Table Of ContentEARLY VASCULAR AGING
(EVA)
This book has been officiallyendorsed by the
European Society of Hypertension (ESH)
EARLY
VASCULAR
AGING
(EVA)
New Directions in
Cardiovascular Protection
Edited by
P M. N MD P D
ETER ILSSON H
ProfessorofCardiovascularResearch,
DepartmentofClinicalSciences,LundUniversity,Ska˚neUniversityHospital,Malmo¨,Sweden
M H. O MD P D
ICHAEL LSEN H
ProfessorinHypertension,
UniversityofSouthernDenmark,and
DepartmentofEndocrinology,
OdenseUniversityHospital,Odense,Denmark
S ´ L MD P D
TEPHANE AURENT H
ProfessorofPharmacology,
HoˆpitalEurope´enGeorgesPompidou,andParisDescartesUniversity,Paris,France
AMSTERDAM(cid:129)BOSTON(cid:129)HEIDELBERG(cid:129)LONDON
NEWYORK(cid:129)OXFORD(cid:129)PARIS(cid:129)SANDIEGO
SANFRANCISCO(cid:129)SINGAPORE(cid:129)SYDNEY(cid:129)TOKYO
AcademicPressisanimprintofElsevier
AcademicPressisanimprintofElsevier
125,LondonWall,EC2Y5AS
525BStreet,Suite1800,SanDiego,CA92101-4495,USA
225WymanStreet,Waltham,MA02451,USA
TheBoulevard,LangfordLane,Kidlington,OxfordOX51GB,UK
Copyrightr2015ElsevierInc.Allrightsreserved.
Nopartofthispublicationmaybereproducedortransmittedinanyformorbyanymeans,electronic
ormechanical,includingphotocopying,recording,oranyinformationstorageandretrievalsystem,without
permissioninwritingfromthepublisher.Detailsonhowtoseekpermission,furtherinformationaboutthe
Publisher’spermissionspoliciesandourarrangementswithorganizationssuchastheCopyrightClearanceCenter
andtheCopyrightLicensingAgency,canbefoundatourwebsite:www.elsevier.com/permissions.
ThisbookandtheindividualcontributionscontainedinitareprotectedundercopyrightbythePublisher
(otherthanasmaybenotedherein).
Notices
Knowledgeandbestpracticeinthisfieldareconstantlychanging.Asnewresearchandexperiencebroaden
ourunderstanding,changesinresearchmethods,professionalpractices,ormedicaltreatmentmaybecomenecessary.
Practitionersandresearchersmustalwaysrelyontheirownexperienceandknowledgeinevaluatingandusingany
information,methods,compounds,orexperimentsdescribedherein.Inusingsuchinformationormethodstheyshouldbe
mindfuloftheirownsafetyandthesafetyofothers,includingpartiesforwhomtheyhaveaprofessionalresponsibility.
Tothefullestextentofthelaw,neitherthePublishernortheauthors,contributors,oreditors,assumeanyliability
foranyinjuryand/ordamagetopersonsorpropertyasamatterofproductsliability,negligenceorotherwise,
orfromanyuseoroperationofanymethods,products,instructions,orideascontainedinthematerialherein.
