Evaluation and interpretation of arterial stiffness in clinical practice

Thomas WEBER, Privat-Dozent
Dr, Cardiology Department
Klinikum Wels-Grieskirchen

Evaluation and interpretation of arterial stiffness in clinical practice

by T. Weber, Austria

Pulsatile hemodynamics are increasingly recognized as the basic principle of blood pressure, and they are fundamentally involved in the pathophysiology of hypertension and its ill-effects. Stiffness of the aorta and large arteries largely determines how pulsatile pressure and flow, as generated by the heart, are transmitted towards the microcirculation. In the last few decades, we have increasingly focused on more and more specific measures of pulsatile hemodynamics. Brachial pulse pressure, a crude estimate of arterial stiffness, can be readily obtained with a simple cuff, by subtracting diastolic blood pressure from systolic. A value above 60 mm Hg indicates subclinical organ damage, according to the latest European Society of Hypertension (ESH)/European Society of Cardiology (ESC) hypertension guidelines. Central (aortic) systolic and pulse pressure are probably more closely related to organ damage and prognosis, but their measurement is more complex; several issues including calibration of the systems and standardization of the methods need to be resolved before they can be integrated widely into daily routine. Wave reflections from peripheral sites are an integral part of the blood pressure curve. They can be assessed, using a variety of techniques, and have been shown repeatedly to carry prognostic information. Again, consensus on methodological issues and simplification of the measurement are necessary next steps before incorporation into clinical practice. Pulse wave velocity (PWV) as a measure of regional arterial stiffness is a relatively simple, robust procedure. If the aorta is included in the arterial pathway (as with carotid-femoral PWV), many studies have consistently shown its independent prognostic value. Therefore, carotid-femoral PWV has been recommended as a measure of subclinical organ damage in the latest ESH/ESC hypertension guidelines. Based on available data, and a consensus regarding measurement details, a cutoff value of 10 m/s has been proposed.

Medicographia. 2015;37:391-398 (see French abstract on page 398)

During the last few decades, considerable scientific effort has been devoted to the investigation of the hemodynamic principles underlying blood pressure itself, its changes with aging, and its influence on development of cardiovascular diseases. Traditionally, the formula “mean blood pressure = cardiac output × peripheral resistance” was used to describe hemodynamics in hypertension, with a focus on diastolic blood pressure (DBP), which is closer to mean blood pressure. this is an overly simplistic approach, however, valid only for steady-flow conditions. in real life, flow and pressure are pulsatile. Measures used to quantify pulsatile hemodynamics depend—to a varying degree—on the properties of the pulsatile pump (ie, the heart) and on the properties of the circulation (ie, the aorta and the large elastic arteries).

Figure 1
Figure 1. Measurement of carotid-femoral pulse wave velocity with the SphygmoCor® device.

Using the electrocardiogram’s R wave as gating, pressure curves are recorded at the carotid artery (upper panel) and at the femoral artery (lower panel) consecutively. The foot of the pressure wave is identified automatically, using a predefined algorithm (the intersecting tangents method is recommended). The system calculates transit time. Travel distance is measured on the surface of the body and entered into the system, which computes pulse wave velocity (in this example 6.5 m/s).
Age-specific reference values are shown in the right lower panel.

Pulse pressure, the difference between sBP and DBP, is the most convenient—but crude—measure of pulsatile hemodynamics, and available as brachial pulse pressure with every cuff blood pressure measurement. Pulse pressure increases with stiffening of the aorta and the large arteries, and decreases with severely impaired systolic left ventricular function. in populations, pulse pressure increases with aging, particularly after the age of 55 years.1 it is more closely related to cardiovascular risk in middle-aged and elderly individuals than other blood pressure components,2-5 and can be used to identify patients with heart failure with preserved ejection fraction.6 Brachial pulse pressure >60 mm Hg is a hallmark of asymptomatic organ damage in the elderly, according to the 2013 European society of Hypertension (ESH)/European society of Cardiology (ESC) guidelines for the management of arterial hypertension.7

