Plaque Characteristics in Coronary Artery Disease. Chourmouzios Arampatzis MD, PhD, FESC

Transcription

1 Plaque Characteristics in Coronary Artery Disease Chourmouzios Arampatzis MD, PhD, FESC

2 Disclosure Statement of Financial Interest Regarding this Presentation NONE

3 Atherosclerosis Model proposed by Stary I II III IV V VI The initial knowledge of atherosclerosis progression was reported in the early 1980s without however understand the relation between lesion progression and ACS. The numeric AHA classification (1994) incomplete described the diversity of human CAD. Adaptive thickening of SMC Macrophage foam cells Standard atherosclerosis development Pools of Internal core Fibrous extracellular of extracellular thickening lipids lipids Complicated lesion Stary et al, Arterioscler Thromb Vasc Biol 1992;12: Lipid accumulation Calcification Hyperplasia Thrombosis hematoma

4 Current Concepts of Atherosclerosis In the modified classification the numeric AHA types I-IV are replaced by descriptive terminology: adaptive intimal thickening, intimal xanthoma (fatty streak), pathologic intimal thickening, and fibroatheroma. Lesions alluded to in types V and VI were discarded since they failed to account for the three different causes of thrombotic morphologies (rupture, erosion and calcified nodule) and their relationship to healed plaque that is representative of stable angina. Type I Type II Type III Type IV Adaptive intimal thickening Intimal xanthoma Pathologic intimal thickening Fibrous cap atheroma Thin-cap fibroatheroma Virmani et al, Arterioscler Thromb Vasc Biol 2000;20:

5 Nonatherosclerotic intimal lesions Progressive atherosclerotic lesions Artery wall Lumen Intimal thickening Intimal xanthoma Pathological intimal thickening Without With macrophage macrophage Early Fibroatheroma Late Thin cap fibroatheroma Smooth muscle cells Macrophage foam cells Extracellular lipid Collagen Necrotic core Cholesterol clefts Calcified plaque Rupture Lesions with acute thrombi Underlying PIT Erosion Calcified nodule Plaque fissure Fibrous plaque Underlying fibroatheroma Angiogenesis Hemorrhage Fibrin Complications of hemorrhage and/or thrombus with healing and stabilization Thrombus Intraplaque hemorrhage Single layer Healed Rupture Multiple layers CTO Fibrocalcific plaque Nodular calcification Healed thrombus Adapted from Nature 2015

6 Arampatzis et al, Circulation 2003;108:34-35 TOMTEC Surgical View

7 Sudden Coronary Death Calcified nodules Erosion 30-40% ACS 50-75% Plaque rupture 60-75% 2-7% 70% remote TCFA Stable CAD 25-50% 30% TCFA 18% TCFA 20% TCFA 43% TCFA 61% of SCD victims show at least one healed plaque rupture lesion, in which the incidence is greatest in the deaths from stable angina with severe stenosis (80%), followed by acute plaque rupture (75%) and the least in plaque erosions. In Coronary Atheroslerosis Arampatzis et al Taylor & Francis 2012

8 Coronary Artery Disease is Changing STEMI plaque rupture erosion Plaque erosion Lipid poor Proteoglycan and glycosaminoglycan rich Non-fibrillar collagen breakdown Few inflammatory cells Endothelial cell apoptosis Secondary neutrophil involvement Female predominance High triglycerides Libby Eur Heart J 2015;43: Plaque rupture Lipid rich Collagen poor, thin fibrous cap Interstitial collagen breakdown Abundant inflammation Smooth muscle cell apoptosis Macrophage predominance Male predominance High LDL NSTEMI plaque rupture erosion

9 Narula et al. J Am Coll Cardiol 2013;61:

10 Image Angiography Grayscale IVUS VH-IVUS Angioscopy OCT IVPA/US Images of blood flow Tomogram Tomogram Surface imaging only Sub-surface tomogram Tomogram Axial resolution Type of radiation X-ray Ultrasound Ultrasound Visible light Near IR light Near IR light + US Lumen area Plaque burden Positive remodeling Necrotic core - ± ++ ± - ++ Fibrous cap thickness - - ± ± ++ ± TCFA - - ± ± ++ ± Plaque rupture ± Erosion Thrombus ± ± ± ++ + ±

11 Boston Atlantis SR 30MHz Ruptured plaque with lipid rich necrotic core Fibrous plaque with deep calcification Fibrofatty plaque with deep attenuation Volcano Revolution TM 45MHz Intraluminal thrombus Fibrous plaque Calcified plaque In Coronary Atheroslerosis Arampatzis et al Taylor & Francis 2012

12 A. Virtual Histology employs spectral radiofrequency analyses with a classification tree algorithm developed from ex-vivo datasets, showing distinct color for each of the fibrous, fibro-fatty, necrotic core and calcific components. B. Integrated Backscatter IVUS utilizes backscatter values, calculated as the average power of the backscattered ultrasound signals from a sample tissue volume, to differentiate tissue types: fibrosis, dense fibrous, lipid pool and calcification. C. imap identifies 4 different types of plaque components (fibrotic, lipidic, necrotic and calcified tissue) based on the degree of spectral similarity between the backscattered signal and a reference library of spectra from known tissue types.

