Circadian Rhythm of Heart Rate Variability Is Reversibly Abolished in Ischemic Stroke
Background and Purpose Acute brain infarction significantly decreases heart rate variability as a result of cardiovascular autonomic dysregulation. However, information regarding circadian rhythms of heart rate and heart rate variability is limited.
Methods In this prospective study, we analyzed 24-hour circadian rhythm of heart rate and the time and frequency domain measures of heart rate variability in 24 patients with hemispheric brain infarction, 8 patients with medullary brainstem infarction, and 32 age- and sex-matched healthy control subjects. ECG data were obtained from the patients in the acute phase and at 6 months after the infarction.
Results In the acute phase of stroke, all the components of heart rate variability, ie, standard deviation of RR intervals, total power, high-frequency power, low-frequency power, and very-low-frequency power, were similar at night (from midnight to 6 am) and during the day (from 9 am to 9 pm), indicating that the circadian oscillation of heart rate variability had been abolished. At 6 months after brain infarction, the circadian rhythm had returned and, as in the control subjects, the values at night were significantly higher than those in the daytime. The values in hemispheric and in brainstem infarction did not differ significantly from each other.
Conclusions These results suggest that circadian fluctuation of heart rate variability is reversibly abolished in the acute phase of ischemic stroke and that it returns during the subsequent 6 months. The loss of the relative vagal nocturnal dominance may contribute to the incidence of cardiac arrhythmias and other cardiovascular complications after acute stroke.
Autonomic cardiovascular regulation, as with many other human physiological functions, follows a distinct circadian rhythm that is mainly of endogenous origin controlled by the hypothalamus but is also modulated by environmental factors.1 For example, arterial blood pressure and heart rate decrease and heart rate variability increases during the night as a result of increased vagal activity.1 2 3 In addition, the occurrence of sudden cardiovascular death also has a circadian rhythm with increased incidence during the early morning hours.1 4
Diminished heart rate variability and especially a loss of its circadian oscillation are associated with an increased risk of cardiac arrhythmia and sudden death in coronary artery disease.5 6 7 In particular, suppressed vagal activity during the night seems to be an unfavorable phenomenon leading to unopposed sympathetic activity and imbalance between the sympathetic and the parasympathetic cardiovascular autonomic regulatory systems.5 6 7 Recent studies8 9 10 11 12 13 suggest that cerebrovascular diseases also cause a prognostically unfavorable suppression of heart rate variability similar to that observed in coronary artery disease, and the sympathetically and parasympathetically mediated components of heart rate variability both are diminished as a consequence of acute stroke. As far as we know, however, the effects of stroke on circadian fluctuation of heart rate variability and on the balance between the sympathetic and the parasympathetic nervous system have not previously been studied.
The present prospective 6-month follow-up study was designed to assess quantitatively the effects of brain infarction on circadian rhythms of heart rate and heart rate variability. We analyzed the time and frequency domain measures of heart rate variability from 24-hour ECG recordings in 24 patients with hemispheric brain infarction, in 8 patients with medullary brainstem infarction, and in 32 age- and sex-matched healthy control subjects.
Subjects and Methods
Thirty-two consecutive patients (22 men and 10 women; mean±SD age, 53.6±12.0 years; range, 19 to 67 years) with acute ischemic stroke located in the hemispheric territory of the brain or at the medulla oblongata were included in the study. Patients with manifestations of other central or peripheral nervous system lesions and patients with acute cardiac and pulmonary diseases were excluded. Patients with any other disease or those taking medication known to affect the autonomic nervous system were also excluded. The protocol of the study was approved by the Ethics Committee of the Medical Faculty, and the informed consent of the patient was obtained in each case.
The infarct was located in the right hemisphere in 15 patients, in the left hemisphere in 9 patients, and at the medulla oblongata in 8 patients. All the patients with hemispheric brain infarction had unilateral signs of the pyramidal tract lesion; most also had sensory deficits, and some had neuropsychological deficits. Six of the 8 patients with medullary infarction had the lateral medullary syndrome of Wallenberg, and 2 additional patients had Horner’s syndrome, bulbar paresis, contralateral sensory deficits, or disorders of equilibrium. Neurological deficits of the patients were scored according to the Scandinavian Stroke Scale,14 and the disability was evaluated with the Barthel Index (Table 1⇓).15
Cerebral CT verified a hemispheric brain infarction in all 24 cases with clinical signs of hemispheric involvement and a medullary infarction in 3 cases. Even the repeat CT with contrast remained normal in 5 of the patients clinically classified as having medullary infarction. The first CT was performed within 24 hours after the infarction and the second CT within 2 weeks.
