epidemiology & genetics of...calcium score thresholds based on correlation with coronary...
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Epidemiology & Genetics of Coronary Calcium:
What it Means to Clinical Medicine
J. Jeffrey Carr, MD, MSCEDept. of Radiology & Public Health SciencesWake Forest University School of Medicine
Winston-Salem, NC USA
No disclosures
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J. Jeffrey Carr, MD, MS
Lecture Outline
• CVD epidemiology & prevention 101• CT measurement of calcified plaque• Consensus Statements and Studies ‘04• Clinical application• Genomics, CTA and beyond
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“We have been consistently unsuccessful in getting Americans to eat healthier and exercise regularly”
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Primary Preventionof Cardiovascular Disease
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Secondary Preventionof Cardiovascular Disease
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Top Five Causes of Death U.S.
1. Cardiovascular diseases2. Cancer3. Chronic obstructive pulmonary disease4. Accidents5. Pneumonia & complications
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0
200
400
600
800
1000
Dea
ths x
1,0
00
CVD Cancer COPD Accid. Pneu.
CVD Mortality U.S.945,836 / yr.
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All CVD Mortality
CHD54%
Stroke18%
Othe28%
512,200 / yr
167,661 / yr
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Aging of the U.S. Population% population > 65 years
12.6% 13.2%16.5%
0%
10%
20%
30%
2000 2010 2020
35 million 47 million
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CHD Death Ratesby age, sex , race
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Measuring Coronary CalciumLeft Anterior Descending (LAD)
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Calcified Coronary Plaque =Subclinical coronary atherosclerosis
• Ca+ in the arterial wall @ 2nd decade
• Ca+ is absent in normal vessel walls
• Ca+ is more common in complex and advanced lesions
• Coronary calcium is not an inevitable part of growing older!!!!!
distalcircumflex
distalright coronary
Single Slice CTi & SmartScore (circa 1999)
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Subclinical Atherosclerosis
Clinical CVD
Events
Everyone
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Consensus Statements
Circulation. 2000; 101:111-116
Circulation. 1996; 94:1175-1192
J Am Coll Cardiol 2000;36:326–40
www.americanheart.org
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Coronary Calcified PlaqueNegative by Cardiac CT
“…when no calcium is detected, does not absolutely rule out the presence of atherosclerotic plaque, including unstable plaque, ……….
but does imply a very low likelihood of significant luminal obstruction….and a low risk of cardiovascular events over the next 2-5 years.”
– American Heart Assoc. Coronary Artery Calcification Writing Group -Circulation 1996; 94:1175-1192
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Coronary Calcified PlaquePositive by Cardiac CT
“…one in which some calcium is detected in at least one vessel, confirms the presence of atherosclerotic plaque….
….and may be consistent with a moderate to high risk of a cardiovascular event within the next 2 to 5 years.”
– American Heart Assoc. Coronary Artery CalcificationWriting Group - Circulation 1996; 94:1175-1192
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Events & Calcified PlaqueSingle Center Studies - Pre 2000
Author Relative Risk 95% C.I.
Detrano 2.3 1.2, 4.4
Agatston 16.9 1.0, 286.3
Arad 22.1 2.7, 179.0
Sulllivan 1.0 0.3, 20.5
Raggi 7.2 2.5, 20.5
Overall 4.2 1.6, 11.3O'Malley, Am J Cardiol 2000; 85:945-948
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Prevention V Conference &2000 Consensus Statement
“The published literature does not completely answer the question of whether the EBCT calcium score is additive to the Framingham score for defining CHD risk in asymptomatic patients.”
“Selected use when a physician is faced with the patient with intermediate coronary disease risk may be appropriate.”
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Risk Stratifications for Asymptomatic CHD
•High Risk (> 20% 10 yr)aggressive risk reduction (+/- Rx)
•Intermediate Risk (10-20%)further evaluation diagnostic testing
•Low Risk (< 10%)healthy life habits
AHA Prevention V – Circulation 2000;101:111-116
NCEP ATP III - 10 year CHD Risk strata
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Traditional Risk Factors:Incomplete in CVD prediction
• 50% of acute MI victims have normal cholesterol profiles
• Sudden death is the first sign of CVD in 150,000-250,000 people/year– 680 deaths per day– 50% of all CHD
AHA Stat Book 2003 Update
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Effective Prevention Strategies are Established for CVD
• Therapeutic Lifestyle Changes• Statin’s
– Reduce blood cholesterol ( ~ 60 mg/dl)– Reduce MI ~ 33%– 25-50 million in US could benefit– 4-5 million on statin therapy in U.S.
