the role of a novel arterial stiffness parameter, cardio

155Journal of Atherosclerosis and Thrombosis　Vol.23, No.2

Review

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 progres-sion of arteriosclerosis. So far, many parameters have been proposed to quantitatively represent arte-rial 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 use-fulness 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 β is an index reflecting arterial stiffness without the influence of blood pressure. Recently, this parameter has been applied to develop a new arterial stiff-ness 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 dis-eases, 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 candi-date surrogate end-point marker for cardiovascular disease.

J Atheroscler Thromb, 2016; 23: 155-168.

Key words: Cardio-ankle vascular index, Arterial stiffness, Stiffness parameter β , 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, JapanE-mail: [email protected]: September 30, 2015Accepted for publication: October 27, 2015

properties accompanying the progression of arterio-sclerosis. Then, many parameters have been proposed to quantitatively represent arterial stiffness1, 2). Among these, pulse wave velocity (PWV)3) has been most fre-quently 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 estab-lished the meaning of measuring arterial wall stiffness. However, PWV essentially depends on the blood pres-sure at the time of measurement6). Therefore, PWV is

156 Saiki et al.

improvement in most of those risk factors decreased CAVI. The role of CAVI as a predictor of cardio-vas-cular 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 cardiovascu-lar disease.

The Principle of CAVI and Measuring Method

CAVI was originally derived from the stiffness parameter β proposed by Hayashi8) and Kawasaki9) and was expanded to some length of the artery with the application of the modified Bramwell-Hill equa-tion7, 10). CAVI adopted PWV from the origin of the aorta to the ankle (heart-ankle PWV; haPWV).

CAVI = a[(2ρ/ΔP)×ln(Ps/Pd)×haPWV2]＋b ----- Equation 1 (Fig.1)

Ps is the systolic blood pressure, Pd is the dia-stolic blood pressure, haPWV is PWV from the origin of the aorta to the tibial artery at the ankle through the femoral artery, ρ is the blood density, and a and b

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 Japan7). CAVI originated from the theory of stiffness parameter β8, 9), which is applied to the local part of the artery expressed as log-arithm Δpressure required for some elongation of the arterial diameter. Stiffness parameter β 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 Δpressure was related to the square of pulse wave veloc-ity7, 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

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 b＋t ba. Blood pressure is measured at the brachial artery. Ps= systolic blood pressure; Pd=diastolic blood pressure; ΔP=pulse pressure, Ps−Pd; ρ=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 ba= time between the rise of bra-chial 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´b= time between aortic valve opening sound and the rise of brachial pulse wave10).

157CAVI as a Surrogate Marker for CVD

Factors Affecting CAVI

Because measuring conditions, room tempera-ture, 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 GenderCAVI of healthy people without cardiovascular

risk factors gradually increases with age from 20 to 70 years17) (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＋0.048×age in men, 4.8＋0.045×age 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.519). 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 isch-emic CAD. Izuhara et al.21) reported the multiple logistic analysis revealing that CAVI, but not baPWV,

are constants to convert the values of CAVI to those of Hasegawa’s heart-femoral PWV (hfPWV)11, 12). Equa-tion 1 indicates that CAVI can be obtained by mea-suring blood pressure and haPWV. The blood pres-sures used in the Equation 1 should be the mean blood pressure from the origin of the aorta to the tib-ial 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 pres-sure in the brachial artery may be representative of the mean blood pressure in the artery of the origin of the aorta to the ankle13).

As CAVI is essentially derived from the stiffness parameter β, CAVI values have good correlations with the β values ultrasonically measured from the local segments of the descending thoracic aorta14). Similar results were also obtained from the common carotid artery. In both arteries, the correlation coefficients between CAVI and β were 0.67 and 0.39, respectively, both with the confidence coefficients of ＜0.01. Hori-naka et al.15) also reported that regional values of stiff-ness parameter β of the ascending and descending aorta were both significantly correlated with the CAVI values (Fig.2). Therefore, application of β 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 β1-blocker, metoprolol (Fig.3a). It is well known that β1-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 α1-blocker, doxazosin, was administered, CAVI decreased as blood pressure decreased (Fig.3b). CAVI is apparently dependent on blood pressure. However, in this case, α1-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 increas-ing year by year and has reached ＞300 in September 2015.

Fig.2. Correlation between CAVI and stiffness parameter β in the thoracic aorta15).

