The Role of a Novel Arterial Stiffness Parameter, Cardio-Ankle Vascular Index (CAVI), as a Surrogate Marker for Cardiovascular Diseases

Review 155 The Role of a Novel Arterial Stiffness Parameter, Cardio-Ankle Vascular Index (CAVI), as a Surrogate Marker for Cardiovascular Diseases Atsuhito Saiki, Yuta Sato, Rena Watanabe, Yasuhiro Watanabe, Haruki Imamura, Takashi Yamaguchi, Noriko Ban, Hidetoshi Kawana, Ayako Nagumo, Daiji Nagayama, Masahiro Ohira, Kei Endo and Ichiro Tatsuno Center of Diabetes, Endocrine and Metabolism, Toho University Sakura Medical Center, Chiba, Japan Measurement of arterial stiffness in routine medical practice is important to assess the progression of arteriosclerosis. So far, many parameters have been proposed to quantitatively represent arterial stiffness. Among these, pulse wave velocity (PWV) has been most frequently applied to clinical medicine because those could be measured simply and non-invasively. PWV had established the usefulness of measuring arterial wall stiffness. However, PWV essentially depends on blood pressure at the time of measurement. Therefore, PWV is not appropriate as a parameter for the evaluation of arterial stiffness, particularly for the studies involving blood pressure changes. On the other hand, stiffness parameter is an index reflecting arterial stiffness without the influence of blood pressure. Recently, this parameter has been applied to develop a new arterial stiffness index called cardio-ankle vascular index (CAVI). Therefore, CAVI does not depend on blood pressure changes during the measurements; CAVI could represent the stiffness of the arterial tree from the origin of the aorta to the ankle. Many clinical studies obtained from CAVI are being accumulated. CAVI showed high value in arteriosclerotic diseases, such as coronary artery diseases, cerebral infarction, and chronic kidney diseases, and also in majority of people with various coronary risk factors. The improvement of those risk factors decreased CAVI. Furthermore, the role of CAVI as a predictor of cardio-vascular events was reported recently. We review the clinical studies on CAVI and discuss the clinical usefulness of CAVI as a candidate surrogate end-point marker for cardiovascular disease. J Atheroscler Thromb, 2016; 23: 155-168. Key words: Cardio-ankle vascular index, Arterial stiffness, Stiffness parameter, Coronary artery disease, Surrogate marker Introduction Arteriosclerosis is difficult to diagnose in routine medical practice. Arterial wall stiffness is one of the Address for correspondence: Atsuhito Saiki, Center of Diabetes, Endocrine and Metabolism, Toho University Sakura Medical Center 564-1, Shimoshizu, Sakura-City, Chiba, 285-8741, Japan E-mail: atsuhito156@sakura.med.toho-u.ac.jp Received: September 30, 2015 Accepted for publication: October 27, 2015 properties accompanying the progression of arteriosclerosis. Then, many parameters have been proposed to quantitatively represent arterial stiffness 1, 2). Among these, pulse wave velocity (PWV) 3) has been most frequently applied to clinical medicine because those could be measured simply and non-invasively. Many studies using carotid-femoral PWV (cfpwv) 4) and brachial-ankle PWV (bapwv) 5) had almost established the meaning of measuring arterial wall stiffness. However, PWV essentially depends on the blood pressure at the time of measurement 6). Therefore, PWV is

156 Fig.1. Equation of CAVI and its measuring method PWV from the heart to the ankle is obtained by measuring the length from the origin of the aorta to the ankle and by calculating T t bt ba. Blood pressure is measured at the brachial artery. Pssystolic blood pressure; Pd diastolic blood pressure; Ppulse pressure, Ps Pd; blood density; L length from the origin of the aorta to the ankle; T time taken for the pulse wave to propagate from the aortic valve to the ankle; t batime between the rise of brachial pulse wave and the rise of ankle pulse wave; t b time between aortic valve closing sound and the notch of brachial pulse wave; t btime between aortic valve opening sound and the rise