Transcript Slide 1

www.drsarma.in
Prof. Dr. Sarma VSN Rachakonda
M.D (Medicine)., M.Sc., (Canada), FCGP,
FICP, FIMSA, FRCP (G), FCCP (USA), FACP (USA)
Hon. National Professor of Medicine, IMA – CGP, India
Senior Consultant Physician & Cardio-metabolic Specialist
Adjunct Professor, Tamilnadu Dr. MGR Medical University, Chennai
Framingham Heart Study—26-Year Follow-up
No CHD
35% of CHD occurs in
people with TC < 200
mg/dL
CHD
150
Castelli WP. Atherosclerosis. 1996;124(suppl):S1-S9.
1996 Reprinted with permission from Elsevier Science.
200
250
Total Cholesterol (mg/dL)
300
• In Indian context more true
• 30% of CAD – No RF
• 60% have only one RF
• This is common in young
• Newer CMRs not evaluated
• CAD is multifactorial
• No single cause
• Early detection - meaningful
Khot et al. JAMA 2003
CVD Risk Factors
Endothelial Dysfunction
Intervene here
Atherosclerosis
CAD Onset
Myocardial Ischemia
Coronary Thrombosis
ACS - Myocardial Infarction
Arrhythmia & Muscle Loss
Remodeling
Ventricular Dilation
Congestive Heart Failure
End stage Heart Disease
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5
Normal
Apoptosis
Vasodilation
NO, PGI2, EDHF,
BK, C-NP
Thrombolysis
Vasoconstrictio
nROS, ET-1, TxA2,
A-II, PGH2
Thrombosis
tPA, Protein C, TF-I,
vWF
PAI-1, TF-α, Tx-A2
Platelet
Disaggregation
Adhesion Molecules
CAMs, P,E Selectins
NO, PGI2
Antiproliferation
Growth Factors
NO, PGI2, TGF-, Hep
ET-1, A-II, PDGF, ILGF, ILs
Lipolysis
Inflammation
LPL
ROS, NF-B
LDL readily enter the artery wall where they may be modified
Vessel Lumen
LDL
Nitric Oxide (NO)
Policing the Endothelium
Endothelium
Oxidation of Lipids
and ApoB
LDL
Aggregation
Hydrolysis of Phosphatidylcholine
to Lysophosphatidylcholine
Other Chemical Modifications
Modified LDL or OX-LDL
Modified LDL is Proinflammatory
Steinberg D et al. N Engl J Med 1989;320:915-924.
Intima
Vessel Lumen
Monocyte
LDL
MCP-1
Monocyte Chemotactic
Protein 1 – MCP 1
Endothelium
LDL
OX-LDL
Intima
Navab M et al. J Clin Invest 1991;88:2039-2046.
Vessel Lumen
Monocyte
LDL
MCP-1
Endothelium
LDL
Intima
OX-LDL
Monocyte Chemotactic
Protein 1 – MCP 1
Macrophage
Steinberg D et al. N Engl J Med 1989;320:915-924.
Modified LDL Promote
Differentiation of
Monocytes into
Macrophages
Vessel Lumen
Monocyte
LDL
Adhesion
Molecules
MCP-1
Cytokines
Endothelium
LDL
OX-LDL
Macrophage
Nathan CF. J Clin Invest 1987;79:319-326.
Intima
Monocyte
Rolling
Sticking
Vessel Lumen
Transmigration
E-Selectin
VCAM-1
ICAM-1
Endothelium
MCP-1
Intima
Charo IF. Curr Opin Lipidol 1992;3:335-343.
Vessel Lumen
Monocyte
LDL
Adhesion
Molecules
MCP-1
Endothelium
LDL
Modified LDL
Taken up by
Macrophage
Foam Cell
Macrophage
Steinberg D et al. N Engl J Med 1989;320:915-924.
Intima
Vessel Lumen
Monocyte
LDL
Adhesion
Molecules
Cytokines
Macrophage
Ross R. N Engl J Med 1999;340:115-126.
MCP-1
Modified
LDL
Foam Cell
Endothelium
LDL
Intima
Growth Factors
Metalloproteinases
Cell Proliferation
Matrix Degradation
Vessel Lumen
Monocyte
Remnant Lipoproteins
Adhesion
Molecules
Cytokines
Macrophage
Doi H et al. Circulation 2000;102:670-676.
