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Cardiovascular Research Technologies

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1 Cardiovascular Research Technologies
The Role of Local Endothelial Shear Stress in the Risk Stratification of Individual Coronary Plaques: Synergy between Plaque Anatomy and Local Low ESS Cardiovascular Research Technologies February 19, 2017 Peter H. Stone, M.D. Professor of Medicine Cardiovascular Division Brigham & Women’s Hospital Harvard Medical School Disclosure: Research support from St Jude Medical, AstraZeneca, and the generosity of the Schaubert Family and the Behrakis Research Program

2 Peter H. Stone, MD Research Support: St Jude Medical
Research Support: St Jude Medical AstraZeneca Pharmaceutical Co Boston Scientific Company

3 Detection of the Presence of High-Risk “Vulnerable” Plaque
Existing Methodologies to Assess Plaque Anatomy: IVUS (gray scale and RF “virtual histology”) Optical Coherence Tomography Near-Infrared Spectroscopy Near-Infrared Fluorescence Imaging Cardiac CT Angiography Magnetic Resonance Imaging Angioscopy

4 TCFA Histology by VH (total n= 595)
Critical Limitation of Morphology-Based Approach of Risk Assessment of Individual Coronary Plaques Only a Very Small Minority of “High Risk” Lesions Actually Progress to Cause New Events TCFA Histology by VH (total n= 595) Only 4.9% were associated with new event Large Plaque Burden (total n = 1570) Only 3.3% were associated with new event Identification of the anatomic substrate at a single point in time is not sufficient to predict actual progression; Ongoing pro-inflammatory stimuli, responsible for the heterogeneity of plaque natural history, should be included to optimally risk-stratify individual plaques (Stone GW, et al. NEJM 2011;364:226)

5 Heterogeneous Trajectories of Coronary Plaque Progression
Plaque natural history is NOT monotonic; patterns of progression are highly variable and heterogeneous 5 serial invasive angiography/IVUS studies (diabetic, hypercholesterolemic Yorkshire pig) (Koskinas, et al. Circ 2010;121:2092)

6 Dynamic Natural History of Thin Cap Fibroatheromas Over Time in Humans
216 non-culprit lesions in 99 pts at baseline and 12-mo followup Pathologic Intimal Thickening Vast majority (75%) of thin cap fibroatheromas evolve to a thick cap fibroatheroma or just a fibrotic plaque over a 12-month period Thin Cap Fibroatheroma Thick Cap Fibroatheroma Fibrotic Plaque Fibro- Calcific Plaque (Kubo T, et al. JACC 2010;55:1590)

7 Undisturbed laminar flow disturbed laminar flow
Areas of Disturbed Local Flow and Low Endothelial Shear Stress (ESS) in Human Coronary Arteries Left Main, Proximal LAD, and Proximal Circumflex Undisturbed laminar flow “Physiologic ESS” vasculoprotective Low and oscillatory disturbed laminar flow “Low ESS” Low Flow and Reversed Flow: - outer waist of a bifurcation inner aspect of a curve, up-, down-stream from an obstruction pro-inflammatory and atherogenic (Asakura and Karino. Circ Res 1990;66:1045)

8 Low ESS Shifts Endothelial Function and Structure To An Atherosclerotic Phenotype
(Chatzizisis, et al. JACC 2007;49:2379)

9 Correlation Between Magnitude of Low ESS and Severity of CAD
Powerful Inverse Relationship between Magnitude of Low ESS at Baseline and Subsequent Severity of Plaque Pathology at 36 Weeks Baseline ESS: (Chatzizisis, et al. Circulation 2008;117:993)

10 + Hypothesis of the Natural History of Vulnerable Plaque
and CAD Progression Low ESS High ESS 5-10% Clinical Manifestations: + 95% • Stable CAD Subclinical Plaque Rupture or Intraplaque Hemorrhage ~5% • Acute Coronary Syndromes/Rapid Plaque Progression Plaque Erosion Plaque Rupture

11 PREDICTION Trial: Low-Risk Japanese Patients
506 patients with ACS undergoing PCI Index ACS Event Presentation Months months PCI of Culprit Lesion 3 Vessel IVUS Clinical Followup Focus on outcomes associated with baseline areas with different local ESS, plaque characteristics, and remodeling environments: Anatomic: Natural history of CAD (374 consecutive patients) Clinical: Attribution of new clinical events to preceding anatomic and hemodynamic conditions (506 patients) (Stone PH, et al. Circulation 2012, 126: )

12 PREDICTION Trial: Anatomic Results
Analysis of Individual Coronary Artery Anatomy: Individual 3-mm Coronary Segments Change in Plaque Burden (%) Change in Lumen Area (mm2) (Stone PH, et al. Circulation 2012, 126: )

