Background: It has been suggested that impaired cerebral autoregulation and vasodilatory capacity may play in role in the pathogenesis of the leukoaraiosis seen in small vessel disease. Adequate perfusion of the deep white matter of the brain depends on the relationships between blood pressure (BP), cerebral vasoreactivity and autoregulation.
Methods: 24 h ambulatory BP measurement, quantitative volumetric MRI analysis of white matter lesion (WML) volume and transcranial Doppler ultrasound assessments of CO2 reactivity in response to hypercapnia and dynamic cerebral autoregulatory index (ARI) were undertaken in 64 patients with cerebral small vessel disease.
Results: Subjects had mean 24 h BP 133/76 mm Hg (SD 13/9), median WML volume 7169 (IQR 20497) mm3, mean CO2 reactivity 83.6 (SD 37.4)% and mean ARI 5.6 (SD 1.4) (range 0–9). In multivariate models, after adjusting for age, gender, vascular risk profile and WML volume, ARI correlated with 24 h mean BP levels (R2 = 0.127, t = 2.440, p = 0.019) and CO2 reactivity correlated with duration of hypertension (R2 = 0.085, t = −2.244, p = 0.029). In individuals with hypertension for more than 10 years, ARI also correlated with nocturnal BP dipping (r = 0.806, p = 0.002). ARI and CO2 reactivity were unaffected by WML volumes, and ARI and CO2 reactivity were unrelated.
Conclusion: Cerebral autoregulation and CO2 reactivity are two distinct processes which are not related to WML volume but are related to BP levels and duration of hypertension, respectively. Greater nocturnal dipping was associated with higher ARI values, suggesting preservation of autoregulation in patients with increased vulnerability to reduced cerebral perfusion.
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With the current emphasis on lowering BP to slow down progression of cerebrovascular disease,1 a better understanding of cerebral vasoreactivity and autoregulation in patients with small vessel disease becomes very important. While studies initially suggested that cerebral vasoreactivity was impaired in patients with small vessel disease,2 3 4 investigations that have excluded individuals with carotid artery stenoses or acute ischaemic events, that may have acted as confounding variables, have provided conflicting results.5 6 7 8 9 Limited evidence also exists on the relationships between small vessel disease and cerebral autoregulation. Cerebral autoregulation has been shown to be impaired in individuals with extensive leukoaraiosis on brain imaging10 11 12 but data are lacking on the integrity of cerebral autoregulation in patients with small vessel disease and no concomitant large vessel disease.
Recent studies have emphasised the importance of physiological variations in BP in the prediction of cerebral blood flow (CBF) and cerebrovascular disease, particularly with reference to nocturnal BP fall.13 14 The integrity of cerebral vasoreactivity and autoregulation is crucial in maintaining a constant CBF in the face of such BP fluctuations. Cerebral autoregulation can be static (ie, adjustments in response to prolonged BP changes) or dynamic (ie, ability to maintain CBF in the face of BP changes occurring over a matter of seconds). Dynamic cerebral autoregulation is more vulnerable to impairment because of the complex neural, metabolic, myogenic and possible endothelium related mechanisms involved.6 15 The objective of this study was to assess vasoreactivity, vascular reserve and dynamic cerebral autoregulation in response to physiological variations in BP in patients with early evidence of cerebral small vessel disease using ambulatory 24 h BP measurement, quantitative volumetric MRI analysis of cerebral small vessel disease and transcranial Doppler ultrasound (TCD) assessments of CO2 reactivity and dynamic cerebral autoregulation.
