plaque detection: how can we identify a vulnerable...

Plaque Detection: How Can We Identify a

Vulnerable Plaque?

Lampros K. Michalis, MRCP, FESC

Professor of Cardiology, University of Ioannina

Fibroatheroma

Acellular necrotic core

Macrophages infiltration

Free cholesterol

Compensatory enlargement

Eccentric morphology

These can lead to TCFA or Plaque erosion – Thrombus formation

Atherosclerosis Pathophysiological Insights

Virmani et al. Atheroscl Thromb Vasc Biol 2000

Atherosclerotic progression –pathophysiological insights

TCFA

Large necrotic core

Thin fibrous cap (cap thickness<65μm)

Macrophage infiltration

Typical precursor lesion

leading to

Acute Coronary Syndromes

Virmani et al. Atheroscl Thromb Vasc Biol 2000

Atherosclerotic progression –pathophysiological insights

Plaque rupture

Disruption of a thin fibrous cap

The necrotic core is in contact with the lumen

Plaque erosion

Thrombus confined to the

lumen wall

The lumen surface beneath the thrombus is devoid from endothelium

Erosion

Plaque Vulnerability

Imaging/Assessment ofPlaque integrity & composition

Inflammatory infiltration

Vulnerable Plaque Detection

Intravascular Imaging

From vulnerable plaque detection to clinical events

Intravascular Ultrasound

The acquired cross-sectional images allow:

Identification of the lumen, stent and vessel wall

Quantification of their dimensions and plaque volume

Classification of the plaque type

Detecting plaque erosion, ruptureand the presence of thrombus

Unable to see microstructures related to increased vulnerability

Mintz et al. J Am Coll Cardiol. 2001

Relatively low resolution - limited

capability in:

IVUS-Virtual Histology

Based on the creation of spectral maps for different tissue types

Classification of obtained spectra in 4 plaque types (necrotic core, fibrofatty, fibrous and calcific tissue)

This approach has been evaluated using histology as gold standard with an accuracyof 93-97% for all tissuecomponents

Mintz et al. J Am Coll Cardiol. 2011

Nair et al. Circulation. 2002Nair et al. EuroIntervention 2007

VH-TCFA: Predictive Value

PROSPECT STUDY – 3yr MACE AtheroREMO – 1yr MACE

Stone GW et al. N Engl J Med 2011Cheng et al. Eur Heart J 2014

Optical Coherence Tomography

The acquired cross-sectional images allow:

Imaging of micro-features related to plaque vulnerability (Cap Thk, Lipid pool, macrophages)

Evaluation of stent endotheliazation

Classification of the plaque type

Identification of plaque rupture/thrombus

Tearney et al. J Am Coll Cardiol. 2012

Poor penetration which often does not allow imaging of the entire vessel wall

Cannot “see” behind lipid tissue

Unable to discriminate deeply embeddedlipid-rich from calcific tissue

Limitations of this modality are:

Plaques that progress have more oftenat baseline

Plaque erosion

Neo-vessels

TCFA phenotype

Macrophages

ThrombusUemura et al. Eur Heart J 2012

OCT

No published study regarding physical history and OCT

IBIS under review

Near InfraRed Spectroscopy

Imaging requires irradiation of the tissue with a NIR light source

Allows identification of lipid component

The chemogram

The block chemogram

The lipid core burden index

Processing of the reflected signal provides:

Provides No information on lumen and plaque anatomy/morphology

Caplan et al. JACC 2006

Jaffer et al. J Am Coll Cardiol 2011

Near Infrared Fluorescence Molecular Imaging

Relies on the use ofactivatable NIRF probesto mark molecules related to inflammation/fibrin

A catheter emits NIR light allowing imaging of thefluorescent molecules

Detection of vessel wall inflammation and fibrin after stent implantation

No info on anatomy/morphology

Νew Invasive Imaging TechniquesPotential Clinical Translation

Still under-development

Not used in humans yet

Was recently implemented in vivo in a rabbits’ aorto-iliac artery

Depicts vascular wall morphological features, atherosclerosis and calcification

Results are promising for the future

Performed with a 3Ts scanner

Image resolution 80-300μm

Image acquisition 2fr/sec

Sathyanarayana et al. JACC Img 2010

Intravascular MRI


Is feasible but the catheter has 5.2F diameter

Time consuming process (51 sec for 1 frame)

Differentiates lipid rich, intermediate and fibrotic areas of atherosclerotic plaque

Regar et al. EuroIntervention 2006

Irradiation of the tissues with laser –

spectral analysis of the Raman scattering

Interrogates the vibration of molecular bonds and is capable to identify the chemical composition of the plaque

There is a catheter for intravascular use but this technique is not available in clinical practice

