Keith A A Fox Edinburgh Centre for Cardiovascular Science New Markers of Myocardial Damage in ACS...

Keith A A Fox

Edinburgh Centre for Cardiovascular Science

New Markers of Myocardial New Markers of Myocardial Damage in ACSDamage in ACS

BCIS Risk Stratification in ACS: Jan 2004BCIS Risk Stratification in ACS: Jan 2004

• Why do we need new markers?

• How good is existing risk stratification?

Acute Coronary Syndrome

• Improve clinical risk stratificationImprove clinical risk stratification• Guide current treatment optionsGuide current treatment options• Identify systemic & plaque inflammationIdentify systemic & plaque inflammation• New targets for therapyNew targets for therapy

Clinical suspicion of ACS

Physical examination, ECG monitoring, Blood samples

No persistentST-Segment elevation

No persistentST-Segment elevation

Heparin (LMWH or UFH), ASA,Clopidogrel, Betablockers, Nitrates

Heparin (LMWH or UFH), ASA,Clopidogrel, Betablockers, Nitrates

New ESC guidelines

Twice negativeTwice negative

Stress testStress testCor. angiographyCor. angiography

Low riskLow risk

PositivePositive

Second troponin measurementSecond troponin measurement

Gp2b/3a

Cor. Angiography

Gp2b/3a

Cor. Angiography

High riskHigh risk

PCI, CABG or medical management

Depending upon clinical and angiographic features

How do we resolve How do we resolve the interface?the interface?

• 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 108mol/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,


Who is at greater risk of death Who is at greater risk of death and, high or low risk?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,


• 64 yr female• 45 min ischaemic pain • No sig prior history• HR 108min BP 138/86• 2mm ST elevation II, III,


Who is at greater risk of Who is at greater risk of death?death?

• 64 yr male• 2mm ST depression II, III,

AVF. HR 115min• 10hr trop T 3.5ng/ml• Creatinine 108mol/L

• 64 yr female • 2mm ST elevation II, III,

AVF, HR 108min• 10hr trop 6.4ng/ml• Creatinine 50mol/L

9.0% death 5.0% death

In-hospital:

6 months:

16% death 11% death

Who is at greater risk of Who is at greater risk of death?death?

GRACE Risk ModelGRACE Risk Model

Variables

• Age (continuous)

• Killip class

• Blood pressure

• ST deviation

• Cardiac arrest

• Creatinine

• Elevated CK-MB or Tn

• Heart rate

Variables

• Age (continuous)

• Killip class

• Blood pressure

• ST deviation

• Cardiac arrest

• Creatinine

• Elevated CK-MB or Tn

• Heart rate

Archives Int Med 2003

KAAFox ESC2003

www.umassmed.edu/outcomes/grace

Derived in 21 688 patients: 1046 in-hospital deaths, 711 post

discharge deathsValidated in GUSTO IIb 12142

C-index = 0.84 death (in-hosp),

C-index = 0.82 death (6 months)

GRACE: Model CalibrationGRACE: Model Calibration

The frequency of death The frequency of death by tertile of GRACE risk scoreby tertile of GRACE risk score

0.71.51.1

3.6

6.7

13.7

0

10

Death (in-hospital) Death (admission to 6months)

Pat

ien

ts (

%)

Lowest tertile (n = 4011)

Middle tertile (n = 4013)

Highest tertile (n = 4025)

P <0.0001 P <0.0001

All ACS patients

Does the frequency of intervention Does the frequency of intervention relate to the risk of the patients?relate to the risk of the patients?

24.9

6.1

22.5

7.5

29.430.2

22.8

5.9

17.5

0

10

20

30

PCI CABG PCI/CABG

Pat

ien

ts (

%)

Lowest tertile (n = 4011)

Middle tertile (n = 4013)

Highest tertile (n = 4025)

P <0.0001 P <0.0001p=0.007

• Key systemic markers

0

5

10

15

20

25

0 30 60 90 120 150 1800

5

10

15

20

25

0 30 60 90 120 150 180

CAPTURE: Event rate in % (Death, AMI)CAPTURE: Event rate in % (Death, AMI)

Follow-up (days)

CRP > 10 mg/LCRP > 10 mg/L

CRP < 10 mg/LCRP < 10 mg/L

OR 1.92; P=0.003

Heeschen, Hamm et.al., JACC 2000Heeschen, Hamm et.al., JACC 2000

• CRP…cause or consequence?CRP…cause or consequence?

