Pulse wave imaging for noninvasive and quantitative measurement of arterial stiffness in vivo.

The relationship between arterial stiffness and cardiovascular risk has been repeatedly demonstrated in several reported studies. The stiffness of large arteries has been shown to be an independent predictor of all-cause and cardiovascular mortalities,1 especially in hypertensive subjects.2 More specifically, aortic stiffness has been shown to be a predictor of primary coronary events3 and of fatal stroke4 in hypertensive patients, an independent risk factor for recurrent acute coronary events in patients with ischemic heart disease,5 or an independent predictor of cardiovascular mortality for patients with end-stage renal disease6. Type-2 diabetes has also been shown to be associated with increased stiffness,7,8,9 and this association is believed to be a major cause for the increased general cardiovascular risk related to diabetes.10 Connective tissue disorders such as Marfan syndrome are also associated with significant changes in arterial elasticity,11,12 which can be an interesting indicator of the progression of the disease.13 In all these cases, the knowledge of the arterial stiffness represents a valuable interest for diagnosis, prognosis and decision regarding therapy, and follow-up of the patient. Measuring the arterial stiffness has been recently recommended as an additional test for hypertension management in a Task Force study appointed by the European Society of Hypertension and the European Society of Cardiology.14 The underlying reason for the correlation between arterial stiffness and cardiovascular risk is related to changes in the cardiac work resulting from arterial stiffening, leading eventually to cardiac hypertrophy, alteration of perfusion and of metabolic demand, and increased systolic dysfunction.15,16 Reliable methods capable of estimating arterial stiffness represent therefore significant clinical interest. Moreover, the existing poor knowledge on the relationship between molecular and other microscopic processes and arterial stiffening is related to the lack of reliable methods for in vivo measurement of arterial mechanical properties.17 For all aforementioned reasons, there is valuable interest for a noninvasive, simple-to-use method for quantitative measurement of arterial stiffness in vivo. The most widespread method for aortic stiffness measurement is the estimation of the pulse wave velocity (PWV), which is directly related to arterial stiffness. In a cylindrical elastic tube filled with an incompressible fluid, the PWV is related to the elastic Young's modulus by the modified Moens–Korteweg equation:18 where E and ν are the aortic wall Young's modulus and Poisson's ratio (ν ≃ 0.5 for soft quasi-incompressible tissues), R is the lumen radius, h is the wall thickness, and ρ is the density of the wall. Measuring the systemic carotid-femoral PWV is currently recognized as the simplest and most robust method to determine arterial stiffness.19 It consists of measuring the temporal pulse profile at two different locations, typically, at the carotid and femoral arteries in order to obtain a PWV value averaged within the whole aorta. This can be performed either transcutaneously or by using Doppler flow probes.19,20 By measuring the time delay Δt of the same point in the waveform (e.g., the foot of the wave) and by estimating the arterial distance ΔD between the two measurement locations, the PWV can be simply estimated as PWV = ΔD/Δt. Several commercially available devices have been developed that allow such measurements.19 Such methods have proved their relevance and their robustness and they are at the core of most clinical studies involving the measurement of arterial stiffness. However, they are associated with significant limitations that cannot be ignored. The most important one is the lack of knowledge of the exact arterial geometry, which in turn yields uncertainty on the distance measurement ΔD and therefore on the PWV estimate. Moreover, assuming a single-longitudinal flow direction between the carotid and the femoral arteries is incorrect and leads generally to an overestimation of ΔD. Fundamental limitations of such methods have been reviewed in details.21 For this reason, the quantitative nature of the PWV estimate becomes limited. Another characteristic of such methods is the global nature of the measurement, as the PWV estimate represents an average global velocity of the pulse wave between the two remote measurement locations. It could be interesting in certain cases to also be able to perform a more localized measurement that could give complementary information of diseases affecting regional arterial stiffness or that could investigate differences in the PWV along the aorta. Ultrasound-based methods have been proposed for the measurement of local arterial stiffness, in contrast with the global arterial stiffness obtained on large regions by the aforementioned methods. They consist of measuring the diameter changes of the aorta at a chosen location in a cross-sectional view, and in evaluating a stiffness parameter by using the additional measurement of the blood pressure. Several parameters, e.g., arterial distensibility, arterial compliance, elastic modulus, volume elastic modulus, Young's elastic modulus, which are all related to the mechanical stiffness of the artery, have previously been proposed and reviewed.18,22 The main limitation of those parameters is that, unlike the PWV methods, their estimation requires arterial pressure measurement. Pressure can only be invasively assessed in deep-seated vessels for on-site measurement via catheterization. Noninvasive assessment of pressure can also be performed at peripheral arteries by tonometry, but differences of pressure profiles along the arterial tree lead to increased measurement inaccuracy.22 In this context, this study presents a simple-to-use, totally noninvasive, ultrasound radio-frequency-based speckle tracking method for imaging of the pulse wave and for regional and quantitative assessment of the PWV. Pulse wave imaging (PWI) is a recent imaging technique developed by our group that uses cross-correlation in order to image the pulse wave during its propagation and to estimate the PWV within the imaged segment.23 It is based on the estimation of 1D radial incremental displacements of the arterial wall in a longitudinal view. The spatiotemporal variations of the displacement allow us to visualize the pulse wave propagation and to estimate the PWV regionally within the field-of-view of the image. The method has been tested in both healthy and diseased mice in vivo.24,25 First, preliminary PWI measurements obtained in human subjects in vivo have been presented in a very limited sample size26 (five subjects, one measurement per subject), in order to illustrate the feasibility of performing such measurements. The purpose of the present study is to assess the reliability and the reproducibility of the method and to evaluate its capability of estimating PWV and stiffness values in a group of healthy subjects. This study addresses these issues, namely (i) the validation of the method using aortic phantoms, whose stiffness is measured by mechanical testing and (ii) the applicability on human subjects by performing in vivo measurement on healthy subjects, estimating therefore the PWV and, by using the measurement of geometrical dimensions of the aorta, the elastic modulus of the aortic wall.