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Prof. M.F. GiannoniVascular Ultrasound Investigations, Vascular Surgery,

Dept. P. Stefanini

Sapienza University of Rome

XVI CONGRESSO NAZIONALE SICVE

Forum Tecnico Sugli Amplificatori di Segnale

DISCLOSURE:

Speaker Name:

MARIA FABRIZIA GIANNONI

X I do not have any potential conflict of interest

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Carotid Plaque = Cerebrovascular Events ( C. Miller Fisher 1951)

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Carotid Plaque Complications = Cerebrovascular Events

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yyears105

endarterectomy group

medical group

CEA is beneficial in pts with high grade symptomatic carotid stenosisNASCET N Eng J Med 1991 . ECST Lancet 1991

Any Stroke or operative death

Background

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CEA is less beneficial in Asymptomatic carotid stenosis with the

largest trials only demonstrating a 1% per year stroke reduction

risk with surgery (ACAS; ACST, ACRS, VT..)

The degree of carotid stenosis alone is a weak predictor of neurologic event

Background

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Carotid Duplex Utrasound in an accredited vascular laboratory isthe initial diagnostic imaging of choice for evaluating the severity of stenosis in both symptomatic and asymptomatic patients.

Identification of stenosis of 50% to 99% in neurologically symptomaticpatients or 70% to 99% in asymptomatic patients is sufficient to make a decision regarding intervention (Grade 1, level of evidence A).

(Updated Society for Vascular Surgery guidelines for management of extracranial carotid disease: Executive

summary, J Vasc Surg 2011)

DUS is the standard technique to evaluate carotid plaques

Background

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DUS is the standard technique to evaluate carotid plaques

Carotid Duplex Utrasound in an accredited vascular laboratory is the

diagnostic imaging of choice for evaluating the severity of stenosis in both

symptomatic and asymptomatic patients.

(Updated Society for Vascular Surgery guidelines for management of extracranial carotid disease:

Executive summary, J Vasc Surg 2011)

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Extensive work on atherosclerotic plaque specimens from CEA: plaque composition is

a major factor determining the risk of cerebral ischemia

Many different ultrasound plaque parameterswere postulated as possible predictors of increased risk of Stroke

Background

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Over the last decades, remarkable advance has been made in quality assessment

of ultrasound investigations

Ultrasound Imaging of Carotid Plaques

• Echomorphologic features correlate withhistopathological criteria

• Echolucent areas represent thrombotic material,hemorrhage or lipid accumulation

• Echolucent, lipid-rich plaques likely more prone to rupture

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Vulnerable plaques, which are prone to rupture, characteristically have a large lipidic core and a thin fibrous cap

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Patients with predominantly echolucent plaques have a higher risk (2.3 fold) to develop neurologic event

50-99% degree of stenosis + mainly echolucent plaques = 2.6 fold higher risk of Stroke(Markus H Neurology 2011, Nicolaides A. Stroke 2015)

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Severe degree of stenosis Heterogeneous Hypoechoic Irregular surface/ulcerations Thin capMobile plaque

… but the pathophysiological mechanism responsible of the progression and changingtowards carotid plaque unstability “in vivo” nowadays has to be the target …

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Carotid Plaque is an Evolving Pathology

and Dynamic Changes Occour

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Halliday a. et al.. Europ J Vasc Endovasc Surg 2017

Needs to distinguish pts with Stable Carotid Plaque from those with Unstable Plaque

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Histological Studies:

pathological plaque neovascularization and inflammation play a central

role in the process of atherosclerosis plaque progression and

destabilization

Jeziorska M. 1999, Mark J. McCarthy 1999, Mofidi R. 2001, 2006 -2008, Moreno P.R. 2001, 2006, Pandya NM 2005,

Hildebrandt HA 2007, Sluimer JC 2008, Michael Fleiner M. 2004, Biedermann BC 2004,Granada J 2008, Naylor R 2007,

