Diabetes Mellitus Mediated Vulnerable Plaque

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Diabetes Mellitus Mediated Vulnerable Plaque

• Saturday, November 12
• Diabetes Summit 2005
• Steven P. Marso MD
• Associate Professor of Medicine
• Clinical Scholar
• Mid America Heart Institute
• Kansas City MO

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Presenter Disclosure Information
Name Steven P. Marso, MD Within the past 12
months, the presenter or their spouse/partner
have had a financial interest/arrangement or
affiliation with the organization(s) listed
below. Company Name Relationship Guidant R
esearch Grant Volcano Research Grant
Consultant ADA Research Grant
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Overview
Diabetesmellitus
NonfatalMI
Vulnerable Plaque
VP11-34
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Worldwide Mortality
WHO Estimates
Roglic et al. Diabetes Care 2005282130-2135
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Leading Causes of Death in the U.S. 1970-2002
CDC Estimates
Rates per 100,000 age-adjusted to the 2000 US
standard population The difference between the
2002 and 1970 rate expressed as percentage of the
1970 rate
Jemal et al. JAMA 2005294L1255-1259
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Trends in CHD Events
CV Event MI, CHD Death and Stroke
Age and Sex Adjusted
DM N430
No DM N7751
?49
?35
Fox et al. JAMA 20042922495-2499
ACS9-4
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Euro Heart Survey on Diabetes110 Centers in 25
ESC Member Countries
N 4,196
Bartnik et al. Karolinska Institutet, Stockholm
2005 (ISBN91-7140-401-5)
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NRMI Registry Diabetes Prevalence
Trend plt0.001
N410,223 20.8 Increase
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TARGET-ACS
Composite Rate of Death, MI or Any TVR in
Patients with ACS
Wald?2 21.8 11.3 6.9 5.4 4.9 3.7 3.3
Odds Ratio(95 CI) 1.55 (1.29-1.86) 1.90
(1.31-2.75) 1.36 (1.08-1.70) 1.27
(1.04-1.55) 0.71 (0.52-0.96) 1.30
(0.99-1.69) 1.18 (0.99-1.41)
Variable LAD intervention Prior angina Previous
Bypass Surgery Diabetes Preprocedure
clopidogrel Hx of heart failure Radomization to
tirofiban
P-value lt0.001 0.001 0.009 0.020 0.027 0.055 0.068
Stone et al. Circ 20021052347-54
ACS6-12
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DM-ACS High Risk

• Death
• Re-MI
• Re-Unstable Angina

Relative Risk 4.9
ACS9-5
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ACC/AHA Guidelines Recommendations for Management
of NSTE ACS American College of
Cardiology/American Heart Association

• Purpose To ensure that evidence-based diagnostic
  tests, procedures, therapies, and management
  strategies are consistently employed.
• Reasoning To help reduce the unacceptably high
  incidence of adverse ischemic events among
  patients presenting with non-ST-segment elevation
  acute coronary syndromes (NSTE ACS).

ACS4-5
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ACC/AHA ACS Guidelines

• Diabetes Mellitus
• Class I
• Diabetes is an independent risk factor in pts
  with UA/NSTEMI. (Level of Evidence A)
• Medical treatment in the acute phase and
  decisions on whether to perform stress testing
  and angiography revascularization should be
  similar in diabetic and nondiabetic patients.(C)
• Attention should be directed toward tight glucose
  control (B)
• For pts with multi-vessel disease, CABG with use
  of the internal mammary arteries is preferred
  over PCI in pts being treated for DM (B)

ACS5-19
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ACC/AHA ACS Guidelines
BUT

• Diabetes is not included in the all-important
  Table 6!

