Η Εξελισσόμενη Προγνωστική Άξια των νεων Απεικονιστικών Βιοδεικτων στην Υποκλινική Αθηροσκληρωτική Νόσο

Η Εξελισσόμενη Προγνωστική Άξια των νεων Απεικονιστικών Βιοδεικτων στην Υποκλινική Αθηροσκληρωτική Νόσο Δρ. Ιωάννης Β. Βασιλειάδης, MD, PhD, FESC, FACC Διευθυντής Καρδιολογος, Ευρωκλινικη Αθηνών Disclosure: No conflict of interest to declare

Each year 1.1 million people have MI First symptom: MI: 500,000 Sudden death: 150,000 the last symptom 63% of women and 50% of men with sudden cardiac death had no prior known CAD 68% of MI s occur due to a lesion representing <50% stenosis 35% of patients with CAD have a total cholesterol <200

Preventing CAD Events: Need for Early Detection of High Risk Individuals ~50% of 1 st CV events (including SCD) Occur in Asymptomatics Screening for Subclinical CHD & Risk of Developing Symptomatic CHD are Major Challenges. Lipid-Lowering Trials Demonstrate Risk Reduction of CHD Events in 1 0 Prevention Some Asymptomatics May Benefit from Risk Reduction w/ Selective Use of Atherosclerosis Imaging to Identify High Risk Persons

Prevalence of atherosclerotic lesions in control populations Author Population Prevalence Enos US soldiers 77% JAMA 1953 killed in Korean war McNamara US soldiers 45% JAMA 1971 killed in Vietnam war Velican Non cardiac death 33% Atherosclerosis 1986 Arbustini 33%(Stenosis) Non cardiac death Cor Art Dis 1993 No clinical ischemia 8% (Trombosis) Baroldi Non cardiac death 74% Int J Cardiol 1998 aged >40 years Berenson Children (Bogalusa Heart Study) 8% Am J Cardiol 1992 middle-aged men 69% Angelini 100 subjects, aged 1-20years 20%plaque Int J Cardiol 1990 Non-cardiac death: Northern Italy Sambuceti G. Eur J Nucl Med Mol Imaging 2005: 385-388

CVD Screening - Benefit Outweighs Risk Early Detection of Atherosclerosis Identification of High Risk Comparative Effectiveness of Screening Strategies Risk Re-Classification Guiding management decisions Assess Burden of Silent CAD in High Risk Cost Exceeds Benefit Era of Finite Resources Expanding Indications and More Testing Escalate Healthcare Costs Does Not Induces Unnecessary Testing

The new diagnostic world for the detection of subclinical CAD Entries in the Diagnostic process Clinical- Risk Scoring Models Atherosclerosis Imaging Biomarkers

The new diagnostic world of the vulnerable people 1 2 3 4 4 Plaque imaging Fusion SPECT-PET-MRI/ CT Epicardial Adipose tissue by CT Coronary Calcium score -EAT by CT

CHD Prediction with Novel Markers Rotterdam Study

Limitations of Traditional Risk Assessment Models

Framingham (FRS) /SCORE Limitations Although powerful at the population level it may still fail at the level of the individual subject. FRS and SCORE underestimate CVD in men <60 & women <70! Age limits- Family Hx CHD-, Metabolic Syndrome- Michos (2006) Cross-Sectional Study of 2,447 Asymptomatic, non-dm Women Majority (84%) of Women w/ Significant CAC ( 75th %ile) were Classified as Low-Risk by FRS Source: Michos Atherosclerosis 2006;184(1):201-6., Nasir JACC 2005 Nov 15;46(10):1931-6.

Atherosclerosis Imaging Opportunities for the Individual Improve risk assessment Improve risk factor profiles Enhance risk communication Individual treatment

Atherosclerosis Imaging: Clinically Used Modalities Carotid Intima Media Thickness Coronary Artery Calcium Scoring Epicardial Fat Volume Plaque Imaging

Development of Atherosclerotic Plaque Coronary Artery Calcium Intima Media thickness- Plaque composition Subcomponents of Atheroma and their theoretical Relationsship to CHD Events Bostrom K, et al. J Clin Invest. 1993;91:1800 1809. Hirota S, et al. Am J Pathol. 1993;143:1003 1008. Shanahan CM, et al. J Clin Invest. 1994;93:2393 2402. O Rourke RA, et al. Circulation. 2000;102:126 140. Nasir K, Blumenthal RS. et al. Am Heart J. 2003;146:949 977. Wexler L, Brundage B, Crouse J, Detrano R, Fuster V, Maddahi J, Rumberger J, et al. Circulation. 1996;94:1175 1192. Blankenhorn DH, et al Ther Nucl Med. 1959;81:772 777. Subclinical Atherosclerosis

IMT typically progresses at an average rate of >0.03 mm per year, and the rate of progression appears to be related to risk of cardiovascular event 1. Υπερηχογραφικη μετρηση του αγγειακού χιτώνα των καρωτίδων cimt

Coronary calcium was a relatively stronger predictor for coronary outcomes, whereas carotid IMT was a stronger predictor of stroke in MESA

Plaque Burden Carotid US,Coronary Calcification

Cross Interactiοn Between Carotid Plaque &CAC

Coronary Calcium Scoring A novel biomarker of asymptomatic CAD

Non-obstructive atherosclerotic plaques ARE NOT INNOCENT Coronary calcium progresses at typically 10% to 20% of the baseline value per year, and among persons >45 years of age, approximately 7% per year of those without calcium develop detectable coronary calcium.