Lindahl. NEJM 2000; 343:1139Lindahl. NEJM 2000; 343:1139

0022446688

10101212141416161818

C-reactive proteinC-reactive protein>10mg/L>10mg/L

C-reactive proteinC-reactive protein10mg/L10mg/L

<0.06<0.06

0.06-0.590.06-0.59

0.60.6

3434

105105

170170

207207

262262

139139

Trop

onin

T

Trop

onin

T (µ

g/L)

(µg/L

)

Death

fro

m C

ard

iac C

au

ses

Death

fro

m C

ard

iac C

au

ses (

%)

(%)

FRISC Study

Death from Cardiac Cause at 2 years: Influence Death from Cardiac Cause at 2 years: Influence of C-R Protein & Troponin T levels at 24 Hoursof C-R Protein & Troponin T levels at 24 Hours

Noninvasive< 5ng/L

>= 5 ng/L

012345

6

7

8

91-

year

mo

rtal

ity

%

833

295

FRISC II 1-year mortality: IL-6 levels

at entry in the noninvasive vs invasive groups

Invasive

820

315

P=0.006

P< 0.001

IL-6

• Angiographic score & CRP only weakly correlated but both predict outcome

CRP and Extent of CAD Predict CRP and Extent of CAD Predict OutcomeOutcome

JACC 2002: 39; 632-7JACC 2002: 39; 632-7

• 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

• Subtle markers of myocardial dysfunction…Subtle markers of myocardial dysfunction…

De Lemos JA, et al. NEJM. 2001.

00

22

44

1010

66

88

00 5050 100100 150150 200200 250250 300300

Mor

talit

y (%

) (

%)

Days after randomization

1st quartile

2nd quartile

3rd quartile

P<0.001

4th quartile

P<0.01

OPUS-TIMI 16 (n=2523)

BNP in Acute Coronary SyndromeBNP in Acute Coronary Syndrome

0

20

40

60

> 0.01 ug/l < 0.01 ug/L

< 401

401-1653

> 1653

Troponin T

NT-proBNP (pg/ml)

Death(%)

T. Jernberg et al. JACC 2002

Interaction of Troponin T Interaction of Troponin T and N Terminal pro BNPand N Terminal pro BNP

VULNERABLE CORONARY ARTERY PLAQUE

Macrophages:CD68 and actinCollagen

Altered growth factor production tissuetissueinjuryinjury

Lipid coreLipid-ladenmacrophages

Plaque formation and progression - inflammatory events

Excessive/uncontrolled adhesion Excessive/uncontrolled adhesion

Altered differentiation/Altered differentiation/apoptotic programmes apoptotic programmes

Failed clearance of Failed clearance of apoptotic cells apoptotic cells

matrix matrix metalloproteinases metalloproteinases

markers of inflammationmarkers of inflammation

Adhesion moleculesE-selectin, ICAM-1, VCAM-1

Permeability

Apoptosis

Leukocyte chemoattractants(MCP-1, IL-8, PDGF, MC-SF)

Procoagulant activity(tissue factor)

Cytokines(TNF, FAS,CD40L)

NOET-1


CD40 on platelets in type I DM vs. controlsCD40 on platelets in type I DM vs. controls

P<0.001

% p

ositi

ve p

late

lets

Role of monocyte-platelet adhesionRole 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-1Signaltransduction

monocyteplatelet

Pro-inflammatory effects of Pro-inflammatory effects of platelet-monocyte bindingplatelet-monocyte binding

Proinflammatory Cytokines

Cell Adhesion Molecule Expression

Tissue FactorChemokines

(IL-8, MCP-1)

0

5

10

15

20

25

Non-cardiacchest pain

Unstable Angina MI

per

cen

tag

e p

late

let-

mo

no

cyte

bin

din

g

Cation independent adhesion( EDTA 10mM)

Sarma et al Circ 2002: 105; 2166-71Sarma et al Circ 2002: 105; 2166-71

Glycoprotein IIb/IIIa does not mediate Glycoprotein IIb/IIIa does not mediate monocyte-platelet interactionmonocyte-platelet interaction

monoclonal antibody

abciximab does not block monocyte-platelet interaction.

BUT, platelet P-selectin and monocyte PSGL-1 mediate adhesion.

0

10

20

30

40

50

60

70

80

90C

on

tro

l

ED

TA

PS

GL

1

P-s

ele

ctin

abc

ixim

ab

perc

ent

bind

ing

Sarma et al Circ 2002: 105; 2166-71Sarma et al Circ 2002: 105; 2166-71

• Markers of protection?Markers of protection?

Adhesion moleculesE-selectin, ICAM-1, VCAM-1

Permeability

Apoptosis

Leukocyte chemoattractants(MCP-1, IL-8, PDGF, MC-SF)

Procoagulant activity(tissue factor)

Cytokines(TNF, FAS,CD40L etc.)

