Nocturnal Fall of Blood Pressure and Silent Cerebrovascular Damage in Elderly Hypertensive Patients
Advanced Silent Cerebrovascular Damage in Extreme Dippers
Abstract To study the relation between diurnal blood pressure variations and silent cerebrovascular damage, we performed both 24-hour ambulatory blood pressure monitoring and brain magnetic resonance imaging in 131 elderly asymptomatic hypertensive patients. Silent cerebrovascular damage was identified by the magnetic resonance imaging findings of lacunae (low intensity in T1-weighted images and high intensity in T2-weighted images) and advanced periventricular hyperintense lesions (on T2-weighted images). The frequency of silent cerebrovascular damage in the 100 patients with sustained hypertension was greater than that in the 31 patients with white coat hypertension. We further classified the former group into nondippers (nocturnal reduction of systolic pressure by <10% of awake systolic pressure; n=46), dippers (reduction by ≥10% to <20%; n=38), and extreme dippers (reduction by ≥20%; n=16). The extent of silent cerebrovascular damage was least severe in the dipper group (P<.05). This J-shaped relation was not found either with the cardiac hypertrophy detected by electrocardiography or with the renal damage assessed by urinary albumin excretion. More than half of the extreme dippers were patients with isolated systolic hypertension, and this prevalence was significantly greater than that in dippers or in nondippers (21% and 30%, respectively). Extreme dippers also had greater variability of pressure (standard deviation of awake systolic pressure) than dippers. Our results indicate that in addition to nondipping, extreme dipping (marked nocturnal fall of blood pressure) should be considered a type of abnormal diurnal blood pressure variation in elderly patients with hypertension who are likely to have advanced silent cerebrovascular damage.
Noninvasive ambulatory BP monitoring can now be used clinically for the evaluation of hypertensive patients. It is well known that ambulatory BP measurements are more highly correlated with target-organ damage than are clinical BP readings.1 The plethora of data obtained with ambulatory monitoring have raised the important but still unanswered question of whether the 24-hour average BP level or some measure of BP variability is a better indicator of risk. In most individuals, the highest BP is observed during the morning hours and the lowest during sleep. In the majority of hypertensive patients, this diurnal BP rhythm is preserved, but in some patients, especially in the elderly, BP remains elevated throughout the night. Subjects who show this abnormal BP diurnal variation are known as “nondippers,” in contrast to “dippers,” who show preserved normal BP rhythm.2 Previous studies have consistently shown that nondippers are more likely than dippers to suffer latent as well as overt hypertensive target-organ damage, including cerebrovascular disease, chronic heart disease, and renal damage.2 3 4 5 6 7 8 Thus, it appears that target-organ damage in hypertensive patients is more closely related to BP during sleep than in the awake state, although the cause-effect relation of these findings remains to be determined.9
We have noticed that unexpected ischemic stroke sometimes occurs during the night in treated elderly hypertensive patients, possibly because of an excessive reduction of BP by antihypertensive therapy. Moreover, ambulatory BP monitoring occasionally reveals a marked nocturnal fall in BP even in untreated elderly subjects with hypertension.10 We speculated that a marked or reduced nocturnal BP fall might be associated with greater severity of ischemic cerebrovascular damage than the “appropriate” nocturnal fall of BP, although the data published to date were too limited to warrant such a hypothesis.
Using brain MRI, which is the most sensitive method of detecting hypertensive cerebrovascular damage,11 we therefore assessed silent cerebrovascular disease in elderly asymptomatic patients with hypertension and examined its relation with nocturnal fall of BP.
We studied 131 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 with patients in the sitting position by standard cuff methods. No patients had received any antihypertensive medication for at least 1 month before the study. All of the subjects were ambulatory, and all gave informed consent. The results of physical and laboratory examinations that included blood and urine tests, chest x-ray, and electrocardiogram at rest were normal or consistent with World Health Organization stages I and II. Those patients with renal failure and hepatic damage (serum creatinine >130 μmol/L, urea nitrogen >10.7 mmol/L, positive glycosuria and proteinuria detected by urostix, and aspartate aminotransferase or alanine aminotransferase >40 IU/L) or with obvious present illness and/or history of coronary artery disease, stroke (including transient ischemic attack), congestive heart failure, or malignancy were excluded from study. Those with possible diabetes mellitus (fasting glucose >5.5 mmol/L and/or hemoglobin A1c >6.2%) were also excluded from study. This study was approved by an institutional review committee.
