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Arterial stiffness

insights from Framingham and Iceland

Mitchell, Gary F.

Current Opinion in Nephrology and Hypertension: January 2015 - Volume 24 - Issue 1 - p 1–7
doi: 10.1097/MNH.0000000000000092
CIRCULATION AND HEMODYNAMICS: Edited by Matthew R. Weir and Roland C. Blantz

Purpose of review To examine the putative measures of arterial stiffness and the mechanisms of adverse effects of stiffness on blood pressure and target organ damage using data from comprehensive hemodynamic profiles obtained in the Framingham Heart Study and the Age, Gene/Environment Susceptibility-Reykjavik Study.

Recent findings Once thought to be a consequence of longstanding hypertension, recent evidence suggests that aortic stiffness antedates and contributes to the pathogenesis of hypertension and target organ damage in the heart, brain, and kidneys. Carotid–femoral pulse-wave velocity (CFPWV) has emerged as the reference standard measure of aortic stiffness and a powerful predictor of cardiovascular disease risk. Augmentation index, a putative measure of arterial stiffness and wave reflection, has complex relations with stiffness and risk. Recent evidence suggests that wave reflection, which is a normal consequence of impedance mismatch between compliant aorta and stiff muscular arteries, is protective and limits the exposure of target organs to potentially harmful pulsatile energy. Aortic stiffening produces impedance matching that reduces wave reflection and exposes the microcirculation to excessive pulsatile stress, resulting in microvascular target organ damage and dysfunction.

Summary CFPWV provides a powerful new tool for risk stratification and elucidation of the pathogenesis of target organ damage in hypertension.

Cardiovascular Engineering, Inc, Norwood, Massachusetts, USA

Correspondence to Gary F. Mitchell, MD, Cardiovascular Engineering, Inc., 1 Edgewater Drive, Suite 201, Norwood, MA 02062, USA. Tel: +1 781 255 6930; e-mail:

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Our understanding of the relations between hypertension, arterial stiffness, excessive pressure pulsatility, and target organ damage has changed dramatically in the recent years. In a traditional paradigm, repetitive pulsatile strain with aging was thought to break down elastin in the wall of the aorta, resulting in aortic dilation and increased engagement of collagen, which is several orders of magnitude stiffer than the elastic fibers that normally bear most of the load in the aortic wall. The resulting increase in aortic wall stiffness increases the pulse-wave velocity (PWV). Progressively higher PWV was posited to result in increasingly premature arrival of the reflected pressure wave, progressive augmentation of the central aortic pressure waveform, and widening of pulse pressure (PP). Importantly, in the foregoing paradigm, excessive aortic stiffness was viewed as a complication of longstanding hypertension, which was thought to amplify stress on the aorta and accelerate the process of aging [1–5]. The clinical implications of these putative measures of arterial stiffness and wave reflection, and their relations with blood pressure (BP) progression and target organ damage, have been studied by using comprehensive hemodynamic profiling of central aortic pressure-flow relations, PWV, and wave reflection in the large, well characterized, community-based cohorts of the Framingham Heart Study and the Age, Gene/Environment Susceptibility (AGES)-Reykjavik Study. Findings from these studies and others have confirmed some of the prior hypotheses and substantially altered our interpretation of others.

Box 1

Box 1

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The gold-standard measure of aortic stiffness is carotid–femoral PWV (CFPWV), which is optimally assessed by using arterial tonometry (Fig. 1). Although a number of alternative approaches have been proposed, tonometric CFPWV benefits from a body of literature that strongly supports its role as a novel cardiovascular disease (CVD) risk factor [6▪▪,7]. Relatively modest equipment and expertise are required to assess CFPWV, rendering it suitable for use in a routine clinical setting. In order to more fully characterize mean and pulsatile load on the heart, assessment of central-pressure–flow relations is required [8]. The test can be performed quickly and robustly by well-trained sonographers. However, the evaluation requires limited cardiac ultrasound and moderate expertise, and hence is suitable for use in a specialty laboratory or research setting.



