Ανάπτυξης Ευάλωτων Αθηρωματικών Πλακών

Transcription

1 Σεμινάριο Ομάδων Εργασίας Ελληνική Καρδιολογική Εταιρεία Φεβρουαρίου 2011 Shear Stress και Νέοι Μοριακοί Μηχανισμοί Ανάπτυξης Ευάλωτων Αθηρωματικών Πλακών Γιάννης Χατζηζήσης, MD, PhD, FAHA, FESC Γεώργιος Γιαννόγλου, MD, PhD Peter Stone, MD, FAHA Charles Feldman, ScD Εργαστήριο Καρδιαγγειακής Μηχανικής και Αθηροσκλήρωσης Α Πανεπιστημιακή Καρδιολογική Κλινική ΑΠΘ Νοσοκομείο ΑΧΕΠΑ Cardiovascular Division Brigham & Women s s Hospital Harvard Medical School

2 Atherosclerosis: A Systemic Disease with Focal Manifestation 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 Vanderlaan PA, et al. ATVB 2004;24:12-22

3 Constant Interplay of Local Hemodynamics with Vascular Biology Determine the Localization of Atherosclerosis LOCAL HEMODYNAMICS VASCULAR BIOLOGY

4 Endothelial Shear Stress (ESS): A Major Local Hemodynamic Factor 1 Pa=1 N/m 2 =10 dyn/cm 2 Giannoglou GD, et al. Int J Cardiol 2002;86:27 Chatzizisis YS, et al. JACC 2007;49: Ku DN, et al. Arteriosclerosis 1985;5:293 Gimbrone MA, et al. Ann N Y Acad Sci 2000 Wentzel JJ, et al. Circulation 2003;108:17 Stone PH, et al. Circulation 2003;108:438

5 Low ESS Co-localizes with Atherosclerosis Ku DN, et al. Arteriosclerosis 1985;5:293 Malek AM, et al. JAMA 1999;282:

6 Low ESS Leads to Early Atherosclerotic Plaque Formation Chatzizisis YS, et al. JACC 2007;49:

7 Nature of the Problem: Coexistence of Heterogeneous Plaques in the Same Patient Stenotic Fibrous Plaque Severe obstruction Minimal lipid core Fibrosis Thick fibrous cap Vulnerable Plaque Minor obstruction Large lipid core Inflammation Thin fibrous cap P. Constandinides Stable Angina Courtesy of Peter H. Stone, MD Plaque Rupture/ACS Unstable angina Acute myocardial infarction Sudden death

8 Low ESS Predicts the Formation of High-Risk Vulnerable Plaque Baseline ESS (Pa) P<0.001 P<0.001 Minimal Int TCFA Chatzizisis YS, et al. Circulation 2008;117:

9 Dose-Response Relationship Between the Magnitude of Low ESS and the Severity of Vulnerable Plaque Characteristics Chatzizisis YS, et al. Circulation 2008;117:

10 Low ESS Promotes Endothelial Dysfunction Chatzizisis YS, et al. Circulation 2011;123:621-30

11 Low ESS Promotes Sub-endothelial Accumulation of Activated Macrophages Chatzizisis YS, et al. Circulation 2011;123:621-30

12 Low ESS Increases mrna Expression and Elastolytic Activity of MMPs vs. TIMPs Chatzizisis YS, et al. Circulation 2011;123:621-30

13 Low ESS Increases mrna Expression and Elastolytic Activity of Cathepsins vs. Cystatin C Chatzizisis YS, et al. Circulation 2011;123:621-30

14 Low ESS Increases mrna Expression and Activity of Heparanase Baker AB, Chatzizisis YS, et al. Atherosclerosis 2010;213:436-42

15 Low ESS Increases Internal Elastic Lamina Fragmentation Chatzizisis YS, et al. Circulation 2011;123:621-30

16 Effect of Baseline Low ESS on Subsequent Vascular Remodeling and Establishment of New Baseline Low ESS Excessive remodeled areas continue to have low ESS vicious cycle of plaque progression, inflammation, and excessive expansive remodeling Koskinas KC, et al. Circulation 2010;121: Papafaklis M, et al. Curr Opin Cardiol 2010;25:

17 Low ESS Promotes Vascular Wall Expansion and Formation of Vulnerable Plaques Low ESS Increased lipid accumulation and inflammation Enhanced activity of matrix proteases Enhanced IEL fragmentation TCFA Early plaque Extension of Inflammation to media Expansive remodeling

