Autonomic Nervous System Dysfunction in Elderly Hypertensive Patients With Abnormal Diurnal Blood Pressure Variation
Relation to Silent Cerebrovascular Disease
Abstract To investigate the relationships among diurnal blood pressure (BP) variations and autonomic nervous system dysfunction, we assessed heart rate variability (HRV) using power spectral analysis of the 24-hour RR interval in 51 asymptomatic elderly hypertensive patients with various patterns of nocturnal BP fall. The extreme-dippers with marked nocturnal BP fall (n=16) had lower asleep low-frequency power (LF)/high-frequency power (HF) ratios (a relative index of sympathetic nervous system activity), while the nondippers without nocturnal BP fall (n=18) had lower awake LF/HF ratios and asleep/awake ratio for HF (an index of parasympathetic nervous activity), when compared with dippers with appropriate nocturnal BP fall (n=17). The incidence of multiple lacunar infarction detected by brain magnetic resonance imaging was 56% in the extreme-dippers and 38% in the nondippers, and both were markedly higher than that (6.3%) in the dippers (both P<.01). There was no significant relationship between the BP level and any HRV parameter for either the daytime or nighttime period. The asleep/awake ratio for systolic BP was significantly correlated with the asleep/awake ratio for HF (r=−.363, P<.01) and with the asleep/awake ratio for the LF/HF ratio (r=.540, P<.001), regardless of whether multiple lacunar infarction was present. In conclusion, the autonomic nervous system activity is not related to high BP level per se, rather its diurnal variation is more important as a determinant of the diurnal BP patterns, regardless of the presence or absence of cerebrovascular disease.
The development of the noninvasive device for ambulatory BP monitoring has enabled us to assess the diurnal BP variation in addition to high BP levels in clinical practice.1 Abnormal pattern of diurnal BP variation has been reported to be associated with both clinically overt and silent target organ damage and to be a predictor of subsequent cardiovascular events independent of high BP level.2 3 4 5 6 7 8 9 The nondipper, with diminished nocturnal BP fall, has been proposed as one subtype of abnormal diurnal BP variation characterized as associated with increased frequency of damage to all target organs (brain, heart, and kidney) and poorer prognosis for cardiovascular events, when compared with dippers with appropriate nocturnal BP fall.2–8 Recently, we identified a subgroup among the dippers, extreme-dippers, with marked nocturnal BP fall, as having a recently recognized subtype of abnormal diurnal BP variation, and we found that among elderly hypertensive patients extreme-dippers have more marked cerebrovascular damage than dippers.9
The mechanism of abnormal BP variation patterns in hypertensive patients remains unclear. The extreme pattern of diurnal BP variations in extreme-dippers or extreme-nondippers (whose asleep BPs are actually higher than their awake BPs) is a relatively persistent trait.10 The pattern of change of diurnal BP pattern is not even altered by very stressful events like a catastrophic earthquake.11,12 We have previously presented a report regarding an elderly hypertensive patient whose diurnal BP pattern was quite changed, from extreme-dipper to nondipper, after a minor ischemic stroke,6 suggesting that abnormal diurnal BP might be related to minor cerebrovascular ischemia. There is one report citing no significant differences between dippers and nondippers in diurnal changes of hormonal profiles, including catecholamine, renin, aldosterone, and cortisol13; whereas another report cited significantly higher plasma catecholamine levels in nondippers than in dippers.14 The diurnal BP variation seems to be closely related to sympathetic nervous system activity, because the plasma catecholamine levels decrease along with the nocturnal BP fall and increase along with the morning BP elevation.15 Currently, Holter ECG is used for the monitoring of spontaneous HRV to assess diurnal cardiac autonomic nervous system function. In a recent study of the relationship between diurnal BP variation and autonomic nervous system activity using HRV, Kohara et al found that among adult hypertensive patients the fluctuation of autonomic nervous system activity was diminished in nondippers.14
We investigated the relationships among diurnal BP variations, autonomic nervous system activity as assessed using HRV, and silent cerebrovascular disease in 51 asymptomatic elderly hypertensive patients with different patterns of nocturnal BP fall.