Smokers were defined as current smokers. Isolated systolic hypertension was defined as mean office SBP ≥140 mm Hg and mean office DBP <90 mm Hg.12 Body mass index was calculated as weight (kg)/height (m)2.
ECG-LVH in hypertensive patients was graded into two classes.13 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. No patient showed the more severe grade of ECG-LVH, with prolonged ventricular activation time, depressed downsloping ST-segments, and asymmetrically inverted T waves in left precordial leads. Patients with normal ECG findings and those with high-voltage QRS complexes alone were both defined as not having ECG-LVH.
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 validated previously.14 Ambulatory data used in the present study were obtained by the oscillometric method. Subjects kept an activities journal in which they recorded information about the exact times they fell asleep and woke up. For four hypertensive patients whose BP data could not be evaluated because of the presence of artifacts in more than 10% of the total measurement, measurements were reexamined. Patients with documented disturbed sleep (frequent awakening during sleep) were not included in the present study. Ambulatory BP criteria were arbitrary, as there are no defined standards for these data. In an attempt to correlate our findings with previously reported ambulatory BP data in normal subjects,1 we classified the 131 hypertensive patients by office BP into 31 patients with white coat hypertension, whose mean 24-hour SBP/24-hour DBP was less than 135/80 mm Hg, and 100 patients with sustained hypertension, whose mean 24-hour SBP was ≥135 mm Hg and/or whose 24-hour DBP was ≥80 mm Hg.15
The asleep BP was defined as the mean BP from the time when the patient went to bed until the time of awakening. The awake BP was defined as the mean BP during the remaining portion of the day. The lowest BP was defined as the mean BP of three consecutive readings that included the lowest BP during sleep. The nocturnal fall of SBP was calculated as (Awake SBP–Asleep SBP)/Awake SBP. Based on nocturnal fall in SBP, we classified hypertensive patients into extreme dippers (nocturnal reduction of SBP ≥20%; n=16), dippers (≥10% but <20%; n=38), and nondippers (<10%; n=46).
MRI was carried out in all 131 patients with a superconducting magnet with a main field strength of 1.5 T (Toshiba MRT200FXII). The brain was imaged in the axial plane at 8-mm slice thickness. T1-weighted images were obtained with use of a short spin-echo pulse sequence with a repetition time of 500 milliseconds and an echo time of 13 milliseconds. T2-weighted images were obtained with use of a long spin-echo pulse sequence with a repetition time of 4000 milliseconds and echo times of 60 and 112 milliseconds. The matrix size was 256×224 pixels.
Images were evaluated for the number and location of lacunae and for the extent of periventricular signal abnormalities. A lacuna was strictly defined as a low signal intensity area (less than 1 cm) on T1-weighted images that was also visible as a hyperintense lesion on T2-weighted images, as described and illustrated previously.15 The number of lacunae per patient was counted. Lacunae as defined above might include lesions other than true infarcts, such as état criblé, especially if their size were small (ie, <5 mm).15 PVH on T2-weighted images was classified into four groups, as described and illustrated previously.15 Briefly, grade I PVH was defined as no abnormality or minimal periventricular signal hyperintensity 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 lateral ventricles or periventricular unifocal patches, and grade III as multiple periventricular hyperintense punctated lesions and their early confluent stages. Multiple areas of high signal intensity that reached confluence in the periventricular region were defined as grade IV. The neuropathological significance of these MRI findings has been discussed in a previous study.15
All of the MRI images were interpreted under blinded conditions by two members of our group. Because only four patients showed PVH of grade IV, these patients and those with grade III were considered as having advanced PVH.
