Arterial Stiffness Using Cardio-Ankle Vascular Index Reflects Cerebral Small Vessel Disease in Healthy Young and Middle Aged Subjects

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1 178 Journal of Atherosclerosis and Thrombosis Vol. 20, No. 2 Original Article Arterial Stiffness Using Cardio-Ankle Vascular Index Reflects Cerebral Small Vessel Disease in Healthy Young and Middle Aged Subjects Su-Yeon Choi 1, Hyo Eun Park 1, Hyobin Seo 2, Minkyung Kim 1, Sang-Heon Cho 1 and Byung-Hee Oh 3 1 Department of Internal Medicine, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea 2 Department of Radiology, Seoul National University Hospital Healthcare System Gangnam Center, Seoul, Korea 3 Department of Internal Medicine, Seoul National University Hospital, Seoul, Korea Aim: The cardio-ankle vascular index (CAVI) reflects overall arterial stiffness from the aorta to the ankle, independent of blood pressure. Cerebral small vessel diseases (SVDs), including white matter lesions (WML), silent lacunar infarction (SLI) and cerebral microbleeds (CMB), are considered to increase the risk of stroke and cognitive impairment further. We aimed to investigate the association of cerebral SVD with CAVI in asymptomatic young and middle-aged subjects. Methods: Asymptomatic Korean individuals aged 30 to 59 years old without neurologic disease who had CAVI and brain magnetic resonance imaging (MRI) were evaluated retrospectively. Results: Among 484 subjects, cerebral SVDs (advanced WML, SLI and CMB) were found in 20 (4.1%). Subjects with SVDs tended to be older and to have higher systolic blood pressure (SBP) and higher CAVI. From multivariate regression analysis, including pulse pressure (PP) or SBP, CAVI showed a significant association with SVD [adjusted OR (95% CI): ( ), p =0.002 and ( ), p =0.043, for PP and SBP, respectively]. When CAVI was assessed by quartiles, the highest quartile of CAVI (CAVI >7.65) showed a significant association with SVD, after adjustment for PP [adjusted OR (95% CI): ( ), p=0.028]. Conclusion: In young and middle-aged subjects, cerebral SVD was significantly associated with arterial stiffness measured by CAVI after adjusting for PP or SBP. J Atheroscler Thromb, 2013; 20: Key words; Cardio-ankle vascular index, Arterial stiffness, Cerebral small-vessel disease Introduction Arterial stiffness, evaluated by various methods, such as pulse-wave velocity (PWV), augmentation index and beta-stiffness index has also been established as a marker of cardiovascular disease and a risk factor in the progression of atherosclerosis 1) ; however, the major hurdle in applying these methods in practice was the effect of blood pressure. Most of these parameters were affected by the blood pressure at the time of measurement. Address for correspondence: Byung-Hee Oh, Seoul National University College of Medicine, Seoul National University Hosptial, 101 Daehak-ro, Jongno-gu, Seoul , Korea ohbhmed@snu.ac.kr Received: May 31, 2012 Accepted for publication: August 20, 2012 Cardio-ankle vascular index (CAVI) 2) is an index that reflects the stiffness of whole arterial segments, including the aorta, femoral artery and tibial artery, and involves the measurement of PWV and blood pressure. Emerging data have shown the association of CAVI with coronary atherosclerosis 3, 4), cardiac function 5, 6), carotid atherosclerosis 7), stroke 8), cognitive function 9), hypertension 10), smoking 11) and kidney disease 12). Cerebral small vessel diseases (SVDs) include white matter lesions (WML), silent lacunar infarction (SLI) and cerebral microbleeds (CMBs) involving small arteries to arteriols. Cerebral SVDs develop before clinical manifestation of cerebrovascular disease and in close relation to traditional cardiovascular risk factors, and further increase the risk of stroke and cognitive impairment 13). Increased arterial stiffness and

2 CAVI and Cerebral Small Vessel Disease 179 cerebral SVDs are both subclinical phenomena and may share pro-atherogenic processes. Recent studies have suggested the relation of arterial stiffness with cerebral SVD or stroke; however, most of these studies were conducted in elderly populations 14, 15) or in patients with hypertension 16), or stroke 17). Arterial stiffness using CAVI has not been evaluated in association with cerebral SVD, especially in young and middle-aged healthy individuals. Aim To evaluate the potential role of CAVI as surrogate marker reflecting subclinical cerebral atherosclerosis, we aimed to investigate the association of cerebral SVD on magnetic resonance imaging (MRI) with arterial stiffness using CAVI in young and