Reflex control of heart rate in normal subjects in relation to age: A data base for cardiac vagal neuropathy

Diabetologia, Mar 1982

We examined the heart rate changes induced by forced breathing and by standing up in 133 healthy subjects in the age range 10–65 years in order to establish a data base for studies on parasympathetic heart rate control in autonomic neuropathy. Test results declined with age. Log-transformation was used to define the lower limit of normal (P0.10) and an uncertainty range (values between P0.10 and P0.025). The lower limit of normal decreased from 22 to 11 beats/ min for forced breathing and from 26 to 16 beats/min for standing up, with age increasing from 10 to 65 years. No subject scored below and only two subjects scored in or below the uncertainty range for both tests. Lack of correlation between both tests (r=0.17) documents the different afferent mechanisms of the reflex heart rate changes. In combination these two tests form a simple and reliable bedside method to establish cardiac vagal neuropathy.

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Reflex control of heart rate in normal subjects in relation to age: A data base for cardiac vagal neuropathy

Diabetologia Reflex Control of Heart Rate in Normal Subjects in Relation to Age: A Data Base for Cardiac Vagal Neuropathy W. Wieling 0 J. F. M. v a n B r e d e r o d e 0 L. G. de Rijk 0 C. Borst a n d A. J. D u n n i n g 0 0 Department of Medicine, Academic Medical Centre, and Department of Physiology, University of Amsterdam , Amsterdam , The Netherlands S u m m a r y . W e e x a m i n e d the h e a r t rate c h a n g e s ind u c e d b y f o r c e d b r e a t h i n g a n d b y s t a n d i n g u p in 133 n o r m a l , we c o m p a r e d i n s t a n t a n e o u s H R c h a n g e s with f o r c e d b r e a t h i n g a n d after s t a n d i n g u p in 133 h e a l t h y subjects in the age r a n g e 10-65 years in o r d e r h e a l t h y v o l u n t e e r s in the age r a n g e 10-65 years. D i a b e t i c a u t o n o m i c n e u r o p a t h y; vagal - 9 Springer-Verlag 1982 c e r t a i n t y r a n g e (values b e t w e e n P0.10 a n d P0.025). T h e l o w e r limit o f n o r m a l d e c r e a s e d f r o m 22 to 11 b e a t s / m i n f o r f o r c e d b r e a t h i n g a n d f r o m 26 to 16 b e a t s / r a i n f o r s t a n d i n g up, with age i n c r e a s i n g f r o m 10 to 65 years. N o subject s c o r e d b e l o w a n d o n l y t w o subjects s c o r e d in o r b e l o w the u n c e r t a i n t y r a n g e f o r b o t h tests. L a c k o f c o r r e l a t i o n b e t w e e n b o t h tests (r = 0.17) d o c u m e n t s the different afferent m e c h a n i s m s o f the reflex h e a r t rate c h a n g e s . I n c o m b i n a t i o n these t w o tests f o r m a simple a n d reliable b e d s i d e m e t h o d to establish c a r d i a c vagal n e u r o p a t h y . h e a r t rate control, f o r c e d b r e a t h i n g , o r t h o s t a t i c reflexes. I m p a i r e d vagal c o n t r o l o f h e a r t rate ( H R ) has b e e n d e s c r i b e d in a variety o f diseases, s u c h as diabetes mellitus [ 1-3 ], u r a e m i a [4] a n d r h e u m a t o i d arthritis [ 5 ]. I n patients with diabetes mellitus, c a r d i a c vagal dysf u n c t i o n is m o s t o f t e n d e t e c t e d in l o n g s t a n d i n g disease, b u t d a m a g e to the a u t o n o m i c n e r v o u s s y s t e m m a y even be p r e s e n t at d i a g n o s i s [ 6 ]. A b n o r m a l a u t o n o m i c c a r d i a c f u n c t i o n is p r o g n o s t i c a l l y i m p o r t a n t b e c a u s e it m a y be a s s o c i a t e d with a h i g h m o r t a l i t y [ 7 ]. I n s t a n t a n e o u s H R c h a n g e s with f o r c e d b r e a t h i n g [ 1-3, 6, 8-10 ] a n d after the t r a n s i t i o n f r o m lying to s t a n d i n g [ 7, 8, 10-12 ] are u s e d as s i m p l e b e d s i d e tests to assess v a g a l H R control. I n o r d e r to establish a d a t a b a s e f o r d e l i n e a t i n g a b n o r m a l vagal H R c o n t r o l f r o m Subjects and Methods Normal subjects consisted of medical students, hospital personnel and community volunteers. No medication other than oral contraceptives was used. Subjects were grouped according to age: 10-29 years (n = 64), 30~49 years (n =48), 50-65 years (n =21). Values for resting HR, blood pressure, weight and height are given in Table 1. Subjects were examined in the morning (70%)or in the afternoon (30%), at least I h after the last meal. They were requested to abstain from coffee and cigarettes on the day ofthe experiment. The instantaneous HR (beats/min) was determined by a cardiotachometer and monitored on a pen recorder (Servogor RE 511). The subjects rested in a supine position for at least 5 min before the measurements were started. The resting