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Arterial stiffness as a noninvasive tissue biomarker of cardiac target organ damage

License. The full terms of the License are available at http://creativecommons.org/licenses/by-nc/3.0/. Non-commercial uses of the work are permitted without any further permission from Dove Medical Press Limited, provided the work is properly attributed. Permissions beyond the scope of the License are administered by Dove Medical Press Limited. Information on how to request permission may be found at: http://www.dovepress.com/permissions.php Current Biomarker Findings 2014:4 23–34 Current Biomarker Findings Dovepress

Desirable features of a biomarker for cTOD are as follows: the biomarker should be reproducible, stable, cost-effective, acceptable to the patients, capture known physiology, provide novel insight into pathophysiology, and be responsive to therapy; it should explain a significant proportion of the outcome independent of other risk factors and aid in incremental risk prediction; it should have established normal/reference limits and standardized methodology; and, finally, change in the biomarker should alter outcome and help guide disease management. 9 This biomarker should be applicable to men and women as well as different ages and different races/ethnicities. 9 In order to truly understand the structural and/or functional changes of target organs, use of novel tissue biomarkers have been proposed. Measurement of arterial stiffness may be such a tissue biomarker. Arterial stiffness integrates the cumulative impact of genetic factors, epigenetic factors, lifestyle factors, CV risk factors, and environmental factors on the arterial wall over time. This is important, as individual risk factors can fluctuate over time and their measurement, recorded at the time of risk assessment, may therefore be unreliable and not reflect their true impact on the arterial wall. The purpose of this review will be to explore the potential utility of measuring arterial stiffness and its associated hemodynamic sequelae (ie, increased pressure from wave reflections and pulse pressure [PP] amplification) as novel biomarkers of subclinical cTOD. Earlier detection and/or prediction of cTOD with measures of arterial stiffness may afford opportunity for prevention before overt damage occurs.

Arterial stiffness as a biomarker for cTOD
Arterial compliance reflects the ability of large central elastic arteries such as the aorta and carotid to expand and recoil during systole and diastole. This buffering capacity functions to dampen the amplitude of fluctuations in pressure and flow in the systemic circulation, thereby preventing transmission of excess pulsatile energy into target organs. 10 Loss of arterial compliance or an increase in the stiffness of the vessel alters ventricular-vascular coupling such that arterial load is increased, contributing to the pathogenesis of cTOD and ultimately heart failure (described in more detail below). [11][12][13] Increased arterial stiffness is associated with systemic subclinical target organ damage, including but not limited to renal dysfunction, brain white matter hyperintensities and infarcts, retinal damage, and peripheral skeletal muscle perfusion. 14-16 Arterial stiffness can be influenced by any factor that alters vascular wall structure (elastin, collagen, smooth muscle) or function (endothelium). Age and blood pressure (BP) remain the most consistent correlates of arterial stiffness 17 and, while traditional CVD risk factors are loosely associated with arterial stiffness, this is not always a consistent finding. 18 Numerous factors that may alter vascular structure (atherosclerosis, calcification/medial calcific sclerosis, tortuosity, elastin breakdown, collagen deposition, fibrosis) and function (inflammation, oxidative stress, autonomic nervous system modulation, renin-angiotensin-aldosterone system activation, and endothelial function) appear to associate with arterial stiffness at any given moment in time, but key moderators of change in arterial stiffness over time include hemodynamic load (quantified as the product of heart rate and BP) 19-22 and change in central obesity. 23 Thus it must be stressed that, although the atherosclerotic process affects arterial stiffness (ie, presence of a plaque/atheroma may alter the mechanical function of the vessel wall), arterial stiffening is a process distinct from atherosclerosis. 24 A weak relationship exists between postmortem aortic plaque burden and antemortem arterial stiffness. 25 The current gold standard measure of arterial stiffness is aortic pulse wave velocity (PWV). Aortic PWV can be measured by assessing the transit time between the PP wave at the carotid and femoral artery. 8,26,27 PWV is simple, noninvasive, and reproducible; 28,29 standardized measurement protocols exist; 8,30 and reference values have been established in adults 31-34 and children. 35 Finally, with recent advances in technology, the measure is on its way toward being almost entirely automated. 36 Aortic stiffness using PWV predicts adverse CV events 26,37-43 independent of traditional risk factors (eg, BP). 37,38 Aortic stiffness also helps to discriminate between patients at low and high risk of adverse CV outcomes when added to conventional risk factors. 42 Addition of aortic PWV to the Framingham Risk Score improves model fit for CVD event prediction, reclassifying 15.7% of intermediate risk patients properly into higher (14.3%) or lower (1.4%) risk. 42,43 Finally, limited data in select patient populations suggest that failure to improve PWV, despite normalizing other risk factors, confers increased risk for CV mortality. 44 Guidelines set out by the European Society of Hypertension have also recognized arterial stiffness in the stratification of CV risk as a marker for asymptomatic target organ damage, 27 but the decision to adopt assessment into US guidelines remains controversial. 45 Arterial stiffness is not only a measure of target organ damage itself, but may prove useful in identifying individuals

