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Small Vessel Disease of the Brain and Stroke: Associationwith Clinic and Ambulatory Blood Pressure
  JOHTN
TARGET ORGAN DAMAGE
Small Vessel Disease of the Brain and Stroke: Association
with Clinic and Ambulatory Blood Pressure
1Puneet Gupta, 2William B White
1,2Professor and Chief
1,2Division of Hypertension and Clinical Pharmacology, CalhounCardiology Center, University of Connecticut School of MedicineFarmington, Connecticut, USA
Correspondence: William B White, Professor and ChiefDepartment of Medicine, Division of Hypertension and ClinicalPharmacology, Calhoun Cardiology Center, University ofConnecticut School of Medicine, Farmington, Connecticut, USA
Phone: +18606792104
e-mail: wwhite@uchc.edu
 
ABSTRACT
Several potential vascular risk factors exist for the developmentand accumulation of small vessel disease of the brainand stroke in older people. In older people followed up forseveral years, we and others have reported that white matterhyperintensity lesions on magnetic resonance imaging nearlydoubled in volume and were associated with alterations inneurologic function. In this article, we review blood pressure(BP) as a risk factor for the development and pathogenesis ofsmall vessel disease and stroke in older persons. The researchefforts have focused on ambulatory BP measurements, whichhave proven to be a stronger indicator than clinic pressuresfor the progression of small vessel disease in older people aswell as the development of stroke. Based on relations among24 hours systolic BP levels, the accrual of small vessel disease,and relations with cognitive function and mobility, we havedesigned the INFINITY trial, a novel interventional studythat uses ambulatory BP to guide antihypertensive therapyaddressed at improving functional decline.
Keywords: Ambulatory blood pressure, Cerebral small vesseldisease, Stroke, Systolic hypertension.
How to cite this article: Gupta P, White WB. Small VesselDisease of the Brain and Stroke: Association with Clinic andAmbulatory Blood Pressure. Hypertens J 2016;2(2):65-73.
Source of support: National Institutes of Health R01AG022092
Conflict of interest: None
 
 
INTRODUCTION

Cerebrovascular Disease, Hypertension,
and Functional Decline


Small vessel brain disease that is represented by whitematter hyperintensity (WMH) lesions on magneticresonance imaging (MRI) is associated with vascularrisk factors, including hypertension, in older people.1,2 Postmortem histopathology of WMH shows nonspecificbrain changes with gliosis, loss of myelin and axons fromarteriosclerosis, tissue rarefaction, and lipohyalinosis.3,4Although the pathophysiology of WMH remains unclear,there are several proposed mechanisms, includinghypoxia, hypoperfusiondue to altered cerebrovascularauto-regulation, blood-brain barrier leakage, inflammation,degeneration, and amyloid angiopathy.5 Marstrandand colleagues demonstratedthat cerebral blood flowand cerebrovascular reactivity were reduced in areasof WMH, making tissue damage more likely duringhypoperfusion states.6

  In most instances, WMH lesions are bilateral andsymmetrical on T2-weighted MRI. They are distributedin the periventricular and deep white matter regions andless frequently in the infratentorial areas of the brain. Oncomputed tomography (CT) scan, WMH lesions appearas hypodensities.1,7 They are commonly assessed usingvisual rating scales, such as Fazekas scale and Scheltensscale.5 Another approach uses semi-automated, computerizedanalyses of the MRIs providing a quantitativedistribution of cerebral SVD lesions suitable for longitudinalnumerical comparisons and regional localizations(Fig. 1).8

Cognitive Function

Higher degrees of small vessel disease burden are associatedwith impaired cognitive function, mobility impairment,depression, and impaired urinary function.1,9,10The frequency of falls even in the absence of obviousneurologic deficits is more common in people withWMH lesions.8 Cognitive dysfunction has been studiedextensively in persons with WMH lesions on MRI.9,11-18Perceived cognitive dysfunction as measured by CognitiveDifficulties Scale was found to be worse with higherWMH burden and the annual rate of decline on the minimentalstatus examination (MMSE) was 0.035 points perstandard deviation increase in periventricular WMH.19In addition, steeper declines in performance have beenfound on measures of speed of processing and executivefunctioning, such as the Stroop Color Word test (p = 0.04)and the Symbol-Digit Substitution Test (p < 0.01) are seenwith WMH lesions, whereas performances on memorytests, such as the 15-word verbal learning test are not asaffected.9,19 Over a decade, the European Leukoaraiosis and DISability Study (LADIS) showed steeper declines inthe Stroop test, Trail Making A test, verbal fluency, andMMSE among patients with cerebral small vessel diseaseand the group found that these abnormalities predicteda doubling of risk for dementia and transition from anautonomous to dependent state.17