The control group consisted of 32 healthy subjects (22 men and 10 women; mean±SD age, 51.9±10.5 years; range, 19 to 67 years) who had no clinical manifestations of any cardiac, pulmonary, or nervous system disease and who were taking no medication known to affect those systems.
A two-channel 24-hour ambulatory ECG recording (Delmar Avionics electroscanner) was performed on all the patients from 1 to 7 (median, 3) days after the onset of stroke and repeated 6 months later. Both of them were inpatient recordings. The ECG recording on the control subjects was performed at home. All the recordings were made with two-channel tape recorders and two bipolar leads. For detection of arrhythmias, a two-channel oscilloscopic display and an arrhythmia analyzer were used. In addition, all the tapes were manually scanned by an experienced observer, and all the areas of questionable accuracy were verified by a direct printout.
The ECG data were digitally sampled and transferred from the Delmar Avionics scanner to a microcomputer for analysis of heart rate variability (Heart Signal Inc). Details of this analysis and the filtering technique have been described previously.16 Briefly, linear trends were abolished from the RR interval data segments of 512 samples to make the data more stationary. This was done by first fitting a straight line to a segment by a standard least-squares method and then subtracting it from the sample values. The RR interval series was passed through a filter that eliminates unwanted premature beats and noise and fills the resulting gaps with an average value computed in the local neighborhood. An RR interval was interpreted as a premature beat if it deviated from the previous qualified interval value by more than a given tolerance, which was programmed on the basis of the prematurity index of ectopic beats in each patient. With this filtering technique, abrupt temporary changes in RR interval sequence, representing noise or ectopic beats, were removed and more stationary data were achieved for analysis. In addition, the RR intervals were reviewed on the computer display by an experienced observer, and the questionable portions were compared with the printouts of the ECG recordings. Only those RR intervals related to normal sinus beats in a stationary state and those segments with greater than 85% of qualified beats were included in the final analysis.
Heart rate variability was measured from the 24-hour ECG recording by using both time and frequency domain analyses.16 17 18 The mean values of the night hours (from midnight to 6 am) and the day hours (from 9 am to 9 pm) and the night-to-day ratios of the different measures of heart rate variability were calculated. The SD of the successive RR intervals and the root mean square of the difference between successive normal RR intervals (RMSSD) were used as the time domain measurements, and the power spectrum of heart rate variability was used as the frequency domain measurement.16 17 18 An autoregressive algorithm was used to estimate the power spectrum densities of RR interval variability with the sampling frequency of 256 Hz. The size of 10 was used for the model order in the analysis of the RR data. The computer program automatically calculates autoregressive coefficients to define the power spectrum densities.
The power spectra of heart rate variability were quantified by measuring the area under the spectral curve in four frequency bands. The area under the spectral curve from 0.005 to 0.4 Hz represents the total power, which is divided into HF power (the area from 0.15 to 0.4 Hz), LF power (the area from 0.04 to 0.15 Hz), and VLF power (the area from 0.005 to 0.15 Hz). The 24-hour average spectral components were calculated from the segments of 512 RR intervals.
Statistical analyses were performed by using the Mann-Whitney two-sample test to compare the values of the control subjects and those of the patients, and to compare the night and day values. The coherence between heart rate and heart rate variability was analyzed by using Spearman rank correlation coefficients.
Table 2⇓ presents the mean values of heart rate and the time and frequency domain measures of heart rate variability at night and during the day and the night-to-day ratios in the patients with acute brain infarction and in the control subjects. The mean heart rate of the patients in the acute phase was significantly (P<.001) higher at night than during the daytime, but all the other measures of heart rate variability of the patients were similar at night and during the day. In the control subjects, the heart rate and all the measured components of heart rate variability in the night hours were significantly (P<.05) higher than those in the day. All the night-to-day ratios of the stroke patients were significantly lower than those of the control subjects, indicating a decreased circadian oscillation.
By 6 months after brain infarction, circadian fluctuation of heart rate variability had returned in the stroke patients. Heart rate and all the measured components of heart rate variability were significantly higher at night than during the day (Table 2⇑). The night-to-day ratios of the stroke patients were also increased during the 6-month follow-up, and only the ratios of the RR interval and the total power were significantly lower in the stroke patients than in the control subjects.
The LF/HF ratio, which reflects the balance between the vagal and the sympathetic activity, had a circadian fluctuation in the control subjects, with the night value of the LF/HF ratio significantly (P<.01) lower than the day value (Table 2⇑). In the stroke patients, the LF/HF ratios at night and during the day were similar, indicating a loss of the relative vagal nocturnal dominance after stroke.
