Abstract
Ambulatory arterial stiffness index (AASI) is associated with microvascular damage in other organs, but the association with microvascular brain damage is unknown. The association of AASI with magnetic resonance imaging (MRI) markers of cerebral small vessel disease in 143 patients with lacunar stroke was investigated. We performed 24‐hour ambulatory blood pressure monitoring and scored the presence of lacunes, white matter hyperintensities, perivascular spaces, and cerebral microbleeds on brain MRI. In logistic regression analyses, AASI was associated with white matter hyperintensities, but, after adjustment for age and sex, this association lost significance. AASI was not associated with lacunes, microbleeds, or perivascular spaces. Systolic and diastolic 24‐hour blood pressure values were associated with lacunes, perivascular spaces, and microbleeds independent of age and sex. Despite its significance and growing interest as a possible prognostic and therapeutic target in (micro)vascular diseases, AASI seems to have no added value over standard 24‐hour blood pressure in cerebral small vessel disease.
Cerebral small vessel disease (cSVD) is a pathological process involving the small arteries and arterioles of the brain.1 Lacunes, white matter hyperintensities, perivascular spaces, and cerebral microbleeds (CMBs) have all been identified as markers of cSVD on brain magnetic resonance imaging (MRI).2 In general, assessment of asymptomatic end‐organ damage has good prognostic significance for cardiovascular risk and may therefore be clinically relevant.3 Indeed, the markers of microvascular brain damage are associated with increased risk of stroke, higher mortality, and worse cognitive functioning.1, 4, 5, 6 Elevated blood pressure (BP) is one of the main risk factors for cSVD.4, 7
Increased arterial stiffness is considered another risk factor for cSVD. It is thought that abnormal flow pulsations extend deep into the microvasculature of the brain, damaging the vessels.8 Studies using arterial pulse wave velocity as a measure of arterial stiffness have found associations with lacunes, deep CMBs, and white matter hyperintensities.9, 10, 11 The ambulatory arterial stiffness index (AASI) was originally introduced as a new measure of arterial stiffness derived from 24‐hour ambulatory BP monitoring data representing the dynamic relationship between systolic and diastolic BP.12 However, other factors such as heart rate and vascular resistance were shown to influence this measure as well.13 Despite the fact that the exact pathophysiological background of this index remains unclear, AASI predicts cardiovascular outcome (especially stroke) and is associated with microvascular renal target organ damage.14, 15, 16 In contrast to these abundant data on the positive association with stroke and renal damage, the association between AASI and microvascular brain damage is unknown.
In the present study we hypothesized that AASI is associated with microvascular brain damage. We investigated the association of AASI with MRI markers of cSVD in patients with a symptomatic small vessel (lacunar) stroke.
Methods
Patient Recruitment
For a lacunar stroke research project, we prospectively recruited patients who presented with a first‐ever lacunar stroke at Maastricht University Medical Centre, the Netherlands, from May 2003 to January 2008 and at Orbis Medical Centre Sittard, the Netherlands, from September 2004 to April 2007. This study was approved by the local ethics committee and informed consent was obtained from all patients. The current research question was formulated after data collection in the lacunar stroke project. Therefore, no power analysis was performed and we used the data of all patients who met the inclusion criteria for the present study. As described earlier, we defined lacunar stroke as an acute symptomatic lacunar stroke syndrome with a recent, small, deep infarct on MRI (basal ganglia, thalamus, internal capsule, or brain stem) compatible with the clinical findings.17 We used established criteria of specific clinical lacunar syndromes if no symptomatic MRI lesion was visible.18 As we aimed to study patients who most likely had their stroke from small vessel disease, patients with a potential cardioembolic source (mostly atrial fibrillation [AF], which was defined as AF on electrocardiography or history of AF) and patients with carotid artery stenosis >50% on carotid ultrasound, were excluded. Electrocardiography and carotid ultrasound were performed in all patients. We documented the following vascular risk factors: age, sex, history of hypertension, diabetes mellitus, current smoking, and hypercholesterolemia (total cholesterol level >5 mmol/L).19