18 Increased Intimal Smooth Muscle Cell Apoptosis in Lesions of Persistently Low ESS p<0.001 TUNEL a-actin TUNEL a-actin Koskinas KC, et al. Circulation, Under review

19 Reduced Intimal Content of Smooth Muscle Cells in Lesions of Persistently Low ESS p<0.01 α-actin α-actin * α-actin α-actin * Low ESS: ESS<1.2 Pa at all time points of in-vivo vascular profiling Koskinas KC, et al. Circulation, Under review

20 Reduced Content of Interstitial Collagen in Lesions of Persistently Low ESS p<0.01 Picrosirius Red Thin Cap p<0.01 Picrosirius Red Thick Cap Koskinas KC, et al. Circulation, Under review

21 Summary: Role of Low ESS on Vulnerable Plaque Formation Koskinas KC, Chatzizisis YS, et al. Curr Opin Cardiol 2009;24:580-90

22 Low ESS and Hyperlipidemia Determine the Progression of Atherosclerosis Chatzizisis YS, Koskinas KC, et al. ATVB 2010,

23 Natural History of Atherosclerosis Chatzizisis YS, et al. JACC 2007;49:

24 Redefining Vulnerable Plaque Histopathologic characteristics Regional characteristics Very low ESS IEL fragmentation Excessive expansive remodeling Increased progression rate Chatzizisis YS, et al. JACC 2007;49: Libby P, et al. Nat Med 2002;8:1257

25 Conceptual Strategy for Risk Stratification of Individual Coronary Lesions Chatzizisis YS, et al. Curr Opin Cardiol 2007;22: Toutouzas K, et al. JACC 2007;49: Thermography OCT

26 Conceptual Strategy for Risk Stratification of Individual Coronary Lesions Chatzizisis YS, et al. Curr Opin Cardiol 2007;22: Toutouzas K, et al. JACC 2007;49: ESS, vascular remodeling and inflammation for risk stratification of early non-stenotic fibroatheromas Very low ESS High risk Severe Inflammation Excessive expansive remodeling Low ESS Moderate risk Less inflammation Compensatory remodeling Normal ESS Low risk Limited inflammation No remodeling

27 Tailor-made Therapy of Individual Atherosclerotic Plaques Low/Moderate-Risk Plaque Systemic therapy Regular follow-up High-Risk Plaque Local Therapy Stent Targeted drug delivery Intensive systemic therapy

28 Opportunities of Systemic Interventions to Avert the Pro-inflammatory Effect of Low ESS P: Placebo V: Valsartan V/S: Valsartan + Simvastatin Chatzizisis YS, et al, Atherosclerosis 2009;203:387-94

29 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 ruptureprone plaques (TCFAs). The major determinant of that evolution is low ESS

30 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

31 Funding Ελληνικό Ίδρυμα Καρδιολογίας Ελληνική Καρδιολογική Εταιρεία Εταιρεία Αθηροσκλήρωσης Βορείου Ελλάδος Ελληνική Εταιρεία Αθηροσκλήρωσης Ίδρυμα Κρατικών Υποτροφιών Επιτροπή Ερευνών ΑΠΘ Ελληνικό Ίδρυμα Harvard Κοινωφελές Ίδρυμα Αλέξανδρος Σ. Ωνάσης Ίδρυμα Προποντίς Ίδρυμα Α.Γ. Λεβέντης European Union (Marie Curie Reintegration Grant -FP7) George D. Behrakis Foundation National Institutes of Health American Heart Association European Society of Cardiology European Atherosclerosis Society Hellenic Medical Society of New York Hellenic University Club of New York

32 Acknowledgements Aristotle University Medical School George D. Giannoglou, MD, PhD Kostas Koskinas, MD, MSc Antonios Antoniadis, MD, PhD Vassilis Giannoglou, MSc Sotiris Katranas, MD, MSc Brigham and Women s Hospital, Harvard Medical School Peter H. Stone, MD Charles L. Feldman, ScD Kostas Koskinas, MD, MSc Michael Papafaklis, MD, PhD Ahmet U. Coskun, PhD Galina K. Sukhova, PhD Guo-Ping Shi, ScD Peter Libby, MD MIT Elazer R. Edelman, MD, PhD Michael Jonas, MD Aaron B. Baker, PhD Roy Beigel, MD Benjamin V. Stone University of Washington Charles Maynard, PhD joc@med.auth.gr

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