Markers of arterial stiffness in peripheral arterial disease

Vasa 2015; 44: 341 – 348 © 2015 Hans Huber Publishers, Hogrefe AG, Bern

M. Husmann et al.: Arterial stiffness in atherosclerosis DOI 10.1024/0301 – 1526/a000452

http://econtent.hogrefe.com/doi/pdf/10.1024/0301-1526/a000452 - Wednesday, September 02, 2015 12:40:48 AM - UZH Hauptbibliothek / Zentralbibliothek Zürich IP Address:144.200.17.40

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Markers of arterial stiffness in peripheral arterial disease Marc Husmann, Vincenzo Jacomella, Christoph Thalhammer, and Beatrice R. Amann-Vesti Clinic for Angiology, University Hospital Zurich and University of Zurich, Switzerland

Summary: Increased arterial stiffness results from reduced elasticity of the arterial wall and is an independent predictor for cardiovascular risk. The gold standard for assessment of arterial stiffness is the carotid-femoral pulse wave velocity. Other parameters such as central aortic pulse pressure and aortic augmentation index are indirect, surrogate markers of arterial stiffness, but provide additional information on the characteristics of wave reflection. Peripheral arterial disease (PAD) is characterised by its association with systolic

hypertension, increased arterial stiffness, disturbed wave reflexion and prognosis depending on ankle-brachial pressure index. This review summarises the physiology of pulse wave propagation and reflection and its changes due to aging and atherosclerosis. We discuss different non-invasive assessment techniques and highlight the importance of the understanding of arterial pulse wave analysis for each vascular specialist and primary care physician alike in the context of PAD.

Key words: Peripheral arterial disease, arterial stiffness, cardiovascular physiology, biomarkers

Introduction In vascular medicine, blood flow velocities as well as measurements of systolic and diastolic blood pressure values and imaging of vascular lesions are relevant for diagnosis [1 – 4]. In contrast to blood pressure evaluations and flow velocity measurements by duplex ultrasound, assessment of pulse wave velocities is currently not part of clinical routine examination. Although pulse wave propagation and reflection were recognised, the assessment of pulse wave velocity in terms of arterial stiffness has not been used in routine diagnostics until recently with their introduction into the guidelines of the European Society of Hypertension and Cardiology [5]. Increased arterial stiffness was long considered to be only related to vascular aging that is associated with stiffening of the arteries and often accompanied by a increased incidence of age-dependent arterial hypertension. Stiffening of the arteries due to the loss of the “Windkessel function” and decreased arterial wall elasticity increases pulse wave velocity of antegrade and returning pulse waves resulting in unfavourable central aortic pressure characteristics such as elevated cardiac afterload and lowered diastolic endocardial perfusion

pressure [6]. Peripheral resistance and arterial bifurcations along the arterial tree as well as atherosclerotic obstructions impact time-point and magnitude of pulse wave reflections [7, 8]. Central aortic pressures are composed of a generated cardiac output pressure wave and the reflected pulse wave and may differ substantially from peripheral blood pressure, as shown for cardiovascular outcome [9 – 11]. Peripheral arterial disease (PAD) has a high cardiovascular event rate that relates in part to peripheral perfusion impairment, as assessed by the ankle brachial pressure index (ABI) [12 – 15]. In addition to extensive atherosclerosis and localised inflammatory processes, central aortic pressures may be of relevance in PAD for increased event rates as a result of rigid arteries and premature pulse wave reflection sites caused by obstructing atherosclerosis along the aorto-femoral arteries. As aging and cardiovascular disease such as PAD influence arterial properties and modify the amplitude and timing of forward and backward waves, it is worth considering the assessment of pulse wave velocity, reflection and central pressure, in order to understand its potential link to the pathophysiology and prognosis in PAD. Therefore, we will provide

an overview of pulse wave propagation and reflection, non-invasive assessment tools, and last but not least available literature and implications for future research, secondary prevention and daily clinical routine in the management of patients with PAD.