We evaluated age relations of BP and key hemodynamic measures in the Framingham Offspring and Third Generation cohorts, which together span the full adult age range [8]. Age relations of CFPWV and PP were complex, and strongly nonlinear. CFPWV increased modestly with age through midlife and rapidly thereafter. In contrast, PP fell substantially from young adulthood through midlife, as has been reported by others [9], and then increased rapidly after the midlife nadir. Augmentation index, a measure of wave reflection, increased substantially with age through midlife, at a time when PP was actually falling, and then fell after midlife, at a time when PP and CFPWV increased rapidly. The opposing age trends of PP and augmentation index indicated that it was extremely unlikely that age-related widening of PP could be attributed to excessive wave reflection. Age relations of PP were paralleled by forward-wave amplitude (Pf) and characteristic impedance of the aorta (Zc), which is a major determinant of Pf. The foregoing observations suggest that age-related differences in PP were attributable to Pf rather than reflected wave amplitude or timing. Consistent with this observation, multivariable models demonstrated that approximately 90% of variance in PP was attributable to variability in Pf, with the remainder attributable to relative wave reflection and timing of the reflected wave [8].

In addition to the strong nonlinearity of age relations of each of the key hemodynamic measures, we also observed prominent dissociation of age relations of CFPWV and Zc. Differing age relations of CFPWV and Zc could be attributable to regional heterogeneity in aortic stiffness. Zc is primarily a measure of proximal aortic properties, whereas CFPWV summarizes the spatially averaged properties of the descending thoracic and abdominal aorta as well as the iliac and proximal femoral arteries. Alternatively, differing behavior of CFPWV and Zc could be a consequence of aortic remodeling. PWV and Zc have similar direct relations with aortic wall stiffness, and both are inversely related to the lumen diameter. However, Zc has a five-fold greater sensitivity to lumen diameter. Thus, with isolated stiffening of the aortic wall, Zc and PWV will increase in parallel. In contrast, if the lumen remodels in association with the alterations in stiffness, Zc and PWV will dissociate and many even change in opposite directions.

The main load-bearing elements of the aortic media are the elastic lamellae, which are formed early in life. After the development of the aortic lamellae has completed in early childhood, the gene program for elastic fiber production is silenced [10,11]. Therefore, subsequent dramatic alterations in the aortic dimensions in response to somatic growth and weight gain represent the remodeling of a fixed pool of elastin to a larger diameter. Aortic diameter increases substantially throughout the life course, particularly in the presence of obesity [12]. Remodeling thins the elastic lamellae and increases wall tension because of the larger radius, as indicted by the Law of Laplace [13–15]. As a result, fiber stress and hence strain will increase, leading to increased fractional engagement of collagen, which is several orders of magnitude stiffer than elastin. The associated increase in wall stiffness can increase PWV even as PP falls because of the extreme inverse sensitivity of Zc to diameter. Thus, aortic remodeling secondary to midlife weight gain could stiffen the wall of the aorta and drive up CFPWV, with no increase or even a fall in PP. One could speculate that the recent epidemic of obesity and glucometabolic disorders may have contributed to nonlinear PP–age relations, with diabetes stiffening the aortic wall and obesity promoting outward remodeling to a larger aortic diameter, which may temporarily obscure the effect of wall stiffness on Zc and PP.

On the basis of hemodynamics, aortic lumen enlargement seems to approach a limit after midlife when PP and CFPWV increase in parallel, suggesting an ongoing increase in aortic wall stiffness with minimal additional diameter remodeling. The evolution of the aortic root diameter over the adult life course was evaluated using measures of aortic root diameter obtained over a 16-year interval in Framingham Offspring Study participants [12]. Aortic root diameter enlarged over the life course in both men and women. Additive aortic enlargement was observed in the presence of hypertension and obesity. Multivariable models indicated that the increase in aortic diameter with increasing BMI was attenuated after the median age (52 years), suggesting that aortic diameter reserve may have been depleted because of enlargement early in life. One could speculate that the relatively rapid onset of the obesity epidemic over the last 3 decades was associated with aortic enlargement that initially reduced Zc, because of the strong inverse relation to aortic diameter (power of 2.5), and contributed to the cross-sectional midlife PP nadir as well as the increase in aortic wall stiffness (higher CFPWV). In support of this hypothesis, the longitudinal study found strong inverse relations between aortic diameter and short-term (4 years) or long-term (16 years) change in PP [12].

