Identification of Biomarkers for Diagnosis

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Identification of Biomarkers for Diagnosis
Prognosis of Cardiovascular Diseases
Jaw-Wen Chen, MD Institute of Pharmacology and
Cardiovascular Research Center, National
Yang-Ming University School of Medicine, and
Division of Cardiology, Department of Medicine,
Taipei Veterans General Hospital Taipei, Taiwan,
R.O.C.
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Initial Presentation of CAD May Be MI or Sudden
Death Framingham Heart Study
ACS
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Pathogenesis of Atherothrombosis
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Traditional risk modification
Risk factors for systemic atherosclerosis
No S/S
Primary prevention
Minimal S/S
Angina, VBI
Secondary prevention
Thrombosis/tissue damage Morbidity/mortality
Thrombolysis and organ protection
AMI, Stroke
JW Chen 2004
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First in vivo Sign of Atherogenesis
Courtesy of K Robinson, MD, Emory University
Hospital, Atlanta, Georgia, USA.
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TNF-? and NF-?B Activation in Endothelial Cells
O2-
NFkB AP-1
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Expression of TNF? in Human Atherosclerosis
Normal human arteries (Immunohistochemistry
study)
TNF-?
Atherosclerotic human arteries
TNF-?
Chen JW 2003
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ICAM-1
PECAM
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Expression of Adhesion Molecules in Human
Atherosclerosis
Normal human arteries (Immunohistochemistry
study)
ICAM-1
VCAM-1
E-selectin
Atherosclerotic human arteries
ICAM-1
VCAM-1
E-selectin
JW Chen 2002
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Plasma Soluble Adhesion Molecule Level is
Increased in CAD Patients
sVCAM-1 sICAM-1
ng/ml
ng/ml



Lin CP Chen JW. 2003
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Endothelial Cell Markers and the Risk of Coronary
Heart Disease The Prospective Epidemiological
Study of Myocardial Infarction (PRIME) Study
Subjects nearly 10 000 healthy men in France
and Northern Ireland (the PRIME Study) Study
design prospective follow-up for 5 years Aims
of this study the association between these
endothelial-cell markers- Tissue factor pathway
inhibitor (TFPI), von Willebrand factor (vWF),
and thrombomodulin (TM) and the incidence of
fatal or nonfatal myocardial infarction (hard
CHD) and stable or unstable angina (angina
pectoris)
Circulation. 20041091343-1348
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Relative Risks of Hard CHD During Follow-Up
According to Plasma Levels of Endothelial Cell
Markers The PRIME Study
OR (95 CI) P VWF     1st quartile 1     2nd
quartile 1.16 (0.592.28) 0.65     3rd
quartile 0.99 (0.482.00) 0.96     4th
quartile 3.34 (1.597.00) 0.001 f-TFPI     gt10th
P 1     lt10th P 2.384 (1.595.13) 0.03 sTM  
   1st quartile 1     2nd quartile 1.43
(0.742.76) 0.29     3rd quartile 1.53
(0.783.03) 0.22     4th quartile 0.92
(0.461.86) 0.82
Variables included in the models BMI, total
cholesterol, HDL cholesterol, systolic blood
pressure, smoking, alcohol, diabetes, fibrinogen,
CRP, TNF- , IL-6, vWF, f-TFPI, and sTM. Relative
risks (95 CIs) are derived from conditional
logistic regression.
Circulation. 20041091343-1348
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Plasma Homocysteine Level
Mg/dl