13 PREDICTION Trial: Anatomic/Clinical Natural History
Independent Baseline Predictors of Minor Luminal Obstructions Treated with PCI during Followup In these low-risk Japanese patients most PCIs were performed on asymptomatic patients with worsening obstruction at routine followup cath (Baseline lumen narrowings < 6 mm2 with followup data [n=250]) (Stone PH, et al. Circulation 2012;126: )

14 PREDICTION: Anatomic/Clinical Natural History
Baseline Predictors of Minor Luminal Obstructions Treated with PCI in Followup (Low-Risk Japanese Patients) Combination (Substrate + Stimulus) Ongoing Pro-Inflammatory Stimulus Alone Substrate Alone p<0.001 p<0.01 p<0.001 Sensitivity 94% 42% 42% Specificity 54% 82% 91% Pos Pred Value 22% 25% 41% Neg Pred Value 98% 91% 92% Prevalence 22% 10% 6%

15 PROSPECT Study: Landmark Natural History Study of CAD in America/Europe
High-Risk US and European Patients Evaluation of Local ESS Affecting Individual Plaques 697 patients with an acute coronary syndrome evaluated with 3-vessel coronary angiography and IVUS after stent for culprit artery All patients followed for median of 3.4 years Major Adverse Cardiovascular Events (MACE) cardiac death, cardiac arrest, MI, or hospitalization for worsening angina (Stone GW, et al. NEJM 2011;364:226)

16 Assessment of Both Plaque Morphology and Local ESS in PROSPECT Study: High-Risk US and European Patients All nc-MACE lesions (n=54) were evaluated, and compared with ~4-fold randomly selected lesions not causing MACE (non-nc-MACE) Imaging was sufficient for vascular profiling analyses in 32 nc-MACE lesions (14 TCFA, 13 ThCFA, 5 nonFA) Final analytic dataset: 23 nc-MACE lesions: 13 TCFA, 10 ThCFA 122 non-nc-MACE lesions: 63 TCFA, 59 ThCFA ESS calculated along course of each artery/lesion Low ESS (<1.3 Pa) compared with Physiologic/High ESS (≥ 1.3 Pa) (Zaromytidou M, Siasos G, et al. ACC 2016; Stone PH, et al AHA, TCT 2015)

17 Example of Acute MI Developing in an Area of local Low Shear Stress
ESS [Pa] 2 4 6 Baseline Acute MI 8-months later LOW ESS (Stone PH, et al. JACC CV Img 2017; in press)

18 Association of Baseline Plaque Characteristics with MACE in Follow-up
Propensity Analysis: Propensity score constructed for each nc-MACE lesion using: - Plaque Burden - Minimal Lumen Area - Lesion type (TCFA vs ThCFA) - Artery (LAD vs Cx vs RCA) - Location (prox vs mid vs distal) Propensity-adjusted Cox regression of association of baseline low ESS with MACE in follow-up: Powerful, independent association of low ESS and MACE (OR 4.34, p<0.001) (Stone PH, et al. JACC CV Img 2017; in press)

19 MACE Outcomes Based on Individual Plaque: Local ESS and Local Anatomy/ESS of Each Lesion
ESS-Based Analysis Anatomic Risk/ESS Analysis High Anatomic Risk, Low ESS Low Anatomic Risk, Low ESS High Anatomic Risk, Physiologic/High ESS Low Anatomic Risk, Physiologic/High ESS % MACE % MACE Anatomic Risk: High-Risk: ≥ 2 anatomic features: Low-Risk: ≤ 1 anatomic feature: -PB ≥70% -MLA ≤4.0mm2 -TCFA MACE occurred ONLY if there was an area of pro-inflammatory low ESS along the lesion (Stone PH, et al. JACC CV Img 2017; in press)

20 MACE Outcomes Based on Local ESS of Each Lesion: Patient-Based Analysis
Likelihood of a patient having a MACE based on Anatomic Risk and ESS Risk of ≥ 1 plaque High Anatomic Risk, Low ESS Low Anatomic Risk, Low ESS High Anatomic Risk, Physiologic/High ESS Low Anatomic Risk, Physiologic/High ESS % MACE MACE occurred ONLY in patients who had a plaque with low ESS (Stone PH, et al. JACC CV Img 2017; in press)

21 Prognostic Synergy Between Plaque Anatomy and Local Low ESS
(Stone GW, et al. NEJM 2011;364:226; Stone PH, et al. JACC CV Img 2017; in press)