To exclude the influence of daily physical activity and to facilitate consistent collection, we asked patients to collect urine on 2 consecutive days between 7 pm and 7 am (12 hours overnight) to be pooled for averaging of urinary albumin measurement.16 17 The urinary albumin concentration was assayed by a nephelometric method (Mitsubishi Yuka Bio-Clinical Laboratories Inc), and the UAE was expressed as micrograms per minute.17 Microalbuminuria was defined as a UAE value of 15 μg/min or more.
After a minimum 12-hour fasting period, blood samples for hemostatic determinations were collected into two disposable siliconized vacuum glass tubes containing 0.1 vol of 3.8% trisodium citrate, and blood samples in the second tube were used for the coagulation assay. Samples were centrifuged at 3000g for 15 minutes at room temperature within 1 hour of collection. Plasma was subsequently separated and stored in plastic tubes at −80°C until laboratory determinations were performed.
Plasma fibrinogen levels were determined by use of a one-stage clotting assay kit (Data-Fi).18 Plasma levels of vWF and prothrombin fragment 1+2 were determined with enzyme-linked immunosorbent assay (ELISA) kits (Diagnostica Stago and Behringwerke AG, respectively).19 For vWF assay, the value obtained by use of commercially available pooled plasma (CTS Standard Plasma, Behringwerke AG) was taken as 100%.
Serum total cholesterol and triglyceride levels were determined by use of commercial enzyme assay kits (Wako). Serum high-density lipoprotein (HDL) cholesterol was determined by use of an enzymatic procedure after precipitation with phosphotungstic acid (Wako). Lipoprotein(a) levels were assayed with an ELISA kit (Biopool).20 Serum glucose was determined by a glucose oxidase method with use of a commercial enzyme assay kit (Kanto Chemicals). Serum creatinine and total protein were also measured with a routine enzyme assay kit.
In our laboratory, the coefficient of variation is 2.5% for fibrinogen, 3.0% for prothrombin fragment 1+2, 3.8% for vWF, and 5.2% for UAE.
Data are expressed as mean (95% confidence interval). The distribution for triglycerides, lipoprotein(a), prothrombin fragment 1+2, vWF, and UAE levels was examined and the data converted to log10 transformation to reduce the skewness and kurtosis of the distribution before statistical analysis. The geometric means of these parameters were determined. One-way ANOVA was performed to detect differences among groups, and unpaired Student’s t test was used for comparison between the mean values for two groups. A value of P<.05 was considered significant.
In the 131 hypertensive patients studied, 31 patients were diagnosed with white coat hypertension and the remaining 100 patients with sustained hypertension by the previously described definition that used 24-hour BP. All of the BP parameters (office, 24-hour, awake, and asleep BPs) were significantly higher in the sustained hypertension group than in the white coat hypertension group, as were prothrombin fragment 1+2 and vWF (1.30 [1.22-1.38] versus 1.09 [0.98-1.24] nmol/L, P<.01; 155% [147-164] versus 132% [120-146], P<.01). Other metabolic parameters measured did not differ between the two groups. The number of lacunae (2.0 [1.5-2.5] versus 0.58 [0.13-1.0], P<.01) and the UAE (23 [19-17] versus 13 [10-18] μg/min, P<.01) as well as the prevalence of patients with lacunae (52% versus 26%, P<.02) and microalbuminuria (66% versus 26%, P<.0001) were also significantly higher in the sustained hypertension group than in the white coat hypertension group. The prevalence of ECG-LVH was marginally higher in the sustained hypertension group (32% versus 16%, P=.0876).
Table 1⇓ shows the characteristics of the three groups of sustained hypertensive patients classified according to the magnitude of nocturnal BP fall. There were no significant differences among the groups in demographic characteristics including age, sex, body mass index, smoking status, and prevalence of previous antihypertensive treatment (31% for extreme dippers, 34% for dippers, and 28% for nondippers). There were no significant differences among these three groups in any other metabolic or hemostatic factor. There were no significant differences among the three groups in office or awake BP, but asleep and lowest nocturnal BPs were significantly higher in nondippers compared with dippers and in dippers compared with extreme dippers. The variability of BP, defined as standard deviation of awake SBP, was greater in extreme dippers than in dippers. Isolated systolic hypertension was significantly more common in the extreme dippers than in other groups.
