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Coronary Artery Calcification and Other CVD Biomarkers Robert A. Vogel, M.D. Professor of Medicine

. Case Study: 49-year old male academic physician Asymptomatic runs 30 miles/week >2 marathons/year (best 2 hrs 23 min) Father - MI in late 60's BMI 24 kg/m2, BP 110/70 mmHg TC 220, LDL 125, HDL 75, TG 100 CRP 0.5, HC 7.0, Lp(a) 10.0, LDL subtype A. . Case Study: 49-year old male academic physician Asymptomatic runs 30 miles/week >2 marathons/year (best 2 hrs 23 min) Father - MI in late 60's BMI 24 kg/m2, BP 110/70 mmHg TC 220, LDL 125, HDL 75, TG 100 CRP 0.5, HC 7.0,25

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Coronary Artery Calcification and Other CVD Biomarkers Robert A. Vogel, M.D. Professor of Medicine

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    1. Coronary Artery Calcification and Other CVD Biomarkers Robert A. Vogel, M.D. Professor of Medicine University of Maryland Disclosures: None

    4. Case Study: CTA

    6. Requisites for Effective Biomarkers Is it accurate and reproducible? Does it add significant prognostic information to standard assessment? Does it direct therapy? Does it improve patient compliance? Does it improve patient outcome? Is it cost effective?

    7. Vogel’s Rule: Minimal Risk Discrimination for an Effective Biomarker

    8. Young LH et al, N Engl J Med 2009;301:1547 DIAD* Study: 1123 Type 2 Diabetic Subjects Randomized to MPI Screening over 4.8 Years

    9. Budoff MJ et al, Circulation 2006;114:1761 AHA Scientific Statement: Assessment of Coronary Artery Disease by Cardiac CT: Technical Issues Use of EBCT or >4-level MDCT Prospective cardiac gating to mid-diastole Gantry rotation <500 msec Slice thickness 2.5-3 mm to reduce radiation EBCT: 0.6-1.0 mSv MDCT: 0.9-2.0 mSv Cath: 2-4 mSv CTA: 3-9 mSv

    10. Agatston Score CAC >130 HU - 3mm slices ROI’s encircle all lesions Peak Density score: 1 = 130 – 199 HU 2 = 200 – 299 HU 3 = 300 – 399 HU 4 = > 400 HU ROI score = Density score x area Agatston Score = S all ROI scores

    11. Rumberger et al, Circulation 1995 CAC vs. Atherosclerotic Segmental Plaque Area

    12. Hoff et al, Circulation 2006;114:1761 Median CAC Scores in Asymptomatic Subjects

    13. Budoff M et al, J Am Coll Cardiol 2009;53:345 MESA Study: Absolute vs. Percentile CAC Scores and CHD Events

    14. CAC vs. Histologic Stenosis

    15. Budoff MJ et al, Circulation 2002;105:1791 Effect of CAC Score on the Sensitivity and Specificity of Detecting >50% Stenosis in 1851 Symptomatic Patients

    16. Ridker PM et al, N Engl J Med 2002;347:1557 Actual Cardiovascular Events Compared with Framingham Estimate in the WHS

    17. Akosah KO et al, J Am Coll Cardiol 2003;41:1475 Characteristics of Young (?<55, ?<65) MI Patients without prior CHD or CHD Equivalent

    19. Greenland P et al, Circulation 2007;115:402 Meta-analysis of CAC Score and CHD Risk

    20. Nasir K et al, J Am Coll Cardiol Ethnic Differences in the 10-Year Prognostic Value of CAC for Death in 14,812 Subjects Referred for Screening

    21. Leber A et al, Am Heart J 2007 (in press) Relative Predictive Value of CAC and Traditional Risk Factors for CHD in 1726 Asymptomatic Subjects over 40 Months: Dichotomous Analysis

    22. Folsom AR et al, Arch Intern Med 2008;168:1333 Hazard Ratio for CVD Event by CAC and CIMT (per SD) in 6698 non-CVD Subjects (MESA Trial)

    23. Arad Y et al, J Am Coll Cardiol 2005;46:158 St. Francis Heart Study: CHD Events in 4,613 Asymptomatic Subjects 50-70 Years Old by CAC and Framingham Risk

    24. Spadaro LA et al. JACC 1996;27:175A 10-Year CHD Event Risk in Intermediate Risk Subjects (FHS 6-10% or >1 Risk Factor)