22 Summary and Conclusions
The Role of Local Endothelial Shear Stress in the Risk Stratification of Individual Coronary Plaques Summary and Conclusions The natural history of high-risk plaque is very dynamic and heterogeneous over time Most new cardiac events originate in plaques with anatomic morphology of large Plaque Burden and small MLA But most plaques remain quiescent…. Local low ESS is an intense pro-inflammatory stimulus responsible for initiation/progression of atherosclerosis Ongoing local low ESS provides the independent pro-inflammatory stimulus for plaque de-stabilization and future MACE Accurate risk stratification of individual plaques requires both plaque anatomy and local pro-inflammatory low ESS

23 Vascular Profiling Co-Investigators
PROSPECT Collaborators Akiko Maehara, MD Gregg Stone, MD Alexandra Lansky, MD Gary Mintz, MD Patrick W. Serruys, MD, PhD BWH/MIT Charles Feldman, ScD Ahmet Umit Coskun, PhD Saeko Takahashi, MD Gerasimos Siasos, MD, PhD Marina Zaromitidou, MD, PhD Antonios Antoniadis, MD, PhD Yannis Andreou, MD, PhD Michail Papafaklis, MD, PhD Charles Maynard, PhD Fred Welt, MD Yiannis Chatzizisis, MD, PhD Kostas Koskinas, MD, MS Masaya Tsuda, MD Shingo Mizuno, MD Koki Shishido, MD Mayo Clinic Amir Lerman, MD Elazer Edelman Lab - MIT Elazer Edelman MD, PhD Michael Jonas, MD Aaron Baker, PhD PREDICTION Collaborators Shigeru Saito, MD Saeko Takahashi, MD Peter Libby Lab Peter Libby, MD Galina Sukhova, PhD Guo Ping Shi, PhD Mass General Hospital Lab Farouc Jaffer, MD, PhD IK Jang, MD University of Ioannina, Greece Dimitris Fotiadis, PhD Kostas Stefanou, PhD Michail Papafaklis, MD, PhD Lampros Michalis, MD Mark Feinberg Lab - BWH Mark Feinberg, MD Xinghui Sun, MD, PhD

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25 Cumulative Distribution of Local ESS Within Lesions: nc-MACE lesions vs non-nc-MACE; TCFA vs ThCFA
TCFAs Separately Combined TCFAs and ThCFAs Mean Low ESS: nc-MACE lesions: 0.60±0.37 Control lesions: ±0.71 p=0.01 Mean Low ESS: nc-MACE lesions: 0.61±0.34 Control lesions: ±0.79 p<0.001 Control nc-MACE ThCFAs Separately Mean Low ESS: nc-MACE lesions: 0.62±0.30 Control lesions: ±0.87 p<0.02 Control nc-MACE (Stone PH, et al. JACC CV Img 2017, in press)

26 Natural History of CAD Progression: Intersection of Plaque Morphology and Low ESS
Summary and Conclusions The natural history of high-risk plaque is very dynamic and heterogeneous over time Most new cardiac events originate in plaques with morphology of large Plaque Burden and small MLA But most remain quiescent Local low ESS is an intense pro-inflammatory stimulus responsible for initiation/progression of atherosclerosis Ongoing local low ESS provides the independent pro-inflammatory stimulus for plaque de-stabilization and future MACE It is essential to assess risk of individual coronary plaques using both plaque morphology and low ESS

27 PREDICTION: Role of Baseline ESS in the Formation of Eccentric Plaques
Low ESS was associated with an increase in max Plaque Thickness Low ESS was associated with an increase in Plaque Eccentricity Baseline ESS Low Higher Percent Delta max Plaque Thickness (%) Baseline ESS Low Higher Percent Delta Eccentricity Index (%) Increased Plaque Eccentricity is associated with high-risk plaque and increased likelihood of plaque rupture. (Papafaklis MI, et al. Circulation 2012;126:A17559 )

28 The “Evolution” of Coronary Atherosclerosis
Progression over time (yrs): Normal Artery Lesion Initiation Fibro-fatty Stage Vulnerable Plaque Plaque Rupture Fibrous, Calcified Plaque Endothelial Erosion (Libby. Circulation 2001;104: 365)

29 Local Regions of Low ESS Lead to Ongoing Increased Inflammatory Cells and Expression of Degrading MMPs Within Coronary Plaque Local Increase in Collagenases: (MMP-1, -8, -13,-14) Decreases collagen content marked fibrous cap thinning Low ESS Region (p< vs High ESS Region) Local Increase in Elastases: (MMP-2, -9; Cathepsin L, K,S) Promotes fragmentation of Internal Elastic Lamina (IEL) expansive remodeling Low ESS Region (p=0.005 vs High ESS Region) (Chatzizisis YS, et al. Circulation 2011;123:621; Koskinas, et al. ATVB 2013;33:1494)