Brachial pulse pressure as a measure of arterial stiffness, however, has several limitations: its dependence on cardiac function,8 which leads to an inverse relationship with outcomes in patients with severely impaired systolic function9; its varying increase from the aorta to the brachial artery (“pulse pressure amplification”),10 which depends among other things on aortic stiffness, cardiac function, heart rate, and arterial geometry; and the fact that brachial pulse pressure is not superior to other blood pressure components in terms of risk prediction in all studies.11 All of these reasons make more specific measurements of arterial stiffness desirable. these measurements can be broadly divided into measurements of pulse wave velocity (PWV), measurements of central blood pressures, measurements of wave reflections, and measurements of local arterial stiffness.12 this latter measurement involves mainly studies of the carotid artery with dedicated ultrasound techniques (echotracking). Its main applications are mechanistic studies in pathophysiology and pharmacology,12 with very limited implementation in clinical practice and few positive outcome studies.13 the present review will focus on the other three measurements of arterial stiffness.

Pulse wave velocity

The speed of propagation of pulse (pressure or flow or distension) waves in an artery is directly related to the stiffness of the vessel (the stiffer the vessel, the higher the velocity) and can be directly assessed, by dividing distance travelled by transit time. As the effects of the aging process (ie, loss of elasticity, increased stiffening) are most pronounced in the human aorta as opposed to the muscular arteries,14 the aortic pathway should be included in the measurement. in addition, the prognostic value is largely limited to pathways including the aorta,15 such as carotid-femoral PWV. “Pure” aortic PWV can be measured invasively16 or with magnetic resonance imaging (MRI).17 Both are of little value in routine clinical practice due to their invasive nature and limited availability, but are very useful for gaining mechanistic insights and for validation of noninvasive methods.18

Carotid-femoral PWV has been used in large epidemiological studies involving thousands of patients. results have been consistently positive and confirmed by a recent individual patient– based meta-analysis19: carotid-femoral PWV is a strong predictor of cardiovascular events in different groups of high and low-risk patients and in the general population. Clinical utility, calculated as “net reclassification improvement”, is best in intermediate-risk patients.19,20

In practice, pulse waves are recorded at the common carotid artery and at the femoral artery, using pressure sensors (mechanotransducers or high-fidelity applanation tonometers), Doppler flow probes, or echotracking ultrasound. With simultaneous recordings, transit time can be determined directly, usually at the end of diastole (“foot-to-foot”). With sequential recordings, the R wave of the ECG is used as a point of reference (Figure 1). the foot point of the travelling wave can be determined with different algorithms, which may lead to different results.21 For the purpose of standardization, the method of intersecting tangents is recommended. the determination of travel distance for carotid-femoral PWV has created more scientific discussion and although often labelled “aortic PWV”, carotid-femoral PWV differs from true aortic PWV in the following respects: the ascending aorta is not covered (as the pulse wave travels up the carotid artery, it will be travelling down the aortic arch and descending aorta at the same time), but the carotid artery and the iliac-femoral pathway are included (where PWV is different from the aorta). in addition, true aortic PWV involves wave travel in only one direction, but carotid-femoral PWV involves wave travel in two opposite directions (upwards into the carotid artery and downwards along the aortic arch) at different wave speeds, which makes exact determination of travel distance elusive and establishes the need for compromise: whereas direct carotid-femoral distance measurement is simple and reproducible, comparisons with invasive22 and Mri-based23,24 aortic PWV have clarified that it overestimates aortic travel distance and, thus, aortic PWV (by roughly 2 m/s). As a solution, 80% of the direct carotid-femoral distance25 or subtraction of the suprasternal notch-carotid distance from the suprasternal notch-femoral distance16 has been recommended recently.

Box 1
Box 1. Practical aspects for the measurement of carotid-femoral
pulse wave velocity.

Abbreviations: ECG, electrocardiogram; PWV, pulse wave velocity.
Adapted from reference 25: Van Bortel et al. J Hypertens. 2012;30:445-448.
© 2012 Wolters Kluwer Health/Lippincott Williams & Wilkins.