Motz et al. J Biomed Opt 2006Chau et al. J Biomed Opt 2008

Intravascular MR Spectroscopy

Raman Spectroscopy


Tissue autofluorescence is collected after excitation with pulsed laser and analyzed according to different wavelengths

Allows detection of the biochemical makeup of the superficial plaque • Cholesterol, collagen, elastin• Necrotic/lipid core• Inflammatory cells

Low penetration (depth 150-205μm)

Identification of markers of vulnerability

Marcu et al. Atherosclerosis. 2009

Time Resolved Fluorescence Spectroscopy (TRFS)


Based on the detection of the sound (acoustic wave) emitted by the irradiated by a laser

tissue

Capability of imaging lipids, and detecting calcium and inflammatory markers (MΦ and MMPs) through application of exogenous contrast agents (Gold Nanoparticles)

Not available for in vivo application in humans

Wang et al. IEEE J Quantum Electron. 2010Jansen et al. Ultrasound Med Biol 2014


Intravascular Photoacoustic Imaging (IVPA)

Hybrid Catheters:Multi-modal


Hybrid catheter – IVUS and NIRS Imaging is performed with the use of the

TVC catheter that combines a NIRS light

source and an IVUS probe

The catheter allows overlay of the NIRS

estimations onto the IVUS images

Provides plaque anatomy and

lipid probability

Clinically availableGarg et al. EuroIntervention 2010

Schultz et al. JACC 2010

Hybrid catheter – IVUS and OCT Recently developed catheters

that include an OCT and an

IVUS probe

– Not clinically applicable yet

– The size of the probe is too

big

– Increased time for combined

image acquisition

– Electromagnetic shielding is

necessary to eliminate the

noise created by the motor

used for rotational scanning

Li et al. Cathet Cardiovasc Interv 2009 Yin et al. J Biomed Opt 2010

Hybrid Catheter – IVUS and IVPA

There is a catheter for in vivo imaging but it has not been used in clinical practice- its safety needs evaluation - requires time for image acquisition

Identification of plaque/volumeby IVUS and lipids/inflammationby photoacoustic imaging (IVPA)

Plaque characterization Detection of stent morphology

Yeager et al. J Biomed Opt 2012Wang et al. IEEE J Quantum Electron 2010

Su et al. Expert Opin Med Diagn 2010Jansen et al. Ultrasound Med Biol 2014

TRFS-US-PA

There is a catheter but it cannot be used in the clinical setting- TRFS signal has poor penetration - concerns about vessel wall trauma

Identification of plaque morphology by IVUS and wall biochemical properties by TRFS

Assessment of the superficial plaque characteristics

Stephens et al. J Biomed Opt 2009Sun at al. Biomed Express 2011Bec et al. J Biomed Opt 2012

Multi-modal catheter

combining TRFS, Ultrasonic

backscatter microscopy and

Photoacoustic imaging

Hybrid catheter – IVUS and TRFS

Intravascular catheter with a 2.7mm diameter

Able to visualize lumen morphology and inflammation

Can detect the presence of fibrin in stented segments

Hybrid catheter – OCT and NIRF

In vivo coronary imaging in animals is in progress but has not been implemented in humans yet

Yoo et al. Nat Med 2011

Fusion of Imaging Data:3D reconstructionESS assessment

Wahle et al. IEEE Trans Med Imag 1999Slager et al. Circulation 2000Bourantas et al. Cathet Cardiovasc Interv 2008

Complete visualization of 3-dimensionalvessel morphology

Precise evaluation of the plaque volume Accurate orientation of the plaque onto the

artery Coupled with Computational Fluid

Dynamics Enables ESS assessment

Fusion of Angiographic & IVUS data

The largest natural history of atherosclerosis study which investigated the

effect of ESS on plaque progression in 506 pts with an ACS

Low ESS was independently associated with disease progression

Large plaque burdenand low ESS appeared as independent predictors of plaque progression

Large plaque burden and low ESS predicted with 41%accuracy worsening lumen obstruction requiring PCI

Fusion of Angiographic and – OCT

Available system that allows co-registration of 3D-QCA and OCT

Integration of X-ray angiographic and OCT data for ESS assessment: association with high-risk plaque characteristics

Papafaklis et al. ESC 2013

Tu et al. JACC Intv 2012

Fusion of Angiographic & OCT data

Intravascular Coronary Imaging: Applicability for Identifying the Vulnerable Plaque

Reduced clinical application:

Requires cardiac catheterization

Most of the fusion algorithms are time consuming and available in limited centres

Still limited prognostic value - Does not affect the final decision

However, here is only one hybrid catheter that can be used in the clinical setting as the rest are under development

Non-Invasive Imaging:Vulnerable Plaque

Detection

Can be used to assess ESS distribution in the coronary tree including bifurcation and main branches