of brachial pulse wave 10). not appropriate as a parameter for the evaluation of arterial stiffness, particularly for the studies involving blood pressure changes. In order to solve the problem of dependency on blood pressure, cardio-ankle vascular index (CAVI) has been developed in Japan 7). CAVI originated from the theory of stiffness parameter 8, 9), which is applied to the local part of the artery expressed as logarithm pressure required for some elongation of the arterial diameter. Stiffness parameter is independent of blood pressure changes during a measuring time. In case of CAVI, the elongation of the arterial diameter was obtained from Brammwell-Hill equation, in which the elongation of the arterial diameter by pressure was related to the square of pulse wave velocity 7, 10). Then, CAVI could represent the stiffness of the arterial tree from the origin of the aorta to the ankle. In many clinical studies, CAVI showed high value in arteriosclerotic diseases, such as coronary artery diseases (CADs), cerebral infarction, and chronic kidney diseases, and in majority of people with various coronary risk factors. Furthermore, the improvement in most of those risk factors decreased CAVI. The role of CAVI as a predictor of cardio-vascular events was reported recently. In this study, we review the clinical studies on CAVI and discuss the clinical usefulness of CAVI as a candidate surrogate end-point marker for cardiovascular disease. The Principle of CAVI and Measuring Method CAVI was originally derived from the stiffness parameter proposed by Hayashi 8) and Kawasaki 9) and was expanded to some length of the artery with the application of the modified Bramwell-Hill equation 7, 10). CAVI adopted PWV from the origin of the aorta to the ankle (heart-ankle PWV; hapwv). CAVI = a[(2/p)ln(ps/pd)hapwv2]b ----- Equation 1 (Fig. 1) Ps is the systolic blood pressure, Pd is the diastolic blood pressure, hapwv is PWV from the origin of the aorta to the tibial artery at the ankle through the femoral artery, is the blood density, and a and b

157 are constants to convert the values of CAVI to those of Hasegawa s heart-femoral PWV (hfpwv) 11, 12). Equation 1 indicates that CAVI can be obtained by measuring blood pressure and hapwv. The blood pressures used in the Equation 1 should be the mean blood pressure from the origin of the aorta to the tibial artery at the ankle. In case of CAVI, the blood pressure in the upper brachial artery was adopted. This is based on the assumption that the blood pressure in the brachial artery may be representative of the mean blood pressure in the artery of the origin of the aorta to the ankle 13). As CAVI is essentially derived from the stiffness parameter, CAVI values have good correlations with the values ultrasonically measured from the local segments of the descending thoracic aorta 14). Similar results were also obtained from the common carotid artery. In both arteries, the correlation coefficients between CAVI and were 0.67 and 0.39, respectively, both with the confidence coefficients of 0.01. Horinaka et al. 15) also reported that regional values of stiffness parameter of the ascending and descending aorta were both significantly correlated with the CAVI values (Fig. 2). Therefore, application of theory to some length of the artery, which reflects the segmental arterial stiffness, is considered to be reasonable. Shirai et al. 16) experimentally showed that CAVI values were not affected by blood pressure when blood pressure was reduced with the administration of 1-blocker, metoprolol (Fig. 3a). It is well known that 1-blocker decreases blood pressure by the reduction of heart muscle contraction, and therefore, arterial stiffness measured as CAVI does not change although blood pressure changes. This result suggests the CAVI is independent of blood pressure variations at the measuring time. When 1-blocker, doxazosin, was administered, CAVI decreased as blood pressure decreased (Fig. 3b). CAVI is apparently dependent on blood pressure. However, in this case, 1-blocker reduces blood pressure by the reduction