Principles and usefulness of the cardio-ankle vascular index (CAVI): a new global arterial stiffness index

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1 European Heart Journal Supplements (2017) 19 (Supplement B), B4 B10 The Heart of the Matter doi: /eurheartj/suw058 Principles and usefulness of the cardio-ankle vascular index (CAVI): a new global arterial stiffness index Roland Asmar* Clinical Research Department, Foundation-Medical Research Institutes (F-MRI), 11 bis boulevard Delessert, Paris, France KEYWORDS Arterial stiffness; Large artery; Cardio-Ankle Vascular Index; Pulse wave velocity; Beta index Arterial stiffness has been reported as an independent predictor of morbidity and mortality in different populations. Although measurement of pulse wave velocity is considered the gold standard for the assessment of arterial stiffness, it has several limitations: sensitivity to the blood pressure level, complexity of the measurement procedure, the bias of distance determination, etc. Recently, the cardio-ankle vascular index (CAVI), based on the beta index, measured using the VaSera device, has been introduced as an index of arterial stiffness from the origin of the aorta to the ankle. Theoretically, this new parameter and device present some advantages such as a relative independency from the blood pressure level at the time of measurement, high reproducibility and sensitivity, and a user-friendly device with a simplified procedure. In this article, several methodological aspects and clinical applications of CAVI have been reviewed: the principles of CAVI, its normal values according to age and gender, the thresholds used for diagnosis, the effect of cardiovascular risk factors and diseases on CAVI, its prognostic value and its eventual improvement after treatment with nonpharmacological intervention and various pharmacological agents. Introduction Arterial functional and structural alterations have been described at early stages of several cardiovascular diseases. 1,2 Recently, there has been growing recognition that the disease of interest is in the arterial wall properties. 3 Therefore, several non-invasive methods have been introduced to assess aspects or parameters of the arterial wall structure and function. 3,4 Some of these methods are used to assess regional arterial stiffness using pulse wave velocity (PWV) or cardio-ankle vascular index (CAVI) whereas others are used to assess either local or systemic arterial stiffness or to measure parameters such as central blood pressure, wave reflection, augmentation index, etc. 4 Among these methods, PWV has been considered as the gold standard measurement of arterial stiffness; thanks to large numbers of studies which show PWV as an independent marker of organ damage and an independent *Corresponding author. Tel: þ , ra@cmcv.org predictor of cardiovascular morbidity as well as cardiovascular and all-cause mortality Several limitations and sources of inaccuracy in the measurement of PWV have been described. First, the determination of the transit distance of the pressure waves using measurements on the body surface may not reliably represent the true length of the arterial segment, especially with obesity and when the arteries become more tortuous with age. Second, carotidfemoral PWV is not a simple unidirectional path length for the pulse wave, thereby determination of the real travelled path length is somewhat approximate. 4 Moreover, several confounding factors (physiological and technical) for PWV have been reported. The most significant physiological factors affecting PWV are blood pressure and heart rate; whereas technical confounders include the algorithm of the device used and the considered arterial pathway (carotid-femoral, brachial-ankle, etc.) Recently, a novel arterial stiffness parameter, the CAVI measured by the automatic VaSera device (Fukuda Denshi, Japan) appeared on the market. Originally, this device was Published on behalf of the European Society of Cardiology. All rights reserved. VC The Author For permissions please journals.permissions@oup.com.

