aging and arterial stiffness

8/3/2019 Aging and Arterial Stiffness

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Circulation Journal Vol.74, November 2010

Circulation Journal

Ofcial Journal o the Japanese Circulation Society

http://www.j-circ.or.jp

rterial walls stien with age. The most consistent andwell-reported changes are luminal enlargement withwall thickening (remodeling) and a reduction o

elastic properties (stiening) at the level o large elasticarteries, namely arteriosclerosis.1 Interestingly, this agingprocess in the arterial tree is heterogeneous, with distal mus-cular arteries not exhibiting these stiening changes, whichis dierent rom the atherosclerotic process.2

The media o large arteries is mainly composed o an inte-grated assembly o vascular smooth muscle cells and elasticand collagen bers, comprising unctional musculoelasticsheets. Cross-links between extracellular matrix componentsand smooth muscle cell – matrix interactions coner adequatemechanical properties.3 The principal structural change withaging is medial degeneration, which leads to progressivestiening o the large elastic arteries. Longstanding arterialpulsation in the central artery has a direct eect on the struc-tural matrix proteins, collagen and elastin in the arterial wall,disrupting muscular attachments and causing elastin bers toatigue and racture.

Accumulation o advanced glycation endproducts (AGE)on the proteins alters their physical properties and causes sti-ness o the bers. Another major change in the arterial wallis calcium deposition. The calcium content o the arterial wallincreases with age, particularly ater the 5th decade, whichmight also contribute to the loss o arterial distensibility.4

Though the struture o the peripheral muscular arteries/ arterioles is only minimally aected by aging, impaired vaso-motor unction associated with endothelial dysunction leadsto thickening o the intima – media layer, and can contributeto peripheral resistance.5,6 Endothelial dysunction is charac-teristic o arterial aging, triggered by a decrease in antioxida-tive capacity and an increase in oxidative stress.7,8

Moreover, Qiu et al recently suggested that, as well aschanges in the extracellular matrix, increased stiness o thevascular smooth muscle cells themselves also mediates aging-associated vascular stiness by increasing adhesion moleculeexpression.9,10

Finally, various comorbid risk actors, which are invariablyhighly prevalent among the elderly, accelerate the atheroscle-rotic process. Age-related changes in the arterial structuremay create a vicious cycle o arterial stiness. Wide pulsepressure is transmitted to other arteries, such as the carotid,which urther aggravates the process o large artery remod-eling to reduce wall stress, leading to intima – media thicken-ing.11

The causes o vascular aging are summarized in Figure 1.

Assessing Arterial Stiness

Several non-invasive methods are currently used to assessvascular stiness.12 Pulse wave velocity (PWV) and the aug-mentation index (AI) are the 2 major non-invasive methodso assessing arterial stiness.

PWV refects the elasticity o the segmental artery. Cardiaccontraction generates a pulse wave, which is propongated dis-tally to the the extremities. PWV is calculated as the distancetraveled by the pulse wave divided by the time taken to travelthe distance.13 Increased arterial stiness results in increasedspeed o the pulse wave in the artery. PWV can be measuredin any arterial segment between 2 regions. Carotid – emoralPWV is considered as the gold standard or assessing centralarterial stiness,14 and is an independent predictor o cardio-vascular mortality and morbidity in elderly subjects,15,16 aswell as in the general population.17,18 However, a relativelyhigh level o skill combined with the need to expose the

Received September 13, 2010; accepted September 14, 2010; released online October 15, 2010

Department o Internal Medicine, Seoul National University College o Medicine, Seoul, Korea

Mailing address: Byung-Hee Oh, MD, PhD, FACC, Department o Internal Medicine, Seoul National University College o Medicine,101 Daehangno, Jongno-gu, Seoul, 110-744, Korea. E-mail: [email protected]

ISSN-1346-9843 doi: 10.1253/circj.CJ-10-0910

All rights are reserved to the Japanese Circulation Society. For permissions, please e-mail: [email protected]

Aging and Arterial StiffnessHae-Young Lee, MD, PhD; Byung-Hee Oh, MD, PhD

Arterial walls stien with age. The most consistent and well-reported changes are luminal enlargement with wallthickening and a reduction o elastic properties at the level o large elastic arteries. Longstanding arterial pulsation

in the central artery causes elastin fber atigue and racture. Increased vascular calcifcation and endothelial dys-

unction are also characteristic o arterial aging. These changes lead to increased pulse wave velocity, especially

along central elastic arteries, and increases in systolic blood pressure and pulse pressure. Vascualar aging is

accelerated by coexsiting cardiovascular risk actors, such as hypertension, metabolic syndrome and diabetes.