The study was undertaken in 64 subjects over the age of 50 years with evidence of small vessel (lacunar infarction, leukoaraiosis) but not large vessel cerebrovascular disease on MR neuroimaging. Subjects were recruited prospectively (January 2003–June 2005) from a hypertension clinic in a teaching hospital where all patients underwent MR brain imaging as an investigation of target organ damage. All patients were receiving antihypertensive treatment at the time of the study. Participants were included in the study if they fulfilled the following criteria: (1) treated BP in the normotensive range (because of the known associations between impaired cerebral autoregulation and high or low BP); (2) no clinical history of a cerebrovascular disturbance (such as stroke, transient ischaemic attack or syncope) in the previous 3 months which may affect the integrity of cerebral autoregulation; (3) no clinical history of intermittent claudication or other symptoms of peripheral vascular disease (precluding autoregulatory assessments using thigh cuff inflation/deflation); (4) no cerebral large artery stenosis (>50%); (5) no intracranial pathology other than cerebral small vessel disease on brain imaging; and (6) no contraindication to MRI such as prosthetic heart valves, pacemakers, cochlear implants or claustrophobia.
A detailed history was taken and a physical examination was performed in all individuals. Data were collected on demography, anthropometry and education, and vascular risk profile including hypertension, diabetes mellitus, hypercholesterolaemia, cigarette smoking and alcohol consumption. Hypertension was further characterised by its duration since diagnosis and drug treatment. Duplex ultrasound studies were performed to rule out significant (>50%) carotid artery stenosis or abnormal blood flows in the carotid, vertebral or intracranial large arteries. The study was approved by King’s College Hospital ethics committee and all patients provided informed consent.
Assessment of 24 h ambulatory BP and cerebral small vessel disease lesion load
Non-invasive 24 h ambulatory BP measurements (Tracker NIBP2; Reynolds Medical Ltd, Hertford, UK) were obtained on weekdays, with measurements being taken every 30 min during the day and every 60 min at night. Ambulatory BP monitor recordings were deemed to be insufficient if less than 70% of readings were successful.16 Daytime episodes were defined from 08:00 to 22:59 and night-time episodes from 23:00 to 07:59. CardioNavigator software (Reynolds Medical Ltd) was used to evaluate 24 h, daytime and night-time systolic, diastolic and mean BP levels and pulse pressures. Nocturnal dipping of BP was calculated as described previously, where nocturnal dip rate is ((mean day BP − mean night BP)/mean day BP).17
Using a 1.0 T Siemens Magnetom Expert MR Scanner, whole brain axial fluid attenuated inversion recovery and turbo spin echo axial T2 weighted images were acquired to allow detailed visualisation of white matter disease. Images were transferred to a Centricity PACS workstation and WML volumes were calculated using a manual tracing technique, as described previously.18 Intra-rater variability of WML volume measurements was assessed on two separate occasions in 10 subjects and the intra-class correlation coefficient was 0.99 (95% confidence interval (CI) 0.95 to 1.0).
Subjects were in a supine position with their heads slightly elevated. TCD was used to measure the changes in middle cerebral artery velocity (MCAV) in response to changes in BP and inspired CO2. MCAV was recorded bilaterally simultaneously via the transtemporal window using 2 MHz transducers (DWL Elektronische Systeme GmbH, Sipplingen, Germany). Continuous BP recording was made via a servo-controlled finger plethysmograph (Finapres 2300; Ohmeda Englewood, California, USA), with the subject’s hand maintained at the same level as the head. Finapres measurements were initially corroborated by standard measurements of BP with an automated arm cuff (Omega 1400 series; In Vivo Laboratories Inc, Orlando, Florida, USA). End-tidal CO2 was measured with an automated capnograph (Normacap 200; Datex, Helsinki, Finland).
