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

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)

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)