Download Lecture 18. The main methods of invest. cardiovasc.dis

The main methods of
investigation of cardiovascular
system.
Cardiovascular disease ?
• Endocardium : valvular heart disease,
infective endocarditis
• Myocardium : Ischemic heart disease,
myocarditis/cardiomyopathy
• Pericardial disease : pericarditis,
pericardial effusion
• Disease of aorta : aortic aneurysm,
aortic dissection
Chest Xray
• Cardiomegaly
• pulmonary vasculature
– Pulmonary hypertension
– Pulmonary congestion
– Shunt
ASD,VSD,MS,congestive heart failure
Aortic dissection/aneurysm
EKG : Assessment of CVD
• For Dx IHD : myocardial ischemia,
myocardial injury,myocardial infarction (
acute,recent,old )
• For Dx cardiac arrhythmias
• For Dx chamber enlargement &
hypertrophy
• For Dx pericarditis
EKG : Assessment IHD
• EKG could be normal in one-half of
patients with chronic stable angina
(
sensitivity about 50% )
• EKG of IHD : inverted T wave, ST
depression, abnormal Q wave (old MI )
• EKG of acute MI : ST elevation, inverted
T and Q wave
Abnormal EKG in absent of
clinical heart disease
• QS complex in AVL,V1-2 . QS or QR complex
in III,AVF.
• Tall R inV1 and V2. High voltage R wave over
left ventricle
• ST elevation : early repolarization
• Inverted T wave : nonspecific T wave
changes
Abnormal EKG in absent of
clinical heart disease
• Nonspecific ST and T wave changes are the most
common EKG abnormality
• About 50% of abnormal tracings recorded in a
general hospital population
• most common cause of “ iatrogenic EKG heart
disease”
• must always be correlated with all available clinical
and laboratory information
Information from
Echocardiography
• Cardiac valves morphology & chamber
enlargement , hypertrophy ?
• LV systolic and diastolic function & regional
wall motion abnormality
• Valves function : stenosis & regurgitation
• Pericardial effusion, vegetation & thrombus
• congenital heart disease : ASD,VSD,PDA
• Aortic dissection
Echocardiography in IHD
• Assess global LV function and RWMA
( abnormal in case with old MI )
• Could be normal in chronic stable
angina
• hypokinesia : myocardial ischemia
• akinesia & dyskinesia : myocardium
infarction
• For Dx IHD
• For assess IHD : high / low risk
• Overall sensitivity about 75% ( negative
test not excluded )
• Limitation in young,middle age female,
abnormal baseline EKG ( false positive
is high )
Exercise stress test
• Specificity is less in women than men
• lower prevalence and extent of CAD in
young and middle-aged women &
catecholamine effect
• LVH, LBBB, WPW syndrome : need
exercise or pharmacologic imaging
study
Exercise stress test
• Result of EST
– Positive VS Negative
– Equivocal
– Inadequate
– assess functional capacity : low,moderate
or high workload
– assess hemodynamic response
Exercise stress test
• Assess myocardial ischemia
• In case of old MI
– EST could be positive or negative
– Negative EST not exclude old MI
Exercise or pharmacologic
stress echocardiography
• Higher specificity
• More extensive evaluation of cardiac
anatomy and function
• Greater convenience,efficacy and
availability
• Lower cost ( compare with stress
perfusion imaging )
Stress perfusion imaging
•
•
•
•
MIBI scan / Thallium
Higher technical success rate
Higher sensitivity
Better accuracy in evaluating possible
ischemia when multiple rest LV wall
motion abnormalities are present
Coronary angiography
•
•
•
•
•
•
Invasive test
Gold standard for Dx IHD
single or double or tripple vessel disease
Left main disease ?
% of stenosis
Assess LV function by LV ventriculogram
Other tests for assess CVD
• Holter’s monitoring : assess symptoms
possibly related to cardiac arrhythmias eg.
