Cross-Sectional and Longitudinal Assessment of Aortic Root Dilation and Valvular Anomalies in Hypermobile and Classic Ehlers-Danlos Syndrome

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To delineate the prevalence of cardiac findings in hypermobile and classic Ehlers-Danlos syndrome and provide longitudinal analysis of aortic root growth.A retrospective chart review was conducted, and data were analyzed for cross-sectional
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  MINI REVIEWARTICLE published: 15 June 2012doi: 10.3389/fphys.2012.00209 Cross-sectional and longitudinal assessment of arterialstiffening with age in European and Chinese populations WiktoriaWojciechowska  1 ,Yan Li  2  , Katarzyna Stolarz-Skrzypek  1 , Kalina Kawecka-Jaszcz  1 ,JanA. Staessen  3,4  *, Ji-GuangWang  2  and on behalf of the European Project on Genes in Hypertension and the JingNing Study Investigators  1 The First Department of Cardiology and Hypertension, Jagiellonian University Medical College, Kraków, Poland  2  Center for Epidemiologic Studies and ClinicalTrials and Center forVascular Evaluations, Shanghai Key Laboratory of Vascular Biology, Shanghai Institute of Hypertension, Ruijin Hospital, Shanghai Jiaotong University School of Medicine, Shanghai, China  3  Division of Hypertension and Cardiovascular Rehabilitation, Department of Cardiovascular Diseases, Studies Coordinating Centre, University of Leuven, Leuven,Belgium 4  Department of Epidemiology, Maastricht University, Maastricht, Netherlands  Edited by:  Steffen-Sebastian Bolz, University of Toronto, Canada  Reviewed by:  Alun Hughes, Imperial College London, UK Giovanni E. Mann, King’s College London, UK  *Correspondence:  Jan A. Staessen, Laboratory of Hypertension, Studies Coordinating Centre, Campus Sint Rafaël,Kapucijnenvoer 35, Block D, Box 7001, BE-3000 Leuven, Belgium.e-mail:  jan.staessen@;;  As arteries become stiffer with aging, reflected waves move faster and augment late sys-tolic pressure. Few studies have described the age-related changes in both peripheraland central systolic blood pressures in populations.We investigated the age dependencyof peripheral (pSBP) and central (cSBP) systolic pressure and pressure amplification (i.e.,difference between peripheral and central SBP) in randomly selected participants fromEuropean and Chinese populations. Data were collected in 1420 Europeans (mean age,41.7years) and 2044 (mean age, 45.1years) Chinese. In cross-sectional analyses of thepopulation samples cSBP consistently increased more with age than pSBP with the age-related increases being greater in women than men. Repeat assessment of pSBP andcSBP in 398 Europeans and 699 Chinese at a median interval approximately 4years offollow-up confirmed that also within subjects cSBP rose steeper with aging than pSBP.In conclusion, with aging, pSBP approximates to cSBP. This might explain why in oldersubjects pSBP becomes the main predictor of cardiovascular complications. Keywords: aging, central blood pressure, peripheral blood pressure, cardiovascular disease, risk factors, epidemi-ology INTRODUCTION Systolic blood pressure substantially rises with aging across thefull human life span. However,because arteries stiffen with higherage and because of differences in wave travel distance and wavereflections,the age-related increase in systolic blood pressure doesnot occur uniformly across the whole arterial tree (O’Rourke andKelly, 1993). Indeed, during systole, the heart generates a for-ward running pressure wave, which is reflected at various sitesin the peripheral arterial system (O’Rourke and Kelly, 1993). Asthe arteries become stiffer with advancing age, the reflected wavesmay cause an augmentation of late systolic pressure. In additiongeometric changes of the aorta with aging may also contribute toage-related increase in systolic blood pressure (Redheuil et al.,2011). Additionally aortic reservoir function and other elasticchanges markedly with aging, which accounts for the age-relatedchangesintheaorticpressurewaveform(Daviesetal.,2010).Thusaugmentation of systolic blood pressure in the central arteriesincreases with advancing age. Because of this phenomenon, theremight be differences in the age dependency of peripheral systolicblood pressure,as measured at the brachial artery,and central sys-tolic blood pressure, as estimated non-invasively by pulse waveanalysis.Systolicaugmentationisnowagenerallyacceptedphysiologicalconcept. However,the initial