Principles of pulse wave propagation and reflection in relation to arterial stiffness Arterial wall compliance and characteristics impact pulse wave propagation [16, 17]. Each heart cycle generates a pulse wave that travels along the arterial tree. While the wave travels to the periphery, the change in characteristic impedance along the route gives rise to the generation of reflected waves resulting in a major backward wave traveling to the heart (Fig. 1) [18]. In normal physiological conditions, the reflected wave pressure, consisting of multiple waves that are reflected at arterial bifurcations and in the terminal vessels, adds to the forward wave and thereby impacts central blood pressure [19]. Hence, the central aortic pulse pressure wave form is a composite of the antegrade and all retrograde pulse waves (Fig. 1a). The time-dependent occur-

M. Husmann et al.: Arterial stiffness in atherosclerosis


in the aortic tube [23]. In other words, the loss in elastic properties is mainly caused by the mechanic stress of myriad cardiac cycles, oxidative stress and increased elastase activity and by cross-linking of the actin-myosin filaments that is putatively caused by advance glycolysated end-products [19, 24 – 28].

wave recordings, the sphygmometers, a tool for tracing arterial pressure waveform from the radial artery was used. After the introduction of the sphygmomanometer by Riva-Rocci, the maximum values of blood pressure recorded as the systolic (SBP) and diastolic (DBP) pressures were thought to provide comprehensive clinical information on vascular haemodynamics and have been used until today as a simple and reliable tool with which to assess both systolic brachial and ankle pressure for the diagnosis of PAD using ABI. Like the measurement of brachial blood pressure extremes, arterial tonometry provides a similarly well-tolerated, reproducible, easy, fast, and non-invasive test providing information on pulse wave patterns [29]. Several studies have confirmed that blood pressure values and arterial


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rence of the reflected pulse wave is determined by heart rate, pulse wave velocity (arterial stiffness), and peripheral resistance (terminal vessels/ atherosclerotic lesions) [20]. Hence, the unfavourable early occurrence of the backward pulse wave during systole of the next cardiac contraction contributes to an elevation in afterload and impairment in diastolic endocardial perfusion (Fig. 1b) [21]. In healthy younger or elastic vessels, the backward pulse wave occurs in diastole of the cardiac cycle with optimal diastolic cardiac perfusion without a relevant impact of the cardiac afterload in systole (Fig. 1a) [22]. Arterial stiffening is caused by multiple factors over the life span and can be considered part of “vascular aging” that is basically characterised by a loss of the aortic “Windkessel” function and lower elastic properties, mainly

Non-invasive measurement of blood pressure, pressure wave forms and arterial stiffness In the second half of the 19th century, the role of arterial blood pressure in cardiovascular diseases was recognised, blood pressure values definition attempted and arterial pressure wave forms recorded [23]. Following the initially invasive methods of pulse

Figure 1: Schematic graphs with antegrade and retrograde pulse waves, that merge in a) healthy young subjects in diastole or in b) in elderly or stiffer arteries in the systole with an increase in the afterload and a decrease during the diastole resulting in lower myocardial perfusion pressure.




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pressure waves recorded non-invasively, by transcutaneous tonometry, are exactly superimposable onto those recorded invasively, by means of intra-arterial catheter [30-32]. There are two methods, both of which are well validated and reliable, to record the central pressure wave: a direct method and an indirect method [33]. The direct method has been widely tested and has shown that the shape of the pressure wave in the ascending aorta is similar to that recorded in the carotid artery, so that the direct application of tonometry in the carotid artery seems to be an easy and reproducible approach for recording central blood pressure [30]. In contrast to direct assessment, there is the indirect method through a transfer function [30]. With this method, tonometry is performed in the radial or the brachial artery; by using an algorithm central pressure waveform is rebuilt, starting from the waveform recorded in the radial artery and the pressure values measured in brachial artery [32, 34]. The indirect method is used by the SphygmoCor (AtCor Medical Pty. Ltd., Sydney, Australia). The main limitation of applanation tonometry is that it does not allow absolute values of arterial pressure to be provided. Brachial blood pressure measurement is needed and central aortic blood pressure is derived from peripheral blood pressures, taking into account the timing of the antegrade and retrograde pulse waves. In addition, it allows calculation of the so-called central pressure augmentation or aortic augmentation index [20]. With this method, P1 (first systolic peak), P2 (second systolic peak) and the central pulse pressure (PP) from the calculated aortic waveform are used to determine the AIx as: AIx ( %) = (P2 – P1) PP * 100 (Fig. 2). Because heart rate is one of the main parameters affecting AIx values, the AIx is normalised for a standard heart rate of 75 beats per minute using the