HR was taken as the mean value over a 30-s period preceding the tests. The subject was instructed to perform six consecutive maximal inspirations in the supine position at a rate of 6 breaths/rain [ 1-3, 6, 8 ]. From the pen recording we measured the mean difference between the maximum and minimum instantaneous HR during each of six consecutive cycles of forced inspiration and expiration:the I E difference (beats/rain) [ 1-3, 6, 8 ]. Standing Upfrom the Supine Position in 3-5 s A marker connected to the pen recorder was used to identify the moment the subject began to stand up (time t = 0 in RR-interval number RRo).A correction of I s was made to allow for the reaction time of the subject and the fact the cardiotachometer lagged one cardiac cycle. The following measurements were made: (a) AHR..... (beats/min), Tmax(s) and the number of the corresponding shortest RR-interval RRmin[ 8,12,13 ] (b) AHRmi,.Trainand the number of the corresponding longest RRinterval RRmax[ 8,12,13 ] For comparison with other studies [8,12,131we also determined the RR30/RRI5 ratio and the RRmax/RRminratio. Blood pressure was measured at rest and after 1rain in the erect posture. W. Wielinget al.: Assessment of Cardiac Vagal Neuropathy 10-29 M 40 stands for test score, X for age). We calculated the 90% confidence limits for individual observations [ 14 ]. In order to establish a range of values from probably normal to probably abnormal - an uncertainty range - we also calculated the lower one-sided 90% and 97.5% confidence limits (P0.10and P0.025).The regression coefficient (b) was tested for deviation from zero. Differences between group means were tested using Student's 't' test. The regression equation and the confidence limits were transformed back into normal scale. Correlation was calculated using Pearson's product moment correlation (r).A p < 0.05 was considered to indicate a significantdifference. R e s u l t s N o i n f l u e n c e o f s e x w a s f o u n d . T e s t r e s u l t s i n t h e m o r n i n g a n d a f t e r n o o n d i d n o t d i f f e r s i g n i f i c a n t l y . C o n s e q u e n t l y a l l r e s u l t s w e r e p o o l e d . Forced Respiratory Sinus Arrhythmia T h e I - E d i f f e r e n c e r a n g e d f r o m 7 t o 51 b e a t s / m i n a n d d e c l i n e d w i t h a g e ( F i g . 1). T h e r e g r e s s i o n o f t h e I - E d i f f e r e n c e w i t h a g e is d e s c r i b e d b y t h e e q u a t i o n l o g Immediate Heart Rate Changes After Standing Up r e s p o n s e : a n a b r u p t H R rise s t a r t i n g a f t e r <~ 1 s, a p e a k a r o u n d t = 1 2 s a n d a t r o u g h a r o u n d t = 2 2 s ( T a b l e 2). H R c o n t i n u e d t o i n c r e a s e v e r y little ( < 5 | - . ~ j 30 L 2 ~0 t I I 4 0 ~ I II 5 0 I t i 6 5 AGE(years) P0.95 PO.05 Test results were log-transformed because the data from each age group gave positively skewed distributions [ 14 ]. The log-normal data were fitted to the linear regression model log Y = a + bX (~( scored in or below the uncertainty range for the I - E difference and AHRmax, and only one in the uncertainty range for the I - E difference and the RRm~x/ RRmin ratio. No subject scored below the uncertainty range for both tests. Discussion Instantaneous H R changes induced by deep breathing and standing up are commonly used to assess vagal damage in diabetic autonomic neuropathy. The principal results of the present investigation in a large number of healthy subjects are: test results showed a huge scatter (for instance largest I - E difference seven times smallest difference) and skewed distributions. Analysis of test results after log-transformation enabled defining an 'uncertainty range' based on parametric statistics. Only two subjects scored within or beats/min) in only 11 subjects after 15s of standing up. For practical purposes the highest H R in the first 15 s was used as a measure for the initial peak H R rise to standing. The AHRma~ ranged from 14 to 47 beats/min and declined with age (Fig. 2). The regression of AHRma~ with age is described by the equation log AHR~a~ = 1.5864 - 0.0039 x age. The regression coefficient was significantly different from 0 (p < 0.001). The median AHRmax decreased from 35 to 22, P0.05 from 22 to 13 and the uncertainty range (Fig.2, hatched area) shifted from 20-25 to 12-15 with age increasing from 10 to 65 years. No subject scored below and 17 subjects scored within the uncertainty range. The correlation between A HRmaxand resting H R was very p o o r (r = 0.23). On average AHRmax was reached around RR15 and A H R m i n around RR30. However, since there were considerable individual differences, the RR30/RR15 ratio underestimated the RRmax/RRminratio (Table 2). The RRmax/RRminratio ranged from 1.08 to 1.98 and declined with age. The regression of the RRma~/ Retain ratio with age is dercribed by the equation log RRmax/RRmin = 0.2009 - 0.0014 x age. The regression coefficient was significantly different from 0 (p <0.001). The median RRmax/RRmin decreased from 1.54 to 1.29, P005from 1.25 to 1.05 and the uncertainty range shifted from 1.31 - 1.20 to 1.09 - 1.01 with age increasing from 10 to 65 years. Three subjects scored below and 8 subjects scored within the uncertainty range. The correlation between the RRmax/ RRmin ratio and resting H R was very poor (r = 0.19). Correlation Between HR ChangesAfter Forced Breathing and Standing Up The correlation between I - E difference and AHRrnax (r = 0.17) and I - E difference and RRm~/RRmin ratio (r = 0.14) was very poor. Two out of 133 subjects Author This study Mackay et al. [ 8 ] Wheeler and Watkins [1] Page and Watkins [ 2 ] Hilsted and Jensen [ 9 ] Dyrberg et al. [ 10 ] a After log-transformed data No. of subjects P0.95 PO.50 Po.05 below the uncertainty range in both tests. The H R changes evoked by forced breathing and by standing up declined with age [ 2, 8 ]. The present results are in general agreement with previous studies [ 1-3, 8-10 ], but comparison of tests scores considered to be the lower limit of normal by different authors (Table 3) shows that the more rigorous analysis in the present study improved the criteria for delineating abnormal from normal in individual testing of reflex vagal heart rate control. The very poor correlation between the H R changes with forced breathing and after standing up emphasizes that different afferent mechanisms are involved [ 3 ]. If we assume that these are entirely independent, there is a 1% chance that a healthy individual would score within or below the uncertainty range in both tests, and a 0.06% chance that scores below the uncertainty range would be obtained. Thus, in combination these two tests are eminently suited for bed-side screening of cardiac vagal neuropathy. No subjects had orthostatic hypotension after 1 rain of standing. The immediate H R response to standing showed a striking pattern in time: the peak HR rise was found after about 12 s, the subsequent relative minimum after about 22 s (Table 2), values almost identical to those reported in previous studies [ 12,15,16 ]. Ewing et al. [ 12 ] characterized the H R response by calculating the ratio between the 30th and 15th RR-interval. Although the maximal H R was reached near RR15 and minimal H R near RR30 (Table 2), there were considerable individual differences and the RR30/RR15 ratio was lower than the RRmax/RRmin ratio (Table 2). Thus, the RRmax/ RRminratio is superior [ 5, 8 ] to the RR30/RR15 ratio [ 10, 17 ] for testing abnormal vagal H R control in diabetic patients. Acknowledgements.We would like to express our appreciation to J. M. Karemaker, Department of Physiology for critical suggestions, and to J. Oosting and A. A. M. Hart, Department of Medical Physics for statistical advice. Wouter Wieling, M. D. Department of Medicine Academic Medical Centre Meibergdreef 9 NL-1105 AZ Amsterdam The Netherlands I. Wheeler T , Watkins PJ ( 1973 ) Cardiac denervation in diabetes . Br Med J 4 : 584 - 586 2. Page MMcB , Watkins PJ ( 1977 ) The heart in diabetes: autonomic neuropathy~ and cardiomyopathy . Clin Endocrinol Metab 6 : 377 - 388 3. Bennett T , Faquhar IK , Hosking DJ , Hampton JR ( 1978 ) Assessment of methods for estimating autonomic nervous control of the heart in patients with diabetes mellitus . Diabetes 27 : 1167 1174 4. 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Dyrberg T , Bern J , Christiansen JS , Hilsted J , Nerup J ( 1981 ) Prevalence of diabetic autonomic neuropathy measured by simple bedside tests . Diabetologia 20 : 190 - 194 11. Clarke BF , Ewing DJ , Campbell IW ( 1979 ) Diabetic autonomic neuropathy . Diabetologia 17 : 195 - 212 12. Ewing DJ , Campbell JW , Murray A , Neilson JMM , Clarke BF ( 1978 ) Immediate heart rate response to standing: simple test for autonomic neuropathy in diabetes . Br Med J 1 : 145 - 147 13. Ewing DJ , Hume L , Campbell JW , Murray A , Neilson JMM , Clarke BF ( 1980 ) Autonomic mechanisms in the initial heart rate response to standing . J Appl Physio149 : 809 - 814 14. Armitage P ( 1971 ) Statistical methods in medical research . Blackwell Scientific Publications , Oxford, pp 163 - 166 , 352 15. Drischel H yon , Fanter H , Gfirtler H , Labitzke H , Priegnitz H (1963) Das Verhalten der Herzfrequenz gesunder Menschen beim Ubergang vom Liegen zum Stehen . Archiv ffir Kreislaufforschung 40 : 135 - 167 16. 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W. Wieling, J. F. M. van Brederode, L. G. de Rijk, C. Borst, A. J. Dunning. Reflex control of heart rate in normal subjects in relation to age: A data base for cardiac vagal neuropathy, Diabetologia, 1982, 163-166, DOI: 10.1007/BF00283745