We studied 51 hypertensive outpatients aged ≥60 years, with mean office SBP of ≥140 mm Hg and/or mean office DBP of ≥90 mm Hg (average for each patient on three or more occasions). Office BP was measured in the sitting position by standard cuff methods. No patient had taken any antihypertensive medication for at least 14 days before the study. All of the subjects were ambulatory, and all gave informed consent. For all physical and laboratory examinations (including blood and urine tests, chest x-ray, and ECG at rest), the results were within the normal range or consistent with World Health Organization stages I and II. We excluded from this study outpatients with renal failure or hepatic damage (serum creatinine level >130 mmol/L, urea nitrogen level >10.7 mmol/L, positive glycosuria and proteinuria detected by multistix, and aspartate aminotransferase or alanine aminotransferase level >40 IU/L), or with obvious present illness, or with a past history of coronary artery disease, stroke (including transient ischemic attack), congestive heart failure, arrhythmia, or malignancy. Those with possible diabetes mellitus (fasting glucose level >5.5 mmol/L or hemoglobin A1c >6.2%) were also excluded from this study. Ten (63%) of the 16 extreme-dippers, 7 (41%) of the 17 dippers, and 8 (44%) of the 18 nondippers also had participated in our previous study of the relationship between nocturnal BP fall and the silent hypertensive cerebrovascular disease in the consecutive elderly hypertensive patients.9 This study was approved by our institutional review committee, and informed consent was obtained from each subject studied.
Smokers were defined as current smokers. The body mass index was calculated as weight (kg)/height (m)2. The ECG-LVH was defined as abnormally high voltages of QRS complexes (R in V5 plus S in V1 >3.5 mV) associated either with flat T waves (<10% of R) or with ST segment depression and diphasic T waves.16
24-Hour BP Monitoring
Noninvasive ambulatory BP monitoring was carried out on a weekday with an automatic ambulatory BP monitor with gas-powered cuff inflation (ABPM-630, Nippon Colin Co), which recorded BP and heart rate every 30 minutes for 24 hours. The accuracy of this device was previously validated.17 The ambulatory data used in the present study were those obtained by the oscillometric method. Each subject recorded an activities journal in which he or she noted information about the exact times of falling asleep and waking up. Reexamination was performed in the two hypertensive patients whose BP data could not be evaluated because of the presence of artifact in more than 10% of the total measurements. Those with documented disturbed sleep (frequent awakening during sleep) were not included in the present study.
Definitions of Extreme-Dippers, Dippers, and Nondippers
For the individual data, the asleep BP was defined as the mean BP from the time at which the patient went to bed until the time of awakening (sleep duration), and the awake BP was defined as the mean BP during the remaining portion of the day.18 In all 51 hypertensive patients the awake SBP was ≥140 mm Hg and/or awake DBP was ≥90 mm Hg. The nocturnal SBP fall was calculated as (awake SBP−asleep SBP)/awake SBP.9 The 51 hypertensive patients were subclassified on the basis of nocturnal SBP fall as follows: 16 extreme-dippers with ≥20% nocturnal reduction of SBP; 17 dippers with ≥10% but <20% reduction; and 18 nondippers with <10% reduction.9
Holter ECG and Power Spectral Analysis of RR Intervals
Ambulatory 24-hour ECG monitoring (SM-50, Fukuda Denshi Co Ltd) was performed to record RR intervals on magnetic tape. The tape of the Holter system incorporates a phase-lock loop system to correct variation in recording speed. The RR intervals recorded on tape were converted to digital signals at 128 samples per second (DMW-9000H, Fukuda Denshi Co Ltd). The power spectral densities were computed with a commercially available program (HPS-RRA version 2.02, Fukuda Denshi Co Ltd) using the fast-Fourier transform method. Subjects who had more than 100 ectopic beats per day were excluded from this study. The power spectral densities of rhythmic oscillations over a frequency range of 0.4 Hz or less were obtained during 512 beats every 30 minutes (256 beats before and after the time of BP measurements by ambulatory BP monitoring) to analyze the total power (≤0.40 Hz), the low-frequency power (LF: 0.04 to 0.15 Hz) as an index of both sympathetic nervous and parasympathetic nervous system activities, and the high-frequency power (HF: 0.15 to 0.40 Hz) as an index of parasympathetic nervous system activity.19,20 We confirmed that ectopic beats were not included among the 512 beats used in the analysis. The LF/HF ratio, an indirect index of sympathetic nervous system activity,19,20 was calculated for each data set.
