BCIS Risk Stratification in ACS: Jan 2004
New Markers of Myocardial
Damage in ACS
Keith A A Fox
Edinburgh Centre for Cardiovascular Science
Acute Coronary Syndrome
• Why do we need new markers?
•
•
•
•
Improve clinical risk stratification
Guide current treatment options
Identify systemic & plaque inflammation
New targets for therapy
• How good is existing risk stratification?
Clinical suspicion of ACS
Physical examination, ECG monitoring, Blood samples
No persistent
ST-Segment elevation
How do we resolve
the interface?
Heparin (LMWH or UFH), ASA,
Clopidogrel, Betablockers, Nitrates
High risk
Low risk
Second troponin measurement
Gp2b/3a
Cor. Angiography
PCI, CABG or medical management
Depending upon clinical and angiographic features
Positive
Twice negative
Stress test
Cor. angiography
New ESC guidelines
Who is at greater risk of death
and, high or low risk?
•
•
•
•
•
•
•
•
•
64 yr male
45 min ischaemic pain
No sig prior history
HR 115min BP 138/86
2mm ST depression II, III,
AVF
Killip class 1
Creatinine 108mmol/L
No complications
10 hr trop T 3.5ng/ml
•
•
•
•
•
•
•
•
•
64 yr female
45 min ischaemic pain
No sig prior history
HR 108min BP 138/86
2mm ST elevation II, III,
AVF
Killip class 1
Creatinine 50mmol/L
No complications
10 hr trop T 6.4ng/ml
Who is at greater risk of
death?
•
•
•
•
•
•
•
•
•
64 yr male
45 min ischaemic pain
No sig prior history
HR 115min BP 138/86
2mm ST depression II, III,
AVF
Killip class 1
Creatinine 108mmol/L
No complications
10 hr trop T 3.5ng/ml
•
•
•
•
•
•
•
•
•
64 yr female
45 min ischaemic pain
No sig prior history
HR 108min BP 138/86
2mm ST elevation II, III,
AVF
Killip class 1
Creatinine 50mmol/L
No complications
10 hr trop T 6.4ng/ml
Who is at greater risk of
death?
• 64 yr male
• 2mm ST depression II,
III, AVF. HR 115min
• 10hr trop T 3.5ng/ml
• Creatinine 108mmol/L
• 64 yr female
• 2mm ST elevation II,
III, AVF, HR 108min
• 10hr trop 6.4ng/ml
• Creatinine 50mmol/L
In-hospital:
9.0% death
5.0% death
6 months:
16% death
11% death
GRACE Risk Model
www.umassmed.edu/outcomes/grace
Variables
• Age (continuous)
• Killip class
• Blood pressure
• ST deviation
• Cardiac arrest
Derived in 21 688 patients:
1046 in-hospital deaths, 711 post
discharge deaths
Validated in GUSTO IIb 12142
• Creatinine
• Elevated CK-MB or Tn
• Heart rate
C-index = 0.84 death (in-hosp),
Archives Int Med 2003
C-index = 0.82 death (6 months)
KAAFox ESC2003
GRACE: Model Calibration
The frequency of death
by tertile of GRACE risk score
All ACS patients
Lowest tertile (n = 4011)
13.7
Middle tertile (n = 4013)
Patients (%)
Highest tertile (n = 4025)
10
P <0.0001
P <0.0001
6.7
3.6
0.7
1.1
1.5
0
Death (in-hospital)
Death (admission to 6
months)
Does the frequency of intervention
relate to the risk of the patients?
Lowest tertile (n = 4011)
Middle tertile (n = 4013)
30
24.9
Highest tertile (n = 4025)
Patients (%)
22.5
20
22.8
17.5
10
0
30.2 29.4
6.1
7.5
5.9
P <0.0001
p=0.007
P <0.0001
PCI
CABG
PCI/CABG
• Key systemic markers
• CRP…cause or consequence?
CAPTURE: Event rate in % (Death, AMI)
25
20
CRP > 10 mg/L
15
OR 1.92; P=0.003
10
CRP < 10 mg/L
5
0
0
30
60
90
120
150
180
Follow-up (days)
Heeschen, Hamm et.al., JACC 2000
Death from Cardiac Cause at 2 years: Influence
of C-R Protein & Troponin T levels at 24 Hours
Death from Cardiac Causes (%)
170
18
16
14
12
10
8
6
4
2
0
207
105
0.6
262
0.06-0.59
34
139
<0.06
C-reactive protein C-reactive protein
>10mg/L
10mg/L
Lindahl. NEJM 2000; 343:1139
FRISC Study
FRISC II 1-year mortality: IL-6 levels
1-year mortality %
at entry in the noninvasive vs invasive groups
9
8
7
6
5
295
4 P< 0.001
3
2
833
1
0
P=0.006
315
>= 5 ng/L
820
< 5ng/L IL-6
Noninvasive
Invasive
CRP and Extent of CAD Predict
Outcome
• Angiographic score & CRP only weakly
correlated but both predict outcome
• Contribution of CRP to risk is especially marked
in patients with minor angiographic stenoses
• CRP may reflect disease activity rather than extent
of obstructive atheroma
JACC 2002: 39; 632-7
• Subtle markers of myocardial dysfunction…
BNP in Acute Coronary Syndrome
OPUS-TIMI 16 (n=2523)
10
4th quartile
Mortality (%)
8
P<0.001
6
3rd quartile
4
2nd quartile
2
P<0.01
1st quartile
0
0
50
100
150
200
250
300
Days after randomization
De Lemos JA, et al. NEJM. 2001.
