Effect of bradycardia on dispersion of ventricular refractoriness

Effect of Bradycardia on Dispersion of Ventricular Refractoriness JERRY C. LUCK, MD, STEVEN T. MINOR, MD, DAVID E. MANN, MD, ANiON P. NIELSEN, MD, JERRY C. GRIFFIN, MD, and CHRISTOPHER R.C. WNDHAM, MD

The effect of bradycardia on dkpersion of ventricular refractoriness was evaluated. Refractory periods were measured at 3 right ventricular sites in 16 patients with severe bradycardia (average heart rate 39 f 5 beats/min) and were compared with those measured in 11 control subjects, (average heart rate 72 f 12 beats/min). Patients with bradycardia had significantly longer effective (377 f 36 ms) and functional (421 f 39 ms) refractory periods (ERP and FRP) than control subjects (ERP 296 f 25 ms, FRP 346 f 16 ms) (p
f 12 ms, and FRP was 36 f 20 ms. Pacing of 120 beats/min significantly decreased ERP and FRP in both groups. Pacing shortened dispersion significantly in control subjects. In patients with bradycardia, pacing failed to significantly decrease dispersion. Compared wfth control subjects with normal heart rates, patients with bradycardia have longer absolute refractory periods but do not have significantly increased dispersion of refractoriness. Single and double, twice threshold ventricular extrastimuli (Sp and Sg) failed to induce ventricular tachycardia in any patient during bradycardia. Bradycardia alone does not appear to be a factor in the induction of ventricular tachyarrhythmias. (Am J Cardiol 1965;55:1009-1014)

Patients with severe bradycardia as a result of atrioventricular (AV) block or sinus node dysfunction are frequently symptomatic with dizziness, easy fatigability and syncope. In the absenceof myocardial infarction the prognosis of patients acquiring complete AV block is variab1e.Q Fifty to 60% of patients who do not undergo pacing, die within 1 to 2 years.2 Death is found to be secondary to ventricular asystole, ventricular tachycardia or ventricular fibrillation.a4 The generation of lethal ventricular tachyarrhythmias in patients with AV block may be linked to severe bradycardia.s5 The site of block is frequently infra-Hisian and results in slow heart rates (less than 40 beats/min).lv6 Slow heart rates prolong both atrial and ventricular refractory periods.y-9 In the dog, the range of ventricular refractory periods is increased at longer basic cycle lengths.spgThis nonuniform recovery of excitability or dispersion of ven-

tricular refractoriness may be a factor in producing ventricular ectopy, tachycardia or fibrillation.8*g In this study, we evaluated the effect of severe bradycardia on dispersion of ventricular refactoriness in humans. We also examined the role of bradycardia as a risk for increased susceptibility to ventricular tachycardia and fibrillation.

From the Baylor College of Medicine, Department of Medicine, Section of Cardiology, HoWOn, Texas. Manuscript received August 20, 1984; revised manuscript received December 12,1984, accepted December 14, 1984. Address for reprints: Jerry C. Luck, MD, Baylor College of Medicine, One Baylor Plaza, Room 512 D, Houston, Texas 77030.

Methods Patients: Ventricular refractory periodsweremeasuredin

27 patients. Elevenpatients (Table I) who underwent cardiac catheterization or electrophysiologictesting for unexplained syncope,dizziness,atypical chest pain or palpitations served as control subjects.There were7 men and 4 women,average age54 f 16years(meen f standarddeviation).All had normal heart rates,sinusnodefunction and intact AV conduction.No control subject had a history of ventricular tachycardia. Ventricular tachycardia (at least 3 consecutiveventricular beats) was not present during at least 24 hours of tape-recorded ambulatory monitoring. Sixteen patients (Table II), mean age68 f 17 years,with persistent bradycardia (ventricular rates lessthan 50 beats/ min) as a result,of high-grade second-degreeor third-degree AV block (14patients) or sinusnodedysfunction (2 patients) constitute the study group.All 16patients weresymptomatic,

