Filippos Triposkiadis, MD, FESC, FACCProfessor of Cardiology,Director, Department of Cardiology, Larissa University Hospital,Larissa, Greece

11th Cardiology Congress of Northern GreeceThessaloniki May 24-26,2012

The Theory of the Vulnerable Plaque: Impact on Diagnosis and Management of CAD

Pathology

•Plaque that is at increased risk of thrombosis (or re-thrombosis) and rapid stenosis progression.

Schaar, et al. Eur Heart J 2004; 25:1077-82

•Non-obstructive, silent coronary lesion that suddenly becomes obstructive and symptomatic.

Moreno, et al. Cardiol Clin 2010; 28:1-30

•Plaque susceptible to disruption with superimposed thrombosis, which is responsible for the majority of acute coronary events.

Fishbein MC. Cardiovasc Pathol 2010; 19:6-11

Definition of the Vulnerable Plaque

Causes of Atherothrombosis and Acute Coronary Syndromes

Plaque rupture (75%) Plaque erosion (25%)

• Farb A, et al. Circulation 1996;93(7):1354–63.• Virmani R, et al. J Am Coll Cardiol 2006;47(8 Suppl):C13–8.• Moreno P, et al. Cardiol Clin 2010; 28:1-30

Characteristics of Thrombosed Plaques

Plaque rupture • Thin fibrous cap (95% ≤64 μm)• Large necrotic core• Increased plaque inflammation• Positive vascular remodeling• Vasa vasorum neovascularization• Intraplaque hemorrhage

Plaque erosion• No specific features suitable for detection• Thick, SMC rich fibrous cap• Premenopausal women• Cigarette smoking

Fishbein MC. Cardiovasc Pathol 2010; 19:6-11

The Thin-Cap Fibroatheroma

•Virmani R, et al. J Am Coll Cardiol 2006;47:C13– 8•Burke AP, et al. N Engl J Med 1997;336:1276–82•Virmani R, et al.Arterioscler Thromb Vasc Biol 2000;20:1262–75

InflammationMacrophages infiltration14±10% in the fibrous cap

Spotty calcifications

Thin fibrous cap< 65 μm

Large necrotic coreoccupying 23±17% of the plaque area

NeoangiogenesisAdventitial vasa vasorum proliferationIntraplaque hemorrhage

Expansive outward remodelingRemodeling index >1.1

Inflammation Occurs in Both Vulnerable and Stable Plaques in Pts Dying of AMI

544 coronary artery segments from 16 patients dying of AMI, 109 segments from 5 patients dying of SA, and 304 coronary segments from 9 patients dying of non-cardiac causes (CTRL) were examined

• 6.8 ±0.5 vulnerable segments/patient in AMI (in addition to culprit lesions) vs. 0.8 ± 0.3 and 1.4 ± 0.3 in SA and CTRL. • In AMI more inflammatory infiltrates vs. SA and CTRL (121.6 ±12.4 cell X mm2 vs. 37.3 ± 11.9 cell X mm2 vs. 26.6 ± 6.8 cell X mm2, p= 0.0001). • In AMI, active inflammationevident within culprit lesion , vulnerable plaques, and stable plaques.• In AMI vulnerable and stable plaques showed 3- to 4-fold higher inflammation vs. SA and CTRL .

Mauriello, et al. J Am Coll Cardiol 2005;45:1585–93

Detection

Stenosis at the Site of OcclusiveThrombosis: Pathologic Studies a

a: Cross-sectional narrowing by plaque

Fishbein MC. Cardiovasc Pathol 2010; 19:6–11

Stenosis at the Site of OcclusiveThrombosis: Angiographic Studies a

a: Cross-sectional narrowing by plaque

Fishbein MC. Cardiovasc Pathol 2010; 19:6–11

• Little, et al. Circulation 1988;78:1157-1166.• Ambrose, et al.J Am Coll Cardiol 1988;12:56–62

Evolution of Angiographic Non-Stenotic Lesions

Thrombolytic recanalization of the obstructed coronary lumen was studied in 32 patientsreceiving intracoronary streptokinase for 60 to 90 min during acute myocardial infarction.

• “Original stenosis" measured 1.25±0.32 mm in minimum diameter and 56 ±14% stenosis when first visualized and was unchanged.

• In 5 patients catheterized 10 ± 12weeks before MI, the original stenosis was1.15 ± 0.22 mm, as compared with 1.17 ±0.23 mm in its faintly defined form during thrombolytic therapy (p = NS).

• In 10 cases, this original lesion was less than a 50% stenosis, and in 21 cases less than 60%.

