Background and Purpose The influence of a nocturnal blood pressure dip on stroke recurrence has not yet been clarified. In this pilot study, we attempted to establish a correlation of the nocturnal blood pressure dip with stroke recurrence and development of new silent ischemic lesions in patients with chronic ischemic cerebrovascular disease.
Methods We monitored circadian blood pressure patterns by use of a portable blood pressure monitoring device in 81 patients with chronic ischemic cerebrovascular disease and divided them into two subgroups according to levels of diurnal and nocturnal blood pressure (nocturnal blood pressure dippers and nondippers). The subgroups were prospectively followed up and compared for stroke recurrence and new silent ischemic lesions on magnetic resonance imaging.
Results The average follow-up period was 27.2±11.3 months (mean±SD). Seventy-six patients completed the study; 43 (36 men and 7 women, aged 63.0±6.3 years) were being treated with antihypertensive agents and 33 (25 men and 8 women, aged 64.7±9.2 years) were not receiving treatment. In the treated group, recurrence was more frequent among the nocturnal dippers (5 of 18 patients, 12.5% per patient-year) than among the nondippers (1 of 25 patients, 1.5% per patient- year) (P<.05). All subjects who developed a recurrent attack during sleep had had a nocturnal blood pressure dip pattern before the attack. Furthermore, the increase in symptomatic (recurrence) and/or asymptomatic (silent) brain lesions was more frequent in the nocturnal dippers than in the nondippers (9 of 14 versus 2 of 18, P<.01). In the nontreated group, no clear difference was found between the two subgroups.
Conclusions This study indicated that the nocturnal blood pressure dip in patients treated with antihypertensive agents may accelerate the increase in ischemic brain lesions.
Because controlling hypertension is widely recognized as an effective measure in preventing stroke recurrence,1 2 3 hypertensive patients with a history of stroke, including brain infarction, are generally treated with antihypertensive agents. Although antihypertensive therapy has a preventive effect on the progression of hypertensive arterial lesions,4 5 6 7 it may trigger a decrease in blood flow in areas supplied by arteries stenotic with atherosclerosis, which in turn increases the possibility of stroke recurrence.8 9 10 From a practical perspective, however, many problems in antihypertensive therapy remain to be solved; one of these is the decrease in blood pressure that occurs during the night, ie, the nocturnal blood pressure dip. Although there are several studies on circadian blood pressure variations in stroke patients,11 12 13 these studies might merely document these variations as the secondary phenomena caused by stroke. There are no prospective studies to examine circadian blood pressure variation as a risk factor for stroke recurrence.
Nocturnal blood pressure dip is a common finding in hypertension and vascular disease and thus may be a risk factor for stroke.13 14 15 16 In this pilot study, we investigated a possible relation of the nocturnal blood pressure dip to stroke recurrence and increases in new brain lesions on MRI.
Subjects and Methods
We monitored circadian blood pressure patterns by use of a portable blood pressure monitoring device in 98 patients with chronic ischemic cerebrovascular disease who were admitted to the National Cardiovascular Center, Osaka, Japan, between January 1, 1989, and June 30, 1992, for stroke treatment, rehabilitation, and evaluation of risk factors. All subjects consented to participate in this study. All of them had had their last ischemic attack more than 1 month before entry into the study and were capable of independent activities in daily life. In this study, ischemic cerebrovascular disease was defined to include atherothrombotic brain infarction, lacunar infarction, and transient ischemic attack; patients with definite or suspected cardioembolic stroke were excluded because blood pressure changes were thought to be a minor factor in the occurrence of cardioembolic events. Details of our diagnostic criteria for these stroke subtypes, which were based mainly on the Classification of Cerebrovascular Diseases III by the National Institute of Neurological Disorders and Stroke,17 have been described previously.18 Of 98 patients, 17 whose sleep was strongly disturbed by blood pressure measurement were excluded from this study. We followed up the remaining 81 patients.
Blood pressure was measured every 30 minutes between 6:00 am and 10:00 pm and every 60 minutes between 10:00 pm and 6:00 am by use of a portable blood pressure monitoring device (ABPM-630, Nippon Colin). In the majority of the patients, blood pressure values obtained by the Korotkoff method were used for analysis. When data were unobtainable by the Korotkoff method, data obtained by the oscillometric method were used. During blood pressure monitoring in the hospital, the patients were allowed to carry out their usual activities in the ward.
From the data thus obtained, averages of the MABP were calculated for daytime (MABP-d; 6:00 am to 10:00 pm) and for nighttime (MABP-n; 10:00 pm to 6:00 am). MABP was computed with the formula MABP=(SBP−DBP)/3+DBP.
