ATVB In Focus
Noninvasive Assessment of Atherosclerosis: from Structure to Function
Previous Brief Reviews in this Series:• Choudhury RP, Fuster V, Badimon JJ, Fisher EA, Fayad ZA. MRI and characterization of atherosclerotic plaque:emerging applications and molecular imaging. 2002;22:1065–1074.
• Bonetti PO, Lerman LO, Lerman A. Endothelial dysfunction: a marker of atherosclerotic risk. 2003;23:168 –175.
Noninvasive Assessment of Arterial Stiffness and Risk of
Atherosclerotic Events
Abstract—Investigation of arterial stiffness, especially of the large arteries, has gathered pace in recent years with the
development of readily available noninvasive assessment techniques. These include the measurement of pulse wave
velocity, the use of ultrasound to relate the change in diameter or area of an artery to distending pressure, and analysis
of arterial waveforms obtained by applanation tonometry. Here, we describe each of these techniques and their
limitations and discuss how the measured parameters relate to established cardiovascular risk factors and clinical
outcome. We also consider which techniques might be most appropriate for wider clinical application. Finally, the
effects of current and future cardiovascular drugs on arterial stiffness are also discussed, as is the relationship between
arterial elasticity and endothelial function. (Arterioscler Thromb Vasc Biol. 2003;23:554-566.)
Key Words: arterial stiffness Ⅲ noninvasive assessment Ⅲ endothelial function Ⅲ cardiovascular risk stratification
Arterial Stiffness
cular risk factor in older people. Thus, SBP has greater Data from the Framingham Heart Study have determined predictive value than DBP for coronary heart disease how systolic blood pressure (SBP), diastolic blood pres- (CHD) in older people (Ͼ60 years).2,3 Isolated systolic sure (DBP) and pulse pressure (PP; the difference between hypertension (ISH; SBP Ն140 mm Hg and DBP SBP and DBP) change with advancing age.1 DBP, largely Ͻ90 mm Hg), is the most common subtype of hyperten- determined by peripheral arterial resistance, increases until sion in the middle aged and is overwhelmingly so in the middle age and then tends to fall. In contrast, SBP and PP, elderly.4 It is a major risk factor for stroke,5 CHD,2,3 and influenced more by the stiffness of large arteries, as well as cardiovascular and total mortality.6,7 Furthermore, mea- peripheral pulse wave reflection and the pattern of left surement of SBP alone identifies Ͼ90% of hypertensives ventricular ejection, increase continuously with age.
according to the Joint National Committee on Prevention, Changes in the stiffness of the large arteries, such as the Detection, Evaluation, and Treatment of High Blood Pres- aorta and its major branches, largely account for the sure VI criteria, whereas DBP alone identifies only changes in SBP, DBP, and PP that occur from 50 years of Ϸ20%.8 The treatment of ISH with conventional antihy- age onward. Although DBP has traditionally been the pertensive drugs is of proven clinical benefit.9,10 However, major focus in the treatment of hypertension, over recent although it is recognized that few hypertensives are con- years SBP has become recognized as a stronger cardiovas- trolled to target pressures,11 it is much more commonly Received October 16, 2002; revision accepted January 27, 2003.
From the Clinical Pharmacology Unit and Research Centre, Centre for Cardiovascular Science, University of Edinburgh, Western General Hospital, Correspondence to James Oliver, Clinical Pharmacology Unit and Research Centre, Centre for Cardiovascular Science, University of Edinburgh, Western General Hospital, Crewe Road South, Edinburgh EH4 2XU, Scotland, UK. E-mail [email protected] 2003 American Heart Association, Inc.
Arterioscler Thromb Vasc Biol. is available at
DOI: 10.1161/01.ATV.0000060460.52916.D6
Oliver and Webb
Arterial Stiffness and Atherosclerotic Events
SBP than DBP that is not adequately controlled.4,8 Al-though the importance of treating raised SBP is increas-ingly recognized in clinical practice, in recent years thebrachial artery PP, the major determinant of which, inolder people, is large artery stiffness, has emerged as aneven stronger predictor of CHD,12 although not consis-tently.13 However, whether specifically targeting raised PPor arterial stiffness, rather than raised SBP, in the treat-ment of hypertension is of greater benefit is not known.
Hence, there is a strong rationale for understanding the mechanisms of arterial stiffness to better treat ISH. Inaddition, other established cardiovascular risk factors are alsoassociated with increased arterial stiffness. Currently, there isa need to quantify the extent to which measures of arterialstiffness can improve risk stratification and to determinewhether its reduction is capable of independently predictingclinical benefit in different at-risk populations.
Following an outline of the mechanisms of arterial stiff- ness, we discuss the methodologies available for the nonin-vasive assessment of arterial stiffness, including how themeasured parameters relate to established cardiovascular risk Schematic representation of pulse pressure amplification. Typi- factors and clinical outcome and indicate which might be cal pressure tracings from the brachial artery and central aorta most appropriate for wider clinical application. The effects of are shown. When the large arteries are compliant, such as in a current and future cardiovascular drugs on arterial stiffness normal healthy young subject (waveforms on the left), the arteri-al waveform is amplified as it travels toward the periphery. As are also discussed, as is the relationship between arterial the large arteries stiffen, for example, with increasing age, dia- elasticity and endothelial function.