Sick sinus syndrome
• Tilt table test : for Dx vagovagal syncope
• Electrophysiologic study in case of cardiac
arrhythmias
• Ambulatory BP monitoring : for exclude whitecoat hypertension
• CT scan for Dx aortic dissection
Cardiac markers in acute
coronary syndrome/acute MI
• Cardiac troponins
– Cardiac troponin T (cTnT)
– Cardiac troponin I (cTnI)
• CK-MB
• CK-MB isoforms
• Myoglobin
Assessment for
disease severity and prognosis
•
•
•
•
Ischemic heart disease
congenital heart disease
valvular heart disease
Hypertension
Is there clinical evidence that novel risk
markers predict future coronary events
and provide additional predictive
information beyond traditional risk
factors?
Fibrinogen and Atherosclerosis
•
•
•
•
•
•
•
Promotes atherosclerosis
Essential component of platelet aggregation
Relates to fibrin deposited and the size of the clot
Increases plasma viscosity
May also have a proinflammatory role
Measurement of fibrinogen, incl. Test variability, remains difficult.
No known therapies to selectively lower fibrinogen levels in order
to test efficacy in CHD risk reduction via clinical trials.
Fibrinogen and CHD Risk: Epidemiologic Studies
• Recent meta-analysis of 18 studies involving 4018 CHD cases
showed a relative risk of CHD of 1.8 (95% CI 1.6-2.0) comparing the
highest vs lowest tertile of fibrinogen levels (mean .35 vs. .25 g/dL)
• ARIC study in 14,477 adults aged 45-64 showed relative risks of 1.8
in men and 1.5 in women, attenuated to 1.5 and 1.2 after risk factor
adjustment.
• Scottish Heart Health Study of 5095 men and 4860 women showed
fibrinogen to be an independent risk factor for new events--RRs 2.23.4 for coronary death and all-cause mortality.
Fibrinogen and CHD Risk Factors
• Fibrinogen levels increase with age and body mass index, and
higher cholesterol levels
• Smoking can reversibly elevated fibrinogen levels, and cessation
of smoking can lower fibrinogen.
• Those who exercise, eat vegetarian diets, and consume alcohol
have lower levels. Exercise may also lower fibrinogen and plasma
viscosity.
• Studies also show statin-fibrate combinations (simvastatinciprofibrate) and estrogen therapy to lower fibrinogen.
P. Ridker
CRP vs hs-CRP
• CRP is an acute-phase protein produced by the liver in response to
cytokine production (IL-6, IL-1, tumor necrosis factor) during tissue
injury, inflammation, or infection.
• Standard CRP tests determine levels which are increased up to 1,000fold in response to infection or tissue destruction, but cannot adequately
assess the normal range
• High-sensitivity CRP (hs-CRP) assays (i.e. Dade Behring) detect levels
of CRP within the normal range, levels proven to predict future
cardiovascular events.
C-Reactive Protein:
Risk Factor or Risk Marker?
• CRP previously known to be a marker of high risk in
cardiovascular disease
• More recent data may implicate CRP as an actual mediator
of atherogenesis
• Multiple hypotheses for the mechanism of CRP-mediated
atherogenesis:
– Endothelial dysfunction via ↑ NO synthesis
– ↑LDL deposition in plaque by CRP-stimulated macrophages
Prevention Cohorts
Kuller MRFIT 1996
CHD Death
Ridker PHS 1997
MI
Ridker PHS 1997
Stroke
Tracy CHS/RHPP 1997
CHD
Ridker PHS 1998,2001
PAD
Ridker WHS 1998,2000,2002
CVD
Koenig MONICA 1999 CHD
Roivainen HELSINKI 2000
CHD
Mendall CAERPHILLY 2000
CHD
Danesh BRHS 2000
CHD
Gussekloo LEIDEN 2001
Fatal Stroke
Lowe SPEEDWELL 2001
CHD
Packard WOSCOPS 2001
CV Events*
Ridker AFCAPS 2001
CV Events*
Rost FHS 2001
Stroke
Pradhan WHI 2002
MI,CVD death
Albert PHS 2002
Sudden Death
Sakkinen HHS 2002
MI
0
Ridker PM. Circulation 2003;107:363-9
1.0
2.0
3.0
4.0
5.0
Relative Risk (upper vs lower quartile)
6.0
hs-CRP Adds to Predictive Value of TC:HDL Ratio in
Determining Risk of First MI
Relative Risk
5,0
4,0
3,0
2,0
1,0
0,0
High
Medium
High
Medium
Low
Total Cholesterol:HDL Ratio
Ridker et al, Circulation. 1998;97:2007–2011.