Ambulatory BP Monitoring
Ambulatory BP was monitored noninvasively during a 24‐hour period (with Mobil‐O‐Graph equipment, IEM GbmH, Stolberg, Germany, using the appropriate cuff size) after the acute stroke phase, between 1 and 6 months post‐stroke (102±43 days). Measurements were obtained every 15 minutes during the day (7 am–11 pm) and every 30 minutes during the night (11 pm–7 am). Patients were encouraged to perform their normal daily activities but were instructed to keep their arm and hand motionless during the measurements. Patients continued their prescribed medications and the use of antihypertensive drugs was registered. Patients kept a record of their rising and retiring times. We determined day and night periods by excluding a 2‐hour transition period around the reported rising and retiring times. Measurement data were not edited manually. Valid recordings required a minimum of 70% valid measurements. For each patient we calculated 24‐hour systolic and diastolic BP and standard deviation (SD) of 24‐hour systolic and diastolic BP. AASI was defined as one minus the regression slope of diastolic BP on systolic BP values according to previously published reports.12 As some studies argue that standard AASI is strongly influenced by nocturnal dipping and correlation between systolic and diastolic BP, we also determined a so‐called “symmetric” AASI equivalent, calculated by 1–1/(systolic SD/diastolic SD) as proposed by Gavish and colleagues.20, 21
MRI Scoring
We acquired standard axial T2‐weighted fast‐spin echo images, axial fluid‐attenuated inversion recovery images (FLAIR), and T2‐weighted gradient echo images on a 1.5T or 3.0T MRI scanner within 6 months after stroke (41±42 days). All images were independently rated by two vascular neurologists for the presence of lacunes, white matter hyperintensities, CMBs, and perivascular spaces. In case of disagreement, a consensus meeting was held. The interobserver agreement for the presence of the different markers of cSVD, determined before the study, was substantial to excellent.22, 23 We defined lacunes as hyperintense lesions on T2‐weighted images with corresponding hypointense lesions with a hyperintense rim on FLAIR, located in the basal ganglia, thalamus, internal or external capsule, or brainstem with a diameter <20 mm and not compatible with clinical findings. Lacunes were scored as present if one or more were visible. The symptomatic lacunar infarct was not counted as a lacune. White matter hyperintensities were graded using the Fazekas score. They were scored present if (early) confluent deep white matter hyperintensities (Fazekas score 2 and 3) and/or irregular periventricular hyperintensities extending into the deep white matter (Fazekas score 3) were present. We used these Fazekas scores because they are histopathologically related to cerebral small vessel disease.24 CMBs were defined as rounded hypointense lesions on T2‐weighted gradient echo images with a diameter <10 mm. Symmetrical hypointensities in the globi pallidi likely to represent calcification, sulcal flow voids from cortical vessels, and hypointensities, possibly the result of partial volume artifacts from bone, were disregarded. CMBs were scored as present if one or more were present irrespective of location. We further distinguished deep CMB (basal ganglia, thalamus, and internal or external capsule) because evidence suggests that these are more specifically associated with (BP‐related) arteriosclerotic cSVD.17 Perivascular spaces were defined as round, oval, or linear lesions with a smooth margin, absence of mass effect, and with signal intensity equal to cerebrospinal fluid on T2‐weighted images and (if visible) hypointense on FLAIR images without a hyperintense rim to distinguish them from lacunes. For the present study we counted only perivascular spaces at the level of the basal ganglia, because at this level they seem specifically associated with cSVD.25 We counted perivascular spaces on the slide with the highest number in one hemisphere and graded them in a formerly used semiquantitative three‐category ordinal scale (0–10, 10–25, and >25).26 Perivascular spaces were scored as present in the case of category 2 or 3 (moderate to extensive).