ISBN:978-0-12-801387-8
BritishLibraryCataloguing-in-PublicationData
AcataloguerecordforthisbookisavailablefromtheBritishLibrary
LibraryofCongressCataloging-in-PublicationData
AcatalogrecordforthisbookisavailablefromtheLibraryofCongress
ForinformationonallAcademicPresspublications
visitourwebsiteathttp://store.elsevier.com/
TypesetbyMPSLimited,Chennai,India
www.adi-mps.com
Publisher:MicaHaley
AcquisitionEditor:StacyMasucci
EditorialProjectManager:ShannonStanton
ProductionProjectManager:Luc´ıaPe´rez
Designer:MariaIneˆsCruz
List of Contributors
Enrico Agabiti-Rosei Clinica Medica, Department of Panagiotis I. Georgianos Section of Nephrology and
Clinical and Experimental Sciences, University of Brescia, Hypertension, 1st Department of Medicine, AHEPA
Brescia,Italy Hospital, Aristotle University of Thessaloniki,
TinedeBacker HeymansInstitute of Pharmacology,Ghent Thessaloniki,Greece
University, Ghent, Belgium; Cardiovascular Center, Isabel Gonc¸alves Experimental Cardiovascular Research
UniversityHospitalGhent,Ghent,Belgium Unit, Department of Clinical Sciences, Lund University,
Malmo¨, Sweden; Department of Cardiology, University
Luc van Bortel Heymans Institute of Pharmacology, Ghent
HospitalofSka˚ne,Malmo¨/Lund,Sweden
University,Ghent,Belgium
Pierre Boutouyrie Department of Pharmacology, Hoˆpital Dagmara Hering Department of Hypertension and
Europe´en Georges Pompidou (cid:1) Assistance Publique Diabetology, Medical University of Gdansk, Gdansk,
Hoˆpitaux de Paris, Paris, France; Institut National de la Poland
Sante´ et de la Recherche Me´dicale—INSERM U970, Paris, Jens Jordan Institute of Clinical Pharmacology, Medical
France;Universite´ Paris-Descartes,Paris,France SchoolHannover,Hannover,Germany
Michel Burnier Service of Nephrology and Hypertension, Vasilios Kotsis Hypertension Centre of Excellence, 3rd
UniversityHospital,Lausanne,Switzerland Department of Internal Medicine, Papageorgiou Hospital,
Mark Caulfield William Harvey Research Institute, NIHR AristotleUniversityThessaloniki,Thessaloniki,Greece
Biomedical Research Unit in Cardiovascular Disease at Michaela Kozakova Department of Clinical and
BartsQueenMaryUniversityofLondon,UK ExperimentalMedicine,UniversityofPisa,Pisa,Italy
PascalChallande Universite´ PierreetMarieCurie,CNRS— Roel J. van de Laar Department of Internal Medicine,
UMR7190,Paris,France Maastricht University Medical Centre, Maastricht, The
Pedro G. Cunha Center for the Research and Treatment of Netherlands
Arterial Hypertension and Cardiovascular Risk, Internal Patrick Lacolley Institut National de la Sante´ et de la
Medicine Department, Guimara˜es—Centro Hospitalar do Recherche Me´dicale—INSERM U116; Universite´ de
AltoAve/MinhoUniversity,Guimara˜es,Portugal;Lifeand
Lorraine,Nancy,France
Health Science Research Institute (ICVS), School of Health
Je´re´my Lagrange Institut National de la Sante´ et de la
Science,UniversityofMinho,Braga,Portugal;ICVS/3B’s—
Recherche Me´dicale—INSERM U116; Universite´ de
PT Government Associate Laboratory, Braga/Guimara˜es,
Lorraine,Nancy,France
Portugal
Edward G. Lakatta Laboratory of Cardiovascular Science,
Stephanie Debette Department of Neurology, University
IntramuralResearchProgram,BiomedicalResearchCenter,
Hospital of Bordeaux, and Center for Epidemiology and
NationalInstituteonAging,NIH,Baltimore,MD,USA
Public Health—INSERM U897, University of Bordeaux,