Spagnoli LG 2001,2007-8,10, Herrmann J 2008

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Carotid Plaque is an Evolving Pathology

and Dynamic Changes Occour

Traditional Imaging

Functional Imaging

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Need to detect Vulnerable Plaque to prevent Cerebrovascular Events

Markers of Carotid Plaque Vulnerability

Functional Imaging Biological Markers

• CEUS

• DCE MRI

• 18F DG-PET-CT

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II nd GENERATIONS CONTRAST AGENTS

IMPLEMENTATIONS OF DEDICATED SOFTWARE

(sophysticated armonic systems, Low Mechanical Index Imaging)

Allowed a widespresd diffusion of CEUS investigations

The clinical application of CEUS gained today a well eshtablished

unique position in the ultrasound imaging field

Contrast Enhanced Vascular Ultrasonography

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MICROCIRCULATION

to better define Anatomy and Morphology

Contrast Enhanced Vascular Ultrasonography

GREAT VESSELS EVALUATION

to evaluate Tissue perfusion

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Contrast Enhanced Vascular Ultrasonography

Possible evaluation of microcirculation characteristics

MICROCIRCULATION EVALUATION

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Histological studies: pathological plaque neovascularization plays

a central role in the process of atherosclerosis plaque progression

and destabilization

Jeziorska M. 1999, Mark J. McCarthy 1999, Mofidi R. 2001, 2006 -2008, Moreno P.R. 2001, 2006, Pandya NM 2005,

Hildebrandt HA 2007, Sluimer JC 2008, Michael Fleiner M. 2004, Biedermann BC 2004,Granada J 2008, Naylor R 2007,

Spagnoli LG 2001,2007-8,10, Herrmann J 2008,

Contrast Carotid Ultrasound is able to detect “in vivo”

histologically correlated plaque angiogenesis

Feinstein SB, JACC 2006

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Pathological plaque neoangiogenesis play a central role in the

process of atherosclerosis plaque progression and destabilization

Contrast Carotid Ultrasound is able to detect “in vivo” histologically

correlated plaque angiogenesis

Vicenzini E, Giannoni MF et al. Stroke, 2007

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CONTRAST ULTRASOUND IMAGING

OF CAROTID PLAQUE MICROVESSELS

Direction of microbubbles from advential toward the plaque surface

Microvessels of different caliber

Vessel of higher caliber under ulcerations

Not homogeneous distribution of the microvessels

Stroke 2007

Contrast carotid ultrasound for the detection of unstable plaque with

neoangiogenesis: a pilot study

Aim of the Study

To evaluate the characteristics of plaque vascularization

in patients to be submitted to CEA

for both asymptomatic and symptomatic carotid disease.

Ultrasound imaging validation with post-operative histology and immunohistochemical.

Contrast carotid ultrasound for the detection of unstable plaque with

neoangiogenesis: a pilot study

Giannoni et al EuroJ Vasc Endovasc Surg 2009

Patients and Methods

77 pts

M 51 F 26 , mean age 67 ys ( 67- 84 yrs)

• 66 Asymptomatic patients (no symptoms <6 mths)

62 atherosclerotic plaques

2 artheritis (HIV e SLE related)

2 intrastent-restenosis

• 11 Acute/recent Symptomatic patients

(2 ICA occlusions not surgically treated)

• 73 CEA (9 CEA within 1 week)