evidence supporting the principle of the age dependency of the amplification of the central blood pres-surecamefromanimalexperiments(O’Rourke,1994)andinvasivestudies in selected subjects (Murgo et al., 1980; O’Rourke, 1994). Among the published population studies on the age dependency of arterial stiffness (Avolio et al., 1983, 1985; Wilkinson et al., 2001; Mitchell et al., 2004; McEniery et al., 2005; Li et al., 2008), most focused on pulse wave velocity (Avolio et al., 1983, 1985; Mitchelletal.,2004;McEniery etal.,2005),the ratioof pulsepres- sure in peripheral vs. central arteries (Wilkinson et al., 2001), orthe augmentation index (McEniery et al., 2005; Li et al., 2008) in selected healthy subjects (Wilkinson et al., 2001; Mitchell et al., 2004;McEnieryetal.,2005;Lietal.,2008)andpatientsatincreased cardiovascular risk (McEniery et al., 2008). The predictive valueof central pressure (both measured invasively and non-invasively)was proved in several studies (Roman et al.,2007; Jankowski et al., 2008). We previously reported reference values for the centraland peripheral pulse pressures and augmentation indexes by agein healthy European (Wojciechowska et al., 2006) and Chinese (Li et al., 2008) reference populations. In the present review, wefocused on the changes with age in central and peripheral systolicblood pressures,based on data collected from randomly recruitedEuropean(Wojciechowskaetal.,2012)andChinese(Lietal.,2012) subjects.Theseage-relatedchangeswereassessedcross-sectionally and in a subsample also longitudinally. Only participants without  June 2012 |Volume 3 | Article 209 |  1  Wojciechowska et al. Age-related arterial stiffening antihypertensive drug treatment were included in all analyses toavoid confounding by blood pressure lowering medications. CROSS-SECTIONALSTUDIES Peripheral and central blood pressures were assessed among 1420participants [731 women (51.5%) and 278 (19.6%) hypertensivepatients] in Europe and 2044 [1066 women (52.2%) and 556(27.2%) hypertensive patients] in China (Wojciechowska et al.,2012; Li et al., 2012). In cross-sectional analyses of both populations, the periph-eral and central systolic blood pressures increased with age (  p   fortrend ≤ 0.01;  Figure 1  for Europe; Wojciechowska et al., 2012). Insingleregressionanalysis,thecross-sectionallyassessedage-relatedincrease in central systolic blood pressure was larger than that inperipheral systolic pressure both in women and in men. Addi-tionally, in a subanalysis of the Chinese sample, systolic bloodincreased more with age in the central than peripheral arteries inwomenbelowage50(1.21vs.1.01mmHgperyear;  p  < 0.001)andin men below age 60 (0.73 vs. 0.48mm Hg per year;  p  < 0.001),whereas in older women (0.64 vs. 0.58mmHg per year;  p  = 0.27)andoldermen(0.45vs.0.44mmHgperyear;  p  = 0.79),theslopesof central and peripheral systolic blood pressures on age weresimilar (Li et al., 2012).Our cross-sectional observations are in agreement with knownphysiologic concepts and also in line with several previously pub-lished cross-sectional population studies (Wilkinson et al., 2001;McEniery et al., 2005; Mitchell et al., 2010), including the Anglo- Cardiff Collaborative Trial (ACCT; McEniery et al., 2005). McE- niery et al. (2005) studied 4001 healthy,normotensive individuals,aged 18–90years. In both women and men, central systolic pres-sure increased more with age than did peripheral systolic bloodpressure(  p  < 0.001).Asinourcurrentcross-sectionalanalyses,theincreaseincentralsystolicpressurewasmoreprominentinwomenthan men (  p  = 0.01). These consistent results were obtained basedon White European populations with a western life style, highprevalence of obesity, and relatively high cholesterol levels. Wecannotsimplyextrapolatethemtootherethnicitiesorpopulationswithdifferentlifestyles.However,ourfindingsweresimilarinleanAsian people, who generally have lower serum cholesterol levels.Stiffeningof thelargearteriesunderliestheage-relatedincreaseinsystolicbloodpressure(Staessenetal.,1990).Thelossof arterialelasticity over a person’s life time is partly due to cyclic stress onthe arterial wall with each heart beat (O’Rourke and Hashimoto,2007). Over time, this causes fracture of elastin fibers, so thatstress is transferred to the more rigid collagenous components of the arterial wall. At a young age, the aorta and proximal arter-ies dilate by approximately 10% with each heart beat, whereasthe more distal muscular arteries dilate by only 