Secondary Logo

Journal Logo

Clinical assessment of arterial stiffness with cardio-ankle vascular index

theory and applications

Hayashi, Kozaburoa; Yamamoto, Tomoyukib , c; Takahara, Akirad; Shirai, Kohjic , e

doi: 10.1097/HJH.0000000000000651
REVIEWS
Open

Arterial stiffness is often assessed in clinical medicine, because it is not only an important factor in the pathophysiology of blood circulation but also a marker for the diagnosis and the prognosis of cardiovascular diseases. Many parameters have so far been proposed to quantitatively represent arterial stiffness and distensibility, such as pressure–strain elastic modulus (Ep), stiffness parameter (β), pulse wave velocity (PWV), and vascular compliance (Cv). Among these, PWV has been most frequently applied to clinical medicine. However, this is dependent on blood pressure at the time of measurement, and therefore it is not appropriate as a parameter for the clinical evaluation of arterial stiffness, especially for the studies on hypertension.

On the contrary, 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 stiffness index called cardio-ankle vascular index (CAVI). Although this index is obtained from the PWV between the heart and the ankle, it is essentially similar to the stiffness parameter β, and therefore it does not depend on blood pressure changes during the measurements. CAVI is being extensively used in clinical medicine as a measure for the evaluation of cardiovascular diseases and risk factors related to arteriosclerosis.

In the present article, we will explain the theoretical background of stiffness parameter β and the process to obtain CAVI. And then, the clinical utility of CAVI will be overviewed by reference to recent studies.

aDepartment of Mechanical Science and Bioengineering, Graduate School of Engineering Science, Osaka University, Toyonaka, Osaka

bBiological Information Analysis Section, Fukuda Denshi Co., Ltd. Tokyo

cDepartment of Vascular Function, Sakura Hospital

dDepartment of Pharmacology and Therapeutics, Faculty of Pharmaceutical Sciences, Toho University

eMihama Hospital, Chiba, Japan

Correspondence to Kohji Shirai, Mihama Hospital, 1-1-5, Utase, Mihama-Ku, Chiba-Shi, 261-0013, Japan. Fax: +81 431 2288; e-mail: kshirai@kb3.so-net.ne.jp

Abbreviations: CAVI, cardio-ankle vascular index; Cv, vascular compliance; EP, pressure–strain elastic modulus; PWV, pulse wave velocity; β, stiffness parameter β

Received 5 May, 2014

Revised 11 May, 2015

Accepted 12 May, 2015

This is an open-access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 License, where it is permissible to download and share the work provided it is properly cited. The work cannot be changed in any way or used commercially. http://creativecommons.org/licenses/by-nc-nd/4.0

Back to Top | Article Outline

INTRODUCTION

Arterial stiffness is often assessed in clinical medicine, because it is considered to be not only an important factor in the pathophysiology of blood circulation but also a good marker for the diagnosis and the prognosis of cardiovascular diseases [1–3]. Increased arterial stiffness is commonly observed in patients having atherosclerosis, hypertension, diabetes, and hyperlipidemia [4–6].

Several methods have been utilized for clinically assessing arterial stiffness [7–10]. For example, arterial diameter and blood pressure are measured with ultrasonic echo-tracking techniques and cuff-type sphygmomanometry, respectively, to determine arterial pressure–diameter relations and wall stiffness [10]. This method has been applied to such conduit arteries as the common carotid artery and the abdominal aorta. For the information and data obtained from such techniques, many parameters have so far been proposed to quantitatively express arterial stiffness and distensibility with simple parameters for practical applications: for example, pressure–strain elastic modulus (Ep), stiffness parameter (β), and vascular compliance (Cv) [10,11].

As another method, pulse wave velocity (PWV) in the arterial tree has been more commonly used in clinical medicine [7,12]. This is based on the idea that the propagation of pressure wave is faster in a stiffer tube than in a softer one. In the cardiovascular system, the velocity is obtained from the measurements of temporal blood pressure waves at two sites along the arterial tree. As this measurement can be done noninvasively and easily, this method has been clinically used for several decades [13].

As is widely known, however, these parameters, except for stiffness parameter β, change depending upon blood pressure at the time of measurement, and therefore they are not always appropriate to be used as patient-specific parameters. Especially, it is difficult to assess the role of blood pressure on the proper arterial stiffness.

More recently, stiffness parameter β was linked with PWV to develop a novel blood pressure-independent stiffness index called cardio-ankle vascular index (CAVI) [14]. Actually, PWV is measured between the heart and the ankle, and then it is transformed into β. CAVI has been applied to many cardiovascular and cerebrovascular diseases, and also their risks. Now, many data and results obtained from CAVI are being accumulated.

In the present article, we will explain about nonlinear pressure–diameter relations of arteries, and several parameters that have been used to represent arterial stiffness. Then, we will deal with the theory of β and demonstrate several applications of the parameter to vascular mechanics and pathophysiology. After briefly touching upon PWV, we will explain the relation between β and PWV, and how to obtain CAVI from β using heart–ankle PWV (haPWV), including practical methods for haPWV. Finally, we will overview several clinical data on CAVI and its clinical applications.

Back to Top | Article Outline

NONLINEAR PRESSURE–DIAMETER RELATIONSHIP AND ARTERIAL STIFFNESS

When an artery is excised from the body, and then internal pressure is gradually increased, its diameter largely increases with increase in pressure in the range of low pressure; however, the rate of diameter increase gradually decreases with increase in pressure (Fig. 1) [10]. Like this, arterial wall deforms largely and nonlinearly, which is one of the characteristics unique to soft biological tissues. Therefore, arterial stiffness, which corresponds to the slope of tangent to a pressure–diameter curve (ΔPD), gradually increases with the increase of pressure. On the contrary, vascular compliance, which means the distensibility of a vessel, is expressed by the inverse of the slope, and therefore it decreases with increase in pressure. Such nonlinear pressure–diameter relations of arteries appear in vivo as well, even between SBP and DBP.

FIGURE 1

FIGURE 1

For practical applications, it is convenient to represent such arterial pressure–diameter relation and wall stiffness with a simple parameter. In particular, for noninvasive diagnoses in clinical medicine, the expression of arterial stiffness or compliance should be simple, yet quantitative. For this purpose, several parameters have so far been proposed [11], which include ‘pressure–strain elastic modulus Ep[15–17] and ‘vascular compliance Cv[17].

These parameters are, respectively, described as follows:

and

where D and V are the diameter of a blood vessel and its volume per unit length, respectively, both at pressure P, and ΔD and ΔV are their increments for the pressure increment ΔP at P. Separately, Gow [18], and Gow and Hadfield [19] used ΔP/(ΔV/V) to represent arterial stiffness, and named it ‘volume elasticity modulus’. The reciprocal expression of this parameter is Cv, as understood from Equation (2), which has been often used to represent vascular distensibility being called ‘vascular compliance’ or ‘volume compliance’. The parameters Ep and Cv are obtained from the slopes of tangent, ΔPD and ΔDP, to pressure–diameter and diameter–pressure curves at pressure P, respectively.

It should be noted, however, that these parameters are defined at specific pressures, and have different values at different pressures, because the pressure–diameter relations of arteries are nonlinear and their slope ΔPD changes depending on pressure as stated above (see Fig. 1). Our blood pressure easily and always changes in a short period of time even in a healthy person, which eventually affects these parameters. Therefore, such parameters as Ep and Cv may not be useful for the representation of definite, patient-specific arterial elasticity.