Table 2⇓ shows the silent target-organ damage in each group of patients with sustained hypertension. The number of lacunae and the prevalence of patients with lacunae and/or advanced PVH (grades III and IV) were significantly higher in the extreme dippers and nondippers compared with dippers. UAE was higher and the prevalence of patients with ECG-LVH or microalbuminuria was more common in nondippers than in either dippers or extreme dippers, whereas there were no significant differences between extreme dippers and dippers.
We then divided the 100 patients with sustained hypertension into quartiles of nocturnal fall of SBP. The nocturnal BP fall ranged from −16% to 33% in the study population. The number of lacunae per patient and the prevalence of patients with lacunae were 2.3 and 52% in the group with the greatest fall (Q1), 1.3 and 40% in the group with the second greatest fall (Q2), 2.0 and 52% in the group with the next greatest fall (Q3), and 2.3 and 64% in the group with the least fall (Q4), indicating a J-shaped relation between nocturnal BP fall and brain MRI findings. Differences among pairs of subgroups, however, did not attain statistical significance.
The location of the 215 lacunae found in the 131 patients was 12 (5.6%) in the brain stem, 139 (65%) in the basal ganglia, 10 (4.7%) in the thalamus, and 54 (25%) in the deep white matter. The lateralization (right or left) was not significant in each location. The distribution pattern of lacunae was not significantly different among extreme dippers, dippers, and nondippers (brain stem: 8.7%, 4.5%, 3.7%; basal ganglia: 57%, 61%, 68%; thalamus: 4.3%, 6.8%, 3.7%; deep white matter: 30%, 27%, 24%, respectively).
Levels of fibrinogen and prothrombin fragment 1+2 were increased in 60 patients with lacunae compared with 71 patients without lacunae (2.89 [2.72-3.05] versus 2.64 [2.52-2.75] g/L fibrinogen, P<.02; 1.35 [1.25-1.45] versus 1.17 [1.08-1.26] nmol/L prothrombin fragment 1+2, P<.01, respectively]. Furthermore, UAE was significantly higher in patients with lacunae than in patients without lacunae (26 [20-35] versus 17 [14-21] μg/min, P<.02). ECG-LVH tended to be more common in the former than in the latter, but this difference was not significant (32% versus 25%).
In the present study, enrolled subjects were confined strictly to asymptomatic hypertensive patients without either previous or currently active cardiovascular disease, because the level and variation of BP might be changed in patients with overt cardiovascular disease.21 22 The present results corroborate previous results1 2 3 4 5 6 7 8 9 indicating that hypertensive target-organ damage of the brain (silent lacunar infarct), heart (ECG-LVH), and kidney (microalbuminuria) are more common in sustained hypertension than in white coat hypertension and that, among sustained hypertensive groups, nondippers with less marked nocturnal BP fall (<10% of awake SBP) show greater hypertensive target-organ damage than dippers with “normal” diurnal BP variation (Table 2⇑). These results underscore the importance of using the average level of BP over prolonged periods of time to determine the adverse effects of high BP on the entire cardiovascular system.
One new finding in the present study is that patients with marked nocturnal BP fall (≥20% of awake SBP) showed more advanced cerebrovascular damage than patients with moderate nocturnal fall in BP (10% to 20% of awake SBP). The cut-off lines, ie, nocturnal fall of 10% and 20%, are rather arbitrary. We then classified the study subjects in a more empirical/mathematical way, by dividing them into four subgroups according to quartiles of nocturnal fall in BP, and we found that this J-shaped relation between nocturnal BP fall and silent cerebrovascular damage was still evident, although not significant, probably due to the small number of subjects in each subgroup.