previously tested transfer function [20]. There are many functional parameters for arterial stiffness such as strain, distensibility coefficient, compliance coefficient, β-stiffness index, Peterson’s elastic modulus and Young’s elastic modulus [8]. However, the gold standard for arterial stiffness is the measurement of the carotid femoral pulse wave velocity (cfPWV) [35]. Carotid-femoral PWV can be measured by the simultaneous assessment of pressure waveforms at two different sites in the arterial tree: a proximal site (i.e. carotid) and a distal one (i.e. femoral). This enables the time delay between pressure waveforms recorded in the distal segment with respect to the proximal one to be calculated. Velocity is equal to distance/time. As a consequence, pulse wave velocity is calculated using the following formula: Pulse wave velocity (m / sec) = Distance between the two site of recordings / Δ time of pulse (Fig. 3). In summary, there are direct and indirect measures for arterial stiffness with different non-invasive tools that

are commercially available. Only the assessment of PWV has been suggested for risk stratification in recent guidelines since cfPWV offers most epidemiological data [19, 36]. Other emerging parameters are central aortic pressures and aortic augmentation index [10, 37]. Hence, the following review will mainly discuss these three parameters in PAD.

Peripheral arterial disease and arterial stiffness PAD bears an increased risk of ischemic events with about a 2-fold increase in myocardial infarction and stroke [38]. This is true for both asymptomatic and symptomatic PAD, but is more pronounced in severe PAD [39]. It is well known that ABI is an independent marker for morbidity and mortality [14, 40]. Although this correlation to the impairment of lower limb perfusion is recognised, its causal relationship is not fully understood. PAD is characterised by obstructive lesions, primarily of atherosclerotic origin, but often accompanied

Figure 2: Schematic illustration of the shape of central aortic pulse wave in a stiff aorta of one cardiac cycle with a first systolic (P1) and second systolic (P2) notch. Augmentation pressure index is derived from the values of P1 and P2 as AIx ( %) = (P2 – P1) x PP x 100.




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Figure 3: Assessment of pulse wave velocity as a function of transit time and distance of the pulse wave derived from the carotid and femoral arteries (modified from[17]).

by cell proliferation, inflammation and fibrosis and calcifications within the tunica media. Considering this and the above-mentioned principles of pulse wave propagation and reflection, PAD may be considered an “endstage disease of arterial stiffening” and evaluation of non-invasive vascular biomarkers for arterial stiffness merits particular interest in this disease with important relevance to both clinical management and outcome and pathophysiological understanding alike. Potential causes of morbidity and mortality in PAD are stroke and heart disease, in addition to impaired physical mobility and disability due to minor or major amputations. Established predictors of outcome for patients with PAD include higher age, gender, smoking, diabetes, and diminished ankle brachial index, with treatment modalities including antiplatelet therapy and HMG-CoA reductase inhibitors (statins)[41, 42]. Identifying and predicting the cardiovascular risk in individuals with PAD allows personalised management, for example by optimising and intensifying medical therapy. From a haemodynamic perspective, cardiac output, systemic

vascular resistance as well as stroke volume of patients with PAD is comparable to controls, but differs by an increased pulse pressure as a characteristic feature [43]. This is thought to be due to arterial stiffening, wave reflections, or both [44]. There is substantial evidence for an interactive relationship between arterial stiffness in different vascular bed such as the carotid or brachial segments in PAD and stiffening is not only limited to arteries of the lower limb [43, 44]. This generalised arterial stiffness in PAD represents an overall alteration of large vessels and has been proposed to be responsible for elevated systolic blood pressure [44]. In addition to this mechanism, premature wave reflection may be relevant. Arterial obstructions along the aortic-femoral tree are sites of early wave reflections that return prematurely to the heart during the next systole and increase afterload and lower myocardial perfusion [45]. Experimental studies in mongrel dogs with invasive pressure measurements in the ascending aorta and balloon clamping along the aortic downstream segment indicated an increased pressure wave in relation to the proximity of clamping [46]. Indi-

