Review article
Central arterial aging and the epidemic of systolic hypertension and atherosclerosis

https://doi.org/10.1016/j.jash.2007.05.001Get rights and content

Abstract

The structure and function of central arteries change throughout the lifetime of humans and animals. Since atherosclerosis and hypertension are prevalent in epidemic proportion among older persons, it is reasonable to hypothesize that specific mechanisms that underlie the arterial substrate that has been altered by an “aging process” are intimately linked to arterial diseases. Indeed, recent studies reveal a profile of arterial cell and matrix properties that emerges with advancing age within the grossly normal appearing aortic wall of both animals and humans. This profile is proinflammatory, and is manifested by intimal infiltration of fetal cells, increased production of angiotensin II (Ang II)-signaling pathway molecules, eg, matrix metalloproteases (MMPs), and monocyte chemoattractant protein (MCP-1), transforming growth factor B1 (TGF-β1), enhanced activation of MMPs, TGF-β, and NADPH oxidase, and reduced nitric oxide (NO) bioavailability. This profile is similar to that induced at younger ages in experimental animal models of hypertension or atherosclerosis. In humans, this proinflammatory state, which occurs in the absence of lipid deposition, appears to be attributable to aging, per se. Other well known human risk factors, eg, altered lipid metabolism, smoking, and lack of exercise, interact with this arterial substrate that is altered by aging and render the aging human artery fertile soil for facilitation of the initiation and progression of arterial diseases. Therapies to reduce or retard this age-associated proinflammatory state within the grossly appearing arterial wall central arteries, in addition to slowing arterial aging, per se, may have a substantial impact on the quintessential age-associated arterial diseases of our society.

Introduction

The structure and function of central arteries change throughout the lifetime of humans and animals. These changes include lumenal dilation, diffuse intimal and medial thickening, increased stiffness, reduced compliance, and endothelial dysfunction. Although such changes in arterial structure and function that accompany advancing age were previously thought to be part of normative aging, this concept was challenged when data emerged showing that these changes are accelerated in the presence of cardiovascular diseases. The nature of age-disease interactions is complex and involves mechanisms of aging, multiple defined arterial disease risk factors, and as yet undefined risk factors, eg, those that may have a genetic basis. While epidemiologic studies have discovered that some aspects of lifestyle are risk factors for hypertension or atherosclerosis, age, per se, confers the major risk (Figure 1).

A steady stream of incremental knowledge indicates that the central arterial wall is more complex in nature than inert material. Indeed, it is a marvel with respect to its regulatory mechanisms and its ability to adapt, repair, and remodel, through the integration of multiple signaling mechanisms. This plasticity of the arterial wall, or its failure, ultimately governs the macroscopic structural and mechanical properties of central arteries in health and disease. The mechanical properties of the central arteries, and of their walls, how these properties relate to arterial impedance and blood flow, and how they become altered in arterial diseases or aging has long been a major focus of investigation. But, in addition to these macroscopic descriptions of how central arteries age, the elucidation of cellular and molecular mechanisms that underlie arterial aging of age-associated alterations in central arterial structure and function in health is essential to unravel age-disease interactions, and to target the specific characteristics of arterial aging that render it such a major risk factor for arterial diseases, eg, hypertension and atherosclerosis (Figures 2A and B), leading to myocardial infarction and stroke (Figures 2C and D), and to heart failure (Figure 2E).

Recent evidence has emerged to indicate that a proinflammatory profile of the central arterial wall generated by smooth muscle and endothelial cells (ECs) that become reprogrammed with advancing age,1 and is involved in this diffuse increase in arterial thickening and stiffening. This profile is not, ipso facto, attributable to subclinical atherosclerosis as it is presently defined, but rather is a pari passu a manifestation of arterial remodeling that occurs over time with advancing age in animals as well as humans. A “megacept” emerges with the realization that these age-associated changes within the arterial wall are strikingly similar to the inflammatory state created in younger animals by experimental induction of early atherosclerosis or hypertension. Thus “aging” and these “diseases” are fundamentally intertwined at the cell and molecular levels. However, a dilemma arises as to whether this arterial proinflammatory state that emerges during aging is a set-up for arterial diseases, or whether arterial aging, like atherosclerosis or hypertension, should be referred to as a disease. Thus, we have a microscopic “replay” of the dilemma posed long ago, based upon macroscopic arterial properties, ie, is aging muted arterial “disease” or is arterial “disease” accelerated aging? In this regard, a recent hypothesis suggests the interaction of aging and disease properties, ie, age-associated cellular and molecular changes render the aging arterial wall a fertile substrate for atherosclerosis and hypertension.2 Thus, novel therapies with a primary endpoint to retard arterial aging may achieve secondary goals of reducing the incidence and severity of these arterial diseases.