To date, the pathogenic significance of “excessive” as well as “reduced” fall of BP at night has remained obscure. The 24-hour and awake BPs in extreme dippers were no different from those in dippers; the advanced cerebrovascular damage observed in this group is not directly related to the mean BP level over time, but to an abnormal diurnal BP variation itself. One reason that marked nocturnal BP fall is associated with cerebrovascular disease may be that the lower limit of BP in the autoregulation of cerebral blood flow is shifted upward, especially in elderly hypertensive patients with brain damage. Marked fall of BP at night (as low as 100 to 116 mm Hg for the lowest nocturnal SBP, as seen in Table 1⇑) might lead to an excessive reduction of cerebral perfusion.23 Some of these patients had been treated before the study, and enhanced fall of nocturnal BP due to antihypertensive medication might have accelerated the brain ischemia.24 Alternatively, widespread atherosclerosis may be the link between excess nocturnal BP fall and cerebrovascular damage. Isolated systolic hypertension was twofold to threefold more common in this group than in other groups. Extreme dippers also had a greater variability of BP (standard deviation of awake systolic BP) than dippers. Subjects with stiffer large arteries are likely to have predominantly systolic hypertension, which may be accompanied by a greater variability of BP, resulting in a marked diurnal variation of BP.25 Recent studies have shown that aortic atherosclerosis may reflect general atherosclerosis and predict symptomatic cardiovascular disease involving various organs.26 This idea certainly merits further investigation. Another possible explanation for the J-shaped relation is that a certain type or location of cerebrovascular lesion might determine the diurnal variation of BP. We previously reported a case in which a change from extreme-dipper to nondipper status occurred in association with development of a small lacunar infarct, suggesting that nondipper hypertension might be a secondary abnormality caused by even minor cerebrovascular damage.10 No major difference in either the pattern or extent of abnormal MRI findings, however, was recognized between nondippers and extreme dippers in the present study. Thus, the J-shaped relation between nocturnal BP fall and cerebrovascular damage can be explained by either of two opposing hypotheses with regard to either a cause-effect relation or underlying common etiologies, such as progression of generalized atherosclerosis.
Although both nondippers and extreme dippers suffer more extensive cerebrovascular damage than dippers, there were no significant differences between the extreme dippers and dippers in terms of cardiac hypertrophy and renal damage, whereas these types of target-organ damage were more frequent in nondippers than in dippers. It appears that nondipper patients show greater hypertensive target-organ damage than do extreme dippers. Therefore, sustained high BP over prolonged periods of time seems to be the most important determinant of hypertensive end-organ damage, whereas marked nocturnal fall of BP may be more specifically related to cerebrovascular damage.
Circulating vWF has been used to assess systemic endothelial cell dysfunction, and its level was recently reported to be increased in hypertensive patients.27 Fibrinogen has been recognized as a cardiovascular risk factor.28 Prothrombin fragment 1+2, an assembly of activation peptides released from prothrombin by factor Xa, is a sensitive marker of coagulation activation, which has been shown to increase with advancing age.29 Levels of vWF and prothrombin fragment 1+2 were significantly higher in patients with sustained hypertension than in patients with white coat hypertension. Fibrinogen and prothrombin fragment 1+2 levels were significantly higher in hypertensives with lacunae than in those without lacunae, suggesting that hypercoagulability is closely related to silent cerebrovascular disease in elderly hypertensive patients. However, there were no significant differences in these levels or in lipid profiles among extreme dippers, dippers, and nondippers.
In conclusion, a J-shaped relation was found between the nocturnal fall of BP and silent cerebrovascular damage in elderly asymptomatic hypertensive patients. The exact pathogenic significance of this finding is unknown. In addition to nondipper pattern, which is known to be associated with overall hypertensive target-organ damage, the extremely marked nocturnal fall of BP should be considered an abnormal diurnal BP variation when observed in elderly hypertensive patients. Extreme dippers with this abnormality are likely to have predominantly systolic hypertension and greater BP variability and more advanced silent cerebrovascular damage than those with normal diurnal BP variation.
Selected Abbreviations and Acronyms
|ECG-LVH||=||electrocardiographic evidence of left ventricular hypertrophy|
|MRI||=||magnetic resonance imaging|
|UAE||=||urinary albumin excretion rate|
|vWF||=||von Willebrand factor|
This study was supported in part by grants-in-aid from the Foundation for the Development of the Community, Tochigi, Japan.
- Received June 13, 1995.
- Revision received August 14, 1995.
- Accepted September 19, 1995.
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