Respiratory sinus arrhythmia in diabetic neuropathy

Diabetologia, Apr 1983

Summary Heart rate variation was measured at different rates of regular deep breathing (2.5 to 13 breaths/min) in 11 normal subjects and 13 diabetic patients with neuropathy, defined clinically by the absence of both ankle jerks or the presence of autonomic symptoms. Subjects were divided into those above and below 30 years old. Normal subjects showed twofold changes in heart rate variation with maximum variation at mean breathing rates of 6.3 and 5.5 breaths/min. Heart rate variation was significantly smaller than normal in the diabetic patients with neuropathy, at all of the frequencies tested in the younger group and 7 of the 13 test frequencies in the older group; the maximum variation occurred at slower mean breathing rates of 4.5 breaths/min (p < 0.005) and 4.1 breaths/ min (p < 0.01) respectively. Seven diabetic patients without neuropathy, with intact leg reflexes and < 30 years old, had normal heart rate variation but the maximum responses occurred at a mean breathing rate of 5.4 breaths/min, significantly slower than normal (p < 0.02). Measuring the breathing rate at which heart rate variation is maximal may be a sensitive way of detecting autonomic (vagal) neuropathy.

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Respiratory sinus arrhythmia in diabetic neuropathy

Diabetologia Respiratory Sinus Arrhythmia in Diabetic Neuropathy J. D. M a c k a y 0 1 0 Diabetic Department, King's College Hospital , London , UK 1 Dr. J. D. Mackay Department of Medicine University Hospital of South Manchester Manchester M20 8LR , UK Summary. Heart rate variation was measured at different rates breathing rates o f 4.5 breaths/min (p < 0.005) and 4.1 breaths/ o f regular deep breathing (2.5 to 13 breaths/min) in 11 normal min ( p < 0.01) respectively. Seven diabetic patients without subjects and 13 diabetic patients with neuropathy, defined neuropathy, with intact leg reflexes and < 30 years old, had clinically by the absence o f both ankle jerks or the presence o f normal heart rate variation but the maximum responses ocautonomic symptoms. Subjects were divided into those above curred at a mean breathing rate of 5.4 breaths/rain, signifiand below 30years old. Normal subjects showed twofold cantly slower than normal (p < 0.02). Measuring the breathing changes in heart rate variation with maximum variation at rate at which heart rate variation is maximal m a y be a sensimean breathing rates o f 6.3 and 5.5 breaths/rain. Heart rate tive way o f detecting autonomic (vagal) neuropathy. Respiratory sinus arrhythmia; heart rate; diabetes - a b n o r m a l reflex r e s p o n s e s [ 1 ]. F a c t o r s c a u s i n g v a r i a t i o n in h e a r t r a t e are c o m p l e x [ 2, 3 ], b u t t h e r e is a c l e a r r e l a t i o n s h i p b e t w e e n h e a r t r a t e v a r i a t i o n ( H R V ) a n d b r e a t h i n g , in p a r t i c u l a r r e g u l a r b r e a t h i n g , well k n o w n as r e s p i r a t o r y sinus a r r h y t h m i a . L o s s o f t h e n o r m a l H R V o n d e e p b r e a t h i n g h a s b e e n u s e d as a s i m p l e a n d sensitive test f o r d i a b e t i c a u t o n o m ic n e u r o p a t h y [ 4, 5 ]: w h e n a b n o r m a l it i n d i c a t e s t h e p r e s e n c e o f v a g a l n e u r o p a t h y [ 4 ]. T h e r o u t i n e test is p e r f o r m e d at a s t a n d a r d i z e d rate o f 6 b r e a t h s / m i n ; this r a t e w a s c h o s e n since, in a d d i t i o n t o c o n v e n i e n c e , t h e a m p l i t u d e o f H R V d e p e n d s o n r e s p i r a t o r y r a t e a n d in n o r m a l subjects is m a x i m a l at 5 - 6 b r e a t h s / m i n [ 6-8 ]. T h e a i m o f this s t u d y w a s t o m e a s u r e H R V at differe n t rates o f b r e a t h i n g in n o r m a l subjects a n d t o c o m p a r e t h e results o b t a i n e d w i t h t h o s e f r o m d i a b e t i c p a t ients w i t h a n d w i t h o u t n e u r o p a t h y . Methods As the amplitude of HRV on deep breathing declines with age [ 5 ],normal and diabetic subjects were divided by age into two sets, each with a narrow age range: those < 30 years old (age range 20-29 years) and autonomic neuropathy, vagus nerve. those 30 years old and over (age range 30-43 years). In the younger set there were three groups: six normal subjects (group 1), seven diabetic patients without neuropathy (group 2) and five diabetic patients with neuropathy (group 3). The