Coronary Artery Calcification and Other CVD Biomarkers

Robert A. Vogel, M.D.

Professor of Medicine University of Maryland

Disclosures: None

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, Lp(a) 10.0, LDL subtype A• Incidental EBT CAC Score 1200

Case Study: CTA

Current Meds:

aspirin 81 mgatorvastatin 40 mgezetimibe 10 mgramapril 10 mgamlodipine 5 mgvalsartan 320 mgvitamin C 1 gm prior to exercise

He continues to run daily.

Mohlenkamp, S. et al. Eur Heart J 2008 29:1903-1910; doi:10.1093/eurheartj/ehn163

Event-free Survival by CAC Score

12% (+) Gd-MRI 21% 10-yr event

rate

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?

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

0

1

2

3

4

5

Dichotomous Tertiles Quartiles Qunitiles 1 SD

3X

4X

5X

1.5X2X

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

0%

2%

4%

6%

8%

10%

12%

14%

CV Events CV Events

(+) MPI(-) MPIScreenedNot Screened

6% per 10 years

* Detection of Ischemia in Asymptomatic Diabetics

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

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 = Σ all ROI scores

Region of interest

Rumberger et al, Circulation 1995

CAC vs. Atherosclerotic Segmental Plaque Area

0

0.5

1

1.5

2

2.5

0-1 1-5 5-10 >10

Histologic Plaque Area (mm2)

CA

C P

laq

ue

Are

a (m

m2 )

1:5 area ratio

CAC = CAD

Hoff et al, Circulation 2006;114:1761

Median CAC Scores in Asymptomatic Subjects

0

50

100

150

200

250

300

350

400

450

500

<40 40-44 45-49 50-54 55-59 60-64 65-69 70-74 >74

Men

Women

Age (Years)

Budoff M et al, J Am Coll Cardiol 2009;53:345

MESA Study: Absolute vs. Percentile CAC Scores and CHD Events

0

5

10

15

20

25

30

35

1-100 100-400 >400

<75%75-90%>90%

CAC (Agatston Score)

CH

D E

ven

ts/1

000

Per

son

Yea

rs

Sangiorgi G et al, Circ 1998;31:126

CAC vs. Histologic Stenosis

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

0%

20%

40%

60%

80%

100%

CAC >0 CAC >80

Sensitivity

Specificity

↑sensitivity ↓specificity with ↑age

Ridker PM et al, N Engl J Med 2002;347:1557

Actual Cardiovascular Events Compared with Framingham Estimate in the WHS

0%

5%

10%

15%

20%

25%

30%

0-1% 2-4% 5-9% >10%

Car

dio

vasc

ula

r E

ven

ts

Framingham Estimate of 10-Year Risk

Age, TC, HDL, BP, Smoking

20:1 discrimination

Akosah KO et al, J Am Coll Cardiol 2003;41:1475

Characteristics of Young (♂<55, ♀<65) MI Patients without prior CHD or CHD Equivalent

0%

10%

20%

30%

40%

50%

60%

70%

80%

Male Obese Smoker 2+ RiskFactors

FamilyHistory

HTN Lipid TxRecomm

TC 190 LDL-C 126 HDL-C 42♂, 45♀ Trig 145

Circulation. 2008;118

Reynolds Risk Score*Physicians Health Study

* AgeSBPTC

HDLSmokerHbA1C (if DM)hsCRPFm Hx

Framingham Model

Reynolds Model

Greenland P et al, Circulation 2007;115:402

Meta-analysis of CAC Score and CHD Risk

0

1

2

3

4

5

6

7

8

9

10

CAC 0 CAC 1-99 CAC 100-399

CAC 400-999

CAC >1000

HR

for

CH

D

0 CAC = 4% 10-Year Risk

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

0

10

20

30

40

50

60

CAC >100 White AA Hispanic Asian

0-10

11-100

101-400

401-1000

>1000

CAC Score

(% Subjects) Relative Risk of Death by CAC Score

Whi

te

A

A

His

pani

c A

sian

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

0

1

2

3

4

5

6

HTN Smoking HC DM CAC>75%

HR

for

CH

D E

ven

ts

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)