The asleep value for each HRV parameter (total power, LF, HF, and the LF/HF ratio) was defined as the mean value from the time at which the patient went to bed until the time of awakening, and the awake value was defined as the mean value during the remaining portion of the day.
The normal values (geometric mean [SD range]) of sympathetic and parasympathetic parameters obtained from 15 normotensive elderly subjects aged 65 years or more were as follows: total power (24-hour, 2838 [range, 1766 to 4560] ms2; awake, 2780 [range, 1758 to 4395] ms2; asleep, 3006 [range, 1687 to 5358] ms2), LF (24-hour, 290 [range, 146 to 575] ms2; awake, 269 [range, 134 to 542] ms2; asleep, 301 [range, 142 to 635] ms2), HF (24-hour, 161 [range, 81 to 321] ms2; awake, 122 [range, 56 to 265] ms2; asleep, 271 [range, 130 to 564] ms2), and LF/HF ratio (24-hour, 2.26 [range, 1.52 to 3.90]; awake, 2.71 [range, 1.52 to 4.83]; asleep, 1.19 [range, 0.68 to 2.06]).
Brain MRI was carried out in all 51 patients using a superconducting magnet with a main field strength of 1.5 T (Toshiba MRT200FXII), as described previously.9 The images were evaluated for the number and location of lacunae and for the extent of periventricular signal abnormalities. A lacuna was defined as a low signal intensity area (<1 cm) on T1-weighted images that was also visible as a hyperintense lesion on T2-weighted images, as described and illustrated previously.18 The number of lacunae per patient was counted. The lacunae as defined might have included lesions other than true infarcts such as état criblé, especially when their size was small (ie, <5 mm).18 PVH depicted on T2-weighted images was classified into four grades, as described and illustrated previously.18 Briefly, grade I PVH was defined as no abnormality or minimal periventricular signal hyperintensities in the form of caps confined exclusively to the anterior horns or rims lining the ventricle, grade II as caps in both the anterior and posterior horns of the lateral ventricles or periventricular unifocal patches, grade III as multiple periventricular hyperintense punctate lesions and their early confluent stages, and grade IV as multiple areas of high signal intensity that reached confluence in the periventricular region. All of the MRI were interpreted under blind conditions by two of the authors. The 3 patients showing PVHs of grade IV or III were considered as collectively showing advanced PVH.9
Blood collection was performed after a minimum fasting period of 12 hours. The serum total cholesterol level was determined using commercial enzyme assay kits (Wako), and the serum high-density lipoprotein cholesterol level using an enzymatic procedure after precipitation with phosphotungstic acid (Wako).
Data are expressed as the mean (SD). The distributions of total power, LF, HF, and LF/HF ratio were highly skewed; these data were normalized after transformation into natural logarithms for parametric analysis. The geometric means (SD range) of these parameters were determined. One-way ANOVA was performed to detect differences among groups, and Fisher’s protected least significant difference test was used to compare the mean values of pairs between groups. The χ2 test was used to detect the differences among groups in the prevalence of male patients, smokers, and patients with target organ damage. Pearson’s correlation coefficient was calculated to test the relationships among parameters. Differences with a value of P<.05 were considered to be significant.
Characteristics of Extreme-Dippers, Dippers, and Nondippers
Table 1⇓ shows the characteristics of the three groups of elderly hypertensive patients classified according to the magnitude of nocturnal BP fall. There were no significant differences among the groups in any demographic characteristic, including age, sex, body mass index, smoking status, and the prevalence of ECG-LVH or previous antihypertensive treatment (63% for extreme-dippers; 59% for dippers; 56% for nondippers). The number of lacunae detected by brain MRI per person and the proportions of those with at least one lacuna and those with multiple (three or more) lacunae were significantly higher in the extreme-dippers compared with the dippers. The nondippers also had lacunae more frequently than the dippers. There were no significant differences among these three groups in any other metabolic factor.
