Cardiac refractoriness

Cardiac Refractoriness Age-dependence

in Normal Subjects

Katherine M. Kavanagh, MD, D. George Wyse, MD, PhD, L. Brent Mitchell, MD, and Henry J. Duff, MD

Abstract: The effects of age on cardiac electrophysiologic measurements were assessed in 30 subjects between the ages of 18 and 73 years and free of structural heart disease. Occult heart disease was excluded by a normal treadmill exercise tolerance test, a rest and exercise radionuclide angiogram, and/or a cardiac catheterization. Effective and functional refractory periods of right atrium, right ventricle, and atrioventricular node were assessed. The relationship between these measurements and age was examined using linear regression. There were significant correlations between age and atria1 effective and functional refractory periods, atrioventricular effective refractory period, and ventricular effective and functional refractory periods. Other electrophysiologic measures showed no such relationship with age. Key words: age, cardiac refractory periods, electrophysiology.

The effects of aging on the electrophysiologic properties of the human heart have not been systematically examined over a wide range of ages in normal subjects without structural heart disease. Previous studies have assessed the relationship between age and change in electrophysiologic parameters only in patients with congenital and acquired heart disease. In addition, no previous studies have examined agedependent changes in ventricular electrophysiologic

parameters. Accordingly, we undertook this study to identify and quantitate the relationships between age and intracardiac measures of conduction and refractoriness.

Methods Subjects

From the *Department ofMedicine and tDivision of Cardiology, University of Calgary. Calgary, Alberta, Canada. + From Foothills Hospital, Calgary, Alberta, Canada. Supported by the Alberta Heart Foundation. Calgary, Alberta.

The records of 30 normal subjects ( 18 men and 12 women) ranging in age from 18 to 73 years were prospectively analyzed. Normality was verified by complete medical history, physical examination, chest roentgenogram, complete blood count, routine screening biochemical measurements, and 12lead electrocardiogram. Furthermore, occult heart disease was excluded by a normal treadmill exercise test, a rest and exercise radionuclide angiogram, and/

Alberta Heritage Foundation for Medical Research, Edmonton, Alberta, and Medical Research Council of Canada, Ottawa, Ontario. Dr. Wyse and Dr. Duff are Scholars of the Alberta Heritage Foundation for Medical Research and Dr. Mitchell is an Investigator of the Alberta Heart Foundation. Dr. Kavanagh is a Fellow of the Alberta Heritage Foundation for.Medical Research. Reprint requests: Katherine M. Kavanagh, MD, e/oDr. H. J. Duff, Department of Medicine, 3330 Hospital Drive N.W., Calgary, Alberta, T2N 4N1 Canada.

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or a cardiac catheterization. Transvenous catheter electrophysiologic studies were done for evaluation of syncope, presyncope, or persistant palpitations in the absence of documentable rhythm disturbances. Any tachyarrhythmia or bradyarrhythmia during the electrophysiologic study or during a minimum of 24 hours of continuous electrocardiographic monitoring excluded the subject from this study.

The Wenckebach cycle length was defined as the cycle length at which atrioventricular nodal Wenckebach block first appears during atria1 pacing. Wenckebach cycle length was determined by pacing the atrium at a rate just above the sinus rate and decreasing the atria1 paced cycle length by lo-msec decrements every 10 set until Wenckebach atrioventicular block occurred.

Electrophysiologic Studies

Statistical Analysis

A transvenous catheter electrophysiologic study was performed in each subject in the drug-free state. Surface ECG leads I, aVF, and V1 were recorded simultaneous with electrograms from the right atrium, right ventricle, and His bundle recording sites. Records were obtained at a paper speed of 100 mm/set. Pacing and extrastimulus techniques’ were applied with a constant current stimulator delivering pulses with a duration of 2 msec and an intensity of twice late diastolic excitability threshold.

The relationship between age and electrophysiologic measurements were assessed with linear regression.2 Linearity of the relationship was verified by analysis of residuals. The null hypothesis was rejected when p I 0.05.

Results Table 1 reviews the demographic the patients.

characteristics of

Definitions Atrial, AV nodal, and ventricular effective and functional refractory periods were determined by a single extrastimulus technique’ after 8-beat train at a basic pacing cycle length of 600 msec. The atria1 effective refractory period was defined as the longest S 1SZ interval without atria1 capture by S2. The atria1 functional refractory period was defined as the minimal AlAz interval created during determination of the atria1 refractory curve. The AV nodal effective refractory period was the longest A1A2 interval (in the His recording) without AV nodal conduction of Aa. The AV nodal functional refractory period was the minimum HIHz interval created during determination of the atria1 refractory curve. The ventricular effective refractory period was defined as the longest S1S2 interval without ventricular capture by Sz. The ventricular functional refractory period was the minimum VIVZ interval created during determination of the ventricular refractory curve. The corrected sinus node recovery time was defined as the longest sinus node recovery time minus the basic sinus cycle length. The sinus node recovery time was defined as the interval between the last paced atria1 electrogram and the first spontaneous sinus beat. The sinus node recovery time was determined by the pacing of the right atrium for 30 seconds at cycle lengths just above the spontaneous sinus cycle length, to a cycle length of 400 msec, in decrements of 50 msec.