Analysis of the Thrombolytic Process

Brown, et al. Circulation 1986;73:653-61

Assessment of Coronary Stenosis:Angiography vs. Pathology

Fishbein and Siegel. Circulation 1996;94:2662-6

DiameterStenosis

% cross-sectionalinvolvement by atheroma

Actual luminalarea decrease

AreaStenosis

Drawbacks of Coronary Angiography

• Depicts rather poor representation of cross-sectional coronary anatomy

from simple planar silhouette or luminogram of the contrast-filled lumen.

• Confounded by observer variability, with differences in the estimation of

stenosis approaching 50%.

• Functional testing often reveals discordance between the severity of

angiographic lesions and physiologic effects.

• Necropsy studies and IVUS demonstrate that coronary lesions,

particularly after plaque rupture, are complex, with distorted luminal

shapes that are difficult to assess using a planar angiographic silhouette.

Nissen S. JACC 2003; 41(4 Suppl S): 103S-112S

Coronary Remodeling ConcealsExtensive Disease

Remodeling and Clinical Presentation

Plaque Rupture

• Schoenhagen, et al. Circulation 2000; 101:598-603• Nissen S. JACC 2003:41:103S-112S

Stable CAD

Unstable CAD

Coronary Intravascular Ultrasound

IVUS Gray-Scale and CorrespondingVirtual Histology Frames

Garcia-Garcia HM, et al. Expert Rev Cardiovasc Ther 2008; 6: 209-22

MLA: Minimum luminal area; PB: Plaque burden; VCSA: Vessel cross-sectional area.Virtual histology color code: green is fibrous, greenish is fibrofatty, red is necrotic core, and white is dense calcium.

IVUS vs. OCT

• Garcia-Garcia HM, et al. Heart 2009;95:1362–1374• Prati F, et al. Eur Heart J 2010; 31:401-15

OCT IVUS

OCT Coronary Imaging

Prati F, et al. Eur Heart J 2010; 31:401-15

CT Coronary Imaging

Williams MC, et al. Heart 2011;97:1198-1205Voros S, et al. JACC Img 2011; 4:537-48

Coronary Imaging With Cardiovascular Magnetic Resonance

Chiribiri A, et al. Prog Cardiovasc Dis 2011; 54:240-52

Natural History

The PROSPECT: A Prospective Natural-History Study of Coronary Atherosclerosis

700 pts with ACS who underwent successful 1V or 2V PCI. Pts underwent 3V imaging of culprit artery and non-culprit arteries, with angiography, IVUS, and virtual histology, as well as palpography (n350 pts). All pts were treated with optimal medical therapy, including aspirin, clopidogrel for one year, and statin therapy.

Stone GW, et al. N Engl J Med 2011;364:226-35

The PROSPECT: Event Rates vs. Lesions

Stone GW, et al. N Engl J Med 2011;364:226-35

The PROSPECT: Plaque Characteristics Associated with Future Events

Plaque burden≥70% Lumen area ≤ 4 mm2

Thin Cap Fibroatheroma

• Moreno P, et al. Cardiol Clin 2010; 28:1-30 • Stone GW, et al. N Engl J Med 2011;364:226-35

The PROSPECT: Characteristics and Significance of Mild Lesions (n=1824) in ACS

Brener SJ, et al. JACC Img 2012;5: S86-94

Incidence of High-Risk CharacteristicsDetected by IVUS

Cumulative Incidence of MACE

Of the 105 MACE-related NCL, approximately one-third

(n =32) originated from angiographically more severe

lesions (DS ≥50%), whereas the remaining two-thirds

originated from angiographically mild (30% to 50%

DS, n=41) or inconspicuous (<30% DS, n =32) lesions.

The PROSPECT: CV Events and Angiographic Progression

Sanidas EA, et al. JACC Img 2012;5: S95-105

Time-to-Event Curves for NCLesion-Related MACEs

Residual Plaque Burden in Pts with ACS after Successful PCI

McPherson JA, et al. JACC Img 2012;5: S76-85

MACE During Follow-Up

MACE /Lesion During Follow-Up

Predictive Performance of Plaque Characteristics

Kaul S, Diamond GA. JACC Img 2012;5: S106-110

Predictive Performance of Patient Characteristics

Management

The PROSPECT: Is There a Role for PCI in Vulnerable Plaque Management ?

• While the combination of 3 characteristic NCL features (plaque burden ≥70%, MLA ≤4.0 mm2 and presence of a TCFA) conferred an HR of 11, almost 90% of patients with similar plaques did not have a MACE during the 3-year follow-up.

