Κεντρικές ή περιφερικές πιέσεις;

ΧαράλαµποςΧαράλαµπος ΒλαχόπουλοςΒλαχόπουλοςΕπίκουροςΕπίκουρος ΚαθηγητήςΚαθηγητής ΚαρδιολογίαςΚαρδιολογίας

ΑΑ’’ ΠανεπιστηµιακήΠανεπιστηµιακή ΚαρδιολογικήΚαρδιολογική

ΚλινικήΚλινική

IIπποκράτειοπποκράτειο ΓΓ..ΝΝ..ΑΑ..

ΔομικοίΔομικοίΔομικοίΔομικοίΔομικοίΔομικοίΔομικοίΔομικοίΛειτουργικοίΛειτουργικοίΛειτουργικοίΛειτουργικοίΛειτουργικοίΛειτουργικοίΛειτουργικοίΛειτουργικοί

Καρωτιδική βλάβη

Σφυροβραχιόνιος

δείκτης

Αρτηριακή

σκληρία

Ανακλώµενα

σφυγµικά

κύµατα – κεντρικές πιέσεις

Ενδοθηλιακή

δυσλειτουργία

Αρτηριακοί βιοδείκτες

Αµφιβληστροειδοπάθεια

Biomarker overload

Criteria of a BiomarkerCriteria of a Biomarker

A theoretical basis

High reproducibility

Ease of use

Incremental value

Ability to monitor and guide therapy

R Vasan 2006

Criteria of a BiomarkerCriteria of a Biomarker

A theoretical basis

High reproducibility

Ease of use

Incremental value

Ability to monitor and guide therapy

R Vasan 2006

• διαστολικής πιέσεως

• στεφανιαίας πίεσης

άρδευσης

• µεταφόρτιου ΑΚ

•συστολικού έργου της AK

•MVΟ2

στεφανιαίας πίεσης άρδευσης

Αρτηριακή σκληρία και ανακλώµενα κύµατα

Αρτηρίες διατάσιµες: φυσιολογικό PWV

Αρτηρίες µε αυξηµένη σκληρία: αυξηµένο PWV

Peripheral and central pressures

Are they the same?

ΤΤhe two Fridas, he two Fridas, 19391939

� amplification

CBPs: theoretical basisCBPs: theoretical basis

� peripheral BP may overestimate central SP and PP, especially in young subjects

CBPs: theoretical basisCBPs: theoretical basis

July 2007

Criteria of a BiomarkerCriteria of a Biomarker

A theoretical basis

High reproducibility

Ease of use

Incremental value

Ability to monitor and guide therapy

R Vasan 2006

Arterial TonometryArterial Tonometry ::

an an Avatar Avatar for central pressuresfor central pressures

Arterial TonometryArterial Tonometry ::

an an Avatar Avatar for central pressuresfor central pressures

CBPs: Reproducibility/RepeatabilityCBPs: Reproducibility/Repeatability

First author Year, country Population Variables - repro ducibility

Wilkinson 1998, UK Healthy, hypertensives,

diabetics

Aortic AIx: intraobserver difference 0.49±5.37%interobserver difference 0.23±3.80%

Liang 1998, Australia Healthy Carotid AIx: coefficient of variation 1.3%

Siebenhoffer 1999, UK Healthy Derived aortic SBP: interobserver difference 0.1±1.7 mmHg Derived aortic DBP: interobserver difference 0.1±0.7 mmHg Aortic AIx: interobserver difference 0.4±6.4%

Filipovsky 2000, Czech Republic

Healthy Aortic AIx: intraobserver variability 7.7% Aortic SBP: intraobserver variability 6.3%

Savage 2002, UK Chronic renal failure

Aortic AIx: intraobserver difference 0±4% interobserver difference 0±3%

Aortic MAP: intraobserver difference 0±3 mmHg interobserver difference 1±9 mmHg

Matsui 2004, Japan Hypertensives Carotid AIx: intraobserver difference 0.5±5.9%

Papaioannou 2004, Greece Cardiogenic shock

Aortic AIx: intraobserver difference 0.10±5.82%

Williams (CAFÉ)

2006, UK-Sweden

Hypertensives Aortic SBP: interobserver difference 0.3±2.9 mmHgAortic AIx: interobserver difference 1.5±5.9%

Roman (Strong Hear

Study)

2007, USA High-risk subjects

Carotid SBP: interobserver CC: 0.99intraobserver CC: 0.99

Carotid DBP: interobserver CC: 0.99 intraobserver CC: 0.99

CBPs: Accuracy/ValidityCBPs: Accuracy/Validity

First author Year, country Population Variables - repro ducibility

Pauca (radial) 2001, Australia Cardiac surgery (mostly CABG)

Resting conditions: SBP 0.0±4.4 mmHg; DBP 0.6±1.7 mmHg; PP-0.7±4.2 mmHg; MAP -0.5±2.0 mmHgNitroglycerin infusion: SBP -0.2±4.3 mmHg; DBP 0.6±1.7 mmHg; PP -0.8±4.1 mmHg; MAP -0.4±1.8 mmHg.