Low
Risk Factors for Future Cardiovascular Events: WHS
Lipoprotein(a)
Homocysteine
IL-6
TC
LDLC
sICAM-1
SAA
Apo B
TC: HDLC
hs-CRP
hs-CRP + TC: HDLC
0
1.0
2.0
4.0
6.0
Relative Risk of Future Cardiovascular Events
Ridker et al, N Engl J Med. 2000;342:836-43
Is there clinical evidence that inflammation can
be modified by preventive therapies?
Percent with CRP 0.22
mg/dL
Elevated CRP Levels in Obesity:
NHANES 1988-1994
25
20
15
10
5
0
Normal
Overweight
Visser M et al. JAMA 1999;282:2131-2135.
Obese
Effects of Weight Loss on CRP
Concentrations in Obese Healthy Women
 83 women (mean BMI 33.8, range 28.2-43.8 kg/m2) placed
on very low fat, energy-restricted diet (6.0 MJ, 15% fat) for
12 weeks
 Baseline CRP positively associated with BMI (r=0.281,
p=0.01)
 CRP reduced by 26% (p<0.001)
 Average weight loss 7.9 kg, associated with change in CRP
 Change in CRP correlated with change in TC (r=0.240,
p=0.03) but not changes in LDL-C, HDL-C, or glucose
 At 12 weeks, CRP concentration highly correlated with TG
(r=0.287, p=0.009), but not with other lipids or glucose
Heilbronn LK et al. Arterioscler Thromb Vasc Biol
2001;21:968-970.
Effect of HRT on hs-CRP: the PEPI Study
hs-CRP (mg/dL)
3.0
CEE + MPA cyclic
CEE + MPA
CEE
+ MP
continuous
CEE
2.0
Placebo
1.0
0
12
Months
36
Cushman M et al. Circulation 1999;100:717-722.
1999 Lippincott Williams & Wilkins.
Long-Term Effect of Statin Therapy on
hs-CRP: Placebo and Pravastatin Groups
0.25
Placebo
Median hs-CRP
Concentration
(mg/dL)
0.24
0.23
-21.6%
(P=0.004)
0.22
0.21
0.20
Pravastatin
0.19
0.18
Baseline
Ridker et al, Circulation. 1999;100:230-235.
5 Years
hs-CRP (mg/L)
Effect of Statin Therapy on hs-CRP Levels
at 6 Weeks
6
*p<0.025 vs. Baseline
5
*
4
*
*
3
2
1
0
Baseline
Prava
Simva
Atorva
(40 mg/d) (20 mg/d) (10 mg/d)
Jialal I et al. Circulation 2001;103:1933-1935.
2001 Lippincott Williams & Wilkins.
AFCAPS/TEXCAPS showed statins to be effective in lowering
risk in the setting of normal LDL-C, but only when inflammation
was present
AFCAPS/TexCAPS Low LDL Subgroups
LowLDL,
LDL,Low
LowhsCRP
hsCRP
Low
[A]
LowLDL,
LDL,High
HighhsCRP
hsCRP
Low
[B]
0.50.5
StatinEffective
Effective
Statin
1.01.0
RR
2.02.0
StatinNot
NotEffective
Effective
Statin
However, while intriguing and of potential public health importance, the
observation in AFCAPS/TexCAPS that statin therapy might be effective
among those with elevated hsCRP but low cholesterol was made on a
post hoc basis. Thus, a large-scale randomized trial of statin therapy was
needed to directly test this hypotheses.
