DISCLOSURES Steven E Nissen MD I have no

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DISCLOSURES Steven E. Nissen, MD I have no real or apparent conflicts of interest

DISCLOSURES Steven E. Nissen, MD I have no real or apparent conflicts of interest to report.

The Vulnerable Plaque “Hype”othesis

The Vulnerable Plaque “Hype”othesis

Plaque Rupture: Sudden Cardiac Death

Plaque Rupture: Sudden Cardiac Death

Vulnerable Plaque: Hype vs. Reality • A Pub. Med search for “vulnerable plaque” or

Vulnerable Plaque: Hype vs. Reality • A Pub. Med search for “vulnerable plaque” or “high-risk” plaque yields >2, 000 references over the past 20 years. • Many techniques to “detect” vulnerable plaques have come and gone with initially promising “findings” followed by a sobering reality check. – Thermography, spectroscopy, palpography, virtual histology, OCT, and many more. • A large number of startup companies with “breakthrough” approaches have come and gone, leaving investors with empty pockets, but no progress.

What Went Wrong? • The exact characteristics of “vulnerable” plaque remain uncertain. The evidence

What Went Wrong? • The exact characteristics of “vulnerable” plaque remain uncertain. The evidence for the importance of “thin cap fibroatheromas” is flimsy at best. • Vulnerability is diffuse and global, not local. • Even if we knew what to look for, we would have to scan every branch of every vessel, a virtual impossibility. • Evidence suggests that atheromatous lesions are everywhere and ruptured plaques ubiquitous. • Even if we could identify such lesions, current treatment modalities increase, not decrease adverse outcomes.

ACS: The Tip of the Atherothrombotic “Iceberg” Acute Plaque Rupture (UA/ NSTEMI/TIA/stroke) Clinical Subclinical

ACS: The Tip of the Atherothrombotic “Iceberg” Acute Plaque Rupture (UA/ NSTEMI/TIA/stroke) Clinical Subclinical Presence of Multiple Coronary Plaques Persistent Hyperreactive Platelets Bhatt DL. Journal of Invasive Cardiology. 2003; Vol. 15: Suppl B, 3 B-10 B. Vascular Inflammation

The “Vulnerable” Patient • The entire concept of “vulnerable plaque” is an overly simplistic

The “Vulnerable” Patient • The entire concept of “vulnerable plaque” is an overly simplistic characterization of an exceedingly complicated phenomenon. • In patients with acute plaque rupture, there is widespread inflammation, white blood cell activation, increased thrombogenicity, and oxidative stress. • These increase biomarkers demonstrate that systemic factors are more important than local anatomy in determining who will have a acute event.

Long-term Outcome in Stented ACS Patients Baseline CRP Predicts 5 Year Survival 1. 0

Long-term Outcome in Stented ACS Patients Baseline CRP Predicts 5 Year Survival 1. 0 Survival (months) CRP < 3 mg/l (n = 412) 0. 9 CRP 3 - 10 mg/l (n = 362) 0. 8 CRP > 10 mg/l (n = 268) p < 0. 0001 by log rank [OR adj. = 4. 1] 0. 7 0 10 20 30 Survival (months) Mueller et al. , Circ 105: 1412– 15, 2002 40 50 60

Multiple Ruptured Plaques in ACS Patients (%) 80% of Patients with 1 plaque Number

Multiple Ruptured Plaques in ACS Patients (%) 80% of Patients with 1 plaque Number of ruptured plaques in addition to culprit lesion Rioufol G et al. Circulation. 2002; 106: 804 -808.

CRP and Multiple Plaques in ACS Patients with Multiple Plaques ≥ 2 (p <

CRP and Multiple Plaques in ACS Patients with Multiple Plaques ≥ 2 (p < 0. 001) Percent of Patients M. N. Zairis et al. Atherosclerosis. 2002; 164. 355 -359. CRP Tertile (mg/L)

CD 40 L in ACS: 6 Month Risk of Death/MI Variable HR (95% CI)

CD 40 L in ACS: 6 Month Risk of Death/MI Variable HR (95% CI) p Age > 65 yr 1. 36 (0. 91 -1. 82) 0. 34 Diabetes mellitus 1. 22 (0. 83 -1. 49) 0. 61 ST-segment 1. 04 (0. 76 -1. 54) 0. 74 Troponin T >0. 1 µg/l 2. 94 (1. 75 -7. 26) <0. 001 C-reactive protein >10. 0 mg/l 2. 03 (1. 11 -3. 59) 0. 02 Soluble CD 40 ligand >5. 0 µg/l 2. 71 (1. 51 -5. 35) 0. 001 Heeschen, et al, NEJM, 348: 1104 -11, 2003

AMI Trial: IVUS in Segment Proximal to Stent

AMI Trial: IVUS in Segment Proximal to Stent

Prevalence: Ulceration Proximal to Culprit Lesion 20% 19% MI All Angina Unstable Angina Stable

Prevalence: Ulceration Proximal to Culprit Lesion 20% 19% MI All Angina Unstable Angina Stable Angina 15% 10% 7% p=0. 014 5% 4% 0% 0% MI All Angina Unstable Angina Stable Angina

Prognostic Value of MPO in Chest Pain Adverse Cardiac Events in Troponin Negative Patients

Prognostic Value of MPO in Chest Pain Adverse Cardiac Events in Troponin Negative Patients 6 months (n=462) 30 days (n=462) 1. 00 Unadjusted Adjusted 0. 75 Sensitivity Q 2 Myeloperoxidase Q 3 0. 50 CRP 0. 25 Q 4 0 Troponin T CK-MB 2 4 6 8 10 0. 00 0. 25 Odds Ratio Brennan et al. , NEJM 349: 1595 -604, 2003 0. 50 0. 75 1 -Specificity 1. 00

Plaque “Sealing” aka Prophylactic Stenting Intervention has many acute and late risks that exceed

Plaque “Sealing” aka Prophylactic Stenting Intervention has many acute and late risks that exceed any projected benefit from treating asymptomatic lesions.

Syntax: Repeat Revascularization Unacceptably high recurrence rates in the first year

Syntax: Repeat Revascularization Unacceptably high recurrence rates in the first year

Restenosis is Not An Entirely Benign Entity STEMI (2. 2%) NSTEMI (7. 3%) Exertional

Restenosis is Not An Entirely Benign Entity STEMI (2. 2%) NSTEMI (7. 3%) Exertional angina (64. 1%) UA requiring hospitalization (26. 4%) M. Chen and colleagues, AHJ 151: 1260, 2006

Summary • Atherosclerosis is a systemic disease with widespread inflammation and multiple ruptured plaques,

Summary • Atherosclerosis is a systemic disease with widespread inflammation and multiple ruptured plaques, not one or two. • Platelets, white cells and other systemic factors play an critical role in determining “patient vulnerability. ” • No imaging technique has shown the ability to reliably predict behavior of individual plaques. • Imaging to guide local treatment would require interrogation of all three major epicardial vessels, a practical impossibility. • No studies have demonstrated improved outcomes following stenting of “vulnerable plaques. ”