betes, or other cardiovascular risk factors, this amplification isreduced (waveforms on the right). The two subjects have similar Mechanisms of Arterial Stiffness
BP at the brachial artery despite striking differences at the aorta,demonstrating the importance of assessing central BP in indi- Windkessel theory treats the circulation as a central elastic viduals. The effect of peripheral wave reflection on the central reservoir (the large arteries), into which the heart pumps, and aortic waveform is illustrated in the lower tracings. When the from which blood travels to the tissues through relatively large arteries are compliant the initial systolic pressure wave, P1,traveling from the heart to the periphery, is responsible for peak nonelastic conduits (peripheral arteries). The elasticity of the SBP. Reflected pressure waves, P2, arrive at the central aorta in proximal large arteries is the result of the high elastin to diastole, augmenting DBP and coronary artery filling. As large collagen ratio in their walls, which progressively declines arteries stiffen, wave reflection occurs earlier so that SBP is toward the periphery. The increase in arterial stiffness that augmented and DBP falls. AIx is calculated as the differencebetween the second (P2) and first (P1) systolic peaks (⌬P) as a occurs with age14 is largely the result of progressive elastic percentage of the PP. Thus, AIx is negative in healthy young fiber degeneration.15 It should be noted that terms such as people, but with aging or increasing cardiovascular risk, arteries large, proximal, and central arteries are frequently used stiffen and AIx becomes increasingly positive.
without any precise definition. Here, we refer to the aorta andits major branches as large arteries, which can be differenti- receptor25 genes are related to stiffness. The angiotensin- ated from the more muscular conduit arteries, such as the converting enzyme (ACE) I/D polymorphism has been asso- radial and brachial, and the smaller predominantly muscular ciated with stiffness,26 but not consistently.24 Ejection of blood from the left ventricle during systole The elasticity of a given arterial segment is not constant but initiates an arterial pressure wave that travels toward the instead depends on its distending pressure.14,16 As distending periphery. At points of impedance mismatch, chiefly at the pressure increases, there is greater recruitment of relatively high-resistance arterioles, wave reflection occurs.27 As a inelastic collagen fibers17–19 and, consequently, a reduction in consequence of differing elastic qualities and wave reflection, elasticity. The background level of distending pressure in the the shape of the arterial waveform varies throughout the circulation is determined by mean arterial pressure (MAP).
arterial tree. In healthy, relatively young subjects, whereas This is important because MAP must be taken into account MAP declines SBP and PP are amplified in the peripheral whenever measurements of arterial stiffness are made so that circulation (Figure).28 This amplification is exaggerated dur- anticipated effects of distending pressure can be differenti- ing exercise29 but reduces with increasing age.30 Although ated from real differences in the elasticity of the arterial wall.
peripheral blood pressure (BP) is most commonly measured, In addition to collagen and elastin, the endothelium20,21 and the information contained within the waveform of the prox- arterial wall smooth muscle bulk and tone19,22 (the latter imal aorta is of particular interest because it is the BP profile under some control from the endothelium) also influence at this site, rather than more peripherally, that determines left elasticity. A number of genetic influences on arterial stiffness ventricular load and coronary blood flow. The effects of have also been identified. Thus, polymorphic variation in the increased arterial stiffness on the central aortic waveform and fibrillin-1,23 angiotensin II type-1 receptor,24 and endothelin BP are illustrated in the Figure. The contour and amplitude of 556
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Definitions of Some Parameters Commonly Measured in the Assessment of Arterial Stiffness
The absolute change in vessel diameter (or area) for a given change in pressure Relationship between decline in pressure and decline in volume in the arterial tree during the exponential component of diastolic pressure decay (said to reflect large artery compliance) Relationship between oscillating pressure change and oscillating volume change around the exponential pressure decay during diastole (said to reflect small artery compliance) The relative change in vessel diameter (or area) for a given change in pressure The pressure change required for (theoretical) 100% stretch from resting diameter The speed with which the pulse wave travels along a length of artery The ratio of the natural logarithm of SBP/DBP to the relative change in diameter Elastic modulus per unit area (accounts for wall thickness) Definitions of some of the parameters commonly measured in the assessment of arterial stiffness: D indicates diameter; P, pressure; A, area; V, volume; t, time; s, systole; d, diastole; h, wall thickness. Augmentation index (AIx) is defined in Figure 1.
the pressure waveform are influenced by large artery pulse radius at the end of diastole, and ␳ is blood density. There are wave velocity (PWV), in that faster traveling pressure waves a number of different ways to measure PWV, and these are arrive at, and are reflected from, the peripheral circulation generally simple to perform. The arterial pulse wave is earlier. When arteries are relatively compliant and PWV is recorded at a proximal artery, such as the common carotid, as relatively slow, reflected waves return to the central aorta in well as at a more distal artery, such as the femoral. The diastole, augmenting DBP and, therefore, coronary blood superficial location of the carotid and femoral arteries means flow, which occurs predominantly during diastole. When that their pulse waveforms are readily measured noninva- arteries are stiffer and PWV is higher, reflected waves arrive sively, and between these 2 sites the pulse wave has to travel earlier and augment central SBP, rather than DBP, increasing through most of the aorta, an artery particularly prone to the left ventricular workload and compromising coronary blood development of atherosclerosis. The time delay between the arrival of a predefined part of the pulse wave, such as the foot,at these 2 points is obtained either by simultaneous measure- Noninvasive Methodologies for the Assessment of
ment, or by gating to the peak of the R-wave of the ECG. The Arterial Stiffness
distance traveled by the pulse wave is measured over the Many methodologies, both invasive and noninvasive, have body surface and PWV is then calculated as distance/time been applied to the assessment of arterial elasticity in vivo.