2–3% with eachheartbeat(Boutouyrieetal.,1992).Atherosclerosisandinflamma- tion thicken the arterial wall and contribute to arterial stiffeningover and beyond the mechanical stress. To differentiate naturaldegeneration of the arterial wall from aging from disease, Avo-lio et al. (1983) highlighted the interest of studies of arterialproperties in population studies with low cholesterol and low prevalence of atherosclerosis,such as Chinese. Avolio et al. (1985)contrastedtheChineselivinginareaswithlowandhighprevalenceof hypertension, Guangzhou (4.9%) and Beijing (15.6%),respectively. In Guangzhou subjects, pulse wave velocity was con-sistently lower in the aorta, arm, and leg, and increased to a lesserdegree with age, compared with Beijing subjects (Avolio et al.,1985). The contemporary cholesterol levels were 4.34mmoll − 1 in Guangzhou subjects and 4.49mmoll − 1 in Beijing subjects. Inour Chinese population, cholesterol levels were of similar mag-nitude (4.73mmoll − 1 ), but the prevalence of hypertension wasmuch higher (27.2%). Our current observations strengthen Avo-lio’s hypothesis (Avolio et al., 1983, 1985) that slowly progressing degeneration of the arterial wall through cyclic stress is the maincause of the age-related increase in systolic blood pressure.The slopes of peripheral and central systolic blood pressureson age were consistently steeper (  p  < 0.001) in women than inmen in both studied populations (Li et al., 2012; Wojciechowska etal.,2012).Intheyoungandmiddle-agedsubjects,theage-relatedincrease in systolic blood pressure ran a steeper course in womenthan men. At all ages, women have a higher heart rate than men(Smulyan et al., 2001). The smaller height of women may be a cardiovascular risk factor, because of the early return of reflectedwaves to the central aorta in systole. The shorter stature of womenalso implies reduced length of the arterial tree,a factor believed tobe responsible for the faster heart rate, a shorter diastolic period,a shorter diastolic time constant,and at the same peripheral resis-tance, lower arterial compliance (Smulyan et al., 2001). In older women, menopause might contribute to the continuing rise insystolic blood pressure, although it is difficult to differentiate theeffects of aging from those of estrogen deprivation (Casiglia et al.,2008). LONGITUDINALASSESSMENTOFAGE-DEPENDENTCHANGESINARTERIALTREE In European study 208 women (24.4%) and 190 men (27.6%),underwent a repeat arterial examination at a median intervalof 4.79years (5th–95th percentile interval, 3.96–5.98years (Woj-ciechowska et al.,2012). In the Chinese study 369 women (34.6%)and 330 men (33.7%) underwent a repeat assessment of periph-eral and central systolic blood pressure at a median interval of 3.60years (5th–95th percentile interval, 3.56–3.96years; Li et al.,2012). In the longitudinal analyses, all changes from baseline tofollow-up were significant (  p  ≤ 0.039). In the Caucasian popu-lations, the annual increases in the peripheral and central systolicbloodpressuresaveraged0.91and1.06mmHginwomen,and1.24and 1.47mmHg in men. The  p  -values for the sex differences were0.12and0.08,respectively(Wojciechowskaetal.,2012).InChinesepopulationperipheralsystolicpressureincreasedmore(  p  ≤ 0.025)thanthecentralsystolicpressurebothinwomen(2.35vs.2.12mmHg)andinmen(1.37vs.1.16mmHg).Onarelativescale,theper-centage increases in peripheral and central systolic blood pressurefrom baseline to follow-up were similar in women (2.14 vs. 2.16%per year;  p  = 0.76), as well as in men (1.33 vs. 1.34% per year;  p  = 0.96;). In sensitivity analyses stratified by quartiles of the agedistribution,the increase in peripheral systolic blood pressure waslarger than that in central systolic blood pressure (  p  ≤ 0.02) abovemedianageinwomenandabovethe75thpercentileof ageinmen,whereasinall othersex–agesubgroups,theincreasesof peripheraland central systolic pressures were similar (  p  ≥ 0.08;  Figure 2 ; Liet al., 2012). Frontiers in Physiology  |Vascular Physiology  June 2012 |Volume 3 | Article 209 |  2  Wojciechowska et al. Age-related arterial stiffening FIGURE 1 | European population.  