of vascular smooth muscle contraction. This reduction of vascular smooth muscle contraction was supposed to induce a decrease in CAVI. This result suggests that CAVI reflects the arterial stiffness composed of vascular smooth muscle contraction and the organic stiffness due to collagen, elastin, and calcification as the main components of arteriosclerosis. The utility of CAVI in clinical medicine is now under investigation by many researchers in the world. The number of published papers on CAVI is increasing year by year and has reached 300 in September 2015. Fig.2. Correlation between CAVI and stiffness parameter in the thoracic aorta 15). Factors Affecting CAVI Because measuring conditions, room temperature, food intake, smoking, and rigorous exercise affected CAVI value, it is recommended that room temperature should be keep at 24-26 during the measurement of CAVI. Moreover, rigorous exercise, smoking, and diet should be avoided 3-4 h prior to the measurement. CAVI is invalid when ankle brachial index (ABI), which is the ratio of mean blood pressure in the tibial artery to that in the brachial artery, is 0.9. 1. Aging and Gender CAVI of healthy people without cardiovascular risk factors gradually increases with age from 20 to 70 years 17) (Fig. 4). CAVI values in men are higher than those in women at all ages by 0.2 in average. Choi et al. 18) reported that CAVI is a sensitive marker of the arterial aging process, above and beyond conventional arm blood pressure in Korean people (CAVI 5.0 0.048age in men, 4.80.045age in women). 2. Arteriosclerotic Diseases (a) CAD As for CAD, CAVI increases as the number of coronary vessels with stenosis increases, as shown in Fig. 5 19). Nakamura et al. 20) reported that the cutoff point of CAVI for the presence of coronary stenosis was 8.91 among the patients with a suspicion of ischemic CAD. Izuhara et al. 21) reported the multiple logistic analysis revealing that CAVI, but not bapwv,

158 MeanSE *P<0.05 **P<0.01vsBaseline Fig.3. Effects of blood pressure on CAVI values in healthy individuals administered (a) 1 blocker and (b) 1 blocker 16). Fig.4. Effects of age on CAVI CAVI was measured in Japanese workers and their families. CAVI increased with age, and the values of CAVI were higher in men than in women at any age. CAVI 0.5 by 10 years; men women by 0.2 (difference of 5 years) 17). was associated with the presence of carotid and coronary arteriosclerosis. Several researchers reported that CAVI was high in patients with CAD 20, 22, 23). Yingchoncharoen et al. 24) reported that the traditional risk score (RAMA-EGAT) has been shown to be an accurate scoring system for predicting CAD. In this study, adding CAVI to the RAMA-EGAT score improved the prediction of CAD incidence, increasing

159 Fig. 5. Comparison between CAVI and bapwv for the number of coronary artery stenosis 19) Figure 6a Figure 6b Fig.6. The study of CAVI and RAMA-EGAT score (a) Comparison of receiver operating characteristic (ROC) curve of modified RAMA-EGAT score (EGATCAVI) and traditional RAMA- EGAT score (EGAT score). (b) CAVI provides additional diagnostic value at all levels of the RAMA-EGAT score 24). C-statistics from 0.72 to 0.85 and resulting in a net reclassification improvement (NRI) of 27.7% (p 0.0001) (Fig. 6). Park et al. 25) reported that the addition of CAVI 8 to traditional risk factors improved the predictive value of coronary stenosis. Park et al. 26) reported that CAVI was related to coronary artery calcification or stenosis in asymptomatic subjects in Korea. These results suggested that CAVI is well correlated with the progression of coronary arteriosclerosis. (b) Cerebral Infarction CAVI values are high in patients with cerebral infarction 27). Choi et al. 28) reported that CAVI reflects cerebral small-vessel diseases in healthy young and middle-aged individuals. On the other hand, cerebral atherosclerosis associated with cognitive impairment in old age is controversial. Otsuka et al. 29) reported that a high CAVI value in community-dwelling elderly people was a greater risk of cognitive impairment.

