ΑΠΟ ΤΗΝ ΑΘΩΟΤΗΤΑ ΣΤΗΝ ΕΝΟΧΗ

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1 ΑΘΗΡΩΜΑΤΙΚΗ ΠΛΑΚΑ ΑΠΟ ΤΗΝ ΑΘΩΟΤΗΤΑ ΣΤΗΝ ΕΝΟΧΗ ΔΗΜΗΤΡΗΣ ΤΟΥΣΟΥΛΗΣ Καθηγητής Καρδιολογίας Ά Πανεπιστημιακή Καρδιολογική Κλινική, Ιπποκράτειο Νοσοκομείο, Αθήνα ΘΕΣΣΑΛΟΝΙΚΗ

3 VALNURABLE PLAQUE FACTORS PRONE TO VALNURABILITY PLAQUE COMPONENTS REMODELLING OF PLAQUE INFLAMMATION CURRENT TREATMENT NOVEL PHARMACEUTICAL APPROACHES

4 Valnurable plaque components

5 Tousoulis et al, JACC 2014

6 Virmani R, et al., JACC Oct 2009 Plaque rupture vs. Plaque erosion Almost half of the women under 50 years old present with fibrous cap erosion!!! Plaque rupture (n=65) Plaque erosion (n=50) p-value Stenosis (%) 77.1± ± Necrotic core area (%) 38.3 ± < Plaque burden 231 ± ± Intimal Macrophages (%) 3.44 ± ± Male Gender (%)

7 Sakakura.. Virmani et al, Heart Lung Circ 2013

10 VALNURABLE PLAQUE FACTORS PRONE TO VALNURABILITY PLAQUE COMPONENTS REMODELLING OF PLAQUE INFLAMMATION CURRENT TREATMENT NOVEL PHARMACEUTICAL APPROACHES

11 Remodelling of atheromatous plaque VASA VASORUM VSMC

15 Vasa vasorum και εξέλιξη της πλάκας (ανθρώπινες στεφανιαίες αρτηρίες) n=28 coronaries IT intimal thickening normal PIT pathological intimal thickenin E-FA early thick fibrous cap atheroma L-FA late fibrous cap atheroma TCFA thin fibrous cap atheroma RPT rupture Η πυκνότητα των µικροαγγείων αυξάνεται αναλογικά µε την εξέλιξη των αθηρωµατικών πλακών από την απλή πάχυνση του έσω χιτώνα έως τη ρήξη. J Sluimer, F Kolodgie et al, J Am Coll Cardiol 2009;53:

16 Vasa vasorum και TCFA (ανθρώπινες στεφανιαίες αρτηρίες) Stable TCFA Τα TCFA έχουν αυξηµένη πυκνότητα vasa vasorum σε σχέση µε τις σταθερές πλάκες. F Kolodgie et al, J Am Coll Cardiol 2007;49:

17 Απεικόνιση των vasa vasorum με IVUS (ανθρώπινες στεφανιαίες αρτηρίες) IVUS απεικόνιση vasa vasorum µε έγχυση µικροφυσαλίδων IVUS απεικόνιση vasa vasorum µε µικροφυσαλίδες & ειδικό λογισµικό Vavuranakis M,..,Stefanadis C, International Journal of Cardiology 130 (2008) 23 29

18 VSMC in atherosclerosis _In the early atherosclerosis VSMC contributes to the development of atheroma through the production of MCP-1 and VCAM-1 and matrix molecules required for the retention of lipoproteins _BMC may rise VSMCs

19 47 patients with stable angina and ACS who underwent culprit vessel PCI p < PR group non-pr group Remodelling index (RI): lesion/reference external elastic membrane area Οι πλάκες µε θετική αναδιαµόρφωση συνοδεύονταν από µικρότερο πάχος κάψας. S. Rathore et al, Atherosclerosis 221 (2012)

20 Πάχος κάψας & ρήξη ένοχη βλάβη Η OCT αποτελεί την τεχνική αναφοράς για την απεικόνιση της ρήξης της πλάκας λόγω της µεγάλης διακριτικής ικανότητας. Υπάρχει θετική συσχέτιση µεταξύ του πάχους της κάψας των ενόχων βλαβών όπως εκτιµάται µε OCT και του ποσοστού επιτυχούς θροµβόλυσης. Toutouzas K,..,Stefanadis C, JACC Cardiovasc Interv May;3(5):507-14

