Norway pharmacy online: Kjøp av viagra uten resept i Norge på nett.

Jeg har selv prøvd dette kamagra Det er billig og fungerer egentlig, jeg likte det) kjøp propecia Ikke prøvd, men du kan eksperimentere med... Hvordan føler du deg, følsomhet etter konsumere piller?.

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 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
Arterioscler Thromb Vasc Biol.
April 2003
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.
Arterioscler Thromb Vasc Biol.
April 2003
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
Arterioscler Thromb Vasc Biol.
April 2003
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
Arterial Stiffness and Atherosclerotic Events
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
Arterioscler Thromb Vasc Biol.
April 2003
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
provide a means of unraveling the influence of genetic factors on 14. Hallock P, Benson IC. Studies on the elastic properties of human isolated both the development of stiffness and its response to treatment.
aorta. J Clin Invest. 1937;16:595– 602.
15. Avolio A, Jones D, Tafazzoli-Shadpour M. Quantification of alterations in There are a number of novel approaches to treatment that structure and function of elastin in the arterial media. Hypertension. 1998; might prove particularly valuable in reducing arterial stiffness and its clinical consequences. For example, breaking advanced 16. Greenfield JC, Patel DJ. Relation between pressure and diameter in the glycation end-product crosslinks, alterations in matrix proteins ascending aorta of man. Circ Res. 1962;10:778 –781.
17. Roach MR, Burton AC. The reason for the shape of the distensibility curves that accumulate in arterial wall elastin and collagen and increase of arteries. Can J Biochem Physiol. 1957;35:681– 690.
wall stiffness, has recently been shown to improve arterial 18. Apter JT. Correlation of visco-elastic properties with microscopic structure compliance in elderly humans.167 The provision of exogenous of large arteries: IV: thermal responses of collagen, elastin, smooth muscle, NO to the arterial wall may also be of benefit, such as with novel and intact arteries. Circ Res. 1967;21:901–918.
19. Bank AJ, Wang H, Holte JE, Mullen K, Shammas R, Kubo SH. Contri- NO donors that do not undergo tolerance.168 Alternatively, the bution of collagen, elastin, and smooth muscle to in vivo human brachial activity of the vascular NO– cGMP pathway might be enhanced artery wall stress and elastic modulus. Circulation. 1996;94:3263–3270.
with inhibitors of phosphodiesterase-5 or stimulators of guanyl- 20. Kinlay S, Creager MA, Fukumoto M, Hikita H, Fang JC, Selwyn AP, Ganz P. Endothelium-derived nitric oxide regulates arterial elasticity in humanarteries in vivo. Hypertension. 2001;38:1049 –1053.
21. Wilkinson IB, Qasem A, McEniery CM, Webb DJ, Avolio AP, Cockcroft Acknowledgments
JR. Nitric oxide regulates local arterial distensibility in vivo. Circulation.
The authors are grateful for support from the British Heart Founda- tion and the Wellcome Trust for their research on pulse contour 22. Bank AJ, Kaiser DR, Rajala S, Cheng A. In vivo human brachial artery elastic mechanics: effects of smooth muscle relaxation. Circulation. 1999;100:41– 47.
23. Medley TL, Cole TJ, Gatzka CD, Wang WY, Dart AM, Kingwell BA.
1. Franklin SS, Gustin W IV, Wong ND, Larson MG, Weber MA, Kannel Fibrillin-1 genotype is associated with aortic stiffness and disease severity in WB, Levy D. Hemodynamic patterns of age-related changes in blood patients with coronary artery disease. Circulation. 2002;105:810 – 815.
pressure: the Framingham Heart Study. Circulation. 1997;96:308 –315.
24. Lajemi M, Labat C, Gautier S, Lacolley P, Safar M, Asmar R, Cambien F, 2. Kannel WB, Gordon T, Schwartz MJ. Systolic versus diastolic blood Benetos A. Angiotensin II type 1 receptor-153A/G and 1166A/C gene pressure and risk of coronary heart disease: the Framingham study. Am J polymorphisms and increase in aortic stiffness with age in hypertensive subjects. J Hypertens. 2001;19:407– 413.
3. Franklin SS, Larson MG, Khan SA, Wong ND, Leip EP, Kannel WB, Levy 25. Lajemi M, Gautier S, Poirier O, Baguet JP, Mimran A, Gosse P, Hanon O, D. Does the relation of blood pressure to coronary heart disease risk change Labat C, Cambien F, Benetos A. Endothelin gene variants and aortic and with aging? The Framingham Heart Study. Circulation. 2001;103: cardiac structure in never-treated hypertensives. Am J Hypertens. 2001;14: 4. Franklin SS, Jacobs MJ, Wong ND, L’Italien GJ, Lapuerta P. Predominance 26. Balkestein EJ, Staessen JA, Wang JG, van Der Heijden-Spek JJ, Van Bortel of isolated systolic hypertension among middle-aged and elderly US hyper- LM, Barlassina C, Bianchi G, Brand E, Herrmann SM, Struijker-Boudier tensives: analysis based on National Health and Nutrition Examination HA. Carotid and femoral artery stiffness in relation to three candidate genes Survey (NHANES) III. Hypertension. 2001;37:869 – 874.
in a white population. Hypertension. 2001;38:1190 –1197.