160 (c) Chronic Kidney Diseases and Maintenance Hemodialysis Several studies about chronic kidney diseases described that CAVI correlated with estimated glomerular filtration rate and cystatine C 30) and that CAVI is high in patients undergoing hemodialysis therapy 30, 31). (d) Carotid Arteriosclerosis There are several studies reporting the relationship between CAVI and carotid arteriosclerosis observed using ultrasonography 19, 21, 22, 32, 33). In summary, the abovementioned results indicated that CAVI could be a good maker of the progression of arteriosclerosis. 3.Coronary Risk Factors (a) Hypertension CAVI is essentially independent of blood pressure at the measuring time. However, arterial stiffness is influenced by the chronic exposure of arterial wall to increased blood pressure. Then, there are many reports that CAVI showed high values in hypertension 31, 32, 34, 35). Most of those reports showed that the correlation coefficients between CAVI and blood pressure were lower than those between PWV and blood pressure 7, 31, 36). In hemodialysis patients, CAVI was correlated weakly with systolic and diastolic blood pressures (r0.175, 0.006), whereas bapwv was correlated significantly with systolic and diastolic blood pressures (r0.463, 0.335) 7). (b) Diabetes Mellitus CAVI is reported to be high in patients with diabetes mellitus 37, 38). Kim et al. 39) reported that diabetic peripheral neuropathy was associated with increased CAVI without changes in carotid IMT in type 2 diabetes. Kim et al. 40) found that increased CAVI in type 2 diabetes was associated with the presence of arterial plaque, increased IMT, and microvascular complication. Furthermore, Tsuboi et al. 41) reported that the 1-h postprandial glucose levels are associated with increased CAVI values in non-diabetic subjects. (c) Dyslipidemia Soska et al. 42) showed that CAVI was not high in heterozygous familiar hypercholesterolemic patients. On the other hand, some reports showed that CAVI is related to low-density lipoprotein (LDL) cholesterol level and also to the cholesterol / high-density lipoprotein (HDL) cholesterol ratio 43). CAVI may increase when complicated lesions occur. (d) Obesity and metabolic syndrome In the studies dealing with healthy people, CAVI is negatively related with body mass index 43). However, Park et al. 44) reported that visceral fat, especially epicardial fat, showed positive association with CAVI, but not subcutaneous fat. These results suggested that CAVI could differentiate between the visceral and subcutaneous obesity. Satoh et al. 43) reported that CAVI is high in metabolic syndrome in which visceral fat is thought to be the main cause of risk factors, such as hypertension, glucose intolerance, and hypertriglyceridemia. (e) Uric Acid Uric acid as a risk factor for arteriosclerosis is controversial because uric acid is known to have both antioxidant 45) and pro-oxidative action in the process of production 46). Recently, Nagayama et al. 47) reported that CAVI increased progressively with increasing serum uric acid tertile after adjusting for age, BMI, and systolic blood pressure in multiple regression analysis. Li et al. 48) also documented that uric acid increased arterial stiffness measured by CAVI. (f) Smoking The harmful effects of smoking are not only respiratory and digestive systems but also cardiovascular organs. CAVI is high in people who smoke 49). (g) Sleep Apnea Syndrome Sleep apnea syndrome is one of the important risk factors of atherosclerosis. CAVI is also high in the patients with sleep apnea syndrome 50). (h) Mental Stress Shimizu et al. 51) reported that people who experienced a severe earthquake had hardened arterial stiffness, indicating that mental stress also increases CAVI. These results indicated that CAVI is correlated with the severities of most of the coronary risk factors (Table 1). These results also suggested that the socalled coronary risk factors were working to stiffen the arterial tree composing the aorta, femoral artery, and tibial artery. The Role of CAVI as a Predictor of Cardiovascular Events Several studies dealing with the relationship between mortality or morbidity and CAVI are being accumulated (Table 2). Kubota et al. 52) reported that the group with CAVI 10 showed a high incidence