Assessment of dynamic cerebral autoregulation
In order to assess dynamic cerebral autoregulation, a sudden stepwise drop in BP was induced by rapid deflation of bilateral thigh cuffs that had been inflated suprasystolically for 3 min. Autoregulatory responses were analysed offline using the time averaged mean velocities of the maximum velocity outlines of the Doppler spectrum and mean BP. Dynamic autoregulation was assessed as previously described using the software program supplied by the TCD manufacturers which compares the rate of return of BP and MCAV to baseline following the drop in BP.15 19 Starting at the moment of cuff release and based on the actual BP curve of the 30 s that followed, a series of 10 hypothetical MCAV autoregulatory curves were calculated that model between a passive MCAV and BP relationship (an autoregulatory index (ARI) of 0) and rapid rates of rise in MCAV with increased ARI (maximum ARI 9; normal range 5–9) (fig 1). Full details of the equations used have been published previously.15 Five cycles of inflation/deflation were performed per subject with a 3 min rest interval between cycles. A mean ARI was calculated for each subject only from runs in which a sufficient magnitude of BP fall (>10 mm Hg) was attained. End-tidal CO2 was recorded during and between repeated assessments of ARI.
Assessment of CO2 reactivity
CO2 was administered as 8% CO2 in air from a Douglas bag reservoir through a mask with inspiratory and expiratory limbs protected by one-way valves. End-tidal CO2 was monitored by continuous sampling from the expiratory limb using the automated capnograph. CO2 was administered until MCAV recordings had plateaued. CO2 reactivity was calculated offline as the percentage increase in MCAV during 8% CO2 inspiration, compared with baseline MCAV while breathing room air.5 7 Assessments of CO2 reactivity and autoregulation were performed on the same day but autoregulation was always evaluated first to avoid lasting effects of CO2 on the cerebral circulation. All reactivity and autoregulation traces were analysed by an experienced researcher blinded to patient identity, and traces of poor quality were excluded prior to data analysis.
Ten subjects consented to assessment of ARI and eight subjects consented to assessment of CO2 reactivity at the same time and in the same environment on two consecutive days in order to assess reproducibility. The subjects were representative of the patients studied. The repeatability coefficient, which is equal to twice the SD of the differences between the pairs of measurements,20 was 2.4 for ARI assessment and 35.4% for CO2 reactivity assessment.
Data were tested for normality using the Komolgorov–Smirnov test. Categorical data were compared using χ2 tests. Pearson’s correlation coefficient (r) was used to examine the correlations between normally distributed variables and logarithmic transformation of non-parametric data. Linear regression models with stepwise deletion were undertaken to examine the independent predictors of ARI and CO2 reactivity after adjusting for covariation in baseline characteristics of age, gender, vascular risk factor profile including BP level and duration of hypertension, and WML load, and for variables significant at p<0.1 on univariate analyses. All evaluations used SPSS statistical analysis software (V.13).
Patient characteristics, including 24 h BP and WML volume measurements, are shown in table 1. Of the 64 patients, 45 were on diuretics, 25 were on calcium channel antagonists, 33 were on angiotensin converting enzyme inhibitors, 15 were on angiotensin II receptor antagonists and 20 were on α-adrenoceptor antagonists. Eight individuals (13%) had a history of diabetes mellitus (mean (SD) duration 7.5 (7.8) years), of whom three were insulin dependent and five were taking oral hypoglycaemic therapy. Twenty-five patients had evidence of nocturnal BP dipping (nocturnal reduction of BP by >10% of daytime BP),19 with a mean (SD) BP drop of 15.7 (5.4) mm Hg.
The MCAV was insonated at a mean (SD) depth of 51.6 (5.4) mm. Mean (SD) MCAV was 56.8 (16.5) cm/s. Measurement of ARI was possible in 45 of the 64 patients. Ten individuals were unable to tolerate thigh cuff inflation/deflation, a stepped BP reduction >10 mm Hg with thigh cuff deflation could not be induced in one individual and in another eight individuals undulations in the continuous BP and/or MCAV recording traces precluded evaluation of ARI. There was no significant change in resting CO2 during or between repeated assessments of dynamic cerebral autoregulation. Mean (SD) ARI was 5.6 (1.4). In univariate analyses, ARI correlated significantly with 24 h systolic BP (r = 0.327, p = 0.030) and 24 h mean BP (r = 0.350, p = 0.020) (fig 2) but not with diastolic BP or WML volume. In those individuals with a history of hypertension for more than 10 years, ARI also correlated significantly with nocturnal BP dipping (r = 0.806, p = 0.002) (fig 3). Regression analyses showed 24 h mean BP to be an independent determinant of ARI (R2 = 0.127, coefficient 0.060 (95% CI 0.010 to 0.109), t = 2.440, p = 0.019).
