and/or intraventricular conduction prior to study. At the time of electrophysiological study, 10/20 patients (50%) had a mean cycle length exceeding 1000 msec, and mean P-V interval exceeded 210 msec in 7/20 (35%). The estimated "sinoatrial conduction time" exceeded 215 msec in 6/16 (38%) patients. The maximum first escape cycle following pacing at six different rates exceeded a value equal 1.3 X the mean value of the control cycle length + 101 msec (slope of regression line + Y intercept + 1 SD) in 13/9 (68%) patients. Nineteen patients received 1 mg atropine intravenously and mean cycle length decreased by 19%, from 891 +/- 175.8 msec to 718 +/- 182.9 msec. Graded infusion of isoproterenol was employed in 19 patients; four patients required an infusion rate greater than 28.3 ng/kg/min to produce a 20% decrease in spontaneous sinus cycle length. These data would indicate that a variety of interventions are required to characterize the disturbance of sinus node automaticiy and sinoatrial conduction in patients with sinus node dysfunction.

The relationship of depressed sinus node function to coronary artery disease (CAD) was evaluated. The sinus node artery (SNA) was easily identified in all of 80 unselected normal coronary arteriograms. Angiographic disease of, or significant obstruction proximal to, the SNA was seen in 21% of 80 unselected CAD patients. Heart rate and sinoatrial recovery times (SART) were obtained in 50 consecutive unmedicated patients prior to arteriography. There was no difference between the SART of 23 CAD patients free of SNA involvement (1092 msec +/- 55 sem) and 18 normals (1070 +/- 40 msec). Nine patients with SNA involvement had shorter SART (941 +/- 52 MSEC) than normals (P less than 0.05) or other CAD patients (NS). Similar results were obtained for heart rate. No patient with SNA involvement had a prolonged SART or sick sinus syndrom (SSS). six of the 50 patients studied were symptomatic with SSS. Five of these SSS patients had CAD but none had angiographic evidence of SNA involvement. Obstructions involving the SNA were common in CAD but were not associated with altered heart rate or SART. Patients with SSS exhibited no angiographic evidence of SNA involvement. Therefore, it is unlikely that SSS is related to CAD of the SNA.

The clinical spectrum of the sick sinus syndrome (SSS) is described in a series of 56 patients who demonstrated either persistent unexplained sinus bradycardia (group I: eight patients); sinus arrest (group II: 15 patients); or bradycardia with episodic supraventricular tachyarrhythmias (group III: 33 patients). Coronary disease was the most common form of heart disease where etiology could be determined, but in 25 patients no clear etiologic diagnoses could be established. Thirty-three patients showed associated electrocardiographic conduction disturbances. Symptoms were common and were produced by both bradycardia and tachycardia. Eight patients in the bradycardia-tachycardia group experienced cerebral embolization. Despite bother-some symptoms, only six of the 56 patients died over an average follow-up of 7 years, and only one of these deaths appeared related to an arrhythmia. Drug therapy of bradycardia was generally ineffective, but digitalis was frequently helpful in patients with tachycardia. Electrical pacing was uniformly successful in treating symptoms of bradycardia but was disappointing in preventing tachyarrhythmias.

Permanent pervenous atrial pacing from the coronary vein has been attempted in 14 patients. Several types of arrhythmias including symptomatic bradycardia, "bradytachy" syndrome, and refractory ventricular tachyarrhythmia-fibrillation have been successfully treated with pervenous atrial pacing in 10 patients for 1 to 30 mo. Longterm atrial pacing was unsuccessful in four patients; in two of these four this was due to high atrial pacing thresholds. To date there has been no evidence of pacemaker perforation or pacemaker-induced coronary vein thrombosis. It is concluded that permanent pervenous atrial pacing from the coronary vein is a reliable method of atrial pacing without resorting to thoracotomy.