(m/s). The measured distance is an estimate of the true Noninvasive measures fall into three broad groups: 1) mea- distance traveled and depends to some extent on body suring PWV, 2) relating change in diameter (or area) of an habitus. Furthermore, the abdominal aorta tends to become artery to distending pressure, and 3) assessing arterial pres- more tortuous with age,34 potentially leading to an underes- sure waveforms. Definitions of the parameters commonly timation of PWV. Arterial pulse waves can be detected by measured are listed in Table 1. There is a large and rapidly using pressure-sensitive transducers,35 Doppler ultrasound expanding number of published studies investigating how the (the pressure pulse and the flow pulse propagate at the same various noninvasive measures of arterial stiffness are related velocity),36 or applanation tonometry,37 where the pressure to both cardiovascular risk factors and prognosis and are within a small micromanometer flattened against an artery influenced by different treatments. Thus, in addition to equates to the pressure within the artery.
describing the major existing technologies and highlightingtheir important limitations, here we summarize and interpret Aortic PWV can also be measured noninvasively by using MRI.38 MRI has the potential advantage of accurate determina-tion of path length, although factors, such as the time required to Pulse Wave Velocity (PWV)
make a recording, lack of availability in the immediate clinical Interest in, and measurement of, the velocity of arterial wave setting, relatively high cost per measurement, and the difficulty propagation as an index of vascular stiffness and vascular in performing clinical studies within a strong magnetic field, health dates back to the early part of the last century.33 The mean that few studies have been performed with this technique.
arterial PWV, especially of the aorta, has emerged as an However, a recent study showed that MRI offers insights not important independent predictor of cardiovascular events.
otherwise possible, in describing greater age-related increase in PWV increases with stiffness and is defined by the Moens– PWV in the proximal than in the distal aorta.39 Korteweg equation, PWVϭ͌(Eh/2␳R), where E is Young’s Increases in distending pressure increase PWV.33 Therefore, modulus of the arterial wall, h is wall thickness, R is arterial account should be taken of the level of BP in studies that use Oliver and Webb
Arterial Stiffness and Atherosclerotic Events
PWV as a marker of cardiovascular risk or as a measure of the PP amplification differs between individuals, so that compar- effects on arterial stiffness of interventions that reduce BP. Heart ing different groups by using stiffness parameters incorporat- rate has also been reported to influence PWV. In one study an ing peripheral BP measurement may not be valid.
increase in heart rate of 40 beats per minute increased PWV by Alternatively, applanation tonometry can be used to assess Ͼ1 m/s,40 a difference that may be relevant to the assessment of carotid BP. Although this technique is not normally used to cardiovascular risk. However, it has been suggested this finding measure absolute pressure, the brachial artery MAP can be may be an artifact of the methodology used.41 assumed to be equal to that in the carotid so that the absolute Raised PWV occurs with a range of established cardiovascu- pressure of the carotid waveform can be calculated. Diam- lar risk factors,42 including age,43,44 hypercholesterolemia,45 type eter–pressure curves over the systolic– diastolic range can II diabetes,46 and sedentary lifestyle.44 In hypertension, carotid– thus be obtained with the simultaneous use of ultrasound and femoral PWV is an independent predictor of both cardiovascular applanation tonometry. These diameter–pressure curves can and all-cause mortality.47 The odds ratio for a 5 m/s increment in then be used to derive distensibility–pressure curves. In this PWV was 1.34 for all-cause mortality and 1.51 for cardiovas- way, carotid artery distensibility has been investigated in cular mortality. In contrast, PP was independently related to hypertensives and matched controls.56 For each group, dis- all-cause mortality but only marginally related to cardiovascular tensibility was calculated at MAP (DistMAP), which, naturally, mortality, indicating that specific assessment of arterial stiffness, is higher in hypertensives, and at 100 mm Hg (Dist100), a level with PWV, may be of greater value in the evaluation of risk. It of carotid BP common to both groups. DistMAP was lower in should be noted that 5 m/s is a relatively large change in PWV.
hypertensives, but Dist100 was similar in the two groups.
In this study PWV ranged from 9 to 13 m/s, whereas recently These findings were confirmed in a subsequent study, at quoted values of carotid–femoral PWV in healthy individuals DistMAPand Dist110.57 The authors of the latter study also with average ages of 24 to 62 years ranged from around 6 to 10 constructed curves of incremental elastic modulus (Einc) m/s.48 Differences between studies regarding the method used to against circumferential wall stress. The cross-sectional area calculate the distance traveled between the carotid and femoral of the arterial wall and, therefore, its thickness, is accounted sites probably explains some of the variation in these normal for in the calculation of Einc. As a result, Einc is independent of arterial geometry and may be considered a measure of the In hypertensives without a history of overt cardiovascular intrinsic stiffness of the arterial wall material. In keeping with disease PWV also predicts the occurrence of cardiovascular the findings for distensibility, Einc increased with stress during events independently of classic risk factors.49 Once again, PP the cardiac cycle and was higher in hypertensives at their was of predictive value in univariate but not multivariate respective mean circumferential wall stresses, but overall analysis. Aortic PWV Ͼ13 m/s is a particularly strong predictor there were no differences between the groups for common of cardiovascular mortality in hypertension.50 Recently pub- wall stress values. An alternative approach proposed to lished data show that carotid–femoral PWV increases at a faster characterize the elastic properties of arteries independently of rate in treated hypertensives than in normotensive controls, distending pressure is to calculate the stiffness index, ␤.
although where BP was well controlled PWV progression was Reducing SBP by up to 40 mm Hg with sodium nitroprusside attenuated.51 High heart rate and plasma creatinine Ͼ8 mg/L infusion in 8 patients with myocardial infarction led to a were other determinants of accelerated progression of PWV in reduction in elastic modulus, a parameter that is dependent on hypertensives in this study. Aortic PWV, assessed by using distending pressure, but had no effect on ␤.58 Although Doppler flow recordings, also independently predicts mortality further validation of ␤ is desirable, elastic modulus of the in patients with end-stage renal failure (ESRF), a population carotid artery was increased in hypertensives compared with with a particularly high rate of cardiovascular disease.52,53 The controls, but ␤ was similar in the 2 groups.59 In a subsequent benefit associated with BP control in ESRF, either by adjustment study, elastic modulus was related to left ventricular hyper- of dry weight or the use of antihypertensives, was independently trophy, whereas ␤ was related to concentric remodeling but related to change in aortic PWV, such that a reduction in PWVof 1 m/s was associated with a relative risk of 0.71 for all-cause not hypertrophy.60 These data indicate that, at least at the carotid artery, distending pressure alone may account forreduced arterial elasticity in hypertension.
