ΜΑθημα ETY-494 «Ειςαγωγη ςτην ΒιοϊατρικΗ ΜηχανικΗ»

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1 ΜΑθημα ETY-494 «Ειςαγωγη ςτην ΒιοϊατρικΗ ΜηχανικΗ»
Τμήμα Επιστήμης και Τεχνολογίας Υλικών, Σχολή Θετικών Επιστημών, Πανεπιστήμιο Κρήτης Δρ. Γεώργιος Βλαστός ( Ιστοσελίδα Μαθήματος: Αλληλεπίδραση Μηχανικών και Γενετικών Παραγόντων στην Αθηροσκλήρωση

2 ΑΘΗΡΟΣΚΛΗΡΩΣΗ Η αθηροσκλήρωση είναι αποτέλεσμα της συγκέντρωσης λιπαρών ουσιών στο αρτηριακό τοίχωμα Η στένωση της αρτηρίας προκαλεί μείωση της αιματικής ροής Έτσι δημιουργούνται κλινικά προβλήματα, όπως εγκεφαλικό, καρδιακή προσβολή

3 ΠΑΡΑΓΟΝΤΕΣ ΚΙΝΔΥΝΟΥ, ΟΞΕΙΔΩΤΙΚΟ ΣΤΡΕΣ ΚΑΙ ΠΡΟΩΡΗ ΑΘΗΡΟΣΚΛΗΡΩΣΗ
Hypertension Hyperglycemia/Diabetes Hypercholesterolemia Oscillatory Shear Stress M Mo ICAM-1 VCAM-1 LDL Ox-LDL O2•- Endothelial Cells MCP-1 Migration Proliferation Neointimal SMC Foam cells Nox Lox, MPO Nox TNF IL-1 Ang II FIGURE 1. Rexcessive low-density lipoprotein (LDL) is trapped in the sucendothelial space and bound to extracellular matrix (proteoglycans). Here it is oxidized (ox-LDL) via macrophage-derived lipooxygenase (Lox), myeloperoxidase (MPO) or NADPH oxidase (Nox). Ox-LDL induces foam cell formation from macrophages and smooth muscle cells as well as secretion of growth factors and cytokine production (Ang II, IL-1, TNF-a). Ang II, in turn, will recruit more circulating monocytes by enhancing both their adhesion (through upregulation of endothelial cell adhesion molecules ICAM-1, VCAM-1) and chemotaxis via MCP-1 secretion. ROS have been implicated in formation and progression of coronary artery disease. For example the risk factors associated with atherosclerosis have been shown to increase the oxidative stress in the in the animal models of vascular disease. (DOCA-salt, Dahl-Salt rat hypertension, diabetes, apoE mice etc) There are two ways how ROS can influence the cellular processes. On one hand the cells like Macrophages (NADPH) or endothelial cells (the source is e-NOS uncoupled from NO production but able to produce O2-) can release ROS extracellulary. This in turn were shown to upregulate adhesion molecules on the EC cells and stimulate local migration and accumulation of macrophages. On the other hand the ox LDL together with Growth factors (Ang II, PDGF) or cytokines (TNF-) released by local macrophages in atherosclerotic human coronary arteries require release of ROS for their downstream signaling cascades in order to activate and recruit the quiescent SMC and fibroblast into a migratory and proliferative state. At this point animal and in vitro studies have shown the most of the cells present in the vessel wall express at least one or more NAD(P)H oxidase subunits and are able to produce ROS in response to agonists like Ang II or TNF alpha. Smooth Muscle Cells Fibroblasts Weiss et al. AJC 2001;87:25-32