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Puneet Gupta, William B White

Small Vessel Disease of the Brain and Stroke: Associationwith Clinic and Ambulatory Blood Pressure
Fig. 1: The figure depicts the location and frequency of white matter hyperintensities (WMHs)captured over three time points during 4 years of prospective evaluation (baseline (left column),2 years (center column), and 4 years (right column) in 67 older study participants. The WMHs areoverlaid on the gray scale slice (0.87 mm thickness) of the common anatomical brain (InternationalConsortium of Brain Mapping). Columns show two slices separated by 12.2 mm. The verticalcolor bar represents the frequency (%) of WMHs (e.g., color corresponding to 70% indicates thepercent of participants with the WMH in that brain area. The lettering below the color bar indicatesright (R), left (L), anterior (A), and posterior (P) brain aspects) (From Wolfson et al (2013)8 discusswith permission from Oxford University Press on behalf of The Gerontological Society of America)


Importantly, among patients with a history of strokeand/or transient ischemic attack in the PerindoprilProtection Against Recurrent Stroke Study (PROGRESS),the dementia risk during a median follow-up period of3.9 years was found to be 7.7 times higher in patientswith white matter disease than those without it at thetime of study enrollment.16 A meta-analysis performedby Debette and Markus20 also showed a significantassociation between white matter disease and risk ofdementia (OR 1.9, 95% confidence intervals (CIs), 1.3 to2.8, p = 0.002) as well as faster declines in global cognitiveperformance, executive function, and processing speeds.

Mobility and Balance

In addition to the aforementioned relationships betweenWMH burden and cognitive function, small vessel disease of the brain is also associated with impairedgait and balance in the older population.8 Furthermore,severe WMH burden has been linked to increased risk offalls (relative risk (RR) = 1.63, 95% CI, 1.11-2.40).10 In theLADIS, walking speed correlated with the white matterdisease burden (1.24 ± 0.28 m/second for mild, 1.18 ±0.32 m/second for moderate, 1.09 ± 0.31 m/second forsevere categorizations respectively; p < 0.001).21 Patientswith mild white matter disease burden performed betterwith single leg stance when compared with those withmoderate and severe diseases (p < 0.001). These findingshave also been found in other studies correlating cerebralsmall vessel disease and mobility in the elderly and willbe the subject of discussion later in this paper.22
 
Ambulatory Blood Pressure in
Risk Assessment for Stroke


There has been mounting evidence for four decades onthe importance of ambulatory blood pressure monitoringparameters for predicting cardiovascular eventsincluding stroke. In a meta-analysis of 17,312 personswith hypertension recently reported by the ABC-H (Ambulatory Blood Pressure Collaboration in PatientsWith Hypertension) investigators,23 reverse dippers(systolic night-to-day BP ratio > 1) had a significantlyhigher risk of strokes (HR 1.89, 95% Cl 1.26-2.82, p < 0.01)compared to those study participants who had a morenormal circadian BP rhythm (systolic night-to-day ratio< 0.9 and > 0.8). In addition, patients with reduction innocturnal BP decline compared with those individualswith at least a 10% decline in BP during sleep, had a 27%greater risk for total cardiovascular events. Similar findingshave also been reported by Verdecchia et al24 in alongitudinal study in Italy of 3,012 hypertensive patientsfollowed up for a mean period of 8.4 years.
 