There were no significant differences among the three groups in the office or 24-hour BP, but the awake SBP in the nondippers was significantly lower than that in the extreme-dippers. The asleep BP was significantly higher in the nondippers compared with the dippers and in the dippers compared with the extreme-dippers. The awake BP variation (SD of awake BP) tended to be greater in the extreme-dippers than in the other two groups.
HRV Analysis in Extreme-Dippers, Dippers, and Nondippers
Table 2⇓ shows the power spectral analysis of HRV in each group of hypertensive patients. The asleep total power was lower in the extreme-dippers and nondippers, and the 24-hour total power was lower in the nondippers, when compared with the dippers. There were no significant differences among the groups for LF or HF. The asleep LF/HF ratio in the extreme-dippers was significantly lower than that in the dippers and nondippers. The 24-hour and awake LF/HF ratios were significantly lower in the nondippers than those in the dippers. The asleep/awake ratio for the LF/HF ratio was significantly lower in the extreme-dippers than that in either the dippers or the nondippers. The asleep/awake ratio for HF was significantly lower, and that for LF/HF ratio significantly higher, in the nondippers than that in the dippers or the extreme-dippers.
HRV Analysis in Hypertensive Patients With Multiple Lacunar Infarction
Table 3⇓ shows the results of HRV using power spectral analysis in all 51 hypertensive patients with or without multiple (three or more lacunae) lacunar infarction. The 24-hour, awake, and asleep total powers and the 24-hour and asleep LF were significantly lower in those with multiple lacunar infarction than in those without, while other parameters were not different in these two subgroups.
The locations of the total of 92 lacunae found in the 51 patients were the brainstem (6 lacunae; 6.5%), the basal ganglia (47; 51%), the thalamus (6; 6.5%), and the deep white matter (33; 36%). The laterality (right or left) was not significant for lacunae in any location. The distribution patterns of lacunae were not significantly different among the extreme-dippers, dippers, or nondippers (brainstem: 5.8%, 9.1%, and 6.9%, respectively; basal ganglia: 50%, 45%, and 55%, respectively; thalamus: 3.9%, 9.1%, and 10%, respectively; and deep white matter: 40%, 36%, and 28%, respectively). The autonomic nervous system activity patterns did not differ in association with these distribution patterns of lacunae (data not shown).
Relationships Between the Values and Variations of BP and Autonomic Nervous System Activity During Awake and Asleep Periods
Concerning the relationships between the levels and variations of BP and autonomic nervous system activity during the awake and asleep periods, there were no significant relationships between BP levels and HRV parameters in either period. The variation (SD) of SBP was positively correlated with that of LF/HF ratio during the awake period (r=.419, P<.01), while this association was not obtained during the asleep period.
Relationship of Asleep/Awake Ratio of BP to Autonomic Nervous System Activity
There was no significant relationship between the awake/asleep SBP ratio and any HRV parameter level except a negative relationship with the awake LF/HF ratio (r=−.353, P<.02). Concerning diurnal variation (asleep/awake ratio), the Figure⇓ shows the scatterplots of the asleep/awake ratio for SBP against the asleep/awake ratios for the three autonomic nervous system activity parameters for all 51 elderly hypertensive patients. The asleep/awake ratio for SBP was significantly correlated negatively with the asleep/awake ratio for HF and positively with that for the LF/HF ratio. For the subgroups with (n=16) and without (n=31) multiple lacunae, the relationships of the asleep/awake ratio of SBP to the asleep/awake ratios for LF, HF, and LF/HF ratio were essentially the same as those for the entire group, except that the negative correlation with the asleep/awake ratio of HF was stronger in the subgroup with multiple lacunae (r=−.630, P<.01), compared with that (r=−.334, P=.05) in the subgroup without multiple lacunae.