13 Pathological intimal thickening (PIT) is considered as a progressive lesion in the early stages of atherosclerosis and represents a precursor lesion to fibroatheroma. It consists of mainly a mixture of fibrotic tissue and fibrofatty plaque with less than 10% each confluent necrotic core and dense calcium respectively. Thin-cap fibroatheroma (TCFA) has been considered as a high-risk lesion causing ACS. Histologically, TCFA is characterized by thin cap overlying a large necrotic core containing numerous cholesterol clefts. On VH, TCFA is characterized as having more than 10% necrotic core,no evidence of fibrous cap and less than 10% of calcium. Thick-cap fibroatheroma (ThCFA) harbors a large lipid-necrotic core comprising large amount of extracellular lipid, cholesterol crystals and necrotic debris, surrounded by a thick fibrous cap. The definition of ThCFA is a lesion with more than 10% confluent necrotic core and a definable fibrous cap. VH-IVUS derived fibrotic plaque is mainly fibrous tissue without confluent necrotic core or calcium. Fibrotic plaque is different from PIT with regard to the presence of fibro-fatty tissue. Fibrotic plaque contains few fibro-fatty tissue (<15%), whereas PIT contains >15% fibro-fatty tissue. Fibrocalcific plaque is a collagen rich lesion with nearly all fibrotic tissue and dense calcium with less than 10% confluent necrotic core. Garcia-Garcia HM, Eurointervention 2009;5:177-89

14 Lessons from the PROSPECT-lesion related factors Independent predictors of lesion level events by Cox proportional Hazards reduction Model Events VS number of high risk factors 18.2 Variable HR (95%CI) P PB MLA 70% 5.03( ) < VH-TCFA 3.35( ) MLA<4mm ( ) Zero One Two Three 5/ / /253 5/29 Stone et al, N Engl J Med 2011;364:226-35

15 Remodeling Proximal Distal Positive remodeling in response to plaque growth helps to prevent luminal narrowing. However Larger lipid core and a greater macrophage burden. More unstable clinical presentation. More CPK elevation after PCI. No reflow in primary PCI. Recurrent ischemia within 1 month after thrombolysis. More TLR. More MACE in patients with UA and any form of revascularization. More intimal hypeprlasia. More in-hospital complications in patients with stable CAD undergoing single vessel PCI. + - Proximal Distal In Coronary Atheroslerosis Arampatzis et al Taylor & Francis 2012

16 Non-culprit MACE (%) Remodeling-Insights from the PROSPECT Trial 697 pts with 3223 NCLs Positive Remodeling Negative Remodeling 2.5% 2.1% 0.7% HR 95% CI p-value RI<0.88 vs RI ( ) RI>1.00 vs RI ( ) Plaque burden >70% 5.03 ( ) < VH TCFA 3.05 ( ) MLA<4mm ( ) Intermediate Remodeling Plaques with negative remodeling were associated with longer and more calcified lesions and more severe stenosis. In addition they had the greatest frequency of VH-TCFA with multiple NCs. The presence of NCs was consistent with more advanced atherosclerosis in which there has been a recurring cycle of rupture and healing. Thus negative remodeling is sometimes a marker of more advanced atherosclerosis. Inaba et al. JACC Cardiovasc Imaging 2014;7:70-8

17 Lessons from the PROSPECT-progression of fibroatheromas Distance from ostium to max NC site, per 10mm Odds Ratio 95% CI P value Mean external elastic < membrane area, per mm 2 Mean plaque burden, per 10% < Calcium < RCA Plaque rupture was associated with large vessel area, greater plaque burden and proximal location within nonculprit coronary arteries. However EEM area was the strongest predictor for plaque rupture in the LAD, LCx and RCA while plaque burden seemed to be the most important risk factor for plaque rupture in the LMCA Zheng et al 2015;8: EEM integrates vessel area, plaque burden and remodeling