JW Chen 2002
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C-Reactive Protein can directly induce
atherosclerosis
CRP may require dissociation from a pentameric to
a monomeric form in order to exert
proatherosclerotic effects.
Circulation. 20041091914-1917
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Inflammatory Markers Cytokines and C-Freactive
Protein (CRP)
CRP ? Total Inflammatory Burden
Rader DJ. N Engl J Med. 20003431179-1182.
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Plasma hs-CRP Level
JW Chen 2002
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Risk Factors for Future Cardiovascular Events in
Healthy Women
Lipoprotein(a) Homocysteine IL-6 TC LDL-C sIC
AM-1 SAA Apo B TCHDL-C hs-CRP hs-CRP
TCHDL-C
0
1.0
2.0
4.0
6.0
Relative Risk of Future Cardiovascular Events
Ridker PM et al. N Engl J Med 2000342836-843.
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Serum hs-CRP Level TC/HDL Ratio Are Independent
Predictors for Future CV events In 75 stable CAD
Patients with Medical Treatment
CV Event Death, MI, repeated PCI or CABG,
admission for refractory angina, stroke
HB Leu JW Chen 2004 Chest
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Matrix Metabolism and Rupture of the Plaques
Fibrous Cap
Weakening Breakdown
X
Matrix synthesis
Collagen-degrading Proteinases (MMPS)
Fibrouscap

IFN-?
CD-40L

IL-1TNF-?MCP-1M-CSF



Lipid core

MN Cells

Tissue Factor, Procoagulant
Macrophage
Libby P. Circulation 1995912844-2850.
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MMPs in plague progression and rupture
Circ Res. 200290251-262
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Increased plasma MMPs level in CAD patients
(n150)
MMP-2
MMP-3
MMP-9
TC Wu JW Chen 2004
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High Baseline Plasma MMP3 Level is Associated
With Low Event Free Survival Rate In 147 CAD
Patients
TC Wu JW Chen 2005
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Baseline serum matrix metalloproteinase-9 level
predicts long-term prognosis after coronary
revascularizations in stable coronary artery
disease
ZX Ye JW Chen 2008
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Vascular hemostatic factors in humans
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Relative risk of subsequent CAD in angina
patients European Concerted Action on Thrombosis
and Disabilities (ECAT) study
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Biomarkers in Acute Cardiovascular Disease
MPO, myeloperoxidase sSSCD40L, soluble SSCD40
ligand PAPP-A, pregnancy-associated plasma
protein A
Journal of Cardiovascular Nursing Vol. 23, No. 2,
pp 124-131
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Oxidative Stress vs. Atherogenesis
TNF-?, Glucose, HCY, LPS, oxLDL (Risk Factors for
Atherosclerosis)
LDL
?
ROS
Antioxidants
Normal
High
Low
Redox-Sensitive Signaling Pathways
Transcriptional Factors (MAPKs, NF-?B, AP-1,
etc.)
Atherogenic Genes
Atheroprotective Genes
Normal
Inflammation Endothelial Dysfunction Leukocyte
Recruitment VSMC Proliferation
Anti-inflammatory Vascular Protection
HY Tsai and JW Chen 2008
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Direct vascular protection effects of HO-1
HO-1 Heme Oxygenase-1
HY Tsai and JW Chen 2008
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HO-1 gene
Serum Bilirubin and Ferritin Levels Link Between
Heme Oxygenase-1 Gene Promoter Polymorphism and
Susceptibility to Coronary Artery Disease in
Diabetic Patients Ying-Hwa Chen, MD, PhD1,4
Lee-Young Chau, PhD2 Jaw-Wen Chen, MD 3,4 Min-Ji
Charng, MD, PhD 4 Tao-Cheng Wu, MD 4 Lung-Ching
Chen, MD 5 and Shing-Jong Lin, MD, PhD
1,2,4 Diabetes Care 2008 on line
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Issues in Evaluation of New Biomarkers

• Is there adequate information/testing on specimen
  collection of the biomarker? What laboratory tube
  is needed and what amount and under what
  conditions should the biomarker be preserved?
• Are results readily available for clinical
  decision making?
• What is the laboratory cost of the biomarker?
• What is the sensitivity and specificity of the
  biomarker?
• Are there established reference values, and has
  the biomarker been tested in both genders, all
  age groups, and in multiple ethnic groups?
• What has the biomarker been compared with, or
  what was used as a gold standard comparison
  and is the comparison appropriate?
• When new biomarkers are compared with previously
  collected samples, were all samples properly
  preserved?

Journal of Cardiovascular Nursing Vol. 23, No. 2,
pp 124-131
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Thank you
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