5. Nielsen WB, Vestbo J, Jensen GB. Isolated systolic hypertension as a major 27. Nichols WW, O’Rourke. Wave reflections. In: McDonald’s Blood Flow in risk factor for stroke and myocardial infarction and an unexploited source of Arteries: Theoretic, Experimental and Critical Principles. London: Arnold; cardiovascular prevention: a prospective population-based study. J Hum 28. Kroeker EJ, Wood EH. Comparison of simultaneously recorded central and 6. Antikainen R, Jousilahti P, Tuomilehto J. Systolic blood pressure, isolated peripheral arterial pressure pulses during rest, exercise and tilted position in systolic hypertension and risk of coronary heart disease, strokes, cardiovas- man. Circ Res. 1955;3:623– 632.
cular disease and all-cause mortality in the middle-aged population.
29. Rowell LB, Brengelmann GL, Blackmon JR, Bruce RA, Murray JA. Dis- J Hypertens. 1998;16:577–583.
parities between aortic and peripheral pulse pressures induced by upright 7. Alli C, Avanzini F, Bettelli G, Colombo F, Torri V, Tognoni G. The exercise and vasomotor changes in man. Circulation. 1968;37:954 –964.
long-term prognostic significance of repeated blood pressure measurements 30. Wilkinson IB, Franklin SS, Hall IR, Tyrrell S, Cockcroft JR. Pressure in the elderly: SPAA (Studio sulla Pressione Arteriosa nell’Anziano) amplification explains why pulse pressure is unrelated to risk in young 10-year follow-up. Arch Intern Med. 1999;159:1205–1212.
subjects. Hypertension. 2001;38:1461–1466.
8. Lloyd-Jones DM, Evans JC, Larson MG, O’Donnell CJ, Levy D. Differ- 31. Bogren HG, Mohiaddin RH, Klipstein RK, Firmin DN, Underwood RS, ential impact of systolic and diastolic blood pressure level on JNC-VI Rees SR, Longmore DB. The function of the aorta in ischemic heart disease: staging: Joint National Committee on Prevention, Detection, Evaluation, a magnetic resonance and angiographic study of aortic compliance and and Treatment of High Blood Pressure. Hypertension. 1999;34:381–385.
blood flow patterns. Am Heart J. 1989;118:234 –247.
9. SHEP Cooperative Research Group. Prevention of stroke by antihyper- 32. Ohtsuka S, Kakihana M, Watanabe H, Sugishita Y. Chronically decreased tensive drug treatment in older persons with isolated systolic hypertension: aortic distensibility causes deterioration of coronary perfusion during final results of the Systolic Hypertension in the Elderly Program (SHEP).
increased left ventricular contraction. J Am Coll Cardiol. 1994;24: 10. Staessen JA, Fagard R, Thijs L, Celis H, Arabidze GG, Birkenhager WH, Bulpitt CJ, de Leeuw PW, Dollery CT, Fletcher AE, Forette F, Leonetti G, 33. Bramwell JC, Hill AV. The velocity of the pulse wave in man. Proc R Soc Nachev C, O’Brien ET, Rosenfeld J, Rodicio JL, Tuomilehto J, Zanchetti A.
Lond B Biol Sci. 1922;93:298 –306.
Randomised double-blind comparison of placebo and active treatment for 34. Wenn CM, Newman DL. Arterial tortuosity. Australas Phys Eng Sci Med.
older patients with isolated systolic hypertension: the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Lancet. 1997;350:757–764.
35. Asmar R, Benetos A, Topouchian J, Laurent P, Pannier B, Brisac AM, 11. The sixth report of the Joint National Committee on prevention, detection, Target R, Levy BI. Assessment of arterial distensibility by automatic pulse evaluation, and treatment of high blood pressure. Arch Intern Med. 1997; wave velocity measurement: validation and clinical application studies.
Hypertension. 1995;26:485– 490.
12. Franklin SS, Khan SA, Wong ND, Larson MG, Levy D. Is pulse pressure 36. Sutton-Tyrrell K, Mackey RH, Holubkov R, Vaitkevicius PV, Spurgeon useful in predicting risk for coronary heart disease? The Framingham heart HA, Lakatta EG. Measurement variation of aortic pulse wave velocity in the study. Circulation. 1999;100:354 –360.
elderly. Am J Hypertens. 2001;14:463– 468.
13. Prospective Studies Collaboration. Age-specific relevance of usual blood 37. Wilkinson IB, Fuchs SA, Jansen IM, Spratt JC, Murray GD, Cockcroft JR, pressure to vascular mortality: a meta-analysis of individual data for one Webb DJ. Reproducibility of pulse wave velocity and augmentation index million adults in 61 prospective studies. Lancet. 2002;360:1903–1913.
measured by pulse wave analysis. J Hypertens. 1998;16:2079 –2084.
Arterioscler Thromb Vasc Biol.
April 2003
38. Mohiaddin RH, Firmin DN, Longmore DB. Age-related changes of human 61. Stefanadis C, Dernellis J, Tsiamis E, Diamantopoulos L, Michaelides A, aortic flow wave velocity measured noninvasively by magnetic resonance Toutouzas P. Assessment of aortic line of elasticity using polynomial imaging. J Appl Physiol. 1993;74:492– 497.
regression analysis. Circulation. 2000;101:1819 –1825.