Vascular aging is an independent risk actor or cardiovascular disease, rom atherosclerosis to target organ dam-

age, including coronary artery disease, stroke and heart ailure. Various strategies, especially controlling hyper-

tension, show beneft in preventing, delaying or attenuating vascular aging. (Circ J 2010; 74: 2257 – 2262)

Key Words: Aging; Stiness; Vasculature; Hypertension

A

REVIEW




2258 LEE HY et al.

inguinal region are barriers to its wide clinical use. In con-trast, the brachial – ankle PWV is easy to measure and haspotential or screening purposes. In small studies, brachial –ankle PWV was an independent predictor o cardiovasculardeath and events in elderly community dwelling people19 andin patients with coronary artery disease.20 Though brachial – ankle PWV reects not only elastic central arterial stinessbut also muscular peripheral arterial stiness,21 it shows aclose correlation with aortic or carotid – emoral PWV.22 Themain limitation o PWV interpretation is that the PWV issignicantly infuenced by blood pressure (BP). Becauseincreased BP increases the arterial wall tension, thus addingunctional stiening o the arteries, BP becomes a conound-ing variable when comparing the degree o structural arterialstiening. The stiness index,β, can be derived with mini-mal infuence o BP; however,βis a marker o regional andnot segmental arterial stiness.13 Becauseβ is estimated atthe same site o PWV measurement, but with an adjustmentor BP, it cannot be used to obtain segmental arterial stinesswhen the BP diers between the proximal and distal parts o the measured segment. Recently, a new arterial stiness index,the cardio-ankle vascular index (CAVI), has been suggestedas a marker o arterial stiness independent o BP.23 CAVI isderived by measuring PWV and then adjusted by the stinessparameter,β, thus enabling BP-independent measurement o arterial stiness. Indeed, early results show good reproduc-ibility, BP-independence, and risk predictability;24 however,urther studies are warranted or wide acceptance.

AI refects stiness o the systemic arterial tree.25 Thearterial pressure wave is a composition o the orward pres-sure wave arising rom let ventricular ejection and the back-ward (refected) pressure wave. Backward pressure occursmainly as a consequence o wave refection and wave refec-tion is mainly created by impedance mismatch at the branchpoint o the arterial system and very small resistance arteri-oles. The interaction between the orward and refected pulsewaves is assessed by pulse wave analysis and expressed as theAI. The pressure waveorm rom the radial artery is recorded

non-invasively with applanation tonometry, and then theaortic pressure waveorm is derived by a generalized transerunction (Sphygmocor, AtCor, Sydney, NSW, Australia).26 Thereore, central arterial stiness and peripheral refectanceare important determinants o the AI. Normally, the refectedwave arrives at the aortic root during diastole and augmentsthe coronary circulation. Increased stiness o the aortaincreases the aortic PWV and the refected wave returns ear-lier to the aortic root during late systole when the ventricle isstill ejecting blood, adding the refected wave to the orwardwave and augmenting the central systolic pressure. Increasedcentral systolic pressure and pulse pressure result in anincrease in arterial wall stress, progression o atherosclerosisand the development o let ventricular hypertrophy becauseo increased let ventricular aterload.27,28 Early return o therefected wave also causes a decrease in central diastolic pres-sure, resulting in reduced coronary artery perusion pres-sure.29 AI is also infuenced by BP30 and, importantly, byheart rate.31 Though brachial systolic BP is not infuenced byheart rate, central BP is signicantly increased by heart ratereduction, which can be a conounding actor.

Age-Sex Eects on Arterial Stiness

A number o studies have investigated the eects o age onaortic PWV and AI.2,32,33 Most studies suggest a linear, age-related increase in both PWV and AI; however, central AIand aortic PWV do not always show a linear correlation, butrather they are dierentially aected by aging.32 Data roma large cohort o healthy individuals in the Anglo-Cardi Collaborative Trial (ACCT) showed these dierent patternsin age-related changes between central AI and aortic PWV.Changes in AI were more prominent in younger individuals(<50 years), whereas the changes in aortic PWV were moremarked in those older than 50 years. Thereore, central AImight be a more sensitive marker o arterial aging in youngerindividuals, and aortic PWV is more sensitive in those over50 years o age. Similarly, Mitchell et al reported that central

Media & Adventitia:Matrix remodeling:

↓Elastin,↑Collagen,

↑MMPs,↑VSMC,↑ICAM

Endothelial cells:Endothelial dysfunction

↑NADPH oxidase

Intima:↑Atheroma,

Macrophages,

↑Smooth muscle cells

Extrinsic Influences:Hypertension, metabolic syndrome,

Diabetes, etc

Deposition:AGEs, Calcium

Figure 1. Causes o arterial aging.