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patient had overt congestive heart failure at the time of study. Patients were excluded if they had an acute myocardial infarction, unstable angina pectoris or were receiving antiarrhythmic agents. No patient was receiving digoxin at the time of evaluation. Stimulation and recording techniques: Ventricular stimulation was performed using the 2 distal poles of a 6Fr quadripolar pacing catheter with an interelectrode distance of 1 cm. The ventricular electrograms were recorded from the proximal poles of the same pacing catheter. Intracardiac and 3 simultaneous surface recordings were made at a paper speed of 100 mm/s with an Electronics for Medicine VR-12 or VR-16 oscilloscopic recorder at filter settings of 30 to 500 Hz. Programmed, twice threshold, single right ventricular extrastimuli were used to define the ERP and FRP at 3 different right ventricular sites during spontaneous rhythm and at the driven rate of 120 beats/min (Fig. 1). The positions chosen were those that resulted in stable pacing at pacing thresholds between 0.2 and 2.5 mA. Programmed double ventricular extrastimuli were applied during both spontaneous rhythm and ventricular drive at 1 right ventricular site (generally the right ventricular apex). The first extrastimulus (Sz) was positioned at 20 ms above refractoriness and the second (Ss) was applied in decrements of 10 or 20 ms of coupling until refractoriness. Analysis of data: The ventricular ERP was the longest interval from the onset of the ventricular electrogram (during

TABLE I Clinical Characteristics of Control Subjects Pt 1 f t 0 i 9

Age 04 & Sex 72F 39M 50M 43M 71F 46M 47F 78M 72F

Heart Rate (beats/min)

Comments

ECG

58

Normal Normal Normal Normal Normal Normal Variable PR RBBB + LAFB RBBB + LAFB; Ant MI RBBB LVH

ii 2 69 1:: 75

48M 30M

Parox A.FI Parox A.Fib Chest pain Chest pain Syncope Syncope Dual AVNP Syncope CAD Parox A.FI 3+ aortic reg.

Ant MI = anterior myocardial infarction; CAD = coronary artery disease; ECG = electrocardiogam; Dual AVNP = dual atrioventricular nodal pathways; LAFB = left anterior fascicular block; LVH = left ventricular hypertrophy; Parox A.Fib = paroxysmal atrial fibrillation; Parox A.FI = paroxysmal atrial flutter: RBBB = right bundle branch block; reg.= regurgitation.

with syncope, dizziness or easy fatigability. All patients had refractory periods measured during placement of a temporary pacing catheter or at the time of permanent pacemaker implantation. No patient with bradycardia had ventricular tachycardia recorded during 6 to 20 hours of tape-recorded monitoring or computer-assisted bedside monitoring. All patients were in hemodynamically stable condition and no

Clinical Characteristics of Patients with Bradycardia

TABLE ii Pt

AawL;’

Heart Rate (beats/min)

68F 92M 64M

Site of Block

ECG

Below Above Below Below Below Below Above Below Above Below Below Above Below Above

3’ AV block 3’ AV block 2’ AV block 3’ AV block 2” AV block 3’ AV block 3’ AV block 3“ AV block 3’ AV block 3” AV block 3’ AV block 2’ AV block 3’ AV block 3” AV block RBBB;SB SB

zi 86M 81F 96M 58M 88F 21M 65M 6lM 70M 79F

Underlvina Disease

H H H H H H H H H H H H H H

PCSD PCSD PCSD PCSD PCSD CAD CAD CAD :: Hypothyroid Myocarditis HCVD HCVD SND SND

AV = atrioventricular; CAD = coronary artery disease; DC = dilated cardiomyopathy; H = His bundle; HCVD = hypertensive cardiovascular disease; PCSD = primary conduction system disease; SB = sinus bradycardia; SND = sinus node dysfunction.

TABLE iii

Comparison of Ventricular Refractoriness Between Control Subjects and Patients with Bradycardia (ms) Average

Dispersion

ERP

FRP

ERP

FRP

37 f 12 43 f 38 NS

36 f 20 48 f 35 NS

23f 11 40 f 47 NS

19 f 15 35 f 49 NS

Spontaneous Rhythm Control (n = 11) Bradycardia (n = 16) p value

296 f 25 “zdo?

Control(n.= rvTzdra

249 f 18 277 f 27 <0.005

Ventricular

ERP = effective

11) (n = 16) refractory

346 f 18 421 f 39
period; FRP = functional refractory

period; NS = not significant.