39. Rogers WJ, Hu YL, Coast D, Vido DA, Kramer CM, Pyeritz RE, Reichek 62. Stefanadis C, Stratos C, Vlachopoulos C, Marakas S, Boudoulas H, Kal- N. Age-associated changes in regional aortic pulse wave velocity. J Am Coll likazaros I, Tsiamis E, Toutouzas K, Sioros L, Toutouzas P. Pressure- Cardiol. 2001;38:1123–1129.
diameter relation of the human aorta: a new method of determination by the 40. Lantelme P, Mestre C, Lievre M, Gressard A, Milon H. Heart rate: an application of a special ultrasonic dimension catheter. Circulation. 1995;92: important confounder of pulse wave velocity assessment. Hypertension.
63. Stefanadis C, Dernellis J, Vlachopoulos C, Tsioufis C, Tsiamis E, 41. Hayward CS, Avolio AP, O’Rourke MF, Lantelme P, Mestre C, Lievre M, Toutouzas K, Pitsavos C, Toutouzas P. Aortic function in arterial hyper- Gressard A, Milon H. Arterial pulse wave velocity and heart rate. Hyper- tension determined by pressure-diameter relation: effects of diltiazem. Cir- culation. 1997;96:1853–1858.
42. Lehmann ED, Hopkins KD, Rawesh A, Joseph RC, Kongola K, Coppack 64. Stefanadis C, Tsiamis E, Vlachopoulos C, Stratos C, Toutouzas K, Pitsavos SW, Gosling RG. Relation between number of cardiovascular risk factors/ C, Marakas S, Boudoulas H, Toutouzas P. Unfavorable effect of smoking on events and noninvasive Doppler ultrasound assessments of aortic com- the elastic properties of the human aorta. Circulation. 1997;95:31–38.
pliance. Hypertension. 1998;32:565–569.
65. Blacher J, Pannier B, Guerin AP, Marchais SJ, Safar ME, London GM.
43. Bramwell JC, Hill AV, McSwiney BA. The velocity of the pulse wave in Carotid arterial stiffness as a predictor of cardiovascular and all-cause man in relation to age as measured by the hot wire sphygmograph. Heart.
mortality in end-stage renal disease. Hypertension. 1998;32:570 –574.
66. Blacher J, Guerin AP, Pannier B, Marchais SJ, London GM. Arterial 44. Vaitkevicius PV, Fleg JL, Engel JH, O’Connor FC, Wright JG, Lakatta LE, calcifications, arterial stiffness, and cardiovascular risk in end-stage renal Yin FC, Lakatta EG. Effects of age and aerobic capacity on arterial stiffness disease. Hypertension. 2001;38:938 –942.
in healthy adults. Circulation. 1993;88:1456 –1462.
67. Barenbrock M, Kosch M, Joster E, Kisters K, Rahn KH, Hausberg M.
45. Lehmann ED, Watts GF, Gosling RG. Aortic distensibility and hypercho- Reduced arterial distensibility is a predictor of cardiovascular disease in lesterolaemia. Lancet. 1992;340:1171–1172.
patients after renal transplantation. J Hypertens. 2002;20:79 – 84.
46. Lehmann ED, Gosling RG, Sonksen PH. Arterial wall compliance in 68. Mohiaddin RH, Underwood SR, Bogren HG, Firmin DN, Klipstein RH, diabetes. Diabet Med. 1992;9:114 –119.
Rees RS, Longmore DB. Regional aortic compliance studied by magnetic 47. Laurent S, Boutouyrie P, Asmar R, Gautier I, Laloux B, Guize L, Duci- resonance imaging: the effects of age, training, and coronary artery disease.
metiere P, Benetos A. Aortic stiffness is an independent predictor of Br Heart J. 1989;62:90 –96.
all-cause and cardiovascular mortality in hypertensive patients. Hyper- 69. Resnick LM, Militianu D, Cunnings AJ, Pipe JG, Evelhoch JL, Soulen RL.
tension. 2001;37:1236 –1241.
Direct magnetic resonance determination of aortic distensibility in essential 48. O’Rourke MF, Staessen JA, Vlachopoulos C, Duprez D, Plante GE. Clinical hypertension—relation to age, abdominal visceral fat, and in situ intra- applications of arterial stiffness; definitions and reference values. Am J cellular free magnesium. Hypertension. 1997;30:654 – 659.
Hypertens. 2002;15:426 – 444.
70. Hundley WG, Kitzman DW, Morgan TM, Hamilton CA, Darty SN, Stewart 49. Boutouyrie P, Tropeano AI, Asmar R, Gautier I, Benetos A, Lacolley P, KP, Herrington DM, Link KM, Little WC. Cardiac cycle-dependent Laurent S. Aortic stiffness is an independent predictor of primary coronary changes in aortic area and distensibility are reduced in older patients with events in hypertensive patients: a longitudinal study. Hypertension. 2002; isolated diastolic heart failure and correlate with exercise intolerance. J Am Coll Cardiol. 2001;38:796 – 802.
50. Blacher J, Asmar R, Djane S, London GM, Safar ME. Aortic pulse wave 71. Kelly RP, Millasseau SC, Ritter JM, Chowienczyk PJ. Vasoactive drugs velocity as a marker of cardiovascular risk in hypertensive patients. Hyper- influence aortic augmentation index independently of pulse-wave velocity tension. 1999;33:1111–1117.
in healthy men. Hypertension. 2001;37:1429 –1433.
