Από την ευάλωτη αθηρωµατική πλάκα στον ευάλωτο ασθενή µε στεφανιαία νόσο Ο εξελισσόµενος ρόλος της αναίµακτης απεικόνισης

Από την ευάλωτη αθηρωµατική πλάκα στον ευάλωτο ασθενή µε στεφανιαία νόσο Ο εξελισσόµενος ρόλος της αναίµακτης απεικόνισης Ιωάννης Β. Βασιλειάδης, MD, Ph.D, FACC, FESC, FASNC Διευθυντης Καρδιολογος - Ευρωκλινικη Αθηνών

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

Prevalence of stenotic lesions in control populations Author Population Prevalence Enos US soldiers 77% JAMA 1953 killed in Korean war Namara US soldiers 45% JAMA 1971 killed in Vietnam war Velican Non cardiac death 33% Atherosclerosis 1986 Arbustini Non cardiac death 33% (Stenosis) 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%

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

Imaging has at least 3 virtues It individualizes risk assessment beyond use of age, which is a less reliable surrogate for atherosclerosis burden It provides an integrated assessment of the lifetime exposure to risk factors It identifies individuals who are susceptible to developing atherosclerosis beyond established risk factors Grundy. Circulation 2008;117:569-

Development of Atherosclerotic Plaque Coronary Artery Calcium A Subcomponent of Atheroma 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

1. 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

NUCLEAR IMAGING APPROACHES TO IMAGING VULNERABLE PLAQUES Nuclear imaging has several advantages over most of the other modalities including its noninvasive nature and its potential to image different vascular beds within one scanning session The main challenge for nuclear imaging of atherosclerotic plaques is the small size of most lesions and their proximity to the blood pool Molecular imaging, complements traditional anatomical imaging approaches that identify plaque structure and composition Techniques, such as single photon emission computed tomography (SPECT) and positron emission tomography (PET) are capable of detecting sufficiently small quantities of tracer uptake to be able to quantify pathophysiologically important molecular and cellular features after the injection of small (and

Imaging of Metabolically Active Macrophages With F-18 PET " Fluorodeoxyglucose (FDG) competes with glucose for uptake into metabolically active cells, where it accumulates in proportion to metabolic activity. Inflammation is a highly metabolically active process and F-18 FDG PET has been used successfully to image vascular inflammation in patients with large-vessel vasculitis " uptake of F-18 FDG occurs predominantly in macrophages involved in the inflammatory response " F-18 FDG PET imaging of human atherosclerosis was used In the first clinical study " The evidence suggests that F-18 FDG PET may have an important role to play in identifying vulnerable plaques and might be able to monitor spontaneous and druginduced changes in plaque inflammation Wykrzykowska J, Nucl Med 2009

PET CT imaging with the Vascular Cell Adhesion Mollecule VCAM-1 targeted tracer 18F-4V! Vascular cell adhesion molecule-1 (VCAM-1), expressed by activated endothelial cells, participates in leukocyte rolling and adhesion primarily by interacting with its counterligand VLA-4 (41) on monocytes and lymphocytes. VCAM-1 expression on the vessel endothelial surface or the underlying vasa vasorum plays an important role in atherosclerotic plaque development by monocyte and T-lymphocyte recruitment before statins after statins SAX LAX! The tetrameric peptide 18F-4V provided the highest specificity and affinity for VCAM-1, and enabled its noninvasive detection in murine plaques. Statin-treated animals demonstrated less in vivo plaque uptake of 18F-4V Aortic root VCAM-1 targeted tracer 18F-4V Nahrendorf M et al Circulation2008

Molecular Imaging of Matrix Metalloproteinase in Atherosclerotic Lesions Resolution With Dietary Modification and Statin, (99mTc conjugated to the broad-spectrum, MMP-inhibiting macrocyclic compound RP805) Active digestion of the fibrous cap by MMPs is an important determinant of plaque instability, noninvasive detection of MMPs could identify those plaques at risk of rupture Fujimoto et al. JACC 2008

Imaging Apoptosis with 99mTc-annexinA5! Death of both VSMCs and macrophages is a characteristic feature of unstable plaques.! Apoptotic cells express high levels of phosphatidyl serine (PS) on their cell surface. Annexin V has a high affinity for PS. The interaction between annexin V and PS is responsible for phagocytosis of apoptotic cells by adjacent cells! A statistically significant correlation (r 0.47, P.04) between tracer accumulation and histologically verified macrophage apoptosis, with no significant annexin V uptake in the normal aortas of control rabbits Kolodgie FD. Circulation 2003