mean durations of diabetes were similar: group 2, 14.0 years (range: 6-21 years); group3, 16.6years (range: 10-23 years). In the older set there were only two groups: five normal subjects (group4) and eight diabetic patients with neuropathy (group 5). The duration of diabetes in group 5 was 24.0 years (range: 9-35 years). Within each set groups were well matched for age. Statistical comparisons were made between the groups in each set of subjects but not between the two age sets. No normal subject had known cardiovascular, respiratory or neurological disease and none was diabetic. The 13 diabetic patients with neuropathy had either peripheral neuropathy (12 patients: 4/5 in group 3, 8/8 in group 5), autonomic neuropathy (seven patients: 5/5 in group 3, 2/8 in group 5), or both (six patients). Diabetic patients without neuropathy had intact leg reflexes and no autonomic symptoms. Both forms of neuropathy were defined clinically: peripheral neuropathy by the absence of both ankle jerks (peripheral nerve conduction studies were not performed); and autonomic neuropathy by the presence of autonomic symptoms. One patient had postural hypotension (fall in systolic blood pressure on standing of > 30 mmHg), four had diarrhoea of characteristic pattern and four had gustatory sweating. All diabetics were receiving insulin but no other medication. Clinical Procedure Subjects were tested in the morning or afternoon. The diabetic patients received their normal insulin and diet. As assessed by clinic visits t t t ~o 2o Time (s) ~o their diabetes was stable; none became clinicallyhypoglycaemic during the test. All remained supine throughout; testing began after a 15 min rest. They were connected to an oscilloscope and a HewlettPackard 8020A heart rate monitor (Palo Alto, CA, USA) which recorded the beat-by-beat heart rate on paper. Heart rate recordings were made during episodes of regular deep breathing, the timing regulated by the experimenter using a clock. The subjects' depth of breathing was not recorded, but they were observed closely, encouraged to maintain deep breathing throughout and to inspire and expire smoothly. Tests were performed at 13 different rates of breathing from fast (15 breaths/min) to slow (3 breaths/rain). In 8 of the 13 diabetic patients with neuropathy testing was performed to even slower rate of breathing (2.5 breaths/min). Eight cycles of breathing were recorded at each test frequency, thus taking 0.5-2.5 rain to perform the test. There was a 2 min rest before each recording. Repeat measurements were obtained in 16 of the 31 subjects (five normal subjects, four diabetic patients without neuropathy, seven diabetic patients with neuropathy) by testing from slow to fast rates of breathing. Analysis Heart rate variation was assessed manually by measuring (from the beat-by-beat heart rate record) the difference between peak and trough heart rates over five deep breaths, taking the mean of ten consecutive readings (in beats/rain, five from trough to peak, five from peak to trough) (Fig. 1) [ 5 ]. These measurements of the amplitude of HRV were plotted against respiratory frequency (on a logarithmic scale) and frequency response curves drawn by eye. Two variables were derived: (1) the 'resonance amplitude', the maximum amplitude of HRV, in beats/rain; (2) the 'resonance frequency', the frequency of respiration, in breaths/min, at which the maximum amplitude of HRV occurred. Mean frequency-response curves were obtained for the five groups: at each breathing rate tested the measurements of HRV made from the traces were pooled and the mean amplitude _+ SEM calculated. Statistieal Analysis Statistical comparisons were made using Student's t-test and a 5% level of significance accepted. However, in the younger set (< 30 years old), to permit multiple comparisons between groups 1 to 3, the test was modified by reducing the accepted level of significance to 2%. This level of significance applied to comparisons of age and also the derived variables of resonance frequency and resonance amplitude. Comparison of the mean amplitudes of HRV at each of 13 frequencies (3-15 breaths/min) between groups 1-3 in the younger set, and groups 4 and 5 in the older set, were made using a two-factor analysis of variance (factor 1 = group, factor 2 = frequencies) with repeated measures of the second factors [ 9 ]. From this the appropriate experimental error term was estimated and then the Tukey multiplecomparison procedure was used to