In the present study, we investigated the relationships among diurnal BP variations, autonomic nervous system activity, and silent cerebrovascular disease in three hypertensive groups with different patterns of nocturnal BP fall (extreme-dippers, dippers, and nondippers). The enrolled hypertensive elderly subjects were exclusively asymptomatic hypertensive outpatients without previous or currently active cardiovascular diseases, since the level and variation of BP and autonomic nervous system activity might be affected in patients with cardiovascular diseases.6,21–24 The 24-hour BP levels were not significantly different among the extreme-dippers, dippers, and nondippers, thus the autonomic nervous system activity in relation to target organ damage would be more strongly affected by the diurnal BP variations than by the high BP level per se. We found that the diurnal autonomic nervous system dysfunction associated with reduced HRV participates in the abnormal diurnal BP variation in asymptomatic elderly hypertensive patients, whereas there were no significant differences in heart rate among the extreme-dippers, dippers, and nondippers, as found in the previous study.9,25
In addition to BP, there are also diurnal variations of HRV. Marked nocturnal increase in HF is accompanied by a slight increase in LF in normal healthy subjects, indicating vagal dominance in the sympathovagal balance in the period of sleep.26 In extreme-dippers who show diminished asleep LF/HF ratios, a relative indicator of sympathetic nervous system activity,20 sympathetic nervous activity is markedly suppressed during the period of sleep. The increase in parasympathetic nervous system activity of extreme-dippers is almost the same as that in dippers, since the HF (an indicator of vagal influence on heart rate20) was no different in the extreme-dippers and in the dippers. Thus, this diminished nocturnal sympathetic nervous system activity might determine in part the extreme fall of nocturnal BP in extreme-dippers. Since the degree of nocturnal increase of HF in the extreme-dippers was almost the same as that of the dippers, the vagal modulation is probably normal in this type of abnormal BP variation.
On the other hand, nondippers have lower awake and 24-hour LF/HF ratios compared with dippers and lower asleep/awake ratio of HF and higher asleep/awake ratio of LF/HF compared with both dippers and extreme-dippers, suggesting decreased daytime sympathetic nervous system activity and suppressed nocturnal increase of parasympathetic nervous system activity. This nocturnal suppression of vagal modulation manifested in reduced HF is also found in patients in the early postinfarction phase and in diabetic patients regardless of whether they have autonomic neuropathy or not.27 This nocturnal suppressed vagal modulation may predispose nondippers to cardiovascular events that occur during the night.
In our series, we found that the extreme-dippers and nondippers have more advanced cerebrovascular disease (lacunae and advanced PVH) compared with the dippers with “appropriate” nocturnal BP fall.9 Cerebrovascular disease frequently causes disturbances of cardiac and other autonomic nervous system function. Sympathetic hyperfunction and parasympathetic hypofunction have been reported in patients with clinically overt cerebrovascular disease.21,22 A recent study using spectral analysis of HRV demonstrated that total power, LF, and HF were markedly reduced in patients with clinically overt hemispheric brain infarction from the acute phase and that the reduction persisted at least 6 months after the ictus, when compared with control subjects.24 Thus, it is unclear whether our results reflect a damaged cerebral autonomic nervous system due to silent cerebral ischemia or not. Although the diurnal BP variation is related to the location of the lesion in patients with clinically overt stroke,22,23 the location of silent lacunae was not found to affect the diurnal patterns of BP and autonomic nervous system activity in the present study.
