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g [E [E [E [E [E [E [E [E [E & : Arterial structure and function in vascular ageing:
Are you as old as your arteries?
Dick H.J. Thijssen1,2
Sophie E. Carter1
Daniel J. Green1,3
1Research Institute for Sport and Exercise Sciences, Liverpool John Moores University, United Kingdom
2Radboud Institute for Health Sciences, Department of Physiology, Radboud University Medical Center, the Netherlands
3School of Sports Science, Exercise and Health, The University of Western Australia
WORD COUNT: 3,237
ABSTRACT WORD COUNT: 218
FIGURES: 1
Author for correspondence:
Prof. Dick Thijssen, Research Institute of Sport and Exercise Sciences, Liverpool John Moores University, Tom Reilly Building, L3 3AF, Liverpool, United Kingdom.
Email: HYPERLINK "mailto:d.thijssen@ljmu.ac.uk" d.thijssen@ljmu.ac.uk, Tel: +44 151 904 62 64
ABSTRACT
Advancingage may be the most potent independent predictor of future cardiovascular events, a relationship that is not fully explained by time-related changes in traditional cardiovascular risk factors. Since some arteries exhibit differential susceptibility to atherosclerosis, generalisations regarding the impact of ageing in humans may be overly simplistic, whereas in vivo assessment of arterial function and health provide direct insight. Coronary and peripheral (conduit, resistance and skin) arteries demonstrate a gradual, age-related impairment in vascular function that is likely related to a reduction in endothelium-derived nitric oxide bioavailability and/or increased production of vasoconstrictors (e.g. endothelin-1). Increased exposure and impaired ability for defence mechanisms to resist oxidative stress and inflammation, but also cellular senescence processes, may contribute to age-related changes in vascular function and health.Arteries also undergo structural changes as they age. Gradual thickening of the arterial wall, changes in wall content (i.e. less elastin, advanced glycation end-products) and increase in conduit artery diameter are observed with older age and occur similarly in central and peripheral arteries. These changes in structure have important interactive effects on artery function, with increases in small and large arterial stiffness representing a characteristic change with older age. Importantly, direct measures of arterial function and structure predict future cardiovascular events, independent of age or other cardiovascular risk factors. Taken together, and given the differential susceptibility of arteries to atherosclerosis in humans, direct measurement of arterial function and health may help to distinguish between biological and chronological age-related change in arterial health in humans.
Cardiovascular disease (CVD) remains the worlds leading cause of death. Predicting the occurrence of future CVD in apparently healthy asymptomatic subjects remains a major challenge in contemporary cardiovascular medicine. Age is a highly predictive risk factor for future CVD ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_47" \o "Lakatta, 2003 #830" Lakatta & Levy, 2003; HYPERLINK \l "_ENREF_57" \o "Najjar, 2005 #9" Najjar et al., 2005). Several studies have reported that advancing age is associated with increased incidence of coronary heart disease, stroke and heart failure ADDIN EN.CITE Lakatta2003830(Lakatta & Levy, 2003)83083017Lakatta, E. G.Levy, D.Gerontology Research Center, Intramural Research Program, Gerontology Research Center, Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, Baltimore, Md 21224-6825, USA. lakattae@grc.nia.nih.govArterial and cardiac aging: major shareholders in cardiovascular disease enterprises: Part I: aging arteries: a "set up" for vascular diseaseCirculationCirculationCirculationCirculation139-461071Aged*AgingArteries/anatomy & histology/*physiologyArteriosclerosis/epidemiologyBlood PressureCarotid Arteries/anatomy & histology/physiologyDemographyElasticityHumansHypertension/epidemiologyPrevalenceRisk FactorsVascular Diseases/*epidemiologyVasodilation2003Jan 71524-4539 (Electronic)
0009-7322 (Linking)12515756http://www.ncbi.nlm.nih.gov/pubmed/12515756( HYPERLINK \l "_ENREF_47" \o "Lakatta, 2003 #830" Lakatta & Levy, 2003). Consequently, the use of chronological age is of great importance in the prediction of CVD ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_43" \o "Kannel, 1961 #726" Kannel et al., 1961; HYPERLINK \l "_ENREF_96" \o "Wilson, 1998 #815" Wilson et al., 1998; HYPERLINK \l "_ENREF_51" \o "Mahmood, 2014 #8" Mahmood et al., 2014). However, the mechanisms through which older age affects future development of CVD are not fully understood and the extent to which chronological age provides a surrogate for biological age of the vasculature remains obscure. In this review, we pose a number of questions to better understand the impact of chronological and biological age on the development of CVD in humans.
Can we successfully predict cardiovascular events?
Several traditional and novel CV risk factors independently predict the future development of CVD ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_43" \o "Kannel, 1961 #726" Kannel et al., 1961; HYPERLINK \l "_ENREF_96" \o "Wilson, 1998 #815" Wilson et al., 1998; HYPERLINK \l "_ENREF_94" \o "Wang, 2006 #810" Wang et al., 2006; HYPERLINK \l "_ENREF_15" \o "D'Agostino, 2008 #512" D'Agostino et al., 2008) and the combination of some of these risk factors predict future events. For example, the Framingham Risk Score (FRS) uses an algorithm, involving traditional CV risk factors like age, cholesterol, HDL, sex, smoking and systolic blood pressure to calculate the 10-yr prediction of a CV event ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_43" \o "Kannel, 1961 #726" Kannel et al., 1961; HYPERLINK \l "_ENREF_96" \o "Wilson, 1998 #815" Wilson et al., 1998; HYPERLINK \l "_ENREF_51" \o "Mahmood, 2014 #8" Mahmood et al., 2014). A systematic review showed that the sensitivity and specificity of the FRS for future CV events, based on the area under the receiver operator curve, ranged between 0.60-0.86 ADDIN EN.CITE Siontis201213(Siontis, 2012)1313017Siontis, G. C.Tzoulaki, I.Siontis, K. C.Ioannidis, J. P.Department of Hygiene and Epidemiology, University of Ioannina School of Medicine, Ioannina, Greece.Comparisons of established risk prediction models for cardiovascular disease: systematic reviewBMJBmjBMJBmjBMJBmje3318344AlgorithmsCardiovascular Diseases/*diagnosis/*etiologyHumans*Models, TheoreticalPredictive Value of TestsPrognosisROC CurveRisk Assessment20121756-1833 (Electronic)
0959-535X (Linking)22628003http://www.ncbi.nlm.nih.gov/pubmed/2262800310.1136/bmj.e3318( HYPERLINK \l "_ENREF_77" \o "Siontis, 2012 #13" Siontis et al., 2012). This indicates that traditional CV risk factors fail to predict future CVD in a large proportion of cases (up to 50%) ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_56" \o "Naghavi, 2003 #846" Naghavi et al., 2003). To support this view, traditional CV risk factors are poorly related to coronary atherosclerotic plaque burden ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_42" \o "Johnson, 2009 #858" Johnson et al., 2009). Moreover, the observation of a receiver operator curve of only 0.53 in an older cohort of ~85 years ADDIN EN.CITE de Ruijter20091(de Ruijter, 2009)11017de Ruijter, W.Westendorp, R. G.Assendelft, W. J.den Elzen, W. P.de Craen, A. J.le Cessie, S.Gussekloo, J.Leiden University Medical Center, Department of Public Health and Primary Care (V0-P), PO Box 9600, 2300 RC Leiden, Netherlands. w.de_ruijter@lumc.nlUse of Framingham risk score and new biomarkers to predict cardiovascular mortality in older people: population based observational cohort studyBMJBmjBMJBmjBMJBmja3083338Aged, 80 and overBiological Markers/*bloodCardiovascular Diseases/blood/*mortalityCohort StudiesFemaleHumansMaleNetherlands/epidemiologyRisk Assessment/methodsRisk Factors20091756-1833 (Electronic)
0959-535X (Linking)19131384http://www.ncbi.nlm.nih.gov/pubmed/19131384261554810.1136/bmj.a3083( HYPERLINK \l "_ENREF_16" \o "de Ruijter, 2009 #1" de Ruijter et al., 2009) suggests that older age affects the ability of the FRS to predict future CVD using risk factors. The inability to accurately predict future events in individual patients is not specific for a single algorithm, since poor agreement is observed between multiple risk calculators when allocating subjects to risk categories ADDIN EN.CITE Allan2013860(Allan, 2013)86086017Allan, G. M.Nouri, F.Korownyk, C.Kolber, M. R.Vandermeer, B.McCormack, J.Evidence-Based Medicine, Department of Family Medicine, University of Alberta, Room 1706 College Plaza, 8215-112 St NW, Edmonton, Alberta T6G 2C8, Canada. michael.allan@ualberta.caAgreement among cardiovascular disease risk calculatorsCirculationCirculationCirculationCirculation1948-5612719Age FactorsBlood Pressure/physiologyCardiovascular Diseases/*diagnosis/*epidemiology/metabolismCholesterol/bloodCohort StudiesDiabetes Mellitus/diagnosis/epidemiology/metabolismHumansResearch Design/*standardsRisk FactorsSex FactorsSmoking/adverse effects/epidemiology2013May 141524-4539 (Electronic)
0009-7322 (Linking)23575355http://www.ncbi.nlm.nih.gov/pubmed/2357535510.1161/CIRCULATIONAHA.112.000412( HYPERLINK \l "_ENREF_2" \o "Allan, 2013 #860" Allan et al., 2013). Taken together, the relative impact or importance of CV risk factors may differ between populations.
