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

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

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

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

Laurent, S. et al. Eur Heart J 2006 27:2588-2605.

Measurement of carotid-femoral PWV with the foot to foot method

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

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]

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)

Pulse wave velocity (PWV) vs. age and MBP

Eur Heart J 2010;eurheartj.ehq165

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

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

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

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

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.

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

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

Future directions – EVA in translation

• Understanding

• Translational Research

• Prevention

Future directions (1)

• Understanding

– Epidemiological studies in different populations

– Molecular biogerontology(www.whyweage.eu)

– Glucose metabolism and EVA (www.diamap.eu)

- 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

Increased Thickness and Cellularity of the Human Intima with Aging

Courtesy of E.Lakatta, NIH, USA

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

AT-1 and ACE in the Human Aortic Media Increase with Aging

Young Old

Courtesy of E.Lakatta, NIH, USA

Future directions (2)

• Translational research

– Genetics, telomere biology– Mechanisms– New drug targets

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

Shorter telomeres in plaques in Shorter telomeres in plaques in art. art. carotiscarotis

Hypertension 2004;43:182

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

”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.

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

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!

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

Baseline 1992-1996

Follow-up in 2007-2009

15 year´s follow-up

Δ z-score for telomere length changes

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

Telomeres and CVD - many unresolved questions

Organisation Committee: Peter M Nilsson, Annika Dejmek, Göran Roos, et al

Future directions (3)

• Prevention

– Lifestyle– Drug treatment– Control of ageing?

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