Statistical Analyses
We divided our cohort into tertiles (low, medium, and high AASI) and explored differences in patient characteristics between tertiles using analysis of variance or chi‐square tests where appropriate. The association of AASI (both as a continuous variable and the lowest vs highest AASI tertile) and the presence of different MRI markers of cSVD was investigated using binary logistic regression analyses adjusting for age and sex. Additional analyses were performed adjusting for 24‐hour mean arterial pressure, vascular risk factors (diabetes, current smoking, history of hypertension, hypercholesterolemia), use of antihypertensive drugs, or the ratio of the number of day to night BP measurements separately. Adjustment for the ratio of day/night BP measurements was performed because this ratio is shown to influence AASI value.27 Similar regression analyses were performed using the “symmetric” AASI equivalent. Finally, we also investigated the associations of 24‐hour systolic and diastolic BP with the MRI markers.
Results
For the present study we recruited 143 patients. A total of 111 patients underwent scanning at 1.5T (78%) and the others at 3.0T MRI. Mean AASI was 0.50±0.14. Patient characteristics are presented in Table 1. Patients with high AASI were older and more often female (P<.01 for both variables).
Table 1.
Patient Characteristics
| Characteristics | All Patients (N=143) | Low AASI (n=47) | Medium AASI (n=48) | High AASI (n=48) |
|---|---|---|---|---|
| Age, y | 62.7±12.1 | 57.8±11.4a | 63.8±10.8a | 66.3±12.5a |
| Male sex | 87 (61) | 34 (72)a | 33 (69)a | 20 (42)a |
| Diabetes mellitus | 19 (13) | 5 (11) | 10 (21) | 4 (8) |
| Hypercholesterolemia | 112 (78) | 32 (68)b | 37 (77)b | 43 (90)b |
| Current smoking | 59 (41) | 24 (51) | 15 (31) | 20 (42) |
| History of hypertension | 93 (65) | 30 (64) | 34 (71) | 29 (60) |
| Use of antihypertensive drugs | 88 (62) | 25 (53) | 36 (75) | 27 (56) |
| 24‐hour MAP, mm Hg | 106.5±13.0 | 111.1±13.6a | 105.6±12.0a | 102.8±12.3a |
| 24‐hour systolic BP, mm Hg | 139.8±17.6 | 143.3±18.1 | 139.9±17.7 | 137.3±16.8 |
| 24‐hour diastolic BP, mm Hg | 83.5±12.1 | 89.5±12.6c | 82.4±10.0c | 78.8±11.1c |
| 24‐hour PP, mm Hg | 56.3±10.8 | 53.9±9.9 | 56.6±11.2 | 58.6±11.1 |
| AASI | 0.50±0.14 | 0.35±0.06 | 0.50±0.04 | 0.65±0.08 |
Abbreviations: AASI, ambulatory arterial stiffness index; BP, blood pressure; MAP, mean arterial pressure; PP, pulse pressure. Data are presented as mean (±standard deviation) or number (percentage). a P <.01, b P<.05, c P <.001 (between tertiles).
Table 2 presents the prevalence of the different MRI markers of cSVD and the association with AASI. Lacunes and perivascular spaces were most prevalent in 64% and 65% of patients, respectively. AASI (analyzed as a continuous variable) was positively associated with white matter hyperintensities in unadjusted analyses. This association lost significance after adjustment for age and sex. None of the other MRI markers of cSVD were associated with AASI. Additional adjustment for 24‐hour mean arterial BP, vascular risk factors, use of antihypertensive drugs, or the ratio of number of night‐to‐day BP readings did not change these results. Analysis of low vs high AASI tertiles provided similar results (not shown).
Table 2.