NOET-1


TT

TT

TTIL-10IL-10

TTIL-10IL-10

IL-10IL-10

IL-10IL-10

TTIL-10IL-10

TThepatocytehepatocytegrowth factorgrowth factor

Prognostic significance of Prognostic significance of HGF serum levels in ACSHGF serum levels in ACS

65432100

De

ath

, MI (

%)

20

10

6-month follow-up

P<0.0001 for the trend among the quartiles

> 6.8 µg/L4.7 – 6.8 µg/L

2.5 – 4.7 µg/L

< 2.5 µg/L

C. Heeschen et al.

Proposed strategy for resolving Proposed strategy for resolving intermediate or uncertain riskintermediate or uncertain risk

Clinical syndrome of non-ST elevation ACSTroponin elevation,ST depression,or other high risk features

AngioYes +

AngioTIMI risk score > 4or GRACE risk of death > 4%? Elevated NT proBNP, hsCRP, PLGF, CD40L

no

Yes +

no

Perfusion scan or stress echoor other stress test Angio

Yes +

Non-invasive management

no

JAMAJAMA 2000;284:831-32 2000;284:831-32

It’s never too late….It’s never too late….

Miller et al Miller et al JAMAJAMA 2000;284:831-32 2000;284:831-32

““Horemkenesi was a foreman of Horemkenesi was a foreman of craftsmen excavating and decorating craftsmen excavating and decorating the tombs of the pharohs of the 20th the tombs of the pharohs of the 20th

dynasty (c 1050 BC) at Thebes…”dynasty (c 1050 BC) at Thebes…”

““He was also a priest of Amun, and his He was also a priest of Amun, and his responsibilities required frequent journeys of responsibilities required frequent journeys of several miles in the desert.”several miles in the desert.”

““Forensic study of his mummy indicates that at Forensic study of his mummy indicates that at about age 60 years he fell face downward in the about age 60 years he fell face downward in the sand and was heavily infested with carrion sand and was heavily infested with carrion beetles before mummification, suggesting beetles before mummification, suggesting sudden cardiac death.”sudden cardiac death.”


MethodsMethods dessicated tissues from Horemkenesi’s dessicated tissues from Horemkenesi’s

abdomen extracted for myofibrillar proteins abdomen extracted for myofibrillar proteins reconstituted with TnI-negative human reconstituted with TnI-negative human serasera

modern positive controls (spleens from modern positive controls (spleens from subjects who died of acute MI) and negative subjects who died of acute MI) and negative controls (tissues from subjects who died of controls (tissues from subjects who died of other causes) were mummified for 40 other causes) were mummified for 40 daysdayslevel of TnI measured level of TnI measured

MethodsMethods dessicated tissues from Horemkenesi’s dessicated tissues from Horemkenesi’s

abdomen extracted for myofibrillar proteins abdomen extracted for myofibrillar proteins reconstituted with TnI-negative human reconstituted with TnI-negative human serasera

modern positive controls (spleens from modern positive controls (spleens from subjects who died of acute MI) and negative subjects who died of acute MI) and negative controls (tissues from subjects who died of controls (tissues from subjects who died of other causes) were mummified for 40 other causes) were mummified for 40 daysdayslevel of TnI measured level of TnI measured

Evidence of MI With Cardiac Evidence of MI With Cardiac Troponin in Mummified TissueTroponin in Mummified Tissue


Evidence of MI With Cardiac Evidence of MI With Cardiac Troponin in Mummified Troponin in Mummified

TissueTissue

cTnI (ng/g)cTnI (ng/g)

HoremkenesiHoremkenesi

12.3-22.212.3-22.2

Modern MI Modern MI MummiesMummies

1.3-3.71.3-3.7

Modern Non-MI Modern Non-MI MummiesMummies

0.7-0.90.7-0.9

“…“…our data suggest that myocardial death can our data suggest that myocardial death can be diagnosed several thousand years after the be diagnosed several thousand years after the

event…”event…”

It’s never It’s never too late to too late to diagnose diagnose

MI!MI!

New Royal Infirmary and Research InstituteUniversity of Edinburgh

New Royal Infirmary and Research InstituteUniversity of Edinburgh

Cardiovascular Research EdinburghCardiovascular Research EdinburghCVRU:CVRU: KAA Fox, DE Newby,RA Riemersma KAA Fox, DE Newby,RA Riemersma

Inflammation:Inflammation: I Dransfield, J Sarma I Dransfield, J Sarma

Molecular cardiology: Molecular cardiology: JR Seckl, BR WalkerJR Seckl, BR Walker

Endothelial Biology:Endothelial Biology: DJ Webb, S Maxwell, I Megson DJ Webb, S Maxwell, I Megson

Molecular Physiology:Molecular Physiology: JJ Mullins, A Bagnall JJ Mullins, A Bagnall

Cardiovascular Imaging:Cardiovascular Imaging: WN McDicken, P Hoskins WN McDicken, P Hoskins

Keith A A Fox Edinburgh Centre for Cardiovascular Science New Markers of Myocardial Damage in ACS...

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