This review provides a landscape of central arterial aging and “age-disease” interactions by attempting to integrate perspectives that range from humans to molecules. The piece begins by illustrating what has been gleaned from noninvasive, macroscopic measures of central arterial structure and function in humans of a broad age range. The action then shifts to the examination of the status of these apparent age-associated changes within central arteries in the context of what the biomedical community has come to refer to as “arterial diseases,” eg, atherosclerosis, hypertension, diabetes, and metabolic syndrome. The first part closes with a delineation of risks for future clinical cardiovascular events that are posed by age-disease-associated alterations in central arterial walls. Arterial aging is then examined under the microscope, by reviewing recent and novel insights about cellular and molecular changes within the central arterial wall that accompany aging in the absence of clinical disease. Finally, thoughts are provoked regarding interventions aimed primarily at reducing or retarding arterial aging, a concept that has not yet been fully integrated into the therapeutic mainstream of clinical medicine.

The structure and function of central arteries change throughout the lifetime of humans2, 3, 4, 5, 6, 7, 8 and have previously been comprehensively reviewed.9 Table 1 summarizes the changes in central macroscopic arterial structural and functional properties with aging.

Cross-sectional studies show that central elastic arteries dilate with age, leading to an increase in lumen size5 (Figure 3A). Post mortem studies have indicated an age-associated increase in arterial wall thickening, which is caused mainly by an increase in intimal thickening (Figure 3B).10 In cross-sectional studies, in vivo, carotid intimal-medial thickening increases nearly 3-fold between the ages of 20 and 90 years6 (Figure 3C). Note in Figure 3C that not only the average intimal-medial thickness increases with advancing age, but that the range of values of intimal-medial thickness is greater at higher ages, indicating heterogeneity among older individuals in the magnitude of the process that underlies the age-associated thickening.

The age-associated intimal-medial thickening observed in humans is often ascribed to “subclinical” atherosclerosis.11 This idea has become so ingrained that intimal-medial thickening is considered a surrogate measure of atherosclerosis. However, intimal-medial thickening, which is usually measured in areas devoid of atherosclerotic plaque,6 is only weakly associated with the extent and severity of coronary artery disease.12 Furthermore, findings in rodent and non-human primate models of aging13, 14, 15 clearly indicate that intimal-medial thickening is an age-related process that is separate from atherosclerosis, because atherosclerosis is absent in both of these animal models (see the following text). Thus, excessive intimal-medial thickening is not necessarily synonymous with early or subclinical atherosclerosis.

ECs play a pivotal role in regulating several arterial properties, including vascular tone, permeability, angiogenesis, and the response to inflammation. Several features of these arterial properties undergo age-associated alterations in function. Endothelial-derived substances (eg, nitric oxide [NO], endothelin-1) modulate arterial structure and function. In brachial or coronary arteries, endothelial function, as assessed by agonist- or flow-mediated vasoreactivity, has been shown to decline with advancing age8 (Figure 4) in the absence of clinical disease. The impairment of endothelial-mediated vasodilatation with aging in humans can, in part, be reversed by L-arginine administration, suggesting that NO production becomes reduced with aging.16 Plasma levels of asymmetric dimethyl arginine, which reduces NO synthase (NOS) activity, also increase with age in humans.16 The effect of age on endothelial function in central arteries, however, has not been directly assessed in humans without clinical disease. The association of changes in large artery arterial stiffness or compliance (see the following text) with changes in endothelial-derived substances17 likely results from structural changes, resulting from deficits in NO signaling that occurs over time.

The increase in arterial wall thickening and reduction in endothelial function with advancing age are accompanied by an increase in arterial stiffening and a reduction in compliance, due to numerous structural changes in the arterial wall.18 Arterial distensibility depends on intrinsic structural properties of the blood vessel wall that determine pressure with a corresponding change in volume.