obtain the least significant difference [ 10 ]. When two mean amplitudes for two groups of subjects measured at the same frequency differed by an amount greater than or equal to the least significant difference value the means were established as significantly different at the chosen significance level. The significance level was set at 5%. Results H e a r t r a t e v a r i a t i o n o n d e e p b r e a t h i n g a k e r e d c o n s i d e r a b l y b e t w e e n t h e d i f f e r e n t b r e a t h i n g r a t e s ; o v e r t h e f r e q u e n c y r a n g e t e s t e d t h e r e w a s a t w o - t o t h r e e f o l d c h a n g e i n a m p l i t u d e . T h i s p a t t e r n o f r e s p o n s e w a s s e e n i n i n d i v i d u a l s u b j e c t s a n d a l s o , w i t h p a r t i c u l a r c l a r i t y , w h e n m e a n a m p l i t u d e s at e a c h t e s t f r e q u e n c y w e r e o b t a i n e d f o r e a c h o f t h e five g r o u p s ( F i g s . 2 a n d 3). T h e s m a l l e s t a m p l i t u d e s w e r e f o u n d a t t h e v e r y f a s t b r e a t h i n g r a t e s . T h e a m p l i t u d e s t h e n i n c r e a s e d e v e n l y i n a l i n e a r f a s h i o n w i t h p r o g r e s s i v e l y s l o w e r b r e a t h i n g r a t e s ( u s i n g a l o g a r i t h m i c p l o t o f r e s p i r a t o r y f r e q u e n c y ) u n t i l a m a x i m u m w a s r e a c h e d ; t h e n t h e y d e c l i n e d w i t h t h e s l o w e s t b r e a t h i n g r a t e s . O v e r a l l a f r e q u e n c y - r e s p o n s e c u r v e w a s o b t a i n e d . Y o u n g n o r m a l s u b j e c t s ( g r o u p 1) h a d a m e a n freq u e n c y r e s p o n s e c u r v e as d e s c r i b e d ( F i g . 2) a n d a r e s o n a n c e f r e q u e n c y o f 6.3 + 0 . 6 b r e a t h s / m i n ( m e a n + 1 S D ) . A g e h a s e f f e c t s o n t h i s r e s p o n s e : t h e o l d e r g r o u p o f n o r m a l s u b j e c t s ( g r o u p 4) o v e r a l l h a d s m a l l e r a m p l i t u d e s o f H R V a n d t h e m e a n r e s o n a n c e f r e q u e n c y w a s a t t h e s l o w e r r a t e o f 5.5 + 0.3 b r e a t h s / r a i n ( F i g . 3). D i a b e t i c p a t i e n t s w i t h o u t n e u r o p a t h y ( g r o u p 2) h a d s i m i l a r a m p l i t u d e r e s p o n s e s to n o r m a l s u b j e c t s ( g r o u p 1) w i t h n o s i g n i f i c a n t d i f f e r e n c e b e t w e e n t h e i r m e a n r e s o n a n c e a m p l i t u d e s o r b e t w e e n t h e m e a n a m p l i t u d e s o f H R V a t t h e i n d i v i d u a l t e s t f r e q u e n c i e s ( F i g . 2 ) . D e s p i t e this, t h e i r f r e q u e n c y - r e s p o n s e c u r v e s w e r e s h i f t e d t o t h e l e f t w i t h a m e a n r e s o n a n c e f r e q u e n c y o f 5.4 + 0.3 b r e a t h s / m i n , s i g n i f i c a n t l y s l o w e r t h a n t h e n o r m a l s u b j e c t s (p < 0.02). ] 25-A =E 20O I 3 I I I 6 9 12 Respiratory frequency (breaths/min) I 15 Diabetic patients with neuropathy, both young (group 3) and older (group 5), also showed an approximately twofold change in the amplitude of H R V within the frequency range studied, but overall the size of their responses was reduced (Figs. 2 and 3). The m e a n resonance amplitudes were significantly smaller than those of equivalent normal subjects (groups 1 versus 3, p < 0.005; groups 4 versus 5, p < 0.02), and also smaller than those of the diabetic patients without neuropathy (groups 2 versus 3, p < 0.001). Using a two-factor analysis of variance the young diabetic patients with neuropathy (group 3) had m e a n amplitudes of H R V significantly smaller than normal (group 1) at all 13 of the fiequencies tested (Fig. 2), and the older subjects (groups 4 versus 5) at 7 of the 13 frequencies tested (Fig.3). Discrimination between the heart rate responses of the diabetic patients with neuropathy and those of the normal subjects was best between the breathing rates of 5 and 7.5 breaths/min. In addition to the reduction in the amplitude of HRV, diabetic patients with neuropathy showed a m a r k e d shift of the resonance frequencies to slower breathing rates (Figs. 2 and 3). The m e a n resonance frequency in those < 30 years old (group 3) was 4.5 _+0.7 breaths/min, significantly slower than normal subjects (group I) (p < 0.005), and also slower than the diabetic patients without neuropathy ( g r o u p 2 ; p<0.02). The older diabetic patients with neuropathy (group 4) h a d a m e a n resonance frequency