April I.1985

spontaneous rhythm) or stimulus artifact (during ventricular drive) to the extrastimulus (Sz) failing to propagate. Ven-

tricular FRP was the shortest coupling interval (VI to V,) recordedon the ventricular electrogram.Dispersion of ventricular refractoriness was calculated from the range of re-

fractory periods measuredin eachpatient as the difference between the longest and the shortest refractory periods (Fig. 1). Vulnerability to ventricular doubleextrastimuli (Szand SQ) was diagnosed when extrastimuli induced 3 or more ventricular responses beyond lead Vs. Dispersion of refractoriness was comparedat the 2 rates (spontaneousrhythm and 120 beats/min) with a paired t test. All results are given as mean

f standard deviation. Results Ventricular refractoriness in control patients (Table III): The 11 control patients had an average heart rate of 72 f 12 beats/min (range 58 to 103). The

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average ERP was 296 f 25 ms in sinus rhythm; it shortened to 249 f 16 ms with ventricular drive at 120 beats/min (p
BASAL ;LpTUM

FIGURE 1. Ventricular effective and functional refractory periods (ERP, FRP) measured from 3 right ventricular (RV) sites during spontaneous rhythm (left) in a representative bradycardic patient. Dispersion of refractoriness is the longest refractory period minus the shortest. During spontaneous rhythm, the cycle length of 1,550 ms, dispersion of ERP is 15 ms (380 ms inferior to 385 ms apex) and dispersion of FRP is 15 ms (440 ms inferior to 425 ms apex). During ventricular drive (right), dispersion of ERP is 10 ms and dispersion of FRP is 15 ms. RVE = right ventricular electrogram.

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OF REFRACTORINESS

averaged 377 f 36 ms (range 327 to 480), which was significantly longer than the control ERP of 296 f 25 ms (p
mart? SD.

Dispersion of ERP is illustrated for all 16 bradycardic patients in Figure 5. During spontaneous rhythm, 4 bradycardic patients (nos. 1,9,13 and 14) had abnormal dispersion of ERP when compared with the mean value for control subjects plus 2 standard deviations (37 + 24 = 61 ms) (Fig. 5). With ventricular drive, dispersion of ERP was normal in all but 2 patients (nos. 6 and 9). Dispersion of ERP increased in patient 6 by 50 ms and in patient 9 by 80 ms with pacing. The upper limits of normal for dispersion of ERP during drive at 120 beats/min was 45 ms (Fig. 5). Despite correction of heart rate by pacing, the bradycardic patients continued to have significantly longer average ERP and FRP. Dispersion of ERP and FRP remained longer in the bradycardic patients despite pacing, but this was not statistically significant. Ventricular vulnerabi!ity to extrastimulation: Fifteen bradycardic patients had 51 echo beat after double extrastimuli during spontaneous rhythm or drive. Patient 4 had the only positive study with 4 repetitive beats only after double ventricular extrastimuli during ventricular drive. The longest escape rhythm recovery time after ventricular pacing was recorded in 7 patients. The escape rhythm recovery time ranged from 2.1 to 10 seconds. In no patient did long periods of asystole promote ventricular ectopy or ventricular fibrillation. Fourteen of the 16 bradycardic patients received permanent ventricular pacemakers. Patient 12, who had transient complete heart block secondary to myocarditis did not receive a permanent pacemaker. Patient 8 died from pneumonia before permanent pacemaker implantation. Fourteen patients were alive an average of 17 f 9 months after their evaluations and pacemakers.

p< .OOl

$i

moon ,* S.D.

-. .

ptooi

p<,OOI

Dispersion of ERP

T

300 * mrrc 200

4-o 60 HEART

Ii0

N4I

RATE

Bradycardii 0 control

l

FIGURE 2. Effect of increasing heart rate by ventricutar pacing on ventricular effective refractory periods (ERP) and dispersion of ventricular refraoto~~ pariods. the group msens of tha right ventricular ERP are shown in the upper portion and dispersion of ERP in the lower portlon. Pacing significantly shortened ERP in both control subjects and patients with bradycardia (p CO.001). Dispersion of ERP signficantly shortened wjth pacing in control subjects. However, pacing did not significantly reduce dispersion in the bradycardla group. NS 7 difference not significant; S.D. = standard deviation.

-

I

mtro!

Bradyoardia

Conlrol

Brady&

FIGURE 3. Group mean effective refractory periods (ERP) during both spontaneous rhythm and ventricular drive. The mean ERP for the 11 control subjects is significantly shorter than that for the 19 patients with bfadycda @
April 1.1985