Traditionally, the impact of age on CV risk has been ascribed to the time-dependent accumulation of harmful CV risk factors ADDIN EN.CITE Najjar20059(Najjar, 2005)99017Najjar, S. S.Scuteri, A.Lakatta, E. G.Laboratory of Cardiovascular Science, National Institute on Aging, National Institutes of Health, 5600 Nathan Shock Dr, Baltimore, MD 21224, USA.Arterial aging: is it an immutable cardiovascular risk factor?HypertensionHypertensionHypertensionHypertensionHypertensionHypertension454-62463*AgingAnimalsArteries/*physiopathologyCardiovascular Diseases/*etiologyHumansRisk Factors2005Sep1524-4563 (Electronic)
0194-911X (Linking)16103272http://www.ncbi.nlm.nih.gov/pubmed/1610327210.1161/01.HYP.0000177474.06749.98( HYPERLINK \l "_ENREF_57" \o "Najjar, 2005 #9" Najjar et al., 2005). Nonetheless, older age predicts future CVD independently of other risk factors ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_96" \o "Wilson, 1998 #815" Wilson et al., 1998; HYPERLINK \l "_ENREF_51" \o "Mahmood, 2014 #8" Mahmood et al., 2014), raising the question of direct impacts of ageing per se. Possibly, changes in the structure and function of the vasculature may directly explain age-related changes in CV risk.
What is the impact of older age on vascular function?
Studies that examined the impact of age on vascular function have typically adopted a cross-sectional design, whereby healthy volunteers with a substantial age range were tested. Studies investigating coronary artery peak blood flow response to intracoronary infusion of acetylcholine, an endothelium-dependent dilator, demonstrate a progressive decline of the maximal response with age ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_91" \o "Vita, 1990 #806" Vita et al., 1990). Comparable observations can be made when examining coronary artery dilator responses to other vasoactive substances and/or manipulations ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_99" \o "Zeiher, 1993 #816" Zeiher et al., 1993).
In peripheral vessels, measurement of conduit artery endothelial function using flow mediated dilation (FMD), also demonstrates a progressive decline with age ADDIN EN.CITE Celermajer1994377(Celermajer, 1994)37737717Celermajer, D. S.Sorensen, K. E.Spiegelhalter, D. J.Georgakopoulos, D.Robinson, J.Deanfield, J. E.Hosp Sick Children,Cardiothorac Unit,London,England
Mrc,Biostat Unit,Cambridge Cb2 2bw,EnglandAging Is Associated with Endothelial Dysfunction in Healthy-Men Years before the Age-Related Decline in WomenJournal of the American College of CardiologyJ Am Coll CardiolJ Am Coll CardiolJournal of the American College of CardiologyJ Am Coll CardiolJournal of the American College of Cardiology471-476242atherosclerotic coronary-arterieshormone replacement therapymyocardial-ischemiaheart-diseaseblood-flowestrogenacetylcholineriskmenopausenitroglycerin1994Aug0735-1097WOS:A1994PH37600029<Go to ISI>://WOS:A1994PH37600029English( HYPERLINK \l "_ENREF_11" \o "Celermajer, 1994 #377" Celermajer et al., 1994). The age-related impairment in conduit artery endothelial function has been reported in the brachial ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_11" \o "Celermajer, 1994 #377" Celermajer et al., 1994; HYPERLINK \l "_ENREF_61" \o "Parker, 2006 #1438" Parker et al., 2006; HYPERLINK \l "_ENREF_6" \o "Black, 2009 #77" Black et al., 2009), femoral ADDIN EN.CITE Thijssen20061139(Thijssen, 2006)1139113917Thijssen, D. H.de Groot, P.Kooijman, M.Smits, P.Hopman, M. T.Dept. of Physiology, Radboud Univ. Nijmegen Medical Centre, PO Box 9101, 6500 HB Nijmegen, The Netherlands. M.Hopman@fysiol.umcn.nl).Sympathetic nervous system contributes to the age-related impairment of flow-mediated dilation of the superficial femoral arteryAm J Physiol Heart Circ PhysiolAm J Physiol Heart Circ PhysiolAmerican journal of physiologyH3122-929162006Dec16844924http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=16844924( HYPERLINK \l "_ENREF_85" \o "Thijssen, 2006 #1139" Thijssen et al., 2006) and popliteal ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_61" \o "Parker, 2006 #1438" Parker et al., 2006) arteries. The onset of the age-related decline in conduit artery endothelial function is reported to occur at an earlier stage in males than females ADDIN EN.CITE Celermajer1994377(Celermajer, 1994)37737717Celermajer, D. S.Sorensen, K. E.Spiegelhalter, D. J.Georgakopoulos, D.Robinson, J.Deanfield, J. E.Hosp Sick Children,Cardiothorac Unit,London,England
Mrc,Biostat Unit,Cambridge Cb2 2bw,EnglandAging Is Associated with Endothelial Dysfunction in Healthy-Men Years before the Age-Related Decline in WomenJournal of the American College of CardiologyJ Am Coll CardiolJ Am Coll CardiolJournal of the American College of CardiologyJ Am Coll CardiolJournal of the American College of Cardiology471-476242atherosclerotic coronary-arterieshormone replacement therapymyocardial-ischemiaheart-diseaseblood-flowestrogenacetylcholineriskmenopausenitroglycerin1994Aug0735-1097WOS:A1994PH37600029<Go to ISI>://WOS:A1994PH37600029English( HYPERLINK \l "_ENREF_11" \o "Celermajer, 1994 #377" Celermajer et al., 1994). However, females may exhibit accelerated functional descent after the onset of decline ADDIN EN.CITE Celermajer1994377(Celermajer, 1994)37737717Celermajer, D. S.Sorensen, K. E.Spiegelhalter, D. J.Georgakopoulos, D.Robinson, J.Deanfield, J. E.Hosp Sick Children,Cardiothorac Unit,London,England
Mrc,Biostat Unit,Cambridge Cb2 2bw,EnglandAging Is Associated with Endothelial Dysfunction in Healthy-Men Years before the Age-Related Decline in WomenJournal of the American College of CardiologyJ Am Coll CardiolJ Am Coll CardiolJournal of the American College of CardiologyJ Am Coll CardiolJournal of the American College of Cardiology471-476242atherosclerotic coronary-arterieshormone replacement therapymyocardial-ischemiaheart-diseaseblood-flowestrogenacetylcholineriskmenopausenitroglycerin1994Aug0735-1097WOS:A1994PH37600029<Go to ISI>://WOS:A1994PH37600029English( HYPERLINK \l "_ENREF_11" \o "Celermajer, 1994 #377" Celermajer et al., 1994). Similar observations of an age-related, gradual decline in endothelial function can be observed when examining forearm resistance artery function by intra-arterial infusion of acetylcholine ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_80" \o "Taddei, 1997 #675" Taddei et al., 1997; HYPERLINK \l "_ENREF_79" \o "Taddei, 2001 #792" Taddei et al., 2001; HYPERLINK \l "_ENREF_35" \o "Higashi, 2006 #118" Higashi et al., 2006) and methacholine chloride ADDIN EN.CITE Gerhard1996238(Gerhard, 1996)23823817Gerhard, M.Roddy, M. A.Creager, S. J.Creager, M. A.Vascular Medicine and Atherosclerosis Unit of the Cardiovascular Division, Brigham and Women's Hospital, Boston, MA 02115, USA.Aging progressively impairs endothelium-dependent vasodilation in forearm resistance vessels of