Shear Stress Shear Stress καικαι

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ΜοριακοίΜοριακοί

ΜηχανισμοίΜηχανισμοί ΑνάπτυξηςΑνάπτυξης

ΕυάλωτωνΕυάλωτων

ΑθηρωματικώνΑθηρωματικών

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ΕργαστήριοΕργαστήριο

ΚαρδιαγγειακήςΚαρδιαγγειακήςΜηχανικήςΜηχανικής

καικαι

ΑθηροσκλήρωσηςΑθηροσκλήρωσης

ΑΑ’’

ΠανεπιστημιακήΠανεπιστημιακή

ΚαρδιολογικήΚαρδιολογική

ΚλινικήΚλινική

ΑΠΘΑΠΘΝοσοκομείοΝοσοκομείο

ΑΧΕΠΑΑΧΕΠΑ

Cardiovascular DivisionCardiovascular DivisionBrigham & WomenBrigham & Women’’s Hospitals Hospital

Harvard Medical SchoolHarvard Medical School

Γιάννης

Χατζηζήσης, MD, PhD, FAHA, FESCΓεώργιος

Γιαννόγλου, MD, PhD

Peter Stone, MD, FAHACharles

Feldman, ScD

Σεμινάριο

Ομάδων

ΕργασίαςΕλληνική

Καρδιολογική

Εταιρεία

17-19 Φεβρουαρίου

2011

•

Although the entire coronary tree is exposed to the systemic risk factors (e.g. hyperlipidemia, smoking, hypertension, diabetes), atherosclerotic lesions have focal

distribution

•

Arterial regions susceptible to atherosclerosis:–

Lateral wall of bifurcations

–

Ostium of branches–

Inner aspect of major curvatures

Atherosclerosis: A Systemic Disease with Focal Manifestation

Vanderlaan PA, et al. ATVB 2004;24:12-22

Constant Interplay of Local Hemodynamics with Vascular Biology Determine the Localization of

Atherosclerosis

LOCAL HEMODYNAMICS

VASCULAR BIOLOGY

Endothelial Shear Stress (ESS): A Major Local Hemodynamic Factor

Giannoglou GD, et al. Int J Cardiol 2002;86:27Chatzizisis YS, et al. JACC 2007;49:2379-93Ku DN, et al. Arteriosclerosis 1985;5:293Gimbrone MA, et al. Ann N Y Acad Sci 2000Wentzel JJ, et al. Circulation 2003;108:17Stone PH, et al. Circulation 2003;108:438

1 Pa=1 N/m2=10 dyn/cm2

Low ESS Co-localizes with Atherosclerosis

Malek AM, et al. JAMA 1999;282:2035-42Ku DN, et al. Arteriosclerosis 1985;5:293

Chatzizisis YS, et al. JACC 2007;49:2379-93

Low ESS Leads to Early Atherosclerotic Plaque Formation

Nature of the Problem:Nature of the Problem: Coexistence of Heterogeneous Plaques

in the Same Patient

Stable Angina

Stenotic FibrousPlaque• Severe obstruction• Minimal lipid core• Fibrosis• Thick fibrous cap

Plaque Rupture/ACS• Unstable angina• Acute myocardial infarction• Sudden death

Vulnerable Plaque• Minor obstruction• Large lipid core• Inflammation• Thin fibrous cap

Courtesy of Peter H. Stone, MD

P. Constandinides

Low ESS Predicts the Formation of High-Risk Vulnerable Plaque

0.0

0.5

1.0

1.5

2.0

Minimal Int TCFA

P<0.001P<0.001

Bas

elin

e ES

S (P

a)

Chatzizisis YS, et al. Circulation 2008;117:993-1002

Dose-Response Relationship Between the Magnitude of Low ESS and the Severity of

Vulnerable Plaque Characteristics

Chatzizisis YS, et al. Circulation 2008;117:993-1002

Chatzizisis YS, et al. Circulation 2011;123:621-30

Low ESS Promotes Endothelial Dysfunction

Low ESS Promotes Sub-endothelialAccumulation of Activated Macrophages

Chatzizisis YS, et al. Circulation 2011;123:621-30

Low ESS Increases mRNA Expression and Elastolytic Activity of MMPs vs. TIMPs

Chatzizisis YS, et al. Circulation 2011;123:621-30

Low ESS Increases mRNA Expression and Elastolytic Activity of Cathepsins vs. Cystatin C

Chatzizisis YS, et al. Circulation 2011;123:621-30

Baker AB, Chatzizisis YS, et al. Atherosclerosis 2010;213:436-42

Low ESS Increases mRNA Expressionand Activity of Heparanase

Low ESS Increases Internal Elastic Lamina Fragmentation

Chatzizisis YS, et al. Circulation 2011;123:621-30

Excessive remodeled areas continue to have low ESSvicious cycle of plaque progression, inflammation, and

excessive expansive remodeling

Effect of Baseline Low ESS on Subsequent Vascular Remodeling

and Establishment of New

Baseline Low ESS

Koskinas KC, et al. Circulation 2010;121:2092-2101Papafaklis M, et al. Curr Opin Cardiol 2010;25:627-638

Increased lipidaccumulation and

inflammation

Enhanced activityof matrix proteases

Enhanced IELfragmentation

Extension ofInflammation

to media

Expansiveremodeling

Low ESS

TCFA

Low ESS Promotes Vascular Wall Expansion and Formation of Vulnerable Plaques

Earlyplaque

Increased Intimal Smooth Muscle Cell Apoptosis in Lesions of Persistently Low ESS

p<0.001

a-actin

a-actin

TUNEL

TUNEL

Koskinas KC, et al. Circulation, Under review

Reduced Intimal Content of Smooth Muscle Cells in Lesions of Persistently Low ESS