Endothelium
MCP-1
Remnants
Modified
Remnants
Foam Cell
Intima
Growth Factors
Metalloproteinases
Cell Proliferation
Matrix Degradation
Established and Conventional CV Risk Factors
Non Modifiable
Modifiable
Age
DM, IR
Gender
Dyslipidaemia
Ethnicity
Hypertension
F H/o pre CAD
Smoking
Phenotype B
MS, Obesity
Type A Person
Physical Inactivity
When We see these, we must, sure evaluate CV Risk
 NAFLD – Non Alcoholic Fatty Liver Disease
 OSAS – Obstructive Sleep Apnea Syndrome
 PCOS – Poly Cystic Ovarian Syndrome
 GDM – Gestational Diabetes Mellitus
 PIH – Pregnancy Induced Hypertension
 PAD – Peripheral Arterial Disease
 Similarly – CKD, CVD, Retinopathy
Advanced and not Commonly Tested
 CIMT – Carotid Intima Media Thickness
 PWV – Pulse Wave Velocity
 FMD – Brachial Flow Mediated Dilatation
 ABPM – Dippers & Non Dippers
 IVUS – Intravascular Ultrasound
 Myocardial Perfusion Studies
The Newer Markers – The experimental Ones
 C Peptide – As a measure of CV Risk
 Uric Acid – Surrogate for Inflammation
 Fibrinogen – Surrogate for Coagulability
 PAI 1 – Plasminogen Activator Inhibitor 1
 Inflam. markers –VCAM, ICAM. SAA, IL-6, MMP
 Sub fractions of LDL and HDL
Novel Risk Makers (? Only Markers)
 hs-CRP
 Lp(a)
 sLDL and high TG molecules
 Endothelial Dysfunction
 Apo B/Apo A1 Ratio, Apo CIII
 Homocysteine
Very Simple, we need to apply in practice
 WC – Waist Circumference – Are we using?
 MAU – Micro Albuminuria – ACR
 ABI – Ankle Brachial Index, IC, Pedal pulse
 LVH – By Echocardiography, ECG
 ED – Erectile Dysfunction; ED = ED
 PP – Pulse Pressure – Importance of ISH
Probability of Event-free Survival
Median LDL 124 mg/dl 1.00
Median CRP 1.5mg/l
Low CRP-low LDL
0.99
Low CRP-high LDL
0.98
High CRP-low LDL
0.97
0.96
0.00
High CRP-high LDL
0
2
4
6
Years of Follow-up
Ridker et al, N Engl J Med. 2002;347:1157-1165.
8
1.00
0.99
0.98
0.97
CRP < 3, Yes Metabolic Syndrome
0.96
CRP > 3, No Metabolic Syndrome
CRP > 3, Yes Metabolic Syndrome
0.95
CVD Event-Free Survival
Probability
CRP < 3, No Metabolic Syndrome
0
2
4
6
Years of Follow-Up
Ridker et al, Circulation 2003;107:391-7
8
Lipoprotein(a)
Homocysteine
IL-6
TC
LDLC
sICAM-1
SAA
Apo B
TC: HDLC
hs-CRP
hs-CRP + TC: HDLC
0
1.0
2.0
4.0
6.0
Relative Risk of Future Cardiovascular Events
Ridker et al, N Engl J Med. 2000;342:836-43
Circulation. 2003;107:391-397.
AHA / CDC Scientific Statement
Markers of Inflammation and Cardiovascular Disease:
Applications to Clinical and Public Health Practice
Circulation January 28, 2003
“Measurement of hs-CRP is an independent marker of risk
and may be used at the discretion of the physician as part
of global coronary risk assessment in adults without known
cardiovascular disease. Weight of evidence favors use
particularly among those judged at intermediate risk by
global risk assessment”.
1 mg/L
Low
Risk
3 mg/L
Moderate
Risk
Ridker PM. Circulation 2003;107:363-9
10 mg/L
High
Risk
>100 mg/L
Acute Phase Response
Ignore Value, Repeat Test in 3 weeks
Relative Risk
5.0
4.0
3.0
2.0
1.0
0.0
High
Medium
High
Medium
Low
Total Cholesterol:HDL Ratio
Ridker et al, Circulation. 1998;97:2007–2011.
Low
Percent with CRP 0.22 mg/dL
25
20
15
10
5
0
Normal
Visser M et al. JAMA 1999;282:2131-2135.
Overweight
Obese
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• Similar to LDL molecule
• Apo B + additional Apo ‘a’ attached by S=S bond
• Primary determinant is genetic
• Normal value 20 mg %, > 30 high risk
• It competes with plasminogen because of its
structural similarity and so interferes with plasmin
synthesis and thrombolytic pathway
• Nicotinic acid, Estrogens ↓it
•
•
•
•
•
•
•
•
Low HDL + High LDL
+
LP(a) excess > 30 mg%
+
LP(a) excess > 30 mg% + LDL high ++
LP(a) excess > 30 mg% + low HDL +++
LP(a) excess > 30 mg% + Incr. tHCy ++++
LP(a) excess + Incr. tHCy + low HDL +++++
Circulating lipids are one aspects
Tissue lipid content is more important
J. Atherosclerosis : Hopkins PN, 1997 – 17, 2792
Measurements
VLDL
VLDLR
IDL
TG-rich lipoproteins
Apolipoprotein B
Non-HDL-C
LDL
SDL
Cholesterol lipoproteins
• Low cholesterol content of LDL particles
–  particle number for given LDL-C level
• Associated with  levels of TG and LDL-C, and
 levels of HDL2
• Marker for common genetic trait associated with
 risk of coronary disease (LDL subclass pattern B)
• Possible mechanisms of  atherogenicity
– Greater arterial uptake
–  uptake by macrophages
–  oxidation susceptibility
Feingold KR et al. Arterioscler Thromb. 1992;12:1496-1502.