2259Vascular Aging

AI changes less with age in older individuals and actuallydeclines ater the age o 60 years.2 McEniery et al suggesteda hypothesis or those discrepant responses.32 In youngerindividuals, the rise in augmented pressure is because o anincrease in the magnitude o wave refection rather thanincreased wave velocity, whereas in older individuals, the risein augmented pressure is driven by an earlier return o therefected wave and a less compliant aorta rather than predomi-nant changes in the magnitude o wave refection. Age-relateddilatation usually occurs in large arteriosclerotic arteries,34 thus increasing PWV, but minimally aecting impedance.35,36

Though it is still controversial, there is a reported greaterincrease in aortic stiness with age among women, par-ticularly with the menopause. In particular, AI is higher inwomen than in men by approximately 7% ater menopause, inpart because o women’s shorter height and thereore closerphysical proximity between the heart and refecting sites.2,37 Another report ound a steeper age-related rise in pulse pres-sure among women ater menopause.38 Central PWV alsoincreases more rapidly with age in women than in men,crossing over around the age o 45 years, whereas there is nosignicant dierence across the sexes in emoral PWV.39

Recently, a Korean vascular research working group per-ormed the Korean Arterial Aging Study (KAAS) to deter-mine the eect o aging on the stiness parameters such asAI and PWV in apparently healthy individuals with or with-out CV risk actors.40 That study enrolled 1,750 subjects aged17–87 years (mean, 46.5 years) who were apparently healthyand not taking any medication or hypertension, diabetes ordyslipidemia. We observed the same tendency in the agingand sex eects. In younger ages (age quartile 1 and 2), both

central and peripheral pulse pressures were lower in womenthan in men, but around 45 years, the pulse pressures o thewomen sharply rose, so that in their 50 s and over, womenhad higher pulse pressures than men. The same tendency o a rapid increase was observed in central pulse wave velocity(Figure 2).

Clinical Signifcance o Aging-AssociatedArterial Stiness

Once, the aging-associated changes in arterial structural andunctional changes were thought to be part o normativeagings, but this concept changed when data emerged show-ing that these changes are acclerated with coexistent cardio-vascular disease. For example, patients with hypertension,41 metabolic syndrome,42 or diabetes43 exhibit increased carotidwall thickness and stiness even ater adjusting or age. Andthis ‘accelerated’ arterial aging is well conrmed to be a risk.

Stiening o large arteries results in various adverse hemo-dynamic consequences. Aging-associated arterial stinessleads to a rise in pulse pressure and isolated systolic hyper-tension. Following aging, systolic BP increases linearly,while diastolic BP increases until approximately age 50 thendeclines.44 Mean arterial pressure increases until approxi-mately age 50 then reaches a plateau, while pulse pressure isconstant until approximately age 50 and then increases. Inindividuals over 60 years o age, isolated systolic hyperten-sion aects more than 50%, and results in excess morbidityand mortality. Increased pulsatile pressure and fow stressesextend to the vulnerable microcirculation o vasodilatedorgans, such as the brain and kidneys, and can predispose to

Figure 2. Means o augmentation index, regional pulse wave velocity and pulse pressures by sex and quartile o age (resultsrom the Korean Arterial Aging Study presented at the 23th Scientifc Meeting o International Society o Hypertension, 2010).




2260 LEE HY et al.

cerebral lacunar inarction and albuminuria. Indeed, isolatedsystolic hypertension caused by widening o pulse pressure isthe most common orm o hypertension among the elderly,33 and carries a 3-old increase in the risk o stroke. Moreover,arterial stiness correlates with cognitive unction in the veryelderly over 80 s.45 Elevated systolic BP because o largearterial stiening also promotes let ventricular hypertrophyand ventricular stiening, thus leading to diastolic dysunc-tion and heart ailure, the incidence o which doubles among

isolated systolic hypertensive patients.46,47 In addition, lowdiastolic pressure reduces coronary blood fow, aggravatingthe situation and predisposing to ischemia.