Circadian blood pressure variations were classified as being one of two patterns according to the difference between MABP-d and MABP-n (ΔMABP); “dip pattern” indicated ΔMABP 10 mm Hg or greater and “nondip pattern” indicated ΔMABP less than 10 mm Hg. We defined the patients who presented with a dip pattern or a nondip pattern on two measurements to be “dippers” or “nondippers,” respectively. Those who presented with a dip pattern on at least one measurement were considered to be “dippers.” We prospectively followed up the subjects until December 31, 1992, and compared the incidence of stroke recurrence in the nondippers with that in the dippers. Recurrence of stroke was diagnosed by history taking and neurological examination. We examined all the subjects at least once a year at the outpatient clinic or upon follow-up admission, and appearance of new neurological deficits was considered to indicate recurrence of stroke.
In addition, in patients who did not have stroke recurrence and underwent MRI examination with the Siemens Magnetom (1.5 T) twice during the follow-up period, we evaluated the changes in ischemic findings on MRI. New lesions more than 5 mm in diameter with low intensity in T1-weighted images and high intensity in T2-weighted images without an episode or additional neurological deficits were defined as new silent ischemic lesions. Furthermore, we defined symptomatic (recurrence) and/or asymptomatic (silent) ischemic lesions as ischemic brain lesions and compared their incidence in the nondippers with that in the dippers. In this comparison we excluded those who did not undergo the second MRI examination because changes in silent brain lesions cannot be evaluated accurately without MRI.
Student’s t test and the χ2 test were used for statistical comparisons between the groups. The log-rank test was used for the comparison of stroke recurrence between the groups to correct the differences in the follow-up period. In analyzing the increase in ischemic brain lesions, we used the χ2 test because it is impossible to determine the exact date of appearance of new silent brain lesions.
Data are presented as mean±SD. A value of P<.05 was considered significant.
Classification by Circadian Blood Pressure Pattern
In 75 of 81 patients entered into the study, the circadian blood pressure profile was monitored twice at different times. Fifty patients had a nondip pattern on both measurements and were considered nondippers. Fifteen patients who had a dip pattern on both measurements and 10 who had a dip pattern on one of two measurements were considered dippers. Of the remaining 6 cases, whose circadian blood pressure profiles were monitored only once, 3 had a dip pattern and were considered dippers. The other 3 patients, who had a nondip pattern, were excluded from this study to avoid the possibility that the nondip pattern was caused by sleep disturbance. Therefore, 78 patients were included in the final study. Forty-four patients were taking antihypertensive agents (group R: 36 men and 8 women; mean age, 63.0±6.3 years). The other 34 were not taking antihypertensive agents (group NR: 26 men and 8 women; mean age, 64.6±9.2 years).
The breakdown of antihypertensive agents administered was as follows: 29 patients were taking a single antihypertensive agent (a calcium antagonist [CA], 28; an angiotensin-converting enzyme inhibitor [ACEI], 1) and 15 were taking various combinations of multiple antihypertensive agents (CA+β-blocker [β], 5; CA+ACEI, 4; CA+ACEI+β, 3; CA+α-blocker [α], 1; ACEI+β, 1; CA+ACEI+α+β, 1).
Two patients (1 nondipper in group R and 1 nondipper in group NR) dropped out because antihypertensive agents were newly introduced or discontinued during the follow-up period. So we examined the incidence of stroke recurrence and increases in new silent ischemic lesions in 76 patients who completed the study. Clinical features of the subjects who completed the study are presented in Table 1⇓.
Among the 43 patients with antihypertensive agents who did not drop out, 25 had the nondip pattern (R-N) and 18 had the dip pattern (R-D). Among the 33 patients without treatment who did not drop out, 23 were classified as nondippers (NR-N) and 10 as dippers (NR-D). No statistical differences were observed between the subgroups R-N and R-D or between the subgroups NR-N and NR-D in terms of age, sex, average levels of 24-hour blood pressure, stroke subtypes, presence or absence of severe stenotic lesions of major cerebral arteries, risk factors, use of antiplatelet treatment, or the follow-up period. There was no statistical difference in diurnal (daytime) blood pressure between dippers and nondippers (R-N, 139.0±16.2/79.9±9.7 mm Hg; R-D, 147.1±17.7/87.1±9.8 mm Hg; NR-N, 131.0±14.6/76.5±8.4 mm Hg; and NR-D, 134.3±21.3/82.2±8.1 mm Hg), although the average levels of diurnal blood pressure seemed to be higher in dippers.