France; Department of Neurology, Boston University Irene Lambrinoudaki Medical School, University of
SchoolofMedicine,Boston,MA,USA Athens,Athens,Greece
Andreas Edsfeldt Experimental Cardiovascular Research Ste´phane Laurent Department of Pharmacology, Hoˆpital
Unit, Department of Clinical Sciences, Lund University, Europe´en Georges Pompidou (cid:1) Assistance Publique
Malmo¨, Sweden; Department of Cardiology, University Hoˆpitaux de Paris, Paris, France; Universite´ Paris-
HospitalofSka˚ne,Malmo¨/Lund,Sweden Descartes,Paris,France;InstitutNationaldelaSante´ etde
laRechercheMe´dicale—INSERMU970,Paris,France
Isabel Ferreira Department of Clinical Epidemiology and
Medical Technology Assessment, and CARIM School for Yimin Lu Service of Nephrology and Hypertension,
Cardiovascular Diseases, Maastricht University Medical UniversityHospital,Lausanne,Switzerland
Centre, Maastricht, The Netherlands; School of Public Carmel M. McEniery Department Experimental Medicine
Health,UniversityofQueensland,Brisbane,Australia and Immunotherapeutics, University of Cambridge,
Stanley S. Franklin Heart Disease Prevention Program, Cambridge,UK
Division of Cardiology, University of California, Irvine,
Krzysztof Narkiewicz Department of Hypertension and
CA,USA
Diabetology, Medical University of Gdansk, Gdansk,
FrejFyhrquist MinervaInstitute,Helsinki,Finland Poland
ix
x
LISTOFCONTRIBUTORS
Jan Nilsson Experimental Cardiovascular Research Unit, Giuseppe Schillaci Department of Medicine, University of
DepartmentofClinicalSciences,LundUniversity,Malmo¨, Perugia, Perugia, Italy; Unit of Internal Medicine, Terni
Sweden UniversityHospital,Terni,Italy
Peter M. Nilsson Department of Clinical Sciences, Lund Arno Schmidt-Truksa¨ss Department of Sport, Exercise and
University,Ska˚neUniversityHospital,Malmo¨,Sweden Health, Sport and Exercise Medicine, University of Basel,
Juan E. Ochoa Department of Cardiovascular Neural and Basel,Switzerland
Metabolic Sciences, S. Luca Hospital, IRCCS Istituto Angelo Scuteri Hospital San Raffaele Pisana, Istituti di
AuxologicoItaliano,Milan,Italy RicoveroeCuraaCarattereScientifico(IRCCS),Rome,Italy
Michael H. Olsen Cardiovascular and Metabolic Patrick Segers IBiTech-bioMMeda, iMinds Medical IT,
Preventive Clinic, Department of Endocrinology, Center GhentUniversity,Gent,Belgium
for Individualized Medicine in Arterial Diseases, Odense
Thomas Sehestedt Department of Cardiology, Herlev
University Hospital, Odense, Denmark; Hypertension
Hospital,Copenhagen,Denmark
in Africa Research Team, School for Physiology,
NutritionandConsumerSciences,North-WestUniversity, Shweta Shukla Laboratory of Cardiovascular Science,
Potchefstroom,SouthAfrica Intramural Research Program, Biomedical Research
Carl J. O¨stgren Department of Medical and Health Center, National Institute on Aging, NIH, Baltimore, MD,
USA
Sciences,Linko¨pingUniversity,Linko¨ping,Sweden
Trine K. Sønder Heymans Institute of Pharmacology and
Carlo Palombo Department of Surgical, Medical,
Complications Research, Ghent University, Ghent,
Molecular and Critical Area Pathology, University of
Belgium;StenoDiabetesCenter,Gentofte,Denmark
Pisa,Pisa,Italy
Ulrike M. Steckelings Department of Cardiovascular and
Gianfranco Parati Department of Health Sciences,
Research, Institute of Molecular Medicine, University of
University of Milano-Bicocca, Milan, Italy; Department
SouthernDenmark,Odense,Denmark
of Cardiovascular Neural and Metabolic Sciences, S.