Relating Change in Vessel Diameter (or Area) to
In contrast, aging appears to have different effects on Distending Pressure
carotid artery stiffness. Increased age correlated with reduced The change in diameter of a number of arteries, such as the Dist100,56 suggesting that structural or functional changes carotid, brachial, radial, and aorta, can be related to the other than those simply associated with greater distending distending pressure, providing a series of direct measures of pressure, account for the aging-associated reduction in arte- stiffness. Ultrasound is the most frequently used imaging rial distensibility. Einc at common circumferential wall stress modality, although MRI has been used rarely. Calculation of increased with age in both hypertensives and controls, and in parameters, such as compliance and distensibility, requires middle-aged and older subjects there was no difference that the incremental pressure of the artery in question be related to BP.57 However, younger hypertensives had a higher known, for example, the carotid PP. However, many authors Einc for a given wall stress. These findings suggest that in have used BP measured at the brachial artery in these hypertension the material of the arterial wall is intrinsically calculations55 whereas, because of PP amplification, this may stiffer only in young subjects, and that age-related, rather than not represent the carotid artery PP. Furthermore, the extent of hypertension-related changes become more important in later life.
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Pressure– diameter relationships can be accurately deter- also determined by the intensity of wave reflection which, in mined invasively with simultaneous measurement of arterial turn, is determined by the diameter and elasticity of small pressure by using a luminal pressure transducer and dimen- arteries and arterioles. AIx increases with MAP72 and is in- sions by using intravascular ultrasound. In a similar manner versely related to heart rate73,74 and body height,75 so these to the noninvasive methods, this technique can differentiate variables should be accounted for when interpreting studies that the effects on elasticity of distending pressure from the use SPCA. Twin studies suggest that AIx is partly heritable, intrinsic properties of the vessel wall. The use of this independent of these variables.76 SPCA is simple, rapid, and can technique in reducing aortic distensibility has been demon- be used in the clinical as well as research setting.
strated with increased age,61 in patients with CHD,62 hyper- Rather than individualizing the transfer function for par- tension61,63 and hypercholesterolemia,61 and acutely after ticular subject characteristics, SPCA uses a generalized trans- smoking.64 This technology has not been applied to the fer function in all situations. This has been subject to a carotid artery, although such studies would help to determine number of validation studies. It was reasonably accurate in the reliability of the non-invasive techniques.
determining central aortic waveforms at rest in patients with Although few studies have related local noninvasive mea- CHD.77 In a study that measured radial waveforms with sures of arterial stiffness to clinical outcome, carotid artery tonometry and aortic waveforms invasively, individualizing stiffness is a predictor of mortality in patients with ESRF.
the transfer function added little to the accuracy of determin- Thus, in prospective studies, Einc emerged as the strongest ing central BP and AIx, even after hemodynamic challenges independent determinant of all-cause mortality in 79 pa- such as the Valsalva maneuver and infusion of nitroglycer- tients65 and also independently predicted mortality risk in a ine.78 However, more recently it has been suggested that larger sample of 110 patients with ESRF.66 Carotid artery gender-specific transfer functions may be more reliable than distensibility was also an independent predictor of cardiovas- a generalized transfer function.79 The use of invasive record- cular events after renal transplantation, although in this study ings at the aorta and radial artery in patients with angina BP was measured at the brachial artery.67 showed that the generalized transfer function tended to MRI can also be used to measure arterial, usually aortic, underestimate aortic SBP by 6 to 8 mm Hg and overestimate distensibility noninvasively, although its value is probably aortic DBP by about 4 mm Hg.80 In two studies81,82 the limited to small mechanistic studies. In healthy subjects MRI correlation coefficient of directly-measured and reconstructed revealed compliance to be greater in the ascending aorta than AIx was around 0.66 and, in both, reconstructed AIx tended the aortic arch where, in turn, it was greater than in the to underestimate the measured value. Furthermore, the cor- proximal descending aorta.68 Aortic compliance was greater relation was weaker after nitroglycerine administration, and in athletes and lower in patients with CHD compared with inter-individual variation in the relationship of AIx obtained matched controls.68 Aortic distensibility was reduced in directly and from the reconstructed waveform was highlight- hypertensives, whether measured at the ascending, descend- ed.82 SPCA is increasingly used in healthy volunteer studies ing thoracic or abdominal aorta,69 but differences in distend- and it should be noted that the transfer function has not been ing pressure (MAP) were not accounted for in either of these validated in young subjects with compliant vessels. The studies. Proximal aortic distensibility decreased with age and generalized nature of the transfer function used in SPCA may was also less in patients with diastolic heart failure, in whom represent a weakness of the technique that could benefit from it was an independent predictor of exercise capacity.70 A further consideration. SPCA shows good reproducibility in limitation of all of these studies is that measures of peripheral, both healthy subjects37 and patients with ESRF.83 rather than central, BP were used in the calculation of SPCA has been used to explain why peripheral DBP, rather than SBP or PP, is a better predictor of CHD risk in theyoung, whereas the strongest predictor of CHD risk in older Analysis of the Arterial Pulse Waveform
people is peripheral PP.30 In young subjects (Ͻ50 years), as Systolic Pulse Contour Analysis (SPCA)
DBP increases early wave reflection also increases, causing a Analyses of specific components of the arterial pressure or flow reduction in peripheral PP amplification. In contrast, in older waveform are used by a number of noninvasive methodologies subjects amplification does not depend on DBP, perhaps designed to measure arterial stiffness. Peripheral artery pressure because wave reflection is already increased due to age- waveforms can be acquired noninvasively by using applanation related arterial stiffening. Therefore, for a given increase in tonometry. When measured at the radial artery the waveform is DBP in younger subjects there is a greater rise in central SBP calibrated to conventionally measured brachial BP. SPCA uses a and PP than occurs in older people. In older subjects transfer function to derive central aortic waveforms from those peripheral PP more accurately predicts central PP, although obtained from a peripheral artery, most commonly the radial.