158 Saiki et al.

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

was associated with the presence of carotid and coro-nary arteriosclerosis. Several researchers reported that CAVI was high in patients with CAD20, 22, 23). Yingchoncharoen et al.24) reported that the traditional

Fig.3. Effects of blood pressure on CAVI values in healthy individuals administered (a) β1 blocker and (b) α1 blocker16).

Mean SE*P < 0.05**P < 0.01 vs Baseline

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).


(b) Cerebral InfarctionCAVI values are high in patients with cerebral

infarction27). 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.

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 addi-tion 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 cal-cification or stenosis in asymptomatic subjects in Korea. These results suggested that CAVI is well cor-related with the progression of coronary arteriosclero-sis.

Fig.5. Comparison between CAVI and baPWV for the number of coronary artery ste-nosis19)

Fig.6. The study of CAVI and RAMA-EGAT score

(a) Comparison of receiver operating characteristic (ROC) curve of modified RAMA-EGAT score (EGAT＋CAVI) and traditional RAMA-EGAT score (EGAT score). (b) CAVI provides additional diagnostic value at all levels of the RAMA-EGAT score24).

Figure 6a Figure 6b

160 Saiki et al.

(d) Obesity and metabolic syndromeIn the studies dealing with healthy people, CAVI

is negatively related with body mass index43). How-ever, 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 hypertriglyc-eridemia.

(e) Uric AcidUric acid as a risk factor for arteriosclerosis is

controversial because uric acid is known to have both antioxidant45) and pro-oxidative action in the process of production46). 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 anal-ysis. Li et al.48) also documented that uric acid increased arterial stiffness measured by CAVI.

(f) SmokingThe harmful effects of smoking are not only

respiratory and digestive systems but also cardiovascu-lar organs. CAVI is high in people who smoke49).

(g) Sleep Apnea SyndromeSleep apnea syndrome is one of the important

risk factors of atherosclerosis. CAVI is also high in the patients with sleep apnea syndrome50).

(h) Mental StressShimizu et al.51) reported that people who experi-

enced a severe earthquake had hardened arterial stiff-ness, 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 so-called 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

(c) Chronic Kidney Diseases and Maintenance Hemodialysis

Several studies about chronic kidney diseases described that CAVI correlated with estimated glo-merular filtration rate and cystatine C30) and that CAVI is high in patients undergoing hemodialysis therapy30, 31).

(d) Carotid ArteriosclerosisThere are several studies reporting the relation-

ship between CAVI and carotid arteriosclerosis observed using ultrasonography19, 21, 22, 32, 33).

In summary, the abovementioned results indi-cated that CAVI could be a good maker of the pro-gression of arteriosclerosis.

3.Coronary Risk Factors(a) Hypertension

CAVI is essentially independent of blood pres-sure 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 hyperten-sion31, 32, 34, 35). Most of those reports showed that the correlation coefficients between CAVI and blood pres-sure were lower than those between PWV and blood pressure7, 31, 36). In hemodialysis patients, CAVI was correlated weakly with systolic and diastolic blood pressures (r=0.175, 0.006), whereas baPWV was cor-related significantly with systolic and diastolic blood pressures (r=0.463, 0.335)7).

(b) Diabetes MellitusCAVI is reported to be high in patients with dia-

betes mellitus37, 38). Kim et al.39) reported that diabetic peripheral neuropathy was associated with increased CAVI without changes in carotid IMT in type 2 dia-betes. Kim et al.40) found that increased CAVI in type 2 diabetes was associated with the presence of arterial plaque, increased IMT, and microvascular complica-tion. Furthermore, Tsuboi et al.41) reported that the 1-h postprandial glucose levels are associated with increased CAVI values in non-diabetic subjects.

(c) DyslipidemiaSoska 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 lipopro-tein (HDL) cholesterol ratio43). CAVI may increase when complicated lesions occur.


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 middle-aged metabolic syndrome patients. CAVI was associ-

of cardiovascular disease and stroke in 3 years. A mul-tivariate analysis showed that the hazard ratio of car-diovascular diseases was significantly higher in this group (hazard ratio, 2.2) (Fig.7).

