From the Vulnerable Atherosclerotic Plaque to CAD Management

33 rd Panhellenic Congress of Cardiology Athens, November 1-3, 2012 From the Vulnerable Atherosclerotic Plaque to CAD Management Filippos Triposkiadis, MD, FESC, FACC Professor of Cardiology Director, Department of Cardiology Larissa University Hospital Larissa, Greece

Introduction

Natural History of CAD Obstructive Non-obstructive Positive Remodelling Stenotic Lesions Stress ischemia (+) Stress angina (-/+) Calcium Score (+) Angiography (+) IVUS (+) Normal Non-Stenotic Lesions Stress ischemia (--/+) Stress angina (--/+) Calcium score (--/+) Angiography (--/+) IVUS (+) Triposkiadis F, et al. Curr Cardiol Rev 2007;2:221-31 Coronary thrombosis Death Unstable angina Myocardial infarction

Presentation of Coronary Artery Disease 80 70 60 50 (%) 50 40 30 20 30 Series1 20 10 0 SCD ACS Stable Angina Only 18% of coronary attacks are preceded by longstanding angina pectoris Myerburg RJ, Junttila J. Circulation 2012; 125:1043-52 Marzocchi A, et al. Int J Cardiol 2012; 157: 419-22 Hemingway H, et al. 2006; 295: 1404-11

Pathology

A Histological Classification of Atherosclerosis Stary HC, et al. Circulation. 1995; 92: 1355-74

Definition of the Vulnerable Plaque 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

Causes of Coronary Thrombosis Plaque rupture (55-60%) Thin fibrous cap (95% 64 μm) Large necrotic core Increased plaque inflammation Positive vascular remodeling Vasa vasorum neovascularization Intraplaque hemorrhage Plaque erosion (30-35%) No specific features suitable for detection Thick, SMC rich fibrous cap Premenopausal women Cigarette smoking Calcified nodule (2-7%) Heavily calcified plaque with or without necrotic core Luminal region of plaque shows disrupted surface fibrous cap and overlying thrombus. More common in older male than women. Virmani R, et al. JACC 2006; 47: Suppl C: C13-8

The Thin-Cap Fibroatheroma Inflammation Macrophages infiltration 14±10% in the fibrous cap Thin fibrous cap < 65 μm Spotty calcifications Large necrotic core occupying 23±17% of the plaque area Expansive outward remodeling Remodeling index >1.1 Neoangiogenesis Adventitial vasa vasorum proliferation Intraplaque hemorrhage 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

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

Frequency and Distribution of TCFA and Ruptured Plaques 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. Cheruvu, et al. JACC 2007;50:940 9

Inflammation 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 inflammation evident 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

Carotid Plaque Composition in Stable and Unstable CAD Twenty-five patients (16 men/9 women, age 63 ± 10 years) with stable coronary artery disease and 61 (41 men/20 women, age 66 ± 16 years) with acute coronary syndromes underwent carotid ultrasonography within 2 days of cardiac catheterization. Triposkiadis F, et al. Am Heart J 2005; 150: 782-9

Detection

Morphology vs. Activity Imaging Thermography, Spectroscopy, Molecular Imaging, (radionuclear, MRI, CT ) targeted to markers of activity (MMP, Ox-LDL, LOX) Different Activity Active and inflamed plaque Similar Morphology Inactive and non-inflamed plaque IVUS OCT MRI w/o CM Naghavi M, et al. Circulation 2003; 108:1664-72

Coronary Intravascular Ultrasound Coronary Remodeling Conceals Extensive Disease Stable CAD Remodeling and Clinical Presentation Plaque Rupture Unstable CAD Schoenhagen, et al. Circulation 2000; 101:598-603 Nissen S. JACC 2003:41:103S-112S

IVUS Gray-Scale and Corresponding Virtual Histology Frames 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. Garcia-Garcia HM, et al. Expert Rev Cardiovasc Ther 2008; 6: 209-22

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

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

Potential Risk of Invasive Assessment of Vulnerable Plaque Stone GW, et al. N Engl J Med 2011;364:226-35

Noninvasive Techniques for Vulnerable Plaque Imaging Vancraeynest D, et al. J Am Coll Cardiol 2011;57:1961 79