Although the measurement of carotid-femoral PWV is straightforward, standardization is necessary. the most important points are summarized in Box 1. if performed correctly, measurement of carotid-femoral PWV may take 15-20 minutes; it requires a trained operator. This may account for the slower than expected dissemination of the method into routine clinical practice. Accordingly, some simplifications have been introduced. A cuff can be used instead of the tonometer to acquire pressure curves at the femoral site.26 in addition, a partial cuff can be used at the carotid site as well.27 A different approach utilizes the CKD interval (the time interval between the onset of the QRS on the ECG and the last Korotkoff sound at the brachial artery).28 Finally, measurements of aortic PWV from single-site waveforms have been suggested.29 A novel device uses regression—based on age, systolic blood pressure (SBP), and waveform characteristics— to estimate aortic PWV.30 We recently compared true aortic PWV (from the ascending aorta to the aortic bifurcation as measured invasively during cardiac catheterization) against carotid-femoral PWV and against the novel, waveform-based approach in almost 1000 patients (Figures 2A and 2B).31 We found that carotid-femoral PWV (using either the subtracted method or the 80% direct distance method for travel distance estimation) agrees well with the invasive gold standard in the majority of patients. the single waveform–based estimate, however, shows even closer agreement with invasive aortic PWV. Based on their ease of use, the novel single-point estimates of PWV, which are obtained with brachial cuffs, have the potential to change routine clinical practice. Before their use can be recommended, large-scale outcome studies showing predictive value (already available for carotid-femoral PWV19) are mandatory (and are currently emerging32).

Figure 2A
Figure 2A. Aortic pulse wave velocity (measured invasively) and
carotid-femoral pulse wave velocities (determined either with the
subtracted method or the direct distance × 0.8 method for travel
distance estimation) according to age group in a cohort of 632

Abbreviations: cf, carotid-femoral; PWV, pulse wave velocity.
Modified from reference 31: Weber et al. J Hypertens. 2015;33:1023-1031.
© 2015, Wolters Kluwer Health, Inc.

Figure 2B
Figure 2B. Aortic pulse wave velocity (measured invasively) and
estimated aortic pulse wave velocity (from single-point waveforms,
determined with a formula based on age, systolic blood pressure,
and waveform characteristics) according to age group in a cohort
of 915 patients.

Abbreviation: PWV, pulse wave velocity.
Modified from reference 31: Weber et al. J Hypertens. 2015;33:1023-1031.
© 2015, Wolters Kluwer Health, Inc.

In Asian countries, measurement of brachial-ankle33 and cardio- ankle34 PWV is frequently performed, using oscillometric cuffs at the limbs. Its prognostic significance has been proven, but currently we lack larger amounts of data from European populations.

According to the latest ESH/ESC guidelines on the management of hypertension,7 a carotid-femoral PWV >10 m/s indicates subclinical organ damage in hypertension, puts the patient at high risk of cardiovascular events, and necessitates comprehensive actions to prevent clinical events (normalization of blood pressure, lifestyle changes such as smoking cessation and regular exercise, normalization of lipids, eventually antiplatelet agents, etc). The use of a single cutoff value for all patients is undoubtedly an attractive approach due to its simplicity (and is in line with the single blood pressure threshold of 140/90 mm Hg in all individuals except the very old). However, it does not take into account the direct relationship of PWV with blood pressure (at the time of measurement) nor the age-related increase of PWV. thanks to a huge reference value project including more than 10 000 individuals, age-specific reference values and age-specific normal values (obtained in individuals free from cardiovascular risk factors) are available.35

Central systolic blood pressure

SBP in the ascending aorta and in the brachial artery, the typical site of noninvasive BP measurement, is not the same, but increases from the aorta to the peripheral arteries10; whereas mean blood pressure and DBP decrease by 1-2 mm Hg. the increase in SBP is related to changes in arterial stiffness and diameter of the arteries involved, and it is modified by the timing and extent of wave reflection from peripheral sites. As a result, the difference between central and brachial SBP varies among individuals. Central SBP is relevant for two reasons: it seems to be more closely linked to cardiovascular outcomes36; and it can be modified differently from brachial SBP by cardiovascular drugs.37

Figure 3
Figure 3. Central systolic blood pressure values according to age
category for men and women in a normal population (n=18 183;
normotensive and free from cardiovascular risk factors) and in a
reference population (n=27 253; normotensive or hypertensive, not
treated for hypertension or diabetes, and free from cardiovascular
disease and chronic kidney disease).