humansHypertensionHypertensionHypertension849-53.274AdultAgedAging/*physiologyBlood Vessels/*physiologyEndothelium, Vascular/*physiologyFemaleForearm/blood supplyHumanMaleMiddle AgeSupport, Non-U.S. Gov'tSupport, U.S. Gov't, P.H.S.Vascular Resistance/*physiologyVasodilation/*physiology19968613259http://www.ncbi.nlm.nih.gov/htbin-post/Entrez/query?db=m&form=6&dopt=r&uid=8613259( HYPERLINK \l "_ENREF_31" \o "Gerhard, 1996 #238" Gerhard et al., 1996). Finally, measures of endothelial function in the cutaneous microcirculation provide evidence that older age leads to an impaired microvascular dilation response to local ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_7" \o "Black, 2008 #142" Black et al., 2008; HYPERLINK \l "_ENREF_83" \o "Tew, 2010 #152" Tew et al., 2010) and systemic ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_36" \o "Holowatz, 2003 #1959" Holowatz et al., 2003) heating, but also to local infusion of acetylcholine ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_7" \o "Black, 2008 #142" Black et al., 2008; HYPERLINK \l "_ENREF_83" \o "Tew, 2010 #152" Tew et al., 2010).
Taken together, these studies demonstrate a gradual, age-related decline in vascular function that occurs throughout the vascular tree, ranging from coronary arteries to peripheral conduit, resistance and microvessels in humans. These conclusions are supported by studies that adopt alternative measures of vascular function, such as measures of arterial compliance and stiffness (see later section ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_81" \o "Tanaka, 2000 #544" Tanaka et al., 2000; HYPERLINK \l "_ENREF_55" \o "Moreau, 2003 #931" Moreau et al., 2003)).
Why is vascular function impaired with older age?
Given the potent anti-atherogenic properties of nitric oxide (NO), many studies have explored the role of this vasodilator pathway in explaining age-related loss of vascular function. Some studies have indicated that older age is associated with diminished forearm vasoconstrictor response to infusion of NO-synthase inhibitor NG-monomethyl-L-Arginine (L-NMMA), suggesting reduced NO bioavailability in resistance arteries ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_78" \o "Taddei, 2000 #677" Taddei et al., 2000; HYPERLINK \l "_ENREF_76" \o "Singh, 2002 #782" Singh et al., 2002). Moreover, in older adults, supplementation of L-arginine, the pre-cursor for NO, improves skin blood flow responses to whole body heating ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_37" \o "Holowatz, 2006 #145" Holowatz et al., 2006) and coronary artery blood flow response to acetylcholine ADDIN EN.CITE Chauhan1996157(Chauhan, 1996)157157017Chauhan, AnoopMore, Ranjit S.Mullins, Paul A.Taylor, GedPetch, Michael C.Schofield, Peter M.Aging-Associated Endothelial Dysfunction in Humans Is Reversed by L-ArginineJournal of the American College of CardiologyJ Am Coll CardiolJournal of the American College of Cardiology1796-180428719960735109710.1016/s0735-1097(96)00394-4( HYPERLINK \l "_ENREF_13" \o "Chauhan, 1996 #157" Chauhan et al., 1996). NO mediates a significant component of the FMD-response ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_32" \o "Green, 2014 #602" Green et al., 2014); a measure that is typically reduced with older age. Age-related decreases in tetrahydrobiopterin (BH4) synthesis, an important co-factor in NO production, provides further support for the presence of impairment of the NO-pathway with older age ADDIN EN.CITE Pierce20083547(Pierce & Larocca, 2008)3547354717Pierce, G. L.Larocca, T. J.Department of Integrative Physiology, University of Colorado, Boulder, CO, USA. gpierce@colorado.eduReduced vascular tetrahydrobiopterin (BH4) and endothelial function with ageing: is it time for a chronic BH4 supplementation trial in middle-aged and older adults?J PhysiolJ PhysiolJ PhysiolThe Journal of physiologyJ PhysiolThe Journal of physiology2673-4586Pt 112008/04/05Administration, OralAging/*metabolismAnimalsBiopterin/administration & dosage/*analogs & derivatives/metabolismEndothelium, Vascular/*drug effects/*physiologyNitric Oxide/*metabolismRats2008Jun 11469-7793 (Electronic)
0022-3751 (Linking)18388135http://www.ncbi.nlm.nih.gov/pubmed/18388135253657610.1113/jphysiol.2008.154229eng( HYPERLINK \l "_ENREF_62" \o "Pierce, 2008 #3547" Pierce & Larocca, 2008). Indeed, BH4-supplementation in older humans enhanced brachial artery FMD ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_27" \o "Eskurza, 2005 #1594" Eskurza et al., 2005) as well as the NO-dependent dilation of forearm blood flow responses to acetylcholine ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_35" \o "Higashi, 2006 #118" Higashi et al., 2006). Although previous reports have consistently reported the presence of lower NO bioavailability, somewhat conflicting results have been reported regarding eNOS expression in vascular endothelial cells in older humans ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_20" \o "Donato, 2009 #9554" Donato et al., 2009; HYPERLINK \l "_ENREF_67" \o "Rippe, 2012 #9562" Rippe et al., 2012).
In addition to this focus on impaired vasodilator mechanisms, some studies have explored the impact of older age on vasoconstrictor pathways, in particular endothelin-1 (ET-1). For example, older men exhibit a greater lower limb vasodilation response to ET-receptor blockade, indicative for a greater contribution of ET-1 to vascular tone with age ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_86" \o "Thijssen, 2007 #127" Thijssen et al., 2007). Comparable results were reported for the forearm resistance vascular bed, as older men demonstrate a bunted forearm blood flow response to exogenous ET-1 ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_90" \o "Van Guilder, 2007 #1393" Van Guilder et al., 2007). It was also demonstrated that an increased ET-1 expression in older men was inversely related to endothelial dependent dilation ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_20" \o "Donato, 2009 #9554" Donato et al., 2009). Mechanistically, these changes in the contribution of ET-1 may relate to changes in sensitivity (and/or density) of ETA-receptors (causing vasoconstriction) and/or ETB-receptors (leading to vasodilation). Previous work in animals demonstrated that the augmented vasoconstrictor response to ET-1 in older rats is mediated through an increased ETA-pathway ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_21" \o "Donato, 2005 #612" Donato et al., 2005), whilst other work provided evidence for impairment in the ETB-receptors ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_3" \o "Asai, 2001 #795" Asai et al., 2001). Impaired ETB-receptors may also contribute to higher ET-1 plasma levels since these receptors contribute to ET-1 clearance. Future work is needed to confirm these hypotheses.