Kato et al.53) reported that baPWV is superior to

Table 1. CAVI in the patients with arteriosclerotic diseases and coronary risks

Arteriosclerotic diseases and coronary risks CAVI value References

Aging, male ↑↑

Namekata T. BMC Cardiovasc Disord 201117)

Choi SY. J Atheroscler Thromb 201318)

Arteriosclerotic diseasesCoronary artery disease

Cerebral infarction

Chronic kidney disease, hemodialysis

↑↑↑↑↑↑↑↑

↑↑↑

↑↑

Nakamura K. J Atheroscler Thromb 200920)

Izuhara M. Circ J 200821)

Miyoshi T. J Atheroscler Thromb 201022)

Horinaka S. Angiology 200919)

Sairaku A. Hypertens Res 201023)

Yingchoncharoen T. Heart Asia 201224)

Park HE. J Cardiol 201225)

Park JB. J Atheroscler Thromb 201326)

Suzuki J. J Stroke Cerebrovasc Dis 201127)

Choi S-Y. J Atheroscler Thromb 201328)

Yamamoto N. Dement Geriatr Cogn Disord 200929)

Kubozono T. J Atheroscler Thromb 200930)

Ueyama K. Hypertens Res 200931)

Coronary risksHypertension

Diabetes mellitus

Dyslipidemia

Metabolic syndrome

Uric acid

↑↑↑↑

↑↑↑↑↑

→↑

↑↑

↑↑

Ueyama K. Hypertens Res 200931)

Suzuki J. J Atheroscler Thromb 201432)

Okura T. Hypertens Res 200734)

Takaki A. Hypertens Res 200835)

Ibata J. Diabetes Res Clin Pract 200837)

Namekata T. J Clin Exp Cardiolog 201238)

Kim ES. Diabetes Care 201139)

Kim KJ. J Atheroscler Thromb 201140)

Tsuboi A. 201541)

Soska V. J Atheroscler Thromb 201242)

Satoh N. Hypertens Res 200843)


Park HE. J Atheroscler Thromb 201244)

Nagayama D. Atherosclerosis 201547)

Li Y. Angiology 201348)

Smoking ↑ Kubozono T. Circ J 201149)

Sleep apnea syndrome ↑ Kumagai T. Chest 200950)

Mental stress ↑ Shimizu K. J Atheroscler Thromb 201351)

162 Saiki et al.

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 indepen-dent predictor of future cardiovascular events in 1080 subjects with metabolic disorders, such as diabetes mellitus, hypertension, and dyslipidemia. In Cox pro-portional hazards regression analysis, every 1.0 incre-ment 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 per-sistently impaired CAVI was an independent predictor of future cardiovascular events (p =0.01), and cardio-vascular outcomes were worse in patients with persis-tently impaired CAVI than in those with improved CAVI (p＜0.001). 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 HypertensionCAVI 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 BlockersThere are several calcium channel blockers

(CCBs), such as L-channel blocker type, T-channel blocker type, and N-channel blocker type. Kurata et

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 car-diovascular 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

Table 2. Summary on cardiovascular prognostic significance of CAVI

Author Subjects Mean Age Duration ofFollow-up

Outcome incidence rate(1000 person-years)

PrognosticValue

Kubota et al. 201152) 400 Patientswith Metabolic Disorders or Past History of CVD

63.2-73.9 26.8-27.4 months

Cardiovascular events Not described Significant

Kato et al. 201253) 135 Hemodialysis Patients 60 63 months Cardiovascular events 52.2 Not significant

Laucevičius et al.201554)

2106Metabolic 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.201555)

425 Obese Patients 51.5 5 years Cardiovascular events 15.8 Significant

Sato et al. 2015(in press)56)

1003Subjects withMetabolic 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 (p＜0.05)52).


CAVI is interesting. Further studies on the compari-son 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 antihyper-tensive agents on proper arterial stiffness in addition to blood pressure control itself.

2.Treatment of Diabetes MellitusCAVI 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 glucose-lowering treatments that lower CAVI and others that do not65). Alpha-glucosidase inhibitor, acarbose, reduces CAVI mediated by an improvement of post-prandial hyperglycemia66). 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 adi-ponectin-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 conven-tional sulfonylurea.

These reports suggest that the improvement of postprandial hyperglycemia and insulin resistance has favorable effect on CAVI in diabetes mellitus treat-ment.

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 efonidip-ine, but not by amlodipine. CAVI can differentiate the effects of different types of CCBs on the proper arterial stiffness.