Data from the AGES-Reykjavik study has shown that variable modulation of aortic diameter may play an important role in the widening of PP after midlife [16]. Contrary to the traditional view that higher PP should be associated with aortic dilation, several studies have found that PP is negatively related to aortic diameter [17–20]. The hypothesis that smaller aortic diameter contributes to the widening of PP was further examined in the AGES-Reykjavik cohort by using high-resolution MRI of the thoracic aorta [21▪▪]. In this older cohort, we found that higher PP was associated with smaller aortic diameter along the full length of the thoracic aorta, suggesting mismatch between diameter and flow in individuals with the highest PP. In a multivariable model, we were able to demonstrate dissociation between cardiac and aortic adaptations to hemodynamic load. Higher PP was associated with a smaller aorta diameter and a larger left ventricular end-diastolic volume, suggesting that the heart may have greater ability to remodel in response to hemodynamic demand, for example, in order to accommodate a requirement for increasing cardiac output secondary to increasing adiposity. The aorta may be more constrained in its ability to remodel because, as noted above, the number of elastic lamellae and pool of elastic fibers is determined by genetics and early-life exposures during childhood [11,22]. As a result, some individuals may have less remodeling reserve than others, resulting in accelerated widening of PP as the hemodynamic demand increases or the aortic wall stiffens in later life.

Consistent with the foregoing, there are important genetic contributions to CFPWV and PP as evidenced by the moderate heritability of each phenotype and the identification of specific genetic loci based on the genomewide association studies [23,24]. Endothelial dysfunction may also contribute to aortic stiffness through modulation of aortic smooth muscle cell tone and stiffness [25▪,26▪]. In addition, nitric oxide has been shown to modulate the activity of tissue transglutaminase-2, which is a cross-linking enzyme found in the aortic wall. Studies have shown that reduced bioavailability of nitric oxide with age is associated with increased transglutaminase-2 activity and increased cross-linking of proteins in the wall of the aorta, resulting in increased aortic stiffness [27].

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A number of recent studies have contributed to our understanding of the role of wave reflection in central hemodynamics. As noted earlier, augmentation of the central pressure waveform by premature return of the reflected wave secondary to increased PWV was once thought to be a major contributor to the widening of PP. However, recent work has demonstrated that, whereas amplitude and timing of the reflected wave are important, the augmentation index is also heavily dependent on the pattern of left ventricular ejection and the shape of the forward and reflected waves [28▪▪,29▪▪,30▪].

Conversely, reduction in apparent wave reflection with vasoactive medications was associated with an unanticipated reduction in stroke volume, suggesting that preload reduction may diminish the ability of the heart to generate augmentation [31▪]. Many vasodilators are also venodilators and may reduce preload. As the end-systolic pressure–volume relation is substantially steeper than the end-diastolic relation, modest venodilation may have a much larger effect on preload than vasodilation has on afterload, resulting in a marked reduction in the augmentation, together with a modest reduction in stroke volume. This mechanism may contribute to the substantial reduction in augmentation that is seen following administration of nitrates, which are potent venodilators that have only modest effects on arterial resistance [29▪▪]. As a result, modulation of preload with venodilator drugs may provide a novel approach to reduce central pressure pulsatility. Modulation of preload rather than peripheral vascular resistance will avoid transmitting potentially harmful pulsatile energy into the periphery where it can exacerbate small-vessel damage, as would be the case with arteriolar dilators.