Prevalence of MRI Markers of cSVD and the Association With AASI
| All Patients (N=143) | Low AASI (n=47) | Medium AASI (n=48) | High AASI (n=48) | OR (95% CI) Per SD Increase of AASI | OR (95% CI) Per SD Increase of AASI Adjusted for Age and Sex | |
|---|---|---|---|---|---|---|
| Lacunes | 91 (64%) | 31 (66%) | 31 (65%) | 29 (60%) | 0.86 (0.60–1.23) | 0.76 (0.51–1.12) |
| WMH | 47 (33%) | 9 (19%) | 18 (38%) | 20 (42%) | 1.69 (1.15–2.50)a | 1.10 (0.86–2.06) |
| PVS | 93 (65%) | 24 (51%) | 33 (69%) | 36 (75%) | 1.41 (0.97–2.04) | 1.01 (0.65–1.59) |
| CMBb | 38 (31%) | 11 (27%) | 14 (34%) | 13 (32%) | 0.99 (0.66–1.48) | 0.85 (0.54–1.32) |
| Deep CMBb | 25 (20%) | 6 (15%) | 8 (20%) | 11 (27%) | 1.24 (0.78–1.97) | 1.13 (0.68–1.88) |
Abbreviations: AASI, ambulatory arterial stiffness index; CI, confidence interval; CMB, cerebral microbleeds; cSVD, cerebral small vessel disease; OR, odds ratio; PVS, perivascular spaces; SD, standard deviation; WMH, white matter hyperintensities. Results of logistic regression with AASI as a continuous variable. a P<.01. bGradient echo magnetic resonance imaging (MRI) was not available in 20 patients (n=123 in these analyses [n=41 per category]).
Analysis using the symmetric AASI equivalent gave similar results. Corrected for age and sex, we found no significant association between any of the MRI markers and symmetric AASI equivalent (see Table S1 for results). Additional adjustment for 24‐hour mean arterial BP, vascular risk factors, use of antihypertensive drugs, or ratio of number of night‐to‐day BP readings did not change these results.
Table 3 presents the associations of 24‐hour systolic and diastolic BP levels with the different MRI markers of cSVD. After correction for age and sex, 24‐hour systolic and diastolic BP levels were associated with lacunes, perivascular spaces, deep CMBs, and CMBs in any location. Additional adjustment for vascular risk factors or use of antihypertensive drugs did not change these results.
Table 3.
Associations of 24‐Hour BP and Markers of cSVD
| 24‐Hour SBP OR (95% CI) | 24‐Hour SBP OR (95% CI) Adjusted for Age and Sex | 24‐Hour DBP OR (95% CI) | 24‐Hour DBP OR (95% CI) Adjusted for Age and Sex | |
|---|---|---|---|---|
| Lacunes | 1.26 (1.02–1.54)a | 1.25 (1.02–1.54)a | 1.12 (0.97–1.30) | 1.19 (1.01–1.40)a |
| WMH | 0.91 (0.75–1.13) | 0.90 (0.72–1.14) | 0.91 (0.78–1.06) | 1.05 (0.88–1.25) |
| Perivascular spaces | 1.25 (1.01–1.54)a | 1.26 (1.01–1.58)a | 1.04 (0.90–1.20) | 1.25 (1.04–1.20)a |
| CMBb | 1.30 (1.02–1.63)a | 1.31 (1.03–1.66)a | 1.20 (1.01–1.42)a | 1.36 (1.10–1.67)c |
| Deep CMBb | 1.48 (1.12–1.93)b | 1.49 (1.13–1.98)b | 1.24 (1.02–1.51)a | 1.38 (1.10–1.74)b |
Abbreviations: BP, blood pressure; CI, confidence interval; CMB, cerebral microbleeds; cSVD, cerebral small vessel disease; PVS, perivascular spaces; SD, standard deviation; WMH, white matter hyperintensities. Odds ratios (ORs) are presented per 10‐mm Hg increase in systolic blood pressure (SBP) or 5 mm Hg in diastolic blood pressure (DBP). a P<.05. bGradient echo magnetic resonance imaging was not present in 20 patients (n=123 patients in these analyses). c P<.01.
Discussion
In the present study, we investigated the association of AASI and MRI markers of cSVD in 143 patients with first‐ever symptomatic lacunar stroke. We found no independent association of AASI with any of the studied MRI markers of cSVD. Using symmetric AASI, an AASI equivalent that was introduced to overcome some biases did not give other results.21 In contrast, 24‐hour systolic and diastolic BPs were associated with lacunes, perivascular spaces, deep CMBs, and CMBs in any location.