For the entire group of 51 elderly hypertensive patients, there were no significant relationships of levels of BP parameters to the HRV parameters during the awake and asleep periods. The variation of SBP was positively correlated with that of LF/HF ratio during the awake period, while this association was not obtained during the asleep period. Thus, BP variation might be related to variation of sympathetic nervous system activity in the awake period only. Furthermore, the asleep/awake ratio for SBP was positively correlated with the asleep/awake ratio for LF/HF ratio, and it was negatively correlated with the asleep/awake ratio for HF but not with the ratio for LF. These results suggest that autonomic nervous system activity is not a determinant of BP level per se but that the diurnal change of autonomic nervous system activity is closely involved in the diurnal BP variation pattern. Specifically, the nocturnal BP fall is associated with the nocturnal fall of sympathetic nervous system activity and with the nocturnal increase of parasympathetic nervous system activity. These diurnal relationships between BP and autonomic nervous system activity were essentially the same in the hypertensive patients with and without multiple lacunar infarction. In a study by Kohara et al of adult hypertensive patients, the degree of nocturnal BP fall was associated positively with LF and the LF/HF ratio but had no relationship with HF.14 This discrepancy might be due to the patient age or due to the study setting. We studied outpatients with a mean age of 71 years, whereas Kohara et al studied inpatients with a mean age of 57 years.14
In a recent prospective study, cardiovascular events were found to occur about 2.8 times more frequently in nondippers than in dippers.8 Total power covers the very LF range that appears to have marked prognostic significance for postmyocardial infarction patients,28 even though the physiological mechanism has not yet been explained. Decreased 24-hour, awake, and asleep total powers were found in nondippers compared with dippers. This reduced HRV might account for the great proclivity to cardiovascular events in nondippers. In extreme-dippers, total power also tended to be decreased compared with that in dippers, while statistical significance was found only in the asleep period, suggesting that the extreme-dippers may also have the poorer prognosis. The 16 patients with multiple lacunar infarction had lower LF during the 24-hour and asleep periods and lower total power during the 24-hour, awake, and asleep periods, compared with those without multiple lacunar infarction.
There are no noninvasive methods of assessing autonomic nervous system activity directly during a 24-hour period. To assess autonomic nervous system function continuously, we have used spectral analysis of HRV recorded using Holter ECG simultaneously with 24-hour ambulatory BP monitoring. Among the limitations of this method, several factors such as posture, respiratory status, and physical activity alter both HRV and BP during daily life.20 Thus, these factors might obscure the relationships of the levels of BP parameters to the HRV parameters during the asleep period and during the awake period under the ambulatory condition. As the majority of the elderly subjects studied were women and nonsmokers, it is not certain whether the obtained results might apply to all hypertensive persons or to only nonsmoking elderly women. There is one report concerning a sex-related difference for silent cerebrovascular disease and nocturnal BP fall, in that a significant relationship was found in only the female subjects.29 We did not confirm a sex-related difference for silent cerebrovascular disease and nocturnal BP fall in the elderly hypertensives in our previous study,9 and we identified no significant sex-related and smoking status-related differences for the values of HRV parameters and BP or for the relationships between them in the present study.
In conclusion, the autonomic nervous system activity is not related to high BP level per se, rather its diurnal variation is more important as a determinant of diurnal BP patterns, regardless of the presence or absence of cerebrovascular disease. In elderly hypertensive patients, abnormal diurnal BP variations, which predispose to cerebrovascular disease, might in part be attributed to abnormal patterns of diurnal autonomic nerve system activity.
Selected Abbreviations and Acronyms
|ECG-LVH||=||electrographically verified left ventricular hypertrophy|
|HRV||=||heart rate variability|
|MRI||=||magnetic resonance imaging|
This study was supported in part by a scientific research grant-in-aid 09670746 from the Ministry of Education of the Government of Japan and grants-in-aid (1992–1997) from the Foundation for the Development of the Community, Tochigi, Japan. We are indebted to Drs Koji Eno (Department of Radiology, Hyogo Prefectural Awaji Hospital) and Masahiro Imiya (Department of Neurology, Awaji-Hokudan Public Clinic and Hyogo Prefectural Awaji Hospital) for their helpful advice regarding MRI findings and to Dr Satoko Fuji (Department of Statistics and Central Laboratory, Hyogo Prefectural Awaji Hospital) for statistical analysis of the data.
Reprint requests to Dr Kazuomi Kario, Department of Cardiology, Jichi Medical School, 3311–1, Yakushiji, Minamikawachi, Kawachi, Tochigi, 329–04, Japan.
- Received March 5, 1997.
- Revision received April 4, 1997.
- Accepted June 19, 1997.
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