In addition to an (age-related) altered endogenous bioavailability of vasoactive substances, impaired vascular function with age may also relate to changes in smooth muscle function. Ultimately, (magnitude of) dilation or constriction of vessels depends on the ability of the smooth muscle cells to alter tone. The capacity of conduit and resistance artery smooth muscle cells to dilate is typically assessed as the dilatory response following sublingual nitroglycerine (GTN) or intra-arterial infusion of sodium nitroprusside (SNP), respectively. A recent meta-analysis demonstrated a small but significant age-related impairment in smooth muscle function in conduit and resistance arteries ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_54" \o "Montero, 2015 #92" Montero et al., 2015). These findings suggest that the age-related impairment in vascular function may, at least partly, be explained by attenuated smooth muscle cell function. A potential mechanistic explanation for this finding may relate to decreased expression of soluble guanylyl cyclase on smooth muscle cells (sGC; the principal receptor of NO and mediating dilation), such as observed in older animals ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_14" \o "Chen, 2000 #9557" Chen et al., 2000; HYPERLINK \l "_ENREF_44" \o "Kloss, 2000 #9556" Kloss et al., 2000).
The mechanisms underlying age-associated vascular dysfunction may relate to increased vascular oxidative stress and inflammation with older age, leading to pro-inflammatory phenotypical changes. In men, ageing is associated with increased endothelial cell oxidative stress and markers of inflammation, both of which are related to the age-related impairment in endothelial function ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_19" \o "Donato, 2007 #9566" Donato et al., 2007; HYPERLINK \l "_ENREF_68" \o "Rodriguez-Manas, 2009 #752" Rodriguez-Manas et al., 2009). Studies in older humans have found increased levels of inflammatory proteins, such as pro-inflammatory nuclear factor- B a n d c y t o k i n e s ( e . g . I L - 6 , T N F - , M C P - 1 ) A D D I N E N . C I T E A D D I N E N . C I T E . D A T A ( H Y P E R L I N K \ l " _ E N R E F _ 1 8 " \ o " D o n a t o , 2 0 0 8 # 9 5 5 9 " D o n a t o e t a l . , 2 0 0 8 ; H Y P E R L I N K \ l " _ E N R E F _ 6 7 " \ o " R i p p e , 2 0 1 2 # 9 5 6 2 " R i p p e e t a l . , 2 0 1 2 ) . A p o t e n t i a l r o l e f o r i n f l a m m a t i o n i n a g e - r e l a t e d c h a n g e s i n v a s c u l a r f u n c t i o n i s p r o v i d e d b y t h e f i n d i n g t h a t i n h i b i t i o n o f n u c l e a r f a c t o r - B i m p r o v e s b r a c h i a l a r t e r y e n d o t h e l i a l f u n c t i o n i n o l d e r i n d i v i d u a l s A D D I N E N . C I T E A D D I N E N . C I T E . D A T A ( H Y P E R L I N K \ l " _ E N R E F _ 6 3 " \ o "Pierce, 2009 #9563" Pierce et al., 2009; HYPERLINK \l "_ENREF_73" \o "Seals, 2011 #9565" Seals et al., 2011). Support for a role of vascular oxidative stress is provided by studies reporting that older humans demonstrate increased markers of oxidative stress (e.g. nitrotyrosine) ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_30" \o "Gano, 2011 #9564" Gano et al., 2011), whilst this marker is inversely related with endothelial function ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_19" \o "Donato, 2007 #9566" Donato et al., 2007). Furthermore, infusion of ascorbic acid (i.e. a reactive oxygen species scavenger) attenuated the impairment in brachial artery FMD ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_26" \o "Eskurza, 2004 #624" Eskurza et al., 2004) and increased acetylcholine-induced vasodilation of the forearm vessels in older adults ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_78" \o "Taddei, 2000 #677" Taddei et al., 2000). The mechanism of increased oxidative stress with older age may relate to elevated levels of reactive oxygen species combined with reduced (or absent compensatory improvements in) antioxidative capacity ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_22" \o "Donato, 2015 #9567" Donato et al., 2015). These data suggest that older age is associated with increased oxidative stress and inflammation that, subsequently, may contribute to the impaired vascular function typically observed in older humans (Figure 1).
Why is vascular function impaired with older age: molecular pathways?
Pathways underlying the development of vascular dysfunction may relate to those involved in senescence ADDIN EN.CITE Kovacic20119571(Kovacic, 2011)9571957117Kovacic, J. C.Moreno, P.Hachinski, V.Nabel, E. G.Fuster, V.The Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai School of Medicine, New York, NY 10029, USA.Cellular senescence, vascular disease, and aging: Part 1 of a 2-part reviewCirculationCirculationCirculation1650-6012315Aging/*genetics/*metabolismAnimalsCell Aging/*geneticsHumansSignal Transduction/geneticsVascular Diseases/*genetics/*metabolism/pathology2011Apr 191524-4539 (Electronic)
0009-7322 (Linking)21502583http://www.ncbi.nlm.nih.gov/pubmed/2150258310.1161/CIRCULATIONAHA.110.007021( HYPERLINK \l "_ENREF_45" \o "Kovacic, 2011 #9571" Kovacic et al., 2011), that is irreversible cell cycle arrest as a result of critically short telomeres or external stress (e.g. oxidative stress, DNA damage), possibly through the p53/p21 pathway ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_25" \o "Erusalimsky, 2009 #9568" Erusalimsky, 2009; HYPERLINK \l "_ENREF_22" \o "Donato, 2015 #9567" Donato et al., 2015). Senescent cells demonstrate an increased rate of apoptosis, impaired proliferation, eNOS inhibition and increases in mediators for inflammation ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_67" \o "Rippe, 2012 #9562" Rippe et al., 2012; HYPERLINK \l "_ENREF_22" \o "Donato, 2015 #9567" Donato et al., 2015). Accumulation of senescent cells have been reported in atherosclerotic lesions ADDIN EN.CITE Minamino20029569(Minamino, 2002)9569956917Minamino, T.Miyauchi, H.Yoshida, T.Ishida, Y.Yoshida, H.Komuro, I.Department of Cardiovascular Science and Medicine, Chiba University Graduate School of Medicine, Chiba, Japan.Endothelial cell senescence in human atherosclerosis: role of telomere in endothelial dysfunctionCirculationCirculationCirculation1541-410513*Cell AgingCells, CulturedCoronary Artery Disease/etiology/*pathologyCoronary Vessels/pathologyEndothelium, Vascular/*pathology/*physiologyHumansIntercellular Adhesion Molecule-1/metabolismNitric Oxide Synthase/metabolismNitric Oxide Synthase Type IIITelomerase/physiologyTelomere/*physiologybeta-Galactosidase/analysis2002Apr 21524-4539 (Electronic)
0009-7322 (Linking)11927518http://www.ncbi.nlm.nih.gov/pubmed/11927518( HYPERLINK \l "_ENREF_53" \o "Minamino, 2002 #9569" Minamino et al., 2002).