Abbreviations: f, female; m, male; SBP, systolic blood pressure.
Modified from reference 43: Herbert et al. Eur Heart J. 2014;35:3122-3133. Oxford
University Press. © 2014, The Author.

Technically, noninvasive estimation of central SBP can be accomplished by: recording peripheral waveforms, typically at the radial (or brachial) artery; calibrating them with brachial blood pressure; and applying mathematical formulae (transfer functions, n-point moving average, waveform characteristics). If waveforms are acquired at the carotid artery, no formula needs to be used, but calibration with brachial pressures is still necessary. the various methods and their invasive validation have been summarized recently.38 Although the different steps have their limitations, the step responsible for introducing most of the deviation from the invasive gold standard is calibration of the waveforms with brachial SBP and DBP.38 it has been suggested that oscillometry is more accurate in determining mean (and diastolic) blood pressure than systolic blood pressure at the brachial artery,39 and therefore using mean/diastolic pressure derived by oscillometry for calibration leads to a more accurate estimate of central sBP.40,41 Although studies with hard clinical endpoints (myocardial infarction, stroke, etc) are pending, it has already been shown that the brachial cuff–based estimate of 24-hour central SBP is more closely related to left ventricular mass than 24-hour brachial SBP. However, this is only true if the more accurate method of calibration (mean/diastolic pressure) is used.42

Figure 4
Figure 4. The effect of aging on blood pressure
curves and wave reflections.

The figure shows radial (left) and derived aortic (right) blood
pressure curves, obtained with tonometry and a transfer
function (SphygmoCor® device), in a young (top), middleaged
(middle), and elderly (bottom) individual. Although
peripheral (brachial) blood pressures in these individuals
are roughly the same (128/70, 128/87, and 133/80 mm Hg,
respectively), the blood pressure curves show dramatic
changes over time. These changes are mainly explained
by a shift of reflected waves toward systole and their consecutive
merging with the incident pressure wave that is
generated by the heart. Arrows indicate reflected pressure
Abbreviations: S, systole; D, diastole.

So how can we apply central pressures in routine clinical practice in 2015? From another large international reference value project comprising more than 45 000 patients,43 age- and gender specific values for a normal population (free from traditional cardiovascular risk factors) and for a reference population (free from diabetes, cardiovascular disease, chronic kidney disease, and antihypertensive treatment) are available (Figure 3). A complementary approach was taken by Chen and coworkers44: based on two large outcome studies, the proposed central thresholds for optimal blood pressure and for hypertension were 110/80 mm Hg and 130/90 mm Hg, respectively. ESH/ESC guidelines7 suggest that central SBP measurement may be useful in young individuals with isolated systolic hypertension: despite having a high brachial SBP, central SBP for some of them is low due to excessive amplification of the central pressure wave. Drug treatment may be unnecessary for these individuals.45

Figure 5
Figure 5. Assessment of wave reflections.