ACS5-21
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ACC/AHA GuidelinesShort-Term Risk of Death or
Nonfatal MI
ACS5-22
ACC/AHA PRACTICE GUIDELINES
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INFORM Registry
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High Risk Features of 2-Year death (Univariate)
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DM-TnI Survival
95
92
91
77
No DM / TnI - No DM / TnI DM / TnI - DM / TnI
310 437 209 243
308 426 204 235
307 421 202 231
301 415 199 217
286 391 189 187
303 418 200 222
299 411 199 204
296 408 196 201
295 404 199 199
ACS5-25
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INFORM Mortality by Diabetes Status and Troponin
P0.02
ACS5-27
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Multivariable Predictorsof Mortality at 2 Years
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Process-of-Care Characteristics
Diabetes
No Diabetes
Tn-I()(n137) 80 8 61 36 59 4 75 90 85 14 76
Tn-I(-) (n209) 60 22 14 60 36 4 65 92 74 2
6 76
Tn-I()(n222) 87 6 64 31 44 2 70 96 84 14 78
Tn-I(-)(n310) 72 15 20 54 65 4 57 93 72 2
2 76
p-value lt0.001 lt0.001 lt0.0001 lt0.001 lt0.001
0.082 lt0.001 0.004 0.878
In-hospital angiography () In-hospital stress
test () In-hospital GP IIb/IIIa administration
() In-hospital treatment strategy () Medical
management PCI CABG Discharge medication
() ACE inhibitor Aspirin Beta blocker
Calcium channel blocker Lipid-lowering
4-way comparison between groups DM-Tn-I() vs
DM-Tn-I(-) and no DM-Tn-I() vs no
DM-Tn-I(-) Plt0.01 within groups Tn-I() vs
Tn-I(-) Plt0.05 within groups Tn-I() vs
Tn-I(-)
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In-Hospital Mortality Trends Over Time for
Depicted Study Groups
AMI
Elective
Patients
Patients
Marso S, et al. Am Heart J. 2003145270-7
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Gersh et al. JAMA 2005293979-986
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Baseline Characteristics EMERALD Diabetic
Sub-study
ACS5-47
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EMERALD
Primary Endpoint ST-Segment Resolution After 30
Minutes
P0.73
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EMERALD Diabetic SubstudyTime from Symptom
Onset to Balloon Inflation
P0.57
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Markers of Reperfusion EMERALD Diabetic
Sub-study
Glucose1-33
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Clinical Endpoints EMERALD Diabetic Sub-study
ACS5-50
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Glucose Mediates Reperfusion
Angiographic No-Reflow
N1253
Glucose Levels
Diabetes Mellitus
P lt.001
Incidence ()
Incidence ()
Ishihara et al. Am Heart J 2005150814-820
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MI Burden
EmergingImagingTechnologies
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Case History

• Ms. PP, a 45 year old woman presented to the
  Emergency Department 3/30/2003 with chest
  discomfort and typical anginal features
• Pain was similar to previous myocardial
  infarction (2000)
• Troponin, CK and CK-MB all normal

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Case History

• May 2003
• PMH of CAD (MI 2000), HTN, DM, Dyslipidemia,
  Tobacco Abuse
• Daily medications
• Lisinopril 10 mg, Plavix 75 mg, aspirin 325 mg,
  Fenofibrate 160 mg, Lipitor 80 mg, Norvasc 5 mg
  and Lopressor XL 100 mg
• Cardiac Catheterization performed

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Left System Culprit LAD Stenosis
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Non-Culprit RCA Disease ? Vulnerable Plaque

• Moderate Disease
• No Sxs
• Decided
• No PCI
• Med Tx

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Recurrent ACS 3 Months later

• On 7/14/2003 she awoke with severe substernal
  chest pain and called 911
• On arrival to the Emergency Department, ST
  Segment elevation in leads II, III, AVF, V4-V6
  with anteroseptal ST Segment depression
• Emergent Cardiac Catheterization performed

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RCA Plaque Rupture
Primary PCI for STEMI
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Recurrent ACS 11 months later

• During the STEMI hospitalization, repeat coronary
  angiography performed due to severe chest pain
  revealed no acute occlusion
• On 4/11/2004 was again admitted with unstable
  angina
• Cardiac catheterization was performed to evaluate
  for restenosis

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Left Circumflex Plaque Rupture
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POSTMORTEM
VP11-31
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Thin Cap Fibroatheroma VP
A FibroticPlaque, Presumably not Vulnerable
Courtesy Dr. Paris Constantinides
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Factors Contributing to Plaque Vulnerability
Low smooth muscle cell count
Large lipid core
Thincap
DANGER
High macrophage content
Davies et al. Circulation 1996942013-2020.
VP4-17
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Intravascular Ultrasound (IVUS)

• Intravascular catheter allows real-time
  tomographic imaging of coronary artery.
• Axial resolution 100 to 200 µm
• Lateral resolution 250 µm (30 Mhz)
• Real-time data - no need for proximal occlusion.
• Allows precise measurement of lumen area, plaque
  size, and plaque distribution.
• Provides valuable information on remodeling state
  of artery and (to some extent) the content of
  plaque.

