Noninvasive Imaging for Atherosclerosis Regression

Allen J. Taylor MDChief, Cardiology

MedStar Heart and Vascular InstituteMedStar Washington Hospital Center

MedStar Georgetown University Hospital

Professor of MedicineGeorgetown University Hospital

Conflicts to disclose:Honoraria: Amgen, Sanofi-Regeneron

Pubmed: Studies of atherosclerosis progression/regression per year 1975 to current

Present status: Clinicaltrials.gov

Recruiting studies: Atherosclerosis InterventionalIMT 58Cardiac CT 31CAC 41IVUS 11MRI 40

Imaging for Atherosclerosis Change

Clinical tool Detect changing cardiovascular risk, control of

disease Coronary calcium

Research tool Atherosclerosis as a surrogate for clinical

benefit Carotid ultrasound, Cardiac CT, MRI

Atherosclerosis progression portends risk

Serial angiographic study in 335 pts, mean age 51, f/u 44 months

Waters et al. Circulation 1993;87:1067-1075

QCA progression

>15% increase in diameter stenosis

42%

50% increase in adjusted risk for cardiac death/MI P < .001

IVUS progression predicts clinical events

Essen University: Serial IVUS study of the left main coronary artery in 56 pts undergoing left coronary PCI

Erbel and colleagues. Circulation 2004;110:1579

Change in plaque area related to clinical risk factors

Most events occurred in those with the greatest progression

P+M 25% vs. 6%

Will a serial scanning refine the risk prediction for CHD?

Scan 1Scan 3Scan 2

Achenbach et al. Circulation 2002;106:1077

How do we clinically monitor successful control of cardiovascular

risk?Attainment of risk factor targets

BP, LDL-C, HDL-C

Use of specific medication classes

Compliance with therapeutic lifestyle changes

Tobacco, physical activity and diet

Inference: Control of risk factors equates to control of the target disease Atherosclerosis

CAC score progression

Raggi et al. ATVB. 2004;24(7):1272-7

progression in individuals with events

Open issues:

Calculation?

%/year

Volume

Determinants uncertain

Groups overlap Raggi et al. AJC. 2003;92:827

Signal vs. Noise

Serial CAC testing depends upon detecting the difference between CAC progression vs. inter-scan variability

CAC progression > inter-scan variability

MESA:Mean SD absolute and % interscan variability and correlation (r) were 19.8 59.620.82%

CAC score progression:Typically exceeds 20% per year

Optimizing scan variability:Cardiac position changes, partial volume effects, image noise, interobserver variation, coronary motion artifacts, attenuation, lesion number

Interscan variability is highest at lower scores

Lu, Budoff et al. Acad Radiol. 2002;9:654

Under OPTIMAL conditions of patient on same day, un-moved, with heart-rate customized ECG trigger

N 5682Serial CAC scans 2.5 years apart7.5 year follow upAnnual CAC score change average: 25 unitsEvents:

Zero baseline: 1.3 per 100 unit changeCAC at baseline: HR 6.3 per 300 unit change

J Am Coll Cardiol 2013;61:12319

Serial CAC scanning over mean of 3 years

Incident CAC: 40% increase likelihood per 5% increase in FRS

Progressive CAC: Increase in CAC score of 7 per 5% increase in FRS

Implication: Clinical response to changing CAC score should be intensification of risk

factor control

What Is IMT ?