0

0.5

1

1.5

2

2.5

CAC CIMT

HR

for

CV

D E

ven

t

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

0%

5%

10%

15%

20%

25%

30%

35%

40%

<10% 10-20% >20%

01--75>75

Agatston Score

CH

D E

ven

ts /

10 Y

ears

Framingham 10-Year CHD Risk

Intermediate Risk

12:1 discrimination

Spadaro LA et al. JACC 1996;27:175A

10-Year CHD Event Risk in Intermediate Risk Subjects (FHS 6-10% or >1 Risk Factor)

0%

5%

10%

15%

20%

25%

CACS 0-99 CACS 100-399 CACS >400

10-Y

ear

CH

D E

ven

t R

isk

Intermediate Risk

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

0

2

4

6

8

10

12

14

16

18

20

0-9% 10-15% 16-20% >20%

0

1-100

101-300

>300

7-Y

ear

CH

D E

ven

t R

ate

(%)

CAC Score

Framingham 10-Year CHD Risk

0 score = 4..7-15% 10-year event rate

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

RECALL Study: CVE Events by ATP III and CAC in 4814 men and women, aged 45 – 75 years

**: p < 0.0001 vs ATPIII

*: p = 0.004 vs ATPIII

Men**: p = 0.18 vs ATPIII

*: p = 0.80 vs ATPIII

Women

Men Women

0.0 0.2 0.4 0.6 0.8 1.0

0.0

0.2

0.4

0.6

0.8

1.0

Sens

itiv

ity

1 - Specificity

ATPIIIlog(CAC+1)ATPIII + log(CAC+1)

0.727 **

0.724 *0.602

0.0 0.2 0.4 0.6 0.8 1.0

0.0

0.2

0.4

0.6

0.8

1.0

1 - Specificity

ATPIIIlog(CAC+1)ATPIII + log(CAC+1)

0.660

0.677 *

0.723 **

Sen

siti

vity

Schmermund A et al Am Heart J 144:212-18, 2002Stang A et al Eur J Epidemiol 20: 489-96, 2005Dragano N et al Eur J Cardvasc Prev Rehab 14:568-74, 2007Presented at ACC Annual Scientific Sessions 3/09

87.3% 9.3% 3.4%

Events Stratified by ATP III & CAC Categories

All Subjects

Data = Event Rates (95%CI)

62.9% 23.1% 14.1% 49.8% 27.4% 22.9%51.5% 28.8% 19.7%

Low risk

0

8

12

20

Eve

nt

Rat

e in

5 Y

ears

[%

]

16

4

<100 100-399 ≥400 <100 100-399 ≥400

Intermediate risk High riskATP III

CAC <100 100-399 ≥400

Framingham Risk Score Adjustment

CAC ♂ ♀0: -5 -51-80: -3 -381-400: +2 +4401-600: +5 +9>600: +8 +12

Grundy S et al, Am J Cardiol

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

<15% change

>15% change

Budoff MJ

Taylor AJ et al, AHA 11/06

Effect of Coronary Calcium Score on Statin and Aspirin Compliance

0%

20%

40%

60%

80%

100%

Statin Aspirin

CAC = 0

CAC > 0% P

atie

nts

Rem

ain

ing

on M

edic

atio

ns

P=0.059 P=0.36

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

1

1.1

1.2

1.3

1.4

1.5

1.6

1.7

KnowledgeCAC

KnowledgeRF's

IntensiveManagement

Od

ds

Rat

io

P=N.S. 1.16-1.75 1.04-2.52

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

Other Biomarkers

Emerging Soluble Biomarkers

Lipids Lp(a) apoA/apoB Particle size/number

Inflammation CRP SAA IL-6 IL-18 TNF Adhesion mols Lp-PLA2 CSF CD40L

Hemostasis/Thrombosis Homocysteine tPA/PAI-1 TAFI Fibrinogen D-dimer

Oxidation Ox-LDL MPO Glutathione

Genetic Asp299Gly polymorphism in TLR4 gene MCP-1 2578G allele CX3CR1 chemokine receptor polymorphism V249I 16Gly variant of 2-adrenergic receptor 260T/T CD14 allele 117 Thr/Thr variant of CSF LIGHT

Adapted from Stampfer MJ et al. Circulation. 2004;109(suppl):IV3-IV5

Bogaty P et al, Arch Int Med 2005;165:221

Variability in hs-CRP Measurements Made Within 30 Days in 159 Stable CHD Subjects