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Arterial stiffness and cTOD at risk for subclinical cTOD. [46][47][48][49][50][51][52] LV mass can increase from either wall thickening in response to pressure overload, termed "concentric remodeling," or from chamber dilation in response to volume overload, termed "eccentric remodeling." The cause for ventricular enlargement comes from the increase in myocardial oxygen demand as a result of the increase in pressure load from the peripheral arteries, referred to as vascular afterload, in an attempt to regulate stress placed upon the ventricle (ie, compensation, preserved wall tension). If left unchecked, the left ventricle may dilate, leading to ischemia, scarring, fibrosis, and, ultimately, heart failure (decompensation). In addition to structural changes in the myocardial wall, cTOD is also associated with alterations in cardiac function, manifesting as diminished myocardial contraction velocity/prolonged myocardial contraction, inadequate relaxation, and reduced diastolic filling.
As alluded to above, elevated BP is considered to be the primary driving factor underlying the development of LVH. 53 Interestingly, changes in arterial stiffness precede longitudinal increases in BP and development of hypertension. [54][55][56] As will be discussed in detail below, changes in arterial stiffness and central hemodynamic burden are intimately entwined in each step of LVH development (Figure 1). Numerous studies now note associations between arterial stiffness and markers of subclinical cTOD [57][58][59] in numerous clinical cohorts (Table 1). 60,61 Regression of LVH via various pharmacological interventions is associated with reductions in arterial stiffness. [62][63][64] Even when BP is controlled with antihypertensive agents, aortic stiffness remains a continued indicator of LV mass in hypertensive patients, 65 suggesting continued utility as a marker of cTOD and true measure of vascular afterload in response to therapy.
Arterial stiffness is associated with LV systolic and diastolic dysfunction. 57,59,[66][67][68][69] Arterial stiffness also contributes to altered LV twist mechanics, reduced LV synchronicity, myocardial deformation, coronary flow reserve, and left atrium enlargement. 68,[70][71][72] Stiffening of the large central arteries (ie, aorta and carotid) has also been implicated in the progression of LVH to heart failure. 12-14 Animal models have demonstrated that experimentally decreasing aortic compliance via prostheses or silicon gel application result in significant increases in LVH/LV mass, without affecting diastolic pressure, cardiac output, or peripheral resistance per se. 73,74 Interestingly, change in arterial stiffness has also been implicated in the transition from chronic compensated to acute decompensated heart failure. 75 Taken together, these findings suggest a strong association between arterial stiffness and cTOD.

Arterial stiffness and pressure from wave reflections: mechanistic insight into cTOD
The association between arterial stiffness and cTOD is partially moderated by effects on pressure from wave reflections. In clinical practice, brachial BP is often used as a crude proxy of vascular afterload; however, brachial pressures are poor surrogates for central pressure (considered a much better indicator of true afterload and coronary perfusion pressure), owing to the elastic properties of the central arteries and subsequent stiffness-mediated effects on timing and magnitude of PP transit and transmission. According to wave transmission/reflection theory, the BP waveform is an amalgam of forward-and backward-traveling waves. LV ejection instigates the genesis of a forward-traveling pressure wave, 76 the magnitude of which depends largely on the ventricular contraction and the elastic properties of the aorta. 77 This pressure wave may be partially reflected from peripheral vessels as it travels down the vascular tree, with the speed and intensity/magnitude of this reflection affected by several hemodynamic factors, including arterial stiffness and physical distance to the peripheral reflection sites (ie, a smaller arteriole, vessel branch point, regional discontinuity in arterial compliance, etc). 78,79 In this manner, increases in forward-and/or backward-traveling waves play a role in determining afterload and PP amplitude via augmentation of systolic pressure. 76 ↑ Arterial stiffness  As the pressure wave travels from the heart to the periphery, both systolic and PP increase markedly, while mean pressures decrease only slightly (∼2 mmHg) due to viscous dampening. 78 Thus, both systolic pressure and PP are greater in the arm and leg than in the ascending aorta. 80 This PP amplification ensures that pulsatile load is lower in central versus peripheral arteries, minimizing excessive cardiac pressure effort and subsequent LV workload. 81 Reduced PP amplification occurs with aging 82, 83 and disease (hypertension, diabetes, hypercholesterolemia, coronary artery disease) 84 and is associated with traditional CV risk factors 84,85 and overall vascular burden. 86 Moreover, PP amplification is associated with overt cTOD 86 and regression of cTOD with therapy (ie, LVH regression with antihypertensive therapy) 87 and independently predicts future CV mortality. 88 Thus, PP amplification has been proposed as a potential mechanical biomarker of CV risk and global arterial function. 88 With an increase in arterial stiffness, as occurs with aging 89 and in the presence of disease, the speed at which the pulse wave travels is increased such that the reflected wave arrives in mid-late systole, augmenting pressure during this phase of the cardiac cycle. 90,91 Reflected waves that arrive during LV ejection increase the mid-to-late systolic workload of the left ventricle. 92