51. Benetos A, Adamopoulos C, Bureau JM, Temmar M, Labat C, Bean K, 72. Wilkinson IB, MacCallum H, Hupperetz PC, van Thoor CJ, Cockcroft JR, Thomas F, Pannier B, Asmar R, Zureik M, Safar M, Guize L. Determinants Webb DJ. Changes in the derived central pressure waveform and pulse of accelerated progression of arterial stiffness in normotensive subjects and pressure in response to angiotensin II and noradrenaline in man. J Physiol.
in treated hypertensive subjects over a 6-year period. Circulation. 2002;105: 73. Wilkinson IB, MacCallum H, Flint L, Cockcroft JR, Newby DE, Webb DJ.
52. Blacher J, Guerin AP, Pannier B, Marchais SJ, Safar ME, London GM.
The influence of heart rate on augmentation index and central arterial Impact of aortic stiffness on survival in end-stage renal disease. Circulation.
pressure in humans. J Physiol. 2000;525:263–270.
74. Gatzka CD, Cameron JD, Dart AM, Berry KL, Kingwell BA, Dewar EM, 53. Safar ME, Blacher J, Pannier B, Guerin AP, Marchais SJ, Guyonvarc’h Reid CM, Jennings GLR. Correction of carotid augmentation index for heart P-M, London GM. Central pulse pressure and mortality in end-stage renal rate in elderly essential hypertensives. Am J Hypertens. 2001;14:573–577.
disease. Hypertension. 2002;39:735–738.
75. Smulyan H, Marchais SJ, Pannier B, Guerin AP, Safar ME, London GM.
54. Guerin AP, Blacher J, Pannier B, Marchais SJ, Safar ME, London GM.
Influence of body height on pulsatile arterial hemodynamic data. J Am Coll Impact of aortic stiffness attenuation on survival of patients in end-stage Cardiol. 1998;31:1103–1109.
renal failure. Circulation. 2001;103:987–992.
76. Snieder H, Hayward CS, Perks U, Kelly RP, Kelly PJ, Spector TD. Heri- 55. van Popele NM, Grobbee DE, Bots ML, Asmar R, Topouchian J, Reneman tability of central systolic pressure augmentation: a twin study. Hyper- RS, Hoeks AP, van der Kuip DA, Hofman A, Witteman JC. Association between arterial stiffness and atherosclerosis: the Rotterdam Study. Stroke.
77. Karamanoglu M, O’Rourke MF, Avolio AP, Kelly RP. An analysis of the relationship between central aortic and peripheral upper limb pressure 56. Laurent S, Caviezel B, Beck L, Girerd X, Billaud E, Boutouyrie P, Hoeks waves in man. Eur Heart J. 1993;14:160 –167.
A, Safar M. Carotid artery distensibility and distending pressure in hyper- 78. Chen CH, Nevo E, Fetics B, Pak PH, Yin FC, Maughan WL, Kass DA.
tensive humans. Hypertension. 1994;23:878 – 883.
Estimation of central aortic pressure waveform by mathematical transfor- 57. Bussy C, Boutouyrie P, Lacolley P, Challande P, Laurent S. Intrinsic mation of radial tonometry pressure: validation of generalized transfer stiffness of the carotid arterial wall material in essential hypertensives.
function. Circulation. 1997;95:1827–1836.
Hypertension. 2000;35:1049 –1054.
79. Hope SA, Tay DB, Meredith IT, Cameron JD. Comparison of generalized 58. Hirai T, Sasayama S, Kawasaki T, Yagi S. Stiffness of systemic arteries in and gender-specific transfer functions for the derivation of aortic patients with myocardial infarction: a noninvasive method to predict waveforms. Am J Physiol. 2002;283:H1150 –1156.
severity of coronary atherosclerosis. Circulation. 1989;80:78 – 86.
80. Soderstrom S, Nyberg G, O’Rourke MF, Sellgren J, Ponten J. Can a 59. Roman MJ, Pini R, Pickering TG, Devereux RB. Non-invasive mea- clinically useful aortic pressure wave be derived from a radial pressure surements of arterial compliance in hypertensive compared with normo- wave? Br J Anaesth. 2002;88:481– 488.
tensive adults. J Hypertens. 1992;10:S115–118.
81. Segers P, Carlier S, Pasquet A, Rabben SI, Hellevik LR, Remme E, De 60. Roman MJ, Ganau A, Saba PS, Pini R, Pickering TG, Devereux RB. Impact Backer T, De Sutter J, Thomas JD, Verdonck P. Individualizing the aorto- of arterial stiffening on left ventricular structure. Hypertension. 2000;36: radial pressure transfer function: feasibility of a model-based approach.
Am J Physiol. 2000;279:H542–549.
Oliver and Webb
Arterial Stiffness and Atherosclerotic Events
82. Segers P, Qasem A, De Backer T, Carlier S, Verdonck P, Avolio A, 105. Rietzschel E-R, Boeykens E, De Buyzere ML, Duprez DA, Clement DL. A Peripheral. “oscillatory” compliance is associated with aortic augmentation comparison between systolic and diastolic pulse contour analysis in the index. Hypertension. 2001;37:1434 –1439.
evaluation of arterial stiffness. Hypertension. 2001;37:E15–22.
83. Savage MT, Ferro CJ, Pinder SJ, Tomson CR. Reproducibility of derived 106. Cohn JN. Techniques for studying arterial elastic properties. Hypertension.
central arterial waveforms in patients with chronic renal failure. Clin Sci.