• Overall, 20.4% of patients had major CV events, of which 11.6% were related to non-culprit lesions; however, only 1% were MIs, while the remaining 10.6% were unstable or progressive angina.

• Eleven patients (1.6%) had complications that were directly attributable to the 3-vessel imaging procedure. These complications resulted in 3 nonfatal MI (in 0.4% of patients).

• As the resolution of IVUS is 150 to 200 μm, it is incapable of identifying the fibrous cap thickness component of TCFA (< 65 μm). Another problem with IVUS–VH histology is its failure to distinguish “lipid pool” from “necrotic core” , which is critical to calling a lesion “fibroatheroma”.

Invasive imaging to locate and then prophylactically treatpresumed high-risk lesions with PCI is not warranted

•Falk E, Willensky RL. JACC Imaging 2012; 5: S38-41•Finn AV, et al. JACC Imaging 2012; 5: 334-6

CTA was performed in 32 pts. Of these, 24 received fluvastatin after the baseline study; 8 subjects who refused statin treatment were followed as the control subjects. Serial imaging was performed after a median interval of 12 months.

Serial CTA–Verified Changes in Plaque Characteristics as an End Point

Inoue K, et al. JACC Im 2010;3: 691-8

Hattori K, et al. JACC Im 2012;5:169-77

Impact of Statin Therapy on Plaque Composition

OCT, grayscale and IB-IVUS of non-target lesions was performed in 42 stable angina pts undergoing elective PCI. 26 received 4 mg pitavastatin, whereas 16 were followed with dietary modification alone. Follow-up imaging was performed after a median interval of 9 months.

Impact of Therapy on Plaque Composition: Diet

Hattori K, et al. JACC Im 2012;5:169-77

Impact of Therapy on Plaque Composition: Statin

Hattori K, et al. JACC Im 2012;5:169-77

Future Perspectives

Multimodality Imaging in Atherosclerosis

Verjans J, et al. J Nucl Cardiol. 2010; 17:1065–1072

Molecular Imaging Targets in Atherosclerosis

Leuschner F, Nahrendorf M. Circ Res 2011;108:593-606

Molecular Imaging Targets in Myocardial Infarction

Leuschner F, Nahrendorf M. Circ Res 2011;108:593-606

Principles of MicroRNA Therapeutics

Broderick JA, Zamore PD. Gene Therapy 2011; 18:1104-10

Therapeutic Modification of Atherosclerosis by MicroRNAs

Martin K, et al. Curr Opin Cardiol 2011;26:569-75

• Atherothrombosis continues to evolve in diagnosis and imaging.

• A single-plaque approach is narrow minded and difficult to prove in clinical practice.

• The PROSPECT trial provides evidence for increased risk for large, stenotic plaques with VH-TCFA morphology on IVUS.

• Modern CTA technology is capable of noninvasively detecting morphological markers of lesion vulnerability (location, attenuation, remodeling).

• Invasive imaging to locate and then prophylactically treat presumed high-risk lesions with PCI is currently not warranted.

• Statins are currently the treatment of choice for vulnerable plaque stabilization

• miRNAs may provide new therapeutic targets in the not so far future.

Conclusions

Pathology, Detection, and Management of the Vulnerable

Atherosclerotic Plaque

Filippos Triposkiadis, MD, FESC, FACCProfessor of CardiologyDirector, Department of CardiologyLarissa University HospitalLarissa, Greece

Metabolic ConferencesAthens, May 2-5, 2012

Fusion between MRA and DE-MRI

Chiribiri A, et al. Prog Cardiovasc Dis 2011;54:240-52

Co-Registered 18F-FDG PET/CT Imaging of Inflammation in Human

Coronary Arteries

Rogers IS, et al. J Am Coll Cardiol Img 2010;3:388–97

The Thin-Cap Fibroatheroma

Kolodgie FD, et al. Heart 2004; 90: 1385-91

Coronary Plaque Vulnerability Assessed with CTA and IVUS

Unstable Angina

Unstable Angina

Unstable Angina

Stable Angina

Pugliese, et al. Journal of Cardiovascular Medicine 2009;10:821–826

Outcomes From Second-GenerationCoronary Stent Trials

1228 patients for were observed 5 years after implantation of second-generation coronary stents. Death, MI, repeat revascularization, and repeat hospitalization for ACS or CHF were attributed to the index stented lesion or other sites in target or other coronary vessels and further classified as procedural,restenosis, or nonrestenosis.