With each systolic contraction of the ventricle, a propagating wave that is generated in the arterial wall travels centrifugally down the arterial tree, slightly preceding the luminal flow wave generated during systole. The velocity of propagation of this wave is proportional to the stiffness of the arterial wall. The velocity of the pulse wave in vivo is determined not only by the intrinsic stress/strain relationship (stiffness) of the vascular wall, but also by the smooth muscle tone, which is reflected by the mean arterial pressure.

The availability of non-invasive measures of the velocity of this pulse wave allow for large-scale epidemiological studies. Pulse wave velocity has been measured in subjects rigorously screened for the absence of overt or silent cardiovascular disease7 and in other populations with varying degrees of prevalence of cardiovascular disease.19 In all studies, a significant age-associated increase in pulse wave velocity has been observed in both men and women (Figure 5A). Of note, in contrast to central arteries, the stiffness of muscular arteries does not increase with advancing age.19 Thus, the manifestations of arterial aging may vary among the different vascular beds, reflecting differences in the structural compositions of the arteries and, perhaps, differences in the age-associated signaling cascades that modulate the arterial properties (see the following text), or differences in the response to these signals across the arterial tree.

In addition to the forward pulse wave, each cardiac cycle generates a reflected wave, originating at areas of arterial impedance mismatch, which travels back up the arterial tree toward the central aorta. Reflected wave alters the arterial pressure waveform. The pressure pulse augmentation provided by the early return of the reflected wave is an added load against which the ventricle must contract.

The velocity of the reflected flow wave is proportional to the stiffness of the arterial wall. Thus, in young individuals whose vascular wall is compliant, the reflected wave does not reach the large elastic arteries until diastole. With advancing age and increasing arterial stiffening, the velocity of the reflected wave increases, and the wave reaches the central circulation earlier in the cardiac cycle, during the systolic phase. This reflected wave can be noninvasively assessed from recordings of the carotid20 or radial21 arterial pulse waveforms by arterial applanation tonometry and high-fidelity micromanometer probes. Inspection of the recorded arterial pulse wave contour often shows an inflection point, which heralds the arrival of the reflected wave (Figure 5B, inset). The height from the inflection point to the peak of the arterial waveform is the pressure pulse augmentation that is due to the early arrival of the reflected wave. Dividing this augmentation by the height from the peak to the trough of the arterial waveform (corresponding to the pulse pressure) yields the augmentation index.22 The augmentation index, like the pulse wave velocity, increases with age7, 20 (Figure 5B).

Because reflected waves originate, in part, in small arteries, the age-associated changes in this index are also probably determined, in part, by age-associated changes in the structure and function of these small arteries,23 and, in part, by age-associated alterations in the structure and function of large elastic arteries. Although attention has been focused on the transmission velocity of reflected waves as an index of arterial stiffness, the reflected wave is markedly modulated, in part, by NO,24 which affects smaller arteries. Evaluation of the diastolic decay of pulse wave contour may provide valuable insight into the characteristics and the pathology of more distal vessels, in which reflected waves originate.24 In some peripheral tissues in which the pulse pressure is not adequately buffered, eg, kidney, brain, and heart, an increase in central arterial stiffness may lead to an increase in the stiffness of small arteries.25, 26 This may account, in part, for the increased renal resistance and reduced renal blood flow in older persons with increased central arterial stiffness but without defined renal disease.

The relationship between the steady and pulsatile components of flow and the resulting pressure wave in the aorta defines the aortic input impedance. The impedance modulus (the ratio of oscillatory pressure and flow) is usually considered in the frequency domain, eg, as the power spectrum of the pressure-flow relation (Figure 6A). The zero frequency impedance modulus (the peripheral vascular resistance [PVR]) is the opposition to steady flow, and the average of impedance moduli of the frequency-dependent terms above those that encompass the heart rate, referred to as the characteristic aortic impedance, is the opposition to pulsatile flow.27, 28 Fluctuations of the impedance modulus about this mean level are determined by reflected pulse waves. The phase relationship between flow and pressure waves varies with frequency. Aging is associated with an increase in the characteristic aortic impedance (Figure 6B), greater fluctuations about the mean value (Figure 6C), and a shift of the characteristic impedance spectrum with the minimum impedance modulus and the pressure flow phase crossover occurring at higher frequencies.28, 29, 30 An increase in the PVR (the zero-frequency impedance term) occurs with aging in some but not all persons usually. Usually, those older individuals in whom predominantly systolic hypertension does not occur are spared from an increase in PVR. It is noteworthy in this regard that increases in aortic stiffness and characteristic aortic impedance can occur in the absence of a substantial increase in PVR.31, 32, 33, 34