107. Franklin SS. Blood pressure and cardiovascular disease: what remains to be 84. Kelly R, Hayward C, Avolio A, O’Rourke M. Noninvasive determination of achieved? J Hypertens. 2001;19(suppl 3):S3–S8.
age-related changes in the human arterial pulse. Circulation. 1989;80: 108. Pannier BM, Avolio AP, Hoeks A, Mancia G, Takazawa K. Methods and devices for measuring arterial compliance in humans. Am J Hypertens.
85. Hayward CS, Kelly RP. Gender-related differences in the central arterial pressure waveform. J Am Coll Cardiol. 1997;30:1863–1871.
109. Van Bortel LM, Duprez D, Starmans-Kool MJ, Safar ME, Giannattasio C, 86. Cameron JD, McGrath BP, Dart AM. Use of radial artery applanation Cockcroft J, Kaiser DR, Thuillez C. Clinical applications of arterial tonometry and a generalized transfer function to determine aortic pressure stiffness, Task Force III: recommendations for user procedures. Am J augmentation in subjects with treated hypertension. J Am Coll Cardiol.
Hypertens. 2002;15:445– 452.
110. Safar ME, Boudier HS, London G, Frohlich ED. Fourth workshop on 87. Wilkinson IB, MacCallum H, Rooijmans DF, Murray GD, Cockcroft JR, structure and function of large arteries. Hypertension. 2001;38:913.
McKnight JA, Webb DJ. Increased augmentation index and systolic stress 111. Yaginuma T, Avolio A, O’Rourke M, Nichols W, Morgan JJ, Roy P, Baron in type 1 diabetes mellitus. QJM. 2000;93:441– 448.
D, Branson J, Feneley M. Effect of glyceryl trinitrate on peripheral arteries 88. Wilkinson IB, Prasad K, Hall IR, Thomas A, MacCallum H, Webb DJ, alters left ventricular hydraulic load in man. Cardiovasc Res. 1986;20: Frenneaux MP, Cockcroft JR. Increased central pulse pressure and augmen- tation index in subjects with hypercholesterolemia. J Am Coll Cardiol.
112. Fitchett DH, Simkus GJ, Beaudry JP, Marpole DG. Reflected pressure waves in the ascending aorta: effect of glyceryl trinitrate. Cardiovasc Res.
89. Kingwell BA, Waddell TK, Medley TL, Cameron JD, Dart AM. Large artery stiffness predicts ischemic threshold in patients with coronary artery 113. Kelly RP, Gibbs HH, O’Rourke MF, Daley JE, Mang K, Morgan JJ, Avolio disease. J Am Coll Cardiol. 2002;40:773–779.
AP. Nitroglycerin has more favourable effects on left ventricular afterload 90. London GM, Blacher J, Pannier B, Guerin AP, Marchais SJ, Safar ME.
than apparent from measurement of pressure in a peripheral artery. Eur Arterial wave reflections and survival in end-stage renal failure. Hyper- tension. 2001;38:434 – 438.
114. Jiang XJ, O’Rourke MF, Jin WQ, Liu LS, Li CW, Tai PC, Zhang XC, Liu 91. Watt TB, Jr, Burrus CS. Arterial pressure contour analysis for estimating SZ. Quantification of glyceryl trinitrate effect through analysis of the syn- human vascular properties. J Appl Physiol. 1976;40:171–176.
thesised ascending aortic pressure waveform. Heart. 2002;88:143–148.
92. Cohn JN, Finkelstein S, McVeigh G, Morgan D, LeMay L, Robinson J, 115. Cohn JN, Archibald DG, Ziesche S, Franciosa JA, Harston WE, Tristani FE, Mock J. Noninvasive pulse wave analysis for the early detection of vascular Dunkman WB, Jacobs W, Francis GS, Flohr KH. Effect of vasodilator disease. Hypertension. 1995;26:503–508.
therapy on mortality in chronic congestive heart failure: results of a Veterans 93. McVeigh GE, Burns DE, Finkelstein SM, McDonald KM, Mock JE, Feske Administration Cooperative Study. N Engl J Med. 1986;314:1547–1552.
W, Carlyle PF, Flack J, Grimm R, Cohn JN. Reduced vascular compliance 116. Gori T, Parker JD. Nitrate tolerance: a unifying hypothesis. Circulation.
as a marker for essential hypertension. Am J Hypertens. 1991;4:245–251.
94. McVeigh GE, Bratteli CW, Morgan DJ, Alinder CM, Glasser SP, 117. London GM, Marchais SJ, Guerin AP, Metivier F, Safar ME, Fabiani F, Finkelstein SM, Cohn JN. Age-related abnormalities in arterial compliance Froment L. Salt and water retention and calcium blockade in uremia.
identified by pressure pulse contour analysis: aging and arterial compliance.
Circulation. 1990;82:105–113.
Hypertension. 1999;33:1392–1398.
118. Safar ME, London GM, Asmar RG, Hugues CJ, Laurent SA. An indirect 95. McVeigh G, Brennan G, Hayes R, Cohn J, Finkelstein S, Johnston D.
approach for the study of the elastic modulus of the brachial artery in Vascular abnormalities in non-insulin– dependent diabetes mellitus iden- patients with essential hypertension. Cardiovasc Res. 1986;20:563–567.
tified by arterial waveform analysis. Am J Med. 1993;95:424 – 430.
119. Safar ME, Laurent S, Bouthier JA, London GM. Comparative effects of 96. McVeigh GE, Morgan DJ, Finkelstein SM, LeMay LA, Cohn JN. Vascular captopril and isosorbide dinitrate on the arterial wall of hypertensive human abnormalities associated with long-term cigarette smoking identified by brachial arteries. J Cardiovasc Pharmacol. 1986;8:1257–1261.
arterial waveform analysis. Am J Med. 1997;102:227–231.