Sirtuins, originally linked to metabolic health, may represent an important molecular regulator of vascular ageing ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_12" \o "Cencioni, 2015 #9572" Cencioni et al., 2015; HYPERLINK \l "_ENREF_60" \o "Paneni, 2015 #9570" Paneni et al., 2015). For example, expression of SIRT1 (through p51 and p66Shc) has been linked with protection against oxidative stress-induced cellular senescence/apoptosis, improved NO bioavailability and lower inflammation ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_12" \o "Cencioni, 2015 #9572" Cencioni et al., 2015; HYPERLINK \l "_ENREF_60" \o "Paneni, 2015 #9570" Paneni et al., 2015). Nonetheless, the role of sirtuins in mediating age-related cardiovascular changes is under debate. Other molecular pathways, such as microRNAs and endothelial progenitor cells, may also contribute to the cellular changes with older age. Future studies should explore the potential role of (novel) molecular pathways related to (accelerated) cellular senescence.
What is the impact of older age on vascular structure: wall thickness?
When exploring the impact of older age on the structure of arteries, a common and frequently reported observation is the age-related increase in carotid artery intima-media thickness (IMT) ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_38" \o "Homma, 2001 #1236" Homma et al., 2001; HYPERLINK \l "_ENREF_82" \o "Tanaka, 2001 #678" Tanaka et al., 2001; HYPERLINK \l "_ENREF_88" \o "van den Munckhof, 2012 #55" van den Munckhof et al., 2012; HYPERLINK \l "_ENREF_24" \o "Engelen, 2013 #44" Engelen et al., 2013) (Figure 1). The increase in carotid IMT occurs linearly (~5 m/year) with older age, in both men and women ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_38" \o "Homma, 2001 #1236" Homma et al., 2001; HYPERLINK \l "_ENREF_24" \o "Engelen, 2013 #44" Engelen et al., 2013). Increased blood pressure, by virtue of exerting a greater distending force on the arterial walls, is suggested to importantly contribute to carotid artery thickening ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_82" \o "Tanaka, 2001 #678" Tanaka et al., 2001). To further support this link, 9-month anti-hypertensive treatment significantly decreased carotid IMT, with the magnitude of decrease in IMT being closely related to the decrease in carotid pulse pressure ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_8" \o "Boutouyrie, 2000 #166" Boutouyrie et al., 2000).
Despite the strong scientific focus on the carotid artery, thickening of the arterial wall with age is also observed in upper and lower limb peripheral vessels ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_17" \o "Dinenno, 2000 #359" Dinenno et al., 2000; HYPERLINK \l "_ENREF_34" \o "Green, 2010 #2106" Green et al., 2010; HYPERLINK \l "_ENREF_88" \o "van den Munckhof, 2012 #55" van den Munckhof et al., 2012). Moreover, the magnitude of age-related thickening seems comparable between central and peripheral arteries ADDIN EN.CITE van den Munckhof201255(van den Munckhof, 2012)5555017van den Munckhof, I.Scholten, R.Cable, N. T.Hopman, M. T.Green, D. J.Thijssen, D. H.Department of Physiology, Radboud University Nijmegen Medical Centre, the Netherlands.Impact of age and sex on carotid and peripheral arterial wall thickness in humansActa Physiol (Oxf)Acta physiologicaActa Physiol (Oxf)Acta physiologicaActa Physiol (Oxf)Acta physiologica220-82064AdultAge DistributionAgedAnalysis of VarianceArteries/*pathologyAtherosclerosis/*pathologyFemaleHumansMaleRisk FactorsSex FactorsYoung Adult2012Dec1748-1716 (Electronic)
1748-1708 (Linking)23088509http://www.ncbi.nlm.nih.gov/pubmed/2308850910.1111/j.1748-1716.2012.02457.x( HYPERLINK \l "_ENREF_88" \o "van den Munckhof, 2012 #55" van den Munckhof et al., 2012). This is of particular importance, since the brachial artery is not considered atherosclerosis-prone ADDIN EN.CITE van den Munckhof201255(van den Munckhof, 2012)5555017van den Munckhof, I.Scholten, R.Cable, N. T.Hopman, M. T.Green, D. J.Thijssen, D. H.Department of Physiology, Radboud University Nijmegen Medical Centre, the Netherlands.Impact of age and sex on carotid and peripheral arterial wall thickness in humansActa Physiol (Oxf)Acta physiologicaActa Physiol (Oxf)Acta physiologicaActa Physiol (Oxf)Acta physiologica220-82064AdultAge DistributionAgedAnalysis of VarianceArteries/*pathologyAtherosclerosis/*pathologyFemaleHumansMaleRisk FactorsSex FactorsYoung Adult2012Dec1748-1716 (Electronic)
1748-1708 (Linking)23088509http://www.ncbi.nlm.nih.gov/pubmed/2308850910.1111/j.1748-1716.2012.02457.x( HYPERLINK \l "_ENREF_88" \o "van den Munckhof, 2012 #55" van den Munckhof et al., 2012), suggesting that thickening of the conduit arterial wall represents a systemic effect of ageing per se ADDIN EN.CITE van den Munckhof201255(van den Munckhof, 2012)5555017van den Munckhof, I.Scholten, R.Cable, N. T.Hopman, M. T.Green, D. J.Thijssen, D. H.Department of Physiology, Radboud University Nijmegen Medical Centre, the Netherlands.Impact of age and sex on carotid and peripheral arterial wall thickness in humansActa Physiol (Oxf)Acta physiologicaActa Physiol (Oxf)Acta physiologicaActa Physiol (Oxf)Acta physiologica220-82064AdultAge DistributionAgedAnalysis of VarianceArteries/*pathologyAtherosclerosis/*pathologyFemaleHumansMaleRisk FactorsSex FactorsYoung Adult2012Dec1748-1716 (Electronic)
1748-1708 (Linking)23088509http://www.ncbi.nlm.nih.gov/pubmed/2308850910.1111/j.1748-1716.2012.02457.x( HYPERLINK \l "_ENREF_88" \o "van den Munckhof, 2012 #55" van den Munckhof et al., 2012). To further support a common pathway for arterial thickening, systolic blood pressure (and therefore distending pressure) is positively correlated to brachial, superficial femoral and popliteal IMT ADDIN EN.CITE van den Munckhof201255(van den Munckhof, 2012)5555017van den Munckhof, I.Scholten, R.Cable, N. T.Hopman, M. T.Green, D. J.Thijssen, D. H.Department of Physiology, Radboud University Nijmegen Medical Centre, the Netherlands.Impact of age and sex on carotid and peripheral arterial wall thickness in humansActa Physiol (Oxf)Acta physiologicaActa Physiol (Oxf)Acta physiologicaActa Physiol (Oxf)Acta physiologica220-82064AdultAge DistributionAgedAnalysis of VarianceArteries/*pathologyAtherosclerosis/*pathologyFemaleHumansMaleRisk FactorsSex FactorsYoung Adult2012Dec1748-1716 (Electronic)
1748-1708 (Linking)23088509http://www.ncbi.nlm.nih.gov/pubmed/2308850910.1111/j.1748-1716.2012.02457.x( HYPERLINK \l "_ENREF_88" \o "van den Munckhof, 2012 #55" van den Munckhof et al., 2012), a finding similar to that observed for the carotid artery ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_82" \o "Tanaka, 2001 #678" Tanaka et al., 2001).
What is the impact of older age on vascular structure: diameter?
