Ο ρόλος ηης γενεηικής ζηην παθογένεια και ηη θεραπεσηική ανηιμεηώπιζη ηων καρδιαγγειακών παθήζεων. Νεόηεροι παράγονηες κινδύνοσ

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1 ΠΑΝΕΠΙΣΗΜΙΟ ΙΩΑΝΝΙΝΩΝ ΕΡΕΤΝΗΣΙΚΟ ΚΕΝΣΡΟ ΑΘΗΡΟΘΡΟΜΒΩΣΗΣ Ο ρόλος ηης γενεηικής ζηην παθογένεια και ηη θεραπεσηική ανηιμεηώπιζη ηων καρδιαγγειακών παθήζεων. Νεόηεροι παράγονηες κινδύνοσ Αλέξανδπορ Γ. Τζελέπηρ, MD, PhD Καθηγηηήρ Βιοχημείαρ Κλινικήρ Χημείαρ

2 Prevalence of major risk factors in men with CHD 2 major risk factors 3 major risk factors 8.9% 4 major risk factors 0.9% 0 major risk factors 19.4% Traditional risk factors are a useful first step in determining who could be at risk for a coronary event 27.8% 43.0% 62.4% 0 to 1 major risk factor Exposure to one or more CHD risk factors is also highly prevalent in individuals who do not develop clinical CHD N=87,869 1 major risk factor Less than 10% of patients have 3 or 4 major risk factor 4 Major modifiable risk factors: hypertension, smoking, hypercholesterolemia, diabetes Khot, et al. JAMA. 2003

4 Secondary testing may be used and new risk factors should be identified to further stratify individuals for CHD risk

5 Role of inflammation in plaque formation and instability Koenig W et al. ATVB. 2007;27;15-26

7 Manhattan plot and QQ plot of association findings Naitza S, et al. PLOS Genetics. 2012; 8: e

8 Top association signals for IL-6, ESR, MCP-1, and hscrp in the ImmunoChip and MetaboChip data-sets Naitza S, et al. PLOS Genetics. 2012; 8: e

9 Markers of inflammation and myocardial damage Adapted from: Rader D. N Engl J Med. 2000

10 hscrp

14 The JUPITER trial Ridker PM, et al. N Engl J Med 2008;359:

15 The JUPITER trial Ridker PM, et al. N Engl J Med 2008;359:

17 Association of 17 genome-wide significant loci with CRP levels Dehghan A, et al. Circulation. 2011; 123:

18 The forest plots show the meta-analysis of the association of the CRP genetic risk score with CVD MI CHD Dehghan A, et al. Circulation. 2011; 123:

19 CONCLUSION We identified 18 loci that were associated with CRP levels However, there was no evidence for these genetic variants explaining the association of CRP with CAD Dehghan A, et al. Circulation. 2011; 123:

20 JAMA. 2009;302(1):37-48

21 Manhattan Plot of Results From the Combined Analysis of Genome-Wide Association Data Elliott P, et al. JAMA. 2009;302(1):37-48

22 Genomic Context, Alleles, Minor Allele Frequency, Association Test Results for Most Associated SNP at Each Locus, and Effect on CRP Levels Elliott P, et al. JAMA. 2009;302(1):37-48

23 Associations of SNPs in LEPR, IL6R, and HNF1A Loci and APOE-CI-CII Cluster in the Genetic Association Study With CHD Leptin Receptor IL6 Receptor Hepatic Nuclear Factor 1A Apo E-CI-CII Elliott P, et al. JAMA. 2009;302(1):37-48

24 CONCLUSION The lack of concordance between the effect on coronary heart disease risk of CRP genotypes and CRP levels argues against a causal association of CRP with coronary heart disease Elliott P, et al. JAMA. 2009;302(1):37-48

25 Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) or PAF-acetylhydrolase

Lp-PLA2 activity, % of total Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) 100 90

26 Lp-PLA2 activity, % of total Lipoprotein-associated phospholipase A 2 (Lp-PLA 2 ) % LDL 10% HDL Lp(a) Τselepis AD, et al, ATVB 1995; 15:

27 The LDL oxidation process: Role of Lp-PLA 2 Phosphatidylcholine (PC) Oxidation Oxidatively-modified PC Lp-PLA 2 + Oxidized fatty acid (oxfa) Lysophosphatidylcholine (Lyso-PC) Tselepis AD, et al. Atheroscler Suppl. 2002

28 Role of Lp-PLA2 in plaque necrotic core formation Wilensky RL, et al. Curr Opin Lipidol 2009, 20:

29 Σα επίπεδα ηηρ Lp-PLA 2 αςξάνονηαι ζηη ζηεθανιαία κςκλοθοπία μόνο όηαν ςπάπσοςν αθηπωμαηικέρ πλάκερ (με IVUS) ζηα ζηεθανιαία αγγεία C oronary Atheros c leros is No Atheros cleros is p < 0.01 p = NS Lp-P LA 2 C R P Lavi S, et al. Circulation 2007

30 Representative immunostaining for Lp-PLA2 showing expression in the core and shoulder area. Mannheim D, et al. Stroke. 2008;39:

31 Contrasting histopathologic characteristics of a stable versus ruptured plaque. Stable plaque Low Lp-PLA 2 content Ruptured plaque High Lp-PLA 2 content Corson MA, et al. Am J Cardiol 2008;101[suppl]:41F 50F

32 Η ζημαζία ηηρ Lp-PLA 2 ωρ δείκηηρ καπδιαγγειακού κινδύνος

33 Elevated Lp-PLA 2 is consistently associated with a doubling of risk for CVD

35 Manhattan plot of genome-wide P values for association with Lp-PLA2 Activity Association with LDL-C APOA5, APOA4, APOC3, APOA1 SR-BI Mass Suchindran S, et al, PLoS Genet 6; 4: e

36 Relative odds of CHD associated with PLA2G7 variants Casas JP, et al. Circulation 2010;121:

38 Regional plots for top SNPs Grallert H, et al. European Heart Journal (2012) 33,

40 Association of the top SNPs in six loci with prevalent CAD in the CARDIoGRAM consortium Grallert H, et al. European Heart Journal (2012) 33,

41 Μέθοδορ για ηη μέηπηζη ηηρ μάζαρ ηηρ Lp-PLA2

42 Substituted Pyrimidones Specific Lp-PLA 2 inhibitors SB (Darapladib) Phase II studies, Phase III trials

43 Darapladib reduces Lp-PLA 2 activity in plasma Mohler ER et al, JACC 2008; 51:

44 Effects of Darapladib on Coronary plaque Serruys PW et al, Circulation 2008; 118:

45 Α phase III outcome trial (NCT ), that is due to be completed in 2012.

46 SOLID-TIMI 52 The Stabilization Of plaques using Darapladib-Σhrombolysis In Myocardial Infarction 52 Trial ClinicalTrials.gov Identifier NCT This study is currently recruiting participants Purpose This study will test whether darapladib (160 mg / day) can safely lower the chances of having a CV event (such as a heart attack or stroke) when treatment is started within 30 days after an ACS.

47 Ioannina

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