AASI was originally introduced as an easy‐to‐obtain surrogate marker of arterial stiffness derived from 24‐hour ambulatory BP monitoring.12 Studies using arterial pulse wave velocity as a measure of arterial stiffness found associations with lacunes, deep CMBs, and white matter hyperintensities.9, 10 It is thought that as a consequence of arterial stiffening, damaging forces of flow pulsations extend into cerebral small vessels.8 There are some studies reporting a positive association of AASI with renal damage indices, an organ with hemodynamic effects comparable to the brain (high‐flow, low‐resistance vascular beds).15, 28 Because of these observations, an association of AASI with cSVD was expected, which would provide an additional BP‐derived parameter that could be a prognostic and therapeutic target. The lack of association in our study could be explained by the fact that AASI is not a pure measure of arterial stiffness. Other factors such as heart rate, peripheral vascular resistance, diurnal BP cycle (nightly BP dipping), and BP variability also influence AASI.13, 29, 30 It is difficult to speculate, however, since the exact pathophysiological mechanism underlying AASI remains unclear. There are no other studies investigating the association of AASI with brain damage markers on MRI to compare with our results.
Patients with high AASI were more often female and were older in our study, which is in line with results of previous studies.15 This observation, along with the positive associations of elevated systolic and diastolic BP with microvascular brain damage on MRI, can be regarded as an internal control and validation for our study. Our finding that AASI is not related to “common” vascular risk factors for arterial stiffness such as male sex, diabetes, and smoking also suggests that AASI is not a straight measure for arterial stiffness, and this might also be why it is not associated with cerebral small vessel disease. Furthermore, the correlation between AASI and pulse pressure, an accepted “indirect” measure of arterial stiffness, was very low (Pearson's correlation coefficient 0.18) in our study, which also suggests that AASI does not measure arterial stiffness adequately.
Another possible explanation for the lack of association is that we performed a cross‐sectional study in patients with already symptomatic cSVD, ie, a clinical lacunar stroke. It might be that AASI is associated with development of microvascular brain damage in an earlier stage of the disease. Longitudinal studies and studies in other populations at risk for cSVD are needed.
AASI gained a lot of attention in recent years as a predictor of cardiovascular events, especially stroke.14 However, none of these studies subtyped stroke in large vessel and small vessel stroke phenotypes, so it is unknown whether this association is valid for all types of stroke or that it is mainly driven by large vessel stroke and does not apply to small vessel (lacunar) stroke. Future cardiovascular outcome studies should determine stroke subtype to investigate the role of AASI in the occurrence of different stroke subtypes.
Study Strengths and Limitations
The main strength of our study is that we investigated a cohort of patients with symptomatic cSVD with a high prevalence of MRI markers of cSVD, which makes it a suitable population to study the association of BP indices and markers of cSVD. Our study also has some limitations. First, it is a cross‐sectional study. Results of ABPM represent the actual BP level without accounting for BP level, course, and treatment in the past. Furthermore, ABPM was performed after the acute stroke phase, and therapy adjustments could have occurred that could have modified AASI. Second, we did not use diffusion‐weighted MRI to confirm a recent small subcortical infarct. However, because all patients had a distinct clinical lacunar stroke syndrome, we feel that this did not lead to unrightfully included patients. Third, not all patients underwent scanning at the same field strength, which potentially introduced bias into our results; however, we repeated our main analyses including only patients scanned at 1.5T (N=111; 78%) and found no substantial change in the results.
Conclusions
We observed no association between AASI and any of the markers of cSVD on brain MRI in lacunar stroke patients. Despite its significance in (micro)vascular‐related diseases in other organs, our study suggests that AASI has no added value over standard 24‐hour BP indices in cerebral small vessel disease. The results of this study should be replicated in other populations, such as healthy aging people or patients with vascular cognitive impairment. In addition, it would be interesting to investigate the association of AASI and renal and cerebral target organ damage in the same population to gain more insight into the similarities and differences between the respective organs.