(b) Angiotensin Ⅱ receptor antagonistsThere are several reports about the effects of

angiotensin Ⅱ receptor antagonists (ARBs) on CAVI. Telmisartan decreased CAVI61), and candesartan reduced CAVI more than telmisartan and losartan62). Bokuda et al.63) studied the effects of candesartan comparing with CCBs. They showed that blood pres-sure 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 cardio-vascular diseases than CCBs64). The coincidence of the superiority of ARBs to CCBs in the long-term pro-spective study with that in the short-term study using

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 patients70).

164 Saiki et al.

decreased by stopping smoking74).

6.Treatment of Sleep Apnea SyndromeCAVI is elevated in the patients with sleep apnea

syndrome50) and is decreased by continuous positive airway pressure treatments75).

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 dis-ease; however, there is no intervention study investi-gating 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 β. CAVI reflects the degree of arte-riosclerosis. Moreover, CAVI shows high values in

3.Treatment of DyslipidemiaIt is controversial whether CAVI in the patients

with hypercholesterolemia is high as mentioned before. On the other hand, cholesterol-lowering agents, such as pitavastatin70), (Fig.9) and the triglyc-eride-lowering agent, eicosapentaenoic acid71), have been reported to decrease CAVI.

4.Treatment of Obesity and Metabolic SyndromeMetabolic syndrome is the accumulation of dia-

betes mellitus, hypertension, and hypertriglyceridemia based on obesity, and now this is one of the most important risk factors for CADs72). CAVI is high in metabolic syndrome as mentioned before. The reduc-tion of body weight improves CAVI in addition to many risk factors in the patients with metabolic syn-drome43). 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 predic-tor of the change in CAVI.

5.Smoking CessationCAVI is high in people who smoke49) and is

Table 3. Effects of various treatments on CAVI

Treatments CAVI value References

Body weight reduction ↓↓


Nagayama D. Obes Res Clin Pract 201173)

Glucose controlInsulinSulfonylureaPioglitazoneα-glucosidase inhibitor

↓ or →↓ or →↓↓

Ohira M. Metabolism 201167)

Nagayama D. Int J Clin Pract 201069)

Ohira M. Diabetes Metab Syndr Obes 201468)

Uzui H. J Diabetes Investig 201166)

Blood pressure controlCa blocker (Amlodipine)

Ca blocker (T-channel blocker type)

angiotensin Ⅱ receptor antagonists

↓→→

↓

↓↓↓

Kurata M. Curr Ther Res Clin Exp 200858)

Sasaki H. J Atheroscler Thromb 200960)

Miyashita Y. J Atheroscler Tromb 200959)

Sasaki H. J Atheroscler Thromb 200960)

Kinouchi K. Kidney Blood Press Res 201061)

Uehara G. J Int Med Res 200862)

Bokuda K. Vasc Health Risk Manag 201063)

Lipid controlStatinsEicosapentaenoic acid

↓↓

Miyashita Y. J Atheroscler Thromb 200970)


Smoking cessation ↓ Noike H. J Atheroscler Thromb 201074)

Continuous positive airway pressure ↓ Kasai T. Am J Hypertens 201175)


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15) Horinaka S, Yagi H, Ishimura K, Fukushima H, Shibata Y, Sugawara R, Ishimitsu T: Cardio-ankle vascular index (CAVI) correlates with aortic stiffness in the thoracic aorta using ECG-gated multidetector row computed tomography. 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 Athero-

patients 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 arte-rial 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 addi-tional diagnostic value of cardiovascular events in sev-eral studies. CAVI could be useful for the cardiovascu-lar 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 function76, 77) and retinal artery pulsa-tion78). 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 circula-tion relating to the left ventricular function and blood flow in the peripheral organs. Routine measurement of CAVI is recommended in clinical practice, in addi-tion to various coronary risk factors.

Conflict of Interest

I Tatsuno received lecture fees from Takeda Phar-maceutical 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.

Acknowledgements

We would like to express our sincere gratitude to Prof. Kohji Shirai in the Department of Vascular Function, Sakura Hospital, Toho University. And we are very grateful to the doctors in the Department of Internal Medicine and the staff of Functional Physio-logical Division and Clinical Physiology Unit in Sakura Hospital, Toho University, for their coopera-tion in conducting research on CAVI.

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the role of a novel arterial stiffness parameter, cardio

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