Interaction of Troponin T
and N Terminal pro BNP
Death
(%)
NT-proBNP
(pg/ml)
60
40
> 1653
401-1653
20
< 401
0
> 0.01 ug/l
< 0.01 ug/L
Troponin T
T. Jernberg et al. JACC 2002
VULNERABLE CORONARY ARTERY PLAQUE
Collagen
Macrophages:CD68 and actin
VULNERABLE CORONARY ARTERY PLAQUE
Collagen
Macrophages:CD68 and actin
Plaque formation and progression - inflammatory events
Excessive/uncontrolled adhesion
tissue
injury
Altered growth factor production
matrix
metalloproteinases
Altered differentiation/
apoptotic programmes
Lipid-laden
macrophages
Lipid core
Failed clearance of
apoptotic cells
markers of inflammation
markers of inflammation
Leukocyte chemoattractants
(MCP-1, IL-8, PDGF, MC-SF)
Adhesion molecules
E-selectin, ICAM-1, VCAM-1
Procoagulant activity
(tissue factor)
Cytokines
(TNFa, FAS,CD40L)
Permeability
Apoptosis
NO
ET-1
CD40 on platelets in type I DM vs. controls
% positive platelets
P<0.001
Role of monocyte-platelet adhesion
• Monocytes may act as a
“sump” for activated platelets.
• Bound platelets modulate
monocyte adhesion
• Influence monocyte signal
transduction
P-selectin
PSGL-1
platelet
Signal
transduction
monocyte
Pro-inflammatory effects of
platelet-monocyte binding
Proinflammatory
Cytokines
Cation independent adhesion
Chemokines
( EDTA 10mM)
Tissue Factor
25
percentage plateletmonocyte binding
(IL-8, MCP-1)
20
15
10
5
Cell Adhesion
0
Molecule Expression
Sarma et al Circ 2002: 105; 2166-71
Non-cardiac Unstable Angina
chest pain
MI
Glycoprotein IIb/IIIa does not mediate
monocyte-platelet interaction
90
80
percent binding
70
60
abciximab does not
block monocyteplatelet interaction.
50
40
30
20
BUT, platelet Pselectin and
monocyte PSGL-1
mediate adhesion.
10
EDTA
P-selectin
PSGL1
abciximab
monoclonal
antibody
Control
0
Sarma et al Circ 2002: 105; 2166-71
• Markers of protection?
IL-10
T
Leukocyte chemoattractants
(MCP-1, IL-8, PDGF, MC-SF)
markers of inflammation
IL-10
Procoagulant activity
(tissue factor)
Adhesion molecules
E-selectin, ICAM-1, VCAM-1
Permeability
IL-10
Cytokines
(TNFa, FAS,CD40L etc.)
T
IL-10
Apoptosis
NO
ET-1
T
IL-10
hepatocyte
growth factor
Prognostic significance of HGF serum levels in ACS
20
Death, MI (%)
< 2.5 µg/L
2.5 – 4.7 µg/L
10
4.7 – 6.8 µg/L
> 6.8 µg/L
P<0.0001 for the trend among the quartiles
0
0
1
2
3
4
5
6
6-month follow-up
C. Heeschen et al.
Proposed strategy for resolving
intermediate or uncertain risk
Clinical syndrome of non-ST elevation ACS
Troponin elevation,
Yes +
ST depression,
or other high risk features
no
TIMI risk score > 4
or GRACE risk of death > 4%
? Elevated NT proBNP, hsCRP, PLGF, CD40L
no
Perfusion scan or stress echo Yes +
or other stress test
no
Non-invasive management
Angio
Yes +
Angio
Angio
It’s never too late….
JAMA 2000;284:831-32
“Horemkenesi was a foreman of
craftsmen excavating and decorating
the tombs of the pharohs of the 20th
dynasty (c 1050 BC) at Thebes…”
“He was also a priest of Amun, and his
responsibilities required frequent journeys of
several miles in the desert.”
“Forensic study of his mummy indicates that at
about age 60 years he fell face downward in the
sand and was heavily infested with carrion
beetles before mummification, suggesting
sudden cardiac death.”
Miller et al JAMA 2000;284:831-32
Evidence of MI With Cardiac
Troponin in Mummified Tissue
Methods

dessicated tissues from Horemkenesi’s
abdomen extracted for myofibrillar proteins
 reconstituted with TnI-negative human
sera

modern positive controls (spleens from
subjects who died of acute MI) and negative
controls (tissues from subjects who died of
other causes) were mummified for 40
dayslevel of TnI measured
Miller et al JAMA 2000;284:831-32
Evidence of MI With Cardiac
Troponin in Mummified
Tissue
Modern MI Modern Non-MI
Mummies
Horemkenesi Mummies
cTnI (ng/g) 12.3-22.2
1.3-3.7
0.7-0.9
“…our data suggest that myocardial death can
be diagnosed several thousand years after the
event…”
Miller et al JAMA 2000;284:831-32
It’s never
too late to
diagnose
MI!
New Royal Infirmary and Research Institute
University of Edinburgh
New Royal Infirmary and Research Institute
University of Edinburgh
Cardiovascular Research Edinburgh
CVRU: KAA Fox, DE Newby,RA Riemersma
Inflammation: I Dransfield, J Sarma
Molecular cardiology: JR Seckl, BR Walker
Endothelial Biology: DJ Webb, S Maxwell, I Megson
Molecular Physiology: JJ Mullins, A Bagnall
Cardiovascular Imaging: WN McDicken, P Hoskins