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
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
Secondary testing may be used and new risk factors should be identified to further stratify individuals for CHD risk
Role of inflammation in plaque formation and instability Koenig W et al. ATVB. 2007;27;15-26
Manhattan plot and QQ plot of association findings Naitza S, et al. PLOS Genetics. 2012; 8: e1002480
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: e1002480
Markers of inflammation and myocardial damage Adapted from: Rader D. N Engl J Med. 2000
hscrp
The JUPITER trial Ridker PM, et al. N Engl J Med 2008;359:2195-207
The JUPITER trial Ridker PM, et al. N Engl J Med 2008;359:2195-207
Association of 17 genome-wide significant loci with CRP levels Dehghan A, et al. Circulation. 2011; 123: 731 738
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: 731 738
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: 731 738
JAMA. 2009;302(1):37-48
Manhattan Plot of Results From the Combined Analysis of Genome-Wide Association Data Elliott P, et al. JAMA. 2009;302(1):37-48
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
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
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
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 80 70 60 50 40 30 20 10 0 90% LDL 10% HDL Lp(a) Τselepis AD, et al, ATVB 1995; 15: 1764-1773
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
Role of Lp-PLA2 in plaque necrotic core formation Wilensky RL, et al. Curr Opin Lipidol 2009, 20:415 420
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
Representative immunostaining for Lp-PLA2 showing expression in the core and shoulder area. Mannheim D, et al. Stroke. 2008;39:1448-1455
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
Η ζημαζία ηηρ Lp-PLA 2 ωρ δείκηηρ καπδιαγγειακού κινδύνος
Elevated Lp-PLA 2 is consistently associated with a doubling of risk for CVD
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: e1000928
Relative odds of CHD associated with PLA2G7 variants Casas JP, et al. Circulation 2010;121:2284-2293
Regional plots for top SNPs Grallert H, et al. European Heart Journal (2012) 33, 238 251
Association of the top SNPs in six loci with prevalent CAD in the CARDIoGRAM consortium Grallert H, et al. European Heart Journal (2012) 33, 238 251
Μέθοδορ για ηη μέηπηζη ηηρ μάζαρ ηηρ Lp-PLA2
Substituted Pyrimidones Specific Lp-PLA 2 inhibitors SB 480848 (Darapladib) Phase II studies, Phase III trials
Darapladib reduces Lp-PLA 2 activity in plasma Mohler ER et al, JACC 2008; 51: 1632-1641
Effects of Darapladib on Coronary plaque Serruys PW et al, Circulation 2008; 118: 1172-1182
Α phase III outcome trial (NCT00799903), that is due to be completed in 2012.
SOLID-TIMI 52 The Stabilization Of plaques using Darapladib-Σhrombolysis In Myocardial Infarction 52 Trial ClinicalTrials.gov Identifier NCT01000727 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.
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