161 Table 1. CAVI in the patients with arteriosclerotic diseases and coronary risks Arteriosclerotic diseases and coronary risks CAVI value References Aging, male Arteriosclerotic diseases Coronary artery disease Cerebral infarction Chronic kidney disease, hemodialysis Coronary risks Hypertension Diabetes mellitus Dyslipidemia Metabolic syndrome Uric acid Namekata T. BMC Cardiovasc Disord 2011 17) Choi SY. J Atheroscler Thromb 2013 18) Nakamura K. J Atheroscler Thromb 2009 20) Izuhara M. Circ J 2008 21) Miyoshi T. J Atheroscler Thromb 2010 22) Horinaka S. Angiology 2009 19) Sairaku A. Hypertens Res 2010 23) Yingchoncharoen T. Heart Asia 2012 24) Park HE. J Cardiol 2012 25) Park JB. J Atheroscler Thromb 2013 26) Suzuki J. J Stroke Cerebrovasc Dis 2011 27) Choi S-Y. J Atheroscler Thromb 2013 28) Yamamoto N. Dement Geriatr Cogn Disord 2009 29) Kubozono T. J Atheroscler Thromb 2009 30) Ueyama K. Hypertens Res 2009 31) Ueyama K. Hypertens Res 2009 31) Suzuki J. J Atheroscler Thromb 2014 32) Okura T. Hypertens Res 2007 34) Takaki A. Hypertens Res 2008 35) Ibata J. Diabetes Res Clin Pract 2008 37) Namekata T. J Clin Exp Cardiolog 2012 38) Kim ES. Diabetes Care 2011 39) Kim KJ. J Atheroscler Thromb 2011 40) Tsuboi A. 2015 41) Soska V. J Atheroscler Thromb 2012 42) Satoh N. Hypertens Res 2008 43) Satoh N. Hypertens Res 2008 43) Park HE. J Atheroscler Thromb 2012 44) Nagayama D. Atherosclerosis 2015 47) Li Y. Angiology 2013 48) Smoking Kubozono T. Circ J 2011 49) Sleep apnea syndrome Kumagai T. Chest 2009 50) Mental stress Shimizu K. J Atheroscler Thromb 2013 51) CAVI as a predictor of cardiovascular outcomes in patients on chronic hemodialysis (n 135). Laucevičius et al. 54) reported the association between CAVI and cardiovascular events in middleaged metabolic syndrome patients. CAVI was associof cardiovascular disease and stroke in 3 years. A multivariate analysis showed that the hazard ratio of cardiovascular diseases was significantly higher in this group (hazard ratio, 2.2) (Fig. 7). Kato et al. 53) reported that bapwv is superior to

162 Table 2. Summary on cardiovascular prognostic significance of CAVI Author Subjects Mean Age Duration of Follow-up Outcome incidence rate (1000 person-years) Prognostic Value Kubota et al. 2011 52) 400 Patients with Metabolic Disorders or Past History of CVD 63.2-73.9 26.8-27.4 months Cardiovascular events Not described Significant Kato et al. 2012 53) 135 Hemodialysis Patients 60 63 months Cardiovascular events 52.2 Not significant Laucevičius et al. 2015 54) 2106 Metabolic Syndrome Patients 53.83 3.8 years All cardiovascular events 11.6 Significant Myocardial infarction 6.9 Significant Cerebrovascular events 4.7 Not significant Satoh-Asahara et al. 425 Obese Patients 51.5 5 years Cardiovascular events 15.8 Significant 2015 55) Sato et al. 2015 1003 (in press) 56) Subjects with Metabolic Disorders 62.5 6.7 years Cardiovascular events 13.4 Significant Fig.7. Cumulative incidence of coronary artery diseases and strokes The group with a CAVI score 10 had significantly higher incidence than the group with CAVI score 9 (p0.05) 52). ated with the occurrence of total cardiovascular events (p 0.045) and myocardial infarction (p 0.027), but not cerebrovascular events, although this association was dependent on age and gender. Satoh-Asahara et al. 55) reported that CAVI could predict the outcome following a 5-year period of cardiovascular diseases in obese patients (n 425). High CAVI was one of the significant prognostic factors for the cardiovascular events in Cox stepwise multivariate analysis when adjusted for age and sex [CAVI (per 1): hazard ratio, 1.44 (1.02-2.02), p 0.037). Adding CAVI improved the prediction of cardiovascular events, increasing C-statistics from 0.712 to 0.736, and NRI was 16.4% (p 0.066). Sato et al. 56) reported that CAVI was an independent predictor of future cardiovascular events in 1080 subjects with metabolic disorders, such as diabetes mellitus, hypertension, and dyslipidemia. In Cox proportional hazards regression analysis, every 1.0 increment