Back to Top | Article Outline

STIFFNESS PARAMETER β

Principle

To overcome the above-mentioned shortcoming, Hayashi et al.[20] proposed the ‘stiffness parameter β’, which does not depend upon blood pressures at the time of measurement. This parameter is obtained as follows. First, we select an arbitrary standard pressure Ps, 100 mmHg as an example, and determine arterial diameter Ds at this pressure (Fig. 2, left) [10], and then calculate the pressure ratio P/Ps and the distension ratio D/Ds. If we calculate ln(P/Ps) and plot it against D/Ds, a linear relation is observed between them in a wide pressure range (between 63 and 200 mmHg in Fig. 2, right). This semi-logarithmic relationship is simply described by:

FIGURE 2

FIGURE 2

The slope of the semi-logarithmic relation gives stiffness parameter β, which represents the stiffness of the arterial wall. In other words, nonlinear pressure–diameter curves (e.g. Fig. 2, left) are described by this equation in a wide pressure range. As can be understood from the above explanation, the stiffness parameter β does not depend on pressure in the pressure range, in which case the formulation can be applied. This is one of the most important advantages of the stiffness parameter β compared with the other parameters.

It should be, however, noted that Equation (3) does not always fit, for example, to pressure–diameter relations of arteries below and above the physiological pressure range (see Fig. 2, right), and also to relations of muscular arteries contracted by the strong activation of smooth muscle [21].

Now, take Ps and P as DBP Pdia and SBP Psys, respectively, in Equation (3), and we can rewrite the equation as follows:

where Dsys and Ddia are arterial diameters at Psys and Pdia, respectively.

As Dsys can be written as Ddia + ΔD, this equation is again rewritten as:

or

where ΔD is the diameter change developed by pulse pressure ΔP.

Back to Top | Article Outline

Application of stiffness parameter β to pathophysiology and clinical medicine

Age-related changes

In-vitro pressure–diameter tests of human arteries indicated that there are large differences in β-values among arteries; the coronary artery has much greater β-values than the intracranial vertebral artery and the common carotid artery, and the intracranial vertebral artery has larger β-values than the common carotid artery (Fig. 3) [22]. Such remarkably high stiffness of the coronary artery in comparison to the other arteries is attributable to the higher ratio of collagen content to elastin content [23,24], as well as to the intimal hyperplasia commonly observed in the human coronary artery. There are no age-related changes in the stiffness of the carotid artery below 40 years; thereafter, however, the stiffness progressively increases with age. Clinical measurements of β-values of the abdominal aorta and the common carotid artery using an ultrasonic echo system demonstrated age-related changes similar to those shown in Fig. 3 [25].

FIGURE 3

FIGURE 3

The above mentioned figure also clearly shows that the intracranial vertebral artery, which has higher β-values than the common carotid artery at birth, starts increasing wall stiffness soon after birth and has significantly high β-values already at the age of 20 years [20]. Above 40 years, the stiffness of the intracranial vertebral artery increases in parallel with that of the common carotid artery. Similar results were also obtained from the human basilar artery. Such features unique to intracranial arteries were considered to be an important factor contributing to the initiation and development of such cerebrovascular diseases as cerebral aneurysms [26].

Back to Top | Article Outline

Atherosclerosis

The wall stiffness of thoracic aortae harvested from experimentally endothelial-denuded and/or cholesterol-fed rabbits was studied from their in-vitro pressure–diameter tests [27]. The grade of atherosclerosis was determined from the percentage fraction of the area occupied by intimal hyperplasia in each histological section; it was approximately 0, 25, 38, and 53% in grades 0, I, II, and III, respectively [28].

The area fraction of the calcified region increased with the progression of atherosclerosis (Fig. 4, upper left); in particular, calcification was remarkable in grade III. The thickness of the bulk wall steadily increased with the progression of atherosclerosis (Fig. 4, lower left), when wall thickening was primarily caused by intimal hyperplasia unique to atherosclerosis. On the contrary, significant increases in stiffness parameter β were observed only in grades II and III; its increase in grade III was remarkable (Fig. 4, upper right). Even if atherosclerosis was advanced to grade II, there was no significant change in elastic modulus E, where this parameter represents the elasticity of wall material itself (Fig. 4, lower right). E became significantly higher only at the most advanced stage of atherosclerosis (say grade III). Theoretically, elastic modulus E is obtained from stress–strain relations, whereas stiffness parameter β is obtained from pressure–diameter relations [10]. Roughly speaking, β is proportional to E and wall thickness, whereas E does not depend on wall thickness. Figure 4 clearly demonstrates this.

FIGURE 4

FIGURE 4

Ogawa et al.[29] reported from their clinical studies that arteriosclerosis assessed by stiffness parameter β is associated with atherosclerotic changes of carotid arteries and with the presence of silent cerebral infarction in hemodialysis patients.

Taken together, we can say that increased wall stiffness in atherosclerosis results from the combined effect of calcification and wall hyperplasia, and that it is not always related to the elastic modulus of wall material.

Back to Top | Article Outline

Hypertension

Hypertension increases wall stress, which activates the vascular smooth muscle cells and then changes the structure and morphology, mechanical properties, and contractility of the arterial wall. It is therefore very important to understand arterial mechanics in hypertension, and there are many papers dealing with the mechanical properties of hypertensive arteries [10,11,28]. For example, studies on the cerebral circulation have shown that alterations in the mechanical properties associated with hypertension are dependent on vessel caliber [30], and the duration and/or the severity of hypertension [31].

Hayashi and Sugimoto [32] reported that deoxycorticosterone acetate (DOCA)-salt hypertension, which is an experimental model of hypertension analogous to human essential hypertension, was induced in the middle-aged (26 weeks) rat, and biomechanical properties and wall dimensions of the common carotid artery were determined in vitro. Elevated blood pressure increased stiffness parameter β (Fig. 5). Although blood pressure increases with hypertension, we can precisely compare arterial stiffness between hypertensive and normotensive patients like this, if we use blood pressure-independent stiffness parameter β. Such an increase in arterial stiffness was ascribed to the increase of wall thickness. Wall hypertrophy occurs as a result of the functional adaptation and tissue remodeling of the arterial wall, maintaining wall stress at the control level even under hypertension. A review article on the adaptation and remodeling of vascular wall developed by hypertension has been published elsewhere [33].

FIGURE 5

FIGURE 5

Back to Top | Article Outline

Diabetes

Araki et al.[34] reported that the treatment with insulin sensitizers pioglitazone and metformin may improve stiffness parameter β in patients with type 2 diabetes mellitus. Hyperglycemia might be working to increase the stiffness of the artery.

Back to Top | Article Outline

PULSE WAVE VELOCITY

Principle

Pulse wave velocity has been more frequently used in clinical medicine than Ep, Cv, and β. To clinically determine the latter parameters, we have to measure pressure–diameter data at in-vivo working blood pressures. For PWV, we measure blood pressure waves at two different sites along the arterial tree, and calculate the velocity of pressure propagation (e.g. see Fig. 6); from this, we can obtain arterial stiffness ΔPD, as will be explained below. Like this, PWV can be easily and noninvasively obtained, and can be used to evaluate arterial stiffness in practical medicine.

FIGURE 6

FIGURE 6

As the velocity of sound in air, Isaac Newton derived the following equation from his second law of motion [35]:

where c, K, and ρ are the velocity of wave propagation, the volume elasticity of wall, and the density of fluid, respectively. Considering that the velocity in air is analogous to that in such a liquid as blood in an elastic tube, and that K is equivalent to ΔP/(ΔV/V) (=VΔPV), Young [36,37] obtained the following formula from Equation (7):

On the basis of Newton's second law of motion, on the other hand, Moens [38] obtained the following formula from his experimental studies using a rubber tube filled with water:

where E and T are the elastic modulus and the thickness of tube wall, respectively, and k is a constant. Moens [38] showed that k is approximately equal to 0.9. This equation implies that a pulse wave in a fluid propagates faster in a stiffer tube than in a softer one; we know this by intuition. As Korteweg [39,40] also obtained the same formula separately, this formula is called Moens–Korteweg equation. Caro et al.[41] claimed that this equation had been first derived by Young [37].