middleaged Korean individuals free of neurological disease. Methods Study Subjects The study population consisted of 485 retrospectively recruited asymptomatic Korean individuals without a history of stroke or transient ischemic attack who underwent general health examinations between March 2011 and July 2011 at Seoul National University Hospital Healthcare System Gangnam Center. All subjects were aged 30 to 59 years old and had undergone medical examinations and brain MRI for screening purposes at their own request. Patients with CAVI and MRI on the same day of the examination were included for analysis. The exclusion criteria of CAVI analysis included patients with previous peripheral artery disease or ankle-brachial index (ABI) <0.9, and those with clinically significant valvular heart disease or cardiomyopathy. One subject was excluded from analysis because of ABI <0.9; therefore, 484 subjects were enrolled in this study. The study protocol was approved by the Institutional Review Board of Seoul National University Hospital and was performed in accordance with the Declaration of Helsinki. Cardiovascular Risk Factors Baseline information on demographic and cardiovascular risk factors was collected during health examinations. Body weight, height, waist circumference and blood pressures were measured. All study subjects fasted for 12 hours or longer before the blood test. Total cholesterol, triglyceride (TG), high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, fasting blood sugar, glycated hemoglobin (HbA1C), serum creatinine, and high-sensitivity C-reactive protein (hscrp) were measured. Past medical histories and current medications such as hypertension, diabetes mellitus and hypercholesterolemia were derived from medical questionnaires. Based on two separate measurements, hypertension was defined as systolic blood pressure (SBP) 140 mmhg or diastolic blood pressure (DBP) 90 mmhg without medication or use of antihypertensive medications. Diabetes mellitus was defined as fasting blood glucose 126 mg/dl, HbA1c 6.5% or use of medication for diabetes. Hypercholesterolemia was defined as total cholesterol 240 mg/dl or LDL cholesterol 160 mg/dl and/or use of lipid-lowering medication Measurement of CAVI CAVI was measured with a VaSera VS-1000 (Fukuda Denshi Co. Ltd, Tokyo, Japan) by the methods described previously 18, 19). After a 5-min rest and with the subject seated, brachial pulse pressure was measured using an automatic cuff oscillometric device, and the average of two readings was used to determine SBP, DBP and pulse pressure (PP). Cuffs were applied to four extremities at both upper arms and ankles, with the subjects lying supine. The measurement was performed after resting for 10 minutes. A phonocardiogram was placed at the right sternum border in the second intercostal space and electrocardiogram leads were attached to both wrists. Pulse wave velocity was calculated by dividing vascular length (L) by the time (T) taken for the pulse wave to propagate from the aortic valve to the ankle. Since the starting time of the blood stream from the aortic valve is difficult to identify from the valve s opening sound, T is difficult to obtain, and thus, T is calculated by summing the time between the rise of brachial pulse wave and the rise of ankle pulse wave and the time between the aortic valve s closing sound and the notch of brachial pulse wave. CAVI was determined using the following equation; CAVI=a [(2ρ/ΔP) ln (Ps/Pd) PWV 2 ]+b Where Ps and Pd are SBP and DBP, respectively, ΔP is Ps-Pd, ρ is blood density, and a and b are constants. The average value of right and left CAVI was used for analysis. Brain MRI and Cerebral SVDs MRI was performed using two 1.5 T MRI systems (Achieva; Philips Medical Systems, Eindhoven, Netherlands and Magnetom Espree; Siemens, Erlangen, Germany). The standardized MRI protocol included axial T2-weighted and T1-weighted spin

3 180 Choi et al. A B C Fig.1. Representative figure of cerebral small vessel disease including advanced white matter lesion (A), silent lacunar infarction (B) and cerebral microbleed (C). Association between CAVI and SVD The demographic and clinical characteristics of participants with versus without cerebral SVD are shown in Table 1. Briefly, subjects with SVD tended to be older and to have higher SBP and higher CAVI. The prevalence of hypertension and the highest quartile of CAVI (CAVI Q4) were higher in subjects with SVD. We evaluated the distribution of SVD according to quartiles of CAVI. As shown in Fig. 2, SVD was more common in subjects with CAVI Q4 (CAVI >7.65) when compared to other