2 The usefulness of CAVI B5 Figure 1 Measurement of CAVI. Adapted from Ref. 16. used by many research and clinical investigation centres, mainly in Japan and then in Asia, where it became very popular and received institutional and governmental awards. 14,15 This popularity seems to be related, at least in part, to its ease of use, its relative independency from blood pressure levels, and other advantages. During the past 5 years, the use of CAVI has increased in Europe and elsewhere. The number of published papers on CAVI is increasing year by year and reached more than 300 in The principles and clinical applications of CAVI will be reviewed hereafter. The principle of CAVI The arterial stiffness Beta index (b index) was proposed by Hayashi et al. in This parameter calculates the pressure ratio P/Ps and the distension ratio D/Ds. If ln(p/ Ps) is plotted against D/Ds, a linear relation is observed between them in a wide pressure range. This semilogarithmic relationship can be described by: ln(p/ps) ¼ b (D/Ds 1). The slope of the semi-logarithmic relation ¼ stiffness parameter b, represents the stiffness of the arterial wall and does not depend on the pressure. If we replace Ps and P as DBP Pdia and SBP Psys, respectively, the equation can be rewritten as follows: ln(psys/pdia) ¼ b (Dsys/Ddia 1), where Dsys and Ddia are arterial diameters at Psys and Pdia, respectively; b ¼ (Ddia/DD) ln(psys/pdia) where DD is the diameter change developed by pulse pressure DP. 16 Elsewhere, according to Bramwell and Hill, 17 the PWV formula is: PWV ¼ [(V/q) (DP/DV)] 1/2 ¼ [(D/2q) (DP/ DD)] 1/2.whereq is the density of blood. This indicates that PWV can be calculated from pulse pressure DP and arterial dilation DD. The substitution in the equation gives the following equation: b ¼ (Ddia/DD) ln(psys/ Pdia) ¼ (2q/DP) PWV 2 ln(psys/pdia) ¼ PWV 2 [2q (Psys Pdia)] ln (Psys/Pdia). The CAVI is defined as stiffness parameter b obtained from replacing PWV in the equation: CAVI ¼ a x (hapwv) 2 [2q/(Psys Pdia)] ln(psys/pdia) þ b. 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, q is the blood density, and a and b are constants to convert the values of CAVI to those of Hasegawa s PWV. 18 The patent of CAVI is owned by Fukuda Denshi Co., Ltd. (Tokyo, Japan). The VaSera device measures CAVI using four cuffs on all four limbs and gates the timing for the pulse wave arrival at the ankle relative to the heart using phonocardiography through a small microphone taped onto the chest 19 and one lead ECG (Figure 1). The VaSera device is available mainly

3 B6 R. Asmar Figure 2 CAVI in healthy Japanese people at different ages. CAVI values increase with age and are higher in men than in women at any age. Adapted from Ref. 22. in the Asian and European markets, its international distribution is in progress with a mean customer price around euros. The CAVI examination is not yet listed in the nomenclature of reimbursed exams in Europe but it is in Japan. The measurement of CAVI reproducibility The measurement of CAVI requires placement of ECG electrodes on both wrists and a microphone for phonocardiography on the sternum, and four blood pressure cuffs wrapped around the four limbs. The upper arm and ankle pulse waves, as well as blood pressure, can all be measured. This machine also subsequently measures the anklebrachial index (ABI), another physiological measure of vascular health. Devices for measuring CAVI are compact and portable, and their operation is relatively simple. Measurement of CAVI takes around 10 min. The CAVI measurement device is widely used in clinical settings (more than units placed in hospitals, clinics/gps, and health centres) especially in Japan because of its ease of use and reproducibility. Measurements should be performed in a quiet room at a stable temperature C; it is recommended that exercise, smoking, and food should be avoided 2 3 h prior to the measurement. CAVI is disregarded if the ABI is <0.9. The VaSera device uses the amplitude adaptive tangent method to detect the foot of the pulse wave. The reproducibility of CAVI has been reported as good. The coefficients of variation of CAVI are relatively small and have been described in different studies at around 3%. Regarding intra-observer reproducibility at different times, studies reported a variability of %. Regarding the inter-observer reproducibility with different operators, studies reported variability around 2.4%. 14,20,21 Diagnostic values of CAVI Age and gender reference values Numerous studies have shown that arterial stiffness is closely related to age, the major factor influencing the mechanical properties of the arteries. Different mechanisms, including the role of the endothelium, intima, and media have been proposed to explain the observed changes with age. An age-dependent increase of arterial stiffness and pulse pressure (both accompanied by an increase of SBP and a decrease of DBP with age) in both healthy populations and populations with cardiovascular disease has been described independently of mean blood pressure or presence of other risk factors. 1,2 The effects of aging are different on central (elastic) arteries, compared to peripheral (muscular) arteries and arterioles. Central arteries stiffen progressively with age whereas the stiffness of muscular arteries changes little with age. 1,2 These results have been reported in both sexes, although arterial diameter and length are lower in women than in men. The extent of the increase of arterial stiffness with age may depend on several environmental or genetic factors. To determine the reference values for CAVI, a large-scale study was conducted first in Japan in healthy individuals. In men, CAVI linearly increased with age, from 20 to 70 years. CAVI in men was higher than that in women at all ages by 0.2 in average. Men and women showed a similar rate of increase in CAVI of approximately 0.5 per year (Figure 2). Other studies performed in Asia and Europe corroborate these results and show that CAVI is a sensitive marker of the arterial aging process beyond blood pressure values. For diagnosis purposes, the CAVI clinical threshold of 9.0 is used in a clinical setting. 