Conduit artery diameter demonstrates a gradual increase with age in both central ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_72" \o "Schmidt-Trucksass, 1999 #779" Schmidt-Trucksass et al., 1999; HYPERLINK \l "_ENREF_88" \o "van den Munckhof, 2012 #55" van den Munckhof et al., 2012) and peripheral ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_69" \o "Sandgren, 1998 #753" Sandgren et al., 1998; HYPERLINK \l "_ENREF_70" \o "Sandgren, 1999 #765" Sandgren et al., 1999; HYPERLINK \l "_ENREF_89" \o "van der Heijden-Spek, 2000 #801" van der Heijden-Spek et al., 2000; HYPERLINK \l "_ENREF_34" \o "Green, 2010 #2106" Green et al., 2010; HYPERLINK \l "_ENREF_88" \o "van den Munckhof, 2012 #55" van den Munckhof et al., 2012) vessels (Figure 1). In fact, the relative increase in diameter with older age is comparable between central and (lower and upper limb) peripheral vessels ADDIN EN.CITE van den Munckhof201255(van den Munckhof, 2012)5555017van den Munckhof, I.Scholten, R.Cable, N. T.Hopman, M. T.Green, D. J.Thijssen, D. H.Department of Physiology, Radboud University Nijmegen Medical Centre, the Netherlands.Impact of age and sex on carotid and peripheral arterial wall thickness in humansActa Physiol (Oxf)Acta physiologicaActa Physiol (Oxf)Acta physiologicaActa Physiol (Oxf)Acta physiologica220-82064AdultAge DistributionAgedAnalysis of VarianceArteries/*pathologyAtherosclerosis/*pathologyFemaleHumansMaleRisk FactorsSex FactorsYoung Adult2012Dec1748-1716 (Electronic)
1748-1708 (Linking)23088509http://www.ncbi.nlm.nih.gov/pubmed/2308850910.1111/j.1748-1716.2012.02457.x( HYPERLINK \l "_ENREF_88" \o "van den Munckhof, 2012 #55" van den Munckhof et al., 2012). Cross sectional analysis of the common carotid artery demonstrates a 0.017 mm/year increase in those without atherosclerosis, while a 0.03 mm/year increase is observed in those with pre-existing disease ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_23" \o "Eigenbrodt, 2006 #844" Eigenbrodt et al., 2006). In lower limb vessels, popliteal and femoral diameter increases between 22-26% and 12-21% across a ~40 year age span (25-67 years), equivalent to a ~0.5% increase in diameter per year, despite maintenance of a constant body surface area ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_69" \o "Sandgren, 1998 #753" Sandgren et al., 1998; HYPERLINK \l "_ENREF_70" \o "Sandgren, 1999 #765" Sandgren et al., 1999).
The mechanisms behind the age-related increase in diameter are unclear. It is suggested that lumen enlargement is a compensatory adaptation to plaque formation and/or increases in wall thickness, in order to maintain luminal area. Whilst evidence supports the presence of this adaptation in the carotid ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_64" \o "Polak, 1996 #734" Polak et al., 1996; HYPERLINK \l "_ENREF_46" \o "Labropoulos, 1998 #954" Labropoulos et al., 1998) and peripheral ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_46" \o "Labropoulos, 1998 #954" Labropoulos et al., 1998) vasculature, enlargement of lumen diameters can occur in the absence of plaque formation ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_41" \o "Jensen-Urstad, 1999 #719" Jensen-Urstad et al., 1999; HYPERLINK \l "_ENREF_23" \o "Eigenbrodt, 2006 #844" Eigenbrodt et al., 2006), suggesting a compensatory enlargement cannot fully explain the increase in diameter with age. Alternatively, dilation may occur due to age-related loss of elastic fibres ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_89" \o "van der Heijden-Spek, 2000 #801" van der Heijden-Spek et al., 2000), fracturing of the elastic lamellae ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_58" \o "O'Rourke, 2007 #11" O'Rourke & Hashimoto, 2007), and/or as an adaptation to stiffening of the vasculature ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_72" \o "Schmidt-Trucksass, 1999 #779" Schmidt-Trucksass et al., 1999). Especially the age-related loss of elastin may be of particular importance in the observed changes in diameter. With older age, elastin content decreases, elastin elongates and loses some of the elastic recoil properties ADDIN EN.CITE Fritze20129573(Fritze, 2012)9573957317Fritze, O.Romero, B.Schleicher, M.Jacob, M. P.Oh, D. Y.Starcher, B.Schenke-Layland, K.Bujan, J.Stock, U. A.Department of Thoracic and Cardiovascular Surgery, University Hospital Tubingen, Tubingen, Germany.Age-related changes in the elastic tissue of the human aortaJ Vasc ResJ Vasc ResJournal of vascular research77-86491AdultAgedAged, 80 and overAging/*pathology/physiologyAorta/metabolism/*pathologyElastic Tissue/metabolism/*pathologyFemaleHumansImmunohistochemistryLogistic ModelsMaleMiddle AgedMuscle, Smooth, Vascular/pathologyRNA, Messenger/analysisTropoelastin/analysis/genetics20121423-0135 (Electronic)
1018-1172 (Linking)22105095http://www.ncbi.nlm.nih.gov/pubmed/2210509510.1159/000331278( HYPERLINK \l "_ENREF_29" \o "Fritze, 2012 #9573" Fritze et al., 2012). Consequently, arteries rely more on the stiffer collagen in the arterial wall and become somewhat larger.
What is the impact of older age on vascular structure: arterial stiffness?
Early studies demonstrated the impact of older age on pulse wave velocity (a measure reflecting stiffness of the arterial system) ADDIN EN.CITE Avolio19859577(Avolio, 1985)9577957717Avolio, A. P.Deng, F. Q.Li, W. Q.Luo, Y. F.Huang, Z. D.Xing, L. F.O'Rourke, M. F.Effects of aging on arterial distensibility in populations with high and low prevalence of hypertension: comparison between urban and rural communities in ChinaCirculationCirculationCirculation202-10712AdolescentAdultAged*AgingAorta/physiopathologyArteries/*physiopathology*Blood PressureChildChild, PreschoolChinaCholesterol/bloodFemaleHumansHypertension/*physiopathologyInfantMaleMiddle AgedPulseRural PopulationTriglycerides/bloodUrban Population1985Feb0009-7322 (Print)
0009-7322 (Linking)3965165http://www.ncbi.nlm.nih.gov/pubmed/3965165( HYPERLINK \l "_ENREF_4" \o "Avolio, 1985 #9577" Avolio et al., 1985). Subsequent large-scale studies (e.g. Atherosclerosis Risk In Communities, Baltimore Longitudinal Study of Aging) reinforced the observation that older age is independently related to an increase in pulse wave velocity ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_1" \o "AlGhatrif, 2013 #9574" AlGhatrif et al., 2013; HYPERLINK \l "_ENREF_52" \o "Meyer, 2015 #9575" Meyer et al., 2015). Interestingly, a steeper age-related increase in pulse wave velocity may be present in men compared to women ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_1" \o "AlGhatrif, 2013 #9574" AlGhatrif et al., 2013) and/or in the presence of CV risk factors.
