Clinical Characteristics of Pre- Symptomatic Vulnerable Patients; are There Different Types?

1. Clinical Characteristics of Pre- Symptomatic Vulnerable Patients; are There Different Types? Attilio Maseri, MD FACC FESC University Vita-Salute San Raffaele, Milan Italy No conflict of interest to disclose

2. Risk stratification Ridker PM, Circulation 2003, 107:363-9

3. Triggers of ACS Subtle differences in clinical presentation and phenotypic features may provide clues suggestive of specific causes of clinical syndromes. In anemic patients, clinical history and red cell features can provide useful information on specific causes of anemia. • Could this also be the case for patients presenting with Acute Coronary Syndromes?

4. TYPE 1 Infarction out of the blue preceded and followed by complete stability TYPE 2 Unstable anginafollowed byinfarctionfollowed by recurrent ACS Different clinical presentation of ACS Maseri A, Italian Heart J 2003, 4:345-6

5. Persisting CRP elevation post discharge predics recurrent instability Biasucci LM et al. Circulation 1999 Bogarty P et al. Circulation 2001 CRP levels > 3mg/l in: ~ 65% of UA (IIIB) ~ 100% of MIs preceded by UA ~ 45% of MIs not preceded by UA Liuzzo et al. NEJM 1994 and JACC 1999

6. CRP Levels> 3 mg/l in UA 100 90 80 70 60 Patients (%) 50 40 30 20 10 0 admission discharge 3 months 1 year Biasucci LM, Circulation 1999

7. CRP<3 mg/L CRP<3 mg/L CRP>3 mg/L CRP>3 mg/L Event free survival according to CRP levels at discharge in UA Cum. Survival % P<0.001 Months Biasucci LM, Circulation 1999

8. Multiple unstable plaques in ACS • Multiple unstable coronary plaques Goldstein et al, NEJM 2000 Zairis M et al, Atherosclerosis 2000 • Widespread coronary inflammation Buffon et al, NEJM 2002

9. Carotid plaques in UA P=0.013 % pts CRP <2.5 mg/L CRP >7.2 mg/L CRP 2.5-7.2 mg/L complex plaques simple plaques no plaques Lombardo A, submitted

10. Mechanisms of inflammation in ACS • Infectious and non infectious agents: bacteria, viruses, oxydants, toxins • Immunological stimuli Circulation: Liuzzo 1999, 2000; Caligiuri 2000, Biasucci 2003 • Enhanced inflammatory responsiveness Maseri NEJM 1997; Liuzzo: Circulation 1998, 2001;JACC 1999

11. Conclusions 1 • In ACS inflammatory response is largely independent from global atherothrombotic burden. • In some patients, but not in all, plaque instability may be prolonged in time and involve multiple vascular sites.

12. Conclusions 2 Inflammatory mechanisms are correlated with recurrence of instability: they may be multiple and not equally important in all patients. Their precise identification is required for a targetted prevention of inflammation Inhibition of key inflammatory final triggers of thrombosis appears an attractive therapeutic target. Patients with recurrent instability and elevated inflammatory markers are ideal candidates for pilot studies

13. Exploring the triggers of ACS Clinical investigators should stop being “lumpers” and become "splitters”, looking for distinctive, rather than for common features, among patients presenting with coronary atherosclerosis and ACS.