of CAVI was one of the factors independently associated with the higher risk of future cardiovascular events (hazard ratio, 1.126, p 0.039). Furthermore, Otsuka et al. 57) reported that persistently impaired CAVI was an independent predictor of future cardiovascular events (p 0.01), and cardiovascular outcomes were worse in patients with persistently impaired CAVI than in those with improved CAVI (p0.001). This report suggests that the change in CAVI is also a predictor of future cardiovascular events. The role of CAVI as a surrogate endpoint of various risks management 1. Treatment of Hypertension CAVI is independent of blood pressure at the measuring time, and CAVI showed high values in the patients with hypertension. Therefore, CAVI may be a good marker of arterial stiffness, reflecting coronary risks control including hypertension treatment. (a) Calcium Channel Blockers There are several calcium channel blockers (CCBs), such as L-channel blocker type, T-channel blocker type, and N-channel blocker type. Kurata et

163 Fig.8. Change in CAVI before and after administration of ARB (olmesartan) and CCBs (amlodipine) 59). Fig.9. After pitavastatin treatment for 12 months, significant decreases in CAVI were observed in type 2 diabetic patients 70). al. 58) reported that amlodipine, L-channel blocker type, decreased CAVI (n 10, 24 weeks). However, Miyashita et al. 59) showed that the decrease of CAVI by amlodipine was negligible and not significant. Sasaki et al. 60) compared the effects of efonidipine, T-channel blocker, and amlodipine. Although blood pressure was reduced at approximately the same extents, CAVI was significantly reduced by efonidipine, but not by amlodipine. CAVI can differentiate the effects of different types of CCBs on the proper arterial stiffness. (b) Angiotensin receptor antagonists There are several reports about the effects of angiotensin receptor antagonists (ARBs) on CAVI. Telmisartan decreased CAVI 61), and candesartan reduced CAVI more than telmisartan and losartan 62). Bokuda et al. 63) studied the effects of candesartan comparing with CCBs. They showed that blood pressure significantly decreased in both the groups at the same extent. However, candesartan significantly reduced CAVI, but not CCBs. Miyashita et al. 59) also reported that olmesartan decreased CAVI significantly, but not amlodipine, although the decreased blood pressure extents were almost the same (Fig. 8). As for the treatments of hypertension, it has been reported that ARBs or angiotensinogen-converting enzyme inhibitor had better effects on the prognosis of cardiovascular diseases than CCBs 64). The coincidence of the superiority of ARBs to CCBs in the long-term prospective study with that in the short-term study using CAVI is interesting. Further studies on the comparison between the prognosis of various antihypertensive drugs and their effects on CAVI are needed. In summary, the abovementioned reports suggest that CAVI could discriminate the effects of antihypertensive agents on proper arterial stiffness in addition to blood pressure control itself. 2. Treatment of Diabetes Mellitus CAVI is high in patients with diabetes mellitus and postprandial hyperglycemia as mentioned before. The values of CAVI are sometimes influenced by the glucose-lowering treatment; there are some glucoselowering treatments that lower CAVI and others that do not 65). Alpha-glucosidase inhibitor, acarbose, reduces CAVI mediated by an improvement of postprandial hyperglycemia 66). Ohira et al. 67) reported that switching biphasic insulin from human insulin 30/70 to insulin aspart 30/70 improved CAVI together with the marker of postprandial hyperglycemia. Ohira et al. 68) reported that an insulin-sensitizer pioglitazone decreased CAVI accompanied with adiponectin-increasing effect. Nagayama et al. 69) reported that Glimepiride, a third generation sulfonylurea, improved CAVI and the marker of insulin resistance and oxidative stress, but not glibenclamide, a conventional sulfonylurea. These reports suggest that the improvement of postprandial hyperglycemia and insulin resistance has favorable effect on CAVI in diabetes mellitus treatment.

