Journal of Atherosclerosis and Thrombosis Vol. 23, No. 2
155
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 progression of arteriosclerosis. So far, many parameters have been proposed to quantitatively represent arterial stiffness. Among these, pulse wave velocity (PWV) has been most frequently applied to clinical medicine because those could be measured simply and non-invasively. PWV had established the usefulness of measuring arterial wall stiffness. However, PWV essentially depends on blood pressure at the time of measurement. Therefore, PWV is not appropriate as a parameter for the evaluation of arterial stiffness, particularly for the studies involving blood pressure changes. On the other hand, stiffness parameter 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). Therefore, CAVI does not depend on blood pressure changes during the measurements; CAVI could represent the stiffness of the arterial tree from the origin of the aorta to the ankle. Many clinical studies obtained from CAVI are being accumulated. CAVI showed high value in arteriosclerotic diseases, such as coronary artery diseases, cerebral infarction, and chronic kidney diseases, and also in majority of people with various coronary risk factors. The improvement of those risk factors decreased CAVI. Furthermore, the role of CAVI as a predictor of cardio-vascular events was reported recently. We review the clinical studies on CAVI and discuss the clinical usefulness of CAVI as a candidate surrogate end-point marker for cardiovascular disease. J Atheroscler Thromb, 2016; 23: 155-168. Key words: Cardio-ankle vascular index, Arterial stiffness, Stiffness parameter 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, 2858741, Japan E-mail: [email protected] Received: September 30, 2015 Accepted for publication: October 27, 2015
properties accompanying the progression of arteriosclerosis. Then, many parameters have been proposed to quantitatively represent arterial stiffness 1, 2). Among these, pulse wave velocity (PWV) 3) has been most frequently applied to clinical medicine because those could be measured simply and non-invasively. Many studies using carotid-femoral PWV (cfPWV) 4) and brachial-ankle PWV (baPWV) 5) had almost established the meaning of measuring arterial wall stiffness. However, PWV essentially depends on the blood pressure at the time of measurement 6). Therefore, PWV is
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Saiki et al .
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 brachial pulse wave and the rise of ankle pulse wave; t b = time between aortic valve closing sound and the notch of brachial pulse wave; t´b = time between aortic valve opening sound and the rise of brachial pulse wave 10).
not appropriate as a parameter for the evaluation of arterial stiffness, particularly for the studies involving blood pressure changes. In order to solve the problem of dependency on blood pressure, cardio-ankle vascular index (CAVI) has been developed in Japan 7). CAVI originated from the theory of stiffness parameter β8, 9), which is applied to the local part of the artery expressed as logarithm 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 Δ pressure was related to the square of pulse wave velocity 7, 10). Then, CAVI could represent the stiffness of the arterial tree from the origin of the aorta to the ankle. In many clinical studies, CAVI showed high value in arteriosclerotic diseases, such as coronary artery diseases (CADs), cerebral infarction, and chronic kidney diseases, and in majority of people with various coronary risk factors. Furthermore, the
improvement in most of those risk factors decreased CAVI. The role of CAVI as a predictor of cardio-vascular events was reported recently. In this study, we review the clinical studies on CAVI and discuss the clinical usefulness of CAVI as a candidate surrogate end-point marker for cardiovascular disease. The Principle of CAVI and Measuring Method CAVI was originally derived from the stiffness parameter β proposed by Hayashi 8) and Kawasaki 9) and was expanded to some length of the artery with the application of the modified Bramwell-Hill equation 7, 10). CAVI adopted PWV from the origin of the aorta to the ankle (heart-ankle PWV; haPWV). CAVI = a[(2ρ/ΔP)×ln(Ps/Pd)×haPWV2]＋b ----Equation 1 (Fig. 1) Ps is the systolic blood pressure, Pd is the diastolic blood pressure, haPWV is PWV from the origin of the aorta to the tibial artery at the ankle through the femoral artery, ρ is the blood density, and a and b
CAVI as a Surrogate Marker for CVD
are constants to convert the values of CAVI to those of Hasegawa’s heart-femoral PWV (hfPWV) 11, 12). Equation 1 indicates that CAVI can be obtained by measuring blood pressure and haPWV. The blood pressures used in the Equation 1 should be the mean blood pressure from the origin of the aorta to the tibial artery at the ankle. In case of CAVI, the blood pressure in the upper brachial artery was adopted. This is based on the assumption that the blood pressure in the brachial artery may be representative of the mean blood pressure in the artery of the origin of the aorta to the ankle 13). As CAVI is essentially derived from the stiffness parameter β, CAVI values have good correlations with the β values ultrasonically measured from the local segments of the descending thoracic aorta 14). Similar results were also obtained from the common carotid artery. In both arteries, the correlation coefficients between CAVI and β were 0.67 and 0.39, respectively, both with the confidence coefficients of ＜ 0.01. Horinaka et al. 15) also reported that regional values of stiffness parameter 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 β 1-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 increasing year by year and has reached ＞ 300 in September 2015.