However CT has low resolution that does not permit assessment of vulnerable plaque characteristics

Coronary Computed Tomography Angiography

Voros et al. JACC Intv 2011

Rybicki et al. Int J Cardiovasc Imag 2009

Non-invasive Molecular ImagingCombination of CT and PET

Rogers et al. JACC Img 2010

Fluorodeoxyglucose

(18F-FDG)

Measure of Glucolysis

Metabolic Activity

Index of Atherosclerotic

Inflammation

Combines coronary anatomy

with functional imaging for

disease assessment

CT and PET: Novel Markers18F-sodium fluoride (18F-NaF)

Surrogate of

Vascular inflammation &

Macrophage burden

More sensitive compared to 18F-FDG

18F-NaF positive plaque

shows high-risk features:

large necrotic core and

microcalcification (IVUS-VH)

Joshi et al. Lancet 2013

18F-NaF 18F-FDG

ACS case

ACS case

Stable case

CONCLUSIONS

Detection of plaque vulnerability requires assessment of:

– Plaque morphology and composition

– Plaque “activity”

– Local hemodynamic milieu


single-modal / multi-modal (hybrid catheters) / fusion of data

- Enables both anatomical and functional-molecular imaging

- Until now: mediocre predictive value shown in clinical studies

- Limited use of many novel ones: Need for translating experimental modalities in clinical practice

Non-invasive imaging

Potential for population screening: improved risk assessment

SUBSTRATE

STIMULUS

Conclusions

Needs to be defined

• What are the characteristics of the patient, whose plaques should be interrogated?

• Can we predict cardiac events by improving identification of vulnerable plaques?

• Which are the pre-emptive strategies?

Hemodynamic Environment

• Local hemodynamic forces

– Flow-generated endothelial shear stress(frictional force per unit area because of blood’s viscous nature)

– Blood pressure-derived tensile stress

Shear Stress = viscosity × velocity gradient

Nerem RM. J Biomech Eng 1992 Papafaklis MI and Michalis LK. Hellenic J Cardiol 2005

Shear Stress: A critical determinant in the natural history of atherosclerosis

Local Hemodynamics and Vascular Biology

Hahn C. and Schwartz MA. Nature Reviews 2009

Laminar

Flow

Athero-

Resistant

Region

Disturbed

Flow

Athero-

Susceptible

Region

Low

ESS

Background

Pathological, cellular and biochemical characteristics of the vulnerable plaque

In vivo identification of the pathological characteristics

Intravascular imaging:Unimodal cathetersHybrid Catheters (Multi-modal)Fusion of Imaging data and the role of blood flow

Non-invasive Imaging

Conclusions

NIRS: Clinical Correlation

Patients

ACS patient

Stable patientMadder et al. Circ Cardiovasc Intv 2012Madder et al. JACC Intv 2013

Fusion of IVUS-VH & Angiography:ESS Assessment

Samady et al. Circulation 2011

LOW SHEAR STRESS

0.7 Pa

HIGH SHEAR STRESS

5.1 Pa 20pts with CAD

underwent serial VH-IVUS imaging at baseline and 6m FU

Serial study that assessed the effect of ESS on plaque composition in humans

Low ESS was associated with an increase in plaque burden and necrotic corecomponent, intermediate ESS with no changes and high ESS with an increase in Ca and necrotic core component

van der Giessen et al. Int J Cardiovasc Imag 2007

Requires extraction of the luminal centerline from the CT data

Identification of correspondence (using anatomical landmarks) between the IVUS images and the cross sections in the CT data

Allows reconstruction of the coronary

bifurcations

Evaluation of the capabilities of CT in

assessing the extent and the

morphology of the plaque

Fusion of CT and IVUS

ESS

computation

Potential for Primary Prevention of EventsPopulation Screening

Falk et al. Curr Atheroscl Rep 2011Nasir et al. AHA Sessions 2012

BioImage Study

Prevention of atherothrombotic

events in the asymptomatic

population

- Improvement of risk

classification compared to

traditional risk score model

Calvert et al. JACC Img. 2011Stone GW et al. N Engl J Med 2011

VH-TCFA and Clinical Events

PROSPECT STUDY – 3yr MACE VIVA-VH STUDY – 2yr MACE

TCFA

Pathological, biochemical and cellular characteristics of

the vulnerable plaque

Wentzel et al. Circ CV Img 2010

Fusion of CT and IVUS-NIRS

CT data are combined with data using the dual-mode IVUS-NIRS catheter

Allows Assessment of 3D vessel morphology and plaque distribution Identification of lipid-rich regions Coupled with Computational Fluid dynamics: ESS assessment

plaque detection: how can we identify a vulnerable...

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