    25. Greenland P et al, JAMA 2004;291:210 7-Year Risk of Non-fatal MI or CHD Death in 146 Asymptomatic Subjects with >1 Risk Factor

    26. Becker a et al, American Heart Journal. 2008;155:154 Predictive Value of CAC vs. Established Risk Scores in 1726 Subjects Referred for Cardiac Evaluation - 40 Mo F/U

    29. Framingham Risk Score Adjustment CAC ? ? 0: -5 -5 1-80: -3 -3 81-400: +2 +4 401-600: +5 +9 >600: +8 +12

    30. MI-free Survival in 495 Subjects by 2-Year CAC Progression

    31. Taylor AJ et al, AHA 11/06 Effect of Coronary Calcium Score on Statin and Aspirin Compliance

    32. O’Malley PG…Taylor AJ et al, JAMA 2003;289:2215 Relative Benefit of CAC, Risk Factor Knowledge, and Intensive Management in Modifying CV Risk in 450 Active-Duty Army Personnel at 1 Year

    33. Appropriate Clinical Uses for CAC Asymptomatic individual with 6-10% 10-year CHD risk Individual with atypical chest pain Individual with resting chest pain and normal ECG (low-risk “R/O MI”) Individual with unexplained CHF

    34. Other Biomarkers

    36. Bogaty P et al, Arch Int Med 2005;165:221 Variability in hs-CRP Measurements Made Within 30 Days in 159 Stable CHD Subjects

    37. Ridker PM et al, N Engl J Med 2002;347:1557 Actual Cardiovascular Events Compared with Framingham Estimate + hs-CRP in the WHS

    38. Ridker PM et al, AHA 11/08 JUPITER Trial: Effect of Rosuvastatin 20 mg in Older, Normolipidemic Subjects with ? CRP 17,802 subjects w/o CVD or DM Men >50, women >60 years old (mean 66) LDL <130 (TC 186, LDL 108, HDL 49, TG 118) CRP >2 mg/L (mean 4.3) BMI 28, BP 134/80, FBG 94, Hgb-A1C 5.7% Metabolic syndrome 41% 13.6% 10-yr CV risk with placebo (intermediate) Study stopped early (1.9 years)

    39. Ridker PM et al, AHA 11/08 JUPITER Trial: Effect of Rosuvastatin 20 mg in Older, Normolipidemic Subjects with ? CRP

    40. Ridker PM et al, NEJM 2001;344:1959 Initial LDL and CRP vs. Efficacy of Lovastatin in the AFCAPS/TexCAPS Study

    41. Studies Evaluating Association of Lp-PLA2 with Incident CHD

    42. ARIC, Circulation 2004;109:837 Interaction of CRP and Lp-PLA2 for CHD Risk in the ARIC Study

    43. Lamarche et al, Circulation 1997;95:69 Coronary Heart Disease Risk Based on LDL Particle Size and Apo B

    45. Melander O et al, JAMA 2009;302:49 CVD Risk Adding Biomarkers* to Conventional Risk Assessment in 5067 CVD-free Subjects over 13 Years Conventional Model with Biomarkers Conventional <6% 6-20% >20% Model <6%: 2% (3092) 6% (123) 6-20%: 2% (143) 11% (920) 25% (35) >20%: 12% (34) 27% (136)

    46. NEJM 1997;337:230 Effect of Homocysteine Levels on Survival in CHD

    47. Bazzano LA et al, JAMA 2006;296:2720 Metaanalysis of 12 RCTs of Folate Therapy in 16,958 Subjects with CVD or CKD

    48. Morgan TM et al, JAMA 2007;297:1551; Samani et al, N Engl J Med 2007;357:443 Genetic Prediction of CHD Risk 85 reported genetic variants prospectively evaluated in 811 ACS subjects and 650 controls: only 1 (ß-fibrinogen promoter) marginally significant (p=0.03) Genome-wide analysis (SNPs) of WTCCC (1926 CHD subjects and 1644 controls) and German MI Family Study (875 MI subjects and 1644 controls) 9p21.3 locus (P = 0.000003) 15% ?CHD Risk in heterozygotes 40% ?CHD Risk in homozygotes

    49. Gerdes LU et al, Circulation 2000;101:1366 4S Study: Apo E Phenotype, CV Risk, and Risk Reduction with Simvastatin

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