(costs ~ $2,000/yr/Rx)
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J. Jeffrey Carr, MD, MS
Calcified Coronary Plaque Predicts Events - ACC 2003
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J. Jeffrey Carr, MD, MS
St. Francis Heart StudyAgatston Score ≥100 & Events
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J. Jeffrey Carr, MD, MS
Calcified Coronary Plaque & Framingham Risk Index:Coronary Event Prediction
St. Francis Heart Study - ACC 2003
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Clinical Application 2004Risk Factor Assessment
Selected use in individual with:
Intermediate CHD risk
Reclassify Risk using Calcium Score
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Positive Family History of Cardiac Death………
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Outcome # 1Total Calcium Score = 0
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Framingham/NCEP CHD risk (7% over 10 years - low risk)
Coronary Calcium Score = Negative / Low↓
Low near term CHD risk(supports Framingham Risk Index)
↓Healthy lifestyle habits
Conservative management
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Outcome #2Total Calcium Score = 287
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Framingham/NCEP CHD risk (7% over 10 years - low risk)
Coronary Calcium Score = Intermediate
↓Intermediate-High CHD risk
↓Treatment based on Global Risk Assessment
(+/- Rx)
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Outcome #3Total Calcium Score = 4,632
3D MIP –Frontal Projection
3D MIP –Projection from below
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Framingham/NCEP CHD risk (7% over 10 years - low risk)
Coronary Calcium Score = High
↓High Burden Atherosclerosis
*** High CHD risk ***↓
Aggressive risk factor modificationand further evaluation for inducible ischemia
and/or flow limiting lesion in coronary circulation
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Coronary Calcium Scores:a Practical Synthesis
CalciumScore
RiskStrata
Recommendationsto reduce CHD risk
0-10 Low<10%
•Healthy lifestyle choices
11-399 Intermediate10-20%
•Mgmt. based on combined risk factor levels (+/- Rx)
> 400 High> 20%
•Aggressive risk factor reduction (+ Rx)•Evaluation for ischemia
Calcium Score thresholds based on correlation with coronary angiography work of Rumberger et. al. Mayo Clinical Proceedings - Risk Strata based on Prevention V Criteria
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J. Jeffrey Carr, MD, MS
Absolute vs. Percentile Score“why you didn’t like being graded on the curve”
66% of Americans are overweight or obese ….
..… do you feel good having a weight at the 50th percentile?
..… likewise during an epidemic of CVD is having the 50th percentile of coronary plaque burden “O.K.”?
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A B
EBCT vs. MSCT Images courtesy - J. Breen – Mayo Clinic
EBCT MDCT
Cardiac CT Technologies
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A B
EBCT vs. MSCT Images courtesy - J. Breen – Mayo Clinic
EBCT MDCT
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“Effect of scanner type and calcium measure on the re-scan variability of
calcium quantity by CT”
Rescan variability similar between EBCT and MDCT
Detrano et. al. Paper @ AHA 2002.
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EBT (N=3454)
Mean Agatston Score
Arit
hmet
ic D
iffer
ence
0 2000 4000 6000 8000 10000 12000
-300
0-2
000
-100
00
MDCT (N=2994)
Mean Agatston Score
Arit
hmet
ic D
iffer
ence
0 2000 4000 6000 8000 10000 12000
-300
0-2
000
-100
00
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P
Agatston Score
Calcium Volume (mm3)
Volume Score (mm3)
MDCT
24.7
15.8
11.9
EBCT
22.7
13.7
11.0
N.S.
N.S.
N.S.
Median Re-Scan Variability |scan2 – scan1|, N = 3190 (Adjusted for mean score, and BMI)
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Genetics Research with Cardiac CT
LAD RCA
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J. Jeffrey Carr, MD, MS
Heritability of CAC 40-50% in Type 2 Diabetes
• Coronary Calcium has significant genetic component• Heritability estimate (h2) =0.40-0.50• Wagenknecht et. al. Diabetes 50:861–866, 2001
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J. Jeffrey Carr, MD, MS
Heritability of CAC 42-44% in Asymptomatic Adults
• 42% variability (44% unadjusted) observed in CAC explained by genetic factors
• Asymptomatic adults in Rochester, NY• Peyser, et. al. Circulation. 2002;106:304-308.
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Diabetes Heart Study @ WFUHeritability Estimate = 0.5
DHS 1002Coronary
Calcium = 1,055
DHS 1001Coronary
Calcium = 1,549
Aortacalcium
DHS 1003Coronary
Calcium = 23
Wagenknecht et. al. Diabetes 2001; 21:463-473
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CT as a tool for Genomics
• Family Study Design (n ~ 3,400)• Genome wide scans & CT exams in all• Sites: UAB, UMN, Framingham, Utah, WFU• Calcified plaque
– Coronary arteries– Abdominal aorta
http://www.biostat.wustl.edu/~scan/
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Conclusions
• CVD will cause increasing morbidity & mortality• Coronary calcified plaque can be measured
accurately with Cardiac gated CT (MDCT & EBCT) and can be used to identify those at risk
• Preliminary studies indicate CAC adds to Traditional CVD risk estimators
• Mounting evidence suggests that CAC will have a significant role in CVD prevention
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Division of Radiologic Sciences
and Public Health Sciences
www.wfubmc.edu/imagelab