Lamarche B et al. Circulation. 1997;95:69-75.
Hypertension
Diabetes
Smoking
LDL
Homocysteine
Estrogen
deficiency
 O2
Endothelial Cells and
 H2O2 Vascular Smooth Muscle
Endothelial Dysfunction
Apoptosis
Leukocyte
adhesion
Lipid
deposition
Vasoconstriction
VSMC
growth
Thrombosis
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Apo B / Apo A1 Ratio
No evidence of threshold
• Normal value is up to 10 μ mols/L
• Folic acid, Vitamin B6 and B12 are essential for
the normal transulfuration and remethylation
cycles
• Excess of homocystine generates oxidative
stress on the cell membranes. DNA and
protein denaturation through ROS formation
• Folic acid 5 mg/ day + Vit. B6 and B12 are to be
given on regular basis
Blood Homocyst(e)ine Levels
Classification
Values in mmol/L
Normal
Moderate
Intermediate
Severe
05 – 10
11 – 30
31 – 100
> 100
Resting and post exercise SBP in ankle & arm
• Normal ABI is 1 to 0.90
• ABI < 0.9 has 95% specificity for angiographic
early PVD
• ABI of 0.6- 0.84 correlates with claudication
• ABI < 0.6 advanced ischemic limb
• Always check pedal pulses
• Question for intermittent claudication
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ABI < 0.9
Sensitivity
Specificity
CHD
16.5 (12.8–20.2)
92.7 (92.1–93.3)
Stroke
16.0 (12.9–19.1)
92.2 (91.9–92.5)
All-cause
mortality
31.2 (27.8–34.6)
88.9 (88.2–89.6)
CV mortality
41.0 (33.8–48.2)
87.9 (87.2–88.6)
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•
•
•
•
•
•
•
•
MAU: 30-300mg albumin in urine over 24 hrs
Occurs in DM and HT
Detected by new dipstick tests for MAU
Most accurate assessment is 24hr collection
Screening by ACR on spot urine (first morning)
MAU is a marker of early stage renal damage
Regression of MAU decreases risk
A marker of generalized CVD risk
10.02
10
8
6.52
6
CHD Odds
Ratio
4
3.20
2.32
2
0
Microalbuminuria
Smoking
Hypertension
Cholesterol
Eastman RC, Keen H. Lancet 1997;350 Suppl 1:29-32.
Normal < 10 mm
This case 26 mm
The Framingham Heart Study
Risk Ratio
3.0
CHD
3.7
3.2
Cupples LA, D’Agostino RB. NIH Publication No 87-2703, Feb 1987.
Stroke
5.3
Parameter
Venous
Arterial
Fibrinogen
–
+++
Factor VII
–
+
vWF: ag
–
++
tPA: ag
–
+++
PAI-1: ag
–
++
Platelet function
–
++
Lp(a)
–
+
hs-CRP / SAA / IL-6 / TNF
–
+++
Parameter
Venous
Arterial
Factor V Leiden
+++
–
Prothrombin mutation
Prothrombin
Factor VIII
Anti-thrombin III
++
+
++
++
–
–
–
–
Protein C
Protein S
+
+
–
–
Homocysteine
++
++
D-dimer
++
++
Atherosclerotic Plaque Formation
LDL, sLDL, oxLDL, Remnants
CRP, IL-6, IL-10, IL-18, TNF-α
Inflammation of Atherosclerotic Plaque
CRP, MPO, MMP
Soluble CD40 ligand(sCD40L)
Vulnerable Plaque Imminent for Rupture
MPO, MMP, PAPP-A
PGF, ICAM, VCAM
Suspected Platelet Activation, Thrombosis
Increasing sCD40L
PAI-1, vWF, D-Dimer
Myocardial Ischemia
IMA, FABP
Choline, BNP
Myocardial Necrosis
Trop I&T, CPK, CPK-MB
Myoglobin, BNP, MMP
Rader, NEJM 2000; 343: 1181.
Circulation 2008, 108: 250-252
Blankenberg, S. et al. Circulation 2010;121:2388-2397
Fully adjusted HRs of biomarkers for incident cardiovascular events
Blankenberg,
S. et al.
Circulation
2010;121:2388-2397
Copyright ©2010 American
Heart
Association
• Conventional Risk Factors do not predict global risk well
• Measurement of certain biomarkers such as hs-CRP may be
useful in conjunction with global risk assessment to
improve risk classification.
• Insufficient data at the present time to recommend novel
biomarkers to screen the population at large, but in
selected intermediate risk groups may be appropriate.
• Individual biomarkers do not markedly improve risk assess.
• None of these are ready for day-to-day clinical application
• Cost-effectiveness and outcome studies needed