4 ΔΙΑΔΙΚΑΣΙΑ ΤΗΣ ΑΘΕΡΟΓΕΝΕΣΗΣ
Endothelial Dysfunction A B Fatty-Streak Formation C Formation of Advanced Lesion D Unstable Fibrous Plaque Figure 1: Endothelial Dysfunction in Atherosclerosis. The earliest changes that precede the formation of lesions of atherosclerosis take place in the endothelium. These changes include increased endothelial permeability to lipoproteins and other plasma constituents, which is mediated by nitric oxide, prostacyclin, platelet-derived growth factor, angiotensin II, and endothelin; up-regulation of leukocyte adhesion molecules, including L-selectin, integrins, and platelet-endothelial-cell adhesion molecule 1, and the up-regulation of endothelial adhesion molecules, which include E-selectin, P-selectin, intercellular adhesion molecule 1, and vascular-cell adhesion molecule 1; and migration of leukocytes into the artery wall, which is mediated by oxidized low-density lipoprotein, monocyte chemotactic protein 1, interleukin-8, platelet-derived growth factor, macrophage colony-stimulating factor, and osteopontin. Figure 2: Fatty-Streak Formation in Atherosclerosis. Fatty streaks initially consist of lipid-laden monocytes and macrophages (foam cells) together with T lymphocytes. Later they are joined by various numbers of smooth-muscle cells. The steps involved in this process include smooth-muscle migration, which is stimulated by platelet-derived growth factor, fibroblast growth factor 2, and transforming growth factor (beta); T-cell activation, which is mediated by tumor necrosis factor (alpha), interleukin-2, and granulocyte-macrophage colony-stimulating factor; foam-cell formation, which is mediated by oxidized low-density lipoprotein, macrophage colony-stimulating factor, tumor necrosis factor (alpha), and interleukin-1; and platelet adherence and aggregation, which are stimulated by integrins, P-selectin, fibrin, thromboxane A2, tissue factor, and the factors described in Figure 1 as responsible for the adherence and migration of leukocytes. Figure 3: Formation of an Advanced, Complicated Lesion of Atherosclerosis. As fatty streaks progress to intermediate and advanced lesions, they tend to form a fibrous cap that walls off the lesion from the lumen. This represents a type of healing or fibrous response to the injury. The fibrous cap covers a mixture of leukocytes, lipid, and debris, which may form a necrotic core. These lesions expand at their shoulders by means of continued leukocyte adhesion and entry caused by the same factors as those listed in Figure 1 and Figure 2. The principal factors associated with macrophage accumulation include macrophage colony-stimulating factor, monocyte chemotactic protein 1, and oxidized low-density lipoprotein. The necrotic core represents the results of apoptosis and necrosis, increased proteolytic activity, and lipid accumulation. The fibrous cap forms as a result of increased activity of platelet-derived growth factor, transforming growth factor (beta), interleukin-1, tumor necrosis factor (alpha), and osteopontin and of decreased connective-tissue degradation. Figure 4: Unstable Fibrous Plaques in Atherosclerosis. Rupture of the fibrous cap or ulceration of the fibrous plaque can rapidly lead to thrombosis and usually occurs at sites of thinning of the fibrous cap that covers the advanced lesion. Thinning of the fibrous cap is apparently due to the continuing influx and activation of macrophages, which release metalloproteinases and other proteolytic enzymes at these sites. These enzymes cause degradation of the matrix, which can lead to hemorrhage from the vasa vasorum or from the lumen of the artery and can result in thrombus formation and occlusion of the artery. Ross R. NEJM 1999;340:

5 ΕΡΩΤΗΜΑ: Γιατί ενώ όλες οι αρτηρίες εκτίθενται στην ίδια συγκέντρωση της λιποπροτεϊνης LDL στο αίμα, έχουμε αθηρωματικές πλάκες μόνο στις διακλαδώσεις και στις καμπυλώσεις των αρτηριών;

6 ΚΑΝΑΛΙ ΡΟΗΣ ΓΙΑ ΜΕΛΕΤΗ ΤΗΣ ΕΠΙΔΡΑΣΗΣ ΤΗΣ ΡΟΗΣ ΣΤΑ ΚΥΤΤΑΡΑ
Τιμές διατμητικής τάσης παρόμοιες με αυτές στο αρτηριακό σύστημα (περίπου 12 dynes/cm2)

7 ΚΑΝΑΛΙ ΡΟΗΣ ΓΙΑ ΜΕΛΕΤΗ ΤΗΣ ΕΠΙΔΡΑΣΗΣ ΤΗΣ ΤΥΡΒΩΔΟΥΣ ΡΟΗΣ ΣΤΑ ΕΝΔΟΘΗΛΙΑΚΑ ΚΥΤΤΑΡΑ
Προσομοίωση των συνθηκών σε διακλάδωση αρτηρίας

8 ΣΥΓΚΡΙΣΗ ΜΕΤΑΞΥ ΤΟΥ ΕΥΘΕΙΟΥ ΚΑΙ ΤΟΥ ΔΙΑΚΛΑΔΩΜΕΝΟΥ ΚΟΜΜΑΤΙΟΥ ΤΗΣ ΑΡΤΗΡΙΑΣ

9 ΕΣΤΙΑΚΗ ΦΥΣΗ ΤΗΣ ΑΘΗΡΟΣΚΛΗΡΩΣΗΣ ΣΤΗΝ ΚΑΡΟΤΙΔΑ
Malek et al. JAMA 282: , 1999

10 ΑΙΜΟΔΥΝΑΜΙΚΗ ΔΙΑΤΜΗΤΙΚΗ ΤΑΣΗ
Malek et al. JAMA 282: , 1999

11 ΜΟΝΤΕΛΟ ΤΗΣ ΑΘΕΡΟΓΕΝΕΣΗΣ
Malek et al., JAMA 1999;282:

