Disclosures Department of Cardiac Sciences and Libin Cardiovascular - PowerPoint PPT Presentation

Disclosures • Department of Cardiac Sciences and Libin Cardiovascular Institute – U of Calgary • Grant support by HSF, AI-HS • Grant support – Roche, Merck, Abbott

Assessment of Vascular Risk Objectives • Characteristics of biomarkers • Imaging Biomarkers for intermediate risk – Carotid ultrasound or MR – Calcium scoring – coronary or abdominal – Cardiac MR

Characteristics of a Surrogate • Biomarker intended to substitute for a clinical endpoint • Expected to predict clinical outcomes (feels, functions or survives, including harm) • Does epidemiological data suggest that the biomarkers adds to the ability to detect risk independently of established risk factors? • Examples: – Blood pressure – LDL cholesterol •

How to evaluate new biomarker • Univariate and multivariate relationship with CV outcomes – Cox proportional hazard • Compared with existing model – individual risk factors or Framingham risk score – Global measures of model fit – Calibration – Discrimination – Reclassification Mc Geechan et al. Arch Int Med 2008;168:2304 •

Assessment of Vascular Risk – Why do we need • ARIC study n=15732 with 461 events • FRS had a C statistic of 0.75 • At cut-off of >20% risk only 22% of those with hard events would have been identified • Negative predictive value was 97%

Inflammation and Proliferation CV Biomarkers Today CRP Lp-PLA2 MCSF PDGF Lipids Imaging FDF lipoproteins Angiography FGF lipoprotein subfractions IVUS Interleukins (1,6,8,10,12,15) (L1-3, V1-6, H1-5) 3D reconstruction IVUS MMPs (1,2,3,9) Apolipoproteins Serum glycoproteins MDCT (coronary Ca++) MIP1 (alpha and beta) (CIII, AII:E, LpB…) Carotid ultrasound – IMT Alpha 1-antitrypsin TNF alpha Lp(a) Alpha 1 acid glycoprotein MRI (carotid, PAD, aortic) Proliferating cell nuclear antigen Lipid ratios Alpha 2-macroglobulin PET Hyaluronan receptors Ceruloplasmin Aortic CT SR-A, SR-B1 haptoglobin Scintigraphy (thallium, sestimibe) TGF Intracoronary endo fct (Ach) SM myacin heavy chains Brachial ultrasound CD 11, 18, 36, 40, 68 Plethysmography MCP-1 Coagulation Adhesion molecules TEE (aortic) CCR2 VWF s-ICAM Skin cholesterol Pentraxin-3 tPA s-VCAM Monoclonal antibody imaging C4b binding protein PAI-1 P-selectin Pulsatile flow visualization (aorta) I kappa B-alpha PF4 E-selectin Regional aortic distensibility Total sialic acid D-dimer Aortic stiffness (Doppler) Osteopontin Tissue factor Coronary thermography Fibrinogen Genetics Coronary elastography Beta thromboglobulin Coronary NIR spectroscopy ACE polymorphism Erythrocyte sed. Rate methylenetetrahydrofolate reductase [MTHFR] RBC adhesiveness/aggreg Immunology apolipoprotein E [apo E] Anti-oxLDL IgG paraoxonase [PON]

2012 CCS Dyslipidemia Guidelines 1. We recommend secondary testing for further risk assessment in “ intermediate risk ” (10-20% FRS after adjustment for family history) subjects who are not candidates for lipid treatment based on conventional risk factors or for whom treatment decisions are uncertain. (Strong/moderate evidence) 2. We suggest that secondary testing may be considered for a selected subset of “ low to intermediate risk ” (5-10% FRS after adjustment for family history) subjects for whom further risk assessment is indicated, e.g. strong family history of premature CAD, abdominal obesity, South Asian ancestry or impaired glucose tolerance. (Weak/low evidence)

Biomarkers that predicted risk of death C statistic increases from 0.76 to 0.77 with all biomarkers added Wang TJ et al. N Engl J Med 2006; 355:2631-2639.