Recurrence of Stroke
Data on the recurrence of stroke are shown in Tables 2⇓ and 3⇓. Of the 43 patients treated with antihypertensive agents, stroke recurred in 6 (1 in subgroup R-N and 5 in subgroup R-D) during the follow-up period. The type of stroke was ischemic in all patients. In those not receiving antihypertensive drugs, recurrence of stroke, all ischemic, occurred in 10 patients (8 in subgroup NR-N and 2 in NR-D). In group R, the frequency of recurrence was higher in dippers (subgroup R-D) than in nondippers (subgroup R-N). There was no difference in stroke recurrence between the subgroups with and without blood pressure dip in group NR. In group R, 4 patients, all of whom were dippers, developed stroke during sleep. In group NR, 3 patients experienced recurrence during sleep, and no particular tendency was detected as to the time of stroke onset and nocturnal blood pressure dip (Table 4⇓).
There was no particular relationship between vascular stenoses and sites of recurrent stroke in either group R or group NR.
Increases in Ischemic Brain Lesions
Of the 37 patients without recurrence in group R, a follow-up MRI was performed in 26 (17 nondippers and 9 dippers). Data on increases in ischemic brain lesions are shown in Tables 2⇑ and 3⇑. Five patients (1 nondipper and 4 dippers) had new silent ischemic lesions. All of the 4 patients with nocturnal blood pressure dip had stenosed arterial lesions. In 3 of them were found new silent brain lesions in the territory supplied by the stenotic major arteries: the frontal-parietal subcortex, corona radiata, or pons. The new lesions in nondippers were located in the corona radiata. New silent ischemic lesions were more frequently observed in the dippers than in the nondippers in group R.
In group NR, 18 (13 nondippers and 5 dippers) of the 23 patients without recurrent lesions had follow-up MRI to evaluate the appearance of new silent brain lesions. Two patients (both nondippers) were found to have increases in new silent ischemic lesions. The new lesions were located in the bilateral corona radiata. In this group, there were no statistical differences in the frequency of newly developed lesions between the two subgroups. The interval between MRI examinations in all the subjects was 17.3±7.9 months (with a range of 6 to 42 months); there were no statistical differences in the interval between MRI examinations between dippers and nondippers or among the subgroups (R-N, 19.6±7.1 months; R-D, 13.8±7.0 months; NR-N, 17.8±9.2 months; NR-D, 14.4±3.8 months).
The number of ischemic brain lesions increased significantly in the dippers compared with the non-dippers among the patients in group R (Table 2⇑). There was no statistical difference between the two subgroups in group NR.
The present study demonstrated that stroke recurrence was more frequent among nocturnal dippers who were treated with antihypertensive agents, and all of those who developed stroke recurrence during sleep were subjects in this group. These results raise the possibility that excessive nocturnal blood pressure reduction (dip) in patients taking antihypertensive agents is related to stroke recurrence. Furthermore, in patients taking antihypertensive agents, the frequency of increases in new silent ischemic lesions was higher in dippers than in nondippers. All the dippers taking hypertensive agents who had increases in new silent ischemic lesions had stenosed arterial lesions, and in some patients the increased new silent lesions were found in the territory supplied by the stenotic major artery. We defined a lesion as ischemic only when it was demonstrated as low-intensity on a T1-weighted image as well as high-intensity on a T2-weighted image and more than 5 mm in diameter, to avoid the overdiagnosis of ischemic lesions.19 20 Therefore, the nocturnal blood pressure dip due to antihypertensive drugs may also have some influences on increases in new silent ischemic lesions.
It is reported that controlling hypertension is effective in preventing stroke recurrence1 2 3 and preserving cerebral blood flow.21 22 Recently, however, the deleterious effect of excessive reduction in blood pressure has been highlighted. Ischemic stroke with a thrombotic mechanism frequently develops during sleep at night.23 Excessive blood pressure reduction at night due to antihypertensive drugs may lead directly to brain ischemia and cause infarction. Supporting evidence for this mechanism, however, has not been demonstrated to date. The purpose of the present study was to determine whether the decrease in blood pressure at night affects the subsequent development of focal ischemia in patients with chronic ischemic stroke. The results suggested that nocturnal blood pressure dip due to drugs may have accelerated the increase in ischemic brain lesions.