Ridker et al, New Engl J Med 2001;344:1959-65
A Randomized Trial of Rosuvastatin in the Prevention
of Cardiovascular Events Among 17,802 Apparently Healthy
Men and Women With Elevated Levels
of C-Reactive Protein (hsCRP):
The JUPITER Trial
Paul Ridker*, Eleanor Danielson, Francisco Fonseca*, Jacques Genest*,
Antonio Gotto*, John Kastelein*, Wolfgang Koenig*, Peter Libby*,
Alberto Lorenzatti*, Jean MacFadyen, Borge Nordestgaard*,
James Shepherd*, James Willerson, and Robert Glynn*
on behalf of the JUPITER Trial Study Group
An Investigator Initiated Trial Funded by AstraZeneca, USA
* These authors have received research grant support and/or consultation fees from one or more
statin manufacturers, including Astra-Zeneca. Dr Ridker is a co-inventor on patents held by the
Brigham and Women’s Hospital that relate to the use of inflammatory biomarkers in
cardiovascular disease that have been licensed to Dade-Behring and AstraZeneca.
Ridker et al NEJM 2008
Justification for the Use of statins in Prevention:
an Intervention Trial Evaluating Rosuvastatin
To investigate whether rosuvastatin 20 mg compared to
placebo would decrease the rate of first major cardiovascular
events among apparently healthy men and women with
LDL < 130 mg/dL (3.36 mmol/L) who are nonetheless
at increased vascular risk on the basis of an enhanced
inflammatory response, as determined by hsCRP > 2 mg/L.
To enroll large numbers of women and individuals of Black or
Hispanic ethnicity, groups for whom little data on primary
prevention with statin therapy exists.
JUPITER
Trial Design
JUPITER
Multi-National Randomized Double Blind Placebo Controlled Trial of
Rosuvastatin in the Prevention of Cardiovascular Events
Among Individuals With Low LDL and Elevated hsCRP
Rosuvastatin 20 mg (N=8901)
No Prior CVD or DM
Men >50, Women >60
LDL <130 mg/dL
hsCRP >2 mg/L
4-week
run-in
Placebo (N=8901)
MI
Stroke
Unstable
Angina
CVD Death
CABG/PTCA
Argentina, Belgium, Brazil, Bulgaria, Canada, Chile, Colombia, Costa Rica,
Denmark, El Salvador, Estonia, Germany, Israel, Mexico, Netherlands,
Norway, Panama, Poland, Romania, Russia, South Africa, Switzerland,
United Kingdom, Uruguay, United States, Venezuela
Ridker et al, Circulation 2003;108:2292-2297.
Ridker et al NEJM 2008
JUPITER
Baseline Blood Levels (median, interquartile range)
Rosuvastatin
(N = 8901)
Placebo
(n = 8901)
hsCRP, mg/L
4.2
(2.8 - 7.1)
4.3
(2.8 - 7.2)
LDL, mg/dL
108
(94 - 119)
108
(94 - 119)
HDL, mg/dL
49
(40 – 60)
49
(40 – 60)
Triglycerides, mg/L
118
(85 - 169)
118
(86 - 169)
Total Cholesterol, mg/dL
186
(168 - 200)
185
(169 - 199)
Glucose, mg/dL
94
(87 – 102)
94
(88 – 102)
HbA1c, %
5.7
(5.4 – 5.9)
5.7
(5.5 – 5.9)
All values are median (interquartile range).
[ Mean LDL = 104 mg/dL ]
JUPITER
Ridker et al NEJM 2008
140
60
120
50
100
80
60
40
20
LDL decrease 50 percent at 12 months
HDL (mg/dL)
LDL (mg/dL)
Effects of rosuvastatin 20 mg on LDL, HDL, TG, and hsCRP
0
20
10
HDL increase 4 percent at 12 months
140
120
4
3
2
hsCRP decrease 37 percent at 12 months
0
TG (mg/dL)
hsCRP (mg/L)
30
0
5
1
40
100
80
60
40
20
TG decrease 17 percent at 12 months
0
0
12
24
Months
36
48
0
12
24
Months
36
48
JUPITER
Ridker et al NEJM 2008
Primary Trial Endpoint : MI, Stroke, UA/Revascularization, CV Death
0.08
HR 0.56, 95% CI 0.46-0.69
P < 0.00001
Placebo 251 / 8901
0.04
0.06
- 44 %
Rosuvastatin 142 / 8901
0.00
0.02
Cumulative Incidence
Number Needed to Treat (NNT5) = 25
0
1
2
4
Follow-up (years)
Number at Risk
Rosuvastatin
Placebo
3
8,901
8,901
8,631
8,621
8,412
8,353
6,540
6,508
3,893
3,872
1,958
1,963
1,353
1,333
983
955
544
534
157
174
Ridker et al NEJM 2008
JUPITER
Secondary Endpoint – All Cause Mortality
HR 0.80, 95%CI 0.67-0.97
P= 0.02
0.06
Placebo 247 / 8901
0.04
0.03
0.02
Rosuvastatin 198 / 8901
0.00
0.01
Cumulative Incidence
0.05
- 20 %
0
Number at Risk
Rosuvastatin 8,901
Placebo
8,901
1
2
3
4
Follow-up (years)
8,847
8,852
8,787
8,775
6,999
6,987
4,312
4,319
2,268
2,295
1,602
1,614
1,192
1,196
683
684
227
246
JUPITER
Ridker et al NEJM 2008
Implications for Primary Prevention
A simple evidence based approach to statin therapy for
primary prevention.