The age-related increase in stiffness of (large and smaller-sized) vessels likely result from mechanical factors such as pressure, but also from pressure-independent factors ADDIN EN.CITE Blacher20059576(Blacher & Safar, 2005)9576957617Blacher, J.Safar, M. E.Diagnosis Center, Hopital Hotel-Dieu, Paris, France.Large-artery stiffness, hypertension and cardiovascular risk in older patientsNat Clin Pract Cardiovasc MedNat Clin Pract Cardiovasc MedNature clinical practice450-529Age FactorsArteries/*physiopathologyBlood Flow Velocity/physiologyBlood Pressure/physiologyCardiovascular Diseases/*etiologyElasticityHemorheologyHumansHypertension/complications/*physiopathologyMiddle AgedPulsatile Flow/physiologyRisk FactorsVascular Resistance/*physiology2005Sep1743-4297 (Print)
1743-4297 (Linking)16265585http://www.ncbi.nlm.nih.gov/pubmed/1626558510.1038/ncpcardio0307( HYPERLINK \l "_ENREF_5" \o "Blacher, 2005 #9576" Blacher & Safar, 2005). Recent studies have suggested a potential role for age-related increases in the formation of advanced glycation end-products (AGEs) in the arterial wall that may contribute to vascular dysfunction ADDIN EN.CITE Zieman20042160(Zieman & Kass, 2004)2160216017Zieman, S. J.Kass, D. A.Division of Cardiology, Johns Hopkins Medical Institutions, Baltimore, Maryland 21287, USA. szieman@jhmi.eduAdvanced glycation endproduct crosslinking in the cardiovascular system: potential therapeutic target for cardiovascular diseaseDrugsDrugsDrugsDrugsDrugsDrugs459-70645Cardiovascular Diseases/*drug therapy/*physiopathology/prevention &controlCardiovascular System/*metabolism/physiopathologyGlycosylation End Products, Advanced/adverse effects/antagonists &inhibitors/biosynthesisHumansModels, ChemicalModels, Molecular20040012-6667 (Print)
0012-6667 (Linking)14977384http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=14977384 eng( HYPERLINK \l "_ENREF_100" \o "Zieman, 2004 #2160" Zieman & Kass, 2004). AGEs represent the end-product of a non-enzymatic reaction with sugar derivates that lead to irreversible crosslinks with proteins ADDIN EN.CITE Brownlee19959558(Brownlee, 1995)9558955817Brownlee, M.Diabetes Research Center, Albert Einstein College of Medicine, Bronx, New York 10461, USA.Advanced protein glycosylation in diabetes and agingAnnu Rev MedAnnual review of medicineAnnu Rev Med223-3446AgedAlzheimer Disease/*physiopathologyAnimalsCell Aging/*physiologyCytokines/physiologyDiabetes Mellitus/*physiopathologyExtracellular Matrix Proteins/physiologyGlycosylation End Products, Advanced/*physiologyHumansReactive Oxygen Species/metabolismReceptors, Immunologic/physiology19950066-4219 (Print)
0066-4219 (Linking)7598459http://www.ncbi.nlm.nih.gov/pubmed/759845910.1146/annurev.med.46.1.223( HYPERLINK \l "_ENREF_9" \o "Brownlee, 1995 #9558" Brownlee, 1995). In the arterial wall, AGEs can bind to collagen, leading to changes in the mechanical properties of the vascular wall. However, the exact importance of these glycation end-products on arterial stiffness and function remains somewhat unclear ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_59" \o "Oudegeest-Sander, 2013 #8741" Oudegeest-Sander et al., 2013).
Is there an interaction between vascular function and structure?
Vascular function and structure are often examined as independent characteristics. However, previous work has repeatedly demonstrated that conduit artery diameter is inversely correlated with vasodilator function ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_10" \o "Celermajer, 1992 #184" Celermajer et al., 1992; HYPERLINK \l "_ENREF_75" \o "Silber, 2005 #1404" Silber et al., 2005; HYPERLINK \l "_ENREF_84" \o "Thijssen, 2008 #1693" Thijssen et al., 2008). Whilst frequently reported for the brachial artery, the strong relation between diameter and dilator response is similarly present in different sized and located arteries and the relation remains present after correcting for the shear rate stimulus ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_84" \o "Thijssen, 2008 #1693" Thijssen et al., 2008). The larger dilator response in smaller vessels may result from structural characteristics, since smaller vessels have more smooth muscle relative to elastic laminae, resulting in a larger wall-to-lumen ratio. Supporting this hypothesis, a positive relation was observed between wall-to-lumen ratio and endothelium-dependent and independent vasodilator responses of upper and lower limb vessels ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_87" \o "Thijssen, 2011 #53" Thijssen et al., 2011). The presence of hyper-responsiveness in vessels with increased wall-to-lumen aligns with work of Folkow who, as early as in 1955, calculated that increased wall-to-lumen ratio would enhance vasodilator responsiveness ADDIN EN.CITE Folkow1978519(Folkow, 1978)51951917Folkow, B.The fourth Volhard lecture: cardiovascular structural adaptation; its role in the initiation and maintenance of primary hypertensionClin Sci Mol Med SupplClinical science and molecular medicine. SupplementClin Sci Mol Med SupplClinical science and molecular medicine. SupplementClin Sci Mol Med SupplClinical science and molecular medicine. Supplement3s-22s4AnimalsCardiomegaly/pathologyCoronary CirculationCoronary Vessels/*pathologyDisease Models, AnimalHumansHypertension/*pathology/physiopathologyHypertension, Renovascular/physiopathologyMuscle, Smooth/physiopathologyPressoreceptors/physiologyRatsVascular ResistanceVasomotor System/physiopathology1978Dec0144-4107 (Print)
0144-4107 (Linking)153216http://www.ncbi.nlm.nih.gov/pubmed/153216( HYPERLINK \l "_ENREF_28" \o "Folkow, 1978 #519" Folkow, 1978). Whilst the strong interaction between vascular function and structure is well-established, the impact of the ageing process on this relationship is an area for future investigation.
Do measures of vascular function or structure predict future CV events?
Earlier sections have clearly demonstrated that older age, independent of other CV risk factors, can impact measures of vascular function and structure. Here, we summarise data to better understand whether changes in these vascular characteristics relate to changes in CV risk. Generally, studies have found evidence that measures of endothelial function are strongly related to the future development of CV events. For example, assessment of coronary artery function, either in response to intra-arterial infusion of drugs or in response to a sympathetic stimulus, is predictive for future CVD ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_91" \o "Vita, 1990 #806" Vita et al., 1990; HYPERLINK \l "_ENREF_71" \o "Schachinger, 2000 #4263" Schachinger et al., 2000). Moreover, the predictive value of the coronary artery dilator response to intra-coronary infusion of acetylcholine is independent of traditional CV risk factors ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_71" \o "Schachinger, 2000 #4263" Schachinger et al., 2000). Other measures of the peripheral vasculature, such as central or peripheral vascular stiffness, also demonstrate independent predictive capacity for future CV events ADDIN EN.CITE Vlachopoulos2010107(Vlachopoulos, 2010)107107017Vlachopoulos, C.Aznaouridis, K.Stefanadis, C.Peripheral Vessels Unit, 1st Department of Cardiology, Athens Medical School, Hippokration Hospital, Athens, Greece. cvlachop@otenet.gr <cvlachop@otenet.gr>Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysisJ Am Coll CardiolJournal of the American College of CardiologyJ Am Coll CardiolJournal of the American College of CardiologyJ Am Coll CardiolJournal of the American College of Cardiology1318-275513Aorta/pathology/*physiopathologyCardiovascular Diseases/*mortality/*physiopathologyElasticityHumansPulsatile Flow/*physiologyRisk AssessmentVascular Resistance/*physiology2010Mar 301558-3597 (Electronic)
0735-1097 (Linking)20338492http://www.ncbi.nlm.nih.gov/pubmed/2033849210.1016/j.jacc.2009.10.061( HYPERLINK \l "_ENREF_92" \o "Vlachopoulos, 2010 #107" Vlachopoulos et al., 2010). For example, a 1 m/s increase in aortic pulse wave velocity was related to an age, sex and risk factor adjusted risk elevation of 14%, 15% and 15% for total CV events, CV mortality and all-cause mortality respectively ADDIN EN.CITE Vlachopoulos2010107(Vlachopoulos, 2010)107107017Vlachopoulos, C.Aznaouridis, K.Stefanadis, C.Peripheral Vessels Unit, 1st Department of Cardiology, Athens Medical School, Hippokration Hospital, Athens, Greece. cvlachop@otenet.gr <cvlachop@otenet.gr>Prediction of cardiovascular events and all-cause mortality with arterial stiffness: a systematic review and meta-analysisJ Am Coll CardiolJournal of the American College of CardiologyJ Am Coll CardiolJournal of the American College of CardiologyJ Am Coll CardiolJournal of the American College of Cardiology1318-275513Aorta/pathology/*physiopathologyCardiovascular Diseases/*mortality/*physiopathologyElasticityHumansPulsatile Flow/*physiologyRisk AssessmentVascular Resistance/*physiology2010Mar 301558-3597 (Electronic)
0735-1097 (Linking)20338492http://www.ncbi.nlm.nih.gov/pubmed/2033849210.1016/j.jacc.2009.10.061( HYPERLINK \l "_ENREF_92" \o "Vlachopoulos, 2010 #107" Vlachopoulos et al., 2010). Even measurements of skin microvessel function correlate with FRS, with impaired microvascular function being related to increased CV risk ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_93" \o "Vuilleumier, 2002 #809" Vuilleumier et al., 2002; HYPERLINK \l "_ENREF_39" \o "IJzerman, 2003 #711" IJzerman et al., 2003).