α-actin

α-actin

α-actin

α-actin

p<0.01

* * Low ESS: ESS<1.2 Pa at all time points of in-vivo vascular profiling

**

Koskinas KC, et al. Circulation, Under review

Reduced Content of Interstitial Collagen in Lesions of Persistently Low ESS

Thin

Cap

Thick Cap

p<0.01

p<0.01

Picrosirius Red

Picrosirius Red

Koskinas KC, et al. Circulation, Under review

Summary: Role of Low ESS on

Vulnerable Plaque Formation

Koskinas KC, Chatzizisis YS, et al. Curr Opin Cardiol 2009;24:580-90

Chatzizisis YS, Koskinas KC, et al. ATVB 2010, b t t

Low ESS and Hyperlipidemia Determine the Progression of Atherosclerosis

Natural History of Atherosclerosis

Chatzizisis YS, et al. JACC 2007;49:2379-93

•

Very low ESS•

IEL fragmentation

•

Excessive expansive remodeling

•

Increased progression rate

Redefining Vulnerable Plaque

“Regional” characteristics

Histopathologiccharacteristics

Libby P, et al. Nat Med 2002;8:1257Chatzizisis YS, et al. JACC 2007;49:2379-93

Conceptual Strategy for Risk Stratification of Individual Coronary Lesions

Chatzizisis YS, et al. Curr Opin Cardiol 2007;22:552-64Toutouzas K, et al. JACC 2007;49:2264-71

Thermography OCT

ESS, vascular remodeling and inflammationfor risk stratification of early non-stenotic fibroatheromas

Very low ESSSevere InflammationExcessive expansive remodeling

Normal ESSLimited inflammationNo remodeling

Low ESSLess inflammationCompensatory remodeling

High

risk

Chatzizisis YS, et al. Curr Opin Cardiol 2007;22:552-64Toutouzas K, et al. JACC 2007;49:2264-71

Moderate

risk

Low

risk

Conceptual Strategy for Risk Stratification of Individual Coronary Lesions

“Tailor-made”

Therapy of Individual Atherosclerotic Plaques

High-Risk PlaqueLocal Therapy

Stent

Targeted drug delivery

Intensive systemic therapy

Low/Moderate-Risk PlaqueSystemic therapyRegular follow-up

Opportunities of Systemic Interventions to Avert the Pro-inflammatory Effect of Low ESS

Chatzizisis YS, et al, Atherosclerosis 2009;203:387-94

P: PlaceboV: ValsartanV/S: Valsartan

+ Simvastatin

Conclusions

•

Atherosclerosis is a systemic disease with focal

and heterogeneous

manifestation

•

Low ESS

is a major factor that determines the location

and formation

of early fibroatheromata

•

A portion of early fibroatheromata

evoles

to rupture- prone plaques (TCFAs). The major determinant of

that evolution is low ESS

Conclusions

•

Low ESS increases plaque

inflammation, increases matrix-degrading enzyme activity, and lead to

internal

elastic lamina degradation and

vascular wall expansion

•

Low ESS increases smooth muscle cell apoptosis reduces

collagen production, and leads to fibrous cap

thinning and

plaque rupture•

Combination of local ESS, vascular remodeling and severity of inflammation

can be utilized to predict

vulnerable plaque formation, thereby creating the perspective of preemptive

local or systemic

intervention

FundingΕλληνικό

Ίδρυμα

Καρδιολογίας

Ελληνική

Καρδιολογική

ΕταιρείαΕταιρεία

Αθηροσκλήρωσης

Βορείου

Ελλάδος

Ελληνική

Εταιρεία

ΑθηροσκλήρωσηςΊδρυμα

Κρατικών

Υποτροφιών

Επιτροπή

Ερευνών

ΑΠΘΕλληνικό

Ίδρυμα

Harvard

Κοινωφελές

Ίδρυμα

Αλέξανδρος

Σ. ΩνάσηςΊδρυμα

Προποντίς

Ίδρυμα

Α.Γ. Λεβέντης

European Union (Marie Curie Reintegration Grant -FP7)George D. Behrakis

Foundation

National Institutes of HealthAmerican Heart AssociationEuropean Society of CardiologyEuropean Atherosclerosis SocietyHellenic Medical Society of New YorkHellenic University Club of New York

Acknowledgements

Brigham and WomenBrigham and Women’’ssHospital, Harvard Medical SchoolHospital, Harvard Medical SchoolPeter H. Stone, MDCharles L. Feldman, ScDKostas Koskinas, MD, MScMichael Papafaklis, MD, PhDAhmet

U. Coskun, PhD

Galina K. Sukhova, PhDGuo-Ping Shi, ScDPeter Libby, MD

MITMITElazer

R. Edelman, MD, PhD

Michael Jonas, MDAaron B. Baker, PhDRoy Beigel, MDBenjamin V. Stone

University of WashingtonUniversity of WashingtonCharles Maynard, PhD

Aristotle University Aristotle University Medical SchoolMedical SchoolGeorge D. Giannoglou, MD, PhDKostas Koskinas, MD, MScAntonios

Antoniadis, MD, PhD

Vassilis

Giannoglou, MScSotiris Katranas, MD, MSc

E-mail: joc@med.auth.gr