VP6-27
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Atheroma Morphology on IVUS
Mixed
Heavily
Soft Atheroma
Fibrous and
Calcified
Calcified
Atheroma
Atheroma
Nissen SE, Yock P. Circulation. 2001 Jan
30103(4)604-616.
VP6-29
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Diabetic Plaque Phenotyping Project
Current Platform
Evolving Platform
Angiography
IVUS
Virtual Histology
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Virtual Histology IVUS
Only the envelope amplitude (echo intensity) is
used in formation of the gray-scale IVUS image
Amplitude AND Frequency are used to generate 8
parameters to create the look-up table
VP4-10
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Ex-Vivo Validation Virtual Histology IVUS
a
b
c
Fibrous Fibro-lipidic Lipid Core Calcium
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In Vivo Resolution Limits of VH

• Longitudinal resolution
• 240 µm ability to accurately discriminate
  different tissues types along the axis of the
  vessel wall
• Axial resolution
• 100-150 µm ability to identify different
  structures from lumen towards adventitia
• If the thickness of fibrotic cap is lt100 µm, no
  fibrotic cap will be displayed

VP4-1
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Generally Stable Plaque Types
Fibrous
Plaque comprised of nearly all fibrous tissue.

Courtesy of Renu Virmani
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Generally Stable Plaque Types
Fibro-Calcific Mainly fibrous plaques, with some
Dense Calcium. Presence of Necrotic Core between
3-10 of plaque volume.
Courtesy of Renu Virmani
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Generally Stable Plaque Types
Pathological Intimal Thickening
Plaque comprising mainly Fibro-Fatty and Fibrous
tissue, with Necrotic Core comprising from 0-3
(to account for specks of Necrotic Core which
occasionally appear on VH, due largely to
micro-calcifications within the Fibro-Fatty
tissue). Indicative of disease and possible
future progression to risky atheroma.
Courtesy of Renu Virmani
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The FibroAtheroma
Fibrous and/or Fibro-Fatty plaques with
significant Necrotic Core (gt10 of total plaque
volume). Goal of using VH to increase the value
of IVUS will very likely be in differentiating
the Fibro-Atheroma from the other three plaque
types.


VP4-3
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Thin-Cap FibroAtheroma (TCFA)
Thin Cap Fibro-Atheroma (TCFA) or Vulnerable
Plaque -- Necrotic Core gt10 of total plaque
volume and located at or near the lumen.

Further sub-classification based on presence of
luminal narrowing may yield further prognostic
value in assessing TCFA risk.
TCFA with significant narrowing (significant
narrowing defined as 50 reduction in Cross
Sectional Area on IVUS or DS25 on angiogram) -
Dr. Virmanis data suggests that TICFA with
significant narrowing represents the highest risk
of all plaques.
TCFA without significant narrowing (lt50 area
reduction on IVUS or lt25 DS on angiogram - Dr.
Virmanis data suggests that TICFA without
significant narrowing is at a considerably lower
risk.
VP4-5
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ANGIO
Non-Culprit Plaque
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Non-culprit
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Culprit
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ANGIO
Non-Culprit Plaque
Culprit Plaque
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ANGIO
3.0 mm x 24 mm PES
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Diabetes and Plaque Phenotype
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Patient DemographicsAll Plaque Burden Patients
N  118
Age Gender Male Female ACS Hypertension
Diabetes CHF Family Hx CAD Current Smoker
62.8 11.4 74 (65.5) 39 (34.5) 49 (41.5) 81
(71.7) 28 (24.8) 7 (6.2) 66 (58.4) 32 (28.6)
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Any Plaque Analysis
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Plaque PhenotypeAny Plaque Latent Modeling
Phenotype 1
Phenotype 2
Phenotype 3
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Diabetic Plaque Phenotype
P0.077
Phenotype 1
Phenotype 2
Phenotype 3
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Elderly Plaque Phenotype
P0.012
Phenotype 1
Phenotype 2
Phenotype 3
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Inflammatory Plaque Phenotype
P0.07
Phenotype 1
Phenotype 2
Phenotype 3
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P0.018
Phenotype 1
Phenotype 2
Phenotype 3
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Patient DemographicsAll 50 Plaque Burden
Patients
N  111
Age Gender Male Female ACS Hypertension
Diabetes CHF Family Hx CAD Current Smoker
63.74 11.27 76 (71.70) 30 (28.30) 46
(41.44) 81 (76.42) 30 (28.30) 6 (5.66) 62
(58.49) 29 (27.62)
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Plaque Burden gt50

• Mean Plaque Burden 58.33 4.81

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Summary

• Diabetes-ACS
• High risk
• Tn-I negative group
• DM-STEMI
• Impaired myocardial reperfusion
• Glucose mediated
• Plaque Phenotype
• Infancy
• ?unique morphology or composition
• ?cluster of vulnerable plaque elements

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Diabetes Vascular Disease Research Team
John House, MS Senior Biostatistician/ Project
Manager
Lindsey Daniels, BS Clinical Research Associate
Jill Blake-Music, RN Clinical Research Nurse
Jaime Barbarena, MD Interventional Cardiology
Fellow