Table 1. Demographics

of Patient Population

Patient

Age

Sex

1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30

18 18 23 25 26 30 32 34 34 39 47 49 51 54 55 55 55 58 58 59 61 61 61 61 62 62 70 73 51 37

M M F F M M M F M F M M M M F F F M M F M F M M M F F M M F

Presentation Palpitations Presyncope Presyncope Palpitations Syncope Palpitations Palpitations Syncope Syncope Syncope Syncope Palpitations Syncope Palpitations Presyncope Presyncope Palpitations Syncope Syncope Presyncope Syncope Syncope Palpitations Syncope Presyncope Syncope Syncope Syncope Syncope Palpitations

There was no evidence of documented electrical disturbances on ECG or 24 Holter in any of these patients.

Age and Cardiac Electrophysiology Table

2. Electrophysiologic Measurements Correlated With Age

l

Kavanagh et al.

223

That

Measurement

n

r

P

AERF AFRF AVNERP VERP VFRF’

23 23 22 14 14

0.41 0.55 0.41 0.58 0.53

0.03 CO.01 0.04 0.03 0.05

AERF, atria1 effective refractory period; AFRP, atria1 functional refractory period; AVNERP, atrioventricular effective refractory period; VERP, ventricular effective refractory period; VFRP, ventricular functional refractory period.

1001 25

35

45

55

55

75

35

45

55

65

75

Refractory Periods Correlations are presented the exception

between refractory periods and age in Table 2 and Figures 1 and 2. With

of the AV nodal functional refractory period, all other measured refractory periods were correlated with age. Progressive prolongation of these refractory periods accompanied aging. For example, the atria1 effective refractory periods predicted by the regression line were approximately 195 msec at age 20 years and 258 msec at age 70 years.

150

1

100 25

Age (ye8K)

Fig. 2. Relationship between ventricular

*

*1

Age

(years)

refractory periods and age. (A) Effective refractory period (ERP). (B) Functional refractory period (FRP). Line of best fit and the 95% confidence interval was determined by regression analysis.

Similarly, the predicted ventricular effective refractory periods were approximately 2 13 msec at age 20 years and 262 msec at age 70 years. The statistical relation between age and changes in refractory periods was documented by linear regression analysis (Table 2). Table 3 shows the means and standard deviations of the atrial, ventricular, and AV nodal effective refractory periods for the younger, middle, and older age groups. The progressive continuum of change can be seen throughout these three age groups. The significance of the relationship between age and refractoriness was assessed by linear regression.

Table 3. Atrial, Ventricular,

and AV Nodal Effective

Refractory

Periods Age Group (Years)

Fig. 1. Relationship between atria1 refractory periods and age. (A) Effective refractory period (ERP). (B) Functional refractory period (FRP). Line of best fit and the 95% confidence interval was determined by regression analysis.

AERF (x 2 SD) VERF (x f SD) AVNERF (x f SD)

18-29

30-49

50-73

198 k 31 220 f 14 275 f 37

221 +- 34 226 2 9 317 2 15

246 f 58 241 2 24 326 f 56

AERP, atria1 effective refractory period; AVNERF, atrioventicular effective refractory period; VERF, ventricular effective refractory period.

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Vol. 22 No. 3 July 1989

Table 4. Correlation of Electrophysiologic Measurement With Age and the Combination of Age and Sinus Cycle Length (RR) Age + Sinus

AERP AFRP AVNERP VERP VFRP

Cycle Length

Age

Electrophysiologic Variable

I

P

I

P

0.41 0.55 0.41 0.58 0.53

0.03 co.01 0.04 0.03 0.05

0.36 0.55 0.50 0.70 0.61

0.07 0.01 0.04 0.02 0.08

AERP, atrial effective refractory period; AFRP, atria1 functional refractory period; AVNBRP, atrioventricular effective refractory period; VERP, ventricular effective refractory period; VFRP, ventricular functional refractory period.

