San Raffaele Hospital and Emo Centro Cuore Columbus Milan- Italy

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1 Stnt-basd Stabilization of Rupturd Carotid Plaqus: Clinical Lssons and Biomarkrs Pattrns from th SUBMARINE Study, and Rlvanc to th Coronary Condition Giuspp Sangiorgi, FESC, FSCAI San Raffal Hospital and Emo Cntro Cuor Columbus Milan- Italy Intrvntional Vulnrabl Plaqu Stratgis and Futur Horizons Washington D.C. - Octobr 26, 26

2 Conflict of Intrst Statmnt Within th past 12 months, I or my spous/partnr hav had a financial intrst/arrangmnt or affiliation with th organization(s) listd blow. I hav th following potntial conflicts of intrst to rport: Consulting Employmnt in industry Stockholdr of a halthcar company Ownr of a halthcar company Othr(s) X I do not hav any potntial conflict of intrst

3 Vulnrabl Plaqu: Invstigation Plan Establish biological, pathological, and mchanical faturs of th vulnrabl plaqu: dfinition Look for th prsnc of vulnrabl plaqus lswhr in th sam patint Dvlop noninvasiv and invasiv tools to dtct vulnrabl plaqu Tst th prformanc of ths tools to idntify ky faturs in plaqus that hav just causd ACS/Strok/TIA Establish th natural history of ths high-risk plaqus Establish th potntial impact of such finding on th procdural stratgy and short-trm outcom Tst systmic and/or local thrapis aiming at improving th natural history

4 Distribution of various plaqu typs in patints affctd by CAD * Plaqu typs CS * of pts without SA who did for non-cardiac causs (CTRL group) (N=34) CS = coronary sgmnts; CS * of pts with SA did for non-cardiac causs (SA group) CS * of pts did for AMI (AMI group) (N=19) (N=544) Culprit plaqus with thromb. 16 (3.%) - associatd to cap ruptur 14 (2.6%) - associatd to cap rosion 2 (.4%) 13 (4.3%) 4 (3.7%) 19 (2.%) - thin-fibrous cap athromata 13 (1.%) 31 (5.7%) - suprficial calcifid nodul 8 (2.6%) 4 (3.7%) 31 (5.7%) - plaqus with stnosis >9% 2 (.7%) 47 (8.6%) - # vulnrabl plaqus/pts 1.4±.3.8±.3 6.8± (95.7%) 15 (96.3%) 419 (77.%) Vulnrabl plaqus Stabl plaqus Maurillo A t al. JACC 25; 45:

5 Thrombotically Activ Plaqus, Cap Ruptur and Cap Erosion by Disas Stat P valu No. of Plaqus Patints with Major Patints with Asymptomatic (N=82) TIA Ipsilatral Strok (N=91) (N=96) Strok vs TIA Strok vs Asympt. TIA vs Asympt. Angiographic stnosis (%) Ipsilatral carotid Controlatral Carotid Thrombotically activ plaqu (n,%) 71 (74.) 32 (35.2) 12 (14.6) <.1 <.1.2 Cap Ruptur 64 (66.7) 21 (23.1) 11 (13.4) <.1 <.1.4 Cap Erosion 7 (7.3) 11 (12.1) 1 (1.2) Spagnoli LG t al, JAMA 24; 292:

6 Frquncy of acut rupturs by dgr of luminal stnosis CAROTID 25 CORONARY CORONAR 15 1 Luminal Stnosis % < 25% < 25 % acut rupturs 2

7 Thrombosis Rlatd to Tim Intrval Btwn Symptom Onst and Surgry in pts with Strok Tim Intrval btwn Acut Crbrovascular Evnt and Endartrctomy, No % Thrombotically activ plaqus (TAPs) Organizd thrombus No thrombosis -2 mo (N=32) 3-6 mo (N=18) 7-12 mo (N=15) mo (N=13) 25-3 mo (n=18) 32 (1) 13 (72.2) 11 (73.3) 7 (53.8) 8 (44) 4 (22.2) 4 (26.7) 5 (38.5) 1 (55.6) 1 (5.6) 1 (7.7) Spagnoli LG t al, JAMA 24; 292:

8 Rapid Tx of Symptomatic Patints # of stroks prvntd pr 1, CEAs at 3 yars -2 wks 2-4 wks 4-12 wks >12 wks Tim from last vnt to randomization Adaptd from Rotwll 24