Among men and women age 50 or over :
If diabetic, treat
If LDLC > 160 mg/dL, treat
If hsCRP > 2 mg/L, treat
AHA / CDC Scientific Statement
Markers of Inflammation and Cardiovascular Disease:
Applications to Clinical and Public Health Practice
Circulation January 28, 2003
“Measurement of hs-CRP is an independent marker of risk
and may be used at the discretion of the physician as part
of global coronary risk assessment in adults without known
cardiovascular disease. Weight of evidence favors use
particularly among those judged at intermediate risk by
global risk assessment”.
Clinical Application of hs-CRP
for
Cardiovascular Risk
Prediction
1 mg/L
Low
Risk
3 mg/L
Moderate
Risk
Ridker PM. Circulation 2003;107:363-9
10 mg/L
High
Risk
>100 mg/L
Acute Phase Response
Ignore Value, Repeat Test in 3 weeks
CRP Improves Net Reclassification Index
• From the Physicians Health Study: hs CRP and parental history improved risk prediction
5.3% overall and 14.2% for patients at intermediate risk by traditional risk scores (both
P<0.001) (Ridker et al., Circulation 2008)
• Framingham Heart Study: hs-CRP improved prediction of cardiovascular disease by
5.6% (P=0.014) and of coronary heart disease by 11.8% (P=0.009) (Wilson et al.
Circulation: Cardiovascular Quality and Outcomes 2008).
Homocysteine
• Intermediary amino acid formed by the conversion of methionine
to cysteine
• Moderate hyperhomocysteinemia occurs in 5-7% of the population
• Recognized as an independent risk factor for the development of
atherosclerotic vascular disease and venous thrombosis
• Can result from genetic defects, drugs, vitamin deficiencies, or
smoking
Homocysteine
• Homocysteine implicated directly in vascular injury including:
–
–
–
–
Intimal thickening
Disruption of elastic lamina
Smooth muscle hypertrophy
Platelet aggregation
• Vascular injury induced by leukocyte recruitment, foam cell
formation, and inhibition of NO synthesis
Homocysteine
• Elevated levels appear to be an independent risk factor, though less
important than the classic CV risk factors
• Screening recommended in patients with premature CV disease (or
unexplained DVT) and absence of other risk factors
• Treatment includes supplementation with folate, B6 and B12
Current Biomarkers for ACS
• Biomarker assessment of high risk patients may include:
–
–
–
–
–
–
–
Inflammatory cytokines
Cellular adhesion molecules
Acute-phase reactants
Plaque destabilization and rupture biomarkers
Biomarkers of ischemia
Biomarkers of myocardial stretch (BNP)
Biomarkers of myocardial necrosis (Troponin, CK-MB, Myoglobin)
Apple Clinical Chemistry March 2005
Progression of Biomarkers in ACS
STABLE CAD
MPO
CRP
IL-6
PLAQUE RUPTURE
MPO
ICAM
sCD40L
PAPP-A
UA/NSTEMI
MPO
D-dimer
IMA
FABP
STEMI
TnI
TnT
Myoglobin
CKMB
Inflammation has been linked to the development of
