USING NON -TRADITIONAL RISK MARKERS IN ASSESSING CV RISK

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1 USING NON -TRADITIONAL RISK MARKERS IN ASSESSING CV RISK JAMES M FALKO MD PROFESSOR OF MEDICINE UNIVERSITY OF COLORADO Adapted from: Rader D. N Engl J Med. 2000

4 hs-crp (mg/l) *p<0.025 vs. Baseline * * * 0 Baseline Prava (40 mg/d) Jialal I et al. Circulation 2001;103: Lippincott Williams & Wilkins. Simva (20 mg/d) Atorva (10 mg/d) Incidence of Recurrent MI or CHD Death by Achieved Levels of Both LDL-C and CRP Recurrent MI or Coronary Death (%) Follow-up (Years) LDL 70 mg/dl, CRP 2 mg/l LDL 70 mg/dl, CRP <2 mg/l LDL <70 mg/dl, CRP 2 mg/l LDL <70 mg/dl, CRP <2 mg/l PROVE IT TIMI 22 Ridker PM et al. N Engl J Med 2005;352: Inflammatory Cytokines Are Released From Omental and Subcutaneous Fat Depots Omental Fat IL-6 TNFα FFA Muscle Liver FFA Adiponectin Leptin Resistin TNFα IL-6 Pancreas FFA TNFα IL-6 IL-6 Brain Subcutaneous Fat 12

Moved to High Risk (36.4%) # Patients Moved to Lower Risk (38.

5 The Problem with a Non-specific Inflammatory Marker : 40% Fluctuation in Risk Category in a Single Month High Risk > 3 mg/l Med Risk 1-3 mg/l Low Risk < 1 mg/l Moved to High Risk (36.4%) # Patients Moved to Lower Risk (38.1%) Moved to Higher Risk (50.0%) Moved to Low Risk (9.1%) Bogaty P et al. Arch Int Med 2005; 165:

The Role of Lp-PLA 2 in Plaque Inflammation

Foam cell MEDIA Lumen Fibrous cap Necrotic

cross-section with monoclonal Ab staining

rupture prone plaque Virmani R, Kolodgie F,

6 The Role of Lp-PLA 2 in Plaque Inflammation LUMEN Oxidized LDL Adhesion molecules Lp-PLA 2 Monocytes Cytokines Plaque formation INTIMA Lyso-PC OxFA Macrophage Foam cell MEDIA Lumen Fibrous cap Necrotic lipid core Human coronary artery cross-section with monoclonal Ab staining (reddish-brown) for Lp-PLA 2 Early plaque with lipid pool Thick cap with small necrotic lipid core stable plaque Thin cap rupture prone plaque Virmani R, Kolodgie F, et al Arterioscler Thromb Vasc Biol 2006 Thr Ruptured plaque with thrombus in lumen

7 Packard (WOSCOPS) - CHD 2000 Blake (WHS) - CHD 2001 Blankenberg (AtheroGENE) - CAD 2003 Ballantyne (ARIC) CHD LDL < Winkler - CHD 2004 Oei (ROTTERDAM) - CHD 2005 Brilakis (Mayo Heart) - CHD 2005 Ballantyne (ARIC) - Stroke 2005 Oei (ROTTERDAM) - Stroke 2005 Winkler (LURIC) - CHD 2005 Khuseyinova (HELICOR) - CHD 2005 Koenig (KAROLA) - CVD 2005 Yang Endothelial dysfunction 2006 Intermountain Heart - CHD 2006 Caslake (PROSPER) - CVD 2006 Jenny (CHS) - MI 2006 Daniels (Rancho Bernardo) - CHD 2006 Elkind (NOMAS) Stroke 2006 O Donoghue (PROVE IT) - CVD 2006 Corsetti (THROMBO) - CHD 2006 Gerber (Olmsted Cty) Death S/P MI 2006 Sabatine (PEACE) - CVD lipids All Packard et al. NEJM 2000 Initial risk assessment and physical examination Low risk 35% Intermediate risk 40% High risk 25% No major risk factors and low At least one major risk Established CHD or CHD Framingham risk score factor or family history risk equivalent 5-year follow up Further testing required to determine appropriate clinical direction Intensive risk intervention < 6% ten year risk 6%-20% ten year risk > 20% ten year risk Major Risk Factors: Age/Gender, Smoking, BP, Family History, Low HDL Greenland P, et al. Improving CHD Risk Assessment in Asymptomatic People. Circ *Pearson TA, et al. AHA/CDC Scientific Statement Markers of Inflammation & CVD Circ