Luca Hospital, IRCCS Istituto Auxologico Italiano, Coen D.A. Stehouwer Department of Internal Medicine
Milan, Italy and Cardiovascular Research Institute (CARIM),
Veronique Regnault Institut National de la Sante´ et de la Maastricht University Medical Centre, Maastricht, The
Recherche Me´dicale—INSERM U116; Universite´ de Netherlands
Lorraine,Nancy,France Costas Tsioufis 1st Department of Cardiology, Athens
Meixia Ren William Harvey Research Institute, Centre for MedicalSchool,HippokrationHospital,Athens,Greece
Clinical Pharmacology, Queen Mary University of Charalambos Vlachopoulos Hypertension Unit and
London,UK Peripheral Vessels Unit, 1st Department of Cardiology,
Ernst Rietzschel Departments of Cardiovascular Diseases Athens Medical School, Hippokration Hospital, Athens,
& Public Health, Ghent University, Ghent, Belgium; Greece
Department of Cardiology, Ghent University Hospital, Mingyi Wang Laboratory of Cardiovascular Sciences
Ghent,Belgium BiomedicalResearchCenter,Baltimore,MD,USA
DamianoRizzoni ClinicaMedica,DepartmentofClinicaland Thomas Weber Cardiology Department, Klinikum Wels-
ExperimentalSciences,UniversityofBrescia,Brescia,Italy Grieskirchen,Wels,Austria
Paolo Salvi Department of Cardiovascular Neural and Kate Witkowska William Harvey Research Institute,
Metabolic Sciences, S. Luca Hospital, IRCCS Istituto CentreforClinicalPharmacology,QueenMaryUniversity
AuxologicoItaliano,Milan,Italy ofLondon,UK
Pantelis A. Sarafidis Department of Nephrology, Panagiotis Xaplanteris Hypertension Unit and Peripheral
Hippokration Hospital, Aristotle University of Vessels Unit, 1st Department of Cardiology, Athens
Thessaloniki,Thessaloniki,Greece MedicalSchool,HippokrationHospital,Athens,Greece
Preface
We welcome the reader to this book on different invite the reader to contribute to the lively discussion
aspects of Early Vascular Aging (EVA), a concept that on EVA with data from different populations and eth-
has attracted considerable attention since it was first nic groups, as well as with data from basic and clinical
described in 2008. A number of skilled authors have science. This could contribute to early detection of at-
contributed to provide a multifaceted description of risk individuals, for example, from at-risk families
the pathophysiological and clinical aspects that are with early onset cardiometabolic disease, for preven-
associated with EVA. Previous research has for dec- tion based on improved life style as well as drug ther-
ades described and investigated atherosclerosis, a pro- apy when needed. This is not to deny the importance
cess that starts in the intima layer of the arterial wall of atherosclerosis and the evidence-based methods that
and becomes proximal to many cardiovascular events exist to prevent cardiovascular events by control of
caused by athero-thrombotic disease. As the core com- hypertension and hyperlipidemia as well as smoking
ponent of EVA is arterial stiffness, arteriosclerosis, cessation, but we consider that EVA is a feature start-
which is mainly influenced by morphological changes ing early in life and that later in life components of
in the arterial media layer, but also in other layers, we arteriosclerosis and atherosclerosis will be intertwined
have focused on different characteristics and mechan- in further promotingcardiovasculardiseaserisk.
isms associated with stiffness of the large elastic arter- In an historical perspective, the interest in arterial
ies. We also consider EVA based on an integrated function and stiffness contributing to hemodynamic
view linking the macro- with the microcirculation. changes predates the clinical measurement of blood
This is because hemodynamic forces influenced by pressure and diagnosis of hypertension as we know it.
stiffness may also cause harm to the peripheral smaller In London, the physician Fredrik Akbar Mahomed car-
vessels due to the increased pulsatile energy that is ried out studies on pulse wave properties in arteria
transmitted, for example, in the brain. Another aspect radialis with his own sphygmograph and published in
of a more integrated approach identifies important 1877:
contributing factors for EVA also from the intima
(endothelial dysfunction) and the adventitia (impaired Itisverycommontomeetwithpeopleapparentlyingood
function of vasa vasorum and innervation, accompanied health who have no albumen in the urine, who constantly
by increased secretion of cytokines from the perivascu- presentaconditionofhigharterialtensionwhenexaminedby
theaidofthesphygmograph.[1]
lar adipose tissue causing local inflammation) when
impaired glucose metabolism could further contribute
We therefore date the interest in large arteries and
to stiffening by glycosylation. Therefore, we consider
stiffness to an era before clinical hypertension was rec-
EVA to be a fruitful scientific concept to promote
ognized [2], and thus the EVA concept [3(cid:1)5] attempts
research on early changes of the arterial wall, pro-
to bridge more than a century to revive the importance
grammed already in utero and early life and influenced
of large arteries and their properties in cardiovascular
by genetic and environmental factors. As meta-
medicine.
analyses have documented that arterial stiffness
(increased aortic pulse wave velocity, aPWV) is an
independent risk marker for future cardiovascular risk Peter M. Nilsson
and total mortality, adjusted for conventional risk fac- Malmo¨,Sweden
tors, we consider it of importance to find new ways to
MichaelH.Olsen
find, diagnose, and treat subjects with signs of EVA.