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Small Vessel Disease of the Brain and Stroke: Association with Clinic and Ambulatory Blood Pressure

The Ohasama study25 has highlighted the additiveimportance of ambulatory BP measurements with homeand office measurements for evaluation of stroke riskin 1,464 persons with a median follow up of 17.1 years.Using normal BP sustained over time as a reference,adjusted hazard ratios for stroke (95% CI; events/N)were 1.38 (0.82-2.32; 19/137) for white coat hypertension(isolated office hypertension), 2.05 (1.24-3.41; 23/100)for masked hypertension (both home and ambulatoryhypertension with office normotension), 2.08 (1.37-3.16;38/180) for partial masked hypertension (either homeor ambulatory hypertension with office normotension),and 2.46 (1.61-3.77; 42/154) for sustained hypertension.The authors concluded that both home and 24 hoursambulatory blood pressure measurements are neededto evaluate stroke risk accurately.

Another major epidemiologic study of ambulatoryBP and stroke outcomes is the International Database onAmbulatory BP and Cardiovascular Outcomes (IDACO).26In a recent report from the IDACO investigators26 involving8,341 people randomly recruited from 12 populationsfollowed up for a median period of 11.2 years, the risksconferred by 24 hours BP were found to be age dependent.In participants above the age of 50 years, 24 hours systolicBP was a major predictor of stroke (HR 1.52, 95% Cl1.32-1.76, p < 0.001), total mortality, CV mortality, and allCV events after multivariate adjustment for cohort, sex,age, body mass index, smoking and drinking, serumcholesterol, history of cardiovascular disease, diabetesmellitus, systolic BP, and diastolic BP. Below the age of50 years, 24 hours diastolic BP was the main driver ofrisk, reaching significance for total and cardiovascularmortality and for all cardiovascular end points combined.The 24 hours ambulatory systolic and diastolic BPs werealso found to be independent predictors of CV events,including stroke, in another observational study of 502patients in Finland with 16.1 years of follow up.27

Several other ambulatory blood pressure parametershave been studied for prediction of cardiovascular events.In a meta-analysis of 13,844 patients with hypertension28 comprising nine cohorts from Europe, Japan, andBrazil, nocturnal (nighttime) systolic BP independentlypredicted higher CV risk. Each 10 mm Hg increase innighttime systolic BP was also an independent risk factorfor stroke (HR 1.95, 95% Cl 1.18-3.20) in a cohort of 859patients with type 2 diabetes29 and in another Japanesecohort of 1,276 patients with hypertension30 followedup for 3.2 years. A recent review from Portugal31 foundthat a 10 mm Hg increase in pre-awakening BP surge,analyzed on a continuous scale, was related to a modestincreased risk of stroke (HR = 1.11 for three studies).There has been some controversy regarding the impactof the early-morning surge in BP vs a sustained increasein nocturnal BP as the more potent risk of future stroke.Verdecchia et al24 addressed this issue in a longitudinalstudy that found that a blunted pre-awakening BP surgedue to high nocturnal BP was an important risk factorfor an increased risk of stroke.

 
Resistant hypertension (lack of hypertension controlon three or more antihypertensive agents) is associatedwith increases in hypertensive target organ disease andhas become a topic of great interest. In a retrospectiveanalysis of 217 patients with resistant hypertension, theambulatory arterial stiffness index (AASI) was found tobe an ABPM marker with the high predictive value forCV events including stroke.32 In a meta-analysis of sevenlongitudinal studies that had followed up 20,505 patientswith a mean follow-up of 7.8 years,33 each standard deviationincrease of AASI was associated with an age, sex, andrisk factor-adjusted increase in relative risk of stroke by30%. There is also evidence that average real variability(ARV) of 24 hours average and nocturnal systolic BP aswell as BP variability during sleep may be independentpredictors of subclinical cerebral small vessel disease.34,35

With growing evidence of increased CV risk withelevated nocturnal BP, a randomized prospective studycomparing bedtime administration of antihypertensivetherapy with conventional dosing time of therapyadministered in the morning - the MAPEC study36 - wasundertaken. With a median follow-up of 5.6 years in 2,156participants with hypertension, the study demonstrateda 67% reduction in major CV events (CV death, nonfatalMI, and nonfatal ischemic and hemorrhagic stroke) insubjects in the bedtime antihypertensive medicationtreatment group. Progressive decrease in sleep BP meanhas been found to be the most significant predictor ofevent-free survival, a novel therapeutic target for primaryprevention.37