Disclosures
The authors report no specific funding in relation to this research and have no conflicts of interest to disclose.
Supporting information
Table S1. Ambulatory arterial stiffness index is not associated with magnetic resonance imaging markers of cerebral small vessel disease in lacunar stroke patients.
Acknowledgments
None.
J Clin Hypertens (Greenwich). 2015;17:352–356. DOI: 10.1111/jch.12504. © 2015 Wiley Periodicals, Inc.
References
- 1. Pantoni L. Cerebral small vessel disease: from pathogenesis and clinical characteristics to therapeutic challenges. Lancet Neurol. 2010;9:689–701. [DOI] [PubMed] [Google Scholar]
- 2. Wardlaw JM, Smith EE, Biessels GJ, et al. Neuroimaging standards for research into small vessel disease and its contribution to ageing and neurodegeneration. Lancet Neurol. 2013;12:822–838. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3. Shlomai G, Grassi G, Grossman E, Mancia G. Assessment of target organ damage in the evaluation and follow‐up of hypertensive patients: where do we stand? J Clin Hypertens (Greenwich). 2013;15:742–747. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Vermeer SE, Longstreth WT Jr, Koudstaal PJ. Silent brain infarcts: a systematic review. Lancet Neurol. 2007;6:611–619. [DOI] [PubMed] [Google Scholar]
- 5. Maclullich AM, Wardlaw JM, Ferguson KJ, et al. Enlarged perivascular spaces are associated with cognitive function in healthy elderly men. J Neurol Neurosurg Psychiatry. 2004;75:1519–1523. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Charidimou A, Werring DJ. Cerebral microbleeds and cognition in cerebrovascular disease: an update. J Neurol Sci. 2012;322:50–55. [DOI] [PubMed] [Google Scholar]
- 7. de Leeuw FE, de Groot JC, Oudkerk M, et al. Hypertension and cerebral white matter lesions in a prospective cohort study. Brain. 2002;125(Pt 4):765–772. [DOI] [PubMed] [Google Scholar]
- 8. O'Rourke MF, Safar ME. Relationship between aortic stiffening and microvascular disease in brain and kidney: cause and logic of therapy. Hypertension. 2005;46:200–204. [DOI] [PubMed] [Google Scholar]
- 9. Henskens LH, Kroon AA, van Oostenbrugge RJ, et al. Increased aortic pulse wave velocity is associated with silent cerebral small‐vessel disease in hypertensive patients. Hypertension. 2008;52:1120–1126. [DOI] [PubMed] [Google Scholar]
- 10. Poels MM, Zaccai K, Verwoert GC, et al. Arterial stiffness and cerebral small vessel disease: the Rotterdam Scan Study. Stroke. 2012;43:2637–2642. [DOI] [PubMed] [Google Scholar]
- 11. Singer J, Trollor JN, Baune BT, et al. Arterial stiffness, the brain and cognition: a systematic review. Ageing Res Rev. 2014;15C:16–27. [DOI] [PubMed] [Google Scholar]
- 12. Dolan E, Li Y, Thijs L, et al. Ambulatory arterial stiffness index: rationale and methodology. Blood Press Monit. 2006;11:103–105. [DOI] [PubMed] [Google Scholar]
- 13. Kips JG, Vermeersch SJ, Reymond P, et al. Ambulatory arterial stiffness index does not accurately assess arterial stiffness. J Hypertens. 2012;30:574–580. [DOI] [PubMed] [Google Scholar]
- 14. Aznaouridis K, Vlachopoulos C, Protogerou A, Stefanadis C. Ambulatory systolic‐diastolic pressure regression index as a predictor of clinical events: a meta‐analysis of longitudinal studies. Stroke. 2012;43:733–739. [DOI] [PubMed] [Google Scholar]
- 15. Kollias A, Stergiou GS, Dolan E, O'Brien E. Ambulatory arterial stiffness index: a systematic review and meta‐analysis. Atherosclerosis. 2012;224:291–301. [DOI] [PubMed] [Google Scholar]