Asymptomatic preclinical type of CAD Example of a 56-year-old asymptomatic man w/ an intermediate SCORE of 5%. Extensive calcification of the three coronary vessels CACS 1940 A

High negative predictive accuracy of CAC

(ROC) curve (blue line) describing the capability of CACS to identify individuals at increased risk for coronary heart disease (MTSC 70% or more), as compared with the reference tool of Heartscore (HS) risk assessment. The area under the curve was 0.895 (95% CI, 0.839 to 0.951) for CACS and 0.708 (95% CI, 0.624 to 0.793) for HeartScore. Can coronary artery calcium score (CACS) outperforms SCORE risk factor analysis as a first step screening for the detection of sub clinical coronary atherosclerosis? I. Vassiliadis,1,2 E. Despotopoulos1, O. Kaitozis1, E. Hatzistamatiou1. Euromedica-Encephalos 1, Euroclinic Hospital2, Athens Purpose: We sought to investigate whether coronary artery calcium score (CACS) can reclassify to an increased likelihood for CAD, individuals initially categorized using SCORE analysis of conventional CAD risk factors Methods: A total of 225 asymptomatic subjects (mean age 54±7 years, 78% males) without known cardiovascular disease, and without typical angina, were enrolled in our study. A pretest probability of CAD was derived using a predicted SCORE risk analysis. CT angiography was used as the reference standard grading luminal stenosis. Results: For a hemodynamically significant coronary artery stenosis, the presence of a calcium score >400 was 64% sensitive, 98,8% specific with a negative likelihood ratio of 0,36 in males and 60% sensitive, 100% specific with a negative likelihood ratio of 0,40 in females. In females the area under the ROC curve was only 0,352 (p=0.285) for HeartScore and 0,957 (p<0.001) for CACS, whereas in males the area under the ROC curve was 0,738 (p<0.001) for HeartScore and 0,878 (p<0.001) for CACS. Conclusions: CACS can identify individuals at increased risk for predicting atherosclerotic heart disease, who otherwise would be considered lowrisk based on clinical assessment.

Distribution of subclinical Atherosclerosis (Imaging) Relation to Framingham Risk Score

Consensus on CAD Screening using CACS CAD screening in asymptomatic adults is NOT justified EXCEPT FOR: 1. Diabetes 2. Men > 45 and women > 55 starting exercise program 3. Subjects with multiple risk factors (Risk Score) 4. Public safety jobs 5. First degree relatives of patients with premature CAD USPSTF 2004 ACC 2002 American college of Physicians/family Physicians American College of Sports Medicine

3. Epicardial adipose Tissue A novel risk marker of asymptomatic CAD ΕΑΤ σε φυσιολογικές συνθήκες. Βιοχημικές ιδιότητες αποδίδεται ο ενεργός ρόλος στη ρύθμιση της ενεργειακής ομοιοστασίας που επιτυγχάνεται μέσω αποδέσμευσης και πρόσληψης μεγαλύτερων ποσοτήτων ελευθέρων λιπαρών οξέων και χρησιμοποίησης σε μικρότερο βαθμό γλυκόζη από το μυοκάρδιο προκειμένου να αντιμετωπίσει αυξημένες μεταβολικές ανάγκες. Μηχανικές ιδιότητες συγκαταλέγεται η έκφραση και έκκριση καρδιοπροστατευτικών αντιφλεγμονωδών- αντιαθηρωματογων πρωτεϊνών, Αdiponectin, Adrenomedulin) Θερμογεννετικές η έκφραση θερμογεννετικής πρωτεΐνης (UCP-1) ως αποτέλεσμα έκθεσης στο ψύχος. Οι Αντιπονεκτίνες διοχετεύονται από το επικαρδιακό λίπος στον αυλό των στεφανιαίων αγγείων είτε μέσω διάχυσης του αγγειακού τοιχώματος εκ των έξω προς τα εσω (παρακρινης μηχανισμός), είτε μέσω των vasa vasorum του αγγειακού τοιχώματος (αγγειοκρινής μηχανισμός) Παθοφυσιολογικος ρόλος ΕΑΤ Πρόοδος της αθηρωματικής διεργασίας στα στεφανιαία αγγεια μεσω αυξημένης έκφρασης και έκλυσης προφλεγμονωδων κυτοκινών TNF, MCP,IL6, ICAM,PROSTAGLANDIN στον αυλό τους με την ταυτόχρονη χαμηλότερη ρύθμιση των αντιφλεγμονωδών αντιπονεκτινων.. Ένα ακόμα πρόσθετο επιβαρυντικό ρόλο στην εμφάνιση αθηρωμάτωσης των στεφανιαίων αγγείων φαίνεται ότι παίζει το επικαρδιακό λίπος με τη συσσώρευση και η αύξηση του αριθμού των μακροφάγων.