Odense,Denmark
Still however,neither an exact definition nor atargeted
treatment exists for EVA, but several attempts are Ste´phane Laurent
being made to find such alternatives. We therefore Paris,France
xi
xii
PREFACE
FrederickH.H.AkbarMahomed(c.1849(cid:1)1884),arterialstudies ScipioneRiva-Rocci(1863(cid:1)1937),measurementofsystolicblood
pressure
References
[5] Nilsson PM, Boutouyrie P, Cunha P, Kotsis V, Narkiewicz K,
[1] MahomedFA.Remarksonarterio-capillaryfibrosisanditsclini- ParatiG,etal.Earlyvascularageingintranslation:fromlabora-
calrecognition.Lancet1877;110(2816):232(cid:1)4. toryinvestigationstoclinicalapplicationsincardiovascularpre-
[2] Riva-Rocci S. Un nuovo sfigmomanometro. Gazz Med Torino vention.JHypertens2013;31:1517(cid:1)26.
1896;50(cid:1)51:1001(cid:1)7.
[3] NilssonPM,LurbeE,LaurentS.Theearlylifeoriginofvascular
ageingandcardiovascularrisk.JHypertens2008;26:1049(cid:1)57.
[4] Nilsson PM, Boutouyrie P, Laurent S. Vascular aging: a tale of
EVAandADAMincardiovascularriskassessmentandpreven-
tion.Hypertension2009;54:3(cid:1)10.
C H A P T E R
1
Historical Aspects and Biology of Aging
Peter M. Nilsson
Department ofClinical Sciences, Lund University,Ska˚ne University Hospital,Malmo¨,Sweden
Aging is a universal finding in humans, afflicting biological processes as well as maturation and deterioration
of organ function. There exist a number of theories on how aging is programmed and develops as presented in
gerontology, the science of normal aging. Not only the “wear and tear” hypothesis exists but also aging models
dependent on the influence of oxidative stress, metabolic processes, and the accumulation of genetic damage on
the DNA and impaired genetic repair functions [1]. Modern discoveries point to the role of longevity-regulating
genes, so-called “gerontogenes” [2]. These gerontogenes are classified as lifespan regulators, mediators, effectors,
housekeeping genes, genes involved in mitochondrial function linked to metabolism, and genes regulating
cellular senescence and programmed cell death (apoptosis) [2]. Intensive research is directed to understand what
regulates aging and how to control this, not at least apoptosis, of vital importance to understand organ develop-
ment and changes in health and disease. The maximum lifespan recorded was 122 years for a French woman
(Jean Calment, France,1875(cid:1)1977).
Even if it is very hard to disentangle the different influences on the aging process and to judge upon the
accuracy of the different hypotheses to explain human aging in general, it comes natural to view aging in its
evolutionary context as all aspects of human biology, and even cognitive function, are supposed to be influenced
by evolutionary selection mechanismsduring millennia perspectives.
EVOLUTIONARY TRAITS, GENES, AND THE ENVIRONMENT INFLUENCING AGING
From an evolutionary perspective the lifespan of mammals has been formed by selective processes based
on genetic regulation of survival and reproduction in relation to available nutrition, environmental hazards,
and competition for resources. According to the “disposable soma hypothesis” by Kirkwood [3] there exists
a trade-off between maintenance of bodily functions, depending on energy investments, and the costs of
reproduction, especially for women. This is why, according to this hypothesis, women with a higher number
of offspring will be at increased risk for a shorter lifespan as compared to women with fewer offspring, if basal
health and social conditions tend to be equal, as studied in British noble families over many centuries [4]. This
is also influenced by nutritional resources, as reproductive capacity in women tends to cease during periods of
famine and starvation.
Behind such traits there must be genetic regulators, as evolution works via genetic adaption and fitness in
relation to a changing environment. A further support for the genetic influence on longevity is the family resem-
blance of longevity as well as risk of some chronic disease conditions that tend to run in families, that is, clusters
of cardiovascular disease [5] and metabolic abnormalities. According to a number of studies the genetic explana-
tion of longevity is approximately 25% [6]. This leaves a substantial proportion of longevity to the influence of
environmental factors or to epigenetic mechanisms (gene(cid:1)environmental interactions). It is still unclear if true
life-prolonging genes exist in humans as in other less-developed organisms (Caenorhabditis elegans), or if a long
lifespan is a marker of the less strong impact or lack of disease-related genes in some individuals. According to
EarlyVascularAging(EVA). 1 ©2015ElsevierInc.Allrightsreserved.