In addition to structural properties, arterial stiffness and impedance in vivo are determined by vascular smooth muscle cell (VSMC) contractile tonus, which is controlled, in part, by neurohumoral factors, eg, catecholamines and angiotensin.35, 36, 37, 38, 39 Vascular tonus is regulated, in part, by VSM cell Ca2+ balance. Increased arterial stiffness in older persons can be reduced by the vasodilator nitroprusside,31 suggesting that a component of the increased in vivo arterial stiffening with aging relates to augmented VSM tone of small arteries, and its effect on reflected pulse waves.

During exercise in younger humans, the aortic input impedance does not appear to increase, probably due to an increase in the aortic diameter.40 The effect of age on vascular impedance during exercise has not been studied in humans. However, in the canine model, it has been observed that aortic impedance, which does not vary with age at rest,41 increases over a wide range of exercise stress in 10- to 12-year-old beagle dogs but not in l- to 3-year-old dogs. Although changes in the passive stiffness characteristics of the aorta in both dog42 and human, as noted in the preceding text, are an apparent cause of an increased aortic impedance, age differences in autonomic modulation of VSMC might also play a role. Thus, in the presence of β-adrenergic blockade effected by propranolol, aortic impedance increased during exercise in younger dogs, and the age-associated differences in impedance seen during exercise in the absence of propranolol were abolished.41

Arterial pressure is determined by the interplay of central arterial compliance, peripheral resistance, and stroke volume (SV). A decline in central arterial compliance accompanies the age-associated increase in arterial wall stiffness, but neither peripheral resistance nor SV change appreciably with advancing age in those who remain normotensive.22 Unfortunately, this normotensive status occurs in only about 30% of older persons (Figure 7A).2 As central arteries stiffen with aging, their diameter increases, which decreases wall strain during each cardiac cycle. Moreover, the combination of arterial wall stiffening and early return of the reflected waves widens the pulse pressure. Indeed, a high systolic blood pressure (BP) generates a similar distention of hardened capacitance vessels, while a lower diastolic BP results, in part, from a reduced storage capacity of the aorta in systole. Thus, pulse pressure, is a useful hemodynamic marker of the central arterial stiffness, increases with age (Figure 7B). While an age-associated increase in mean arterial pressure contributes to the age-associated increase in central arterial stiffness, the latter is largely due to multiple changes intrinsic to the arterial wall that result from aging, per se, in most societies worldwide.

Age-associated changes in the structure, size, and reactivity of the arterial bed affect myocardial performance by their contributions to the vascular impedance to left ventricular (LV) ejection. Because pulsatile ascending aortic pressure and flow fluctuate around mean values, the total arterial load the LV must overcome to eject blood includes several components: frequency-dependent dynamic elastic components related to the characteristic aortic impedance (Figure 6B), reflective components related to reflected pulse waves (Figure 6A), as well as frequency-independent static-resistive components determined by PVR.30 In other words, the LV load is affected not only by aortic distensibility and arteriolar caliber but also by reflected waves from arterial reflecting sites. Changes in these components individually or in any combination affect ventricular ejection and function.43, 44, 45, 46 Properties intrinsic to the aorta permit the characteristic aortic impedance to be least over a range of frequencies (−3 to 7 Hz) (Figure 6A) in which the energy of the flow wave is greatest, and this favorable matching permits pulsatile ejection of blood to occur at a minimal energy expenditure, eg, only −10% of total ventricular work.28