18 Non-Invasive Imaging Apart from being a gate keeper for CAG, one of the most appealing features of CCTA is the ability to look beyond luminal stenosis and provide a detailed evaluation of the coronary wall depicting several features like plaque composition (calcified, non-calcified, mixed), plaque burden, remodeling index and degree of attenuation (HU). Spotty calcification, positive remodeling and low attenuation

19 Plaque Characteristics with CCTA Plaque composition Non-calcified Partially calcified Calcified High risk plaque features Low attenuation Spotty calcification Positive remodeling Plaque attenuation pattern Napkin-ring sign Heterogeneous Homogenous

20 The CONFIRM multicenter observational registry All Cause Mortality Composite (death/mi) 7590pts without chest pain and without known CAD Cho et al, Circulation 2012;126:304-13

21 The CONFIRM multicenter observational registry C-Statistics Model FRS Individual Risk Factors All-cause mortality (n=3900) Model I: RFs only 0.62( ) 0.76 ( ) Model II: RFs+CACS 0.71( ) 0.78( ) Model III: RFs+CACS+NIV 0.73( ) 0.78( ) Model IV: RFs+CACS+Duke 0.72( ) 0.78( ) Model V: RFs+CACS+SSS 0.72( ) 0.78( ) Model VI: RFs+CACS+SIS 0.72( ) 0.78( ) Cho et al, Circulation 2012;126:304-13

22 Lessons from the CONFIRM Adjusted survival probability Mixed or calcified plaques Stenosis > 50% No proximal segment No proximal segment One or more proximal segments One or more proximal segments Two or more proximal segments Two or more proximal segments Deseive et al Eur Heart J Cardiovasc Imaging 2017;18:286-93

23 CCTA with FFR Incremental risk prediction Global χ 2 252pts 407 lesions with clinically indicated CAG 50% CT Sten 50% CT Sten +SC 50% CT Sten +SC+LAP 50% CT Sten +SC+LAP+PR 50% CT Sten +SC+LAP +PR+ %APV Park et al JACC Cardiovasc Imaging 2015;8:1-10

24 CCTA with FFR multivariate analysis of APCs Obstructive lesions ( 50%) Model 1 OR (95% CI) p Lumen area stenosis (per 5%) 1.10 ( ) 0.07 Lesion length 1.03 ( ) 0.01 PR 3.60 ( ) <0.001 LAP 2.50 ( ) SC 1.40 ( ) 0.42 Model 2 Lumen area stenosis (per 5%) 1.10 ( ) 0.12 % APV (per 5%) 1.80 ( ) < APC 1.00 (reference) - 1 APC 2.30 ( ) >2 APC 8.60 ( ) <0.001 Park et al JACC Cardiovasc Imaging 2015;8:1-10 Non-Obstructive lesions (<50%) Model 3 OR (95% CI) p Lumen area stenosis (per 5%) 1.30 ( ) 0.01 Lesion length 1.02 ( ) 0.44 PR 10.5 ( ) <0.001 LAP 1.30 ( ) 0.74 SC 1.80 ( ) 0.40 Model 4 Lumen area stenosis (per 5%) 1.30 ( ) 0.03 % APV (per 5%) 1.30 ( ) APC 1.00 (reference) - 1 APC 7.80 ( ) >2 APC 25.2 ( ) PR: positive remodeling, LAP: low attenuation plaque, SC: spotty calcification, %APV: percent aggregate plaque volume, APC: atherosclerotic plaque characteristic

25 CCTA and 5-year Risk of MI-The SCOT-HEART trial pts with stable chest pain Routine clinical Exercise test, stress imaging, CAG Routine clinical Exercise test, stress imaging, CAG R 1:1 Standard Care Standard Care +CCTA Median f-up 4.7 years (3-7) comprising pts/years Coronary Angio Coronary Revasc N Engl J Med 2018;379:924-33

26 CCTA and 5-year Risk of MI-The SCOT-HEART trial CAG beyond 1 year Cardiac death or non-fatal MI Standard care CCTA CCTA 2.3%vs3.9% HR 0.59 CI p=0.004 PCI beyond 1 year Non-fatal MI Standard care CCTA CCTA N Engl J Med 2018;379:924-33

27 Limitations The effect of plaque composition on mortality remains controversial. Imaging protocols, tube voltage settings, intracoronary contrast attenuation values, reconstruction algorithms filters and noise influence attenuation values. Remodeling is less conditional to image noise and having a more quantitative definition as the NRS might become a more robust marker. Even though CCTA is capable of identifying vulnerable markers witch correlate with pathology findings, we must focus on stenosis severity and overall plaque burden. Spotty calcification, positive remodeling and low attenuation

28 Prevalence and characteristics of TCFA and degree of stenosis STEMI 12%, NSTEMI 47% STABLE 41% 255pts, 643 plaques, 3vessel OCT Tian et al J Am Coll Cardiol 2014;64: The absolute number of TCFA is 3 times greater in non-severe stenosis. It is however, twice as likely for a lesion to be TCFA in cases of severe stenosis. Moreover TCFA in severely stenotic areas had more features of plaque vulnerability.