of 4.1 _+1.1 breaths/min, significantly slower than the normal subjects (group 5; p < 0.01). Diabetic patients with neuropathy have smaller amplitudes of HRV because of less slowing of the heart rate during each respiratory cycle (Fig. 1). This is illustrated by analysis of the peak and trough heart rates at the m a x i m u m recorded amplitudes of H R V in all the 11 normal subjects and the 13 diabetic patients with neuropathy (Table 1). The m e a n peak heart rates are similar but the m e a n trough heart rates are significantly different; this entirely accounts for the difference in the amplitudes of HRV. The heart rate response on testing from fast to slow rates of breathing (first series) was compared with the response on testing from slow to fast rates of breathing (second series) in the 16 subjects who had such studies performed. At each test frequency the 13 amplitudes from the first series were compared with the 13 amplitudes from the second series, using the paired t-test. No significant differences were detected at any of the test frequencies, suggesting that systematic errors were not developing during the procedure. Discussion Respiratory sinus arrhythmia, the variation of heart rate with respiration, may reflect a reflex adjustment of the heart to cyclic changes in systemic venous return inof coherence of neural impulses in a reflex system where synchrony is important. Such defects of temporal dispersion can occur when there are only minor changes in conduction velocity [ 13 ]. This change in the resonance frequency has been found even in young diabetic patients without clinically detectable neuropathy. It suggests that measurement of the resonance frequency may provide a sensitive way of detecting early autonomic (vagal) neuropathy. Secondly, there is reduction in the amplitude of HRV on deep breathing with more advanced neuropathy [ 4, 5, 14, 15 ]. This may reflect a m o r e severe pathology such as nerve fibre loss, which has been observed histologically in diabetic patients with severe autonomic neuropathy [11]. Acknowledgements. I am grateful to Dr. P.J. Watkins for his encouragement and support, and particularly to my wife, Dr. B.A. Mackay, for helpful scientific discussions. Statistical help was given by Mr. E. B. Farragher. Financial support was kindly provided by King's College Hospital Voluntary Research Trust Fund and by Sterling Winthrop Ltd. 1. Ewing DJ ( 1978 ) Cardiovascular reflexes and autonomicneuropathy . Clin Sci 55 : 321 - 327 2. Sayers B McA ( 1973 ) Analysis of heart rate variability . Ergonomics 16 : 17 - 32 3. Melcher A ( 1976 ) Respiratory sinus arrhythmia in man. A study in heart rate regulating mechanisms . Acta Physiol Scand [Suppl] 435 : 1 - 31 4. Wheeler T , Watkins PJ ( 1973 ) Cardiac denervation in diabetes . Br Med J 4 : 584 - 586 5. Mackay JD , Page M McB , Cambridge J , Watkins PJ ( 1980 ) Diabetic autonomic neuropathy. The diagnostic value of heart rate monitoring . Diabetologia 18 : 471 - 478 6. Angelone A , Coulter NA ( 1964 ) Respiratory sinus arrhythmia: a frequency dependent phenomenon . J Appl Physio119 : 479 - 482 7. Womack BF ( 1971 ) The analysis of respiratory sinus arrhythmia using spectral analysis of digital filtering . IEEE Trans Biomed Eng 18 : 399 - 409 8. Kelman GR , Warm KT ( 1971 ) Studies in sinus arrhythmia . J Physiol (Lond) 213 : 59 - 60P 9. Wines BJ ( 1971 ) Statistical principles in experimental design, 2nd edn, McGraw- Hill , New York, pp 518 - 539 10. Wines BJ ( 1971 ) Statistical principles in experimental design, 2rid edn, McGraw- Hill , New York, pp 185 - 196 11. Duchen LW , AnjorinA, Watkins PJ , Mackay JD ( 1980 ) Pathology of autonomic neuropathy in diabetes mellitus . Ann Intern Med 92 : 301 - 302 12. Bennet T , Farquhar ID , 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 13. Gilliat RW , Willison RG ( 1962 ) Peripheral nerve conduction in diabetic neuropathy . J Neurol Neurosurg Psychiatry 25 : 11 - 18 14. Sundkvist G , Almer L-O , Lilja B ( 1979 ) Respiratory influence on heart rate in diabetes mellitus . Br Med J 1 : 924 - 925 15. Ewing DJ , Borsey DQ , Bellavere F , Clarke BF ( 1981 ) Cardiac autonomic neuropathy in diabetes: comparison of measures of R-R interval variation . Diabetologia 21 : 18 -24 Received: 5 May 1982 and in revised form: 15 November 1982


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J. D. Mackay. Respiratory sinus arrhythmia in diabetic neuropathy, Diabetologia, 1983, 253-256, DOI: 10.1007/BF00282709