EAT associated with Calcium scoring (MESA Multiethnic study atherosclerosis, Am J Clin Nutr 2009 Vascular calcification (FHS Framingham Heart study, Circulation 2008; Coronary calcium and MACE (EISNER Atherosclerosis 2010 Diagnostic ICA Gorter Am. J Cardiol 2008 Luminal stenosis and plaque Alexopoulos Atherosclerosis 2010 Luminal stenosis, remodeling plaque Schlett Atherosclerosis 2012 Inducible ischemia SPECT Tamarappo JACC Imag 2010 Inducible ischemia PET Janik J Nuc. Cardiol 2010 Metabolic syndrome Iakobellis Obesity 2008 Impaired LV fx decrease in EAT Khawaja Am J Cardiol. 2011 PAF Chekakie JACC 2010

Epicardial fat volume. A novel risk biomarker for the subclinical coronary artery disease. Coronary CTA CT Scanner GE 64-slice CT (Light speed VCT, XT Low dose acquisition (1mSv) for the sequential measurements of Coronary Artery Calcium Score-CACS- and epicardial adipose tissue- ΕΑΤ- Upper Threshold for abnormal: 139-119 cm 3 Plaque characterization Coronary calcification Epicardial Fat volume Reformat images with parasternal short axis view at basal, mid-ventricular and apical levels and horizontal long axis view as the sum of the EAT areas with 2mm thick from the whole heart Manual or semi-quantitative calculation Αttenuation volume for non-contrast CT identified as -190 to -30 HU Approximately 1200 pericardial contours Vassiliadis,.Despotopoulos,.Kaitozis, Eur. Heart J.(Suppl)16 2014

2-fold 2-2 Φ Ο Λ Δ

4 Molecular Plaque Imaging. A novel biomarker of asymptomatic CAD The 2 leading clinical platforms remain 18Ffluorodeoxyglucose (18FDG) imaging of plaque metabolic activity/inflammation by PET) and ultrasmall superparamagnetic iron oxide (USPIO) nanoparticle LE CMR of plaque macrophages. These modalities primarily interrogate the carotid arteries and larger vascular beds, although recent preliminary reports suggest the potential for noninvasive coronary plaque imaging molecular imaging The benefit of molecular imaging as a biomarker for drug development by the pharmaceutical industry was considered an important goal in the field Molecular imaging has shown its worth and future potential in oncology, but it has lagged in achieving progress to clinical application in cardiology

Co-registration with high-resolution MRI and 18F-FDG PET Imaging with Hybrid Device can identify vulnerable plaques MR-PET FUSION MOLLECULAR IMAGING IF ATHEROSCLEROSIS CLASS III: NO BENEFIT MRI for detection of vascular plaque is not recommended for cardiovascular risk assessment in asymptomatic adults. (Level of Evidence: C) A) PET-CT B) MR-PET: Απεικόνιση καρωτίδων ασθνόυς με αθηροσκληρυντικη νόσο με χρήση FDG. Η διαγραφή του τοιχώματος των αγγείων και η ενδογενής αντίθεση των μαλακών ιστών είναι βελτιωμένες με τη χρήση του MR σαν συνδυασμένη απεικόνιση με το PET όπως καταδεικνύεται με το ενθετο. Με λευκα βέλη οι καρωτίδες Fayad ZA. 2010 BUT

Radiation Burden

Συμπεράσματα -Μυνήματα Η προσπαθεια μεσω προγνωστικων μοντελλων και κλινικων δεικτων για την προληψη της ΣΝ εχει ισχυρη προγνωστικη αξια στον γενικό πληθυσμό αλλα υστερει ακομη σε εξατομικευμένο επιπεδο Η λογικη της πρωιμης διαγνωσης υποκλινικης μορφης της νοσου επιτρεπει την αναγνωριση των υψηλου κινδύνου ατομων, πολλοι από τους οποιους μαθαινουν για την παθηση τους όταν υποστουν το πρωτο οξυ στεφανιαιο επεισοδιο το οποιο στο 50% είναι θανατηφόρο. ώστε με την τροποποιηση των παραγόντων κινδύνου εγκαιρα να εφαρμοστουν προληπτικα και θεραπευτικα μετρα βελτιωνοντας την προγνωση τους Η προσθηκη της μετρησης του IMT, CACS, ΕΑΤ και της απεικονισης της ευάλωτης αθηρωματικής πλάκας στους αλγοριθμους των συμβατικων κλινικων προβλεπτικων μοντελλων περιορίζει την εμφανιση μειζόνων καρδιακων συμβαματων στον ασυμπτωματικό πληθυσμό.