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

The CONFIRM Registry: ccta and Outcome in Subjects Without Chest Pain Syndrome A registry of 27, 125 pts undergoing ccta and CACS was queried. 7590 subjects without CPS or CAD history were included. All-cause mortality and the composite of all-cause mortality and nonfatal MI were measured. Median follow-up was 24 (18 35) months. 136 individuals died. The net reclassification improvement resulting from the addition of ccta to a model based on standard risk factors and CACS was negligible! Cho I, et al. Circulation 2012;126: 304-313

Natural History of Vulnerable Plaque

Dynamic Nature of Coronary Plaque Morphology Baseline and 12-month follow-up VH-IVUS studies of 216 non-culprit lesions (plaque burden 40%) in 99 patients. Kubo T, et al. J Am Coll Cardiol 2010;55:1590 7

Changes in Plaque Characteristics Assessed by VH-IVUS VH-TCFA ThCFA VH-TCFA Fibrous plaque VH-TCFA VH-TCFA PIT VH-TCFA ThCFA VH-TCFA Kubo T, et al. J Am Coll Cardiol 2010;55:1590 7

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 (n 350 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 Thin Cap Fibroatheroma Plaque burden 70% Lumen area 4 mm 2 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 in ACS Incidence of High-Risk Characteristics Detected by IVUS Cumulative Incidence of MACE Brener SJ, et al. JACC Img 2012;5: S86-94

The PROSPECT: CV Events and Angiographic Progression Time-to-Event Curves for NC Lesion-Related MACEs Sanidas EA, et al. JACC Img 2012;5: S95-105

Residual Plaque Burden in Pts with ACS after Successful PCI MACE During Follow-Up MACE /Lesion During Follow-Up McPherson JA, et al. JACC Img 2012;5: S76-85

Predictive Performance of Plaque Characteristics Predictive Performance of Patient Characteristics Kaul S, Diamond GA. JACC Img 2012;5: S106-110

Management

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

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 mm 2 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 treat presumed 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

Serial CTA Verified Changes in Plaque Characteristics as an End Point 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. Inoue K, et al. JACC Im 2010;3: 691-8

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

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

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

Conclusions 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.

The CONFIRM Registry Risk Stratification by Cardiac CTA CCTA pts with LVEF data were screened. Pts with MI history, coronary Rx, or cardiac Tx were excluded. The NCEP- ATP III risk was calculated for each pt, and CCTA was evaluated for CAD severity (normal, non-obstructive, non high-risk, or high-risk CAD) and LVEF <50%. End point was all-cause mortality; 14,064 pts met the analysis criteria. Mean follow-up was 22.5 (95% CI, 22.3-22.7) months. Chow BJW, et al. Circ Cardiovasc Imaging 2011;4:463-472

The VIVA (VH-IVUS in Vulnerable Atherosclerosis) Study 170 pts with stable angina or troponin (+) ACS referred for PCI underwent 3V VH-IVUS pre- PCI and also post-pci in culprit vessel. 30,372 mm of VH-IVUS were analyzed. 18 MACE occurred in 16 pts over a median follow-up of 625 days. MACE: 11 PCI, 3 CABG, 2MIs, 2 deaths Calvert PA, et al. JACC Imaging 2011; 4: 894-901

CTA Characteristics of Plaques 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. 22.2% 3.7% 0.5% 0 Motoyama, et al. J Am Coll Cardiol 2009;54:49 57

Causes of Coronary Thrombosis Rupture Erosion Calcified nodule Virmani R, et al. ATVB 2000; 20:1262-75 Virmani R, et al. JACC 2006; 47: Suppl C: C13-8

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

Prognosis of Chronic Obstructive CAD Swedish low-dose aspirin trial (SAPAT; 2035 patients; median follow-up 4.2 years). Cardiac death rate of 0.9% per year. Lancet 1992;12;340:1421-5 Total Ischaemic Burden European Trial (TIBET; 682 patients; 2 years) Cardiac death rate of 1% per year among patients with a positive exercise test. Eur Heart J 1996;17:96-103 Angina Prognosis Study In Stockholm (APSIS;809 patients; 3.4 years). Cardiac death rate of 1.2% per year. Eur Heart J 1996;17:76-89 ACTION trial. Cardiovascular mortality rate of 0.9% per year. Lancet 2004;364:849-57 Jabbour, et al (693 patients; 4.6 years). Cardiac death rate 0.8 per year. Am J Cardiol 2004; 93: 294-99 Rates of non-fatal myocardial infarction ranged from 1.0% (APSIS) to 2.6% (TIBET) per year.