2
1. HISTORICALASPECTSANDBIOLOGYOFAGING
environmental factors, there are many such detrimental factors well known to decrease lifespan, for example,
smoking, infectious disease, and malnutrition, but the only environmental factor known to prolong life in
mammals, at least in rodents and monkeys, is continuous calorie restriction [7]. This is believed to exert similar
effects in humans but still not proven. Nevertheless some individuals have adopted a lifestyle based on calorie
restriction andbalanced physical activity, hoping for a prolonged life.
CHANGES DURING THE TWENTIETH CENTURY IN LIFE EXPECTANCY
There is no doubt that the rapid increase in longevity during the past twentieth century is an indication
of the strong influence of environmental factors on human lifespan, reflecting better nutrition and housing,
improved hygiene and conditions in early life, as well as the progress of healthcare and improved medical
treatment, even if temporary setbacks have also been noticed, for example, in Russia during the 1990s [8].
The negative socioeconomic changes for many citizens in Russia during this period could be one compo-
nent of the increased cardiovascular risk based on gene(cid:1)environmental interactions in high-risk popula-
tions [9]. On the other hand, it is still necessary to understand the biology (and genetics) behind the aging
process, as there are still many examples of differential aging also in developed countries. A proof of the
role of genetic influences on aging and shortened lifespan are the rare conditions of Hutchinson(cid:1)Gilford
progeria in children and Werner’s syndrome in middle-aged subjects [10]. Even if these rare conditions are
not possible to causally treat today, they represent an opportunity to learn more about biological changes
taking place during the aging process, especially when it is upregulated in the progeria syndromes with
shortened lifespan.
EARLY LIFE PROGRAMMING EFFECTS
Human life starts at the conception followed by a growth during 9 months in fetal life in utero when organs
are formed and developed based on numerous cell divisions under genetic regulation. Nutritional factors are of
great importance for this process, as mediated by the feto-placental unit and influenced by maternal dietary
intakes. For more than 30 years now, researchers have documented the importance of fetal growth and birth
weight for bodily development and health also in adult life. Starting with early observations from northern
Norway by Forsdahl [11] and by Gennser [12] in Sweden, David Barker and many other colleagues developed a
concept based on the detrimental health consequences of fetal growth retardation leading to the small-for-
gestational age (SGA) phenotype in newborn babies. This condition in early life was associated with increased
levels of cardiovascular risk factors (hypertension, dyslipidemia, and hyperglycemia) and even overt type 2
diabetes in adult life, but also with impaired neurocognitive developments and a number of other adverse health
conditions, summarized in the so-called “Barker hypothesis” [13]. In more recent years a new paradigm has
evolved with a focus not only on fetal growth and birth weight as outcomes but also on postnatal growth
patterns. Of special importance for adult health is the combination of impaired fetal growth, causing SGA at
birth, combined with a rapid catch-up growth pattern in the first few years of life. This has been named the
“mismatch” growth pattern when different organs are programmed in utero for a life with scarce resources and
calorie depletion but later on the newborn child will experience the opposite, an environment with a surplus of
calories and nutritional abundance. This may negatively impact on organ development and increase the risk
of cardiometabolic disturbances in adult life. The most well-known protagonists of the “mismatch” hypothesis
today are Peter Gluckman and Mark Hanson, with important reviews on the topic [14]. They are both active
in the “Developmental Origins of Health and Disease” (DOHaD) society, to further explore the mismatch
hypothesis.
An even more recent hypothesis of early life programming of adult disease risk is linked to the impact on
child gut microbiota from the mother during delivery [15], as a detrimental gut microbiota pattern could be one
factor increasing the risk of obesity in adult life and adverse health conditions such as cardiovascular disease [16]
and type 2 diabetes [17]. It is believed that the mother’s gut bacteria will normally colonize the gastrointestinal
system of the newborn child and that this will protect from overgrowth of more deleterious skin bacteria that
could beassociated with later disease risk [15].
EARLYVASCULARAGING(EVA)