In 61 patients sinus node function was tested by programmed (sinoatrial conduction time, SACT) and overdrive atrial pacing (sinus node recovery time, SRT). In the control group (N = 20), mean sinus cycle length was 773 +/- 140.2 msec, mean absolute SRT 1044 +/- 215.8 msec [corrected SRT (CSRT) 270 +/- 112.5 msec; mean +/- SD] and calculated SACT was 82 +/-19.2 msec. The upper limit of normal SACT was defined as 120 msec. In 41 patients with sinus node dysfunction, mean age (55 +/- 14.7 years), mean spontaneous cycle length during the study (1094 +/- 248.0 msec), the lowest heart rate observed (42 +/- 7.5 beats/min), maximal SRT (2110 +/- 1269.1 msec), maximal CSRT (1016 +/- 1182.8 msec), and calculated SACT (126 +/- 47.3 msec) were significantly longer than in the control group. Abnormalities of sinus node function, as evidenced by the degree of spontaneous bradycardia, SRT and calculated SACT were more frequent in patients with bradycardia-tachycardia syndrome or spontaneous sinoatrial block than in those exhibiting isolated sinus bradycardia. We conclude 1) that in patients with sinus node dysfunction both sinus node automaticity and sinoatrial conduction may be abnormal, and 2) that overdrive and programmed premature atrial stimulation can separate patients with sinus node dysfunction according to their clinical presentation.

Electrophysiological studies were conducted in 13 patients with normal sinus node function and 14 with sinus node dysfunction before and after intravenous lidocaine. Mean +/- SEM sinus cycle length significantly shortened from 810 +/- 34.3 to 774 +/- 34.3 msec in patients with normal sinus node (P less than 0.001) and from 1061 +/- 67.6 to 1016 +/- 64.5 msec in patients with sinus node dysfunction (P less than 0.025) after lidocaine. Mean sinus recovery time was 1027 +/- 49.4 before and 1026 +/- 52.5 msec after lidocaine in patients with normal sinus node (NS) and 1269 +/- 97.7 before and 1170 +/- 73.8 msec after lidocaine in patients with sinus node dysfunction (P less than 0.05). Mean calculated sinoatrial conduction time was 87 +/- 9.5 before and 90 +/- 9.2 msec after lidocaine in patients with normal sinus node (NS) and 80 +/- 10.3 before and 96 +/- 10.2 msec after lidocaine in patients with sinus node dysfunction (P less than 0.001). Mean atrial effective and functional refractory periods were not significantly changed with lidocaine. Thus lidocaine shortened sinus cycle length in both groups, without affecting atrial refractoriness. Lidocaine appeared to depress perinodal tissue only in patients with sinus node dysfunction. The abbreviation of sinus recovery time in patients with sinus node dysfunction could reflect increased sinus automaticity and/or increased perinodal refractoriness, allowing entrance block to occur. This mechanism may explain why sinus arrest has been noted in some patients during lidocaine administration.

Prolonged (greater than 152 msec) calculated sinoatrial conduction times (SACT) were found in 24 of 470 patients studied by the atrial extrastimulus technique, ranging from 155 to 220 msec (180+/-4.4; mean+/-SEM). There were 18 males and six females with ages of 29 to 85 (mean 65+/-2.6). Electrocardiographic monitoring revealed significant sinus or atrial dysrhythmias in 19 (79%) patients. Of these 19, 15 had persistent sinus bradycardia and/or sinoatrial block, three had sinus bradyarrhythmia with paroxysmal atrial tachycardia, and one had isolated atrial tachycardia. Additional electrophysiological evidence of sinus node or atrial dysfunction was present in 11 patients. Four patients needed permanent pacing during follow-up (mean follow-up period of 427+/-39 days) because of symptomatic bradyarrhythmia. Three patients died, none suddenly. In conclusion, prolonged calculated SACT was associated with a high incidence of electrocardiographic and electrophysiologic abnormalities of sinus node and/or atrium. Despite this, bradyarrhythmic morbidity was relatively low, suggesting that prolonged sinoatrial conduction time in the absence of symptoms is not an indication for prophylactic pacing.

Twenty-three children underwent electrophysiological studies during routine postoperative catheterization two months to five years after complete correction of tetralogy of Fallot. The aim of the study was to investigate the whole conduction system, including sinus node function, suing His bundle recordings and atrial pacing. H-V intervals were normal at rest and with pacing in twenty-two patients, including four patients with evidence of bifascicular block on the surface ECG. One patient with cardiomegaly and evidence of diffuse myocardial damage had a prolonged H-V interval but did not develop a block at this level during pacing A-H interval was slightly prolonged in four patients and normal in all others. The threshold of pacing-induced atrioventricular block ranged from 75 to 240/min and was somewhat age dependent (r = -0.55). Two patients fell below the 95% confidence limit of this regression and are considered abnormal. One returned to normal after intravenous injectionof atropine. Corrected sinus node recovery time ranged from 60 to 2000 msec. Three patients had values above 500 msec which are considered abnormal. These patients had other minor signs of sinus node dysfunction, i.e., episodes of sino-atrial block at rest or intermittent sinus bradycardia. Thus, while the His Purkinje system performed satisfactorily in all patients, sinus node dysfunctional and A-V node dysfunction were demonstrated in a few patients after correction of tetralogy of Fallot.