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Though often viewed as a complication, recent studies provide evidence that arterial stiffness may precede and contribute to the pathogenesis of hypertension. Using data from a nonhypertensive subgroup of the Framingham Offspring cohort, Kaess et al.[32▪▪] demonstrated that higher aortic stiffness, assessed as greater Pf amplitude or higher CFPWV, was a risk factor for BP progression and incident hypertension during 7 years of follow-up. In contrast, when the model was reversed, no BP measure entered the model for follow-up CFPWV once baseline CFPWV was considered, providing strong support for the hypothesis that aortic stiffness is a cause rather than a complication of hypertension. A recently reported mouse model of aortic stiffness produced by a high-fat, high-sucrose diet demonstrated similar temporal relations between aortic stiffness and hypertension [33▪▪]. Several studies in humans have shown that increased aortic stiffness can precede the development of hypertension [32▪▪,34–37], and others have suggested that the relation may be bidirectional [38–40].

A traditional view of the pathogenesis of hypertension posits initiation of the disease by an increase in cardiac output that may be a consequence of various lesions in sodium handling, hyperactivity of the renin–angiotensin system or the sympathetic nervous system, or other causes [41]. In this paradigm, the increase in cardiac output triggers secondary changes in resistance vessel structure and function, a progressive increase in peripheral resistance, and a fixed elevation of mean arterial pressure. To evaluate this potential mechanism, we defined reference values (95th percentile) for key central hemodynamic measures in healthy participants less than 50 years of age in the Framingham Offspring and Third Generations cohorts [8]. We then examined the prevalence of high values in the full cohort. We found a modest prevalence of elevated cardiac output (7%) and peripheral resistance (28%). In contrast, prevalence of high CFPWV (>8.1 m/s) was substantial (69%). In light of our findings that elevated CFPWV is associated with increased risk for incident hypertension and CVD, it seems that aortic stiffness and pulsatile load, rather than mean pressure and steady-flow load, may contribute substantially to the burden of hypertension and CVD, particularly after midlife [7,32▪▪].

Although additional work will be required in order to clarify the predominant directionality of longitudinal relations between arterial stiffness and hypertension, it is clear that hypertension is very commonly associated with increased aortic stiffness and that stiffness complicates the attempts to control BP. The overwhelming majority of cases with uncontrolled hypertension have persistent (mostly isolated) SBP elevation, meaning that failure to control BP represents failure to control PP and hence failure to control aortic stiffness [42]. Although this observation gives cause for concern, it also represents an opportunity because we have never really tried to control PP or stiffness. All drugs currently approved to treat hypertension were designed and approved based on their ability to reduce mean arterial pressure. The epidemiology of uncontrolled hypertension provides an urgent public health imperative to refocus our efforts in order to define and implement interventions that target prevention or amelioration of abnormal arterial stiffness and increased PP.

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Hypertension and arterial stiffening are associated with an increased risk for damage in various target organs, including the heart, brain, and kidneys. Effects on the heart are largely attributable to excessive load or ischemia because of atherosclerosis or small-vessel disease. Excessive pulsatile load is associated with left ventricular hypertrophy and impaired diastolic relaxation, which may contribute to the link between arterial stiffness and heart failure with preserved systolic function [43]. Excessive aortic stiffness and high levels of pressure and flow pulsatility are particularly deleterious in high-flow organs such as the brain [44,45▪] and kidneys (AGES-II) [46▪▪,47▪▪]. Aortic stiffening is generally associated with minimal change or even a reduction in the stiffness of muscular arteries [8,48]. The resulting ‘impedance matching’ between aorta and muscular arteries reduces wave reflection and therefore facilitates transmission of potentially harmful pulsatile energy into the peripheral vascular bed [44,46▪▪,47▪▪]. In addition, high-flow organs are necessarily low impedance, meaning that more of the pulsatility transmitted into the main conduit vessels supplying the organ will penetrate into the microcirculation, where it can cause damage and remodeling that may impair microvascular function. The combination of BP lability [49] and blunted microvascular reactivity [50] in individuals with stiff arteries may predispose to repeated episodes of ischemia and tissue damage leading to functional consequences, such as a reduction in cognitive scores [44,45▪] or glomerular filtration rate [34,35].