Thereafter, Bramwell and Hill [42] derived the following equation for pulsatile blood flow:

where ρ is the density of blood. This form is clinically very useful, because it indicates that PWV can be calculated from pulse pressure ΔP and arterial dilation ΔD, both of which can be measured in vivo. Using Equation (2), this is related to vascular compliance Cv by:

As seen from the above two equations, PWV is proportional to (ΔPV)1/2 and to the inverse of Cv1/2, and therefore this represents arterial stiffness.

Equation (10) can be modified to the following:

This equation will be used later again.

Back to Top | Article Outline

Relation between stiffness parameter and pulse wave velocity

As mentioned above, stiffness parameter β does not depend on pressure and therefore it is considered to be very useful as a definite, patient-specific parameter representing arterial stiffness. On the other hand, PWV reflecting the stiffness of some length of an artery can be measured easily and noninvasively in practical medicine. Thus, it would be very profitable, if we could link stiffness parameter β with PWV.

The substitution of Equation (12) to Equation (6) gives the following equation:

The above equation indicates that pressure-independent stiffness parameter β is obtained from PWV, and SBP Psys and DBP Pdia, all of which can be measured clinically [14,43].

It should be noted at this point whether it is acceptable to link β determined from a short arterial segment with PWV measured from a long arterial tree. In general, arterial structure and morphology are heterogeneous even in normal, apparently healthy individuals; the structural and morphological irregularity of the arteries is remarkable in the advanced stage of atherosclerosis. In such cases, there should be locational differences in wall stiffness, and the stiffness of local arterial segment may be different from that in the long arterial tree. However, local lesions and stiffness are more or less reflected in the whole arteries, namely in the arterial tree, and therefore it would be reasonable to assume that PWV in the long arterial tree represents the average of local arterial stiffness. This question will be discussed later again.

Back to Top | Article Outline

Measurement of pulse wave velocity

Several methods have been utilized for the clinical measurement of PWV, which include carotid–femoral PWV (cfPWV) [44] and hfPWV proposed by Hasegawa [45].

Carotid–femoral PWV is the PWV obtained by dividing the distance between the common carotid artery and the femoral artery by the time difference between the time when the pulse reached the common carotid artery and the time when the pulse reached the femoral artery.

The measurement of this PWV is easy and has been widely used. However, the above mentioned time difference is not the real pulse propagation time, because the direction of pulse propagation to the carotid artery is opposite to that to the femoral artery. Although cfPWV has such a problem, many studies using this method have clarified the significance of arterial stiffness in many clinical aspects, such as its correlation with the severities of many arteriosclerotic diseases and the good predictor of cardiovascular events [13,46,47].

Hasegawa [45] proposed the hfPWV, which is the PWV between the origin of the aorta and the inguinal area including the iliac and the femoral arteries. The distance between the heart and the femoral artery is calculated from 1.3 times of the distance between the left side of the sternum at the second lib and the groin. As for the propagation time, it is difficult to identify the starting time of a pulse from the first heart sound. Therefore, the time (Tcf) between the starting time of the pulse at the origin of the aorta and its arrival time at the groin was divided into two time intervals: the time interval between the first heart sound and the pulse arrival time at the common carotid artery (Tc), and the time interval between the pulse-arriving time at the common carotid artery and the time when the pulse arrives at the groin (Tci). And, in place of Tc, the time interval between the second heart sound and the corresponding notch of the pulse in the common carotid artery (Tsc) is adopted, because Tc is essentially equal to Tsc.

Furthermore, Hasegawa [45], and Hasegawa and Arai [48] proposed modified hfPWV compensated by DBP at 80 mmHg to get rid of the influence of blood pressure at the time of measurement. So, Hasegawa's hfPWV was theoretically independent from blood pressure during measuring.

Considering the accessibility and the combination of the elastic artery and the muscular artery, Shirai et al.[14] recommended using PWV [heart-ankle PWV (haPWV)] between the heart and the ankle for Equation (13). This PWV is calculated from dividing the length (L) between the aortic valve and the ankle (tibial artery) by the pulse propagation time between the two locations.

The method for the determination of the propagation time is analogous to Hasegawa's method. Briefly, the time interval (T) between the starting time of pulse at the aortic valve and the reaching time to the ankle is divided into two: the time between the beginning of the first heart sound and the reaching time of pulse to the brachial artery (tb’), and the time between the reaching time to the upper brachial artery and that to the ankle (tba) (Fig. 7). In fact, it is difficult to accurately obtain tb’. Instead of tb’, therefore, the time between the beginning of the second heart sound and its corresponding notch of the pulse in the upper brachial artery (tb) is adopted; tb’ is essentially the same as tb. We evaluated T (=tab + tb’) using rabbits, and found that there was 4% difference (unpublished data). We think it is negligible, but this is one of the limitations of CAVI. Much better method might be pursued.

FIGURE 7

FIGURE 7

Regarding the utility of PWV as a marker of arterial stiffness, there have been many contributions to the field of surrogate markers of arteriosclerosis, predictor of cardiovascular events, and mortality. Laurent et al.[49] reported that PWV was significantly associated with all-cause and cardiovascular mortality, independent of previous cardiovascular diseases, age, and diabetes. Vlachopoulos et al.[50] also reported that aortic stiffness expressed as aortic PWV is a strong predictor of future cardiovascular events and all-cause mortality. Furthermore, the arterial stiffness measured with PWV is reported to be high in inflammatory bowel diseases [51], and Schillaci et al.[52] reported that PWV was high in polymyalgia rheumatica, and steroid therapy reduced it. Therefore, it can be concluded that the usefulness of measuring PWV for arterial stiffness has been almost established as surrogate markers not only of arteriosclerosis but also of the inflammatory reaction of the aorta. But, there remains the problem of the dependency of PWV on blood pressure at measuring time. It is difficult to evaluate the real role of hypertension on arterial stiffness, and also the effect of blood pressure control by various drugs in hypertensive patients.

Back to Top | Article Outline

CARDIO-ANKLE VASCULAR INDEX

The principle of cardio-ankle vascular index

Cardio-ankle vascular index has been defined as stiffness parameter β obtained from replacing PWV by the haPWV in Equation (13):

where Psys is the SBP, Pdia is the DBP, haPWV is PWV from the origin of the aorta to tibial artery at the ankle through the femoral artery, ρ is the blood density, and a and b are constants to convert the values of CAVI to those of Hasegawa's hfPWV [45,48]. The patent of CAVI equation was owned by Fukuda Denshi Co., Ltd. (Tokyo, Japan).

The Equation (14) indicates that CAVI is obtained by measuring blood pressure and haPWV. Blood pressure measured at the upper brachial artery is applied to CAVI. The blood pressures used in the Equation (14) should be the whole blood pressure from the origin of the aorta to the tibial artery at the ankle. But, it is impossible to measure the whole blood pressure. 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 might be representative of the whole blood pressure in the artery of the origin of aorta to the ankle [53]. This is one of the limitations of CAVI. The merits of CAVI are: it is obtained by noninvasively measuring PWV and blood pressure, and it is theoretically independent of blood pressure at the time of measurement.

The conversion of CAVI value to Hasegawa's PWV was due to the convenience in order to easily interpret the CAVI value referring to Hasegawa's PWV, the data of which were already available [48]. The population of the study using Hasegawa's PWV was 106 968 Japanese normal individuals without any arteriosclerotic diseases and risks such as hypertension, diabetes mellitus, and hyperlipidemia. But, CAVI was different from Hasegawa's PWV, reflecting the stiffness of the aorta, whereas CAVI reflected the stiffness of the arterial tree including the aorta, femoral artery, and tibial artery. Then, the interpretation of CAVI is quite different from Hasegawa's hfPWV in many aspects. This conversion is another limitation of CAVI.

Furthermore, there are questions we have to consider. First, is it acceptable to apply the stiffness parameter β determined at the segment of the artery to an index reflecting the stiffness of a long arterial tree? Second, is CAVI really independent of blood pressure?