- 16. Wang C, Zhang J, Li CC, et al. The ambulatory arterial stiffness index and target‐organ damage in Chinese patients with chronic kidney disease. BMC Nephrol. 2013;14:257. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Staals J, van Oostenbrugge RJ, Knottnerus IL, et al. Brain microbleeds relate to higher ambulatory blood pressure levels in first‐ever lacunar stroke patients. Stroke. 2009;40:3264–3268. [DOI] [PubMed] [Google Scholar]
- 18. Bamford J, Sandercock P, Jones L, Warlow C. The natural history of lacunar infarction: the Oxfordshire Community Stroke Project. Stroke. 1987;18:545–551. [DOI] [PubMed] [Google Scholar]
- 19. Rouhl RP, Damoiseaux JG, Lodder J, et al. Vascular inflammation in cerebral small vessel disease. Neurobiol Aging. 2012;33:1800–1806. [DOI] [PubMed] [Google Scholar]
- 20. Gavish B, Ben‐Dov IZ, Bursztyn M. Linear relationship between systolic and diastolic blood pressure monitored over 24 h: assessment and correlates. J Hypertens. 2008;26:199–209. [DOI] [PubMed] [Google Scholar]
- 21. Gavish B, Ben‐Dov IZ, Kark JD, et al. The association of a simple blood pressure‐independent parameter derived from ambulatory blood pressure variability with short‐term mortality. Hypertens Res. 2009;32:488–495. [DOI] [PubMed] [Google Scholar]
- 22. Rouhl RP, van Oostenbrugge RJ, Knottnerus IL, et al. Virchow‐Robin spaces relate to cerebral small vessel disease severity. J Neurol. 2008;255:692–696. [DOI] [PubMed] [Google Scholar]
- 23. Henskens LH, van Oostenbrugge RJ, Kroon AA, et al. Brain microbleeds are associated with ambulatory blood pressure levels in a hypertensive population. Hypertension. 2008;51:62–68. [DOI] [PubMed] [Google Scholar]
- 24. Fazekas F, Kleinert R, Offenbacher H, et al. Pathologic correlates of incidental MRI white matter signal hyperintensities. Neurology. 1993;43:1683–1689. [DOI] [PubMed] [Google Scholar]
- 25. Doubal FN, MacLullich AM, Ferguson KJ, et al. Enlarged perivascular spaces on MRI are a feature of cerebral small vessel disease. Stroke. 2010;41:450–454. [DOI] [PubMed] [Google Scholar]
- 26. Klarenbeek P, van Oostenbrugge RJ, Lodder J, et al. Higher ambulatory blood pressure relates to enlarged Virchow‐Robin spaces in first‐ever lacunar stroke patients. J Neurol. 2013;260:115–121. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 27. Dechering DG, Adiyaman A, van der Steen M, Thien T. Interstudy variability in the ambulatory arterial stiffness index. Hypertension 2007;50:e65; author reply e66. [DOI] [PubMed] [Google Scholar]
- 28. Mogi M, Horiuchi M. Clinical interaction between brain and kidney in small vessel disease. Cardiol Res Pract. 2011;2011:306189. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 29. Laugesen E, Erlandsen M, Knudsen ST, et al. Ambulatory arterial stiffness index: a composite index reflecting arterial stiffness, blood pressure variability and patients' diurnal cycle. J Hypertens. 2011;29:2278–2279. [DOI] [PubMed] [Google Scholar]
- 30. Gomez‐Marcos MA, Recio‐Rodriguez JI, Patino‐Alonso MC, et al. Relationship between intima‐media thickness of the common carotid artery and arterial stiffness in subjects with and without type 2 diabetes: a case‐series report. Cardiovasc Diabetol. 2011;10:3. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
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Supplementary Materials
Table S1. Ambulatory arterial stiffness index is not associated with magnetic resonance imaging markers of cerebral small vessel disease in lacunar stroke patients.