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

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

Stenosis at the Site of Occlusive Thrombosis: Pathologic Studies a a : Cross-sectional narrowing by plaque Fishbein MC. Cardiovasc Pathol 2010; 19:6 11

Stenosis at the Site of Occlusive Thrombosis: Angiographic Studies a a : Cross-sectional narrowing by plaque Fishbein MC. Cardiovasc Pathol 2010; 19:6 11

Evolution of Angiographic Non-Stenotic Lesions Little, et al. Circulation 1988;78:1157-1166. Ambrose, et al.j Am Coll Cardiol 1988;12:56 62

Analysis of the Thrombolytic Process Thrombolytic recanalization of the obstructed coronary lumen was studied in 32 patients receiving 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 ± 12 weeks before MI, the original stenosis was 1.15 ± 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%. Brown, et al. Circulation 1986;73:653-61

Assessment of Coronary Stenosis: Angiography vs. Pathology Diameter Stenosis Area Stenosis % cross-sectional involvement by atheroma Actual luminal area decrease Fishbein and Siegel. Circulation 1996;94:2662-6

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 Imaging With Cardiovascular Magnetic Resonance Chiribiri A, et al. Prog Cardiovasc Dis 2011; 54:240-52

Natural History of Vulnerable Plaque

The Fate of the Vulnerable Plaque

The Fate of the Vulnerable Plaque: Additional Factors (1)

The Fate of the Vulnerable Plaque: Additional Factors (2)

The Fate of the Vulnerable Plaque: Additional Factors (3)

Prediction of Hard Events within 5 Years in the Heinz Nixdorf Recall Study Erbel R, Budoff M. Eur Heart J 2012; 33: 1201-17

Fusion between MRA and DE-MRI Chiribiri A, et al. Prog Cardiovasc Dis 2011;54:240-52

Co-Registered 18 F-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-Generation Coronary 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 Asymptomatic Lesions 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 lesion PCI for clinical plaque progression at 1 year (59% presented with new UA, and 9.3% with nonfatal MI. A B C The majority (86.9%) of lesions requiring subsequent PCI were 60% in severity during original PCI, with the mean lesion stenosis 41.8±20.8% at the time of the initial PCI and 83.9 ± 13.9% during the recurrent event. Glaser, et al. Circulation 2005;111:143-9

Vasa Vasorum Imaging, by Using Contrast-Enhanced IVUS Vavuranakis, et al. Int J Cardiol 2008; 130:23-9

IVUS Morphology of Vulnerable Coronary Plaque 114 coronary sites without significant stenosis by angiography (<50% diameter stenosis) in 106 patients undergoing ICA and IVUS were examined. All sites exhibited atherosclerotic lesions by IVUS. These lesions consisted 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 an eccentric 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 mm 2 ). 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). Yamagishi, et al. J Am Coll Cardiol 2000; 35:106 11

Summary of Invasive Technologies for Vulnerable Plaque Imaging Moreno P, et al. Cardiol Clin 2010; 28:1-30

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

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

OCT-Characterization of Coronary Atherosclerosis 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

Angioscopy--Characterization of Coronary Atherosclerosis Ohtani T, et al. J Am Coll Cardiol 2006;47:2194 200

CT evaluation of Vulnerable Plaque Opolski MP, et al. Int J Cardiovasc Imaging April 21, 2011

11 th Cardiology Congress of Northern Greece Thessaloniki May 24-26,2012 The Theory of the Vulnerable Plaque: Impact on Diagnosis and Management of CAD Filippos Triposkiadis, MD, FESC, FACC Professor of Cardiology, Director, Department of Cardiology, Larissa University Hospital, Larissa, Greece

Manifestations of Coronary Artery Disease Sudden cardiac death is the initial CAD manifestation in 25% of pts. Sudden cardiac death accounts for 50% of all CAD related deaths. ACS is the initial CAD manifestation in 30% of patients. Only 18% of coronary attacks are preceded by longstanding angina pectoris. Stable angina is the initial CAD manifestation in 50% of patients. In approximately half of the cases the initial CAD manifestation may be detrimental. Approximately half of CAD patients die suddenly. Davies SW. Br Med Bull. 2001;59:17-27 Fox CS, et al. Circulation 2004; 110:522-7 Myerburg RJ, Junttila J. Circulation 2012; 125:1043-52

If human life were long enough to find the ultimate theory, everything would have been solved by previous generations. Nothing would be left to be discovered.