rect evidence has been found by the assessment of subjects following traumatic amputation of the lower limbs. These subjects have a higher incidence of systolic hypertension over 50 years of age, potentially caused by a shorter length of the arterial system due to the loss of a limb [47]. Direct experimental human in vivo evidence has been reported by Khir et al. by assessing pulse pressure and blood flow velocity simultaneously in the ascending aorta intraoperatively during clamping for surgery of aortic-iliac disease [48]. They found an earlier return of the reflected pulse wave of 30 milliseconds and a likewise increase in left ventricular hydraulic systolic work. The authors concluded that the earlier arrival of the reflected waves causes an increase in the afterload because the left ventricle has to overcome earlier reflected compression waves [48]. Although this has so far not been demonstrated for chronic PAD, based on these experimental findings and other investigations on arterial stiffness in PAD, a possible haemodynamic pathomechanism is emerging. The pulsatile component of blood pressure, which reflects changes in the buffering function of large arteries, might influence the reductions in walking distance and vascular bed reserve, as observed in patients with PAD. Indeed, Brewer et al. found that lower cAIx was associated with longer walking distance in patients with PAD [49]. In agreement with this observation, a significant correlation between ABI and aortic augmentation index and subendocardial viability ratio, another non-invasive haemodynamic marker derived from pulse wave analysis, in PAD patients was reported by our group [50]. Khalegi and Kullo found that cAIx is elevated in asymptomatic PAD compared to age- and sex-matched controls [51]. There was further support for an interaction between lower limb perfusion and systemic vascular




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effects in a non-randomised controlled trial in patients with PAD undergoing lower limb revascularisation when compared to PAD patients receiving best medical treatment [52]. Patients with revascularisation showed a decrease in cAIx by approximately 10 %, from cAIx 31.5 ± 1.1 % at baseline to 28.8 ± 1.1 % at 3 months follow-up (p = 0.01), whereas the conservatively treated group remained unchanged. Although this is only an associated and not a causative finding, there is substantial evidence that endothelial cell function is impaired in PAD. Claudicants have lower flow-mediated dilatation than controls or asymptomatic patients with PAD [53]. Endothelialdependent vasodilation is improved following both exercise rehabilitation and lower limb revascularisation [54, 55]. McErniery et al. have shown that a decline in endothelial function is accompanied by an increase in pulse wave velocity (r = 0.69; p < 0.001), aortic augmentation index (r = – 0.59; p < 0.001) and central pulse pressure (r = – 034, p < 0.001) in healthy subjects [56]. Similarly, Soga et al. showed that flow-mediated dilation inversely correlates with cAIx (r = – 0.38, p < 0.0001) in patients with cardiovascular disease [57]. In symptomatic PAD, oxidative stress caused by repeated muscle ischaemia during walking and low shear stress due to impaired ambulatory activity potentially contributes to lower NO bioavailability [27]. This is at least indirect evidence for a molecular background for vascular dysfunction in PAD related to arterial stiffening (Fig. 4). There are further data that support a potential association between arterial stiffness, PWV and walking capacity in PAD. For example, Yokoyama et al. reported that brachial-ankle PWV is increased in diabetic patients, whereas it is decreased in the affected legs in diabetic patients with PAD [58]. Their

Figure 4: Structural and functional factors affecting pulse wave velocity and role of peripheral arterial disease (modified from [17]).