vulnerable plaque and to plaque rupture
ACS, acute coronary syndrome; UA, unstable angina; NSTEMI, non–ST-segment elevation myocardial infarction; STEMI, ST-segment
elevation myocardial infarction
Adapted from: Apple Clinical Chemistry March 2005
Stefan Blankenberg, MD; Renate Schnabel, MD; Edith Lubos, MD, et al., Myeloperoxidase Early Indicator of Acute Coronary Syndrome and
Predictor of Future Cardiovascular Events 2005
History: Troponin
• Troponin I first described as a biomarker specific for AMI in 19871;
Troponin T in 19892
• Now the biochemical “gold standard” for the diagnosis of acute
myocardial infarction via consensus of ESC/ACC
1 Am Heart J 113: 1333-44
2 J Mol Cell Cardiol 21: 1349-53
Troponins
• Elevated serum levels are an independent predictor of prognosis,
morbidity and mortality
• Meta-analysis of 21 studies involving ~20,000 patients with ACS
revealed that those with elevated serum troponin had 3x risk of cardiac
death or reinfarction at 30 days1
1 Am J Heart (140): 917
All-Cause Mortality by Cardiac Troponin T (n=733)
100
cTnT <0.01 g/L
80
Cumulative
survival
(%)
cTnT 0.04 g/L
60
40
cTnT 0.04
to 0.10 g/L
20
cTnT 0.10 g/L
0
0.0
0.5
1.0
1.5
2.0
2.5
3.0
Time since blood draw (years)
Patients at risk (no.) Baseline
cTnT <0.01 g/L
132
cTnT 0.01 to <0.04 g/L 214
cTnT 0.04 to <0.10 g/L 239
cTnT 0.10 g/L
148
Circulation 106:2944, 2002
1 yr
106
166
180
93
2 yr
25
41
63
20
2.5 yr
12
15
18
8
CP1090800-14
cTnT and Survival (Rancho Bernardo)
All Subjects
100
80
Survival (%)
Survival (%)
100
Subjects Without
Baseline CHD
TnT undetectable
60
40
80
TnT undetectable
60
TnT 0.01 ng/mL
40
TnT 0.01 ng/mL
P<0.001
P<0.001
20
20
0
2
4
Years
6
8
0
2
4
6
8
Years
Daniels et al: JACC 52:450, 2008
CP1322078-9
BNP
• BNP has also shown utility as a prognostic marker in acute
coronary syndrome
• It is associated with increased risk of death at 10 months as
concentration at 40 hours post-infarct increased
• Also associated with increased risk for new or recurrent MI
BNP as a Predictor of Risk in Asymptomatic Adults:
The Framingham Heart Study
Wang et al., NEJM 2004
Association of increasing BNP levels
and outcomes
End point
Hazard ratio for 1 SD
increment in log BNP
value
Death
1.27
First major CV 1.28
event
HF
1.77
Atrial
1.66
fibrillation
SD=standard
Stroke or TIA deviation
1.53
p
0.009
0.03
<0.001
<0.001
0.002
Wang
TJ et al. N1.1
Engl J Med 2004; 350:655-63.
CHD event
0.37
B-Type Natriuretic Peptides and CVD Risk (Circulation 2009;
120: 2177-2187)
• Meta-analysis of 40 long-term prospective studies involving 87,474 patients.
• Highest vs. lowest tertile, adjusted RR=2.82 (2.40-3.33).
• RRs similar for BNP (2.89) or NT-pro BNP (2.82) and in general
populations (2.68), increased risk factors (3.35), and stable CVD (2.60).
• Modest improvements in risk discrimination (increase in C-statistic of 0.01
to 0.1).