IMT is the distance between the lumen-intima interface and the media-adventitia interface

First described by Pignoli et al when imaging, with ultrasound, the wall of the abdominal aorta

Pignoli et al. Circulation. 1986;74:1399

Ultrasound Image of the Aorta in Vitro

near wall

far wall

Media-adventitia InterfaceLumen-Intima Interface

B-Mode Image of theCarotid Artery Wall

5 mmcarotid artery wall

plaque

Courtesy of W. Riley

media

adventitia

intima

plaque

Carotid Intima-media Thickness

Far wallAcoustic shadowing in near wall

Which site? CCA most reproducibleICA/Bulb: more difficult

Plaque more commonGreater magnitude of change

MeasurementABD or manual, 1cm lengthEasy- takes minutesAccurate- .0x mm

Mean CIMT 1.174 mm

Bulb Lumen

Far wall IMT

Selection of end-diastolic imagesSystolic expansion/IMT thinning

IMT Variability: Improving signal:noise

Sources of variability for measuring changes in IMT progression

Proposed solutions Replicates Increase time

interval

Implicit solution Increase sample size

Espeland et al. Stroke. 1996;27:480

0.007

0.006

0.005

0.004

0.003

0.002

0.001

0.000 Single Duplicate Single Duplicate Single Duplicate Single Duplicate2 years 3 years 6 years 8 years

Varia

nce

of M

easu

red

Pro

gres

sion

Rat

e Readers Noise Subjects

CIMT: Variance of serial measurement is low!

Present Protocol13 MHz

ECG gated, diastolic images

Common carotid

2 views

2 full sets

Analysis

Single observer, masked

Manual and ABD

All measurements performed twice on each image set

Mean CC IMT, Max CC IMT

Reproducibility with Present ProtocolCIMT images from 148 participants of a clinical trial were examined.

Imaging protocol:2 complete sets of anterior and lateral views of the far wall of the distal CCASingle sonographer using a 13 MHz linear probeQuantified by a single observer using an off-line workstation with manual and automated border detection (ABD) softwareDigital image acquisition was gated to diastole

Mean CIMT of the cohort in the anterior and lateral views was approximately 0.90 mmNo relationship between the mean difference between measurement pairs and image quality. Reader drift was .0001 mm or less.

Difference between image sets

95% CI P

Anterior- manual .0045 mm -.0139 to .0049 mm .35Lateral- manual .0029 mm -.0162 to .0033 mm .59Anterior- ABD .0087 mm -.0182 to .0008 mm .07Lateral- ABD .0073 mm -.0037 to .0184 mm .19

CIMT Progression: Related to risk factors

Am J Epidemiol 2002;155:3847.

age 4564 years

n = 15,792

DM (yes/no) 1.97 micronsSmoker 1.82 micronsHDL (17.1 mg/dL) -.59 micronsLDL (39.4 mg/dL) .22 micronsTriglycerices (90 mg/dL) .43 micronsSystolic BP 19 mm Hg .36 microns

Current reference standard for quantifying plaque volume is the expert observer

Time-consuming Variable

Coronary CT angiography

Schmid et al AJC 2008, Leber et al JACC 2006, Cheng et al JCCT 2009

Coronary CT Angiography (CTA) can characterize non-calcified (NCP) and calcified plaque (CP)

Software approaches

Voros JACC Interventions 2011

ATLANTA

TRIAL

- Prospective

-60 patients

- CTA, invasive cathand VH-IVUS

Correlation R = 0.6 - 0.84 for CP, NCP volume with VH-IVUS

APQ comparison with IVUS

Dey et al Radiology 2010

Lumen intima border

External elastic membrane

Coronary CTA

IVUS

NCP volume measurement

NCP volume measurement (N=22)

116.6100.8105.9

0

50

100

150

200

IVUS Manual CCTA

APQ

NCP Volume

P=NSP=NS

Volu

me

(mm

3 )

Dey et al Radiology 2010

Chart2

105.983.5

100.881.7

116.680.1

Sheet1

IVUSCCTA manualCCTA APQall in mm3

105.9100.8116.6

83.581.780.1

Sheet1

83.5

81.7

80.1

Sheet2

Sheet3

y = 1.03x

0

100

200

300

400

0 100 200 300Plaque volume IVUS (mm3)

Plaq

ue V

olum

e A

PQ (m

m3)

Comparison with IVUS (N=22)

R =0.94, p

Rinehart, Vasquez, Qian, Voros. J InvCardiol 2009; 21(7):367-372.