quartiles (p=0.019). When analyses were computed by including CAVI as a continuous variable, CAVI was significantly assoecho, fluid-attenuated inversion recovery (FLAIR) and T2 * -weighted gradient echo (GRE) sequences. The imaging protocol consisted of T2-weighted spin-echo (repetition time/echo time [TR/TE] =800/96 ms), T1-weighted spin-echo (TR/TE=520/14 ms), and FLAIR (TR/TE=8500/96 ms; inversion time=2100 ms) imaging. Images were obtained as 27 transaxial slices per scan. Slice thickness was 5 mm without an interslice gap. WML were classified as absent or present as punctuate, early confluent, or confluent lesions based on FLAIR image evaluations 20, 21), and early confluent or confluent lesions were defined as advanced WML. SLI were defined as focal lesions measuring 3-15 mm in diameter with signal intensities corresponding to alcohol, and surrounded by a hyperintense gliotic rim on FLAIR images 22). CMBs were defined as homogeneous, round signal loss lesions with diameter up to 5 mm on GRE images 23) (Fig. 1). An experienced neuroradiologist (H.S.) and a trained physician (S.-Y.C) assessed all brain MRI scans for the presence of cerebral WML, SLI and CMB independently, blinded to the participants clinical data. Disagreements were settled by discussion with a third reviewer (H.E.P.). Statistical Analysis Data are expressed as the mean±standard deviation and as frequencies and percentages of categorical variables. For continuous variables, t -test and analysis of variance (ANOVA) were used for comparison, depending on the number of groups to be assessed. For highly skewed TG and hscrp, the nonparametric Mann-Whitney U test was used. Categorical variables were compared using chi-square analysis. Logistic regression analysis was applied to estimate the odds ratios (ORs) and 95% confidence intervals (CIs) of cerebral SVD. All statistical analyses were performed with the statistical software package (SPSS 19.0; SPSS Inc., Chicago, IL) and p<0.05 was considered significant. Results Baseline Characteristics Among 484 participants, 312 (64.5%) were male, 118 (24.4%) had hypertension, 62 (12.8%) had diabetes mellitus and 146 (30.2%) had hypercholesterolemia. Mean SBP, DBP and PP were 115, 77, and 38 mmhg, respectively. The mean CAVI was 7.3. The cut-off values of quartiles (Q) of CAVI were 6.80, 7.25, and In the 484 young and middle-aged subjects, 20 (4.1%) had cerebral SVDs, and the prevalence of advanced WML, SLI, and CMB was 0.4%, 1.9%, and 1.9 %, respectively.

4 CAVI and Cerebral Small Vessel Disease 181 Table 1. Baseline characteristics Parameters Total (n =484) SVD Present (n =20) Absent (n =464) p Age, years (range years) Age group, n (%) years years years Male, n (%) Hypertension, n (%) Diabetes mellitus, n (%) Hypercholesterolemia, n (%) Current smoker, n (%) Antihypertensive medication, n (%) Diabetes mellitus medication, n (%) Lipid-lowering medication, n (%) Body mass index, kg/m 2 Waist circumference, cm SBP, mmhg DBP, mmhg PP, mmhg Fasting blood glucose, mg/dl HbA1C, % Total cholesterol, mg/dl Triglyceride, mg/dl HDL cholesterol, mg/dl LDL cholesterol, mg/dl Creatinine, mg/dl hscrp, mg/dl CAVI, mean CAVI Q4 >7.65, n (%) 50±7 42 (8.7) 153 (31.6) 289 (59.7) 312 (64.5) 118 (24.4) 62 (12.8) 146 (30.2) 94 (20.9) 103 (23.4) 41 (9.4) 69 (15.8) 24.2± ± ±12 77±10 38±8 101±22 5.7± ±37 128±91 51±11 129± ± ± ± (23.3) 54±5 1 (5.0) 3 (15.0) 16 (80.0) 11 (55.0) 14 (70.0) 4 (20.0) 6 (30.0) 5 (26.3) 12 (60.0) 4 (22.2) 5 (27.8) 24.5± ± ±14 81±11 40±7 107±26 5.9± ±30 148±111 51±12 116± ± ± ±0.8 9 (45.0) 50±7 41 (8.8) 150 (32.3) 273 (58.8) 301 (64.9) 104 (22.5) 59 (12.5) 140 (30.2) 89 (20.7) 91 (21.6) 37 (8.9) 64 (15.2) 24.2± ± ±12 77±10 38±8 101±22 5.7± ±37 127±90 51±11 129± ± ± ± (22.4) < < Values are presented as the mean±standard deviations or numbers (%). CAVI: cardio-ankle vascular index, CMB: cerebral microbleed, DBP: diastolic blood pressure, HbA1C: glycated hemoglobin, HDL: high-density lipoprotein, hscrp: high-sensitivity C-reactive protein, LDL: low-density lipoprotein, PP: pulse pressure, SBP: systolic blood pressure, SLI: silent lacunar infarction, SVD: cerebral small vessel disease, Q4: fourth quartile, WML: white matter lesion. 9 8 * 7 6 Percent (%) CAVI Q1,2, and 3 CAVI Q4 CMB SLI advanced WML Fig.2. Distribution of cerebral small vessel disease including white matter lesion, silent lacunar infarction and cerebral microbleeds according to quartiles of CAVI ( * ; p=0.019). CAVI: cardio-ankle vascular index, CMB: cerebral microbleed, SLI: silent lacunar infarction, SVD: cerebral small vessel disease, Q: quartile of CAVI, WML: white matter lesion.