19,23 The effect of blood pressure Studies show various relationships between arterial stiffness and blood pressure. Such a discrepancy among the studies is not surprising since the correlation between these two parameters differ significantly whether we consider central or peripheral arteries and whether we consider systolic, diastolic, mean or pulse pressure. 1,2 As mentioned before, arterial stiffness is related to the distension pressure. Several studies have shown that carotidfemoral (aortic) PWV is closely and highly correlated with blood pressure. Thanks to its principles, CAVI has been reported to be independent from blood pressure or much less sensitive to the blood pressure values than PWV. In fact, clinical and experimental studies have shown that unlike PWV, CAVI is independent of blood pressure at the time of measurement. To better understand the effects of blood pressure on arterial stiffness and CAVI, acute and chronic effects of high blood pressure should be considered differently. In this regard, the impact of acute blood pressure variations on arterial stiffness using different laboratory tests should be interpreted with caution because of the difficulty of eliminating the autonomic nerve effect. Elsewhere, pharmacological studies assessed the acute effect of several blood pressure-modifying drugs, such as the b 1 -adrenoceptor blocker metoprolol. CAVI was measured hourly for 6 h after the drug intake. In the metoprolol group, despite a significant reduction of systolic and diastolic blood pressure, no modification of CAVI was seen. Similar results showing CAVI s independence from blood pressure were also found after treatment with the a1 adrenoceptor blocker doxazosin. 24,25

4 The usefulness of CAVI B7 CAVI and cardiovascular risk factors Hypertension It is well established now that arterial abnormalities are observed in hypertension even at an early stage of the disease. These abnormalities cannot be attributed solely to the stretching effect of elevated blood pressure, but also to intrinsic alterations of the arterial wall which could represent either adaptive changes to the increase in arterial pressure, or primary abnormalities of the vessel wall. In sustained hypertension, studies have reported stiffer arteries in patients with established hypertension at any given age. Hypertension increases wall stress, which activates the vascular smooth muscle cells and then changes the mechanical properties of the arterial wall. 1,4,6 Several studies reported that CAVI is influenced by chronic exposure of the arterial wall to increased blood pressure such as hypertension with high values of CAVI in hypertension. In most of these studies, the correlation coefficients between CAVI and blood pressure were lower than those observed between PWV and blood pressure. 16,26 Diabetes mellitus Whether in type 1 or 2 diabetes, most authors have reported stiffer arteries in diabetic than in non-diabetic patients even during early stages of the disease. The stiffness changes predominated on the central aorta and the lower limbs. Moreover, some authors found relationships between arterial stiffness and glycaemia control or duration of disease, findings which are disputed by others. Several mechanisms have been proposed to explain the stiffer arteries: hyperinsulinemia, non-enzymatic glycosylation, changes in the autonomic nervous system, and clustering of other risk factors. 1,2 CAVI has been reported to be high in patients with diabetes mellitus. CAVI values were associated with the presence of arterial plaques, increased intima-media thickness, microvascular complications, and peripheral neuropathy in diabetic patients. 16,27,28 Dyslipidaemia Based on experimental and clinical studies, it has been reported that cholesterol excess substantially alters the endothelial function, leading to a decreased ability to relax the arterial vessels. Further studies are needed to clarify whether this abnormality is associated with an increased stiffness of the arterial wall in humans. In this regard, studies with CAVI have shown that heterozygous familiar hypercholesterolemia was not associated with high CAVI values, whereas others reported that CAVI is related to low-density lipoprotein cholesterol levels. 29,30 Smoking Smoking increases arterial stiffness in both medium and large arteries. Whether the arterial effect of smoking is pressure-independent remains debatable. Higher CAVI values have been reported among smokers in comparison to non-smokers. 31 Obesity and metabolic syndrome Even though numerous studies reported stiffer arteries, in general, in patients with obesity and/or metabolic syndrome, this needs careful interpretation. In fact, obesity is a heterogeneous condition according to the type of obesity and the impact of the various components of metabolic syndrome on arterial stiffness, which may differ according to the patient s age and other conditions. Studies performed in healthy people, reported CAVI to be negatively related with body mass index. Elsewhere, others reported that visceral fat, especially epicardial fat, was positively associated with CAVI which was not the case with subcutaneous fat. Regarding the impact of metabolic syndrome and its components on CAVI, data from the literature showed higher CAVI values in metabolic syndrome patients with differences between genders. 