Van Bortel (carotid)

2001, Belgium, Netherlands

Coronary angiography

PP -10.2±14.3 mmHg

Smulyan(radial)

2003, USA-France

Coronary angiography

SBP 1.5±11.3 mmHg; DBP -10.4±12.7 mmHg; PP 11.5±13.6 mmHg

Hope (radial) 2004, Australia Cardiac catheterization

SBP (invasive calibration) -1±8 mmHgSBP (non-invasive calibration) 7±12 mmHg

Sharman (radial)

2006, Australia Coronary angiography

Rest SBP -1.3±3.2 mmHgExercise SBP -4.7±3.3 mmHg

Criteria of a BiomarkerCriteria of a Biomarker

A theoretical basis

High reproducibility

Ease of use

Incremental value

Ability to monitor and guide therapy

R Vasan 2006

CBPs/indices as markers of disease and predictors of CBPs/indices as markers of disease and predictors of surrogate endsurrogate end--pointspoints

Cross-sectional and longitudinal studiesFirst author Year, country Population Design Parameter End-point

Saba*† 1993, USA Normotensives Cross-sectional Carotid AIx LVMI, carotid thickness

Boutouyrie*† 1999, France Hypertensives Cross-sectional Carotid PP Carotid thickness

Boutouyrie*† 2000, France Hypertensives Longitudinal (9-month FU)

Carotid PP Carotid IMT reduction with treatment

Roman 2000, USA Normotensives, Hypertensives

Cross-sectional Carotid systolic BP Relative LV wall thickness

Waddell*† 2001, Australia CAD Cross-sectional Carotid BP Extent of CAD

Nishijima* 2001, Japan Suspected CAD Cross-sectional Aortic fractional PP Incident CAD

Nurnberger 2002, Germany Healthy + CVD Cross-sectional Carotid AIx CV risk scores

Philippe* 2002, France CAD Cross-sectional Aortic PP Extent of CAD

Hayashi* 2002, Japan Suspected CAD Cross-sectional Aortic AIx Incident CAD

De Luca † 2004, REASON study Hypertensives Longitudinal (1-year FU) Carotid PP LVMI reduction

Weber 2004, Austria Suspected CAD Cross-sectional Aortic AP, AIx Incident CAD

Jankowski* 2004, Poland CAD Cross-sectional Aortic BP Extent of CAD

Danchin* 2004, France Suspected CAD Cross-sectional Aortic PP Incidence and extent of CAD

Booth 2004, UK Systemic vasculitis

Cross-sectional Aortic AIx Disease activity

Roman 2007, USA High-risk pts Cross-sectional Aortic PP Carotid IMT and mass

Hashimoto † 2007, Japan Hypertensives Longitudinal (1-year FU) Aortic AIx LVMI reduction with treatment

Dart 2007, Australia Eledrly hypertensives

Longitudinal (4-year FU) Carotid/Brachial BP BP with treatment

Jiang 2007, China Hypertensives Longitudinal (2-mo FU) Central SP BP with treatment

* Measured invasively Incremental value

CBPs/indices as a predictors of eventsCBPs/indices as a predictors of events

* Measured invasively

Longitudinal studies

Incremental value

First author Year, country

Population Design Parameter End-point

Nakayama * 2000, Japan CAD-PTCA Longitudinal (3-month FU) Aortic fractional PP restenosis

Lu * 2001, China CAD-PTCA Longitudinal (6-month FU) Aortic PP restenosis

London † 2001, France

ESRD Longitudinal (52-month FU) Carotid AIx CV mortality

Safar † 2002, France

ESRD Longitudinal (52-month FU) Carotid PP, PP amplification

All-cause and CV mortality

Ueda* 2004, Japan CAD-PTCA Longitudinal (6-month FU) Aortic AIx restenosis

Chirinos *† 2005, USA CAD Longitudinal (3.2-year FU) Aortic AP CV mortality and events