One of the answers to the first question is shown in Fig. 8, which indicates that CAVI values have good correlations with the β-values ultrasonically measured from local segments of the descending thoracic aorta [54]. 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 less than 0.01. Horinaka et al.[55] also reported that regional values of stiffness parameter β of the ascending and descending aorta were both significantly correlated with the CAVI values. Furthermore, as described in next section (Clinical applications of Cardio-Ankle Vascular Index), CAVI showed high values in the patients with several arteriosclerotic diseases and coronary risk factors (refer to Table 1 and Table 2). Especially, Wohlfahrt et al.[56] studied the utility of transformed stiffness index β for some length of the artery [BETA = ln(systolic/diastolic pressure) × 2 blood viscosity/pulse pressure PWV2], which is essentially the same equation as that used to obtain CAVI. When carotid-ankle BETA and carotid-ankle PWV were compared, caBETA was more closely associated with coronary heart disease presence than caPWV. And, they concluded that beta transformation of PWV may increase its power in cardiovascular risk prediction. This study might also support the application of β theory to some length of the artery.

FIGURE 8

FIGURE 8

TABLE 1

TABLE 1

TABLE 2

TABLE 2

With regard to the second question, Shirai et al.[57] experimentally showed that CAVI values were not affected by blood pressure when blood pressure was reduced with the administration of β1 blocker, metoprolol (Fig. 9a). As is well known, β1 blocker decreases blood pressure by the reduction of heart muscle contraction, and therefore arterial stiffness measured as CAVI is not changed even though blood pressure changes.

FIGURE 9

FIGURE 9

Furthermore, we measured blood pressure, haPWV, and CAVI from six humans for 2 days six times per day, and studied the correlations of haPWV and CAVI with blood pressure. SBP and DBP were significantly correlated with haPWV, but not with CAVI (Fig. 10, unpublished data). These results support the independency of CAVI from blood pressure variations at the measuring time. Of course, arterial stiffness is influenced by chronic exposure of arterial wall to increased blood pressure. Resultantly, CAVI showed high values in patients with hypertension [69–71]. And most of those studies showed that the CAVI was less dependent on blood pressure than PWV [14,56,69], as described later.

FIGURE 10

FIGURE 10

As for the independency of CAVI from blood pressure at measuring time, there might be some range of applied blood pressure value. Hayashi et al. showed that the linear relationship between distension ratio and log P/Ps is observed between 50 and 200 mmHg, as shown in Fig. 2. Therefore, it might be said that CAVI is independent of blood pressure variations between 50 and 200 mmHg.

When α1 blocker, doxazosin, was administered, CAVI decreased as blood pressure decreased (shown in Fig. 9b). CAVI is apparently dependent on blood pressure. But, in this case, α1 blocker reduces blood pressure by the reduction of vascular smooth muscle contraction. This reduction of vascular smooth muscle contraction induced a decrease in arterial stiffness. Resultantly, CAVI was supposed to decrease. This result might imply that CAVI is reflecting the arterial stiffness composed of vascular smooth muscle contraction, as well as organic stiffness due to collagen, elastin, and calcification as the main components of arteriosclerosis.

Another feature of CAVI is that CAVI is measuring the stiffness of the various types of arteries such as the aorta, femoral artery, and tibial artery as a whole. The aorta is an elastic type, and the femoral and tibial arteries are muscular types. Each artery develops arteriosclerosis in different ways, and contraction response to vasoactive compounds might be different. Then, CAVI might be influenced by several factors or components concerning organic stiffness and functional stiffness. The analysis of those components and the merit of CAVI as a predictor of cardiovascular events require further studies.

In case of the patients with arteriosclerotic obliteration in the femoral artery, haPWV is extremely delayed. Resultantly, CAVI shows apparent lower values. 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 less than 0.9 (unpublished data).

Haesler et al.[58] reported that heart rate is a modulator of PWV. Then, we have studied the effect of heart rate on CAVI using rabbits by ventricular pacing with atrioventricular block under anesthesia. The results showed that CAVI did not change by heart rate change as shown in Fig. 11 (unpublished data). Therefore, it might be said that the CAVI is not affected by heart rate itself.

FIGURE 11

FIGURE 11

As for measuring conditions of CAVI, the daily rhythm of CAVI is essentially not observed in healthy people. But, in cases of pathological conditions such as hypertensive patients with morning surge, further studies were required. The effects of room temperature, food intake, smoking, and exercise on CAVI might be expected. It would be recommended that room temperature should be keep at 24–26°C during the measurement of CAVI. Moreover, hard exercise, smoking, and diet should be avoided 3–4 h prior to the measurement.

The reproducibility study of CAVI values measured in the same person (n = 22) five times on different days showed that the mean value of the coefficients of variation of persons was 3.8% [14].

Back to Top | Article Outline

Clinical applications of cardio-ankle vascular index

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 more than 250 in October 2014 (see Table 1). The implication of CAVI and its clinical significance will be discussed here.

Back to Top | Article Outline

Arteriosclerotic diseases

Effect of aging: Aging is known to be a strong risk factor for arteriosclerosis. CAVI of healthy people without cardiovascular risk factors gradually increases with aging from 20 to 70 years [59]. CAVI values in men are higher than those in women at all ages by 0.2 in average. Interestingly, CAVI clearly differentiates arterial stiffness between men and women.

Cerebral infarction: Cerebral infarctions are mainly caused by arteriosclerosis in cerebral arteries. CAVI values are high in patients with cerebral infarction [60]. Choi et al.[61] have reported that CAVI reflects cerebral small-vessel diseases in healthy young and middle-aged individuals.

Coronary arterial diseases: Several studies reported that CAVI showed high values in patients with coronary artery diseases [62,63]. Horinaka et al.[63] reported that CAVI increases as the number of coronary vessels with stenosis (>75%) increases (Fig. 12). Moreover, he used the analysis of receiver-operating characteristic curves, and reported that the diagnostic accuracy of coronary artery diseases was significantly higher in CAVI than in baPWV [63]. And they concluded better performance of CAVI than that of baPWV in predicting coronary artery diseases. The cut-off point of CAVI for the presence of coronary stenosis was 8.81 among patients with the suspicion of ischemic coronary artery diseases [62]. Essentially similar results have been reported by Yingchoncharoen et al.[64]. Izuhara et al.[65] also reported that CAVI, but not baPWV, was associated with the presence of arteriosclerosis in the carotid and the coronary arteries.

FIGURE 12

FIGURE 12

Carotid arteriosclerosis: There are several studies reporting the relationship between CAVI and carotid arteriosclerosis observed with ultrasonography [63,65,66]. Izuhara et al.[65] reported that CAVI has strong correlations with intima-medial thickness (IMT) and much stronger correlations with the plaque score. The combination of CAVI and IMT might be a very significant predictor of cerebral thrombosis in highly atherosclerotic patients.

Chronic kidney diseases: There are several studies describing that CAVI correlated with estimated glomerular filtration rate and cystatine C [67,68], and that CAVI is high in patients taking hemodialysis therapy [68,69].

Back to Top | Article Outline

Coronary risk factors and their control

Hypertension and its control: CAVI is essentially independent of the blood pressure at the measuring time, but is influenced by chronic exposure of arterial wall to increased blood pressure. Then, there are many reports that CAVI showed high values in hypertension [69–71]. And most of those reports showed that the correlation rates between CAVI and blood pressure were lower than those between PWV and blood pressure [69].

When alpha blocker, doxazosin, was administered, CAVI decreased with decrease in blood pressure (shown in Fig. 9b), as mentioned before. This correlation indicates that CAVI reflects smooth muscle contraction. The measurement of CAVI might contribute to the studies on the pathogenesis of hypertension.

When sunitinib maleate, which interferes with the growth of cancer cells and raises blood pressure as a side effect, was administered to a patient, the increase of CAVI was observed before the elevation of blood pressure [72]. This finding suggests that CAVI may reflect the stress to arteries induced by sunitinib maleate before hypertension occurs. Recently, Yoshida et al.[73] reported that CAVI was high in pregnant women complicated with preeclampsia. The effects of various hypertensive agents were described below.