1. Centerline extraction2. Lumen segmentation3. Anatomical segments4. Measurements

1. MLD2. %DS3. MLA4. %AS5. Plaque volume6. Percent atheroma volume7. Remodeling index8. Plaque components

Quantitative Plaque AnalysisReproducibility: Quantitative Measurements

Akram, Rinehart, Voros. J Nucl Cardiol 2008;15:818-29.

Plaque

Calcified Plaque(CAP)

Non-Calcified Plaque(NCP)

Low-Densitiy NCP(LD-NCP)

High-Densitiy NCP(HD-NCP)

?Lipid-richnecrotic core?

?Fibrous andfibro-fatty

tissue?

Quantitative Plaque AnalysisReproducibility: Quantitative Measurements

Voros et al. JACC Cardiovasc Imaging. 2011 May;4(5):537-48.

Quantitative Plaque AnalysisReproducibility

Challenges Plaque quantification requires good-excellent image quality

Artifacts - effect on automated plaque quantification

CTA Characteristics of Plaques Subsequently Resulting in ACS

Motoyama. JACC 2009;54:4957

ACS+ ACS- pPR 127 % 113 % .003PV 135 mm3 58 mm3 .001 LAP V 20 mm3 1.1mm3 .001%LAP/ 21.4% 7.7% .001 plaque area

1059 pts suspected or known CAD 27+10 mo f/u

Lehman l. JACCImg 2009;2:126270.

69 chest pain pts; 8311 coregisteredcross sectionsRepeat imaging 2 yrs% of slices with either CP or NCP

Plaque Progression on CTA

Significant by multivariate analysisbaseline plaquenumber of risk factors smoking

% of slices Any NCP Baseline 16.5 3.12 yrs 18.6 4.4 p 0.01 0.04

KIntraobserver 0.95Interobserver 0.93

Decreased total plaque volume due to decreased LAPNo change in lumen volume

Inoue. JACC Img 2010;3:6918.

32 treatment nave pts: 24 fluvastatin 20 mg, 8 no rx15: 16 slice, 17 : 64 slice12 month rescan

Serial Coronary CTA Verified Changes in Plaque Characteristics : Effect of Statin Intervention

MR Plaque Imaging

High SNR High resolution Clear delineation between the blood, vessel wall and

surrounding tissues Black-blood imaging

In-flow suppression (IS), double inversion recovery (DIR) and motion-sensitized driven equilibrium (MSDE)

Evaluation of imaging biomakers

2012 MFMER | slide-37

Balu et al. Current Techniques for MR Imaging of Atherosclerosis. Top Magn Reson Imaging 2009;20: 203-215

Multi-Contrast Carotid Artery Images

Ota H et al. Arterioscler Thromb Vasc Biol 2009;29:1696-1701

Arrows = LRNC Arrowheads = thick fibrous cap

Saam T, et al. Arteriosclerosis, Thrombosis, and Vascular Biology. 2005; 25: 234-239

Plaque Component

T1-weighted T2-weighted Proton density-

weighted

Time-of-flight Post-Gadolinium

based contrastLipid rich, Necrotic core

Isointense to slightly hyper-intense

Hypointense Isointense to hyperintense

Isointense Slower uptake, less

enhancement

Hemorrhage (recent)

Hyperintense Enhancement

Calcification HypointenseLoose Matrix

Hypointense to isointense

Hyperintense Hyperintense Hypointense No change

Multi-Contrast MR Imaging

MR Imaging Biomarkers of Atheroslcerosis

Morphology Lumen and plaque dimensions

(6-10% measurement error) Composition

Calcification (sens 76%, spec 86%) Lipid-rich necrotic core (sens 85-95%, spec 76-92%) Hemorrhage (sens 87-97%, spec 70-98%) Thrombus (sens 88%, spec 98%) Fibrous cap (sens 89%, spec 96%)

Activity Inflammation Neovasculature

Balu et al. Current Techniques for MR Imaging of Atherosclerosis. Top Magn Reson Imaging 2009;20: 203-215

2012 MFMER | slide-41

Clinical Trials

Aorta FemoralCarotid

Clinical Trials using MR Based Evaluation of Atherosclerotic Plaque

Aorta

27 patients with known atherosclerosis followed for 6 months after beginning simvastatin (Lima et al.) Serial MRI of thoracic aorta LDL-C decreased from 125+/-32 to 97+/-27

18 patients with known carotid or aortic atherosclerotic disease (Corti et al.) Reduction in LDL-C by 38% and TC by 21%

(1) Lima, JA et al. Circulation. 2004; 110: 2336-2341.(2) Corti R et al. Circulation 2001;104:249-252

Serial T2-weighted images of the same patient

Corti R et al. Circulation 2001;104:249-252

Copyright American Heart Association

Serial MRI after simvastatin therapy

Corti R et al. Circulation 2001;104:249-252Copyright American Heart Association

Change in Carotid Plaque Composition with Lipid Therapy

33 patients with measurable lipid-rich necrotic core at baseline started on atorvastatin therapy and followed for 3 years

Decrease in plaque lipids after 1 year This preceded plaque regression

2012 MFMER | slide-45

Zhao X-Q, et al. J Am Coll Cardiol Img. 2011;4(9):977-986

Copyright The American College of Cardiology. All rights reserved.

From: MR Imaging of Carotid Plaque Composition During Lipid-Lowering Therapy: Title and subTitle BreakA Prospective Assessment of Effect and Time Course

J Am Coll Cardiol Img. 2011;4(9):977-986. doi:10.1016/j.jcmg.2011.06.013

Copyright The American College of Cardiology. All rights reserved.

From: MR Imaging of Carotid Plaque Composition During Lipid-Lowering Therapy: Title and subTitle BreakA Prospective Assessment of Effect and Time Course

J Am Coll Cardiol Img. 2011;4(9):977-986. doi:10.1016/j.jcmg.2011.06.013

Noninvasive imaging for atherosclerosis regression

Clinical tool: CAC Progression on serial scans predicts events

independent of baseline score Research tools:

IMT: Simple, reproducible, small changes Questions about relationship to events

Coronary CT: Robust, accurate Plaque volume and characteristics

MRI: Peripheral arteries

Noninvasive Imaging for Atherosclerosis RegressionSlide Number 2Slide Number 3Imaging for Atherosclerosis ChangeAtherosclerosis progression portends riskIVUS progression predicts clinical eventsWill a serial scanning refine the risk prediction for CHD?How do we clinically monitor successful control of cardiovascular risk?CAC score progressionSignal vs. NoiseInterscan variability is highest at lower scoresSlide Number 12Slide Number 13Slide Number 14What Is IMT ?B-Mode Image of theCarotid Artery WallCarotid Intima-media ThicknessCIMT: Variance of serial measurement is low!Present ProtocolReproducibility with Present ProtocolCIMT Progression: Related to risk factorsSlide Number 22Slide Number 23Slide Number 24Software approachesAPQ comparison with IVUS Slide Number 27Slide Number 28Comparison with IVUS (N=22)Quantitative Plaque AnalysisReproducibility: Quantitative MeasurementsQuantitative Plaque AnalysisReproducibility: Quantitative MeasurementsQuantitative Plaque AnalysisReproducibilitySlide Number 33Slide Number 34Slide Number 35Slide Number 36MR Plaque ImagingSlide Number 38Multi-Contrast MR ImagingMR Imaging Biomarkers of AtheroslcerosisClinical Trials using MR Based Evaluation of Atherosclerotic PlaqueAortaSlide Number 43Slide Number 44Change in Carotid Plaque Composition with Lipid TherapySlide Number 46Slide Number 47Noninvasive imaging for atherosclerosis regression