Conjoint Effects of cTnT and NT-proBNP on Prognosis
(Rancho Bernardo)
All Subjects
100
Subjects Without
Baseline CHD
100
Low NT-proBNP
(n=667)
80
60
Survival (%)
Survival (%)
Low NT-proBNP
(n=758)
High NT-proBNP,
low TnT (n=171)
High NT-proBNP,
high TnT (n=27)
40
80
60
High NT-proBNP,
low TnT (n=122)
40
High NT-proBNP,
high TnT (n=16)
20
P<0.001 for all comparisons
0
2
4
Years
6
P<0.001 for all comparisons
20
8
0
2
4
6
8
Years
Daniels et al: JACC 52:450, 2008
CP1322078-12
• MPO is an enzymeMyeloperoxidase
that aids white blood cells in destroying
bacteria and viral particles
• MPO catalyzes the conversion of hydrogen peroxide and chloride
ions (Cl-) into hypochlorous acid
• Hypochlorous acid is 50 times more potent in microbial killing
than hydrogen peroxide
• MPO is released in response to infection and inflammation
• EPIC Norfolk Study showed its predictive value for future
Sugiyama Am J Pathology 2001
Summary of MPO and ACS
• MPO leads to oxidized LDL cholesterol
– Oxidized LDL is phagocytosed by macrophages producing foam cells*
• MPO leads to the consumption of nitric oxide
– Vasoconstriction and endothelial dysfunction
• MPO can cause endothelial denuding and superficial platelet
aggregation
• MPO indicates activated immune cells
– Activated immune cells and inflammation lead to unstable plaque*
• Inflammatory plaque is inherently less stable
– Thin fibrous cap/fissured/denuded
Brennan, NEJM 2003
*Hansson, NEJM 2005
MPO and MI in Asymptomatic Subjects: EPICNORFOLK
Death or MI (%)
20
15
1st tertile
2nd tertile
3rd tertile
10
5
0
24 hours
72 hours
Tertile 1 MPO < 222 ug/L
Tertile 2 MPO 222 – 350 ug/L
Tertile 3 MPO > 350 ug/L
Baldus, et al. Circulation 2003;108: 1440-5.
30 days
6 months
Figure 2
MPO and CVD Event Risk (%)
5,0
4,5
4,0
3,5
3,0
2,5
2,0
1,5
1,0
0,5
0,0
4,9
4,3
2,5
2,2
MPO Quartile
1st
2nd
3rd
4th
P-trend = 0.05 (Wong et al. JACC Cardiovasc Img 2009 )
Figure 3
CVD Events (%)
Combined MPO-CAC Groups and CVD Event Risk
(%)
14,0%
12,0%
10,0%
8,0%
6,0%
4,0%
2,0%
0,0%
14,0%
7,1%
CAC>=100
3,2%
0,3%
MPO<257pm
3,9%
0,9%
CAC 10-99
CAC 0-9
MPO>=257pm
Log-rank test for trend P<0.0001; Wong et al., JACC Cardiovasc Img
2009
The Future of Cardiac Biomarkers
• Many experts are advocating the move towards a multimarker
strategy for the purposes of diagnosis, prognosis, and treatment
design
• As the pathophysiology of ACS is heterogeneous, so must be the
diagnostic strategies
A Multimarker Approach Should Focus
on Multiple Mechanisms / Pathologies
Circulation 108: 250-252
An Integrated Strategy
Multiple
Biomarkers
Intermediate Risk
Non-redundant
pathobiology
Low Risk
Potential Components of a
“Multimarker” Approach
Daniels LB. Curr CV Risk Rep 2009.
Multiple Biomarkers for Prediction of CV Death in
Older Adults
Variables
C statistic
P value
Established risk factors
0.66
Ref
+ cTnI
0.72
0.002
+ NT-proBNP
0.75
<0.001
+ cystatin C
0.69
0.07
+ CRP
0.69
0.07
+ all biomarkers
0.77
<0.001
Zethelius B et al. N Engl J Med 2008;358:2107-2116
Malmö, Sweden
Population-based cohort free of CVD at baseline (n=4483, mean age 58)
• 5 biomarkers assessed in backward elimination models
– CRP, cystatin C, LP-PLA2, MR-proADM, MR-proANP, NT-proBNP
• Results:
• 2 markers retained for CVD events
– NT-proBNP and CRP
• 2 markers retained for CHD events
– NT-proBNP and MR-proADM
Melander et al. JAMA 2009.