There are several calcium channel blockers such as L-channel blocker type, T-channel blocker type, and N-channel blocker type. Kurata et al.[74] reported that amlodipine, L-channel blocker type, decreased CAVI (n = 10, 24 weeks); however, Miyashita et al.[75] showed that the decrease of CAVI by amlodipine was negligible, and not significant.

Sasaki et al.[76] compared the effects of efonidipine, T-channel blocker, and amlodipine (L-channel blocker). Although blood pressure was reduced at nearly the same rates (Fig. 13), CAVI was significantly reduced by efonidipine, but not by amlodipine. CAVI can differentiate the effects of different types of calcium channel blockers on the proper arterial stiffness.

FIGURE 13

FIGURE 13

The rennin–angiotensin–aldosterone system is an important regulator of blood pressure. There are several reports about the effects of angiotensin II receptor antagonists (ARBs) on CAVI. For example, telmisartan decreased CAVI [77], and candesartan reduced CAVI more than telmisartan and losartan [78]. Bokuda et al.[79] studied the effects of candesartan comparing with calcium channel blockers (CCBs). They showed that blood pressure significantly decreased in both groups at the same rates. However, candesartan significantly reduced CAVI, but not CCBs. Miyashita et al.[75] also reported that olmesartan decreased CAVI significantly, but not amlodipine, even though the decreased blood pressure rates were almost the same.

As for the treatments of hypertension, it has been reported that angiotensin 2 receptor antagonists or angiotensinogen-converting enzyme inhibitor had better effects on the prognosis of cardiovascular diseases than CCBs [80]. The coincidence of the superiority of ARB 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.

Diuretics such as thiazides are known to decrease blood pressure, but it is reported that insulin resistance might be provoked by diuretics. The direct effects of diuretics on CAVI have not been reported. But, it is reported that the combination of olmesartan and a thiazide had no advantage over the combination of olmesartan and azelnidipine with respect to improving CAVI in patients with hypertension [81].

At present, there are no available reports on the long-term effects of other antihypertensive agents such as α-blocker, β-blocker, and spironolactone on the CAVI values.

In summary, the above-mentioned reports suggest that CAVI could discriminate the effects of antihypertensive agents on proper arterial stiffness in addition to blood pressure control itself.

Diabetes mellitus and its control: CAVI is reported to be high in patients with diabetes mellitus [82,83]. Recent studies have shown that the glucose-lowering therapy decreased CAVI. Glimepiride decreases CAVI accompanied with improved glucose level [84]. CAVI is decreased by diphasic insulin aspart30/70 [85]. CAVI might be sensitive marker of diabetic angiopathy.

Dyslipidemia and its control: It has been reported that CAVI is related to low-density lipoprotein (LDL)-cholesterol level and also to cholesterol/high-density lipoprotein (HDL)-cholesterol ratio [86]. Whereas, Soska et al.[87] showed that CAVI was not high in heterozygous familiar hypercholesterolemic patients. Lipidosis induced by the infiltration of LDL to the arterial wall may not directly stiffen the arterial wall. CAVI may increase, when complicated lesions are developed. Administrations of strong statin, pitavastatin [88], and triglyceride-lowering agent eicosapentaenoic acid [89] were reported to decrease CAVI.

Metabolic syndrome and its control: Metabolic syndrome is the accumulation of diabetes mellitus, hypertension, and hypertriglyceridemia based on visceral fat accumulation, and now this is one of the most important risk factors for coronary artery diseases [90]. It is reported that CAVI is high in metabolic syndrome [86]. Moreover, the reduction of body weight improves CAVI in addition to many risk factors [86,91].

Miscellaneous factors: CAVI is high in smoking people [92], and is decreased by stopping smoking [93]. CAVI is elevated in the patients with sleep apnea syndrome [94], and is decreased by continuous positive airway pressure treatments [95].

The above-mentioned 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 (Tables 1 and 2).

Back to Top | Article Outline

Prognosis and cardio-ankle vascular index

There are a few studies dealing with the relationship between prognosis and CAVI. Kubota et al.[96] reported that the group with CAVI over 10 showed the high incidence of heart diseases and cerebrovascular accidents in 3 years (Fig. 14). As for the comparison with cfPWV, which is now regarded as the gold standard method, there still remains a question whether adding lower limbs in the evaluation of arterial stiffness could improve its prognostic power or the association with organ damage. Further studies comparing cfPWV, CAVI, and other measures of arterial stiffness are required.

FIGURE 14

FIGURE 14

Back to Top | Article Outline

Cardiac function and cardio-ankle vascular index

Arteries transport the blood ejected from the left ventricle to the peripheral organs. It is known that the elasticity of the arterial wall is involved in this function as Windkessel. High elasticity of the arterial wall reduces the load of the left ventricle. Takaki et al.[71] investigated the heart function in angina pectoris patients, in particular, the relationship between left ventricular diastolic function and CAVI. They studied CAVI and the peak velocities of early and late mitral inflow (E and A, respectively), and obtained the results showing that the E/A ratio negatively correlated with CAVI, and that the deceleration time of the E wave (EDCT) positively correlated with CAVI (Fig. 15).

FIGURE 15

FIGURE 15

Zhang et al. [97] measured CAVI during the therapy of congestive heart failure patients. CAVI decreased during the therapy, and the improvement of heart functions such as ejection fraction strongly correlated with CAVI.

These results indicate that there is a relationship between left ventricular function and vascular function as detected with CAVI, by which blood flow from the heart is smoothly and efficiently transported to peripheral organs. CAVI could be a useful indicator of vascular function.

Back to Top | Article Outline

Peripheral circulation and cardio-ankle vascular index

The aorta and large artery play the role of changing pulsatile flow from the heart to steady flow in the peripheral organs. The relationship between this vascular function and peripheral circulatory dynamics has not been adequately examined. CAVI might be used as a marker of the compliance of arteries (Fig. 16). Shiba et al.[98] reported that the magnitude of retinal artery pulsation correlated with CAVI, indicating that the arterial stiffness of large and middle-sized arteries regulates peripheral blood flow conditions.

FIGURE 16

FIGURE 16

Furthermore, it is occasionally observed that CAVI changes, whereas blood pressure does not change. Shimizu et al.[99] reported that CAVI increased significantly just after a huge earthquake, whereas blood pressure did not change significantly. Takahashi et al.[100] reported that the administration of beraprost sodium decreased CAVI, but did not change blood pressure.

These results suggest that CAVI might be another indicator of systemic circulation, in addition to blood pressure, in routine medical practice. It could be done by CAVI, not by PWV, because PWV is dependent on blood pressure at the time of measurement.

Back to Top | Article Outline

Summary of clinical studies

Cardio-ankle vascular index reflects the degree of arteriosclerosis. Moreover, CAVI shows high values in patients with coronary risk factors, and the control of the risks improves CAVI. The latter fact strongly indicates that CAVI reflects not only the organic stiffness of the arterial wall but also the functional stiffness composed of smooth muscle cell contracture. Further studies are required to confirm these, and also detailed studies should be carried out on the merits as a predictor of cardiovascular events.

Moreover, the relationships between the left ventricular function and CAVI, and also between the retinal artery pulsation and CAVI, may suggest that CAVI could be an adequate marker of vascular function as Windkessel.

In conclusion, CAVI, reflecting the arterial stiffness from the origin of the aorta to the tibial artery at the ankle, has been developed. It was based on the theory of stiffness parameter β. It was shown that 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. CAVI might open a new field for the studies on vascular functions.

Back to Top | Article Outline

ACKNOWLEDGEMENTS

Funding: No funding for this review paper.

Back to Top | Article Outline

Conflicts of interest

K.H. had no conflict of interest concerning this review paper.

T.Y. belongs to the Fukuda Denshi Co. Ltd, and was involved in the development of Vasera measuring CAVI.

A.T. had no conflict of interest concerning this review paper.

K.S. was a visiting professor of the Department of Vascular Function in Toho University, donated by Fukuda Denshi Co. Ltd., but has no patent and no financial profit.