Association with age of peripheral andcentral systolic blood pressures  (A,B) , peripheral, and central non-augmentedsystolic blood pressures  (A,B) , pressure amplification  (C,D) , and peripheraland central systolic augmentation  (E,F)  in women  (A,C,E)  and men  (B,D,F) .Peripheral systolic blood pressure was the average of three blood pressurereadings at the brachial artery. Central systolic blood pressure was themaximum pressure of the central waveform. Systolic augmentation wasobtained by subtracting the first systolic peak from systolic blood pressure.Pressure amplification is peripheral minus central systolic blood pressure.Plotted values are means for each age group. Numbers indicate the subjectscontributing to the group means. All  p  -values for trend with age werestatistically significant ( p  < 0.0001). Significance of the difference with zero:* p  < 0.05 and  † p  < 0.001. Reproduced with permission from Blood PressureJournal.  June 2012 |Volume 3 | Article 209 |  3  Wojciechowska et al. Age-related arterial stiffening FIGURE 2 | Chinese population.  Peripheral and central SBPs at baseline andfollow-up by quartiles of the age distribution in 369 women  (A)  and 330 men (B) . All  p  -values for trend with age were statistically significant ( p  < 0.0001).Significance of the difference between baseline and follow-up: * p  < 0.05, ‡ p  < 0.01, and  † p  < 0.001. Reproduced with permission from HypertensionResearch Journal. In an early Framingham report, Kannel and Gordan (1978)noticed that the age-related increase in systolic blood pressure wassteeperoncross-sectionalthanlongitudinalassessmentinwomen,whereas the opposite was the case in men. The reasons for thedifference in BP trends obtained cross-sectionally and longitudi-nallyinthesameFraminghamcohortwerenotclear.Onepossibleexplanation is that subjects at the higher end of the distributionof systolic blood pressure are more likely to experience cardio-vascular complications or die, and therefore to disappear fromfollow-up. The unmeasured attrition in our populations availablefor cross-sectional analysis might have contributed to the largerestimates of the age-related increase in systolic blood pressure inthe longitudinal analyses. CONCLUSION The effects of aging on arterial function have often beenunderestimated, because of the sole reliance on the brachialcuff systolic pressure. With aging, peripheral systolic bloodpressure approximates to the central systolic blood pressure.These findings support the point of view that age-related stiff-ness of arteries represents a vicious circle, in which increas-ing systolic blood pressure is, at the same time, the causeand the consequence of a self-sustaining process that leadsto major cardiovascular complications. Breaking the viciouscircle is the key to slowing the age-related rise in systolicblood pressure and preventing the associated cardiovascularcomplications. REFERENCES Avolio, A. P., Chen, S. G., Wang, R. P.,Zhang,C.L.,Li,M.F.,andO’Rourke,M. F. (1983). 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Res. 29, 475–483.Wojciechowska, W., Stolarz-Skrzypek,K., Tikhonoff, V., Richart, T., Sei-dlerová, J., Cwynar, M., Thijs, L.,Li, Y., Kuznetsova, T., Filipovský, J.,Casiglia, E., Grodzicki, T., Kawecka-Jaszcz, K., O’Rourke, M., Staessen, J.A., and European Project on Genesin Hypertension (Epogh) Investiga-tors.(2012).Agedependencyof cen-tral and peripheral systolic bloodpressures: cross-sectional and lon-gitudinal observations in Europeanpopulations.  Blood Press.  21, 58–68. Conflict of Interest Statement:  Theauthors declare that the research wasconducted in the absence of any com-mercial or financial relationships thatcould be construed as a potential con-flict of interest. Received: 20 February 2012; accepted:28 May 2012; published online: 15 June 2012.Citation: Wojciechowska W, Li Y,Stolarz-Skrzypek K, Kawecka-Jaszcz K,Staessen JA, Wang J-G and on behalf of  the European Project on Genes in Hyper-tension and the JingNing Study Inves-tigators (2012) Cross-sectional and lon-gitudinal assessment of arterial stiffen-ing with age in European and Chinese  populations. Front. Physio.  3  :209. doi:10.3389/fphys.2012.00209 This article was submitted to Frontiers in Vascular Physiology, a specialty of  Frontiers in Physiology.Copyright © 2012 Wojciechowska,Li, Stolarz-Skrzypek, Kawecka-Jaszcz,Staessen, Wang and on behalf of  the European Project on Genes in Hypertension and the JingNing Study Investigators. This is an open-access article distributed under the terms of  the Creative Commons Attribution Non Commercial License, which permits non-commercial use, distribution, and reproduction in other forums, provided the srcinal authors and source are credited.  June 2012 |Volume 3 | Article 209 |  5
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