12 ΜΟΡΦΟΛΟΓΙΑ ΕΝΔΟΘΗΛΙΑΚΩΝ ΚΥΤΤΑΡΩΝ ΚΑΙ ΔΙΑΤΜΗΤΙΚΗ ΤΑΣΗ
Malek et al. JAMA 282: , 1999

13 ΧΡΟΝΙΚΗ ΑΝΤΑΠΟΚΡΙΣΗ ΤΗΣ ΜΕΤΑΔΟΣΗΣ ΣΗΜΑΤΟΣ ΚΑΙ ΤΗΣ ΓΟΝΙΔΙΑΚΗΣ ΕΚΦΡΑΣΗΣ ΕΝΔΟΘΗΛΙΑΚΩΝ ΚΥΤΤΑΡΩΝ ΣΤΗΝ ΔΙΑΤΜΗΤΙΚΗ ΤΑΣΗ Activation 30 60 min Ras ERK JNK Basal activity Maximum activation Signal transduction Basal activity Maximum activation Activation 60 120 180 240 min MCP-1 mRNA c-fos mRNA Gene expression Figure 1. Temporal responses of signal transduction and gene expression in ECs to shear stress. The application of shear stress on cultured ECs induces an activation of Ras with the peak activity at > 1 minute and returns to the basal level comparable with that in the static controls represented by 0 shearing time. [42] This rapid and transient Ras activation is followed by an increase in the kinase activities of ERK and JNK with peak activities at 10 and 30 minutes, respectively. [42] The activities of these MAPKs in ECs exposed to prolonged shearing become lower than those in the static controls. Downstream to these signaling events, the genes encoding for c-Fos and MCP-1 are also transiently induced with maximum levels of mRNA at 30 minutes and 1.5 hours, respectively. [15,27] From: Chien: Hypertension, Volume 31(1).January Chien et al. Hypertension 1998;31:

14 ΠΡΩΤΑ ΣΥΜΠΕΡΑΣΜΑΤΑ Οι αιμοδυναμικές δυνάμεις μπορούν να μεταβάλλουν τη δομή και τη λειτουργία των ενδοθηλιακών κυττάρων και των κυττάρων του μυϊκού ιστού Οι αιμοδυναμικές δυνάμεις αλλάζουν το γονιδιακό προφίλ των παραπάνω κυττάρων ανάλογα με τη συγκεκριμένη ροή (στρωτή η τυρβώδης) Υπάρχουν επιπτώσεις στην αγγειοχειρουργική, όπως π.χ. στην χειρουργική bypass. Θα πρέπει να λαμβάνεται υπ’όψη το μηχανικό ταίριασμα μεταξύ του εμφυτεύματος και του αγγείου, ώστε να να αποφεύγεται η δημιουργία περίπλοκων συνθηκών ροής

15 Προτεινόμενα βιβλία για μελέτη
Physics of the Human Body Irving P. Herman 2007, Springer Verlag ISBN , ISBN Vascular Mechanics and Pathology Thubrikar, Mano J. 2006, XXIV, 496 p., 255 illus., 21 in colour, Hardcover ISBN-10: , ISBN-13: The Physics of Coronary Blood Flow Series: Biological and Medical Physics, Biomedical Engineering Zamir, M. 2005, XVIII, 410 p., 269 illus., 4 in colour, Hardcover ISBN-10: , ISBN-13: Textbook of Medical Physiology A.C. Guyton & J.E. Hall 2006, Elsevier, ISBN , International Edition ISBN X …όπως επίσης και πάρα πολλά papers! Αιμοδυναμική των Αγγειακών Παθήσεων Κατσαμούρης Α.Ν. και Χατζηνικολάου Ν.Σ. 2001, Εκδόσεις Σταμούλης, ISBN-10: , ISBN-13: Introduction to Bioengineering. Advanced Series in Biomechanics-Vol. 2 Y.C. Fung (Ed.), World Scientific, 2001 ISBN , ISBN (pbk) Transport Phenomena in Biological Systems. George A. Truskey, Fan Yuan and David F.Katz. Pearson Prentice Hall. ISBN: Mechanosensing and Mechanochemical Transduction in Extracellular Matrix Biological, Chemical, Engineering, and Physiological Aspects Silver, Frederick H. 2006, XVI, 296 p., 145 illus., Hardcover ISBN-10: , ISBN-13: Tissue Mechanics Cowin, Stephen C., Doty, Stephen B. Springer Verlag, 2007, XVI, 682 p., 300 illus., Hardcover ISBN-10: , ISBN-13: