Imaging Vulnerable Plaque to Stratify Individual Patient Risk

Dr Marc Dweck BHF Senior Lecturer Edinburgh Heart Centre & University of Edinburgh Objectives

1. Rationale for detecting vulnerable plaque

2. Methods for detecting vulnerable plaque

Luminal MI arising from a non- obstructive plaque

Dweck JACC 2016 Majority of MI Arise from Mild or Moderate Lesions on Antecedent

Falk Circulation 1995 COURAGE

HR for PCI group, 1.05; 95% CI, 0.87 to 1.27; P=0.62).

Boden WE et al. NEJM 2007 Histological Characteristics of the Vulnerable Plaque

Inflammation Thin Fibrous Cap

Large Micro- Necrotic All Potential Calcification Core Imaging Targets

Positive Remodeling Neovascularisation

Adapted from Vancraeynest et al, JACC 2011 Potential Imaging Targets

18F-FDG Inflammation Thin Fibrous 11C-PK11195 Cap 18F-FMCH 68Ga-Dotate USPIO MRI Large CT Micro- Necrotic 18F-FMISO Calcification Core (hypoxia)

18F-Fluoride Positive Remodeling Angiogenesis & Plaque Haemorrhage CT 18F-Fluciclatide PET Adapted from Vancraeynest et al, JACC 2011 T1 weighted MRI PROSPECT

• 697 patients

• 595 VH-IVUS TcFA identified

• Median follow up 3.4 years

• Only 6 resulted in myocardial

Stone et al. NEJM 2011 Major Limitation of Vulnerable Plaque Strategy

• In retrospective studies vulnerable plaque consistently associated with rupture and MI

• However prospective studies suggest they are relatively common and go on to cause in only a minority of cases

Arbab-Zadeh, Fuster JACC 2015 Why do Vulnerable Plaques Outnumber Cardiac Events?

STABLE PLAQUE

VULNERABLE PLAQUE

SUBLCINICAL PLAQUE GROWTH

MYOCARDIAL PLAQUE RUPTURE INFARCTION Why do Vulnerable Plaques Outnumber Cardiac Events?

1)Vulnerable plaques heal and stabilise

2)Even if they do rupture most plaque rupture events are sub-clinical The Myth of the Vulnerable Plaque?

• If the majority of vulnerable plaques do not themselves go on to cause events how can we justify going on to treat individual lesions?

• We should focus more on identifying the vulnerable patient……..

Arbab-Zadeh, Fuster JACC 2015 Identification of vulnerable plaque may still be useful at the patient level Pan Coronary Vulnerability Vulnerable Plaques to Identify Vulnerable Patients

• Vulnerable plaques do not exist in isolation.

• However patients with active disease tend to develop multiple high risk plaques, increasing that subject’s probability of a clinical rupture event: the vulnerable patient Methods for Detecting Vulnerable Plaque Imaging Methods to Identify Vulnerable Plaque

• Computed Tomography (CT)

• Magnetic Resonance Imaging (MRI)

• Positron Emission Tomography (PET) Vulnerable Plaques on CT

Positive remodelling and low attenuation plaque (necrotic core) Motoyama JACC 2015 CT Vulnerable Plaques Identify High Risk Patients

N=3158 patients: 294 had high risk plaques ACS 16% patients (n=48) 2864 did not ACS 1.4% (N=40)

Motoyama JACC 2015 CT Vulnerable Plaques Identify High Risk Patients

Motoyama JACC 2015 Vulnerable Plaques on MRI

• T1-weighted MRI

• High signal due to methaemoglobin

• Marker of acute luminal or intraplaque haemorrhage

Noguchi JACC 2014 Noguchi JACC 2014 MRI Vulnerable Plaque Identify High Risk Patients

• Single Centre study of 568 patients • 55 patients had high intensity plaque • Patients with these plaques had a 9-fold increased risk of future coronary events (HR: 8.93; 95% CI: 3.23 to 24.7; p < 0.001) Noguchi JACC 2014 Positron Emission Tomography

PET

FUSEDCT PET/CT 18F-FDG

Glucose analogue Marker of vascular inflammation FDG Uptake Reflects Infiltration In Carotid

Tawakol et al JACC 2006 18Fluoro-Deoxy Glucose SymptomaticCulprit Carotid Plaque plaque Post (ipsilateral /TIA to TIA)

PET CT PET/CT

AsymptomaticContralateral Plaque plaque (contralateral to TIA)

PET CT PET/CT Rudd et al. Circulation 2002 Rogers et al, JACC Imaging 2010 Measurement of Coronary 18F-FDG Activity was Difficult

ACS Max ACS Max Stable Culprit Non-Culprit . Not possible in >50% of the coronary vessel territories examined . No important differences observed between our populations Joshi, Dweck, Newby. The Lancet. 2014 18F-Fluoromisonidazole FMISO- HYPOXIA

Joshi, Rudd. JACC 2017

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- Somatastatin receptor sub-type 2

- Upregulated on the surface of activated

- Localises to culprit and high-risk plaque

Tarkin Rudd JACC 2017 18F-Fluoride Binds preferentially to newly developing microcalcification 18F-Fluoride Predicts Where New Calcium Will Develop

Baseline CT Baseline PET/ CT Repeat CT 2 yrs

Irkle et al. Nature Communications 2015 Jenkins & Vesey JACC 2015

INFLAMMED HIGH RISK PLAQUE STABILISED PLAQUE

Inflammation Micro-calcification Macro-calcification

Plaque rupture 18F-Fluoride CT

Dweck et al Myocardial Infarction Circulation Research 2016 18F-Fluoride & Coronary Disease

Rubeaux JNM 2016 Different Information from CT

SuppleComputedmentary figPositronure Emission2 Fused PET-CT Tomography Tomography

A B C A E I Fused PET-CT

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18F-Fluoride vs. VH-IVUS & Histology

SupplemenHISTOLOGYtary figure 2 VH-IVUS

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D H L 18F-Fluoride Identifies Adverse Plaques

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NaF Positive: 73% NaF Positive: 25% (21-29) NaF Negative: 21% NaF Negative: 18% (14-22) P<0.001 P<0.001 Positive Remodeling NaF Positive NaF Negative Minimal Luminal Area mm2: 9 (6-14) 7 (5-10) P<0.001 Plaque Area mm2: 24(21-29) 14 (12-18) P<0.001 Identifies High Risk Patients

Framingham Risk Scores

Dweck JACC 2012 18F-Fluoride post STEMI

Coronary Angiogram (LCA) Fused 18F-Fluoride PET CT

Joshi, Dweck, Newby. The Lancet. 2014 Joshi, Dweck, Newby. The Lancet. 2014 Fused 18F-Fluoride PET Coronary Angiogram (RCA) CT Dweck et al JACC 2012 PET/MR Imaging

<5mSv Robson, Dweck, Fayad JACC Imaging 2017 Carotid 18F-Fluoride

Vesey Circulation CVS Imaging 2017 Carotid 18F-Fluoride

Cocker, Beanlands JACC Imaging 2017 Prediction of Recurrent Events with 18F-Fluoride to Identify Ruptured and High-risk Coronary Artery Plaques in Patients with Myocardial Infarction Will 18F-Fluoride Predict Events?

Disease Progression

Clinical Events (Cardiac Death or MI) MULTI-MODALITY IMAGING

PLAQUE DISEASE BURDEN ACTIVITY

HIGH RISK PLAQUE FEATURES PET/CT IMAGING Dweck. Nature Review Cardiology 2016 Conclusions

• Plaques that rupture and cause myocardial infarction have certain characteristics that can be identified on imaging “the vulnerable plaque”

• These are actually relatively common and often heal without clinical consequence. Predicting individual lesions that will cause events is unlikely to be successful

• However identifying vulnerable plaques can help identify patients with active disease and an increased risk of events.

• These vulnerable patients could then be targeted with aggressive systemic therapies to prevent events Acknowledgements

University of Edinburgh Prof David Newby The British Heart Foundation Prof Nick Mills - BHF Clinical Research Training Fellowship (FS/10/026) Prof Edwin van Beek - Extension to Clinical Research Training Fellowship (FS- Prof Keith Fox 10/026) Dr Nicholas Boon - BHF Clinical Research Training Fellowship (FS/12/84/29814) Dr Tania Pawade - BHF Project Grant (PG/12/8/29371) Dr Russell Everett - BHF Intermediate Clinical Research Fellowship Dr Anoop Shah (FS/14/78/31020) Dr Mhairi Doris Dr Jack Andrews - BHF Programme Grant (RG/16/10/32375). Dr Tim Cartlidge - BHF Centre of Research Excellence Award. Dr Alastair Moss - BHF Outstanding Researcher Award 2015 Dr Phil Adamson The Chief Scientist Office University of Cambridge Wellcome Trust Dr James Rudd Dr Anthony Davenport Cedars Sinai Hospital LA Mount Sinai Hospital, NY Dr Agnese Irkle Prof Dan Berman Prof Zahi Fayad Prof Martin Bennet Prof Piotr Slomka Prof Valentin Fuster Dr Damini Dey Prof Jagat Narula Increased Inflammation in Remote Atheroma Post-MI 18F-FDG of the Aortae

Joshi et al. JAHA. 2015 In press Binds to Hydroxyapatite Crystal Vesey et al. Circ CVS Imaging 2017 Detects newly developing calcium beyond resolution of CT

Calcium on histology Micro CT Micro CT

Autoradiography Micro PET Autoradiography

Irkle et al. Nature Communications 2015