Management o Arterial Aging

There are a large number o studies reporting changes in arte-rial stiness and wave refection ater various interventions,either non-pharmacological or pharmacological.13 Non-phar-macological treatments that are able to reduce arterial sti-ness include exercise training, weight loss, and various dietarymodications, including low-salt diet, moderate alcohol con-sumption, garlic powder,α-linoleic acid, dark chocolate, andsh oil.48 Pharmacological treatments include (1) antihyper-tensive treatment such as diuretics,α-blockers, angiotensin-converting enzyme (ACE) inhibitors, angiotensin-receptorblockers (ARB), and calcium-channel antagonists;49 (2) treat-ment o congestive heart ailure, such as with ACE inhibitors,nitrates,50 and aldosterone antagonists;51 (3) lipid-loweringagents such as statins;52,53 (4) antidiabetic agents, such asthiazolidinediones; 54 and (5) AGE breakers.55

It is still debated whether the reduction in arterial stinessater antihypertensive treatment is only attributable to BPlowering, or i additional BP-independent eects are in-volved.48 However, renin – angiotensin – aldosterone system(RAAS) inhibitors, such as the ACE inhibitors and ARBs,have been widely suggested to have a BP-independent eecton arterial stiness.56–64 Those observations are relevant tothe widely reported brosis-inducing eect o the RAAS. Incontrast,β-blockers has been suggested to be inerior toother classes o drugs in reducing vascular stiness becauseβ-blockers devoid o vasodilating properties are less eec-tive or reducing central pulse pressure and AI than other anti-hypertensive drugs.13 Indeed, non-vasodilatingβ-blockersmay increase vasoconstriction and acilitate the return o wave refection in late systole rather than in diastole, therebyincreasing the AI. All o these actors contribute to an im-pedance mismatch between the heart and the arterial system,raising central pulse pressure in the case o β-blockers.

The roles o arterial stiness and wave refections in themechanisms o central BP reduction in subjects under anti-hypertensive drug therapy might be best demonstrated inthe ASCOT and CAFE studies. In both trials, an ACE inhibi-tor, perindopril, was used with a calcium-channel blocker,amlodipine, and compared with an association o diureticandβ-blockers. In the ASCOT study, amlodipine-based treat-ments proved to be more eective than atenolol-based treat-ments or reducing cardiovascular events.65 The CAFE studyshowed that the reduction in central systolic BP and pulsepressure was higher in the amlodipine- than in the atenolol-based treatment group, despite similar reductions in bothpressures at the brachial level.66

The results o the REASON study (Preterax in Regressiono Arterial Stiness in a Controlled Double-Blind Study),which compared the antihypertensive eects o the very-low-dose combination o indapamide (0.625 mg) and perindopril

(2 mg) with theβ-blocking agent atenolol (50 mg), showed asuperior eect o the ACE inhibitor, perindopril, to atenololin reducing both aortic PWV and wave refections.60 Inthe primary results o 1-year ollow-up or the same diastolicBP reduction, perindopril/indapamide lowered brachial andcarotid systolic BP and thus pulse pressure more than ateno-lol. This dierence was signicantly more pronounced orthe carotid artery than or the brachial artery. Also, the wave-refection changes resulting rom the reduction o peripheral

(arteriolar) refection coecients were the principal actor toconsider in explaining the dierence between atenolol andperindopril/indapamide with regard to systolic BP reduction.

Finally, the eect on central BP reduction by the ARB,olmesartan, in combination with either a calcium-channelblocker or a diuretic was compared in hypertensive patients(mean age, 68.4 years).67 Though brachial systolic BP wassimilar between the 2 groups, the reduction in central systolicBP in the olmesartan/calcium-channel blocker group wassignicantly greater than in the olmesartan/diuretic group.In addition, aortic PWV was signicantly more reduced inthe olmesartan/calcium-channel blocker group. Again, theseresults suggest that the regulating capacity o arterial stinessand wave refections might dier among antihypertensivepatients.

Conclusions

Though arterial walls stien with age, it is not solely nor-mative. Vascular aging is accelerated by the coexistence o cardiovascular risk actors and well conrmed to be a risk actor or cardiovascular disease. Various strategies, espe-cially controlling hypertension, show benet in attenuatingvascular aging. Currently, reducing pulse pressure is the mosteective strategy to prevent arterial stiness and decreasewave refections in elderly patients with systolic hyper-tension. In addition, the roles o newer therapies targeting atbreaking collagen cross-links or preventing their ormationshould be investigated.

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