Figs 1 through 3⇓⇓⇓ illustrate the 24-hour circadian rhythm of the HF, LF, and VLF components (means) of heart rate variability in the control subjects and in the patients with acute stroke. All of these spectral components had a clear circadian oscillation in the control subjects, with higher values at night. In the patients with acute stroke, however, all the circadian oscillations of these spectral components were abolished.
The results from the patients with hemispheric stroke did not differ significantly from those with medullary brainstem stroke (data not shown). The observed oscillation of the different measures of heart rate variability did not correlate with the severity of the clinical deficits scored by the Scandinavian Stroke Scale or with the disability evaluated by the Barthel Index. The values of the patients with right- and left-sided infarct were similar, and the values of the ambulatory patients did not differ significantly from those of the nonambulatory patients. All of the comparisons were done separately in the acute phase and at 6 months after the stroke.
There was no normal coherence of heart rate and heart rate variability in the stroke patients either in the acute phase or at 6 months after the stroke. The Spearman correlation coefficients between heart rate and the LF/HF ratios were in the acute phase.21 (night) and.32 (day) and at 6 months.16 (night) and.19 (day).
The results of this prospective study reveal the abolition of the circadian rhythm of heart rate variability and a loss of the relative vagal nocturnal dominance in patients with acute ischemic stroke. The phenomenon seems to be reversible, because circadian oscillation of heart rate variability returned by the 6-month follow-up study, and the values at night were significantly higher than those during the day. The oscillation was absent both in hemispheric and in medullary brainstem infarction, and it was not related to the side of the lesion, the severity of the clinical deficits of the patients, or the disability of the patients.
Many physiological functions show diurnal variation.1 Body temperature is lowest in the early morning, peak values of corticosteroid secretion are found just before awakening, and the heart rate decreases while excretion of urine increases during the night.1 Physiological changes may also contribute to the circadian rhythm of some pathological conditions. For example, there is an increase in the incidence of sudden death during the early morning hours.1 4 Whether these rhythms are of endogenous origin, that is, due to an internal “clock” or produced by environmental effects, remains unclear. There is, however, evidence that the circadian clock is located in the suprachiasmatic nuclei of the hypothalamus that, in turn, has intensive connections with the cerebral cortex and several neuroendocrinological systems.1 The most powerful environmental rhythmic regulator is presumably daylight.1
The effects of stroke on physiological circadian rhythms are incompletely understood; and as far as we know, the present study is the first to focus on the circadian rhythms of heart rate and heart rate variability. Our results agree with the previous findings of reduced heart rate variability after cerebrovascular diseases.8 9 10 11 12 13 It has been shown that both ischemic and hemorrhagic lesions located either in the hemispheric or in the brainstem level of the brain may result in impaired heart rate variability.8 9 10 11 12 13 19 20 In those studies, however, only the overall 24-hour heart rate variability was reported12 13 or the duration of ECG recording was only a few minutes.8 9 10 11 19 20 The present results indicate that a 24-hour or even longer recording time should be used in studying heart rate variability in stroke and probably in other diseases of the central nervous system as well. Shorter recording times may miss the abnormalities of the circadian or other long-term rhythms.
The abolished circadian rhythm of heart rate variability in the present patients may be related either to the brain lesion itself or its neurohumoral consequences. It is well known that brain infarction causes alterations of the serum levels of different hormones such as antidiuretic hormone, catecholamines, and cortisol.21 22 23 It is possible that these endocrinological disturbances are associated with the abnormalities of heart rate variability. More probable, however, is that the brain lesion itself damages the cortical or subcortical structures known to regulate the cardiovascular circadian rhythms, ie, the hypothalamus or its neural connections.1 It is also possible that cortical structures known to regulate the cardiovascular autonomic system may influence the circadian rhythms as well. In particular the insular cortex lying within the middle cerebral artery territory has extensive connections with the other important autonomic regulatory areas located in the subcortical limbic and forebrain regions.24 However, the results of the present study do not give any further evidence for the pathophysiological mechanism of this phenomenon. It seems that the circadian rhythm of heart rate variability may be abolished as a consequence of a brain infarction located either in the hemispheric level or in the brainstem.
Physical activity in an upright position normally increases heart rate, decreases the HF spectral component, and increases the LF component, resulting in an increased LF/HF ratio.6 The opposite effects occur in the supine position. Although many of our patients spent considerable time in a supine position during the first 24-hour ECG recording, the position of the patients and the presence or absence of ambulatory activity did not significantly affect the results. The observed differences between the patients and the control subjects were most pronounced during the night, when all the patients and control subjects were in a supine position. Moreover, the HF, LF, and LF/HF values of the ambulatory and nonambulatory patients were similar. Thus, our results obviously reflect the effects of brain infarction on the cardiovascular autonomic regulatory system that controls circadian rhythms. A limited daytime activity of the patients particularly in the acute phase may have an additional effect on the recorded values.