Patient 7 died from an acute infarction 5 days after permanent pacemaker implantation. Discussion Bradycardia-dependent ventricular ectopy is well recognized in the setting of complete AV block in humans.5 In laboratory investigations bradycardia prolongs relative refractory periods and increases nonuniformity of refractory periods.a10 This increase in dispersion of refractoriness should facilitate reentry, which may be the mechanism for bradycardia-dependent tachyarrhythmias. g~loIn the present study, we found that severe bradycardia in patients with sinus node dysfunction or AV block prolonged ventricular refractory periods significantly. However, bradycardia did not significantly increase dispersion of ventricular refractoriness over control values. Pacing significantly reduced dispersion of refractoriness in our control subjects. This is consistent with animal studies.slO Pacing failed to significantly decrease dispersion in our bradycardic group. Although not signficant, bradycardic patients had longer average dispersion of ERP and FRP than control subjects despite pacing. Five patients had exceedingly wide dispersion of ERP (Fig. 5) and 11 had normal dispersion of refractoriness. Because abnormal dispersion of refractoriness was not universally present in patients with bradycardia, the abnormalities observed may simply reflect intrinsic ventricular disease. Our bradycardic patients did not have bradycardiadependent ventricular ectopy. Thus, the presence of abnormalities of refractoriness does not imply that ventricular ectopy will be present. Bradycardia may predispose to ventricular tachycardia and fibrillation.@-lo Patients with complete AV block presumably die from these arrhythmias. We used double ventricular extrastimuli during severe bradycardia to attempt induction of ventricular tachyarrhythmias, but failed to induce any arrhythmia in our

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patients. Bradycardia alone probably does not create enough nonuniformity of ventricular refractoriness to predispose to lethal ventricular tachyarrhythmias. These arrhythmias in bradycardic patients probably result from a combination of underlying ventricular disease and hemodynamic decompensation. Our data are consistent with ambulatory monitoring data in patients with sinus node dysfunction and long pauses. Mazuz and Friedmanll did not find that prolonged sinoatrial pauses correlated with or predicted sudden death. The data from our patients on dispersion of ventricular refractoriness are similar to data reported by others.12J3Spielman et all2 reported a mean dispersion of ERP of 43 ms (range 35 to 60) from the endocardial surface of the left ventricle. Schechter et all3 reported 54 f 16 ms (mean f standard error of the mean) from the right ventricular endocardial surface in 12 patients. In the dog, Han et al9 found an average dispersion of 43 ms on the epicardial surface. Dispersion of ERP narrowed significantly with pacing at faster heart rates (range 700 to 300 ms). We compared a similar range in our bradycardic patients (1,500 to 500 ms). Some of our bradycardic patients failed to have narrower dispersion with pacing. The failure to reduce dispersion of refractoriness with pacing may point to underlying ventricular disease. There are several potential problems with our study. First, our measurements were limited only to the right ventricle. However, we assumedthat bradycardia affects both ventricles equally. Second, we measured refractory periods at only 3 sites, fewer than Spielman et ali2 and Han et al9 measured. Further measurements may have increased the degree of dispersion, but this seems un-

210 120

IOf 75

.

m66

-

-------

A B

SC !

v

25 I

Control Bradycardii

Spontaneous Rhythm

Control Bradycardia vantrkular DhflZQMrn)

FIGURE 4. Mean dispersion of effective refractory periods (ERP) for the 2 groups during’ both spontaneous rhythm and ventricular drive. Despite significant differences in heart rate between control subjects and bradycardic patients (72 vs 39 beats/min, respectively), dispersion of ERP is not significantly different (NS). There is no significant difference with control of heart rate at 120 beats/min.

2

3 4

5

6 7 6 9 IO II l2 13 14 l5 I6 PATIENT NUMBERS 0 Spantanoour Rhythm l v~alklr orlw FIGURE 5. The effect of increasing heart rate on dispersion of the effective refractory period (5RP) for each of the 16 bradycardic patients. During spontaneous rhythm, 4 patients (nos. 1, 9, 13 and 14) had abnormal dispersion when compared to the mean value for control subjects plus 2 standard deviations (61 ms, dashed llpe A). With ventricular pacing, dispersion of ERP was normal in all but 2 patients (nos. 6 and 9). The upper l!mits of normal for dispersion of ERP during ventricular pacing is shown at da@+ line B (45 ms).