Ambulatory BP Monitoring in Evaluating
Outcomes for Recurrent Stroke


Hypertension is well known to be associated with increasedrisk of recurrent stroke in patients with a history of a prior ischemic or hemorrhagic event.38 A recent metaanalysisof 16 randomized controlled trials and 40,292patients with history of stroke (ischemic, transient ischemicattack [TIA], or hemorrhagic), with and without hypertension,demonstrated that antihypertensive therapy reducedthe risk of recurrent stroke (relative risk reduction, 18%95% confidence interval [CI], 9-26%). The meta-regressionanalysis also revealed that each 10 mm Hg reduction in systolicBP is associated with a 33% (95% CI, 9-51%) reductionin the risks of recurrent stroke.39 In an observational studyof 426 patients with acute cerebral infarction followed upfor an average 7.6 years, daytime systolic BP on ambulatorymonitoring was a significant predictor of recurrenceof cerebral infarction.40

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Ambulatory BP has demonstrated a higher sensitivitycompared to office BP for evaluation of the effectivenessof antihypertensive treatment among stroke survivors.38In a study of 51 patients with a recent TIA syndromeand 225 clinically healthy control subjects, ambulatoryBP monitoring revealed a highly significant proportionof these patients (90%) whose hypertension was notwell controlled.41 In another study of 187 consecutivefirst-ever hypertensive stroke survivors who underwentoffice and ambulatory BP measurements at 120 ± 30 days,effective BP control was documented in significantly(p < 0.001) fewer pat ients using ambulatory BPmonitoring (32.1%) than those using office recordings(43.3%), whereas in 16% of the study population, therewas a masked pattern (elevated ambulatory bloodpressure in the presence of normal office blood pressurelevels) identified.42

Castilla-Guerra et al43 reported a chronic disruptionof circadian rhythm of BP after the acute phase of strokein a prospective study of 101 patients admitted within24 hours after stroke onset and followed up for 1 year.The normal diurnal variation in BP was abolished in87.1% of patients during the acute phase of stroke, in76.9% after 6 months, and in 74.6% after 1 year. Anotherstudy44 found that the nocturnal BP reduction was bluntedin most (∼90%) of 48 elderly bedridden hypertensivepatients assessed within 1 to 3 months after stroke. Inan interesting observational study,40 a reverse dipperpattern and high nighttime heart rate in patients withacute cerebral infarction were independently associatedwith total mortality.

A meta-analysis of studies of acute ischemicstroke patients admitted within 24 hours of onset andundergoing ABPM within 24 hours of admission showedthat both high systolic and diastolic BP levels derivedfrom ambulatory BP monitoring were associated withpoor short-, intermediate-, and long-term outcomes,but the same was not found for casual (clinic) BPmeasurements.45 Additionally, in a study of 128 initial acute stroke patients who underwent ABPM within24 hours of stroke onset and computerized tomographyscans of the brain on both admission to the hospital and5 days later, multivariate logistic regression analysisshowed that each 0.1 mm Hg/minutes increase in the timerate of 24 hours SBP variation was associated with a 13.9%increased probability of presence of brain edema.46Alonger-term study of 109 patients with stroke whose24 hours BP variability was assessed within 24 hours ofonset showed that higher systolic BP variation at baselinepromoted negative outcomes at 1 year.47
 
Higher 24 hours, daytime, and nighttime systolic anddiastolic BPs at baseline in patients with new lacunarinfarctions have also been associated with the developmentof new cerebral microbleeds at 2 years follow-up.48 A3 months follow-up study of acute ischemic strokepatients found that mean values of systolic BP, diastolicBP, pulse pressure, and HR on day 1 of admission onambulatory BP monitoring were inversely associatedwith their independence.49

The data mentioned before highlight the importance ofambulatory BP monitoring for potentially improving thesecondary prevention of stroke using several parametersin the acute phase. Ambulatory BP monitoring not onlyhelps in identifying patients with inadequate bloodpressure control despite "apparently" well-controlledoffice BP, but can also help decide the appropriate timingof medications individualized to circadian rhythm.Furthermore, inadvertent excessive lowering of BP -which has been associated with recurrence of stroke50-52 -may be avoided with assessment of 24 hours BP levelsand patterns. Further research might best focus on usingambulatory BP parameters to guide antihypertensivetherapy in patients with a history of stroke to facilitatefurther fine-tuning of secondary prevention strategiesprevalent at this point.