Malmö, Sweden
Quartiles of Multimarker Score and Risk of CV Events
HR 1.6 vs 1st Q
P=0.001 for trend
HR 1.4 vs 1st Q
HR 1.1 vs 1st Q
Multimarker score: standardized values for each marker (# of SD units from
the mean) summed, then pts divided into quartiles.
CRP, cystatin C, LP-PLA2, MR-proADM, MR-proANP, NT-proBNP
Melander et al. JAMA 2009.
Malmö, Sweden
Multiple Biomarkers and Incident CV Events
HR per 1-SD increase in BM
C-statistic without BMs: 0.758 for CVD, 0.760 for CHD
• NRI is not significant
• In intermediate risk individuals: NRI 7% (CVD) and 15% (CHD), both
significant
Melander et al. JAMA 2009.
Additional Utility of Multiple Biomarkers for Prediction of Death:
FHS
ROC Curves for Death
Biomarker
BNP
Adj HR Death per 1 SD
1.40
CRP
1.39
Urine Alb/Cr
1.22
Homocysteine
1.20
Renin
1.17
SCORE
4.08*
Sensitivity
0.82
0.80
* HR for highest quintile v. lowest 2 quintiles
1-Specificity
Wang TJ et al. NEJM 2006;355:2631
Multiple biomarkers and reclassification
Standard
risk factors alone
Standard risk factors
plus multimarker score
<10%
10-20%
>20%
<10%
79%
3%
0%
10-20%
3%
9%
1%
>20%
0%
1%
3%
Blankenberg, S. et al. Circulation 2010;121:2388-2397
Blankenberg,
S. et al.
Circulation
2010;121:2388-2397
Copyright ©2010 American
Heart
Association
Fully adjusted HRs of biomarkers for incident cardiovascular events
Only hs-CRP,
NT-pro-BNP
and Troponin I
levels
consistently
predicted risk
of CVD events
Blankenberg,
S. et al.
Circulation
2010;121:2388-2397
Copyright ©2010 American
Heart
Association
Results of the biomarker score including troponin I, NTbroBNP, and C-reactive protein in the Belfast PRIME Men
validation cohort
Blankenberg, S. et al. Circulation 2010;121:2388-2397
Changing Targets for
Biomarkers and Imaging?
ASA +
LDL <70
High
Risk
ASA +
Statin +
Intermediate
Risk
CAC ≥ 100
↑ biomarker
No ASA
No Statin
CAC ≥ 300
Elevated Biomarker
ASA +
LDL <100
Low Risk
Budoff et al Circ 2006;114:1761-1791
Greenland et al Circ 2007;115:402-426
Multimarker Panel and CAC
ESAM ≥95%, PGLYRP-1 ≥95%, sRAGE ≤5%
CRP ≥95%, OPG ≥95%,NT-proBNP ≥95%,
0
N per Group
Adjusted OR
1
2
>3
Number of Markers
1951
419
71
38
REF
1.9
3.8
5.1
DeLemos, AHA Epi and Prevention Conf., 2010
Comparing Model Performance of
Predicting CAC Score > 10
C index
Likelihood χ2
BIC
AIC
FRS
0.731*
373
2209
2180
FRS +
Biomarker Score
0.760*
414
2191
2145
BIC=Bayesian Information criterion (lower indicates better model selection)
FRS=Framingham Risk Categories
* p < 0.0001 for comparison
DeLemos, AHA Epi and Prevention Conf., 2010
Total Biomarker Quartile vs.
CAC and TAC Prevalence (n=1302) (Wong ND et al., AHA Epi 2010)
80
70
60
48
52 53
64
59
68
70
57
45
50
Prevalence
40
(%)
30
33
50
39
20
10
0
CAC
TAC
CAC +/- TAC
Biomarker Quartile
Q1
P-trend =0.007 for CAC
and <0.0001 for TAC
and =0.0001 for CAC
+/- TAC
Q2
Q3
Q4
Biomarkers include high sensitivity C-reactive protein
(hs-CRP), interleukin-6 (IL-6), brain natriuretic peptide
(BNP), myleoperoxidase (MPO), plasminogen activator
inhibitor-1 (PAI-1) and angiotensinogen