Contrast carotid ultrasound for the detection of unstable plaque with

neoangiogenesis: a pilot study

CONTRAST ULTRASOUND RESULTS

Acute/Recent Symptomatic

Asymptomatic

- Diffuse vascularization pattern

- Small microvessels, high density

- Base/Shoulder of the plaque

- High Angiogenesis

- Less evident vascularization pattern

- Rare microvessels of higher caliber

- Lower Angiogenesis

Contrast carotid ultrasound for the detection of unstable plaque with

neoangiogenesis: a pilot study

CONTRAST ULTRASOUND RESULTS

Asymptomatic

Fibro-calcific plaque

Contrast carotid ultrasound for the detection of unstable plaque with

neoangiogenesis: a pilot study

CONTRAST ULTRASOUND RESULTS

Asymptomatic

Contrast Ultrasound: few microvessels Isolated, mature, major caliber

Contrast carotid ultrasound for the detection of unstable plaque with

neoangiogenesis: a pilot study

CONTRAST ULTRASOUND RESULTS

Acute/Recent Symptomatic

Ulcerated, haemorrhagic plaque Contrast Enhanced Ultrasound & histology:

diffuse vascularization with small caliber

microvessels and high angiogenesis

Contrast carotid ultrasound for the detection of unstable plaque with

neoangiogenesis: a pilot study

CONTRAST ULTRASOUND RESULTS

Acute/recent Symptomatic

Contrast carotid ultrasound for the detection of unstable plaque with

neoangiogenesis: a pilot study

Different pattern of vascularization are detectable, in real-time

with contrast ultrasound as confirmed by immunohistochemical

CONCLUSIONS 1

Contrast Carotid Ultrasound is able to detect histologically

correlated plaque angiogenesis

Contrast carotid ultrasound for the detection of unstable plaque with

neoangiogenesis: a pilot study

Europ.J. Vasc. Endov. Surg.2009

THE PRESENT

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CONTRAST ULTRASOUND FINDINGS IN “STABLE STROKE”

Contrast carotid ultrasound for the detection of unstable plaque with

neoangiogenesis: a pilot study

“STABLE STROKE”I.O. Macroscopic findings, Histology Immunohystochemical

CD31, CD 34

Contrast carotid ultrasound for the detection of unstable plaque with

neoangiogenesis: a pilot study

Indice di attività della placca

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THE PRESENT

The limits of the method:

-- Quantitative evaluation of neoangiogenesis

-- 3D

Contrast Enhanced Carotid Ultrasound

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Attività della Placca

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Defining the Asymptomatic Plaque2013

2016

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Defining the Asymptomatic Plaque

, right-side emiparesis and aphasia > 6 mths ago

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Defining the Asymptomatic Plaque

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Contrast Enhanced Carotid Ultrasound for the detection of

Neoangiogenesis is a new approach for the evaluation of the

Vulnerable Plaque, in vivo and in real-time

Different vascularization patterns are detectable:

Plaque neovascularization is associated with plaquevulnerability and symptomatic disease

Link between Neoangiogenesis and Inflammation in vivo

Conclusions

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Grazie della vostra attenzione

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zari

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The value of plaque vascularization with CEUS

• Xiong L, Deng YB, Zhu Y, Liu YN, Bi XJ.

Correlation of carotid plaque neovascularization detected by using contrast-enhanced US

with clinical symptoms. Radiology. 2009

• Staub D, Patel MB, Tibrewala A et al

Vasa vasorum and plaque neovascularization on contrast-enhanced carotid ultrasound imaging

correlates with cardiovascular disease and past cardiovascular events. Stroke. 2010

• Chowdhury M, Ghosh J, Slevin M, et al

A comparative study of carotid atherosclerotic plaque microvessel density and

angiogenic growth factor expression in symptomatic versus asymptomatic patients

Eur J Vasc Endovasc Surg. 2010

THE PRESENT

2010

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BioMarkers

Inflammatory markersCRP, FibrinogenCytokines (TNF-a, IFN-g, IL-1b, IL-6, IL-8, IL-4, IL-10)MMPs (MMP-7, MMP-8, MMP-9, MMP-12)

Infectious markersChlamydia pneumoniae

Helicobacter

Cytomegalovirus

Haemostatic markersFibrinogen, D-dimers

Plasminogen activator inhibitor (PAI)

Procoagulant factor VII

Vascular calcification markersOsteopontin

Osteoprotegerin

Liapis C. Int J Stroke 2011

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