Recently, several studies focused on the association between the nocturnal blood pressure and target organ damage. Shimada et al24 have shown that in untreated hypertensive patients without a history of cerebrovascular disease, silent brain lesions were more frequently found in patients without nocturnal blood pressure dip than in those with blood pressure dip. Verdecchia et al14 demonstrated the association between the reduction or absence of the usual nocturnal fall in blood pressure and future cardiovascular (including cerebrovascular) morbid events in white women with essential hypertension. These results led them to presume that a low nocturnal blood pressure is generally preferable from the standpoint of preventing the progression of organ (vascular) damage. In contrast to the results of these studies, our results indicated that the excessive drug-induced nocturnal blood pressure dip may adversely affect the brain in patients with advanced arteriosclerosis who have already experienced ischemic stroke. The difference in the results seems to be caused by differences in the subjects (with and without stroke) and the treatment (with and without antihypertensive drugs). The effect of nocturnal blood pressure dip may differ depending on the severity of arterial lesions in the brain; the nocturnal blood pressure dip adversely affects patients with advanced arteriosclerosis. This may be similar to the fact that blood pressure control is effective in the primary prevention of stroke25 26 but may have some adverse effects in secondary prevention.27 Modification of circadian blood pressure variation by antihypertensive agents may influence the role of the physiological nocturnal blood pressure dip. In the present study there was no difference in the increase in ischemic brain lesions between nondippers and dippers in patients without antihypertensive drugs. This result suggests that in ischemic stroke patients, a nonphysiological or “artificial” blood pressure dip probably induced by antihypertensive agents may have unfavorable effects compared with the physiological or “natural” nocturnal blood pressure dip. In fact, in patients taking antihypertensive agents, the most frequently used drugs were calcium antagonists, followed by angiotensin converting enzyme inhibitors, which are reported to decrease nocturnal blood pressure remarkably as well as diurnal blood pressure.28
There is a great deal of controversy regarding the criteria and definition of a nocturnal blood pressure dip. In several studies on the relationship of the circadian blood pressure variation to ischemic brain lesions, SBP was used as an indicator.11 12 24 Considering that DBP is strongly related to the recurrence of ischemic stroke,27 however, we should also take note of the influence of reduction in DBP. Therefore, we used MABP as an indicator for analysis in the present study. A study on acute blood pressure reduction in chronic ischemic stroke indicated that blood flow started to decrease when MABP dropped by 10% to 15%.29 Taking this into consideration, we arbitrarily defined the nocturnal blood pressure dip to be a decrease in MABP by 10 mm Hg or greater, and used the difference between diurnal and nocturnal blood pressure instead of the ratio of nocturnal to diurnal blood pressure to minimize the influence of measurement error. Because previous studies of hypertensive patients demonstrated that nocturnal blood pressure dropped by about 10%,14 12.0% to 12.2%,15 or 9.8 to 10 mm Hg16 in systole and by 14%,14 12.2% to 13.1%,15 or 9.4 to 9.6 mm Hg16 in diastole, the definition of “dipper” in this study is not entirely irrelevant. However, widely accepted criteria for diagnosis of the blood pressure dip have not yet been established and should be validated prospectively in a study of stroke survivors, asymptomatic hypertensive subjects, and age- and sex-matched healthy control subjects on several random occasions.
In studies of blood pressure drop caused by sleep, blood pressure must be measured when the subject is truly asleep. White et al30 confirmed the reliability of blood pressure values obtained from a portable blood pressure monitoring device. However, that method has some disadvantages, one of which is that the nocturnal blood pressure measured with such a device does not necessarily reflect the usual blood pressure during sleep. To resolve this problem, we excluded the subjects who complained of sleep disturbance due to blood pressure measurement during the night. Furthermore, a subject was classified as a nondipper only when the nondip pattern was detected on two separate examinations to exclude the possibility that the nondip pattern was caused by sleep disturbance.
Because the criteria for nocturnal blood pressure dip and validation in classifying the subjects have not been established and because the small number of subjects in the present study may have led to a type I error, the role of the nocturnal blood pressure dip in stroke survivors is not fully determined from our preliminary study alone. The present results, however, raise a question as to the conventional uniform guidelines for management of hypertension in the chronic stage of ischemic stroke. Even if excessive nocturnal blood pressure dip truly has an unfavorable effect on focal cerebral circulation, the true mechanism of development of ischemic lesions is unclear: these lesions may be caused not only by nocturnal blood pressure reduction, but also by an excessive morning increase in blood pressure, which may promote development of the ischemic lesion.31
Further studies are needed to confirm these results by closely following up the patients with nocturnal dip to see whether they develop overnight neurological dysfunction when overnight blood pressure is reduced with the drug treatment. A large-scale prospective trial comparing a group of treated dippers to a group of less-treated dippers is necessary to establish the validity of this concept.