data are in part in agreement with the work by Catalano et al., who reported higher carotid-femoral PWV in PAD than in controls and a significant correlation to pulse pressure [59]. An interaction between walking capacity and brachial-ankle PWV was found as well [60]. PAD patients with a higher brachial-ankle PWV had a reduced walking capacity. This was also reported by Watson and colleagues who showed that carotid–femoral PWV was inversely related to gait speed in patients with PAD [61]. These data are conflicting, as the affected limb in the diabetic PAD group showed lower brachial-ankle PWV, which would be attributable to occlusive disease that impaired functional capacity in the affect limb resulting in the clinical complaint of intermittent claudication. Brand et al. found an increased aortic pulse pressure and reduced cfPWV in patients with critical limb ischaemia (CLI) [62]. This can be explained by the fact that CLI is based on multilevel obstructive disease along the aorto-iliac or infrain-

guinal or infrapopliteal arteries [63]. Pulse wave/volume recordings are known to be delayed in the affected limbs [63]. This results in lower PWV due to obstructions in the lower limb arteries. Hence, PWV assessment in PAD has to be considered with caution in the presence of aorto-iliac lesion for the carotid-femoral assessments and even more so when assessing a longer distance further down the ankle, such as for brachialankle PWV, where occlusive lesions will always result in a delayed pulse wave and hence in falsely low PWV. This notion is supported by the recent data on brachial-ankle PWV and ankle-brachial pressure measurements (ABPI) in haemodialysis patients in which only ABPI has been shown to be useful for risk stratification of systemic atherosclerotic morbidity and mortality[64]. Haemodialysis patients show accelerated atherosclerosis and are prone to infrapopliteal atherosclerotic disease which may alter both ankle-brachial pressure measurements due to me-




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diacalcinosis and brachial-ankle PWV assessments due to occlusive disease. Of note, not only the site of measurements of PWV have to be taken into account, but arterial assessment to test for arterial patency prior to determination of PWV is of great importance. Despite the problems in techniques related to PWV assessment, there is a growing body of evidence that increased arterial stiffness is not only found in different cardiovascular diseases such as PAD, cerebrovascular and coronary heart disease, but that it is also an independent risk predictor in addition to standard risk factors [19]. Therefore, more thorough investigation and evaluation of the assessment of different markers of arterial stiffness in PAD are needed for both risk prediction and improvement of medical management with the foremost improved antihypertensive treatment in these specific high risk atherosclerosis subgroup, and ultimately for secondary prevention. Being aware of the haemodynamic and functional changes observed in patients with PAD, the possible link between PAD and mortality due to coronary heart and cerebrovascular disease may be better understood [65]. Myocardial perfusion and metabolic needs of the left ventricle are strongly influenced by systolic blood pressure, by an increase in systemic arterial stiffness as well as by the modification of timing and amplitude of reflected waves initiated and/or favoured by PAD [66]. On the other hand, myocardial blood supply depends on diastolic blood pressure and coronary perfusion during diastole [67]. Since the pressure amplitude is elevated in PAD and partly attributable to lower diastolic blood pressures, the supply/demand ratio may be unfavourably altered in PAD patients [43]. Hence, the changes in arterial wall structure in PAD with increased arterial stiffness resulting

in increased SBP and decreased DBP) are likely to be detrimental to both the heart and the brain. Clearly, this is an important field for further research in patients with PAD and underscores the use of appropriate non-invasive assessment tools to determine arterial stiffness and their utility in PAD. Considering the role of pulse wave propagation in the presence of systemic atherosclerosis, invasive evaluation of all non-invasive assessment techniques needs to be evaluated in the presence of PAD, irrespective of whether measurements are estimated from a radial, brachial, or carotidfemoral site.

Conclusions Increased arterial stiffness is an agedependent vascular modification of vascular wall function and structure and is independently associated with cardiovascular morbidity and mortality. PAD shows unfavourable central aortic pressure augmentation, which might be a potential link to the cardiovascular pathophysiology observed in these patients. Since stroke and coronary disease are major causes of morbidity and mortality in PAD, assessment of different parameters of arterial stiffness in PAD may be of value to further examine and define the pathophysiology and improve risk stratification, therapeutic management, and secondary prevention in these patients.

Acknowledgements Research of the authors is supported by the Swiss Heart Foundation and by Matching Funds of the University of Zürich.

Conflicts of interest There are no conflicts of interest existing.

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Correspondence address Dr. Marc Husmann, MD Clinic for Angiology University Hospital Zurich Raemistrasse 100 8091 Zürich Switzerland [email protected]

Submitted: 29.12.2014 Accepted after revision: 12.03.2015