Cutlip, et al. Circulation 2004;110:1226-1230

Progression of AsymptomaticLesions Discovered During PCI

Retrospective study to determine features of clinical plaque progression using the NHLBI Dynamic Registry of patients undergoing PCI in 1997 to 1998 and 1999. Of 3747 PCI patients, 276 (7.4%)pts underwent target lesion PCI for restenosis and 216 (5.8%) required additional non-target lesionPCI for clinical plaque progression at 1 year (59% presented with new UA, and 9.3% with nonfatal MI.

A

B

C

Glaser, et al. Circulation 2005;111:143-9

The majority (86.9%) of lesions requiring subsequent PCI were ≤ 60% in severity during original PCI, with the mean lesion stenosis41.8±20.8% at the time of the initial PCI and 83.9 ± 13.9% during the recurrent event.

CTA Characteristics ofPlaques Resulting in ACS

In 1,059 patients who underwent CTA, atherosclerotic lesions were analyzed for PR and LAP. The remodeling index, and plaque and LAP areas and volumes were calculated. The plaque characteristics of lesions resulting in ACS during the follow-up of 27±10 months were evaluated.

Motoyama, et al. J Am Coll Cardiol 2009;54:49–57

22.2% 3.7% 0.5% 0

Vasa Vasorum Imaging, by Using Contrast-Enhanced IVUS

Vavuranakis, et al. Int J Cardiol 2008; 130:23-9

114 coronary sites without significant stenosis by angiography (<50% diameter stenosis) in 106 patientsundergoing ICA and IVUS were examined. All sites exhibited atherosclerotic lesions by IVUS. These lesionsconsisted of 22 concentric and 92 eccentric plaques with a % plaque area averaging 59±12%. Follow-up period of 21.8 ± 6 6.4 months (range 1 to 24).

• 12 pts had an ACS 4.0 ± 3.4

months after initial IVUS study.

• All plaques related to ACS had aneccentric pattern and their mean percent plaque area was greater than in pts without ACS (67 ± 9% vs. 57 ± 12%, p < 0.05).

• No difference in lumen area between two patient groups (6.7 ±3.0 vs. 7.5 ± 3.7 mm2).

• Among 12 coronary sites with an acute occlusion, 10 sites contained echolucent zones, 8 of these shallow and 2 deep, likely representing a lipid-rich core.

• In 90 sites without ACS, an echolucent zone in the shallow portion was seen at only 4 sites (p <0.05).

IVUS Morphology of VulnerableCoronary Plaque

Yamagishi, et al. J Am Coll Cardiol 2000; 35:106 –11

Arterial Remodeling

Schoenhagen P, et al. Circulation 2000;101:598–603

Summary of Invasive Technologies for Vulnerable Plaque Imaging

Moreno P, et al. Cardiol Clin 2010; 28:1-30

Calcified Nodule

Virmani R, et al. J Am Coll Cardiol 2006;47(8 Suppl):C13–8.

Sudden Coronary Death Caused by PIT without Plaque Formation

Tavora F, et al. Cardiovasc Pathol 2011; 20:51-7

The Non-Stenotic Lesion as Culprit

Nissen S. JACC 2003:41:103S-112S

Vancraeynest D, et al. J Am Coll Cardiol 2011;57:1961–79

Noninvasive Coronary Imaging

OCT-Characterization of CoronaryAtherosclerosis

Jang IK, et al. Circulation 2005;111(12):1551–5

OCT-Based Plaque Characteristics

Uemura S, et al. Eur Heart J 2012; 33: 78-85

Ohtani T, et al. J Am Coll Cardiol 2006;47:2194–200

Angioscopy--Characterization of Coronary Atherosclerosis

CT evaluation of Vulnerable Plaque

Opolski MP, et al. Int J Cardiovasc Imaging April 21, 2011

Spatial Distribution of Advanced Coronary Lesions

Cheruvu, et al. JACC 2007;50:940–9

Section of coronary arteries from 50 whole hearts taken from pts (mean age 74 years, 64% men)) dying of CV (n=33) non-CV (n=13) and unknown (n=4) causes).

The majority of TFCA and ruptured plaque localized in the proximal third of the major coronary arteries.

Noninvasive Techniques for Vulnerable Plaque Imaging

Vancraeynest D, et al. J Am Coll Cardiol 2011;57:1961–79

The Vulnerable Plaque “Hypothesis”Promise, but Little Progress

• Is there is a direct 1-to-1 relationship between a TCFA and

a high-risk plaque?

• Is plaque instability a focal, a multifocal, or a disseminated

phenomenon?

• If a plaque is high risk today, will it be high risk in 1 month, 3 months,

or a year from now?

• If we classify a plaque as stable, can we be certain that it not undergo

acute conversion to a vulnerable lesion a few weeks later ?

Nissen S. JACC Cardiovascular Img 2009;2: 483 – 5