157
Fig. 2. Correlation between CAVI and stiffness parameter β in the thoracic aorta 15).
Factors Affecting CAVI Because measuring conditions, room temperature, food intake, smoking, and rigorous exercise affected CAVI value, it is recommended that room temperature should be keep at 24-26 ℃ during the measurement of CAVI. Moreover, rigorous exercise, smoking, and diet should be avoided 3-4 h prior to the measurement. CAVI is invalid when ankle brachial index (ABI), which is the ratio of mean blood pressure in the tibial artery to that in the brachial artery, is ＜ 0.9. 1. Aging and Gender CAVI of healthy people without cardiovascular risk factors gradually increases with age from 20 to 70 years 17) (Fig. 4). CAVI values in men are higher than those in women at all ages by 0.2 in average. Choi et al. 18) reported that CAVI is a sensitive marker of the arterial aging process, above and beyond conventional arm blood pressure in Korean people (CAVI = 5.0＋ 0.048×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. 5 19). Nakamura et al. 20) reported that the cutoff point of CAVI for the presence of coronary stenosis was 8.91 among the patients with a suspicion of ischemic CAD. Izuhara et al. 21) reported the multiple logistic analysis revealing that CAVI, but not baPWV,
158
Saiki et al .
Mean㼼SE *P
155
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 progression of arteriosclerosis. So far, many parameters have been proposed to quantitatively represent arterial stiffness. Among these, pulse wave velocity (PWV) has been most frequently applied to clinical medicine because those could be measured simply and non-invasively. PWV had established the usefulness of measuring arterial wall stiffness. However, PWV essentially depends on blood pressure at the time of measurement. Therefore, PWV is not appropriate as a parameter for the evaluation of arterial stiffness, particularly for the studies involving blood pressure changes. On the other hand, stiffness parameter 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). Therefore, CAVI does not depend on blood pressure changes during the measurements; CAVI could represent the stiffness of the arterial tree from the origin of the aorta to the ankle. Many clinical studies obtained from CAVI are being accumulated. CAVI showed high value in arteriosclerotic diseases, such as coronary artery diseases, cerebral infarction, and chronic kidney diseases, and also in majority of people with various coronary risk factors. The improvement of those risk factors decreased CAVI. Furthermore, the role of CAVI as a predictor of cardio-vascular events was reported recently. We review the clinical studies on CAVI and discuss the clinical usefulness of CAVI as a candidate surrogate end-point marker for cardiovascular disease. J Atheroscler Thromb, 2016; 23: 155-168. Key words: Cardio-ankle vascular index, Arterial stiffness, Stiffness parameter 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, 2858741, Japan E-mail: [email protected] Received: September 30, 2015 Accepted for publication: October 27, 2015
properties accompanying the progression of arteriosclerosis. Then, many parameters have been proposed to quantitatively represent arterial stiffness 1, 2). Among these, pulse wave velocity (PWV) 3) has been most frequently applied to clinical medicine because those could be measured simply and non-invasively. Many studies using carotid-femoral PWV (cfPWV) 4) and brachial-ankle PWV (baPWV) 5) had almost established the meaning of measuring arterial wall stiffness. However, PWV essentially depends on the blood pressure at the time of measurement 6). Therefore, PWV is
156
Saiki et al .