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Arterial stiffness and cTOD because the myocardium appears to be particularly vulnerable to late systolic load. Changes in late systolic pressure are particularly crucial, as animal-based research has shown greater hypertrophy and fibrosis compared to early systolic loading, independent of pressure. 95 In vivo research has demonstrated that cardiac myosin heavy chain synthesis increases approximately 35% within hours after a pressure overload, 96 suggesting that reflection-based increases in afterload may precipitate cardiac remodeling in various clinical populations. 81,97-100 Moreover, chronic pressure wave reflection-based increases in afterload adversely affect coronary perfusion and ventricular function. 78 Wave reflections influence myocardial work during late systole, resulting in greater myocardial stress, 101 a primary determinant of systolic function and myocardial oxygen demand. 102,103 Wave reflections arriving in late systole rather than diastole can impair diastolic function through decreased perfusion time, 104 and are inversely associated with the isovolumetric relaxation period. 105 Furthermore, LV early diastolic velocity, a measure of ventricular relaxation, is strongly associated with late systolic load, 106 which is substantially determined by wave reflections and central arterial stiffness. 107 Wave reflections have been associated with altered ventricular-vascular coupling, 108 and may have sufficient magnitude to directly alter ventricular wall motion. 109 Reflected wave pressure adds to incident wave pressure but subtracts from forward flow, thereby negatively impacting ventricular ejection. 110 Thus, the combination of increased cardiac stress, work, and oxygen demand, together with decreased cardiac perfusion, ejection, and relaxation, has been speculated by some as sufficient to precipitate exertional angina. 103,111 Two primary measures of wave reflection are augmentation index (AIx) and backward/reflected wave pressure (Pb) obtained from wave separation analysis. AIx is a measure of global wave reflections and is typically defined as the ratio of the reflected wave contribution to PP (known as augmentation pressure) relative to PP (Figure 2). 78 AIx is dependent on both the timing of the reflected wave and magnitude, 112 and cannot differentiate between the two. By simultaneously measuring pressure and flow in a vessel (or deriving a pseudo-flow waveform from the contour of the BP waveform), Pb can be measured. This method has been suggested as a more robust measure of pressure attributable to wave reflections (ie, wave reflection magnitude). 113 Recently, Pb and AIx have been shown to be independently predictive of CV events, with Pb further predictive of all CV events and strongly predictive of congestive heart failure development following a median follow-up of 7.61 years. 114 Additional findings suggest that Pb predicts CV mortality independent of conventional risk factors in men and women 115 and highrisk patients, 116 and is associated with hypertensive end organ damage. 116 Moreover, changes in pressure from wave reflections are strong determinants of change in LV mass index following antihypertensive treatment, independent of changes in conventionally measured brachial BP. 87,93,117 Taken together, these findings suggest that pressure from wave reflections with subsequent increases in late systolic load contributes to altered ventricular-vascular coupling, increased LV work, reduced coronary perfusion, and, ultimately, LVH (Figure 1).

Developmental origins of arterial stiffness and cTOD
It is well established that arterial stiffness and pressure from wave reflections increase with advancing age. 118 In fact, it has been posited that one is only as old as his/her arteries. 119 Factors in early adulthood and even childhood may, however, impact vascular and hemodynamic properties in later adulthood, importantly contributing to cTOD long before "old age" sets in. [120][121][122] Our arteries may be the first organ to age, beginning from the moment we are born, and possibly even before we are born. Genomic analysis from the Framingham Heart Study suggests that the heritability of pressure wave reflections and PWV range from approximately 40%-66%. 123,124 Heritability of PWV and AIx were 19% and 41%, respectively, and were significant, in a study of European families. 125 Data from the Strong Heart Family Study revealed statistically significant heritability of arterial stiffness and AIx to range from approximately 18%-23%. 126 Heritability of arterial stiffness has been estimated to be as high as 54% in young African Americans. 127 During prenatal life, if conditions in the intrauterine environment are suboptimal (due to poor maternal diet or other stressors), growth is restricted. The fetus responds by choosing a developmental pathway that will ensure survival given the particular intrauterine environment, and this is known as "fetal programming." 128,129 Fetal programming likely induces morphological and physiological changes that predispose the individual to increased arterial stiffness. [130][131][132][133][134][135] This is extremely important, as elevated arterial stiffness in adolescence is highly associated with LV mass, independent of BP and traditional CVD risk factors. 136 Low birth weight is associated with LV mass in adolescents 137 and with higher arterial stiffness in mid-adulthood. 138 The fetal programming response within blood vessels may lead to increased

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Spartano et al intima-media thickness, smaller arterial diameters, and overall stiffer arteries (possibly due to reduced production of elastin). 134 The life-long consequence of these adaptations is an increased risk for cTOD.