In this study, age was not related to sinus cycle length (r = 0.30, NS). However, consideration of sinus cycle length as a covariable when assessing the relationships between age and other electrophysiologic parameters did improve the overall regression coefficients (Table 4) for the AV nodal and ventricular refractoriness periods. For example, ventricular effective refractory period is significantly related to age (r = 0.58, p = 0.03). Consideration of the measured ventricular effective refractory period as corelated to both age and sinus cycle length improved the overall correlation coefficient to r = 0.7 (p < 0.02). While the overall correlation coefficients were somewhat improved by this corelationship, the overall probability values were not significantly improved. The consideration of sinus cycle length did not improve the correlation coefficients of the atria1 refractory periods with age (Table 4).

Other Measurements Surface ECG intervals, intracardiac electrophysiologic intervals, corrected sinus nodal recovery times, and the AV nodal Wenckebach cycle length were not correlated with age (Table 5). Table 5. Electrophysiologic Measurement That Did Not Correlate With Age Measurement

n

r

P

PR

28 28 28 27 27 28 25

0.29 0.001 0.093 0.122 -0.212 0.084 0.29

0.13 0.997 0.64 0.543 0.288 0.67 0.158

QRS QTc AH HV CSNRT WBCL

CSNRT, correlated sinus node recovery time; WBCL, Wenckebach cycle length.

Discussion

The relationships between aging and intracardiac physiologic parameters have not been systematically assessed in individuals without structural heart disease. DuBrow et a1.3 studied the effects of aging on supraventricular electrophysiologic parameters in a population consisting predominantly of patients with structural heart disease (at least 71% of patients). In their study it is not clear that the agerelated changes were independent of structural heart disease. In contrast, our study was designed to address this question. We assessed the relationship between aging and intracardiac electrophysiologic parameters in individuals defined as being clinically normal. Furthermore, previously unassessed measures, such as ventricular refractory periods, are included. These data indicate that atria1 and ventricular effective and functional refractory periods and the AV nodal effective refractory period increase progressively with advancing age. In contrast, a continuum of change was not evident for the measures of cardiac conduction assessed, as well as for the QTc. The determinants of cardiac refractoriness are numerous. Two of these have been reported to be effected by aging in a manner that might contribute to an understanding of our observations. First, the action potential characteristics of cardiac tissue from both rabbits and humans are age-dependent. Toda4 reported progressive age-related changes in both action potential duration and resting membrane potential in dispersed rabbit heart cells. The direction of these changes would be compatible with the changes in refractoriness reported here. Escanade et al., 5 in their study of human tissue, attributed these changes in action potential duration to age-related differences in the kinetics of the outward potassium currents. Another potential explanation for the increase in cardiac refractoriness with age is altered autonomic nervous system tone. This hypothesis is supported by studies that show an age-dependent decrease in responsiveness to exogenous and endogenous catecholarnines,“,’ as well as an age-dependent decrease in adrenoceptor number.‘f9 While change in ventricular effective refractory period correlated with age in this study, there was no such correlation of QTc with age. Clearly, action potential is a determinant of refractoriness. However, many other parameters may also alter refractoriness, including resting membrane potential and the time constant of recovery of the sodium channel. In addition, QTc is a reflection of global left ventricular repolarization time but may not reflect the local right ventricular repolarization time. Therefore, age-de-

Age and Cardiac Electrophysiology

pendent changes in right ventricular refractoriness are not necessarily related to changes in global QTc interval. In review, our data do not allow us to conclude that age-dependent changes in action potential duration result in the age-dependent changes in ventricular effective refractory periods observed in this study. In this study, age was not related to the sinus cycle length. However, sinus cycle length has been reported to be an important determinant of measured The correlation coefficients of electrophysiology.” the relationships between age on refractory periods were somewhat improved for AV nodal and ventricular refractory periods by considering sinus cycle length as a covariable; however, the overall probability values were not significantly improved. There was no significant relationship between age and surface electrocardiographic intervals in this study. Both age-dependence and age-independence of these intervals have been previously reported. 11*12 Resolution of this controversy requires further study. The observation that cardiac refractory periods increase progressively with age is relevant to definition of normal and abnormal refractory period ranges. Furthermore, this age-dependence of refractoriness may be important in the natural history of rhythm disturbances dependent upon critical differences in refractory periods. For example, the frequency of ventricular arrhythmias in individuals without structural heart disease is known to increase with agel and symptomatic arrhythmias in patients with AV nodal reentrant tachycardia and the Wolff-Parkinson-white syndrome increase with age.14

manuscript was typed Laura-Lee Christiansen.

Kavanagh et al.

by Gregory

Douglas

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and

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Acknowledgment 13.

The authors acknowledge the valuable contributions of P. Cassidy, BN, RN, and K. Hillier, RN. The

l

14.

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