Back to Top | Article Outline

Reviewers’ Summary Evaluations Reviewer 1

Cardio-Ankle Vascular Index (CAVI) has been proposed as a new index for the clinical assessment of arterial stiffness. This review explain the theoretical and experimental background of this index. A complete review of the literature of clinical applications of CAVI is presented, regarding various pathological conditions, the response to pharmacologic therapy and the relationship with the pathophysiology of systemic circulation.

Back to Top | Article Outline

Reviewer 2

This review article provides the theoretical background behind the calculation of the pressure-independent arterial stiffness index β. The authors calculate this index from cardio-ankle pulse wave velocity (haPWV) and blood pressure, which they term the cardio-ankle vascular index (CAVI). The authors present a growing body of evidence suggesting that CAVI may be a good marker for cardiovascular disease. It has been suggested haPWV has advantages over established heart-femoral pulse wave velocity due to technical ease and acceptability to the recipient. However, it is uncertain from this review if the calculation of a pressure independent parameter actually increases the prognostic potential.

Back to Top | Article Outline

REFERENCES

1. Asmar R. Asmar R, O’Rourke MF, Safar M. Pulse wave velocity principles and measurement. Arterial stiffness and pulse wave velocity . Amsterdam: Elsevier; 1999. 25–55.
2. Oliver JJ, Webb DJ. Noninvasive assessment of arterial stiffness and risk of atherosclerotic events. Arterioscler Thromb Vasc Biol 2003; 23:554–566.
3. Mattace-Raso FU, van der Cammen TJ, Hofman A, van Popele NM, Bos ML, Schalekamp MA, et al. Arterial stiffness and risk of coronary heart disease and stroke: the Rotterdam Study. Circulation 2006; 113:657–663.
4. O’Rourke MF, Staessen JA, Vlachopoulos C, Duprez D, Plante GE. Clinical applications of arterial stiffness: definitions and reference values. Am J Hypertens 2002; 15:426–444.
5. Koizumi M, Shimizu H, Shimomura K, Tomita Y, Oh-I S, Kudo T. Relationship between hyperinsulinemia and pulse wave velocity in moderately hyperglycemic patients. Diabetes Res Clin Pract 2003; 62:17–21.
6. Avest E, Holewijn S, Bredie SJ, van Tits LJ, Stalenhoef AF, de Graaf J. Pulse wave velocity in familial combined hyperlipidemia. Am J Hypertens 2007; 20:263–269.
7. Asmar R, Benetos SA, Topuchian J, Laurent P, Pannier B, Brisac AM, et al. Assessment of arterial distensibility by automatic pulse wave velocity measurement: Validation and clinical application studies. Hypertension 1995; 26:485–490.
8. Lemogoum D, Flores G, Van den Abeele W, Ciarka A, Leeman M, Degaute JP, et al. Validity of pulse pressure and augmentation index as surrogate measures of arterial stiffness during beta-adrenergic stimulation. J Hypertens 2004; 22:511–517.
9. Tanaka H, Munakata M, Kawano Y, Ohishi M, Shoji T, Sugawara J, et al. Comparison between carotid-femoral and brachial-ankle pulse wave velocity as measures of arterial stiffness. J Hypertens 2009; 27:2022–2027.
10. Hayashi K, Stergiopulos N, Meister J-J, Greenwald SE, Rachev A. Leondes C. Techniques in the determination of the mechanical properties and constitutive laws of arterial walls. Cardiovascular techniques, Vol II: biomechanical systems techniques and applications (Chapter 6) . Boca Raton: CRC Press; 2001. 1–61.
11. Hayashi K. Experimental approaches on measuring the mechanical properties and constitutive laws of arterial walls. J Biomech Eng 1993; 115:481–488.
12. Kimoto E, Shoji T, Shinohara K, Inaba M, Okuno Y, Miki T, et al. Preferential stiffening of central over peripheral arteries in type 2 diabetes mellitus. Diabetes 2003; 52:448–452.
13. Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L, et al. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertension 2001; 37:1236–1241.
14. Shirai K, Utino J, Otsuka K, Takata M. A novel blood pressure-independent arterial wall stiffness parameter: cardio-ankle vascular index (CAVI). J Atheroscler Thromb 2006; 13:101–107.
15. Peterson LH, Jensen RE, Parnell J. Mechanical properties of arteries in vivo. Circ Res 2006; 8:622–639.
16. Greenfield JC, Griggs DM Jr. Relation between pressure and diameter in main pulmonary artery of man. J Appl Physiol 1963; 18:557–559.
17. Gow BS, Taylor MG. Measurement of viscoelastic properties in the living dog. Circ Res 1968; 23:111–122.
18. Gow BS. The influence of vascular smooth muscle on the viscoelastic properties of blood vessels. Cardiovascular fluid dynamics (Bergel DH), vol. 2 . New York: Academic Press; 1972; 65–110.
19. Gow BS, Hadfield CD. The elasticity of canine and human coronary arteries with reference to post mortem changes. Circ Res 1979; 45:588–594.
20. Hayashi K, Handa H, Nagasawa S, Okumura A, Moritake K. Stiffness and elastic behavior of human intracranial and extracranial arteries. J Biomech 1980; 13:175–184.
21. Nagasawa S, Naruo Y, Okumura A, Moritake K, Hayashi K, Handa H. Mechanical properties of canine saphenous artery smooth muscle. Japanese Coll Angiol 1980; 20:313–320.
22. Hayashi K, Igarashi Y, Takamizawa K. Mechanical properties and hemodynamics in coronary arteries, New approaches in cardiac mechanics (Kitamura K, Abe H, Sagawa K). 1986; Tokyo: Gordon & Breach Science Publisher, 285–294.
23. Fischer GM, Llaurado JG. Collagen and elastin content in canine arteries selected from functionally different vascular beds. Circ Res 1966; 19:394–399.
24. Cox RH. Passive mechanics and connective tissue composition of canine arteries. Am J Physiol 1978; 234:H533–H541.
25. Kawasaki T, Sasayama S, Yagi S, Asakawa T, Hirai T. Noninvasive assessment of the age related changes in stiffness of major branches of the human arteries. Cardiovasc Res 1987; 21:678–687.
26. Moritake K, Handa H, Okumura A, Hayashi K, Niimi H. Stiffness of cerebral arteries: its role in the pathogenesis of cerebral aneurysms. Neurol Med Chir (Tokyo) 1974; 14 (Pt 1):47–53.
27. Hayashi K, Ide K, Matsumoto T. Aortic walls in atherosclerotic rabbits: mechanical study. J Biomech Eng 1994; 116:284–293.
28. Hayashi K. Mechanical properties of soft tissues and arterial walls, Biomechanics of soft tissue in cardiovascular systems (Holzapfel GA, Ogden RW). 2003; Wien: Springer-Verlag, 15–64.
29. Ogawa T, Shimada M, Ishida H, Matsuda N, Fujiu A, Ando Y, et al. Relation of stiffness parameter beta to carotid arteriosclerosis and silent cerebral infarction in patients on chronic hemodialysis. Int Urol Nephrol 2009; 41:739–745.
30. Hajdu MA1, Baumbach GL. Mechanics of large and small cerebral arteries in chronic hypertension. Am J Physiol 1994; 266 (3 Pt 2):H1027–H1033.
31. Izzard AS, Horton S, Heerkens EH, Shaw L, Heagerty AM. Middle cerebral artery structure and distensibility during developing and established phases of hypertension in the spontaneously hypertensive rat. J Hypertens 2006; 24:875–880.