Previously, the circadian rhythm of heart rate variability was shown to be blunted in uncomplicated coronary artery disease,5 6 7 in diabetes mellitus,25 and in hypertension.26 The clinical significance of blunted circadian fluctuation has not yet been established in diabetes and in hypertension, but in coronary artery disease abolished circadian fluctuation seems to be related to lethal arrhythmic events after myocardial infarction.5 7 The previous studies also suggest that myocardial infarction results in a loss of the relative vagal nocturnal dominance, and the most useful indicator of this imbalance between the vagal and the sympathetic activities is the LF/HF ratio.7 It was also suggested that this imbalance might be associated with the increased incidence of sudden cardiogenic death during the early morning hours.7 In our patients, the circadian rhythm of the LF/HF ratio after stroke was abnormal as previously observed in patients with coronary artery disease, although the pathophysiological mechanisms may be different in these diseases.7
In conclusion, circadian fluctuation of heart rate variability is abolished in the acute phase of ischemic stroke and returns during the subsequent 6 months. This reversible abolition, which reflects both sympathetic and parasympathetic autonomic dysfunction, may be caused by an infarction located either in the hemispheric or brainstem level of the brain. The loss of the relative vagal nocturnal dominance may contribute to the incidence of cardiac arrhythmias and other known cardiovascular complications commonly found in the acute phase of stroke.
Selected Abbreviations and Acronyms
- Received April 4, 1997.
- Revision received July 8, 1997.
- Accepted July 25, 1997.
- Copyright © 1997 by American Heart Association
Appenzeller O. Circadian rhythms. In: Appenzeller O, ed. The Autonomic Nervous System. 4th ed. Amsterdam, Netherlands: Elsevier Science Publishers; 1990:393-402.
Muller JE, Tofler GH, Stone PH. Circadian variation and triggers of onset of acute cardiovascular disease. Circulation. 1989;79:733-743.
Huikuri HV, Niemelä MJ, Ojala S, Rantala A, Ikäheimo MJ, Airaksinen KEJ. Circadian rhythms of frequency domain measures of heart rate variability in healthy subjects and patients with coronary artery disease. Circulation. 1994;90:121-126.
Vanoli E, Adamson PB, Ba-Lin MPH, Pinna GD, Lazzara R, Orr WC. Heart rate variability during specific sleep stages: a comparison of healthy subjects with patients after myocardial infarction. Circulation. 1995;91:1918-1922.
Barron SA, Rogovski Z, Hemli J. Autonomic consequences of cerebral hemisphere infarction. Stroke. 1994;25:113-116.
Korpelainen JT, Sotaniemi KA, Suominen K, Tolonen U, Myllylä VV. Cardiovascular autonomic reflexes in brain infarction. Stroke. 1994;25:787-792.
Naver HK, Blomstrand C, Wallin BG. Reduced heart rate variability after right-sided stroke. Stroke. 1996;27:247-251.
Korpelainen JT, Sotaniemi KA, Huikuri HV, Myllylä VV. Abnormal heart rate variability as a manifestation of autonomic dysfunction in hemispheric brain infarction. Stroke. 1996;27:2059-2063.
Scandinavian Stroke Study Group. Multicenter trial of hemodilution in ischemic stroke: background and study protocol. Stroke. 1985;16:885-890.
Huikuri HV, Valkama JO, Airaksinen KEJ, Seppänen T, Kessler KM, Takkunen JT, Myerburg RJ. Frequency domain measures of heart rate variability before the onset of nonsustained and sustained ventricular tachycardia in patients with coronary artery disease. Circulation. 1993;87:1220-1228.
Malliani A, Pagani M, Lombardi F, Cerutti S. Cardiovascular neural regulation explored in the frequency domain. Circulation. 1991;84:482-493.
Myers MG, Norris JW, Hachinski VC, Sole MJ. Plasma norepinephrine in stroke. Stroke. 1981;12:200-204.
Goldstein DS. Stress-induced activation of the sympathetic nervous system. Baillieres Clin Endocrinol Metab. 1987;4:253-278.
Oppenheimer S. The anatomy and physiology of cortical mechanisms of cardiac control. Stroke. 1993;24(suppl I):I-3-I-5.
Bernardi L, Ricordi L, Lazzari P, Solda P, Calciati A, Ferrari MR, Vandea I, Finardi G, Fratino P. Impaired circadian modulation of sympathovagal activity in diabetes: a possible explanation for altered temporal onset of cardiovascular disease. Circulation. 1992;86:1443-1452.