CO2 reactivity was assessed in 57 patients. Three individuals were unable to tolerate CO2 inhalation and in another four individuals, undulations in the continuous BP and/or MCAV recording traces precluded assessment of CO2 reactivity. CO2 reactivity was not affected by patients’ BP levels or WML volume but correlated negatively with duration of hypertension (r = −0.292, p = 0.027) (fig 4). Duration of hypertension remained an independent predictor of CO2 reactivity in regression analyses (R2 = 0.085, coefficient −0.974 (95% CI −1.845 to −0.104), t = −2.244, p = 0.029). No significant relationships existed between ARI and CO2 reactivity, and results were not affected by the class of antihypertensive treatment.
This study in hypertensive patients with WML on MRI as a manifestation of cerebral small vessel disease showed that autoregulatory capacity was determined by BP levels and correlated with nocturnal BP dipping in individuals with longstanding hypertension. CO2 reactivity was not affected by patients’ BP levels but was dependent on duration of hypertension. Neither ARI nor CO2 reactivity were significant determinants of WML volume.
While cerebral autoregulation has previously been suggested to be impaired in patients with small vessel disease,10 11 12 the mean (SD) ARI in this study population was 5.6 (1.4) (normal range 5–9),15 suggesting that ARI is preserved in patients with early cerebral small vessel disease. This study differed from previous investigations in terms of excluding patients with large vessel cerebrovascular disease and/or recent stroke that may have acted as confounding variables.6 21 While ARI was unrelated to small vessel disease lesion load, ARI was associated with BP levels consistent with studies in normal volunteers.22 23 ARI increased with elevated 24 h mean BP levels and also with nocturnal BP dipping in individuals with longstanding hypertension. The former relationship may be explained by ARI improving by increased vascular tone; acute elevation of BP with agents such as noradrenaline is associated with increased ARI.23 The latter relationship suggests that ARI is preserved even in longstanding hypertensives with cerebral small vessel disease. Recent studies have suggested that the threshold of BP needed to maintain CBF may shift to a higher level in elderly hypertensive individuals with small vessel disease and that physiological episodes of low BP may provoke ischaemic injury.24 Preservation of autoregulatory function in patients with small vessel disease at greatest risk of reduced CBF may be a protective response analogous to the increase in oxygen extraction fraction seen in such patients.25
The linear relationship demonstrated between impaired CO2 reactivity and duration of hypertension has been suggested previously in animal studies.26 It has been proposed that an increased duration of exposure to systemic hypertension accelerates arteriosclerotic changes in the cerebral vasculature predisposing to increasing vessel wall rigidity and impaired cerebrovascular vasodilatory capacity. CO2 reactivity was unrelated to WML volume and this is consistent with previous studies that similarly excluded patients with concomitant large vessel disease or recent stroke.8 9
The findings of this study support the view that impaired cerebral autoregulation and limited vasodilatatory capacity are not pathogenetic hallmarks of leukoaraiosis.27 In addition, they support the concept that the cerebrovascular responsiveness to CO2 operates independently from cerebral autoregulation. In hypertensive subjects, cerebral autoregulation appears to be determined by the level of BP and is preserved in longstanding hypertensives, whereas responsiveness to CO2 is influenced by the duration of hypertension. The literature supports the concept of the two processes being distinct, having separate effector mechanisms, and interacting in a complex way.21 28 29 Although the physiology responsible for controlling CBF autoregulation and vasoreactivity is not fully understood,27 dynamic cerebral autoregulation has been suggested to be a more sensitive measure of haemodynamic impairment than CO2 reactivity.21
In contrast with studies undertaken in untreated hypertensives or in patients whose antihypertensive treatment was discontinued, this study allowed patients to remain on pre-existing antihypertensive medications. This ensured the study population was representative of the “norm”, facilitating generalisability to the general population and it prevented participants having poorly controlled hypertension (clinic BP >160/100 mm Hg) that could act as a confounding influence. However, antihypertensive medications taken by patients may have exerted effects on the cerebral vasculature,30 and the duration of undetected hypertension and effectiveness of previous BP control remain unquantifiable variables.