32. Hayashi K, Sugimoto T. Biomechanical response of arterial wall to DOCA-salt hypertension in growing and middle-aged rats. J Biomech 2007; 40:1583–1593.
33. Hayashi K, Naiki T. Adaptation and remodeling of vascular wall: biomechanical response to hypertension. J Mech Behav Biomed Mater 2009; 2:3–19.
34. Araki T, Emoto M, Teramura M, Yokoyama H, Mori K, Hatsuda S, et al. Effect of adiponectin on carotid arterial stiffness in type 2 diabetic patients treated with pioglitazone and metformin. Metabolism 2006; 55:996–1001.
35. Nichols WM, O’Rourke MF. McDonald's blood flow in arteries. Sevenoaks, Kent: Edward Arnold; 1990.
36. Young T. Hydraulic Investigations. Subservient to an Intended Croonian Lecture on the motion of the blood. Phil Trans R Soc Lond 1808; 98:164–186.
37. Young T. The Croonian Lecture: on the functions of the heart and arteries. Phil Trans R Soc Lond 1809; 99:1–31.
38. Moens AI Die Pulskurve [The Pulse Curve]. Leiden, The Netherlands: E. J. Brill; 1898.
39. Korteweg DJ Over de Voortplantingssnelheid van den Pols (On the speed of propagation of the pulse), PhD Thesis, Leiden; 1877; Bd. V, pp.525–542.
40. Korteweg DJ. Uber die Fortpflanzungsgeschwindigkeit des Schalles in Elastischen Rohren. Ann Phys Chem 1878; 5:52–539.
41. Caro CG, Pedley TJ, Schroter RC, Seed WA. The mechanics of the circulation. Oxford: Oxford University Press; 1978.
42. Bramwell JC, Hill AV. The velocity of the pulse wave in man. Proc R Soc London Series B 1926; 93:298–306.
43. Shirai K, Hiruta N, Song M-Q, Kurosu T, Suzuki J, Tomaru T, et al. Cardio-ankle vascular index (CAVI) as a novel indicator of arterial stiffness: theory, evidence and perspectives. J Atheroscler Thromb 2011; 18:924–938.
44. Frank O. Theorie der Pulswellen. Zeitschrift fur Biologie 1926; 85:91–130.
45. Hasegawa M. Fundamental research on human aortic pulse wave velocity. Jikei Med J 1970; 85:742–760.
46. Laurent S, Katsahian S, Fassot C, Tropeano AI, Gautier I, Laloux B, et al. Aortic stiffness is an independent predictor of fatal stroke in essential hypertension. Stroke 2003; 34:1203–1206.
47. Benetos A, Waeber B, Izzo J, Mitchell G, Resnick L, Asmar R, et al. Influence of age, risk factors, and cardiovascular and renal disease on arterial stiffness: clinical applications. Am J Hypertens 2002; 15:1101–1108.
48. Hasegawa M, Arai C. Clinical estimation of vascular elastic function and practical application. Connect Tissue 1995; 27:149–157.
49. Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L, et al. Aortic stiffness is an independent predictor of all-cause and cardiovascular mortality in hypertensive patients. Hypertens 2001; 37:1236–1241.
50. Vlachopoulos C, Aznaouridis K, Stefanadis C. Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysis. J Am Coll Cardiol 2010; 55:1318–1327.
51. Zanoli L, Rastelli S, Inserra G, Lentini P, Valvo E, Calcagno E, et al. Increased arterial stiffness in inflammatory bowel diseases is dependent upon inflammation and reduced by immunomodulatory drugs. Atheroscler 2014; 234:346–351.
52. Schillaci G, Bartoloni E, Pucci G, Pirro M, Settimi L, Alunno A, et al. Aortic stiffness is increased in polymyalgia rheumatica and improves after steroid treatment. Ann Rheum Dis 2012; 71:1151–1156.
53. Nichols W O’Rourke McDonald's blood flow in arteries. M Hodder Arnold fifth edition CRC Press; 2005. pp. 88.
54. Takaki A, Ogawa H, Wakeyama T, Iwami T, Kimura M, Hadano Y, et al. Cardio-ankle vascular index is a new noninvasive parameter of arterial stiffness. Circ J 2007; 71:1710–1714.
55. Horinaka S, Yagi H, Ishimura K, Fukushima H, Shibata Y, Sugawara R, et al. 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.
56. Wohlfahrt P, Krajčoviechová A, Seidlerová J, Mayer O, Bruthans J, Filipovský J, et al. Arterial stiffness parameters: how do they differ? Atheroscler 2013; 231:359–364.
57. Shirai K, Song M, Suzuki J, Kurosu T, Oyama T, Nagayama D, et al. Contradictory effects of β1- and α1-aderenergic receptor blockers on cardio-ankle vascular stiffness index (CAVI): the independency of CAVI from blood pressure. J Atheroscler Thromb 2011; 18:49–55.
58. Haesler E, Lyon X, Pruvot E, Kappenberger L, Hayoz D. Confounding effects of heart rate on pulse wave velocity in paced patients with a low degree of atherosclerosis. J Hypertens 2004; 22:1317–1322.
59. Namekata T, Suzuki K, Ishizuka N, Shirai K. Establishing baseline criteria of cardio-ankle vascular index as a new indicator of arteriosclerosis: a cross-sectional study. BMC Cardiovasc Disord 2011; 11:51 doi:10.1186/1471-2261-11-51.
60. Suzuki J, Sakakibara R, Tomaru T, Tateno F, Kishi M, Ogawa E, et al. Stroke and cardio-ankle vascular stiffness index. J Stroke Cerebrovasc Dis 2011; 22:171–175.
61. Choi S-Y, Park HE, Seo H, Kim M, Cho S-H, Oh B-H. Arterial stiffness using cardio-ankle vascular index reflects cerebral small vessel disease in healthy young and middle aged subjects. J Atheroscler Thromb 2013; 20:178–185.
62. Nakamura K, Tomaru T, Yamamura S, Miyashita Y, Shirai K, Noike H. Cardio-ankle vascular index is a candidate predictor of coronary atherosclerosis. Circ J 2008; 72:598–604.
63. Horinaka S, Yabe A, Yagi H, Ishimura K, Hara H, Iemura T, et al. Comparison of atherosclerotic indicators between cardio ankle vascular index and brachial ankle pulse wave velocity. Angiology 2009; 60:468–476.
64. Yingchoncharoen T, Limpijankit T, Jongjirasirl S, Laothamatas J, Yamwong S, Sritara P. Arterial stiffness contributes to coronary artery disease risk prediction beyond the traditional risk score (RAMA-EGAT score). Heart Asia 2012; 4:77–82.
65. Izuhara M, Shioji K, Kadota Y, Baba O, Takeuchi Y, Uegaito T, et al. Relationship of cardio-vascular index (CAVI) to carotid and coronary arteriosclerosis. Circ J 2008; 72:1762–1767.
66. Miyoshi T, Doi M, Hirohata S, Sakane K, Kamikawa S, Kitawaki T, et al. Cardio-ankle vascular index is independently associated with the severity of coronary atherosclerosis and left ventricular function in patients with ischemic heart disease. J Atheroscler Thromb 2010; 17:249–258.
67. Nakamura K, Iiduka T, Takahashi M, Shimizu S, Mikamo H, Nakagami T, et al. Association between cardio-ankle vascular index and serum cystain c levels in patients with cardiovascular risk factor. J Atheroscler Thromb 2009; 16:371–379.
68. Kubozono T, Miyata H, Uegama K, Nagaki A, Hamasaki S, Kusano K, et al. Association between arterial stiffness and estimated glomerular filtration rate in the Japanese general population. J Atheroscler Thromb 2009; 16:840–845.
69. Ueyama K, Miyata M, Kubozono T, Nagaki A, Hamasaki S, Ueyama S, et al. Noninvasive indices of arterial stiffness in hemodialysis patients. Hypertens Res 2009; 32:716–720.
70. Okura T, Watanabe S, Kurata M, Manabe S, Koresawa M, Irita J, et al. Relationship between cardio-ankle vascular index (CAVI) and carotid atherosclerosis in patients with essential hypertension. Hypertens Res 2007; 30:335–340.