Weber † 2005, Austria

CAD-PTCA Longitudinal (2-year FU) Aortic AIx CV mortality and events

Dart 2006, Australia

Elderly female hypertensives

Longitudinal (4.1-year FU) Carotid AIx, Brachial BP CV mortality and events

Williams † 2006 CAFE study

Hypertensives Longitudinal (up to 4-year FU) Aortic PP CV mortality and events during

treatment

Roman † 2005 and 2007, USA

High-risk pts Longitudinal (4.8-year FU) Aortic PP CV mortality and events

Negative value

Central Hemodynamics

† equal contribution

Vlachopoulos C / Aznaouridis K, et al. Eur Heart J 2010

5,648 pts / mean FU 45 months

For 10% increase in AIx increase in RR: 32% and 38% respectively

Central Hemodynamics

Central vs. Peripheral Pressures

Central Hemodynamics

Vlachopoulos C / Aznaouridis K, et al. Eur Heart J 2010

Reference values

Reference Values for Central Pressures Collaboratio n Project

UNDER CONSTRUCTION

Criteria of a BiomarkerCriteria of a Biomarker

A theoretical basis

High reproducibility

Ease of use

Incremental value

Ability to monitor and guide therapy

R Vasan 2006

Vlachopoulos C et al. Am J Hypertens 2005

no consumption

low consumption

high consumption

no consumption

low consumption

high consumption

no consumption

low consumption

high consumption

Vlachopoulos C, et al. Am J Cardiol 2007

Dark Chocolate and Arterial StiffnessDark Chocolate and Arterial Stiffness

ARTERIAL STIFFNESS AND

PSYCHOLOGICAL FACTORS

∆ράµα

0 min 15 min 30 minBaseline

0.4

0

0.2

dPWV

2009

2009

0 min 15 min 30 minBaseline

-0.4

0

-0.2

dPWV

ARTERIAL STIFFNESS AND

PSYCHOLOGICAL FACTORS

Pharmacological Interventions

Protogerou et al. Curr Pharm Des 2009

Lowering central pressures:not all drugs are created equal

Boutouyrie et al, Hypertension 2010

The EXPLOR study

Amlodipine+valsartan

Amlodipine+atenolol

Lowering central pressures:not all drugs are created equal

The J-CORE study

ASCOT endpointsASCOT endpoints

The area of the yellow square is proportional to the amount of statistical information

Amlodipine ± perindopril better Atenolol ± thiazide better0.50 0.70 1.00 1.45

PrimaryPrimaryNon-fatal MI (incl silent) + fatal CHD

SecondaryNon-fatal MI (exc. Silent) +fatal CHDTotal coronary end pointTotal CV event and proceduresAll-cause mortalityCardiovascular mortalityFatal and non-fatal strokeFatal and non-fatal heart failure

TertiarySilent MIUnstable anginaChronic stable anginaPeripheral arterial diseaseLife-threatening arrhythmiasNew-onset diabetes mellitusNew-onset renal impairment

Post hocPrimary end point+coronary revasc procsCV death + MI + stroke

2.00

ΣΚ (95% CI)0.90 (0.79-1.02)

0.87 (0.76-1.00)0.87 (0.79-0.96)0.84 (0.78-0.90)0.89 (0.81-0.99)0.76 (0.65-0.90)0.77 (0.66-0.89)0.84 (0.66-1.05)

1.27 (0.80-2.00)0.68 (0.51-0.92)0.98 (0.81-1.19)0.65 (0.52-0.81)1.07 (0.62-1.85)0.70 (0.63-.078)0.85 (0.75-0.97)

0.86 (0.77-0.96)0.84 (0.76-0.92)

CAFÉ Study

CBPs: Ability to monitor and guide therapyCBPs: Ability to monitor and guide therapy

Williams B, et al. Circulation 2006

CBPs, therapy and CBPs, therapy and prognosisprognosis

CAFÉ Study

Peripheral

Central

Williams B, et al. Circulation 2006

Amlodipine ± perindopril

Atenolol ± thiazide

CBPs: Where do we stand today?CBPs: Where do we stand today?

“ Though a wider use of PWV and AIx measurements may add further precision to the assessment of arterial damage, the availability of these techniques is largely limited to research centres.”

CBPs: Where do we stand today?CBPs: Where do we stand today?

July 2007

Robert Doisneau, Paris 1948Robert Doisneau, Paris 1948

Biomarkers: Biomarkers: Seeing what is importantSeeing what is important