there is, of course, substantial individual variation. These From the central aortic waveform central BP values and the findings regarding PP amplification may be relevant to the augmentation index (AIx; Figure) can be calculated. The AIx is clinical management of young people with high peripheral the proportion of central PP that results from arterial wave SBP or PP. Even though these BP parameters are not reflection and is a commonly used measure of arterial stiffness.
important predictors of risk in this age group, performing Although the timing of the arrival of the reflected wave at the SPCA may provide some reassurance that the peripheral proximal aorta is largely determined by large artery PWV, AIx pressures are the result of exaggerated PP amplification, with is not simply a surrogate measure of PWV. It is influenced by normal central SBP and PP, so that subjects are unlikely to vasoactive drugs independently of PWV,71 suggesting that it is gain from antihypertensive treatment.
Oliver and Webb
Arterial Stiffness and Atherosclerotic Events
SPCA has been performed in a number of at-risk populations.
whether assessed invasively or noninvasively.94 Although the AIx increases with age84–86 and, compared with matched con- relationship between age and large artery compliance was trols, is also higher in patients with type I diabetes87 and similar however measured, the decline in small vessel compli- hypercholesterolemia,88 despite similar peripheral BP. Thus far, ance was greater when measured noninvasively. SBP was there are no data on the prognostic value of AIx calculated from independently associated with reduced large artery compliance, the central aortic waveform when derived from radial artery but small artery compliance was not associated with any BP tonometry. However, SPCA has been incorporated into a num- parameter. DPCA has been proposed as a sensitive marker of ber of prospective cohort studies with hard clinical endpoints, early vascular disease. In particular, reduced C2, considered an including the Anglo-Scandinavian Cardiac Outcomes Trial (AS- early feature of impaired pulsatile arterial function, might be COT) in hypertensives, the Edinburgh Artery Study in athero- capable of identifying those at risk, providing an opportunity for sclerosis, the Study of the Effectiveness of Additional Reduction early intervention. Although there were no differences in heart in Cholesterol and Homocysteine with Simvastatin and Folic rate or BP, compared with matched controls, C2, but not C1, was Acid/Vitamin B12 (SEARCH), and the Fenofibrate Intervention decreased in patients with type II diabetes.95 Analysis of brachial and Event Lowering in Diabetes (FIELD) study. AIx can also be artery waveforms revealed that, compared with age-matched directly measured by using applanation tonometry, relatively controls, C2 was reduced to a much greater extent than C1 in close to the central aorta, at the carotid artery. High carotid AIx young hypertensives, whereas C2 was reduced to a similar is an independent predictor both of cardiac ischemic threshold degree in older hypertensives and controls.93 Using radial artery during exercise in patients with CHD89 and of all-cause and waveforms obtained noninvasively, compared with matched cardiovascular mortality in patients with ESRF.90 Of particular healthy controls C2 was reduced in both hypertensives and note from the latter study, AIx predicted mortality even in postmenopausal women with CHD, whereas there were no patients considered to have a normal PWV (Ͻ11 m/s), high- differences in C1.92 Similarly, smoking was associated with lighting the importance of assessing arterial wave reflection, impaired C2, but not C1.96 Longitudinal studies investigating the rather than just arterial stiffness. In a further study on ESRF value of DPCA are still to be performed.
patients that used carotid artery tonometry, reduction in periph- The validity of DPCA has been subject to a number of eral PP amplification, in addition to raised aortic PWV, also criticisms. Referred to as distal, reflective, or oscillatory com- independently predicted all-cause mortality.53 pliance, there is confusion as to precisely what C2 measures,82especially given that it does not refer to a well-defined arterial Diastolic Pulse Contour Analysis (DPCA)
territory. As an overall measure of proximal and distal compli- By using a modified Windkessel model, the analysis of the ance of the entire circulation, it would, in theory, be expected diastolic portion of the pressure pulse contour can be used to that there would be no significant variation in the calculated derive information on the compliance of both proximal and values with the site of measurement. However, an invasive study distal arteries. Two components of the diastolic waveform are performed in dogs found that there was little or no correlation distinguished in DPCA. An exponential decay curve represents between compliance values obtained at the ascending and large (capacitative) artery compliance, sometimes referred to as terminal aorta.97 There was also poor agreement between the C1. The other component, referred to variously as C2, oscillatory two sites for the effect of vasoactive agents on compliance. In compliance or reflective compliance, consists of peripheral wave reflections which are superimposed on the basic waveform and 1 and C2 measured at the radial artery were not significantly correlated with those measured at the posterior provide a measure of small artery compliance.91 As with SPCA, tibial artery.98 Rather than a reliable measure of overall proximal the waveform of the radial artery can be determined noninva- and distal compliance, it is likely that regional circulatory sively by using tonometry and calibrated for BP by using properties, such as arterial length, number of reflection sites and standard sphygmomanometry, potentially allowing for wide stiffness of individual arteries, have significant influence on clinical application. Values obtained by using the noninvasive these measures. Furthermore, despite good quality tonometry methodology have been compared with those obtained from recordings, application of the model used in the technique waveforms obtained invasively.92 Tonometry-measured pressure yielded uninterpretable values for compliance in some sub- tended to underestimate, but was tightly correlated to, pressure jects.98 For example, where negative compliance values were determined invasively. The waveform obtained by using tonom- obtained further analysis revealed wave peaks late in diastole, etry also exhibited fewer high frequency components compared although the origin of these was uncertain. These findings with that obtained invasively. Compliance calculated from currently cast doubts over the reliability of this methodology in invasive and noninvasive methods correlated significantly, al- accurately determining arterial compliance variables.
