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EarlyEarly VascularVascular AgeingAgeing (EVA) (EVA) syndromesyndrome–– couldcould it be it be defineddefined??
Peter M Nilsson, MD, PhDDepartment of Clinical Sciences
University Hospital, MalmöSweden
Summer School, Athens, 3rd July 2010Hellenic Atherosclerosis Society
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Age and cardiovascular disease• Age - a greater risk factor than traditional risk factors• Age-related changes in vascular structure and function,
in association with metabolic disturbances, are likely to be responsible for increased cardiovascular risk
Najjar et al. Hypertension 2005; 46:454-462.
Increase in CAD, Hypertension, CHF,
stroke
Increased exposure to risk factors
Changes in the vessel wall
Increasing Age
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IntermediateLesion
Minamino T, Circ Res 2007;100;15-26
Early Vascular Ageing (EVA): Early Vascular Ageing (EVA): Atherosclerosis and arterial stiffeningAtherosclerosis and arterial stiffening
FoamCells
FattyStreak Atheroma
FibrousPlaque
ComplicatedLesion/Rupture
Endothelial Dysfunction
From First Decade From Third Decade From Fourth Decade
Growth of the Lipid CoreSmooth
Muscle and Collagen
Thrombosis
Nilsson PM, et al. J Hypertens 2008, Hypertension 2009
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Core characteristics of EVA
• Arteriosclerosis• Arterial stiffness: PWV ↑ , Aix ↑, central BP ↑
• Endothelial dysfunction• NO deficiency, dysfunction, local inflammation
• Atherosclerosis• Imaging (IMT, plaque), biomarkers
Nilsson PM, et al. Hypertension 2009
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Laurent, S. et al. Eur Heart J 2006 27:2588-2605.
Measurement of carotid-femoral PWV with the foot to foot method
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EVA definitions – Three options
• No definition needed– EVA is only a model for (dynamic) thinking about
CV risk, beyond Framingham, SCORE and the Metabolic syndrome
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EVA definitions – Three options
• No definition needed– EVA is only a model for (dynamic) thinking about
CV risk
• Outside normal range of PWV– Define outliers (+ 2SD) of PWV distribution
The Reference Values for Arterial Stiffness' Collaboration.Determinants of pulse wave velocity in healthy people and in the presence of cardiovascular risk factors: 'establishing normal and reference values'. Eur Heart J. 2010 Jun 7. [Epub ahead of print]
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Normal values for pulse wave velocityaverage according to age (1455 healthy NT subjects)
Eur Heart J 2010;eurheartj.ehq165Laurent S, et al, for a Collaborative Group
NT = normotensives (out of a total 16,867 subjects from 8 European countries)
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Pulse wave velocity (PWV) vs. age and MBP
Eur Heart J 2010;eurheartj.ehq165
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Reference values for pulse wave velocity (PWV): mean values according to age and blood pressure (BP) categories (11 092 subjects)
Eur Heart J 2010;eurheartj.ehq165
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PWV distribution and age in Malmö
• Population-based screening study in elderly subjects; mean 70 years (Malmo Diet Cancer Re-exam Study)
• Sphygmocor for PWV measurement in 2380 subjects
• Elevated PWV ( �12 m/s) för men (M) and women (W) in different age-ranges (quartiles of age distribution):
– 62-67 years: 10.2% (M: 15.1, W: 6.7)– 68-72 years: 17.2% (M: 20.5, W: 14.9)– 73-77 years: 31.7% (M: 38.3, W: 27.8)– 78-84 years: 41.2% (M: 42.4, W: 40.1)
Nilsson P, Östling G, 2010
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PWV and risk prediction• Two new studies based on meta-analysis
• 17 studies, 15,877 subjects. Pooled RRs for high-risk category were:– CV events RR 2.26 (95%CI: 1.89-2.70)– CV mortality RR 2.02 (95%CI: 1.68-2.42)– All-cause mortality RR 1.90 (95%CI: 1.61-2.24)
• Vlachopoulos C, et al. J Am Coll Cardiol 2010; 55:1318-27
• 12 studies, 15,220 subjects, 1779 combined events, analysis based on individual data– CV events HR 1.27 for 1 SD– CHD HR 1.19 for 1 SD– Stroke HR 1.25 for 1 SD
• McEniery C, et al. Abstract, ESH XX Meeting, Oslo 17-21 June 2010
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EVA definitions – Three options
• No definition needed– EVA is only a model for (dynamic) thinking about CV risk
• Outside normal range of PWV– Define outliers (+ 2SD) of PWV distribution
• The unexplained component of PWV– What remains after full adjustment for conventional risk
factors (age, gender, blood pressure, lipids, smoking, glucose, etc.) in multiple regression analysis
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Put EVA to the test!
• Genetics of arterial stiffness and EVA– Do genetic markers also predict CV events?
• Reversibility of arterial stiffness– Possible with or without BP reduction?
• New drugs for vascular protection– AT2 agonists, endothelial modulators,
incretins (GIP, GLP-1), etc.
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DPP-4=dipeptidyl peptidase-4; T2DM=type 2 diabetes mellitusAdapted from Unger RH. Metabolism. 1974; 23: 581–593. Ahrén B. Curr Enzyme Inhib. 2005; 1: 65–73.