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BRADYCARDIA AND DISPERSION OF REFRACTORINESS

likely, given the similarity between data at comparable cycle lengths. Third, we measured refractory periods from the endocardial surface. Han et al8ls stimulated the epicardial surface in dogs. Moore et all4 observed that epicardial muscle cells have a shorter FRP than endocardial His-Purkinje system cells in the dog. However, abrupt shortening of cycle length with a premature beat can reverse FRP duration on the 2 surfaces and favor ventricular fibrillation. Divergence exists between refractoriness of the His-Purkinje system and ventricular muscle in humans.15 Refractoriness of ventricular muscle tends to vary directly with faster heart rates, whereas His-Purkinje fibers vary inversely.15 Had we stimulated the epicardial surface of our patients, we may have made different observations and arrived at different conclusions. The effect of bradycardia on dispersion of ventricular refractoriness in humans may be dependent on autonomic innervation.16 In the canine experiments, the dogs were anesthetized and the stellate ganglia excised. In work on the denervated human heart, Goodman et al16 found an increase in nonhomogeneous repolarization. They suggested that an intact autonomic nervous system acts to reduce ventricular dispersion of refractoriness. Our patient populations were biased. The control group was not normal. All had undergone electrophysiologic procedures for symptoms, electrocardiographic abnormalities or cardiac catheterization for chest pain. There may have been greater differences between a truly normal population and our bradycardic patients. The population of bradycardic patients studied may not represent the typical group with high-grade AV block. Our patients were mildly symptomatic, hemodynamitally stable, and had little or no ventricular ectopy during severe bradycardia. Our study design probably minimizes ventricular dispersion. To maximize such differences would require studying patients who are in

unstable condition. Such patients with paroxysmal AV block may not survive to be hospitalized. Acknowledgment: We appreciate the help of Valerie Sakun, PAC, and Sharon A. Magro, PAC, in our electrophysiology laboratory; Kathy J. Kyper for the illustrations and Carolyn M. Ferrante for her patient preparation of this manuscript.

References 1. MeridfthJ, Pruftf RD. Disturbancesin cardiac conductionand their management.Circulation1973;47:1998-1107. 2. Edhag 0, Swahn A. Prognosisof patientswith complete heart block or arrhythmicsyncopewho were nottreatedwith artificialpacemakers.Acta Med scand 1976;200:457-463. 3. EsoharDJW, Fqn&t S. Pacemakertherapyfor chronicrhythmdisorders. ProgCardiovascDis 1972; 14459-474. 4. Jansen G, Sfgurd8, Sandoe E. Adams-Stokesseizuresdue to ventricular tachyarrhythmiasin patientswith heart block: prevalence and problems of management.Chest 1975;67:43-48. 5. Schwartz SP. Studieson transientventricularflbrillatlcn.Ill. The oreflbrillatorymechanismdwing establlsbedauriculoventriculardlssoci&on. Am J Med Sci 1936:19212kl53-163. 8. RosenKM, UhfngraRC. Loeb HS, RahfmtoofaSH. Chronicheart block in adults.Arch InternMed 1973;131:663-672. 7. Danes P, Wu D, Uhfngra R, Pfetras RJ, Rosen KM. The effects of cycle lengthon cardfacrefractoryperiodsin man. Circulation1974;49:32-41. 8. Haa J, Moe GK. NonunIformrecoveryof excftabilityin ventricularmuscle. Circ Res 1964;14:44-60. 8. Han J, Milfet 0, ChlzzonfttfB, Mea OK. Temporaldispersionof recovery of excitabilityIn atriumandventricleas a functionof heart rate. Am Heart J 1966;72(4):481-487. 10. Srachman J, Scherfag SJ, RosenshtraukhLV, Lazrara R. Bradycardtadependenttdggwedactivity:relevanceto druginducedmultifwn ventrfculw tachycardia.Circulation1983;68:846-856. 11. Mszur M, Frfedman HS. Significanceof prolongedelectrocardl rapbic gu&si! sinoatrlaldisease:sick sinussyndrome.Am J Card1011 3 83:52: 12. 8piefman R, Untereker WJ, Horowftr LW, Kastor JA, Josqhson ME. EndocardYactivationand refractorinessin the ncrmalhumanleft ventricle fabstr).Am J Cardiol 1982:49:982. IS. &he&r JA, Caine R, F&flug T, KOwey PR, Engel Tf?.Effect of procainamkfe on dispersion of ventricular refractoriness. Am J Cardiol 1983:52:279-282. i4. Moore EN, f%estokJB, Moe OK. Durationof transmembraneaction PO_ tentlalsand functionalrefractoryperiodsof canine false tendonand venUlcufarmyocardium.Circ Res 1965;17:259-273. 15. Daafrer S, Lefunann MH, Yahmud R, GffbeH C, AkMar Y. Divergence betweenrefractorinessof HisPurkinjesystemand ventricularmusclewith abruptchangesin cycle length.Circulation19X%6&1212-1221. 16. oooaMnW,R~RM,RkkrAK,HlvrhonDC.Theeffectofcyclelength on cardiac refractoryperiodsIn the denervatedhumanheart. Am Heart J 1976;91:332-338.