MRI Plaque imaging " MRI Plaque Ultrasmall Superparamagnetic nanoparticles of Iron Oxide in Human Atherosclerotic Plaques with MRI Kooi et al. Circulation 2003 " PET-CT PET-MRI: Carotid artery imaging of a pt with atherosclerotic disease using FDG. The delineation of the vessel wall and the endogenous contrast of the soft tissyews is improved with MRI compared to CTA Fayad ZA. Aterioscler Thromb Vasc Biol 2009;

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

2. Coronary Calcium Scoring A novel biomarker of asymptomatic CAD

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! Coronary calcification is defined as a plaque of at least 3 consecutive pixels (area, 1.03 mm2) with attenuation of 130 HU or greater. The total CAC score is determined by summing individual lesion scores from each of 4 anatomic sites (left main, left anterior descending, circumflex, and right coronary arteries)! Plaque characterization as calcified, structures of >1mm2 consisting of calcified tissue occupying>50% of the plaque area (density >130Hounsfield units), <50% calcium as mixed and without calcium as soft

Annual CHD Death or MI Rate in Pts w/ Intermediate FRS or >1 Risk Factor 5.00% Annual CHD Death or MI Rate 3.75% 2.50% 1.25% 1.25% 2.37% 0% 0.37% Tertile I Tertile II Tertile III CAC 0-99 CAC 100-399 CAC 400 Source: Greenland Circulation 2007 Jan 23;115(3):402-26.

Annual CHD Death or MI Rate in Pts w/ Intermediate FRS or >1 Risk Factor 5.00% Annual CHD Death or MI Rate 3.75% 2.50% 1.25% 1.25% 2.37% 0% 0.37% Tertile I Tertile II Tertile III CAC 0-99 CAC 100-399 CAC 400 Source: Greenland Circulation 2007 Jan 23;115(3):402-26.

Framingham (FRS) /SCORE 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 were Classified as Low-Risk by FRS Source: Michos Atherosclerosis 2006;184(1):201-6., Nasir JACC 2005 Nov 15;46(10):1931-6.

NIH-NHLBI MESA Source: Detrano NEJM 2008 Mar 27;358(13):1336-45.

Event Rates by CAC Scores Event Rate at 5 Yrs [%] 20 16 12 8 4 0 All Subjects Men Women 73% 17% 10% 59% 24% 17% 85% 11% 5% p<0.0001 p<0.0001 p<0.0001 p=0.0004 p=0.02 p=0.004 p=0.0002 p=0.002 p=0.48 <100 100-399 400 <100 100-399 400 <100 100-399 400 CAC Categories Data = Event Rates (95%CI) CAC scoring of persons at intermediate risk results in a Net Reclassification Improvement (NRI) of 21% (P ¼ 0.0003) after 5 years of follow-up, and an Integrated Discrimination Improvement (IDI) 1.52% (P, 0.0001).

Near- & Long-Term Survival from 2 EBT Centers: Nashville, TN and Los Angeles, CA n=10,377 n=25,257 1.00 0.95 0-10: 99.4% 11-100: 97.8% 101-399: 95.2% 1.00 0.95 0-10: 99.4% 11-100: 97.8% 101-399: 94.5% 0.90 400-999: 90.4% 0.90 0.85 0.85 400-999: 87.8% 0.80 1,000: 81.8% 0.80 0.75 0.75 1,000: 76.9% 0.0 1.0 2.0 3.0 4.0 5.0 Time to Follow-up (Years) 0.0 2.0 4.0 6.0 8.0 10.0 12.0 Time to Follow-up (Years) χ 2 =1503, p<0.0001 Source: Budoff JACC 2007 May 8;49(18):1860-70.

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 low-risk based on clinical assessment. (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.

! Asymptomatic patients with intermediate CHD risk may be reasonable to consider use of CAC measurement an available evidence that demonstrates incremental risk prediction information in this group, based on the possibility that such patients might be reclassified to a higher risk status based on high CAC score, and subsequent patient management may be modified! CAD screening in asymptomatic adults is not recommended exept 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 ACCF/AHA Expert Consensus 2007 American college of Physicians/family Physicians American College of Sports Medicine

3. (a) EAT exerts three distinct properties -Release of FFAs as energy to the myocardium in condition of high metabolic demand -expression of the thermogenic protein UCP-1 in response of cold exposur -expression and secretion of cardioprotective adipokines (b) Putative mechanisms adipokines might reach the coronary artery lumen from the epicardial fat. Adipokines from periadventitial epicardial fat could traverse the coronary wall by diffusion from outside to inside, via a paracrine mechanism. Adipokines might also be released from epicardial tissue directly into the vasa vasorum and be transported downstream into the arterial wall via a vasocrine mechanism. (c) Putative pathophysiological role in promoting atheroscler proinflammatory cytokines are highly expressed and secreted into the coronary lumen and antiinflammatory adipokines are thought to be downregulated. In high-risk subjects, as well as those with metabolic syndrome and

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 ischemnia 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