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