164 Table 3. Effects of various treatments on CAVI Treatments CAVI value References Body weight reduction Glucose control Insulin Sulfonylurea Pioglitazone -glucosidase inhibitor Blood pressure control Ca blocker (Amlodipine) Ca blocker (T-channel blocker type) angiotensin receptor antagonists Lipid control Statins Eicosapentaenoic acid or or Satoh N. Hypertens Res 2008 43) Nagayama D. Obes Res Clin Pract 2011 73) Ohira M. Metabolism 2011 67) Nagayama D. Int J Clin Pract 2010 69) Ohira M. Diabetes Metab Syndr Obes 2014 68) Uzui H. J Diabetes Investig 2011 66) Kurata M. Curr Ther Res Clin Exp 2008 58) Sasaki H. J Atheroscler Thromb 2009 60) Miyashita Y. J Atheroscler Tromb 2009 59) Sasaki H. J Atheroscler Thromb 2009 60) Kinouchi K. Kidney Blood Press Res 2010 61) Uehara G. J Int Med Res 2008 62) Bokuda K. Vasc Health Risk Manag 2010 63) Miyashita Y. J Atheroscler Thromb 2009 70) Satoh N. Hypertens Res 2009 71) Smoking cessation Noike H. J Atheroscler Thromb 2010 74) Continuous positive airway pressure Kasai T. Am J Hypertens 2011 75) 3.Treatment of Dyslipidemia It is controversial whether CAVI in the patients with hypercholesterolemia is high as mentioned before. On the other hand, cholesterol-lowering agents, such as pitavastatin 70), (Fig. 9) and the triglyceride-lowering agent, eicosapentaenoic acid 71), have been reported to decrease CAVI. 4.Treatment of Obesity and Metabolic Syndrome Metabolic syndrome is the accumulation of diabetes mellitus, hypertension, and hypertriglyceridemia based on obesity, and now this is one of the most important risk factors for CADs 72). CAVI is high in metabolic syndrome as mentioned before. The reduction of body weight improves CAVI in addition to many risk factors in the patients with metabolic syndrome 43). Nagayama et al. 73) reported that weight reduction using a calorie restriction diet decreased CAVI in obese patients with type 2 diabetes. The change in VFA was a significant independent predictor of the change in CAVI. 5.Smoking Cessation CAVI is high in people who smoke 49) and is decreased by stopping smoking 74). 6. Treatment of Sleep Apnea Syndrome CAVI is elevated in the patients with sleep apnea syndrome 50) and is decreased by continuous positive airway pressure treatments 75). The abovementioned results indicated that CAVI could be a good maker of arteriosclerosis and is also a marker of arterial stiffness raised by several coronary risk factors (Table 3). Therefore, CAVI is a candidate of surrogate endpoint marker for cardiovascular disease; however, there is no intervention study investigating the association of CAVI with cardiovascular event. Further studies are required to investigate the association of CAVI with cardiovascular event and mortality, by various interventions. Conclusions CAVI, reflecting the arterial stiffness from the origin of the aorta to the tibial artery at the ankle, has been developed in Japan. It was based on the theory of stiffness parameter. CAVI reflects the degree of arteriosclerosis. Moreover, CAVI shows high values in

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Atheroscler, 2014; 235: 239-245 16) Shirai K, Song M, Suzuki J, Kurosu T, Oyama T, Nagayama D, Miyashita Y, Yamamura S, Takahashi M: Contradictory effects of b1- and a1-aderenergic receptor blockers on cardio-ankle vascular stiffness index (CAVI): the independency of CAVI from blood pressure. J Atheropatients with coronary risk factors, and the control of the risks improves CAVI. The latter fact indicates that CAVI reflects not only the organic stiffness of the arterial wall but also the functional stiffness composed of smooth muscle cell contracture. Furthermore, several prognostic studies of cardiovascular events using CAVI have emerged, and CAVI is reported as a prognostic factor for cardiovascular disease. CAVI has an additional diagnostic value of cardiovascular events in several studies. CAVI could be useful for the cardiovascular risk stratification in future guideline of patients with coronary risk factors, although further studies are required to confirm these. Moreover, CAVI has relationships with the left ventricular function 76, 77) and retinal artery pulsation 78). These results suggest that CAVI is an adequate marker of vascular function as Windkessel. CAVI may open a new field for the studies on vascular functions. In summary, CAVI could be a marker for the diagnosis of arteriosclerotic diseases and also for the evaluation of the pathophysiology of systemic circulation relating to the left ventricular function and blood flow in the peripheral organs. Routine measurement of CAVI is recommended in clinical practice, in addition to various coronary risk factors. Conflict of Interest I Tatsuno received lecture fees from Takeda Pharmaceutical Company Ltd, Eli Lilly Japan K.K., and Boehringer Ingelheim Japan; received research grants from Takeda Pharmaceutical Company, Johnson & Johnson K.K., and Taisho Pharmaceutical Co., Ltd; and was endowed a course at his affiliation by Fukuda Denshi Co., Ltd. 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