30 Natural History of “Vulnerable Plaque” in Stable CAD Is Often Not ACS, but Worsening of Stable CAD
Outcomes in Non-culprit Lesions During Followup Outcome PROSPECT(n=697) PREDICTION (n=506) ATHEROREMO-IVUS (n=581) VIVA (n=170) Cardiac Death (%) 0.002 0.2 1.2 ACS: STEMI (%) 1.0 0.5 Non-STEMI (%) Unstable Angina (%) 2.2 Stable CAD: Worsening Stable Angina (%) 10.8* 4.0 3.0 8.2 Asymptomatic Severe Obstruction(%) 7.8 * Includes rehospitalization for both unstable and progressive angina (Stone GW, et al. NEJM 2011;364; Stone PH, et al. Circulation 2012;126:172; Cheng JM .et al. Eur Heart J 2014;35:639; Calvert PA, et al. JACC CV Imaging 2011;4:894)

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33 Individual Vascular Anatomic Components of
PROSPECT Trial: 3.4 Year Followup Individual Vascular Anatomic Components of Risk Prediction TCFA = Thin-Cap Fibroatheroma MLA = Minimal Lumen Area PB = Plaque Burden (Stone GW, et al. NEJM 2011;364:226)

34 Association of Lesion Characteristics and Subsequent MACE: PROSPECT
Baseline Characteristic Major Adverse Cardiac Events p value Yes (n=23) No (n=122) Lesion Length (mm) 33 ± 21 21 ± 12 0.015 Plaque Burden (%) 68 ± 8 ± 9 <0.0001 Minimal Lumen Area (mm2) 4.2 ± 1.0 5.4 ± 2.0 Lowest local ESS (Pa) 0.61 ± 0.34 1.13 ± 0.79 Highest local ESS (Pa) 6.02 ± 1.52 4.69 ± 2.11 0.12 Plaque Area (mm2) 0.22 TCFA Morphology (%) 56 52 0.67 Specific coronary artery (%) 0.97 LAD 35 34 Cx 33 RCA 30 Location within Artery (%) 0.25 Proximal 65 48 Mid 26 Distal 9 22

35 + Hypothesis of the Natural History of Vulnerable Plaque
and CAD Progression Low ESS High ESS 5-10% Clinical Manifestations: + 95% • Stable CAD Subclinical Plaque Rupture or Intraplaque Hemorrhage ~5% • Acute Coronary Syndromes/Rapid Plaque Progression Plaque Erosion Plaque Rupture

36 Natural History of “Vulnerable Plaque” in Stable CAD Is Often Not ACS, but Worsening of Stable CAD
Outcomes in Non-culprit Lesions During Followup Outcome PROSPECT(n=697) PREDICTION (n=506) ATHEROREMO-IVUS (n=581) VIVA (n=170) Cardiac Death (%) 0.002 0.2 1.2 ACS: STEMI (%) 1.0 0.5 Non-STEMI (%) Unstable Angina (%) 2.2 Stable CAD: Worsening Stable Angina/CAD (%) 10.8* 11.8 3.0 8.2 * Includes rehospitalization for both unstable and progressive angina (Stone GW, et al. NEJM 2011;364; Stone PH, et al. Circulation 2012;126:172; Cheng JM .et al. Eur Heart J 2014;35:639; Calvert PA, et al. JACC CV Imaging 2011;4:894)

37 Increase in Stable Angina
Hypothesis of the Natural History of Vulnerable Plaque and CAD Progression - Implications for Risk Stratification/Imaging of Individual Plaques TCFA Inflammation-related proteases weaken plaque cap; Mechanical forces  RUPTURE Expansive remodeling resolves low ESS, reducing inflammation  QUIESCENCE Ongoing Low ESS Hypoxia, Intraplaque hemorrhage (vasa vasorum or subclinical rupture)  FIBROSIS/SCARRING Acute Coronary Syndrome Quiescence; Stable Angina Clinical Outcomes: Worse Obstruction; Increase in Stable Angina (Michel J-B, Virmani R, et al. Eur Heart J 2011;32:1977; Jeney V, et al. Front Physiol 2014;5:1)

38 Dynamic Natural History of Local ESS Affecting Plaque Segments – Heterogeneity Over Time
Local ESS in individual plaque segments frequently change between low ESS and higher ESS over consecutive time points vasculoprotective pro-inflammatory (n=184 plaque segments) As the ESS value changes over time the pro-inflammatory/pro-atherogenic stimulus changes over time (Diabetic, Hypercholesterolemic Pig Model) (Koskinas, et al. ATVB 2013;33:1494)


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