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11 Clinical prsntation, plaqu typs and PAPP-A lvls obsrvd in 65 carotid plaqus submittd to histologic xamination Histological Dfinition Strok (N=19) TIA (N=24) Asymptomatic (N=29) PAPP-A Srum Lvls (miu/l) Rupturd plaqus (n=14) 7 (41.2%) 4 (2.%) 3 (1.7%) 6.97±.75 Vulnrabl plaqus (n=13) 5 (29.4%) 4 (2.%) 4 (14.3%) 7.43±.97 Stabl plaqus (N=38) 5 (29.4%) 12 (6.%) 21 (75.%) 4.2±.18* *p<.2 Rupt/vuln vs. stabl Sangiorgi G t al, JACC 26;47:

12 Corrlation PAPP-A / Cap Thicknss Cap Thicknss (microns) 35 3 Corrlation Cofficint = P< y = -53,177x + 219,96 R2 =, ,5 1 1,5 2 PAPP scor 2,5 3 3,5

13 Corrlation PAPP-A / Plaqu Inflammation 1 9 Corrlation Cofficint =.741 P<.1 8 y = 12,736x + 13,84 R2 =,4957 Cap Inflammation (cll/mm2) ,5 1 1,5 2 PAPP scor 2,5 3 3,5

14 PAPP-A Srologic Lvls in Pts with Singl Coronary Lsion aftr Stnting PAPP-A srum lvls (miu/l) 6 5 * 4 3 AMI (n=2) Stabl (n=2) Unstabl (n=2) * 2 1 Baslin On-Month Thr months Sangiorgi G. t al. Eur Hart J 22 P <.5 Baslin vs. 1 month vs. 3months

15 SUBMARINE Study Dsign SERUM AND URINARY PLAQUE VULNERABILITY BIOMARKERS DETECTION BEFORE AND AFTER CAROTID STENT IMPLANTATION Minor Strok or First/Rcurrnt TIAs Nurologic Assssmnt Duplx Examination Early CAS with NP Filtr

16 SUBMARINE Study Dsign SERUM AND URINARY PLAQUE VULNERABILITY BIOMARKERS DETECTION BEFORE AND AFTER CAROTID STENT IMPLANTATION Minor Strok or First/Rcurrnt TIAs Nurologic Assssmnt Duplx Examination Histologic valuation of plaqu dbris TIA 24/48 hrs Minor Strok 14-3 days PAPP-A hs-crp MMP-2/MMP-9 IL-6/IL-8 TNF alpha CD4L Assssmnt of Vulnrability Biomarkrs at PrPost- and FU

17 PAPP-A Srologic Lvls at Diffrnt Tim Intrvals Pr -p Po s t- ro c d pr oc (miu/l) ur 8.8 Ovrall TIA Minor Strok du r U 6.9 P<.1 [IC 1,8 15,3] 1 -m of 15.1

18 hs-crp Srologic Lvls at Diffrnt Tim Intrvals Pr -p s t- ro c d pr oc 5 1 ur du r U Ovrall TIA Minor Strok P<.1 [IC 6,7 19,9] 1 -m of 25 P<.1 [IC 16,1 5,] Po

19 IL-6 Srologic Lvls at Diffrnt Tim Intrvals Pr -p s t- ro c d pr oc ur du r U Ovrall TIA Minor Strok P<.1 [IC 3,6 9,1] 1 -m of 2 P<.1 [IC 8,1 2,7] Po

20 IL-8 Srologic Lvls at Diffrnt Tim Intrvals Pr -p Po s t- ro c d pr oc ur du r 1 -m of U Ovrall TIA Minor Strok 4

21 MMP-2 Srologic Lvls at Diffrnt Tim Intrvals Pr -p s t- ro c d pr oc ur 83.5 du r Ovrall TIA Minor Strok U 96.2 P<.1 [IC 186,9 57] 1 -m of 12 P<.1 [IC 177,9 77,6] Po

22 MMP-9 Srologic Lvls at Diffrnt Tim Intrvals Pr -p Po ro c d pr oc ur du r 1 -m of Ovrall TIA Minor Strok U P<.1 [IC 43,5 5,1] s t

23 Conclusions Plaqu vulnrability biomarkrs ar lvatd at symptoms onst both in coronary and carotids plaqus du to th rlatd complx plaqu charactristics Diffrnt biomarkrs lvls incras aftr stnting and at 1 month follow-up ar significantly rducd to a lvl similar to th corrsponding baslin tim. Longr follow-up data ar xpctd to dmonstrat possibl complt mchanical plaqu stabilization