The prognostic role of the cardio‐ankle vascular index

The intrinsic importance of generalized stiffness of the arterial tree as a hallmark of normal aging has been recognized even in ancient medical texts, dating back thousands of years to the Chinese masters who used their fingertips and their powers of observation to associate “hardening of the pulse” with adverse outcomes in people who ingested too much salt.1 Nearly four centuries ago, the famous English physician Thomas Sydenham (1624‐1689) commented that "a man is as old as his arteries.” However, only in last decades, systematic scientific evaluation of viscoelastic properties of large arteries (ie, the aortic system and its central branches) has matured as a clinical and research discipline.

The measurement of pulse wave velocity (PWV) is generally accepted today as the most simple, noninvasive, and reproducible method with which to determine arterial stiffness.1, 2, 3 It 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.

Carotid‐femoral PWV (cfPWV) is considered the gold standard measure of aortic stiffness.1, 2, 3 There is a very large and highly consistent body of evidence indicating that aortic PWV is strongly and independently related to other indices of organ damage and to the development of fatal and nonfatal cardiovascular (CV) events.1, 2, 3, 4, 5, 6, 7, 8 In an individual participant meta‐analysis, an increase in one standard deviation of log cfPWV was related to a 28% elevation in CV mortality.8 The same meta‐analysis showed that measurement of aortic stiffness is effective in reclassifying the risk of individuals at intermediate CV risk beyond that provided by standard risk factors.8

However, cfPWV measurement has not become part of the daily routine in clinical work so far, probably because the methods available are sometimes complicated and time‐consuming, partly operator dependent, and can cause discomfort for the patient with the manipulation in the inguinal region. New instruments, using an oscillometric technique and a procedure that takes only 2‐3 minutes, seem to offer a solution allowing estimation of aortic PWV by using a simple upper arm cuff.3, 9 Some of these devices have versions developed for 24‐hour blood pressure and arterial stiffness monitoring, opening a new field of research interest.9, 10 Even if some of these methods provide PWV values very close to those recorded by widely accepted and clinically validated devices or by invasive techniques,2, 9 none of these new methods are currently recommended by an alternative to cfPWV because there is limited evidence of cardiovascular outcome prediction in longitudinal studies.2, 3, 9

Moreover, all techniques based on PWV used to assess arterial stiffness are intrinsically dependent on the BP values at the time of measurement, because the arterial wall becomes stiffer when distending pressure increases. This is due to the transfer of stress from the stretchable elastin to the stiff collagen fibers in the arterial wall, as blood pressure increases.1, 11 In other words, the pressure‐volume (or pressure‐diameter or stress‐strain) relationship is nonlinear, with concavity toward the distension axis, such that there is diminishing distension with increasing force.

This places some limitations on the clinical utility of PWV as a measure of arterial stiffness, with higher values being caused by either intrinsic changes in arterial structure or higher distending pressure.

One of the methods proposed to correct PWV for its blood pressure dependency is the cardio‐ankle vascular index (CAVI). Its measurement is performed using a portable machine that requires placement of ECG electrodes on both wrists, a microphone for phonocardiography on the sternum, and four blood pressure cuffs wrapped around the four limbs (Figure 1A). The upper arm and ankle pulse waves, as well as blood pressures, can all be measured.11

Figure 1.

(A) Measurement of cardio‐ankle vascular index (CAVI). Patients were placed in the supine position. ECG and phonocardiogram were placed to monitor the heart rhythm and heart sound, respectively. Pulse wave velocity (PWV) was obtained by measuring the distance between the aortic valve to the ankle (L) divided by time for the pulse wave to propagate from the aortic valve to the ankle (T). The PWV was then put into the equation for scale conversion. SBP, systolic blood pressure; DBP, diastolic blood pressure; a and b, scale conversion constants; ρ, blood density; tba, time between rise in brachial pulse wave and rise in ankle pulse wave; tb, time between closing sound of aortic valve and notch in brachial pulse wave; At′b, time between opening sound of aortic valve and rise in brachial pulse wave. (B) Exponential relationship between blood pressure and arterial diameter under stable physiological condition. 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, gradually increases with the increase of pressure. (C) Linear relation between natural logarithm of systolic (SBP)‐diastolic (DBP)pressure ratio and arterial wall distensibility. Two lines (pressure‐distensibility relationships) with different slopes (ie, stiffness parameter, β) are reported in stiff vessel compared to normal.