8 Kaplan Meier Survival Curve for Incident CVD Events Perrson M, et al. Elevated Lp-PLA2 Levels Add Prognostic Information to The Metabolic Syndrome on Incidence of Cardiovascular Events Among Middle-Aged Nondiabetic Subjects (Malmö). ATVB 2007 April. Percent reduction in Lp-PLA 2 Average Statin 1,2,3 Fenofibrate 3 Niaspan added to statin 4 Statin Niacin Added To Statin 1. Albert M, et al. Atherosclerosis 2005;182: Schaefer EJ, et al. Am J Cardiol. 2005;95: Muhlestein JB, et al. Am H Journal. 2006;48: Kuvin J, et al. Am J Cardiol Statins Lower Lp-PLA 2 Independently of Their LDL Cholesterol Lowering Effect - PRINCE Change in LpPLA2 Levels (ng/ml) R 2 =0.06 P< Change in LDL-C Levels (mg/dl) Albert MA, et al. Atherosclerosis Sep;182(1):

Initial Risk Assessment and Physical Examination Low Risk Moderate Risk High Risk Very High Risk 0-1 major risk factors Low Framingham risk score, ten year risk: < 10% 2+ risk factors and ten year

9 Initial Risk Assessment and Physical Examination Low Risk Moderate Risk High Risk Very High Risk 0-1 major risk factors Low Framingham risk score, ten year risk: < 10% 2+ risk factors and ten year risk: 10-20% OR Age 65 or older OR HTN > 135/85mmHg OR Smoker OR FB Glucose > 100mg/dl Established CHD OR CHD risk equivalent (DM, stroke, PAD, ESRD) OR ABI <.9 OR >50% stenosis on carotid ultrasound OR hs-crp > 3.0mg/L Established CVD PLUS 3 risk factors OR Poorly controlled severe risk factors OR Metabolic syndrome OR Acute CVS 1 year follow-up If the PLAC test is > 235ng/ml then it would be reasonable to treat LDL to the target for the next higher risk category; either 100mg/dl or 70mg/dl, respectively. Intensify treatment of non-lipid risk factors as well CV Risk Stratification Panel: Davidson MH, Braun LT, Corson MA, Gorelick P Lipoprotein (a) apob 100 LDL Particle n S S apo (a) J Cardiovasc Risk 1995;2:206-15

10 Genetic Homology: Lp (a) and Plasminogen 5 1 S T P 3 1 Plasminogen 791 AA apo (a) 4529 AA 5 1 S P % Homology S signal peptide T tail region P protease Untranslated regions Nature 1987;330: Lp(a) NHLBI Recommendations 1. It is essential that Lp(a) assays used in clinical and epidemiologic studies be validated for their ability to provide accurate values independently of the size of apo(a) in the samples. 2. The expression of Lp(a) values in terms of total Lp(a) mass (mg/dl) should be abandoned as this reflects protein component of Lp(a) and not its lipid and carbohydrate content. 3. To correctly reflect the number of Lp(a) particles and to compare data from different studies, the values should be expressed in terms of nmol/l of Lp(a). Marcovina SM, et al. Clin Chem 2003;49: Lp(a) NHLBI Recommendations 4. Lp(a) screening in the general population is not recommended. Measurement of Lp(a) is recommended in individuals with an increased risk of CVD, particularly those with borderline LDL-C or high apo B. 5. On the basis of currently available data, individuals with Lp(a) values exceeding the 75th percentile are at increased risk for CVD. For Caucasians, based on the Framingham data, this corresponds to an Lp(a) value of > 75 nmol/l. 6. If methods sensitive to apo(a) isoform size are used for risk assessment, samples with values > 50 nmol/l should be remeasured by referral laboratories using validated methods. Marcovina SM, et al. Clin Chem 2003;49:

11 Flow Divider ICA Bulb CCA

magnitude of change Computer-assisted 1 cm longitudinal measurement

0x mm CCA = common carotid artery, ICA = internal carotid artery

12 CIMT Which site? CCA, ICA, bulb CCA most reproducible ICA/Bulb: Plaque Greater magnitude of change Computer-assisted 1 cm longitudinal measurement Easy- takes minutes Accurate-.0x mm CCA = common carotid artery, ICA = internal carotid artery Ultrasound Contrast-enhanced Vascular Imaging Plaque neovascularization highlighted with ultrasound contrast agents Contrast-enhanced, common carotid artery lumen

Inflammation: Novel Target for Cardiovascular Risk Reduction

Inflammation: Novel Target for Cardiovascular Risk Reduction Andrew Zalewski, M.D. Thomas Jefferson University, Philadelphia GlaxoSmithKline, Philadelphia Why inflammation? Population-based studies: low