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CFPWV has emerged as the gold-standard measure of aortic stiffness and a powerful new noninvasive tool for risk stratification. Using data from the Framingham Heart Study, we demonstrated that CFPWV reclassified risk in a model that considered standard CVD risk factors, including SBP [7]. A recent individual participant meta-analysis of 16 studies and 17 635 participants with 1785 major CVD events confirmed the ability of CFPWV to reclassify risk [6▪▪]. The hazard ratio associated with CFPWV was particularly high in younger participants, suggesting that CFPWV may be an effective tool for early screening before potentially irreversible changes in arterial structure have occurred.

Numerous studies have demonstrated that higher PP is associated with increased risk [51–55], although it is difficult to demonstrate that PP reclassifies risk in a model that includes SBP because SBP and PP are highly correlated. Nevertheless, Franklin et al.[56] were able to demonstrate that PP and mean arterial pressure in a dual-component model stratified risk better than individual BP components and, in contrast to SBP and DBP, had readily interpretable linear relations with risk. Elucidation of hypertension pathophysiology and treatment will be facilitated by the consideration of the separate roles played by mean arterial pressure and PP, which are key components of BP that have markedly different anatomic and physiologic determinants.

Much has been written in recent years regarding the potential prognostic implications of central pressure compared with peripheral PP for risk stratification. Arguments generally were based on the not unreasonable assumption that central pressure better reflects local load on the heart, brain and kidneys, and therefore should be a better marker of risk. However, regardless of whether the absolute values differ, central and peripheral pressures are very highly correlated (R2 > 0.9) [57]. Thus, it will be difficult to demonstrate that either measure is superior to the other as a predictor of risk. In addition, the SphygmoCor device, which many studies have used to estimate central pressure from a radial pressure waveform by using a generalized transfer function, is known to utilize a faulty calibration procedure that results in substantial underestimation of central pressure and hence overestimation of the apparent difference between central and conventional BP [58▪,59]. We evaluated the direct measures of central pressure based on carotid tonometry in the Framingham Heart Study, and did not find any incremental value of central pressure in a model that included standard risk factors and arm SBP [7]. In light of these observations, it seems that focusing efforts on improved awareness of the importance of conventional PP and CFPWV rather than the potential differences between central and peripheral pressure would be reasonable.

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Arterial stiffness research has progressed remarkably over the last decade and has emerged as an area of interest across multiple medical specialties. Essentially, all tissues in the body are perfused and therefore potentially susceptible to the adverse effects of vascular dysfunction and excessive pressure pulsatility. The contribution of stiffness to pathogenesis, complications, and refractoriness to conventional treatment of hypertension underscores an important opportunity for the focused discovery of novel interventions that prevent or ameliorate aortic stiffness.

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Financial support and sponsorship

Sources of funding: Work presented in this review performed at the NHLBI Framingham Heart Study was supported by the NHLBI (NHLBI/NIH Contract #N01-HC-25195) and the Boston University School of Medicine and by HL076784, G028321, HL070100, HL060040, HL080124, HL071039, HL077447, HL107385, and 2-K24-HL04334. Work presented in this review performed at the AGES-Reykjavik Study was supported by the National Institutes of Health (contract N01-AG-12100); the National Institute on Aging Intramural Research Program; Hjartavernd (the Icelandic Heart Association); the Althingi (the Icelandic Parliament); and a grant from the National Institutes of Health, National Heart, Lung and Blood Institute (grant number HL094898).

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Conflicts of interest

Disclosures: G.F.M. is the owner of Cardiovascular Engineering, Inc., a company that develops and manufactures devices to measure vascular stiffness, serves as a consultant to, and receives honoraria from, Novartis and Merck, and is funded by the research grants HL094898, DK082447, HL107385, and HL104184 from the National Institutes of Health.

