Shear Stress Shear Stress καικαι
ΝέοιΝέοι
ΜοριακοίΜοριακοί
ΜηχανισμοίΜηχανισμοί ΑνάπτυξηςΑνάπτυξης
ΕυάλωτωνΕυάλωτων
ΑθηρωματικώνΑθηρωματικών
ΠλακώνΠλακών
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: [email protected]
Top Related