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Keith A A Fox

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

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Keith A A Fox

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  1. BCIS Risk Stratification in ACS: Jan 2004 New Markers of Myocardial Damage in ACS Keith A A Fox Edinburgh Centre for Cardiovascular Science

  2. 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?

  3. No persistent ST-Segmentelevation 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 Positive Twice negative PCI, CABG or medical management Depending upon clinical and angiographic features Stress testCor. angiography Clinical suspicion of ACS Physical examination, ECG monitoring, Blood samples New ESC guidelines

  4. 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 and, high or low risk?

  5. 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 Creatinine50mmol/L No complications 10 hr trop T 6.4ng/ml Who is at greater risk of death?

  6. 64 yr male 2mm ST depression II, III, AVF. HR 115min 10hr trop T 3.5ng/ml Creatinine108mmol/L 64 yr female 2mm ST elevation II, III, AVF, HR 108min 10hr trop 6.4ng/ml Creatinine50mmol/L 9.0% death 5.0% death 11% death 16% death Who is at greater risk of death? In-hospital: 6 months:

  7. GRACE Risk Model www.umassmed.edu/outcomes/grace Variables • Age (continuous) • Killip class • Blood pressure • ST deviation • Cardiac arrest • Creatinine • Elevated CK-MB or Tn • Heart rate Derived in 21 688 patients: 1046 in-hospital deaths, 711 post discharge deaths Validated in GUSTO IIb 12142 C-index = 0.84 death (in-hosp), C-index = 0.82 death (6 months) Archives Int Med 2003 KAAFox ESC2003

  8. GRACE: Model Calibration

  9. P <0.0001 P <0.0001 The frequency of death by tertile of GRACE risk score All ACS patients

  10. P <0.0001 P <0.0001 p=0.007 Does the frequency of intervention relate to the risk of the patients?

  11. Key systemic markers

  12. CRP…cause or consequence? CAPTURE: Event rate in % (Death, AMI) CRP > 10 mg/L OR 1.92; P=0.003 CRP < 10 mg/L Follow-up (days) Heeschen, Hamm et.al., JACC 2000

  13. Death from Cardiac Cause at 2 years: Influence of C-R Protein & Troponin T levels at 24 Hours 170 18 16 14 207 12 105 10 Death from Cardiac Causes (%) 8 0.6 262 6 0.06-0.59 4 2 Troponin T (µg/L) 34 <0.06 139 0 C-reactive protein>10mg/L C-reactive protein10mg/L FRISC Study Lindahl. NEJM 2000; 343:1139

  14. FRISC II 1-year mortality: IL-6 levels at entry in the noninvasive vs invasive groups 9 8 7 6 P=0.006 5 295 1-year mortality % P< 0.001 4 315 3 2 833 >= 5 ng/L 1 820 0 IL-6 < 5ng/L Noninvasive Invasive

  15. 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

  16. Subtle markers of myocardial dysfunction…

  17. 10 4th quartile 8 P<0.001 6 Mortality (%) 3rd quartile 4 2nd quartile 2 1st quartile 0 0 50 100 150 200 250 300 Days after randomization BNP in Acute Coronary Syndrome OPUS-TIMI 16 (n=2523) P<0.01 De Lemos JA, et al. NEJM. 2001.

  18. 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

  19. VULNERABLE CORONARY ARTERY PLAQUE Macrophages:CD68 and actin Collagen

  20. VULNERABLE CORONARY ARTERY PLAQUE Macrophages:CD68 and actin Collagen

  21. Altered growth factor production Excessive/uncontrolled adhesion tissue injury Failed clearance of apoptotic cells Plaque formation and progression - inflammatory events matrix metalloproteinases Altered differentiation/ apoptotic programmes Lipid core Lipid-laden macrophages

  22. markers of inflammation

  23. Leukocyte chemoattractants(MCP-1, IL-8, PDGF, MC-SF) Adhesion moleculesE-selectin, ICAM-1, VCAM-1 Procoagulant activity(tissue factor) Permeability Cytokines(TNFa, FAS,CD40L) Apoptosis NOET-1 markers of inflammation

  24. CD40 on platelets in type I DM vs. controls P<0.001 % positive platelets

  25. 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 Signal transduction PSGL-1 platelet monocyte

  26. Proinflammatory Cytokines Cation independent adhesion ( EDTA 10mM) 25 Chemokines (IL-8, MCP-1) Tissue Factor 20 15 percentage platelet- monocyte binding 10 5 0 Non-cardiac chest pain Unstable Angina MI Cell Adhesion Molecule Expression Pro-inflammatory effects of platelet-monocyte binding Sarma et al Circ 2002: 105; 2166-71

  27. 90 80 70 60 50 40 percent binding 30 20 10 0 abciximab P-selectin PSGL1 Control EDTA Glycoprotein IIb/IIIa does not mediate monocyte-platelet interaction abciximab does not block monocyte-platelet interaction. BUT, platelet P-selectin and monocyte PSGL-1 mediate adhesion. monoclonal antibody Sarma et al Circ 2002: 105; 2166-71

  28. Markers of protection?

  29. IL-10 T IL-10 Leukocyte chemoattractants(MCP-1, IL-8, PDGF, MC-SF) Adhesion moleculesE-selectin, ICAM-1, VCAM-1 T Procoagulant activity(tissue factor) Permeability T IL-10 Cytokines(TNFa, FAS,CD40L etc.) T T Apoptosis NOET-1 IL-10 IL-10 T hepatocyte growth factor markers of inflammation

  30. Prognostic significance of HGF serum levels in ACS 20 < 2.5 µg/L 2.5 – 4.7 µg/L Death, MI (%) 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.

  31. no TIMI risk score > 4 or GRACE risk of death > 4% ? Elevated NT proBNP, hsCRP, PLGF, CD40L Yes + Angio no Yes + Perfusion scan or stress echo or other stress test Angio no Non-invasive management Proposed strategy for resolving intermediate or uncertain risk Clinical syndrome of non-ST elevation ACS Troponin elevation, ST depression, or other high risk features Yes + Angio

  32. It’s never too late…. JAMA 2000;284:831-32

  33. “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

  34. 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

  35. Evidence of MI With Cardiac Troponin in Mummified Tissue Modern MI Mummies 1.3-3.7 Modern Non-MI Mummies 0.7-0.9 Horemkenesi 12.3-22.2 cTnI (ng/g) “…our data suggest that myocardial death can be diagnosed several thousand years after the event…” Miller et al JAMA 2000;284:831-32

  36. It’s never too late to diagnose MI!

  37. New Royal Infirmary and Research InstituteUniversity of Edinburgh

  38. New Royal Infirmary and Research InstituteUniversity 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

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