Selected Abbreviations and Acronyms
|DBP||=||diastolic blood pressure|
|MABP||=||mean arterial blood pressure|
|MRI||=||magnetic resonance imaging|
|SBP||=||systolic blood pressure|
This study was supported in part by the research grants for cardiovascular diseases 2-A2, 5-A5, and 6-A2 from the Ministry of Health and Welfare, Japan.
- Received October 12, 1994.
- Revision received May 16, 1995.
- Accepted May 16, 1995.
- Copyright © 1995 by American Heart Association
Johnston JH, Beevers DG, Dunn FG, Larkin H, Titterington DM. The importance of good blood pressure control in the prevention of stroke recurrence in hypertensive patients. Postgrad Med J. 1981;57:690-693.
Spence JD. Antihypertensive drugs and prevention of atherosclerotic stroke. Stroke. 1986;17:808-810.
Harper SL. Effects of antihypertensive treatment on the cerebral microvasculature of spontaneously hypertensive rats. Stroke. 1987;18:450-456.
Ibayashi S, Ogata J, Sadoshima S, Fujii K, Yao H, Fujishima M. The effect of long-term antihypertensive treatment on medial hypertrophy of cerebral arteries in spontaneously hypertensive rats. Stroke. 1986;17:515-519.
Strandgaard S, Olesen J, Skinhøj E, Lassen NA. Autoregulation of brain circulation in severe arterial hypertension. Br Med J. 1973;1:507-510.
Jansen PA, Schulte BPM, Meyboom RHB, Gribnau FWJ. Antihypertensive treatment as a possible cause of stroke in the elderly. Age Aging. 1986;15:129-138.
Yamamoto Y, Akiguchi I, Oiwa K, Satoi S, Kimura J. Cerebrovascular disease and circadian blood pressure change: influence of site of lesion on nocturnal blood pressure fall and the correlation of heart rate and blood pressure [in Japanese with English abstract]. Jpn J Stroke. 1992;14:343-348.
Tohgi H, Chiba K, Kimura M. Twenty-four–hour variation of blood pressure in vascular dementia of the Binswanger type. Stroke. 1991;22:603-608.
Verdecchia P, Schillaci G, Gatteschi C, Zampi I, Battistelli M, Bartoccini C, Porcellati C. Blunted nocturnal fall in blood pressure in hypertensive women with future cardiovascular morbid events. Circulation. 1993;88:986-992.
National Institute of Neurological Disorders and Stroke Ad Hoc Committee. Classification of cerebrovascular diseases III. Stroke. 1990;21:637-676.
Minematsu K, Yamaguchi T, Omae T. ‘Spectacular shrinking deficit’: rapid recovery from a major hemispheric syndrome by migration of an embolus. Neurology. 1992;42:157-162.
Braffman BH, Zimmerman RA, Trojanowski JQ, Gonatas NK, Hickey WF, Schlaepfer WW. Brain MR: pathologic correlation with gross and histopathology, 1: lacunar infarction and Virchow-Robin spaces. AJNR Am J Neuroradiol. 1988;9:621-628.
Révész T, Hawkins CP, du Boulay EPGH, Barnard RO, McDonald WI. Pathological findings correlated with magnetic resonance imaging in subcortical arteriosclerotic encephalopathy (Binswanger’s disease). J Neurol Neurosurg Psychiatry. 1989;52:1337-1344.
Globus M, Keren A, Eldad M, Granot C, Tzivoni D, Lavy S, Stern S. The effect of chronic propranolol therapy on regional cerebral blood flow in hypertensive patients. Stroke. 1983;14:964-967.
Meyer JS, Rogers RL, Mortel KF. Prospective analysis of long term control of mild hypertension on cerebral blood flow. Stroke. 1985;16:985-990.
Marshall J. Diurnal variation in occurrence of strokes. Stroke. 1977;8:230-231.
Collins R, Peto R, MacMahon S, Hebert P, Fiebach NH, Eberlein KA, Godwin J, Qizilbash N, Taylor JO, Hennekens CH. Blood pressure, stroke, and coronary heart disease, part 2: short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet. 1990;335:827-838.
Irie K, Yamaguchi T, Minematsu K, Omae T. The J-curve phenomenon in stroke recurrence. Stroke. 1993;24:1844-1849.
Stanton A, Atkins N, O’Malley K, O’Brien E. Circadian blood pressure and antihypertensive drugs. Am J Hypertens. 1990;3:107A. Abstract.
Kaneko T, Sawada T, Kuriyama Y, Naritomi H, Kikuchi H. The lower limit of autoregulation in the cases with ischemic cerebrovascular diseases: relations between the site of arterial occlusive change and the autoregulation of cerebral blood flow [in Japanese with English abstract]. Jpn J Stroke. 1987;9:14-21.