The Importance of Blood Pressure as a Risk
Factor for Cerebral Small Vessel Disease and
Functional Decline in Older Persons


White matter hyperintensities and its progression, presentin the MRIs of older people, have been associatedwith hypertension, and evidence suggests that WMHsoccur as a result of arteriosclerosis within the wall of thearteriole.53-56 Large arterial and small vessel disease of thecerebral circulation share risk factors (e.g., hypertensionand diabetes) and may coexist in individuals as notedearlier. Although given the differences noted in Table 1,it is unclear if they both produce white matter tissuedamage through similar mechanisms.57,58

White matter lesions have also been associated with deteriorationof mobility, urinary control, and cognition.59-64Evidence of WMHs within brain pathways known to support mobility, cognition, or voiding confirms thisassociation.63,64 Details seen on MRI of the brain have allowedlocalization and quantification of the disseminatedWMHs.65 Cross-sectional and prospective cohort studieshave documented the relationships among WMHs andneurologic function in older people and the distinctivenature of the distribution and volume of brain WMHsthat are responsible for deterioration of these functions,particularly in older groups. Approximately two-thirdsof individuals over 75 years of age have detectable WMHsusing MRI of the brain.54 The lower limit of detection ofWMH by experts in neuroradiology is approximately 0.2to 0.3% of intracranial contents, and 0.5% is easily visibleto the naked eye based on our experience.8,54,65 Our cohortstudies have demonstrated an increase of WMH volume from 0.99 to 1.47 to 1.7% of the intracranial contents volumefrom baseline to 2 and 4 years respectively.8,54 Thisincrease was even present in participants with normalmobility throughout the study period.
 
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Small Vessel Disease of the Brain and Stroke: Association with Clinic and Ambulatory Blood Pressure

Table 1: Comparison of some characteristics of stroke andwhite matter hyperintensity lesions*
Small Vessel Disease of the Brain and Stroke: Associationwith Clinic and Ambulatory Blood Pressure
 
We have also observed that progression of WMHover time was strongly linked to the initial presence ofWMH.8,66 The accumulation of WMH often occurred byexpansion of preexisting periventricular lesions in a stereotypedmanner. Regional analysis of the distribution ofWMH lesions demonstrated a robust link to expansion oflesions in the splenium of the corpus callosum, a posteriorperiventricular structure important for the integration ofcortical sensorimotor function.66

Blood pressure and other cardiovascular risk factorshave been related to brain WMH, although predictors ofquantitative WMH progression and their effect on thefunction of older persons have not been well understood.In our past work in this area, we have evaluated theprogression of WMH over 2 and 4 years in a cohort of95 patients 75 to 90 years (mean baseline age, 82 years) whohad office and ambulatory BP and volumetric MRI.54,65Neither clinic BP nor changes in clinic BP predictedprogression of WMH, while the 24 hours ambulatory BPand changes in ambulatory BP significantly correlatedwith both WMH volume (p < 0.04) and changes in WMH(p < 0.003).54 Further analyses demonstrated associationsfor WMH and mobility indexes with level of systolic BPbased on tertiles of the cohort - i.e., those in the higher(24 hours systolic BP = 144 mm Hg) ambulatory BPgroup showed increases in WMH and slower mobilitycompared with the middle tertile (ambulatory systolicBP = 130 mm Hg) (Table 2). Furthermore, gait speed in the higher ambulatory BP group decreased 0.15 m/secondmore than that in the low BP group and while thisdifference appears small, it represents a between-groupchange after only 2 years of observation.54 Mobilitylimitation linked to WMH occurs gradually so thatthis decrement may be part of a long-term process thatcompromises gait velocity over 10 or more years. Thesedata have suggested that an intervention using mean24 hours systolic BP as the target could reduce progressionof microvascular disease in the elderly and thus favorablyimpact function.