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 brachial pulse wave and the rise of ankle pulse wave; t b = time between aortic valve closing sound and the notch of brachial pulse wave; t´b = time between aortic valve opening sound and the rise of brachial pulse wave 10).
not appropriate as a parameter for the evaluation of arterial stiffness, particularly for the studies involving blood pressure changes. In order to solve the problem of dependency on blood pressure, cardio-ankle vascular index (CAVI) has been developed in Japan 7). CAVI originated from the theory of stiffness parameter β8, 9), which is applied to the local part of the artery expressed as logarithm 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 Δ pressure was related to the square of pulse wave velocity 7, 10). Then, CAVI could represent the stiffness of the arterial tree from the origin of the aorta to the ankle. In many clinical studies, CAVI showed high value in arteriosclerotic diseases, such as coronary artery diseases (CADs), cerebral infarction, and chronic kidney diseases, and in majority of people with various coronary risk factors. Furthermore, the
improvement in most of those risk factors decreased CAVI. The role of CAVI as a predictor of cardio-vascular events was reported recently. In this study, we review the clinical studies on CAVI and discuss the clinical usefulness of CAVI as a candidate surrogate end-point marker for cardiovascular disease. The Principle of CAVI and Measuring Method CAVI was originally derived from the stiffness parameter β proposed by Hayashi 8) and Kawasaki 9) and was expanded to some length of the artery with the application of the modified Bramwell-Hill equation 7, 10). CAVI adopted PWV from the origin of the aorta to the ankle (heart-ankle PWV; haPWV). CAVI = a[(2ρ/ΔP)×ln(Ps/Pd)×haPWV2]＋b ----Equation 1 (Fig. 1) Ps is the systolic blood pressure, Pd is the diastolic blood pressure, haPWV is PWV from the origin of the aorta to the tibial artery at the ankle through the femoral artery, ρ is the blood density, and a and b
CAVI as a Surrogate Marker for CVD
are constants to convert the values of CAVI to those of Hasegawa’s heart-femoral PWV (hfPWV) 11, 12). Equation 1 indicates that CAVI can be obtained by measuring blood pressure and haPWV. The blood pressures used in the Equation 1 should be the mean blood pressure from the origin of the aorta to the tibial artery at the ankle. In case of CAVI, the blood pressure in the upper brachial artery was adopted. This is based on the assumption that the blood pressure in the brachial artery may be representative of the mean blood pressure in the artery of the origin of the aorta to the ankle 13). As CAVI is essentially derived from the stiffness parameter β, CAVI values have good correlations with the β values ultrasonically measured from the local segments of the descending thoracic aorta 14). Similar results were also obtained from the common carotid artery. In both arteries, the correlation coefficients between CAVI and β were 0.67 and 0.39, respectively, both with the confidence coefficients of ＜ 0.01. Horinaka et al. 15) also reported that regional values of stiffness parameter 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 β 1-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 increasing year by year and has reached ＞ 300 in September 2015.
157
Fig. 2. Correlation between CAVI and stiffness parameter β in the thoracic aorta 15).
Factors Affecting CAVI Because measuring conditions, room temperature, food intake, smoking, and rigorous exercise affected CAVI value, it is recommended that room temperature should be keep at 24-26 ℃ during the measurement of CAVI. Moreover, rigorous exercise, smoking, and diet should be avoided 3-4 h prior to the measurement. CAVI is invalid when ankle brachial index (ABI), which is the ratio of mean blood pressure in the tibial artery to that in the brachial artery, is ＜ 0.9. 1. Aging and Gender CAVI of healthy people without cardiovascular risk factors gradually increases with age from 20 to 70 years 17) (Fig. 4). CAVI values in men are higher than those in women at all ages by 0.2 in average. Choi et al. 18) reported that CAVI is a sensitive marker of the arterial aging process, above and beyond conventional arm blood pressure in Korean people (CAVI = 5.0＋ 0.048×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. 5 19). Nakamura et al. 20) reported that the cutoff point of CAVI for the presence of coronary stenosis was 8.91 among the patients with a suspicion of ischemic CAD. Izuhara et al. 21) reported the multiple logistic analysis revealing that CAVI, but not baPWV,
158
Saiki et al .
Mean㼼SE *P