120. Asmar RG, Pannier B, Santoni JP, Laurent S, London GM, Levy BI, Safar 97. Fogliardi R, Burattini R, Shroff SG, Campbell KB. Fit to diastolic arterial ME. Reversion of cardiac hypertrophy and reduced arterial compliance after pressure by third-order lumped model yields unreliable estimates of arterial converting enzyme inhibition in essential hypertension. Circulation. 1988; compliance. Med Eng Phys. 1996;18:225–233.
98. Manning TS, Shykoff BE, Izzo JL Jr. Validity and reliability of diastolic 121. London GM, Pannier B, Vicaut E, Guerin AP, Marchais SJ, Safar ME, pulse contour analysis (Windkessel model) in humans. Hypertension. 2002; Cuche JL. Antihypertensive effects and arterial haemodynamic alterations during angiotensin converting enzyme inhibition. J Hypertens. 1996;14: 99. Millasseau SC, Guigui FG, Kelly RP, Prasad K, Cockcroft JR, Ritter JM, Chowienczyk PJ. Noninvasive assessment of the digital volume pulse: 122. Benetos A, Cambien F, Gautier S, Ricard S, Safar M, Laurent S, Lacolley comparison with the peripheral pressure pulse. Hypertension. 2000;36: P, Poirier O, Topouchian J, Asmar R. Influence of the angiotensin II type 1 receptor gene polymorphism on the effects of perindopril and nitrendipine 100. Chowienczyk PJ, Kelly RP, MacCallum H, Millasseau SC, Andersson TL, on arterial stiffness in hypertensive individuals. Hypertension. 1996;28: Gosling RG, Ritter JM, Anggard EE. Photoplethysmographic assessment of pulse wave reflection: blunted response to endothelium-dependent beta2- 123. Mahmud A, Feely J. Reduction in arterial stiffness with angiotensin II adrenergic vasodilation in type II diabetes mellitus. J Am Coll Cardiol.
antagonist is comparable with and additive to ACE inhibition. Am J Hypertens. 2002;15:321–325.
101. Chemla D, Hebert J-L, Coirault C, Zamani K, Suard I, Colin P, Lecarpentier 124. Giannattasio C, Achilli F, Failla M, Capra A, Vincenzi A, Valagussa F, Y. Total arterial compliance estimated by stroke volume-to-aortic pulse Mancia G, Radial, carotid and aortic distensibility in congestive heart pressure ratio in humans. Am J Physiol. 1998;274:H500 –505.
failure: effects of high-dose angiotensin-converting enzyme inhibitor or 102. Resnick LM, Militianu D, Cunnings AJ, Pipe JG, Evelhoch JL, Soulen RL, low-dose association with angiotensin type 1 receptor blockade. J Am Coll Lester MA. Pulse waveform analysis of arterial compliance: relation to other Cardiol. 2002;39:1275–1282.
techniques, age, and metabolic variables. Am J Hypertens. 2000;13: 125. Mitchell GF, Izzo JL Jr, Lacourcière Y, Ouellet J-P, Neutel J, Qian C, Kerwin LJ, Block AJ, Pfeffer MA. Omapatrilat reduces pulse pressure and 103. Izzo JL, Jr, Manning TS, Shykoff BE. Office blood pressures, arterial proximal aortic stiffness in patients with systolic hypertension: results of the compliance characteristics, and estimated cardiac load. Hypertension. 2001; conduit hemodynamics of omapatrilat international research study. Circu- lation. 2002;105:2955–2961.
104. Sarnoff SJ, Braunwald E, Welch GH, Case RB, Stainsby WN, Macruz R.
126. London GM, Pannier B, Guerin AP, Marchais SJ, Safar ME, Cuche JL.
Hemodynamic determinants of oxygen consumption of the heart with Cardiac hypertrophy, aortic compliance, peripheral resistance, and wave special reference to the tension time index. Am J Physiol. 1958;192: reflection in end-stage renal disease: comparative effects of ACE inhibition and calcium channel blockade. Circulation. 1994;90:2786 –2796.
Arterioscler Thromb Vasc Biol.
April 2003
127. Shimamoto H, Shimamoto Y. Lisinopril improves aortic compliance and 147. De Vriese AS, Verbeuren TJ, Van de Voorde J, Lameire NH, Vanhoutte renal flow: comparison with nifedipine. Hypertension. 1995;25:327–334.
PM. Endothelial dysfunction in diabetes. Br J Pharmacol. 2000;130: 128. Tomiyama H, Kimura Y, Sakuma Y, Shiojima K, Yamamoto A, Saito I, Ishikawa Y, Yoshida H, Morita S, Doba N. Effects of an ACE inhibitor and 148. Zeiher AM, Schachinger V, Minners J. Long-term cigarette smoking a calcium channel blocker on cardiovascular autonomic nervous system and impairs endothelium-dependent coronary arterial vasodilator function. Cir- carotid distensibility in patients with mild to moderate hypertension. Am J culation. 1995;92:1094 –1100.
Hypertens. 1998;11:682– 689.