Table 2: Functional parameters at 24 months of observation according to clinic and ambulatory blood pressure
Small Vessel Disease of the Brain and Stroke: Associationwith Clinic and Ambulatory Blood Pressure
Unpublished data from our cohort study54; WMH: White matter hyperintensity lesions; m/s: meters/second; Significant values arebold typeface
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The results of our cohort studies have been supportedby a larger longitudinal population-based study of 665persons from the Rotterdam study.55 Over a 5 years period,clinic BP and WMH lesion progression were measured3.5 years apart, and after adjusting for baseline WMH,only systolic BP was significantly associated with progression(0.05 mL/year of standard deviation (SD) increase).Of interest, people with uncontrolled and untreatedhypertension had significantly greater white matter lesionprogression than people with uncontrolled but treatedhypertension (Fig. 2). These studies suggest that antihypertensivetreatment could reduce white matter lesionprogression in uncontrolled hypertension. However, guidingtherapy through the use of ambulatory BP monitoringcould make this process more precise since ambulatoryBP is more reproducible than clinic BP in older people67 and ambulatory BP recordings would provide a means totarget BP elevations during sleep, a period that is stronglyrelated to WMH and cerebrovascular disease.54,68
 
The INFINITY Study

The Intensive versus Standard Ambulatory BloodPressure Lowering to Prevent Functional DecliNe inThe ElderlY (INFINITY) study69 has been designed toevaluate the functional impact of a clinically relevantseparation in 24 hours mean ambulatory systolic BP inan older population (i.e., < 130 mm Hg vs < 145 mm Hg).The study has been designed to evaluate these two levelsof ambulatory BP control in hypertensive individuals75 years or older with normal or mildly impairedmobility and cognition who already have detectablecerebrovascular disease (= 0.5%WMH fraction of intracranialvolume). The key outcomes monitored over the3 years of the trial are white matter lesion progressionand measures of mobility and cognition. INFINITY is aprospective, randomized, open-label trial with blindedend points that will evaluate the changes from baselinein mobility and cognitive function and accumulation ofWMH volume and changes in diffusion tensor imaging.

Our objective is to achieve a 24 hours systolic BP of≤ 130 mm Hg in an intensively treated group or standardgoal of 24 hours systolic BP of ≤ 145 mm Hg for a totalof 36 months using similar classes of antihypertensive therapies. Data from the Hypertension in the Very ElderlyTrial (HYVET) demonstrated that antihypertensivetherapy decreases stroke mortality in patients in theirmid-80s.70 In HYVET, the goal of therapy was to reducesystolic BP to < 150 mm Hg, and this intervention didresult in a 39% reduction in stroke mortality that wasrelated to a 15 mm Hg difference in systolic BP betweenthe active treatment and placebo groups. The goal of thestandard of care 24 hours mean ambulatory systolic BPin this age group is 140 to 145 mm Hg. No clinical trialin older patients with systolic hypertension has usedambulatory BP to guide therapy and to specifically assesscerebrovascular outcomes. The INFINITY trial will bethe first study to guide antihypertensive therapy usingambulatory BP monitoring rather than clinic BP to reducesmall vessel disease of the brain. Initiated in 2012, weproject that the study will be completed in 2018.69

Small Vessel Disease of the Brain and Stroke: Associationwith Clinic and Ambulatory Blood Pressure
Fig. 2: Mean WML progression in mL (95% confidence interval [CI]; black bars) on top of thebaseline WML volume (gray bars) for four blood pressure categories. Categories were defined asfollows based on their mean blood pressure and medication use in the 5 years before the first scan:(1) Normotensives: Normal mean blood pressure and receiving no antihypertensive medication(n = 255); (2) controlled treated hypertensives: Normal mean blood pressure and receivingantihypertensive medication (n = 83); (3) uncontrolled treated hypertensives: Hypertensive meanblood pressure and receiving antihypertensive medication (n = 155); and (4) uncontrolled untreatedhypertensives: Hypertensive mean blood pressure and receiving no antihypertensive medication(n = 172). Hypertensive mean blood pressure was defined as diastolic blood pressure ≥ 90 mm Hgor systolic blood pressure ≥ 140 mm Hg. A statistically significant difference in WML progressionwas observed between the uncontrolled untreated hypertensive group and the uncontrolled treatedhypertensive group, after adjusting age, sex, intracranial volume, time between scans, and thebaseline WML load (p < 0.05) (From Verhaaren et al (2013)55 with permission from the AmericanHeart Association)
 
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Small Vessel Disease of the Brain and Stroke: Association with Clinic and Ambulatory Blood Pressure

DISCLOSURES

Neither of the authors has any disclosures related to thecontent and topic of this manuscript.

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