30,32,33 More clarification will be provided by the currently running Triple A study, whose primary results are expected to be published in Others Other conditions, such as sleep apnoea, mental stress, and hyperuricemia have been associated with high CAVI values. 34,35 CAVI and cardiovascular diseases Coronary artery disease Studies reported high CAVI values in patients with coronary artery disease (CAD). Values of CAVI are associated with the severity of the CAD estimated by the number of vessels with significant stenosis. Moreover, CAVI has been said to perform better than bapwv in predicting coronary artery disease. 36,37 Cerebral artery disease Studies have shown that CAVI, but not bapwv, was associated with the presence of arteriosclerosis in the carotid arteries. Several other studies reported the association between CAVI and carotid arteriosclerosis assessed by ultrasound with strong correlations with intima-medial thickness (IMT) and the plaque score. 38 Chronic kidney disease Studies in patients with end stage renal disease (ESRD) have shown a high prevalence of systolic hypertension, due to increased arterial stiffness. In comparison with nonuraemic patients, aortic PWV is increased in ESRD, especially in younger subjects. Several studies reported that CAVI correlated with estimated glomerular filtration rate with high CAVI values in patients with ESRD taking haemodialysis therapy. 39 CAVI as a predictor of cardiovascular events Several studies have reported the CAVI prognostic value as a predictor of cardiovascular events in different populations. In patients with metabolic disorders or a history of CV disease, patients with a CAVI value 10 showed a

5 B8 R. Asmar Figure 3 (A) The cumulative incidence of coronary artery disease and stroke in different CAVI groups. Adapted from Ref. 40. (B) Cumulative event-free survival and CAVI groups in outpatients. Adapted from Ref. 41. (C) Cumulative cardiovascular event-free rate of acute coronary syndrome in low CAVI (8.325) and high CAVI (>8.325) groups, adapted from Ref. 42. (D) Cumulative cardiovascular events and CAVI changes, adapted from Ref. 43. high incidence of heart disease and cerebrovascular events during the 3 year follow-up period (Figure 3A). In middle-aged metabolic syndrome patients, CAVI was associated with the occurrence of total CV events and myocardial infarction but not with cerebrovascular events. In obese patients, CAVI has been reported to predict outcomes during a 5 year follow-up period; a high CAVI was a significant prognostic factor for cardiovascular events (Figure 3B). More recent studies reported CAVI as an independent predictor of CV events in subjects with acute coronary syndrome (Figure 3C). Furthermore, in patients with CAD, a high CAVI value was an independent predictor of CV events, more so in patients with persistent impaired CAVI than in those with improved CAVI (Figure 3D). Further specific prospective longitudinal studies focusing on morbidity and mortality are still needed. In this regard, the CAVI-J study ( Prospective study of the CAVI as a predictive factor for cardiovascular events ) was launched in Japan to conduct a 5-year prospective study of CAVI. This study aims to examine the additional benefits of using CAVI as a predictive indicator of cardiovascular events in 3000 high-risk patients (ClinicalTrials.gov identifier: NCT ) CAVI as a surrogate endpoint the effect of treatments Several interventional studies showed that nonpharmacological treatments such as smoking cessation, weight reduction, and continuous positive airway pressure (CPAP) are associated with an improvement in CAVI. Elsewhere, pharmacological studies report that antihypertensive, lipid-lowering, and anti-diabetic drugs may improve CAVI in a different manner according to the agent used; suggesting that CAVI could discriminate between the different drugs and their arterial effects. Details of these interventional studies have been published elsewhere. 16,40,46,47 Additional specific clinical trials and meta-analysis are needed to differentiate the various classes of antihypertensive and other cardiovascular drugs according to their effects on CAVI. Applications and future perspectives The evaluation of regional arterial stiffness using the PWV measurement has been recently recognized as the Gold Standard measurement of arterial stiffness. Other methods such as CAVI are now available and allow various

6 The usefulness of CAVI B9 arterial parameters to be measured to evaluate the arterial wall properties. Each method should be used with an understanding of the theory underlying its own principles, features, limitations, and advantages to achieve better patient care and prevent cardiovascular events. CAVI could be applied in primary and secondary prevention in patients with cardiovascular risk factors and/or diseases to detect sub-clinical arterial alterations and to evaluate the effect of treatment and its monitoring. Evidence is now available demonstrating the clinical value of arterial stiffness; consequently, inclusion of arterial stiffness in future guidelines may be suitable. Better targeting of the existing pharmacological agents and development of specific agents to enhancearterialwallpropertieswillbeveryusefulinthe management of cardiovascular diseases. 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