149. Liang YL, Shiel LM, Teede H, Kotsopoulos D, McNeil J, Cameron JD, 129. Savolainen A, Keto P, Poutanen VP, Hekali P, Standertskjold-Nordenstam McGrath BP. Effects of blood pressure, smoking, and their interaction on CG, Rames A, Kupari M. Effects of angiotensin-converting enzyme inhi- carotid artery structure and function. Hypertension. 2001;37:6 –11.
bition versus beta-adrenergic blockade on aortic stiffness in essential hyper- 150. Martin H, Hu J, Gennser G, Norman M. Impaired endothelial function and tension. J Cardiovasc Pharmacol. 1996;27:99 –104.
increased carotid stiffness in 9-year-old children with low birthweight.
130. Chen CH, Ting CT, Lin SJ, Hsu TL, Yin FC, Siu CO, Chou P, Wang SP, Circulation. 2000;102:2739 –2744.
Chang MS. Different effects of fosinopril and atenolol on wave reflections 151. Aggoun Y, Bonnet D, Sidi D, Girardet JP, Brucker E, Polak M, Safar ME, in hypertensive patients. Hypertension. 1995;25:1034 –1041.
Levy BI. Arterial mechanical changes in children with familial hypercho-lesterolemia. Arterioscler Thromb Vasc Biol. 2000;20:2070 –2075.
131. Pannier BM, Guerin AP, Marchais SJ, London GM. Different aortic 152. Tounian P, Aggoun Y, Dubern B, Varille V, Guy-Grand B, Sidi D, Girardet reflection wave responses following long-term angiotensin-converting JP, Bonnet D. Presence of increased stiffness of the common carotid artery enzyme inhibition and beta-blocker in essential hypertension. Clin Exp and endothelial dysfunction in severely obese children: a prospective study.
Pharmacol Physiol. 2001;28:1074 –1077.
Lancet. 2001;358:1400 –1404.
132. Asmar RG, London GM, O’Rourke ME, Safar ME. Improvement in blood 153. Boutouyrie P, Bezie Y, Lacolley P, Challande P, Chamiot-Clerc P, Benetos pressure, arterial stiffness and wave reflections with a very-low-dose per- A, de la Faverie JF, Safar M, Laurent S. In vivo/in vitro comparison of rat indopril/indapamide combination in hypertensive patient: a comparison with abdominal aorta wall viscosity: influence of endothelial function. Arte- atenolol. Hypertension. 2001;38:922–926.
rioscler Thromb Vasc Biol. 1997;17:1346 –1355.
133. Laurent S, Lacolley PM, Cuche JL, Safar ME. Influence of diuretics on 154. Safar M, Chamiot-Clerc P, Dagher G, Renaud JF. Pulse pressure, endothe- brachial artery diameter and distensibility in hypertensive patients. Fundam lium function, and arterial stiffness in spontaneously hypertensive rats.
Clin Pharmacol. 1990;4:685– 693.
Hypertension. 2001;38:1416 –1421.
134. Girerd X, Giannattasio C, Moulin C, Safar M, Mancia G, Laurent S.
155. Wilkinson IB, MacCallum H, Cockcroft JR, Webb DJ. Inhibition of basal Regression of radial artery wall hypertrophy and improvement of carotid nitric oxide synthesis increases aortic augmentation index and pulse wave artery compliance after long-term antihypertensive treatment in elderly velocity in vivo. Br J Clin Pharmacol. 2002;53:189 –192.
patients. J Am Coll Cardiol. 1998;31:1064 –1073.
156. Joannides R, Richard V, Haefeli WE, Benoist A, Linder L, Luscher TF, 135. Kool MJ, Lustermans FA, Breed JG, Struyker Boudier HA, Hoeks AP, Thuillez C. Role of nitric oxide in the regulation of the mechanical prop- Reneman RS, Van Bortel LM. The influence of perindopril and the diuretic erties of peripheral conduit arteries in humans. Hypertension. 1997;30: combination amilorideϩhydrochlorothiazide on the vessel wall properties of large arteries in hypertensive patients. J Hypertens. 1995;13:839 – 848.
157. McVeigh GE, Allen PB, Morgan DR, Hanratty CG, Silke B. Nitric oxide 136. Asmar RG, Benetos A, Chaouche-Teyara K, Raveau-Landon CM, Safar modulation of blood vessel tone identified by arterial waveform analysis.
ME. Comparison of effects of felodipine versus hydrochlorothiazide on Clin Sci. 2001;100:387–393.
arterial diameter and pulse-wave velocity in essential hypertension. Am J 158. Rudic RD, Shesely EG, Maeda N, Smithies O, Segal SS, Sessa WC. Direct evidence for the importance of endothelium-derived nitric oxide in vascular 137. Smilde TJ, van den Berkmortel FW, Wollersheim H, van Langen H, remodeling. J Clin Invest. 1998;101:731–736.
Kastelein JJ, Stalenhoef AF. The effect of cholesterol lowering on carotid 159. Ramsey MW, Goodfellow J, Jones CJH, Luddington LA, Lewis MJ, Hen- and femoral artery wall stiffness and thickness in patients with familial derson AH. Endothelial control of arterial distensibility is impaired in hypercholesterolaemia. Eur J Clin Invest. 2000;30:473– 480.
chronic heart failure. Circulation. 1995;92:3212–3219.
138. Tomochika Y, Okuda F, Tanaka N, Wasaki Y, Tokisawa I, Aoyagi S, 160. Higashi Y, Sasaki S, Nakagawa K, Matsuura H, Kajiyama G, Oshima T.