Eva Lonn

Novel markers of atherosclerotic risk Met-analysis of 37197 subjects 8 studies, 12 pubs of IMT Lorenz et al. Circ 2007 115:459

IMT and Discrimination, Reclassification • USE-IMT meta-analysis – 15 large cohort studies – 45,000 subjects – 4007 first MI or stroke – C-statistic 0.757 and not changed with IMT – NRI significant but 0.8% given sample size – NCRI for intermediate risk 3.6% Den Ruijiter JAMA 2012; 308:796-

Plaque Burden 6101 aSx BioImage Study Carotid Plaque, CIMT, ABI, AAD and CAC Mean age 69 yrs, Carotid plaque burden was most strongly correlated with CAC Sillesen et al. JACC CVI 2012;5:681

Plaque, IMT and Discrimination, Reclassification Framingham offspring 2965 with 296 events NRI 0% for CCA NRI 7.6% for ICA And 7.3% for ICA Plaque 7.2 y follow-up Pollak NEJM 2011;365:213

ASE recommendations - CIMT • aSx subjects – Carotid IMT might be useful – Intermediate risk subjects – IIa AHA/ACC – Subjects with strongly positive family Hx of CAD – Women less than 60 years with > 2 risk factors – Genetic dyslipidemia – Use should be restricted to centres with specific research experience – Use of 3D plaque measurements being evaluated Roman et al. J Am S of Echo 2006; 19:943. Stein et al. J Am S of Echo 2008;21:93 Greenland et al. JACC 2010;56:Dec 2010 Atherosclerosis 2011; 214:43-46

Coronary Artery Calcium Due to atherosclerosis Related to age and risk factors Not related to stenosis but is related to plaque volume Can be detected by EBCT or MDCT Radiation dose is moderate (0.5-1.5 mSev and acquisition very quick Variance about 40% for repeated measures

Coronary calcium score – Prevalence aSx group 44,052 CAC related to all cause mortality across age range Tota-Maharaj EHJ 2012;33:2955

Coronary calcium score – Related to Risk factors MESA – n=6783 Cross X Inflammatory markers weakly correlated after adjusting for traditional factors Jenny et al. Athero 2010;209:226

Coronary calcium score - Prognosis MESA – 6722 subjects 162 events HR 7.08 for major Coronary event With CAC >100 Detrano NEJM 2008;356:1336

Coronary calcium score – Prognosis aSx group 44,052 CAC related to all cause mortality across age range Tota-Maharaj EHJ 2012;33:2955

CAC and Discrimination, Reclassification 5878 MESA subjects 209 CHD events CAC added to multiple risk factors NRI 25% CAC >300 Polonsky JAMA 2010;303:1610

CAC and Discrimination, Reclassification Rotterdam 2028 aSx subjects 9.2 years with 135 hard EPs 52% of IR reclassified CAC < 50 or >615 Elias Smale JACC 2010;56:1407

AHA/ACC recommendations - CT • aSx subjects – MDCT calcium scores – Low or high risk subjects – Class III – Level B evidence – Middle risk subjects – Class IIa – Level B evidence • aSx subjects – MDCT coronary angiography – All subjects – Class III – Level B evidence • Serial imaging for athero progression – Class III Greenland et al. JACC 2010;56:Dec 2010

Comparison of novel risk markers MESA 1330 IR subjects CAC, IMT, CRP, FH and ABI 123 CVD events Carotid IMT not associated with events while others were CAC was best Yeboah JAMA 2012;308:788

Abdominal Calcification Framingham cohort - N=3285 50y of age Compared with healthy ref pop - Agaston Ca++ score of AA AAC widely prevalent and associated FRS Chuang AJC 2012;110:891

Carotid MR for plaque evaluation Fayed et al. Lancet Sept 2011

Measuring Atherosclerosis PET/CT Positron emission tomography (PET) 18F-FDG-PET/CT • PET with 18F-fluorodeoxyglucose (18F-FDG) can identify cells with increased metabolic activity 1,2 imaging 5 • 18F-FDG-PET can be used to detect inflammation; e.g. in atherosclerotic plaques 1,2 CT – a potential marker for vulnerable plaques • Serial PET imaging can assess changes in plaque inflammation over time, including responses to therapy 2 – 4 Positron emission tomography (PET)/Computed PET/CT tomography (CT) • CT facilitates anatomic location of plaque, allowing assessment by PET of changes over time in response to therapy 2 1 Rudd et al. Circulation . 2002;105;2708 – 2711; 2 Rudd et al. J Am Coll Cardiol. 2010;55:2527 – 2735; 3 Tahara et al. J Am Coll Cardiol . 2006;48:1825 – 1831; 4 Lee et al. J Nucl Med. 2008;49:1277 – 1282; 26 5 Fayad et al. Lancet. 2011.

Cardiac MR for Risk Stratification 5004 subjects in MESA CMR, followed for 7.2 y LV structure and Fx LVGFI = SV/LV total V 579 events Independent predictor of HF and hard events – better than EF HR 0.79 adjusted including CAC Mewton et al. Hypertension 2013;61:ahead of press

Assessment of Vascular Risk • Vascular risk can be assessed using risk engines such as Framingham • Risk stratification for intermediate risk subjects is difficult • The use of imaging biomarkers in these subjects may aid in risk stratification but randomized trials utilizing these approaches are required