Sex differences in arterial stiffness, wave reflections, and cTOD
Women are more likely than men to present with concentric remodeling, while chamber dilation is more common in men. 139 A potential reason for this has been predicted to be due to sex differences in arterial hemodynamics. 46 Namely, it is well established that women have higher arterial stiffness when compared to age-matched men. 140 Women have larger reflected wave magnitude than men due to their shorter height and reduced distance between the heart and the peripheral reflecting sites. 121,143 Additionally, smaller PP amplifications in women have been reported across studies. 118,141,142 A recent study examined prepubescent children and showed that girls had a significantly higher aortic pulse wave augmentation when compared to boys of the same age and height. 143 This is important, as this study also implies that body height does not account for all sex differences in wave reflections. 143 Given that women have greater pressure from wave reflections compared to men, sex differences in central hemodynamic burden may contribute to greater LV diastolic dysfunction and afterload in women. 142,144,145 Interestingly, associations between arterial stiffness and LV mass may be greater in women compared to men. 146 Similarly, the correlation between AIx and LV diastolic function has also been reported to be greater in women than in men. 147

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Arterial stiffness and cTOD therapy is attenuated in women compared to men, and it has been suggested that this is due to sex differences in arterial stiffness and pressure from wave reflections. 148 Therefore, women may be particularly susceptible to the deleterious effects of increased arterial load from increased arterial stiffness and pressure from wave reflections. 144 Racial differences in arterial stiffness, wave reflections, and cTOD cTOD is not only common but epidemic in African Americans, irrespective of the presence or absence of hypertension. [149][150][151] cTOD occurs earlier in African Americans than in Caucasians and is associated with greater CV mortality in the African American population. 152 African Americans are more susceptible than Caucasians to BP-mediated cTOD. 153 Several studies note increased arterial stiffness, augmented pressure from wave reflections, and lower PP amplification in African Americans. [154][155][156][157][158] Interestingly, these detrimental modulations are directly associated with wasted LV pressure effort, 159,160 increased myocardial work, reduced coronary perfusion, 160 and cTOD, 161,162 even in individuals with brachial BP within accepted normal reference ranges. Racial differences in arterial stiffness manifest at an early age, 163 and subsequent changes in central pressures are associated with LV mass in young African American adolescents. 164

Concluding remarks
Throughout this review, we have discussed the research supporting the utility of aortic PWV and pressure from wave reflections as biomarkers of subclinical cTOD in both sexes, across a wide age range, in different races/ethnicities, and across numerous pathologies. [57][58][59]65 Measuring aortic PWV may also be a useful means of improving CV risk stratification due to its ability to detect early cTOD, which is an important indicator of future CV events. 165 The American Heart Association (AHA) recently reviewed the requirements that must be met to warrant inclusion of novel biomarkers into CV risk assessment. 166 These requirements include: 1) proof of concept; 2) prospective validation; 3) incremental value (adding predictive information to traditional risk markers); 4) clinical utility; 5) clinical outcomes; and 6) cost-effectiveness. 3. Incremental value: aortic PWV provides CV risk prediction value above and beyond established risk factors, which has been demonstrated to improve incremental CV risk stratification. 43,44 4. Clinical utility: improvement of CV risk stratification using aortic PWV allows for reclassification of individuals into higher or lower CV risk categories. 39,43,44 5-6. Clinical outcomes and cost-effectiveness: more research is needed on cost-effectiveness and whether reductions in arterial stiffness lead to a regression in cTOD and decreased risk of morbidity/mortality. 42 Although aortic PWV currently falls short of meeting all requirements as a novel biomarker in CV risk assessment set out by the AHA, current literature evidence supports its use in identifying subclinical cTOD. [57][58][59] Use of this biomarker has the potential to improve CV risk stratification through detection of early cTOD and to provide opportunities for the development of interventions that may prevent and possibly reverse cTOD. Future prospective randomized clinical studies will determine whether improvement in aortic PWV, or another measure of arterial stiffness, will improve clinical outcome and support utility of PWV as an effective biomarker for early detection of cTOD risk.

Disclosure
The authors report no conflicts of interest in this work. For personal use only.