5 182 Choi et al. Table 2. Logistic regression analysis of the relation between increased CAVI and cerebral small vessel disease CAVI CAVI Q ( ) ( ) Univariate analysis Adjusted for PP Adjusted for SBP OR (95% CI) p OR (95% CI) p OR (95% CI) p ( ) ( ) ( ) ( ) OR: odds ratio, CAVI: cardio-ankle vascular index, CAVI Q4: fourth quartile of CAVI, CAVI >7.65, CI: confidence interval, SBP: systolic blood pressure, PP: pulse pressure. per one point increase, for the comparison with Q1, 2, and ciated with cerebral SVD after adjustment with PP or SBP [adjusted OR (95% CI): ( ), p=0.002 and ( ), p=0.043, respectively] (Table 2). As shown in Table 2, CAVI Q4 (>7.65) was also significantly associated with SVD. After adjustment for PP, CAVI Q4 was still an independent predictor of asymptomatic SVDs [adjusted OR (95% CI): ( ) p = 0.028]. Subgroup Analysis with/without Hypertension We performed subgroup analysis with versus without hypertension and SVD. CAVI was lower in normotensive subjects without SVD. CAVI showed a step-wise increment in hypertensive subjects without SVD, in normotensive subjects with SVD, and in hypertensive subjects with SVD (p =0.001) (Fig. 3). ROC Curve for Predicting the Presence of the Cerebral SVD ROC curve analysis demonstrated a significant association between CAVI and cerebral SVD by brain MRI. Cut-off of CAVI to predict the presence of SVD detected by brain MRI was 7.38, with sensitivity of 65% and specificity of 61%, and the area-under curve (AUC) was (95% CI , p=0.029). Moreover, additional inclusion of CAVI improved the predictive power for predicting the presence of cerebral SVD in the models based on clinical variables. Specifically, the AUC for CAVI in addition to age and PP or age and SBP increased from (95% CI , p=0.002) to 0.731(95% CI , p<0.001), and the AUC for CAVI in addition to age and SBP increased from (95% CI , p =0.001) to (95% CI , p<0.001), respectively (Supplemental Fig. 1). Discussion In our study, arterial stiffness measured by CAVI reflected cerebral SVD in asymptomatic young and CAVI HTN (-) SVD (-) HTN (+) SVD (-) HTN (-) SVD (+) P for trend = HTN (+) SVD (+) Fig.3. CAVI score by clinical characteristics according to presence versus absence of hypertension and cerebral small vessel disease. CAVI: cardio-ankle vascular index, HTN: hypertension, SVD: cerebral small vessel disease. middle-aged subjects. CAVI may provide additional information in predicting subclinical cerebral atherosclerosis. CAVI as an Index of Arterial Stiffness and Atherosclerosis Recently, considerable emphasis has been placed on the contribution of arterial stiffness to the development of atherosclerosis and consequently, the risk of cardiovascular disease 1). CAVI is a novel arterial stiffness parameter which is superior to previously established parameters 2). Carotid-femoral PWV is the gold standard for arterial stiffness, but has a similar limitation, which is the effect of blood pressure during the measurement 1). CAVI is easy to measure 18), is highly reproducible 24), and above all, is not influenced by blood pressure at the time of examination. CAVI has been demonstrated as a superior index of arterial stiffness to brachial-ankle PWV (bapwv) because CAVI reflects the stiffness of whole arterial segments, including the aorta, femoral artery and tibial artery 2). CAVI,

6 CAVI and Cerebral Small Vessel Disease 183 A B Supplemental Fig.1. Comparison of the area under curves for CAVI in addition to age and pulse pressure or age and systolic blood pressure. The AUC for predicting the presence of cerebral SVD (A) increased from to for CAVI quartiles in addition to age and PP. The AUC for predicting the presence of cerebral SVD (B) increased from to for CAVI quartiles in addition to age and SBP. CAVI: cardio-ankle vascular index. SBP: systolic blood pressure, PP: pulse pressure. not bapwv, was significantly higher in the group with angina pectoris than in the normal group 25), and Horinaka et al. also reported that CAVI may be superior to bapwv for discerning the presence of coronary artery disease 26). CAVI has consistently shown good correlation with known cardiovascular risk factors and atherosclerotic diseases, such as coronary artery disease 3, 4, 27) and cerebrovascular disease 8, 14). Furthermore, the usefulness of CAVI was evaluated in different population subsets, including hypertensive 