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

Overall Low Risk Average Risk High Risk

Inci

den

ce o

f S

ame

Cla

ss Variability not dependent on clinical parametersNo Variability

Pure chance

↑22% ↓18%

Ridker PM et al, N Engl J Med 2002;347:1557

Actual Cardiovascular Events Compared with Framingham Estimate + hs-CRP in the WHS

0%

5%

10%

15%

20%

25%

30%

0-1% 2-4% 5-9% >10%

<1.0

1.0-3.0

>3.0

Car

dio

vasc

ula

r E

ven

ts

Framingham Risk Estimate

hs-CRP

1.3X

2X

2.2X

1.9X

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)

Ridker PM et al, AHA 11/08

JUPITER Trial: Effect of Rosuvastatin 20 mg in Older,

Normolipidemic Subjects with ↑ CRP

-50%

-40%

-30%

-20%

-10%

0%

LDL-C CRP CVE MajorCVE

Death

Tre

atm

ent

Eff

ect

MI, stroke, USA, revasc,

CV death

MI, stroke, CV death

All P <0.01 NNT 26-120

Ridker PM et al, NEJM 2001;344:1959

Initial LDL and CRP vs. Efficacy of Lovastatin in the AFCAPS/TexCAPS Study

RR P 1 RF: 0.84 (NS) 2+ RF: 0.57 (<.001)

Studies Evaluating Association of Lp-PLA2 with Incident CHD

HR 1.23 per 1 SD General population

97 cases, 837 controls

Koenig et al

HR 1.97 4th vs 1st quartile

General population

418 cases, 1820 controls

Oei et al

HR 1.78 tertile 3 vs. tertile 1

General population

608 cases, 740 controls

Ballantyne et al

RR 1.18 per 1 SD WOSCOPS subgroup 580 cases, 1160 controls

Packard et al

Findings*SubjectsStudy

*Adjusted relative risk (RR) or hazard ratio (HR)

Packard CJ et al. N Engl J Med. 2000;343:1148-55.Ballantyne CM et al. Circulation. 2004;109:837-42.

Koenig W et al. Circulation. 2004;110:1903-8.Oei H-HS et al. Circulation. 2005;111:570-5.

ARIC, Circulation 2004;109:837

Interaction of CRP and Lp-PLA2 for CHD Risk in the ARIC Study

0

0.5

1

1.5

2

2.5

3

Low-Medium CRP High CRP

Low-MediumLpPLA2

HighLpPLA2

Rel

ativ

e R

isk

for

CH

D

3X

Lamarche et al, Circulation 1997;95:69

Coronary Heart Disease Risk Based on LDL Particle Size and Apo B

0

1

2

3

4

5

6

7

Apo B < 120 mg/dl Apo B >120 mg/dl

>25.64 nm

<25.64 nm

Mean Particle Size

Rel

ativ

e R

isk

for

CH

D

3X

1X

Death Major CVE

without biomarkers

with biomarkers

without biomarkers

with biomarkers

Wang TJ, et al. N Engl J Med 2006;355:2631

Framingham Heart Study: Prognostic Value of 10 Biomarkers* in 3209 Subjects - 7.4 Years

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)

* CRP, Cystatin C, proADM, BNP

NEJM 1997;337:230

Effect of Homocysteine Levels on Survival in CHD

0 1 2 3 4 5 6

Years

Pro

por

tion

Su

rviv

ing

1.00

0.90

0.80

0.70

<9 mol/L

9-15 mol/L

15-20 mol/L

>20 mol/L

4:1 RR

Bazzano LA et al, JAMA 2006;296:2720

Metaanalysis of 12 RCTs of Folate Therapy in 16,958 Subjects with CVD or CKD

0

0.2

0.4

0.6

0.8

1

1.2

CVD CHD Stroke Death

Rel

ativ

e R

isk

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 (β-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

Gerdes LU et al, Circulation 2000;101:1366

4S Study: Apo E Phenotype, CV Risk, and Risk Reduction with Simvastatin

-70%

-60%

-50%

-40%

-30%

-20%

-10%

0%

10%

20%

CV Risk CV RiskReduction

E2/E3

E45-Y

ear

Ris

k /

RR

SummaryCAC = atherosclerosis, but correlates poorly with %S.

CAC improves the risk prediction of standard risk factors (e.g. FRS).

CAC is an appropriate risk stratification filter in intermediate risk pts.

Soluble biomarkers do not yet add clinically useful risk or management info.