The findings of this study are limited by the relatively small sample size, its cross sectional nature and the lack of a control group for comparison. This makes it possible that more subtle disturbances in haemodynamics or non-linear relations with small effect size in subjects with WML may have been missed. In addition, causal inferences should be made with caution, particularly with reference to the relationships between nocturnal BP falls and autoregulation, where both may be interlinked via other factors. Indeed, controversy exists in the literature with regard to prolonged and/or marked nocturnal dipping being physiological or abnormal, beneficial or harmful, and representing the cause or effect of end organ damage.14 17 31
The high temporal resolution of TCD has made it the recognised method for estimating changes in CBF velocity in studies of cerebral autoregulation and vasoreactivity.4 32 33 MCA blood flow velocity rather than blood flow has been used to determine cerebral haemodynamics. This is based on observations that changes in MCAV induced by BP drops during surgery correlate very closely with changes in internal carotid artery flow19 and that there is little change in MCA diameter during CO2 inhalation,34 suggesting that any change in MCAV measured by TCD is directly proportional to the change in flow. As TCD assessments measure the entire MCA territory and more blood flow goes to the grey matter than to the white matter, it is likely that TCD assessments reflect cortical more than the subcortical blood flow change.35 Although this is a potential limitation, it is likely that the pathology of small vessel disease is diffuse and TCD measurements provide a simple, non-invasive method for assessing cerebral autoregulation and vasoreactivity in these patients.
The Finapres continuous BP recording used provided a reliable assessment of rapid changes in BP, but its accuracy for absolute measurement is affected by baseline shifts and unpredictable offsets.21 For the purposes of the autoregulation model, absolute measures of BP were not required but a lack of such values during assessment of CO2 reactivity did not demonstrate if CO2 inhalation produced a significant increase in BP that may have affected cerebrovascular reactivity.36 CO2 inhalation was not tolerated by all patients and the thigh cuff technique was associated with pain on cuff inflation/deflation and difficulties in inducing significant BP drops with cuff deflation. The thigh cuff technique also could not be undertaken in subjects with peripheral vascular disease and it has been suggested that the technique may produce sympathetic activation.37 Although the thigh cuff method has been the most common approach for assessment of dynamic cerebral autoregulation, a number of other dynamic pressor or depressor stimuli exist but all have methodological limitations.33 Computerised coherent averaging of the CBF velocity response to spontaneous BP transients has also been developed, allowing calculation of ARI from spontaneous BP oscillations, but this was not available.38
In conclusion, this study demonstrated that cerebral autoregulation and CO2 reactivity appear to be two distinct processes that are not related to WML volume but are related to BP levels and duration of hypertension, respectively. Greater nocturnal dipping was associated with higher ARI values in longstanding hypertensives with cerebral small vessel disease, suggesting preservation of autoregulation in patients with increased vulnerability to reduced cerebral perfusion. These findings suggest a complex interaction between BP, cerebral haemodynamics and chronic ischaemic injury to the brain that merits further investigation in the context of the increasing importance of cerebral small vessel disease and dementia in recent years.39
Competing interests None.
Ethics approval The study was approved by King’s College Hospital ethics committee.
Provenance and Peer review Not commissioned; externally peer reviewed.
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