Five years of cardio-ankle vascular index ( CAVI ) and CAVI 0 : How close are we to a pressure-independent index of arterial stiffness ?

Pulse wave velocity, a common metric of arterial stiffness, is an established predictor for cardiovascular events and mortality. However, its intrinsic pressure-dependency complicates the discrimination of acute and chronic impacts of increased blood pressure on arterial stiffness. Cardio-ankle vascular index (CAVI) represented a significant step towards the development of a pressure-independent arterial stiffness metric. However, some potential limitations of CAVI might render this arterial stiffness metric less pressure-independent than originally thought. For this reason, we later introduced CAVI0. Nevertheless, advantages of one approach over the other are left debated. This review aims to shed light on the pressure (in)dependency of both CAVI and CAVI0. By critically reviewing results from studies reporting both CAVI and CAVI0 and using simple analytical methods, we show that CAVI0 may enhance the pressure-independent assessment of arterial stiffness, especially in the presence of large inter-individual differences in blood pressure.


2) CAVI and Pm
Eq. 1 is defined with respect to a generic pressure ./0 . If ./0 is set to the mid pressure 1 , Eq. 1 becomes: where 1 is the diameter at 1 and 1 is the value of 7 when ./0 = 1 . Using Eq. A6, the derivative term in Eq. 3 becomes: If the derivative d /d is calculated at 1 (i.e., when = 1 ), Eq. A7 simplifies to Then, substituting d /d in Eq. 3 with Eq. A8 and opportunely rearranging leads to the following relationship: Note that, unlike Kawasaki's , 1 is linked to Hayashi's 7 by the relationship

3) Estimation of the haPWV-relevant pressure
We follow the assumption at the basis of CAVI and CAVI0: constant 7 throughout the arterial tree and in particular in the heart-to-ankle and heart-to-brachial artery pathways. In this example, we will use a person with 7 = 8.50, DBP = 80 mmHg and SBP = 120 mmHg. Further, we also assume that the length of the heart-to-ankle arterial pathway ( 89 ) is 148 cm and that of the heart-to-brachial pathway Hence, in this case *;<=8 = 98 mmHg. Inverting the CAVI0 equation (Eq. 9) we obtain the following relationship: It is worth noting that the CAVI0 formula is based on the derivative of the pressure-diameter relationship at diastolic pressure and, therefore, Eq. A11 determines PWV at DBP (PWV >?@ PWV & %&'() and tba = 89 − 8: Substituting values in Eq. A14 leads to tb = 56 ms and tba = 228 ms. Therefore, PWV is calculated at *;<=8 over the first 56 ms of wave travel and at DBP for the remaining 228 ms. A "representative" haPWV pressure can finally be estimated using a weighted average: For the proposed person, this amounts to: Further, it can be shown that the "0.09" herein is only mildly affected by changes in the choice of the haemodynamic parameters, slightly increasing with increasing DBP and 7 , and decreasing for higher pulse pressure.

4) Conceptual differences between haPWV, cfPWV, and baPWV
We would like to point out a conceptual difference between haPWV (and its derived indices CAVI/CAVI0) and e.g., baPWV and cfPWV. Notably, a haPWV is "physically sound" in the sense that there is a physical pressure wave that arises at the heart and travels towards the ankles. This contrasts with e.g., baPWV, where there is no such wave arising at the brachial artery. Figure A1 summarises the differences between haPWV and baPWV. This has an important consequence: when the brachial artery stiffens, this directly leads to a lower baPWV (Eq. A19, below). In haPWV, this effect will be much smaller, as only the difference between notch and diastolic wave speeds / transit times (TTs) will have an influence (Eq. A17; Figure A1). With stiffening, in general, both notch and diastolic TTs will decrease and likely their difference will also decrease. This would imply a (modest) increase in haPWV.
The transit time equations corresponding to haPWV, baPWV, and cfPWV are: Points a, c, f, h, and y are defined in Figure A1. In addition to these "subtraction effects", haPWV includes the proximal aorta, whereas this segment is excluded in baPWV and cfPWV. Finally, haPWV and baPWV include the lower leg segment, whereas this is excluded in cfPWV.
4 Figure A1 -Schematic representation of the differences between the brachial-ankle (baPWV) and the heart-ankle pulse wave velocities (haPWV). Three main elements differentiate the two techniques: 1) the haPWV-relevant pathway includes the proximal aorta which is excluded from the baPWV, 2) unlike heart-to-ankle, brachial-to-ankle is not a real arterial pathway and this affects the estimation of the transit time (see Appendix 4), and 3) while the baPWV transit time relies solely on the foot of the wave (i.e., at diastolic pressure), the determination of haPWV transit time is more complex and involves both foot and dicrotic notch fiducial points.
cfPWV is conceptually similar to baPWV, however, 1) it includes the carotid vs. the brachial artery, and 2) it excludes the femoral-to-ankle segment which is included in baPWV. a, b, c, f, ankle, brachial, carotid, and femoral measurement sites, respectively; h, heart; y, bifurcation between the aorta and brachiocephalic artery.