29 Low Prediction Risk limited number of events Annualized Risk of MI or CV death (%) PROSPECT STUDY High risk TCFA Intimal Thickening Rates are based on the occurrence of 6 MIs after 3.4 years of f-up among 1005 arterial sites with PIT and 595 TCFAs. Considering equal risk among the 3160 plaques detected at baseline (best case scenario) the event rate associated with each plaque is 0.06% per year. Stone et al, N Engl J Med 2011;364: Of 20 TCFAs only 5 remained unchanged (located proximally with and had large lumen areas), while 15 (75%) lost vulnerable characteristics. None of the 99 pts experienced any events during 1 year f-up. Thus many of the observed changes were likely the result of subclinical (silent) plaque ruptures. Kubo et al, J Am Coll Cardiol 2010;55:

30 Extend of plaque Disease and Adverse Events-CCTA study 3242 consecutive pts with a median f-up of 3.6 years Prediction of CV death or MI p< Annualized Risk of MI or CV Death (%) Global χ p< P= Non-obstructive limited Non-obstructive extensive Obstructive limited 10 0 Clinical probability Model 1 +CAD presence and severity Model 2 +CAD extend Bittencourt et al, Circ Cardiovasc Imaging 2014;7:282-91

31 Lessons from Pathology-260 with SCD PR TCFA FA The distribution of the extend of stenosis in TCFA and PR may suggest that the plaques that rupture are substantially narrowed at the time of an acute event, and it is rare to find disrupted but non-stenotic plaques. % Stenosis Narula et al. J Am Coll Cardiol 2013;61:

32 Plaque Vulnerability and Coronary Stenosis 0% Absolute number of plaque Absolute number of TCFA 50% Percentage of coronary stenosis Relative prevalence of TCFA High-risk TCFA 100% Patients with ACS, plaque ruptures are frequently found apart from culprit lesions, indicating that vulnerability is disseminated throughout the coronary tree. The absolute number of plaque and TCFA is greater in the area with mild stenosis. The relative prevalence of TCFA increases as the degree of coronary stenosis increases. Furthermore, TCFA at a higher degree of stenosis has more features of plaque vulnerability. Tian et al J Am Coll Cardiol 2014;64:

33 Thrombosis promoting factors Vascular thrombosis/acs Thrombosis promoting factors Vascular thrombosis/acs Fuster, J Am Coll Cardiol 2015;65: Thrombosis resting factors Asymptomatic plaque healing Thrombosis resting factors Asymptomatic plaque healing Most common scenario, small thrombus formation associated with plaque rupture is contained and vascular occlusive thrombus is inhibited Less common scenario of several prothrombotic factors coinciding (inflammatory state, large lesion plaque burden, vasoconstriction, circadian rheological changes) local thrombosis associated with plaque rupture cannot be contained, and clinically significant vascular thrombosis occur. The constellation of factors leading to these different outcomes is unknown.

34 Fusion Imaging Imaging modalities Lumen dimensions Plaque burden and positive remodeling Lipid component Cap thickness Neoangiogenesis Inflammation ESS Fast analysis IVUS + X-ray OCT + X-ray IVUS + CCTA OCT + CCTA NIRS-IVUS _ IVUS-OCT OCT-NIRF NK IVUS-NIRF NK OCT-NIRS NK IVUS-IVPA NK IVUS-FLIm NK Bourantas et al, Eurointervention 2017;38:400-12

35 Fusion Imaging

36 Conclusions Plaque ruptures and erosions are indeed responsible for most culprit lesions in patients with ACS. The frequency of subclinical plaque rupture is vastly underestimated and the assumption that identifying lesions prone to rupture will prevent ACS is unrealistic. Patients with high grade stenosis may carry an increased risk of death or MI since these lesions are markers for advanced disease in the coronary tree. Non obstructive and obstructive disease carry similar risk for death and MI if the former affects a larger number of arterial segments.

37 Conclusions Clinical imaging studies have not demonstrated improved risk prediction. Managing patients at risk of ACS mandates a greater focus on the disease burden rather than on features of individual plaques. This suggests that detection of a state of vulnerability in a patient is more important than detection of individual sites. Invasive and non-invasive imaging modalities provide such information to properly stratify patients at increased risk for cardiac events.

38 Thank you