This method is based on the estimate of the arterial stiffness index, β, of the aorta and the iliac, femoral, and tibial arteries. It is a surrogate measure of the increase in arterial stiffness occurring from end‐diastole to end‐systole (diastolic‐to‐systolic “stiffening”), and incorporates information on arterial properties during the entirety of systole. The stiffness parameter β is obtained by linearization of logarithmic expression of the ratio between internal pressure in blood vessels and change in vascular diameter. In other words, the slope of this line represents arterial stiffness.11 Although a residual BP‐dependence of this index has been recently suggested in a mathematical model,12 its value is less pressure dependent than PWV that samples arterial stiffness at a given point of the cardiac cycle—usually end‐diastole—and is therefore inherently influenced by BP.11

The β index was first proposed by Hayashi et al13 in 1975 to assess the local stiffness of a vessel according to the change in vascular diameter in response to arterial pressure variance.13 To fit into clinical practice, this parameter was later defined by Kawasaki et al14 as:

$$\beta =Ln(\text{SBP}/\text{DBP}\times \left(D/\mathrm{\Delta }D\right).$$ (1)

The proportional change in luminal diameter (ie, ∆D/D) can be measured by sonographic methods.14 Provided that, as above described, an exponential relation exists between intravascular pressure and arterial diameter, due to the increased amount of recruitment of stiffer collagen fibers when distending pressure increases (Figure 1B), plotting the natural logarithm of systolic‐diastolic pressure ratio against the arterial wall distensibility (∆D/D) would give a linear relation11 (Figure 1C). Therefore, the stiffness parameter β, which is the slope of the plot, is theoretically independent of BP at the time of measurement.14 Hence, the higher the value of β, the lower the distensibility of the arterial wall, and the steeper the plot. Clinically, since accurate assessment of arterial stiffness according to the change in vascular luminal diameter is hampered by the measurement on merely a local segment of artery and also the requirement for specific sonographic equipment, the proportional change in luminal diameter in Equation (1) can be replaced by substituting D/∆D with (2ρ/∆P) × PWV². Therefore, β may be calculated as follows:

$$Ln\left(\text{SBP}/\text{DBP}\right)\times \left(2\rho /\mathrm{\Delta }P\right)\times {\text{PWV}}^2.$$ (2)

For scale conversion from PWV, the following formula can be applied:

$$\text{CAVI}=a\beta +b,$$ (3)

where a and b are unpublished scale conversion constants.11 Hence, substituting (2) into (3) gives:

$$\text{CAVI}=a\times \left[\left(2\rho /\text{SBP}-\text{DBP}\right)\times Ln\left(\text{SBP}/\text{DBP}\right)\times {\text{PWV}}^2\right]+b,$$ (4)

where PWV is pulse wave velocity from cardiac valves to ankle; SBP and DBP are systolic and diastolic blood pressures; and ρ is blood density.

CAVI has been widely applied in clinical studies mostly performed in Asian subjects with known cardiovascular disease as well as with hypertension, diabetes, and obesity.11, 15

In the current issue of J Clin Hypertens, Matsushita and coll15 reported the results of a comprehensive evaluation of the prognostic role of CAVI. They carried out a systematic review and meta‐analysis aimed to assess the association between CAVI and CVD in prospective and cross‐sectional studies.15 The pooled adjusted hazard ratio for CVD events per 1 standard deviation increment of CAVI in four longitudinal studies was 1.20 (95% CI, 1.05‐1.36, P = 0.006). A total of 13 studies compared CAVI values between patients with and without CVD and all found greater values of this parameter in those with CVD. The authors identify only three studies, all conducted in ESRD patients on dialysis, analyzing the relationships of CAVI with all‐cause mortality. No significant association was observed.15

Some caveats need to be considered when assessing the clinical meaning of CAVI. First, the tenet that β and CAVI are unaffected by BP has been recently questioned.12 In order to avoid erroneous conclusions, when the prognostic implications of CAVI are investigated, it may be important to take into account the effect of this BP dependency, even if it is less than that of PWV.

Furthermore, it is worth noting that CAVI measures the properties of the aorta, femoral artery and tibial artery as a whole.11 The aorta is an elastic vessel, while the femoral artery and tibial artery are muscular vessels under the control of nerves. Accordingly, an elevated CAVI may represent not only vascular stiffness caused by pathological changes in the arterial wall, but can also be attributed to an increased vascular tone brought about by smooth muscle contraction.

Moreover, patients with an ankle‐brachial index <0.9, indicative of peripheral arterial disease, have falsely low CAVI. In these subjects, arterial stiffness must be evaluated with techniques other than CAVI.

CONCLUSIONS

In conclusion, the well‐performed meta‐analysis of Matsushita et al represents an important contribution to the knowledge about the clinical meaning of arterial stiffness parameters, suggesting that CAVI is associated positively with a slightly increased risk of CV events, but not of total mortality. However, caution is needed in interpreting these findings, due to the limited number of prospective studies eligible for the meta‐analysis and the relatively low number of subjects included, mostly living in Japan or China. Therefore, additional studies, preferably with a prospective design and involving participants also from non‐Asian countries, are required to better define the prognostic role and the clinical utility of CAVI.

CONFLICT OF INTEREST

The authors have no conflict of interest to declare.