21 _ Type VIII Collagen Mediates Vessel Wall Remodeling after Arterial Injury and Fibrous Cap Formation in Atherosclerosis _ Lopez et al, AJ Physiol 2013 _ Collagens in the atherosclerotic plaque signal regulation of cell behavior and provide tensile strength to the fibrous cap. Type VIII collagen, a short-chain collagen, is up-regulated in atherosclerosis; however, little is known about its functions in vivo. We studied the response to arterial injury and the development of atherosclerosis in type VIII collagen knockout mice (Col8 / mice). After wire injury of the femoral artery, Col8 / mice had decreased vessel wall thickening and outward remodeling when compared with Col8 +/+ mice. We discovered that apolipoprotein E (ApoE) is an endogenous repressor of the Col8a1 chain, and, therefore, in ApoE knockout mice, type VIII collagen was up-regulated. Deficiency of type VIII collagen in ApoE / mice (Col8 / ;ApoE / ) resulted in development of plaques with thin fibrous caps because of decreased smooth muscle cell migration and proliferation and reduced accumulation of fibrillar type I collagen. In contrast, macrophage accumulation was not affected, and the plaques had large lipid-rich necrotic cores. We conclude that in atherosclerosis, type VIII collagen is up-regulated in the absence of ApoE and functions to increase smooth muscle cell proliferation and migration. This is an important mechanism for formation of a thick fibrous cap to protect the atherosclerotic plaque from rupture.

22 VALNURABLE PLAQUE FACTORS PRONE TO VALNURABILITY PLAQUE COMPONENTS REMODELLING OF PLAQUE INFLAMMATION CURRENT TREATMENT NOVEL PHARMACEUTICAL APPROACHES

24 Tousoulis D..Stefanadis C. JACC 2014

29 Tousoulis et al, Cytokines and GF Reviews 2006

30 Kampoli AM, Tousoulis D Stefanadis C. Trends Mol Med Jul;15(7):

31 Tousoulis et al, Cytokines and GF Review 2006

35 VALNURABLE PLAQUE FACTORS PRONE TO VALNURABILITY PLAQUE COMPONENTS REMODELLING OF PLAQUE INFLAMMATION CURRENT TREATMENT NOVEL PHARMACEUTICAL APPROACHES

36 Στατίνες & πάχος κάψας ΟΕΜ 40 AMI patients with hyperlipidemia were enrolled and underwent PCI. They were divided into statin group (n = 23) or control group (n = 17). Serial OCT analyses were performed at baseline and 9-month follow-up for a non-pci lipid-rich plaque lesion Η αγωγή µε στατίνες για 9 µήνες µετά το ΟΕΜ, αύξησε σηµαντικά το πάχος της κάψας σε υπερλιπιδαιµικούς ασθενείς (εκτίµηση µε OCT), φαινόµενο που ήταν εντονότερο σε πιο ευάλωτες πλάκες µε µικρότερο πάχος κάψας. S Takarada et al, Atherosclerosis 202 (2009)

38 Πιταβαστατίνη & πάχος κάψας Σταθερή ΣΝ Prospective serial OCT & BaselineIVUS of nontarget lesions 9 months was performed in 42 stable angina pts undergoing elective PCI. 26 received 4 mg pitavastatin, 16 dietary modification alone. FU 9 mths (median interval) Η αγωγή µε πιταβαστατίνη 9 µήνες σταθερή ΣΝ αύξησε σηµαντικά το πάχος της κάψας. K Hattori,,PW Serruys, J Narula, J Am Coll Cardiol Img 2012;5:169 77

39 Στατίνες & αναδιαμόρφωση n= 210 pts with focal coronary lesions with mild luminal narrowing who received atorvastatin or pravastatin Fu with angiography & IVUS at 18 ms Baseline Follow-up Remodeling ratio (RR) : ratio of EEM area at the lesion to that at the proximal reference site. Στη θέση της βλάβης σηµειώθηκε µείωση στο λόγο αναδιαµόρφωσης (-3.0%) Τα αποτελέσµατα αυτά αποδεικνύουν ότι η χορήγηση στατινών οδηγεί σε υποστροφή της θετικής αναδιαµόρφωσης. P Schoenhagen et al, Circulation 2006;113;