though this was closer for C1 than C2, with noninvasive measurestending to overestimate. C2 was also reduced in hypertensives Digital Volume Pulse (DVP)
compared with age-matched controls, although the use of Digital arterial pressure and volume waveforms are also tonometry appeared to be less sensitive in detecting this differ- readily measurable. The digital pressure pulse closely mirrors ence than was previously reported in an invasive study.93 the radial pressure pulse. The DVP, measured by using Assessment of arterial compliance by using DPCA has been photoplethysmography, has a different contour, but can pre- applied to a number of at-risk populations. Using both brachial dict both digital and radial pressure pulses through a gener- artery waveforms obtained invasively and radial artery wave- alized transfer function that appears to be appropriate for use forms obtained noninvasively with tonometry, increased age was in healthy subjects, hypertensives and after nitroglycerine associated with reduced large and small artery compliance, administration.99 The DVP is characterized by an inflection 560
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Comparison of Major Methods Used in the Noninvasive Assessment of
Arterial Stiffness With Regard to Their Potential For Wider Clinical Use
*Excluding MRI†Potential for practical application to the noninvasive assessment of endothelial functionComparison of the major methods used in the noninvasive assessment of arterial stiffness with regard to their potential for wider clinical use. Carotid AIx, directly measured noninvasively usingapplanation tonometry, is considered separately to SPCA, which uses a generalized transfer functionto derive central aortic AIx.
point, or notch, and the height of this has been suggested as most beneficial. Currently, none of the methodologies available a measure of peripheral pressure wave reflection.100 How- are yet suitable for use in widespread clinical practice. However, ever, although inexpensive and easy to use, there is, to date, internationally recognized standards are being developed. In little experience in the use of the DVP for the assessment of 2000 the First Consensus Conference on Arterial Stiffness was arterial stiffness. Further work to validate the technique, as held in Paris and articles focusing on validation and reproduc- well as establishing its precise relationship with the central ibility,108 recommended procedures109 and reference values48 for arterial waveform, needs to be done.
the different methodologies have recently been published. Inaddition, regular workshops on the structure and function of Comparison of the Different Methodologies
large arteries have been held, which include discussion of The relationship between different measures of arterial stiff- methodology.110 A summary of our views on the relative ness has been assessed in a number of studies. Using DPCA, strengths and weaknesses of the major technologies is given in C1 was closely correlated to both the ratio of stroke volume Table 2. Arterial waveform analysis by using tonometry of the (SV; determined non-invasively) to PP (SV/PP has been radial artery requires minimal training and can be rapidly proposed as a measure of total arterial compliance,101 and measured, such that it could easily be incorporated into an office aortic distensibility measured by MRI, whereas C2 correlated visit as part of a clinical trial. In contrast, PWV and ultrasonog- with SV/PP, but not aortic distensibility.102 In a further study raphy are more time consuming and ultrasonography in partic- the correlation between stiffness parameters obtained by ular requires substantial training and is likely to require dedi- using SPCA, DPCA, and a third method that uses cuff cated staff. The limitations of DPCA make it less likely that it plethysmography to measure brachial artery compliance was will emerge as the preferred method of arterial waveform investigated.103 Overall, different measures of compliance analysis. With regard to prognostic value, currently the most were only weakly correlated among themselves and with BP, characterized of the measured parameters is aortic PWV. How- although the cardiac time-tension index, the integral of the ever, data on the prognostic value of AIx are emerging and in central pulse waveform from its beginning to the dichrotic some cases suggest it is more powerful than PWV.90 The results notch, which is considered a measure of cardiac load,104 was of ongoing studies are eagerly awaited.
reasonably correlated with SBP and MAP. SPCA and DPCAhave also been compared in a further study.105 C2 was Effects of Cardiovascular Drugs on Arterial Stiffness
significantly and inversely correlated with AIx, providing As arterial stiffness has become established as a cardiovas- support for the notion that C2 is determined, at least in part, by cular risk factor in its own right, it has also emerged as a arterial wave reflections. The authors also reported inferior potential target for intervention. Indeed, it is conceivable that reproducibility in the measurement of C2 compared with AIx, reduction of arterial stiffness may become a major primary although this finding has been challenged.106 Invasive mea- goal of treatment in particular patients at risk of cardiovas- sures of aortic and radial artery waveforms in patients with cular disease. However, for this situation to arise increased CHD and hypertension have been used to investigate the arterial stiffness will not only have to be established as an relationship between AIx and C2.82 The two parameters were important independent cardiovascular risk factor, but also significantly, but not strongly, correlated. Thus, C2 reflected, reducing arterial stiffness will need to be shown to reduce at least in part, hemodynamic changes affecting central aortic risk, independent of other effects of treatment. In the first pressure. AIx was more sensitive to the hemodynamic effects instance, establishing whether currently used cardiovascular of glyceryl trinitrate (GTN) than C2.
drugs potentially exert their clinical benefit through improve- As has previously been argued,107 there is a need for a simple, ments in arterial elasticity may lead to more appropriate reliable, noninvasive method of detecting early disturbances in targeting of these treatments. However, many of these agents arterial stiffness at a time when therapeutic intervention can be also lower BP and this effect must be differentiated from any Oliver and Webb
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intrinsic effects, either structural or functional, on arterial benefits of treating ISH. However, although ␤-blockers may reduce large artery stiffness, their effects on peripheral wave The effects of organic nitrates, especially GTN, on the central reflection and the central arterial waveform are less favorable, aortic waveform have been well characterized. GTN effectively highlighting a potential limitation in the use of SPCA both as a reduces central measures of AIx, SBP and PP but has little or no marker of prognosis and of treatment benefit. After 6 months of effect on peripheral arterial resistance, peripheral BP, or aortic treatment in hypertensives, atenolol was as effective as the ACE PWV.111–113 The greater effect of GTN on central than periph- inhibitor cilazapril in increasing aortic elasticity.129 However, eral arteries is particularly evident at lower doses and probably atenolol was less effective than either fosinopril after 8 weeks of the result of reduced peripheral wave reflection due to dilatation treatment130 or perindopril after 1 month of treatment131 in of muscular conduit arteries.114 Indeed, direct measurement of lowering directly measured carotid AIx. In a further study, brachial artery compliance with ultrasound has demonstrated treatment for 1 year with atenolol or perindopril/indapamide improvements with GTN that are independent of distending similarly reduced aortic PWV but only the ACE inhibitor/diuret- pressure.22 Other than when combined with hydralazine for the ic combination reduced carotid AIx.132 As a confounding vari- treatment of heart failure,115 organic nitrates are not known to able heart rate reduction with atenolol largely accounts for these improve clinically important endpoints such as mortality and differences, although functional or structural changes in the vascular events. The likely explanation for this is that their use is peripheral circulation might also affect the pattern of wave associated with increased production of superoxide anions, endothelial dysfunction and the development of tolerance to There are conflicting data regarding the effects of diuretics on their effects.116 However, the potential clinical benefits of arterial wall stiffness. For example, despite reducing BP, neither specifically targeting organic nitrate therapy to patients with indapamide nor canrenoate changed PWV.133 However, in increased arterial stiffness have not been fully investigated.
hypertension, there was a comparable improvement in arterial Both calcium channel blockers (CCBs) and ACE inhibitors stiffness following treatment with perindopril or combined also appear to have beneficial effects on arterial elasticity hydrochlorothiazide and amiloride in one study,134 although independent of effects on distending pressure. For example, perindopril was more effective than the diuretic combination in favorable effects on stiffness have been recorded with nitrendip- reducing arterial stiffness in a further study.135 In the latter study ine in patients with ESRF117 and hypertension,118 and with a arterial properties returned to baseline within 7 weeks, perhaps number of ACE inhibitors in hypertension.119–121 The degree to suggesting that the beneficial changes were functional, rather which ACE inhibition reduces arterial stiffness may be, at least than structural. The CCB felodipine more effectively improved in part, genetically determined. Polymorphism of the angiotensin brachial artery compliance than hydrochlorothiazide, although II type-1 receptor gene influences the extent to which perindopril the effects on MAP were slightly greater with felodipine.136 reduces both BP and PWV independently of BP.122 Polymorphic The effect of cholesterol lowering with 3-hydroxyl-3-methyl variation in this gene also influenced the effect of nitrendipine on coenzyme A reductase inhibitors (statins) on arterial stiffness has PWV, although there was no influence on the BP response.122 also been investigated. In familial hypercholesterolemia im- Angiotensin II receptor antagonists have similar effects to ACE provements in elasticity have been demonstrated in the common inhibitors on arterial stiffness in hypertension123 and congestive femoral but not the carotid artery after 1 year of simvastatin or heart failure (CHF),124 although the latter study did not use BP atorvastatin,137 in the aorta after 13 months of cholesterol- at the artery under investigation when calculating distensibility.
lowering treatment that included pravastatin,138 and in the radial The dual ACE and neutral endopeptidase inhibitor omapatrilat artery after 2 years but not 6 months of simvastatin.139 In was more effective than enalapril in reducing proximal aortic nonfamilial hypercholesterolemia, simvastatin improved stiffness in hypertensives withdrawn from other treatment.125 femoral-posterior tibial but not aortofemoral PWV, although A number of studies have compared the effects on arterial treatment was only given for 4 weeks.140 In patients with ISH stiffness of ACE inhibitors and CCBs. In ESRF treatment for 1 and relatively normal plasma cholesterol concentrations, not year with perindopril or nitrendipine similarly reduced BP and taking antihypertensive medication, atorvastatin for 3 months more effectively reduced carotid than brachial pressure, restor- reduced systemic arterial compliance, assessed noninvasively.141 ing physiological peripheral amplification of SBP and PP.126 SBP was also reduced by atorvastatin in this study. Although Both similarly reduced PWV and carotid AIx, although only there was a reduction in peripheral resistance and MAP, these perindopril reduced left ventricular hypertrophy, suggesting changes were small and it is likely that the reduction in SBP was additional modification by perindopril of factors other than left secondary to reduced arterial stiffness. Using DPCA a reduction ventricular afterload. In hypertension, 8 weeks of treatment with in small artery compliance after 4 weeks of atorvastatin has also lisinopril more effectively reduced PWV than nifedipine127 and, been reported, although this was an open study without a after 20 weeks of treatment, derapril improved carotid distensi- bility whereas manidipine did not.128 Using invasively- Drugs may improve the stiffness of the arterial wall through determined pressure-diameter curves, the acute administration of either functional or structural mechanisms. Although there are a diltiazem improved aortic elasticity through, at least in part, number of approaches to investigating these mechanisms, such effects on the intrinsic elastic properties of its wall.63 In contrast, as the use of animal models, some insight can be gained from the acute administration of enalapril had no effect on the intrinsic noninvasive assessment of arterial stiffness. For example, the time on treatment required for benefit to occur might be The ␤-adrenoceptor blocker atenolol was one of the antihy- informative. Although ACE inhibitors have no effect on the pertensives used in the SHEP study,9 which demonstrated the intrinsic stiffness of the aorta when given acutely61 there is 562