7), diabetic 4), and dialysis patients 28). Association Arterial Stiffness and Cerebral SVD In this study, even among asymptomatic young and middle-aged subjects, 4.1% of participants had silent cerebral SVDs. CAVI, an index of arterial stiffness and atherosclerosis, has shown an association with cerebral SVD. In particular, CAVI Q4 (CAVI >7.65) was independently related with cerebral SVD adjusted for PP. Recent studies have suggested the relation of arterial stiffness with cerebral SVD. Some studies have reported that aortic PWV is associated with cerebral WML and SLI in hypertensive patients 16), and that bapwv is higher in CMB patients with stroke 17), and CAVI is greater in patients with WML and small vessel occlusion in patients with stroke 8), and silent brain infarction is associated with arterial stiffness measured by CAVI in the elderly (mean age, 69 years) 14), and increased arterial stiffness with bapwv is associated with WML in elderly subjects (mean age, 70 years) 15) ; however, most of the subjects were elderly and had diseases such as hypertension or stroke. There is a paucity of study assessing the correlation between CAVI and subclinical cerebral atherosclerosis such as SVD in asymptomatic young and middle-aged subjects. Our data showed, for the first time, the significant association of CAVI with cerebral SVD in an asymptomatic young and middle-aged Korean population. Our results showed that in contrast to CAVI, PP was not significantly different among subjects with versus without SVD. Peripheral PP is an indirect measurement of arterial stiffness. Furthermore, according to the amplification phenomenon, the amplitude of the pressure wave is higher in peripheral arteries than in central arteries, and brachial PP overestimates central PP, especially in young subjects who have less stiff arteries 29). Thus, aortic PWV, not bapwv or CAVI, which include the stiffness of the aorta, better reflects central arterial stiffening. O Rourke et al. hypothesized that torrential flow

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J Atheroscler Thromb, 2009; 16: ) Gallego J, Martinez-Vila E: Asymptomatic cerebrovascuand low resistance to flow in the brain exposes small arterial vessels to high-pressure fluctuations that exist in the carotid and vertebral arteries, and cerebral microvascular disease results from the damaging forces of abnormal flow pulsations extending into small cerebral arteries as a consequence of arterial stiffening 30). Despite the different radiological phenomena in cerebral SVDs, such as WML, SLI, and CMB, risk factors and genetic factors aggravate the accumulation of vascular wall pathology and loss of smooth muscle cells with luminal narrowing and ultimately lead to blood brain barrier damage and microscopic vascular rupture, thus causing cerebral SVD 31). Although brain MRI seems to be the most validated test of subclinical cerebral atherosclerosis and stroke among non-invasive imaging modalities, especially considering repetitive evaluation, cost-effectiveness is the major hurdle for MRI-based screening. As shown in this study, CAVI may serve as a surrogate marker for subclinical cerebral atherosclerosis, in asymptomatic middle-aged subjects; however, this study had some limitations because of its cross-sectional design, retrospective nature, and limited sample size. Furthermore, healthy volunteer effects in one center may limit generalizations based on our results. In the current study, the association of CAVI with a specific type of SVD was not evaluated due to the limited small sample size. Further studies are needed to analyze clinical outcome data according to CAVI and the cost-effectiveness of CAVI. Because long-term prognosis of the presence of SVD in asymptomatic individuals is not yet clear, studies are warranted to properly address the clinical application of CAVI to detect cerebral SVD. Conclusions In young and middle-aged subjects, cerebral SVD was significantly associated with arterial stiffness measured by CAVI after adjusting for PP or SBP. This may suggest the usefulness of CAVI as a screening tool for predicting subclinical cerebral atherosclerosis even in asymptomatic young and middle-aged populations. Acknowledgement We thank Suk-Ju Jung for measurements, and acquiring and handling of raw data. None. Disclosures

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