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Papers of particular interest, published within the annual period of review, have been highlighted as:

  • ▪ of special interest
  • ▪▪ of outstanding interest
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This large meta-analysis confirmed that CFPWV is an important risk factor for cardiovascular disease that reclassifies risk in models that include standard risk factors. Relations were particularly robust in younger individuals.

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This study was the first to perform detailed analysis of aortic structure and function and ventricular structure and function, and demonstrated that dissociation between aortic and left ventricular adaptations to hemodynamic demand contributes to elevated pulse pressure in older people.

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This study underscores the importance of aortic smooth muscle as a dynamic modulator of aortic stiffness.

26▪. Saphirstein RJ, Gao YZ, Jensen MH, et al. The focal adhesion: a regulated component of aortic stiffness. PLoS One 2013; 8:e62461.

This study underscores the importance of aortic smooth muscle cytoskeletal connections to the matrix as a modulator of aortic function.

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This study presents a detailed analysis of the hemodynamic correlates of central pressure augmentation and demonstrates that considerable variability is attributable to the differences in forward-wave amplitude and shape and reflected wave shape.

29▪▪. Fok H, Guilcher A, Li Y, et al. Augmentation pressure is influenced by ventricular contractility/relaxation dynamics: novel mechanism of reduction of pulse pressure by nitrates. Hypertension 2014; 63:1050–1055.

This study demonstrated that reductions in augmented pressure following administration of nitroglycerin are mostly related to alterations in ventricular contraction pattern and forward wave amplitude rather than reduced wave reflection.

30▪. Schultz MG, Davies JE, Roberts-Thomson P, et al. Exercise central (aortic) blood pressure is predominantly driven by forward traveling waves, not wave reflection. Hypertension 2013; 62:175–182.

This study provides further evidence of the importance of forward-wave amplitude to the genesis of wide pulse pressure, in this case because of acute (exercise induced) mismatch between aortic lumen area and flow.

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This study demonstrated an unexpected reduction in the stroke volume following administration of a vasodilator despite a substantial reduction in the augmentation index, presumably because of an associated reduction in preload that prevented the left ventricle from augmenting pressure in late systole.

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The first study to evaluate bidirectional longitudinal relations between aortic stiffness and blood pressure progression. This study demonstrated that aortic stiffness predicted risk for blood pressure progression and incident hypertension, whereas no blood pressure component predicted progression in aortic stiffness (CFPWV).

33▪▪. Weisbrod RM, Shiang T, Al Sayah L, et al. Arterial stiffening precedes systolic hypertension in diet-induced obesity. Hypertension 2013; 62:1105–1110.

This study demonstrated in a mouse model that aortic stiffening can precede and contribute to the development of hypertension.

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This study demonstrated important relations between aortic stiffness, brain lesions, and cognitive impairment.

46▪▪. Woodard T, Sigurdsson S, Gotal JD, et al. Mediation analysis of aortic stiffness and renal microvascular function. J Am Soc Nephrol 2014; pii:ASN.2014050450. [Epub ahead of print].

This study performed a formal mediation analysis of the relation between aortic stiffness and measured glomerular filtration rate. The effects of increased stiffness were mediated by increased pulsatility of renal artery blood flow, reduced vascular fraction in the renal cortex, and increased renal vascular resistance. The findings were consistent with the hypothesis that excessive aortic stiffness increased the transmission of excessive pulsatile energy into the microcirculation, where it causes damage.

47▪▪. Woodard T, Sigurdsson S, Gotal JD, et al. Segmental kidney volumes measured by dynamic contrast-enhanced magnetic resonance imaging and their association with CKD in older people. Am J Kidney Dis 2014; pii:S0272-6386(14)00908-1. doi: 10.1053/j.ajkd.2014.05.017. [Epub ahead of print].

This study used a novel approach to segment the kidney, and demonstrated risk factor and functional correlates of abnormal kidney structure.

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This detailed meta-analysis and review examines the errors implicit in the approach to calibration employed by the SphygmoCor device.

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augmentation index; characteristic impedance; pulse pressure; pulse-wave velocity

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