Given the relatively simple procedures, several studies have examined the predictive capacity of the brachial artery FMD and have shown, both in asymptomatic and symptomatic subjects, FMD can predict future CV events ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_98" \o "Yeboah, 2009 #1879" Yeboah et al., 2009; HYPERLINK \l "_ENREF_40" \o "Inaba, 2010 #2187" Inaba et al., 2010; HYPERLINK \l "_ENREF_33" \o "Green, 2011 #2314" Green et al., 2011; HYPERLINK \l "_ENREF_66" \o "Ras, 2013 #6005" Ras et al., 2013; HYPERLINK \l "_ENREF_74" \o "Shechter, 2014 #85" Shechter et al., 2014). Importantly, these studies have typically found that the predictive capacity of the brachial artery FMD is independent of other CV risk factors. Combining brachial FMD with the FRS enhanced CV risk classification compared to the FRS in isolation ADDIN EN.CITE Yeboah20091879(Yeboah, 2009)1879187917Yeboah, J.Folsom, A. R.Burke, G. L.Johnson, C.Polak, J. F.Post, W.Lima, J. A.Crouse, J. R.Herrington, D. M.Department of Internal Medicine/Cardiology, University of Virginia Medical Center, Charlottesville, VA 22908, USA. jy5y@hscmail.mcc.virginia.eduPredictive value of brachial flow-mediated dilation for incident cardiovascular events in a population-based study: the multi-ethnic study of atherosclerosisCirculationCirculationCirculationCirculationCirculationCirculation502-912062009Aug 111524-4539 (Electronic)19635967http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=19635967 eng( HYPERLINK \l "_ENREF_98" \o "Yeboah, 2009 #1879" Yeboah et al., 2009). However, the predictive capacity of the FMD may be reduced in older populations ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_97" \o "Yeboah, 2007 #1805" Yeboah et al., 2007). Age-related stiffening of the arteries and increases in diameter, and consequently attenuated dilator capacity, may contribute to these findings. In fact, the same authors found that brachial artery diameter (but not FMD) demonstrates independent predictive value for future CV events in older adults ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_97" \o "Yeboah, 2007 #1805" Yeboah et al., 2007).
Regarding other structural aspects of conduit arteries, studies have demonstrated that thickening of the arterial wall of carotid and peripheral vessels are both strong independent predictors of future CVD. A large number of studies have demonstrated that increased carotid ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_50" \o "Lorenz, 2006 #38" Lorenz et al., 2006; HYPERLINK \l "_ENREF_48" \o "Lorenz, 2007 #1807" Lorenz et al., 2007; HYPERLINK \l "_ENREF_49" \o "Lorenz, 2010 #2440" Lorenz et al., 2010; HYPERLINK \l "_ENREF_65" \o "Polak, 2010 #735" Polak et al., 2010) and peripheral artery ADDIN EN.CITE ADDIN EN.CITE.DATA ( HYPERLINK \l "_ENREF_95" \o "Weidinger, 2002 #2415" Weidinger et al., 2002) IMT is independently associated with future CV events. Specifically for carotid artery IMT, a meta-analysis showed that a 0.1 mm increase in IMT is associated with an increase in relative risk for myocardial infarction of 10-15% ADDIN EN.CITE Lorenz20071807(Lorenz, 2007)1807180717Lorenz, M. W.Markus, H. S.Bots, M. L.Rosvall, M.Sitzer, M.Johann Wolfgang Goethe-University, Department for Neurology, Schleusenweg 2-16, D-60528 Frankfurt/Main, Germany. matthias.lorenz@em.uni-frankfurt.dePrediction of clinical cardiovascular events with carotid intima-media thickness: a systematic review and meta-analysisCirculationCirculationCirculationCirculationCirculationCirculation459-671154Carotid Arteries/*pathologyCarotid Artery Diseases/*epidemiology/*pathologyHumansMyocardial Infarction/*epidemiologyPredictive Value of TestsRisk FactorsStroke/*epidemiologyTunica Intima/pathologyTunica Media/pathology2007Jan 301524-4539 (Electronic)17242284http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=PubMed&dopt=Citation&list_uids=17242284 eng( HYPERLINK \l "_ENREF_48" \o "Lorenz, 2007 #1807" Lorenz et al., 2007). Taken together, data provide strong evidence that functional and structural characteristics of peripheral and central arteries are strongly related to future CV events in humans.
Vascular health to distinguish biological versus chronological age of arteries?
There is strong evidence that older age leads to a gradual change in vascular function and structure in several arterial beds, by various measures of function. This may explain why chronological age is strongly and independently related to CV risk. However, this does not necessarily inform us about the biological age of vessels. Repeated exposure to potentially harmful stimuli across the lifespan can ultimately lead to between-subject differences in vascular function, structure and health, with consequential dissociation between biological and chronological age. These differences may, in part, relate to inter-individual differences in susceptibility for vascular adaptations and/or atherosclerosis. An integrative measure of vascular structure and function, scaled for chronological age, could conceivably provide better prediction of the true biological age of human arteries.
Conclusion
Advancing age has direct effects on the structure and function of the vasculature. More specifically, older age results in a systemic, gradual loss of vascular endothelial function, possibly due to down-regulation of vasodilator pathways (e.g. NO) and/or up-regulation of vasoconstrictor pathways (e.g. ET-1). Increased oxidative stress and inflammation, possibly the development of cellular senescence and apoptosis, may contribute to age-related impairment in vascular function. Structurally, older arteries demonstrate thicker walls, which are stiffer and exhibit a larger diameter. Importantly, these functional and structural changes represent independent predictors of future CVD. These changes in the vasculature may provide a potential explanation for the age-related increase in CVD risk, especially since traditional risk factors cannot fully explain the impact of age on future CVD. Taken together, given the differential susceptibility of arteries to atherosclerosis and the predictive capacity of measures of vascular function and structure, direct assessment of vascular function and structure may help to distinguish between the biological and chronological age of arteries in humans in vivo.
Funding
Prof. Green is a National Health and Medical Research Council of Australia Principal Research Fellow and holds grants from that agency (APP1045204) and the National Heart Foundation of Australia (NHF G12P6417).
Prof. Thijssen is financially supported by the Netherlands Heart Foundation (E Dekker 2009T064).
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