↑ Insulin
↓ Glucagon
Improved glycemic control
Incretin activity
prolonged
Improved islet function
DPP-4 inhibitor
↓ Insulin
↑ Glucagon
HyperglycemiaIncretin
response diminished
Further impaired islet function
T2DM
Blocking DPP-4 Can Improve Incretin Activity and Correct the Insulin:Glucagon Ratio in T2DM
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New studies with incretins for evaluation of CV prevention
• Randomised controlled trials
• TECOS – sitagliptin (2009)• SAVOR – saxagliptin (2010)• CAROLINA – linagliptin (2010)• LEADER - liraglutide (2010)
• Observational study
• EDGE - vildagliptin (2009)
PN 2010
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Future directions – EVA in translation
• Understanding
• Translational Research
• Prevention
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Future directions (1)
• Understanding
– Epidemiological studies in different populations
– Molecular biogerontology(www.whyweage.eu)
– Glucose metabolism and EVA (www.diamap.eu)
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- A research network across Europe, aiming for writing backgrounddocuments for future EU Research calls and funding.
- Final meeting held in Brussels on 17-19th May 2010.
- Increasing interest shown in telomere biology, e.g. in relationto cellular senescence and vascular ageing.
www.whyweage.eu HEALTH-F4-2008-200970 Dec 1st 2008 - May 30th 2010
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Increased Thickness and Cellularity of the Human Intima with Aging
Courtesy of E.Lakatta, NIH, USA
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Local Aortic Wall Angiotensin Signaling Components Increase with Aging in Humans
AC
EA
ngII
L
M
L
M
L
M
L
M
L
M
L
M
AT1
Courtesy of E.Lakatta, NIH, USA
Ang II
AT1 r
ACE
Young Old
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AT-1 and ACE in the Human Aortic Media Increase with Aging
Young Old
Courtesy of E.Lakatta, NIH, USA
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Future directions (2)
• Translational research
– Genetics, telomere biology– Mechanisms– New drug targets
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Telomere length has been associated with cardiovascular risk – but not in a constant way
• Smoking• Obesity• Arterial stiffness• Oxidative stress• Diabetes mellitus, type 1 and type 2
• Atherosclerotic plaques• Aortic aneurysm• Intima media thickness• Left ventricular mass (LVM)• Coronary artery disease
Nordfjäll K, et al. 2008
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Shorter telomeres in plaques in Shorter telomeres in plaques in art. art. carotiscarotis
Hypertension 2004;43:182
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Association between IMTcc (cm) and quartiles of LTL after adjusting for age, sex, smoking in pack-years, diabetes, hypertension, T-Chol and BMI in men and women
Leukocyte telomere length is associated with measuresof subclinical atherosclerosis
Panayiotou AG, et al. Atherosclerosis. 2010 Feb 4 - online
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”Our data show that patients with AAA have shorter leukocyte telomerelength compared to controls. This suggests that vascular biological agingmay have a role in the pathogenesis of AAA”.
Abdominal Aortic Aneurysm (AAA)
Atturu G, et al. Eur J Vasc Endovasc Surg. 2010 May;39(5):559-64.
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T/S means and standard deviation in 272 subjects: CTR, Type2DM and Type2DM + MI. p < 0.01 One-way analysis of variance adjusted for age and gender, F = 34.37, df = 2, p = 0.005.
Olivieri F, et al. Atherosclerosis. 2009 Oct;206:588-93
Telomere length in patients with DM2 and myocardial infarction
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Telomere attrition is associated with markers of cardiovascular ageing – the
Malmo Diet Cancer Study
Peter Nilsson, Disa Dahlman, Göran Roos, Olle Melander, et al.
Lund and Umeå University2010
Preliminary analyses!
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Malmo Diet Cancer –CV cohort
• Baseline examination in 1992-1996 (n= 6050)
• MI cases and matched controls (n= 710)
• Re-exam in 2007-2009 (n= 353)
• Telomere length determination in 750 at baseline and in 333 subjects at follow-up after mean 15 years
• Lab: q-PCR for LTL, as used at Umeå Lab, Dept. of Pathology (Göran Roos)
PN 2010
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Baseline 1992-1996
Follow-up in 2007-2009
15 year´s follow-up
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Δ z-score for telomere length changes
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Results
• Increased Z-score Δ changes (reflecting telomere attrition) was associated with:
– History of myocardial infarction (prevalent or incident)
– Treatment with anti-hypertensive drugs (a marker of long-standing hypertension)
– Pulse pressure at baseline (a marker of arterial stiffness)
• These entities are markers of cardiovascular ageing
PN 2010
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Telomeres and CVD - many unresolved questions
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Organisation Committee: Peter M Nilsson, Annika Dejmek, Göran Roos, et al
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Future directions (3)
• Prevention
– Lifestyle– Drug treatment– Control of ageing?
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Summary
• Early vascular ageing (EVA) is a useful concept for new understanding of vascular disease progression and increased CV risk
• Definitions of EVA are still preliminary and should be further evaluated, as well as the association with changes in telomere biology
• New drugs are under development for vascular protection, besides traditional BP lowering drugs
PN 2010