41 Antoniades C, Tousoulis D Stefanadis C. Circulation 2010

42 _ 2013 Jan;99(1): doi: /heartjnl Epub 2012 Oct 25. _ Vasa vasorum and plaque progression, and responses to atorvastatin in a rabbit model of atherosclerosis: contrast-enhanced ultrasound imaging and intravascular ultrasound study. _ Tian J, Hu S, Sun Y, Yu H, Han X, Cheng W, Ban X, Zhang S, Yu B, Jang IK. _ To serially investigate the relationship between vasa vasorum (VV) proliferation and plaque progression in vivo, and the effects of atorvastatin on VV and atherosclerosis as assessed by contrast-enhanced ultrasound (CEUS) and intravascular ultrasound (IVUS) imaging. Carotid atherosclerosis was induced in rabbits with a high-cholesterol diet for 20 weeks and balloon injury. At week 16, following the imaging of the right common carotid arteries by CEUS and IVUS, 20 rabbits were randomised into a control or atorvastatin group (2 mg/kg/day). At week 20, CEUS and IVUS were repeated. Normalised maximal video-intensity enhancement (MVE) was calculated to quantify the density of VV. Plaque volume was determined by IVUS. _ When compared with the control group, lipid levels were not significantly lower following 4 weeks of atorvastatin administration. The increases in the normalised MVE over time were greater in the control group than in the atorvastatin group (p=0.001). The increase in plaque volume from 16 to 20 weeks was significantly greater in the control group than in the atorvastatin group (p=0.001). There was a positive relationship between changes in normalised MVE and plaque volume (r=0.72, p=0.002). _ There was a positive correlation between VV density and plaque progression. Atorvastatin significantly inhibits the development of adventitial VV and progression of atherosclerosis independent of lowering the cholesterol level.

43 VALNURABLE PLAQUE FACTORS PRONE TO VALNURABILITY PLAQUE COMPONENTS REMODELLING OF PLAQUE INFLAMMATION CURRENT TREATMENT NOVEL PHARMACEUTICAL APPROACHES

45 Arginase inhibition reduces interleukin-1β-stimulated vascular smooth muscle cell proliferation by increasing nitric oxide synthase-dependent nitric oxide production. Yoon J, Ryoo S. Source Department of Biology, College of Natural Sciences, Kangwon National University, Chuncheon, Republic of Korea. Abstract We investigated whether arginase inhibition suppressed interleukin (IL)-1β-stimulated proliferation in vascular smooth muscle cells (VSMCs) and the possible mechanisms involved. IL-1β stimulation increased VSMC proliferation, while the arginase inhibitor BEC and transfection of the antisense (AS) oligonucleotide against arginase I decreased VSMC proliferation and was associated with increased protein content of the cell cycle regulator p21waf1/cip1. IL-1β incubation induced inducible nitric oxide synthase (inos) mrna expression and protein levels in a dose-dependent manner, but did not affect arginase I and II expression. Consistent with this data, IL-1β stimulation resulted in increase in NO production that was significantly augmented by arginase inhibition. The specific inos inhibitor 1400W abolished IL-1β-mediated NO production and further accentuated IL-1β-stimulated cell proliferation. Incubation with NO donors GSNO and DETA/NO in the presence of IL-1β abolished VSMCs proliferation and increased p21waf1/cip1 protein content. Furthermore, incubation with the cgmp analogue 8-Br-cGMP prevented IL-1β-induced VSMCs proliferation. In conclusion, arginase inhibition augmented inos-dependent NO production that resulted in suppression of IL-1β-induced VSMCs proliferation in a cgmp-dependent manner

54 G-CSF treatment significantly reduced IL 6 levels 6 weeks post treatment compared to baseline. Similar were the effects of lin /sca-1+ cells and EPCs on interleukin 6 levels 7 days and 6 weeks posttreatment compared to baseline. No significant differences among treatment groups at 7 days and 6 weeks were detected.

55 CONCLUSIONS

57 Thromb Haemost 2009;102:

61 Zotarolimus Everolimus Sirolimus

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