Sinus node dysfunction in patients after repair of the secundum atrial septal defect has been ascribed to surgical damage. We studied 15 consecutive patients with secundum atrial septal defect before operative intervention. Noninvasive testing included 34-hour electrocardiographic monitoring and a standard 13-lead ECG. Intracardiac electrophysiologic techniques included corrected sinus node recovery time, sinoatrial conduction time, His bundle recording to measure AH and HV intervals, the atrial pacing rate at which atrioventricular node Wenckebach occurred, and atrioventricular nodal refractory period. The ECG revealed an ectopic atrial rhythm in two patients. Intracardiac electrophysiology showed an abnormal corrected sinus node recovery time (range -40 to 800 msec) in 10 patients. Five patients had evidence of atrioventricular nodal dysfunction with prolonged AH interval or abnormal atrial pacing rate at which atrioventricular Wenckebach occurred. These data indicate that sinus node dysfunction or atrioventricular node dysfunction were present before surgical intervention.

A transvenous electrode catheter technique was used for direct recording of bipolar sinus node electrograms during postpacing atrial pauses. Multiple repetitive local sinus node electrograms during atrial quiescence validate sinus node electrograms. Such atrial pauses with sinus node electrograms are due to sinoatrial block; atrial pauses without sinus node electrograms are due to overdrive suppression or improper recording. Eight consecutive patients were prospectively selected on the basis of a corrected sinus node recovery time greater than 1500 msec during diagnostic electrophysiologic evaluation. Six patients had atrial pauses with sinus node electrograms; three patterns of sinus node electrograms during atrial pauses were observed. We conclude that (1) sinus node electrogram recording is of value in understanding the mechanism underlying postpacing atrial pauses; (2) atrial pauses are usually (6/8) caused by sinoatrial block; (3) three patterns of sinus node electrograms are observed, thus making indirect interpretation unreliable.

SUMMARY Sinus node electrograms (SNEs) were recorded in 44 patients using a standard quadripolar electrode catheter (USCI #6) with 10-mm interelectrode distance. In 23 patients, the catheter was positioned at the junction of the superior vena cava (SVC) and right atrial (RA) wall so that the concave curve of the catheter was facing the concave surface of the RA wall. The distal poles of the catheter were close to but not in direct contact with the RA endocardium underlying the anatomic location of the sinus node (method 1). In 21 patients, the catheter was looped in the RA and advanced to the junction of the SVC-RA wall so that the distal poles of the catheter were in direct contact with the RA endocardium underlying the area of the sinus node (method 2). Stable SNEs could be obtained in 10 of 23 patients (43%) by method 1 and in 18 of 21 (86%) by method 2. SNEs by both methods showed two negatively directed deflections (diastolic and upstroke slope of the sinus node) of low frequency and amplitude occurring after the deflections of the T and U waves but before the P wave and intraatrial electrograms from various atrial sites. Unlike method 1, atrial activation by method 2 was characterized by an atrial injury potential. SNEs by method 2 were more stable and less prone to baseline drifts. Carotid sinus massage performed in 10 patients resulted in prolongation of the onset of the upstroke slope to atrial activation. In one patient, it resulted in marked first-degree sinoatrial block. SNEs were recorded in one patient during and after a run of spontaneous atrial flutter. After termination of atrial flutter, sinoatrial conduction time (SACT) prolonged for the first postflutter sinus beat and normalized by the third sinus beat. Direct SACTwas assessed on the SNE in all 28 patients, 12 of whom had sick sinus syndrome (SSS). SACT was also estimated indirectly by continuous pacing in 28 patients and by premature stimulation in 20 patients. Direct SACT was significantly (p < 0.001) longer in patients with SSS (135 30 msec, mean SD) than in patients without SSS (87 12 msec).There was a good correlation between direct SACT and SACT by continuous pacing (r = 0.843, n = 28) and direct SACT and SACT by premature stimulation (r = 0.778, n = 18). However, in certain patients, there were appreciable differences and direct SACTwas longer than estimated SACT by continuous pacing or premature stimulation. We conclude that (1) the success rate of stable SNEs with no appreciable baseline drift is increased with direct contact of the catheter with atrial endocardium underlying the sinus node area (method 2); (2) carotid sinus massage results in depression of sinus node automaticity and prolongation of SACT; (3) direct SACT is significantly longer in patients with SSS and can separate most patients with from those without SSS; and (4) there is a good correlation between direct SACT and indirectly estimated SACT, although the latter underestimates the actual SACT.

The phenomenon of postpacing depression of cardiac pacemakers was utilized to evaluate the sinus-node function in 56 patients by analyzing the sinus-node recovery time (SRT), that is, the interval between the last paced P wave and the following sinus P wave. Corrected SRT (CSRT) is defined as the recovery interval in excess of the sinus cycle (SRT — sinus cycle length). The SRT was measured following sinus-node suppression by (1) isolated premature beats (PABs) and (2) atrial pacing (AP) at rates of 100 to 140/min for periods of 2 to 5 min at each level. Twenty-eight patients had normal heart rates (group A), and 28 patients had sinus bradycardia (SB; group B). Ten of the 28 patients with SB were restudied after receiving atropine (2 mg intravenously). The CSRT with PABs was similar in both group A and group B patients and remained essentially unchanged after atropine despite a decrease in sinus cycle length. The phenomenon of interpolated PABs was demonstrated in seven of the 56 patients. In 27 of the 28 patients with normal heart rates (group A), the CSRT with AP ranged from 110 to 525 msec and was essentially independent of the rate and duration of AP. In the remaining one patient of group A, despite a normal heart rate, the CSRT was prolonged (1810 msec) and directly dependent on the rate and duration of AP. In 12 of the 28 patients with SB, the CSRT was comparable to that in group A (≦525 msec). In the remaining 16 patients with SB (group B), the CSRT ranged from 560 to 3740 msec and was usually directly proportional to the rate and duration of AP. After atropine in most of the patients with a prolonged CSRT, the CSRT remained abnormal whereas in others junctional escape beats appeared first, followed eventually by normal sinus rhythm. In a single patient with SB and an abnormal CSRT, restudy 7½ months later again showed a prolonged CSRT indicating the reproducibility of the measurement. The CSRT with AP provides a potentially useful clinical means of assessing the sinus-node function and thereby aids in the diagnosis of the "sick sinus syndrome." It is stressed that AP was found to be more reliable than PABs in eliciting an abnormal response. Furthermore, a normal sinus (atrial) rate does not necessarily provide assurance of a normal sinus-node response to AP, that is, normal sinus-node function.

Since recording potentials directly from the sinoatrial node (SAN) is not yet possible, the electrophysiologic evaluation of this structure in intact human subjects must be accomplished with indirect technics. Two technics have been used to study SAN function in man: premature atrial stimulation (PAS) and rapid atrial pacing. Recent discussions of data using these technics have emphasized their role in determining SAN automaticity, but their role in evaluating conduction from atrium to SAN or SAN to atrium has not been fully explored. Using the technic of PAS, we have studied five patients with sinus bradycardia and symptoms of dizziness or syncope. Our analysis of the results obtained from these studies discloses the unique ability of this technic to evaluate conduction into and out of the SAN. An atrial premature depolarization (APD) elicited late in atrial diastole is followed by a compensatory pause (nonreset of the SAN pacemaker). An APD elicited earlier in atrial diastole is followed by a pause that is less than compensatory (SAN reset). From these responses estimates of sinoatrial conduction time were made. In one patient reset was never seen, suggesting markedly prolonged sinoatrial conduction. With these results in mind, the literature was reviewed and an alternate interpretation posed for existing data. PAS is not only a means of determining SAN automaticity, but also a very useful means of unmasking sinoatrial conduction abnormalities.

A case is presented in which an ectopic atrial pacemaker manifested "pacemaker block," a phenomenon analogous to sinoatrial block in the sinoatrial node. This is believed to be the first recorded instance of such a phenomenon.

The effect of digitalis in patients with sinoatrial node dysfunction was studied. Atrial pacing studies were performed while His bundle electrograms were recorded in fourteen patients with sinus bradyeardia, syncope, or related symptoms. Measurements were repeated after 0.01 mg/kg ouabain, followed in some by 1 mg atropine. Ouabain produced a significant shortening of sinoatrial recovery time, but no significant change in heart rate. Atropine normalized sinoatrial recovery times in most patients. This study demonstrates that digitalis causes an increase in automaticity in the sick sinus syndrome as reflected by a shortened sinoatrial recovery time. The efficacy of contemplated therapeutic agents in sick sinus syndrome can be evaluated by rapid atrial pacing. When clinically indicated, digitalis may be used for congestive heart failure or tachyarrhythmias in the sick sinus syndrome in the absence of significant A-V conduction disease.