A radial pressure wave is obtained with tonometry (upper panel, left). Using a generalized transfer function, the corresponding central pressure curve is calculated (upper panel, right). Pulse waveform analysis provides details of the curve: the inflection point is derived mathematically; and the part of the curve following the inflection point is ascribed to wave reflection (quantified as: AP = augmented pressure; and AIx [augmentation index], the ratio of AP/PP [pulse pressure]). Doppler flow curves are obtained at the left ventricular outflow tract (lower panel, left) and are digitized and aligned with the pressure curves (lower panel, right). Wave separation analysis, using pressure and flow curves, yields the amplitudes of the forward (Pf ) and the backward (reflected; Pb) pressure waves (middle panel, far right).
Abbreviations: ED, ejection duration; P1, difference in height between minimum pressure and pressure at the first peak; P2, second systolic peak.
Modified from reference 47: Parragh et al. Non-invasive wave reflection quantification in patients with reduced ejection fraction. Physiol Meas. 2015;36:179-190.
© 2015, IOP Publishing.

Wave reflections

The ejecting heart does not only propel the blood column, but also initiates a pressure wave, travelling in the wall of the aorta and the arteries towards the periphery. At locations with impedance mismatch (bifurcations), some of the energy is reflected and travels back towards the ascending aorta (and continues into carotid artery, subclavian artery, etc).46 As the human arterial system is only 1-2 meters long and as wave speed (PWV) is roughly 5-15 m/s, the antegrade and the reflected waves merge during the cardiac cycle. This superimposition of the two waves causes prominent and visible changes to the waveforms of the aorta and peripheral arteries, which change with aging: in younger individuals, propagation of the pressure wave occurs at a lower PWV, and, thus, the reflected wave will return to the ascending aorta mainly in diastole (and will positively affect coronary perfusion). With increasing age, PWV rises, and the reflected wave is shifted more and more towards systole (and increases left ventricular afterload) (Figure 4, page 395). The technique of pulse waveform analysis (PWA), developed by Michael O’Rourke and coworkers,46 utilizes these changes (Figure 5)47: an early systolic shoulder is identified mathematically on the upstroke of the pulse wave, which is thought to correspond exclusively to the forward wave (P1). the following inflection point is due to the merging of the forward wave with the incoming reflected wave, and the second systolic peak (P2) is due to the maximum effect of the reflected wave on the central pressure contour. Wave reflection thus can be quantified by (P2- P1), called augmented pressure (AP). AP is often related to pulse pressure (PP), and their ratio is the augmentation index (Aix = AP/PP).

As the pulse contour (and, thus, Aix and AP) depends not only on the magnitude, but also on the timing of wave reflection in relation to the duration of left ventricular systole (determined among other things by heart rate and systolic function), wave separation analysis (WSA) has been developed, using simultaneously acquired pressure and flow waves at the same location to separate the pressure wave into its forward (Pf) and backward (Pb) components (Figure 5).47,48 in addition, reflection magnitude (RM), the ratio of Pb/Pf, can be calculated. Whereas pressure waves can be easily recorded, it is inconvenient in clinical practice to record flow waves simultaneously. As a substitute, triangular,49 averaged,50 or model-derived flow waveforms51 have been developed and clinically validated (ie, outcome studies have shown the additive predictive values of WSA-derived measures of wave reflection). A further advanced method is wave intensity analysis (WIA), where a time-domain based analysis of simultaneously acquired pressure and flow waves yields forward and backward compression and decompression waves and wave reflection index.52

All analyses are typically performed at central arteries (aorta and carotid artery). For the latter, waveforms can be used directly; whereas aortic waveforms are derived from peripheral arteries, typically radial or brachial, by the use of transfer functions.46 Waveforms are acquired with tonometers or with recently introduced brachial cuffs. The latter method makes 24-hour recordings feasible42 and may facilitate the performance of large epidemiological and clinical studies as well as the dissemination of wave analysis into everyday clinical practice. Although the concept of wave reflections is scientifically sound, current guidelines do not recommend their use in clinical practice. Reasons for this include the complexity of the various measures (compared to a single value for carotid femoral PWV), the fact that the indices cannot be used interchangeably, and their failure in some population studies.20 Consensus on the “best” parameter to assess wave reflections and simplification of their assessment (eg, with cuffs instead of tonometers) are likely to be the next steps on the way towards the incorporation of wave reflection analysis into routine clinical practice.

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Keywords: arterial stiffness; pulse wave velocity; wave reflections; central blood pressure