Chronic abnormalities in aortic distensibility such as those associated with advancing age, as described in the preceding text, create a chronic mismatch between ventricular ejection and aortic flow energies.27 It has been suggested that earlier wave reflection in older individuals, caused by increase in pulse wave velocity due to arterial stiffening,28 would be expected to increase the LV hydraulic load more than would an increase in characteristic impedance alone.27, 28, 30 However, since most LV ejection takes place in early systole, the magnitude of the load imposed by late systolic augmentation is controversial. In any event, the increases in arterial stiffness and in PVR, when these occur, with aging,29 via their effect to change the aortic impedance spectrum, result in an age-associated increase in arterial loading of the heart.29, 30

The increased arterial loading of the myocardium with aging appears to be a major cause of the increase in cardiac myocyte size that occurs with aging,47, 48 leading in some older individuals to an increase in LV wall thickness.5, 49, 50 Stroke work index, measured as the product of arterial pressure and SV index, increases with age in normotensive men,32, 34 due largely to the increase in systolic pressure, but in some older individuals, in part, to an increase in SV as well. When measurements from normotensives and hypertensives of a given age range are analyzed concurrently, the aortic elastic modulus and cardiac mass index are highly correlated.51 Additionally, in hypertensives a reduction in arterial distensibility correlates with the increase in LV mass-to-volume ratio. In pondering the association between peripheral arterial pressure and heart mass, which is influenced by the aortic pressure, it is important to recall that the amplification of arterial pressure from the aorta to peripheral arterial sites that normally occurs in younger individuals does not occur or is markedly blunted in older individuals.27, 30 Hence, identical brachial arterial pressures measured in a younger and an older individual indicate a higher aortic pressure in the older individual.

Theoretically, an acute increase in arterial impedance is accompanied by an acute reduction in SV. This has been observed experimentally.28 A chronic reduction in SV has also been observed in some older vs. younger individuals in whom aortic impedance has been quantified.29 In contrast, other studies in which arterial stiffness, pulse wave velocity, and systolic arterial pressure (and presumably aortic impedance) increase with age indicate that resting SV is preserved in older men, as is the ejection fraction (EF). Thus, a normal SV and EF (at rest) can be maintained in the presence of aortic stiffening in some older men. Preservation of SV is enabled via chronic myocardial adaptations, which include a mild augmentation of cardiac size at end diastole and modest myocardial wall thickening to reduce wall stress, and prolonged Ca2+ activation of the myofilaments, permitting a prolonged myocardial force-bearing capacity following excitation.

The blunted increase in EF during exercise (eg, EF reserve)52, 53 suggests age-associated differences in the shift of the arterial-ventricular coupling ratio and its components during exercise. Age-associated differences in Ea/ELV occur in both genders during exercise. In both genders, Ea/ELV decreases during exercise (because ELV increases more than Ea), but the ratio declines to a lesser extent in older subjects. There are gender differences in the components of Ea/ELV during exercise: Ea is greater in older vs. young women but is unaffected by age in men. ELV increases to a greater extent in young vs. older subjects. Thus, suboptimal ventricular-vascular coupling helps to explain the age-associated blunting of maximal exercise EF, and its underlying mechanisms appear to differ between men and women.

Section snippets

Hypertension

Age-associated endothelial dysfunction, arterial stiffening, and intimal-medial thickening are risk factors for arterial diseases, even after accounting for other risk factors, such as arterial pressure, plasma lipids, smoking, etc. Patients with hypertension exhibit increased central arterial wall thickness, greater carotid wall thickness54 and central pressure augmentation55 than normotensive subjects, even after adjusting for age. They are thought to have larger central arterial diameters,56

Matrix

The close association of elastin, collagen, and smooth muscle in the mammalian aortic media results in viscoelastic properties that account for many of its static and dynamic mechanical features. The arrangement and interrelation of the structural components of the aorta are demonstrated in the classic studies of Wolinsky and Glagov.99, 100, 101 At physiological distending pressures, aortic elastin and collagen fibers and smooth muscle cells form well defined layers: thick elastin bands form

MMPs

Increased MMP-2 activity is a candidate mechanism for age-associated arterial remodeling and a potent risk factor for vascular diseases with advancing age.13, 14, 15 Dedifferentiated VSMCs and ECs are capable of producing significant activation of MMP-2.165 Both in vitro and in vivo studies in rodents suggest that VSMC migration is dependent on MMP-2 activity, which is regulated by the phenotypic state of VSMCs, and increases as these cells undergo the transition from a quiescent and

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