71. Takaki A, Ogawa H, Wakeyama T, Iwami T, Kimura M, Hadano Y, et al. Cardio-ankle vascular index is superior to brachial-ankle pulse wave velocity as an index of arterial stiffness. Hypertens Res 2008; 31:1347–1355.
72. Masugata H, Senda S, Himoto T, Okuyama H, Inukai M, Murao K, et al. Early detection of hypertension in a patient treated with sunitinib by measuring cardio-ankle vascular index. Tohoku J Exp Med 2009; 218:115–119.
73. Yoshida A, Suhiyama T, Sagawa N. Assessment of the cardio-ankle vascular index in pregnant women complicated with hypertensive disorders. ISRN Obstet Gynecol 2011; 2011:919816 doi:10.5402/2011/919816.
74. Kurata M, Okura T, Watanabe S, Enomoto D, Johtoku M, Miyoshi K, et al. Effects of amlodipine and candesartan on arterial stiffness estimated by cardio-ankle vascular index in patients with essential hypertension: a 24-week study. Curr Ther Res Clin Exp 2008; 69:412–422.
75. Miyashita Y, Saiki A, Endo K, Ban N, Yamaguchi T, Kawana H, et al. Effects of olmesartan, an angiotensin II receptor blocker, and amlodipine, a calcium channel blocker, on cardio-ankle vascular index (CAVI) in type 2 diabetic patients with hypertension. J Atheroscler Tromb 2009; 16:621–626.
76. Sasaki H, Saiki A, Endo K, Ban N, Yamaguchi T, Kawana H, et al. Protective effects of efonidipine, a T- and L-type calcium channel blocker, on renal function and arterial stiffness in type 2 diabetic patients with hypertension and nephropathy. J Atheroscler Thromb 2009; 16:568–575.
77. Kinouchi K, Ichihara A, Sakoda M, Kurauchi-Mito A, Murohashi-Bokuda K, Itoh H. Effects of telmisartan on arterial stiffness assessed by the cardiac-ankle vascular index in hypertensive patients. Kidney Blood Press Res 2010; 33:304–312.
78. Uehara G, Takeda H. Relative effects of telmisartan, candesartan and losartan on alleviating arterial stiffness inpatients with hypertension complicated by diabetes mellitus: an evaluation using the cardiovascular index. J Int Med Res 2008; 36:1094–1102.
79. Bokuda K, Ichihara A, Sakoda M, Mito A, Kinouchi K, Itoh H. Blood pressure-independent effect of candesartan on cardio-ankle vascular index in hypertensive patients with metabolic syndrome. Vasc Health Risk Manag 2010; 6:571–578.
80. Ogihara T, Fujimoto A, Nakao K, Saruta T. ARB candesartan and CCB amlodipine in hypertensive patients: the CASE-J trial. Exert Rev Cardiovasc Ther 2008; 6:1195–1201.
81. Ishimitsu T, Numabe A, Masuda T, Akabane T, Okamura A, Minami J, et al. Angiotensin-II receptor antagonist combined with calcium channel blocker or diuretic for essential hypertension. Hypertens Res 2009; 32:962–968.
82. Namekata T, Suzuki K, Ishizuka N, Nakata M, Shirai K. Association of cardio-ankle vascular index with cardiovascular disease risk factors and coronary heart disease among Japanese urban workers and their families. J Clin Exp Cardiolog 2012; doi:10.4172/2155-9880.51-003.
83. Ibata J, Sasaki H, Kakimoto T, Matsuno S, Nakatani M, Kobayashi M, et al. Cardio-ankle vascular index measures arterial wall stiffness independent of blood pressure. Diabetes Res Clin Pract 2008; 80:265–270.
84. Nagayama D, Saiki A, Endo K, Yamaguchi T, Ban N, Kawana H, et al. Improvement of cardio-vascular vascular index by glimepiride in type 2 diabetic patients. Int J Clin Pract 2010; 64:1796–1801.
85. Ohira M, Endo K, Oyama T, Yamaguchi T, Ban N, Kawana H, et al. Improvement of postprandial hyperglycemia and arterial stiffness upon switching from premixed human insulin 30/70 to biphasic insulin aspart 30/70. Metabolism 2011; 60:78–85.
86. Satoh N, Shimatsu A, Kato Y, Araki K, Koyama K, Okajima T, et al. Evaluation of the cardio-ankle vascular index, a new indicator of arterial stiffness independent of blood pressure, in obese and metabolic syndrome. Hypertens Res 2008; 31:1921–1930.
87. Soska V, Dobsak P, Dusek L, Shirai K, Jarkovsky J, Novakova M, et al. Cardio-ankle vascular index in heterozygous familial hypercholesterolemia. J Atheroscler Thromb 2012; 19:453–461.
88. Miyashita Y, Endo K, Saiki A, Ban N, Yamaguchi T, Kawana H, et al. Effects of pitavastatin, a 3-hydroxy-3-methylglutaryl coenzyme a reductase inhibitor, on cardio-ankle vascular index in type 2 diabetic patients. J Atheroscler Thromb 2009; 16:539–545.
89. Satoh N, Shimatsu A, Kotani K, Himeno A, Majima T, Yamada K, et al. Highly purified eicosapentaenoic acid reduces cardio-ankle vascular index in association with decreased serum amyloid A-LDL in metabolic syndrome. Hypertens Res 2009; 32:1004–1008.
90. Matsuzawa Y, Funahashi T, Nakamura T. The concept of metabolic syndrome: contribution of visceral fat accumulation and its molecular mechanism. J Atheroscler Thromb 2011; 18:629–639.
91. Nagayama D, Endo K, Ohira M, Yamaguchi T, Nagumo A, Saiki A, et al. Effects of body weight reduction on cardio-ankle vascular index (CAVI). Obes Res Clin Pract 2011; 7:e139–e145.
92. Kubozono T, Miyata M, Uegama K, Hamasaki S, Kusano K, Kubosono O, Tei C. Acute and chronic effects of smoking on arterial stiffness. Circ J 2011; 95:698–702.
93. Noike H, Nakamura K, Sugiyama Y, Iizuka T, Shimizu K, Takahashi M, et al. Changes in cardio-ankle vascular índex in smoking cessation. J Atheroscler Thromb 2010; 17:517–525.
94. Kumagai T, Kasai T, Kato M, Naito R, Maeno K, Kasagi S, et al. Establishment of the cardio-ankle vascular index in patients with obstructive sleep apnea. Chest 2009; 36:779–786.
95. Kasai T, Inoue K, Kumagai T, Kato M, Kawana F, Sagara M, et al. Plasma pentraxin3 and arterial stiffness in men with obstructive sleep apnea. Am J Hypertens 2011; 24:401–407.
96. Kubota Y, Maebuchim D, Takei M, Inui Y, Sudo Y, Ikegami Y, et al. Cardio-Ankle Vascular Index is a predictor of cardiovascular events. Artery Res 2011; 5:91–96.
97. Zhang C, Ohira M, Iizuka T, Mikamo H, Nakagami T, Suzuki M, et al. Cardio-ankle vascular index relates to left ventricular ejection fraction in patients with heart failure. A retrospective study. Int Heart J 2013; 54:216–221.
98. Shiba T, Takahashi M, Hori Y, Maeno T, Shirai K. Optic nerve head circulation determined by pulse wave analysis is significantly correlated with cardio ankle vascular index, left ventricular diastolic function, and age. J Atheroscler Thromb 2012; 19:999–1005.
99. Shimizu K, Takahashi M, Shirai K. A huge earthquake hardened arterial stiffness monitored with cardio-ankle vascular index. J Atheroscler Thromb 2013; 20:503–511.
100. Takahashi M, Shiba T, Hirano K, Hitsumoto T, Shirai K. Acute decrease of cardio-ankle vascular index with the administration of beraprost sodium. J Atheroscler Thromb 2012; 19:479–484.
Keywords:

arterial stiffness; arteriosclerosis; cardio-ankle vascular index; cardiovascular risk; pulse wave velocity; stiffness parameter β

Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.