Morikuni C, Ono S, Okada K, Matsuzaki M. Improvement of atheroscle- Effect of the angiotensin-converting enzyme inhibitor imidapril on reactive rosis and stiffness of the thoracic descending aorta with cholesterol-lowering hyperemia in patients with essential hypertension: relationship between therapies in familial hypercholesterolemia. Arterioscler Thromb Vasc Biol.
treatment periods and resistance artery endothelial function. J Am Coll 139. Giannattasio C, Mangoni AA, Failla M, Carugo S, Stella ML, Stefanoni P, 161. Uehata A, Takase B, Nishioka T, Kitamura K, Akima T, Kurita A, Isojima Grassi G, Vergani C, Mancia G. Impaired radial artery compliance in K. Effect of quinapril versus nitrendipine on endothelial dysfunction in normotensive subjects with familial hypercholesterolemia. Atherosclerosis.
patients with systemic hypertension. Am J Cardiol. 2001;87:1414 –1416.
162. Dupuis J, Tardif JC, Cernacek P, Theroux P. Cholesterol reduction rapidly improves endothelial function after acute coronary syndromes: the RECIFE 140. Shige H, Dart A, Nestel P. Simvastatin improves arterial compliance in the (reduction of cholesterol in ischemia and function of the endothelium) trial.
lower limb but not in the aorta. Atherosclerosis. 2001;155:245–250.
Circulation. 1999;99:3227–3233.
141. Ferrier KE, Muhlmann MH, Baguet JP, Cameron JD, Jennings GL, Dart 163. Alonso R, Mata P, De Andres R, Villacastin BP, Martinez-Gonzalez J, AM, Kingwell BA. Intensive cholesterol reduction lowers blood pressure Badimon L. Sustained long-term improvement of arterial endothelial and large artery stiffness in isolated systolic hypertension. J Am Coll function in heterozygous familial hypercholesterolemia patients treated with Cardiol. 2002;39:1020 –1025.
simvastatin. Atherosclerosis. 2001;157:423– 429.
142. Leibovitz E, Hazanov N, Zimlichman R, Shargorodsky M, Gavish D.
164. Joannides R, Bizet-Nafeh C, Costentin A, Iacob M, Derumeaux G, Cribier Treatment with atorvastatin improves small artery compliance in patients A, Thuillez C. Chronic ACE inhibition enhances the endothelial control of with severe hypercholesterolemia. Am J Hypertens. 2001;14:1096 –1098.
arterial mechanics and flow-dependent vasodilatation in heart failure.
143. Suwaidi JA, Hamasaki S, Higano ST, Nishimura RA, Holmes DR Jr, Hypertension. 2001;38:1446 –1450.
Lerman A. Long-term follow-up of patients with mild coronary artery 165. Smith JC, Evans LM, Wilkinson I, Goodfellow J, Cockcroft JR, Scanlon disease and endothelial dysfunction. Circulation. 2000;101:948 –954.
MF, Davies JS. Effects of GH replacement on endothelial function and 144. Perticone F, Ceravolo R, Pujia A, Ventura G, Iacopino S, Scozzafava A, large-artery stiffness in GH-deficient adults: a randomized, double-blind, Ferraro A, Chello M, Mastroroberto P, Verdecchia P, Schillaci G. Prog- placebo-controlled study. Clin Endocrinol. 2002;56:493–501.
nostic significance of endothelial dysfunction in hypertensive patients. Cir- 166. Wilkinson IB, Hall IR, MacCallum H, Mackenzie IS, McEniery CM, van der culation. 2001;104:191–196.
Arend BJ, Shu YE, MacKay LS, Webb DJ, Cockcroft JR. Pulse-wave analysis: 145. Gokce N, Keaney JF Jr, Hunter LM, Watkins MT, Menzoian JO, Vita JA.
clinical evaluation of a noninvasive, widely applicable method for assessing Risk stratification for postoperative cardiovascular events via noninvasive endothelial function. Arterioscler Thromb Vasc Biol. 2002;22:147–152.
assessment of endothelial function: a prospective study. Circulation. 2002; 167. Kass DA, Shapiro EP, Kawaguchi M, Capriotti AR, Scuteri A, deGroof RC, Lakatta EG. Improved arterial compliance by a novel advanced glycation 146. Halcox JPJ, Schenke WH, Zalos G, Mincemoyer R, Prasad A, Waclawiw end-product crosslink breaker. Circulation. 2001;104:1464 –1470.
MA, Nour KRA, Quyyumi AA. Prognostic value of coronary vascular 168. Maxwell S, Megson I, Webb D, S-nitrosothiols for nitrate tolerance. Lancet.
endothelial dysfunction. Circulation. 2002;106:653– 658.



Scholarship Eligibility Deadline Submit Application Pleae note: If a link is broken or says Page Cannot be Displayed, simply copy and paste the address from under the Scholarship Name or type the address in the browser bar. If all else fails, do a search of the scholarship name. Active in your community, led a project that AXA Achievement Scholarship Senior 3.0+ GPA

Sugar Prot Serv Size Allergen Fat G Fat G INGREDIENTS Apples (canned -apples or frozen), sugar, cinnamon Plain Applesauce Cups : Apples, com syrup, high fructose com syrup, sugar, waler, erythorbic acid (to maintain color). Cinnamon Applesauce Cups : Apples, com syrup, high fructose corn syrup, sugar, water, CInnamon, erythorbic add (to maintain colOr), Grape Applesauce Cups:

Copyright © 2010-2014 Drug Shortages pdf