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abundant evidence that regular ACE inhibition over several A number of interventions that reduce arterial stiffness also months or more reduces arterial stiffness. Structural changes to improve endothelial function, particularly ACE inhibitors160,161 the arterial wall would be expected to accrue over time and may, and statins.162,163 To date, there have been few studies specifi- therefore, explain these differences between acute and chronic cally investigating the relationship between these two markers of effects. The changes in arterial elasticity that occur following vascular function after treatment. However, in CHF patients 2 cholesterol lowering with statins also appear to be related to time months treatment with perindopril improves both flow- on treatment, suggesting that structural changes occur. In con- dependent dilatation and flow-dependent change in distensibility trast, CCBs reduce stiffness with regular treatment, but also do of the radial artery.164 Patients with growth hormone deficiency, so acutely.61 Thus, CCBs appear to improve elastic properties in who are at increased risk of vascular disease, have impaired a functional manner, although later structural changes cannot be endothelial function and increased AIx compared with con- excluded. It should be noted that structural changes might not be trols.165 Indeed, endothelial dysfunction, assessed as flow- the only explanation for improvement in elasticity related to time mediated dilatation of the brachial artery, independently pre- on treatment, because interventions that improve endothelial dicted AIx in this population. Replacement of growth hormone function, thus reducing stiffness in a functional manner, may resulted in improvement of both endothelial function and AIx, without changing BP.165 Further studies are required to fullydefine the link between endothelial function and arterial stiff- Endothelial Function
ness. Although most studies suggest that the endothelium regu- There are now a number of published studies demonstrating lates stiffness, impaired elastic function itself might have adverse the independent prognostic value of endothelial dysfunc- effects on endothelial function, and future work needs to address tion.143–146 Both endothelial dysfunction and increased arte- this issue. Investigation of the relationship between arterial rial stiffness commonly coexist in patients at increased risk of stiffness and endothelial function, as well as of the clinical value cardiovascular disease, for example in diabetes87,147 and in of assessment of endothelial function, will be aided by the recent smokers.148,149 Indeed, some studies in children have directly development of a noninvasive methodology that measures en- related increased stiffness with impaired endothelial function, dothelial function by using SPCA. The ␤2-adrenergic receptor for example in low birth weight,150 familial hypercholester- agonist albuterol lowers both the inflection point of the DVP,100 olemia,151 and severe obesity.152 These observations lead to and AIx measured by SPCA.166 These actions of albuterol are the hypothesis that cardiovascular risk factors may exert their mediated, at least in part, through the NO pathway. Furthermore, detrimental effects on arterial stiffness through endothelial in patients with hypercholesterolemia, known to have impaired endothelial function, the effect of albuterol on AIx was blunted, Evidence from both animal153,154 and human studies suggests and this correlated well with impaired endothelial function that the endothelium is an important regulator of arterial stiff- measured as acetylcholine-induced vasodilatation in the forearm ness, both functionally and structurally. Inhibition of basal nitric by using strain gauge plethysmography. In contrast to other oxide (NO) production in the endothelium with L-monomethyl- methodologies, assessment of endothelial function with SPCA, NG-arginine (L-NMMA) increases iliac PWV in sheep21 and, in and potentially also by using the DVP, can readily be applied to humans, increases AIx155 and brachial artery stiffness.20 The large numbers of subjects in clinical trials.
reduction in arterial stiffness with acetylcholine, an endotheli-um-dependent vasodilator, is also inhibited by L-NMMA in The Future
large arteries.21 However, in one human study, although acetyl- A number of technologies can measure arterial stiffness nonin- choline increased brachial artery elasticity, L-NMMA paradox- vasively. The relatively low cost, ease of use, and acceptability ically increased compliance of the artery.156 Using DPCA in to patients of many of these technologies has resulted in a rapid healthy volunteers, inhibition of endogenous NO synthesis expansion of work in this field, although the full clinical impact increased BP and decreased small artery compliance, but had no of these measurements is not yet clear. Where possible, there- effect on large artery compliance.157 These changes were re- fore, these technologies should now be incorporated into longi- versed with L- but not D-arginine. The importance of endothe- tudinal studies, so that the prognostic value, relative to estab- lium-derived NO to the structural integrity of the arterial wall is lished predictors of risk, of the various parameters can be fully emphasized by a study in which disruption of the endothelial NO defined. Although the prognostic value of some technologies, synthase gene in mice promoted abnormal arterial remodel- especially PWV, has been investigated, these studies have ling.158 In healthy subjects, increased vessel wall shear stress generally been small and have been performed in a limited (resulting from increased flow that occurs with distal vasodila- number of at-risk groups. Larger studies, in a greater number of tation secondary to, for example, reactive hyperemia) leads to at-risk populations, are required. This knowledge will facilitate endothelium-dependent arterial dilatation. The same stimulus greater confidence that the effects of drugs and other interven- also increases local arterial distensibility.159 At the brachial tions on these parameters may truly be relevant to important artery both endothelial function and shear stress-stimulated clinical outcomes. It is of paramount importance that studies are increased distensibility are impaired in patients with CHF. In standardized109 and take into account known confounding fac- contrast, the increase in distensibility that occurred with endo- tors. Noninvasive technologies should also be used to more fully thelium-independent stimuli was retained in patients with characterize the effects of existing drugs on arterial stiffness, CHF.159 Furthermore, acetylcholine reduced local PWV of the including quantifying the degree to which their beneficial effects right common iliac artery in healthy subjects but not in those are the result of improvements in the elastic properties of the arterial wall. Furthermore, these methodologies should also Oliver and Webb
Arterial Stiffness and Atherosclerotic Events
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