www.drsarma.inwww.drsarma.in
Prof. Dr. Sarma VSN RachakondaProf. Dr. Sarma VSN RachakondaM.D (Medicine)., M.Sc., (Canada), FCGP, M.D (Medicine)., M.Sc., (Canada), FCGP,
FICP, FIMSA, FRCP (G), FCCP (USA), FACP (USA)FICP, FIMSA, FRCP (G), FCCP (USA), FACP (USA)
Hon. National Professor of Medicine, IMA – CGP, IndiaHon. National Professor of Medicine, IMA – CGP, India
Senior Consultant Physician & Cardio-metabolic SpecialistSenior Consultant Physician & Cardio-metabolic Specialist
Adjunct Professor, Tamilnadu Dr. MGR Medical University, Chennai Adjunct Professor, Tamilnadu Dr. MGR Medical University, Chennai
Castelli WP. Atherosclerosis. 1996;124(suppl):S1-S9.1996 Reprinted with permission from Elsevier Science.
35% of CHD occurs in 35% of CHD occurs in people with TC < 200 people with TC < 200 mg/dLmg/dL
150 200
Total Cholesterol (mg/dL)
250 300
No CHD
CHD
Framingham Heart Study—26-Year Follow-up
Khot et al. JAMA 2003
• 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
End stage Heart Disease
Congestive Heart Failure
Ventricular Dilation
Remodeling
Arrhythmia & Muscle Loss
ACS - Myocardial Infarction
Myocardial Ischemia
CAD Onset
Atherosclerosis
Endothelial DysfunctionCVD Risk Factors
Coronary Thrombosis
Intervene here
www.drsarma.in 5
Normal Apoptosis
Vasodilation
NO, PGI2, EDHF, BK, C-NP
Thrombolysis
Platelet Disaggregation
NO, PGI2
Antiproliferation
NO, PGI2, TGF-, Hep
Lipolysis
tPA, Protein C, TF-I, vWF
LPL
VasoconstrictionROS, ET-1, TxA2,
A-II, PGH2
Thrombosis
Adhesion Molecules
CAMs, P,E Selectins
Growth Factors
ET-1, A-II, PDGF, ILGF, ILs
Inflammation
ROS, NF-B
PAI-1, TF-α, Tx-A2
Steinberg D et al. N Engl J Med 1989;320:915-924.
Endothelium
Vessel LumenLDL
LDL readily enter the artery wall where they may be modified
LDL
Intima
Modified LDL or OX-LDL
Modified LDL is Proinflammatory
Hydrolysis of Phosphatidylcholineto Lysophosphatidylcholine
Other Chemical Modifications
Oxidation of Lipidsand ApoB
Aggregation
Nitric Oxide (NO) Policing the Endothelium
LDL
LDL
Navab M et al. J Clin Invest 1991;88:2039-2046.
Endothelium
Vessel Lumen
Intima
Monocyte
OX-LDL
MCP-1
Monocyte Chemotactic Protein 1 – MCP 1
LDL
LDL
Steinberg D et al. N Engl J Med 1989;320:915-924.
Endothelium
Vessel Lumen
Intima
Monocyte
OX-LDL
Modified LDL PromoteDifferentiation ofMonocytes intoMacrophages
MCP-1
Macrophage
Monocyte Chemotactic Protein 1 – MCP 1
LDL
LDL
Nathan CF. J Clin Invest 1987;79:319-326.
Endothelium
Vessel LumenMonocyte
OX-LDL
Macrophage
MCP-1
AdhesionMolecules
Cytokines
Intima
Endothelium
Vessel Lumen
MCP-1E-Selectin
Charo IF. Curr Opin Lipidol 1992;3:335-343.
Intima
VCAM-1ICAM-1
StickingMonocyte Rolling
Transmigration
LDL
LDLEndothelium
Vessel LumenMonocyte
Macrophage
MCP-1
AdhesionMolecules
Steinberg D et al. N Engl J Med 1989;320:915-924.
Foam Cell
Modified LDL Taken up by Macrophage
Intima
LDL
LDLEndothelium
Vessel LumenMonocyte
Macrophage
AdhesionMolecules
Foam Cell
IntimaModified
LDLCytokines
Cell ProliferationMatrix Degradation
Growth FactorsMetalloproteinases
Ross R. N Engl J Med 1999;340:115-126.
MCP-1MCP-1
Endothelium
Vessel LumenMonocyte
Macrophage
MCP-1MCP-1AdhesionMolecules
Foam Cell
IntimaModifiedRemnantsCytokines
Cell ProliferationMatrix Degradation
Doi H et al. Circulation 2000;102:670-676.
Growth FactorsMetalloproteinases
Remnant Lipoproteins
Remnants
Established and Conventional CV Risk Factors
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
1.00
0.99
0.98
0.97
0.96
0.000 2 4 6 8
Years of Follow-up
Low CRP-low LDL
Low CRP-high LDL
High CRP-low LDL
High CRP-high LDL
Ridker et al, N Engl J Med. 2002;347:1157-1165.
Prob
abili
ty o
f Eve
nt-f
ree
Surv
ival
Median LDL 124 mg/dlMedian CRP 1.5mg/l
0 2 4 6 8Years of Follow-Up
0.95
0.96
0.97
0.98
0.99
1.00
CVD
Eve
nt-F
ree
Surv
ival
Pr
obab
ility
CRP < 3, No Metabolic SyndromeCRP < 3, No Metabolic Syndrome
CRP > 3, No Metabolic SyndromeCRP > 3, No Metabolic Syndrome
CRP < 3, Yes Metabolic SyndromeCRP < 3, Yes Metabolic Syndrome
CRP > 3, Yes Metabolic SyndromeCRP > 3, Yes Metabolic Syndrome
Ridker et al, Circulation 2003;107:391-7
0 1.0 2.0 4.0 6.0
Lipoprotein(a)
Homocysteine
IL-6
TC
LDLC
sICAM-1
SAA
Apo B
TC: HDLC
hs-CRP
hs-CRP + TC: HDLC
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 StatementAHA / CDC Scientific StatementMarkers of Inflammation and Cardiovascular Disease:Markers of Inflammation and Cardiovascular Disease:
Applications to Clinical and Public Health PracticeApplications to Clinical and Public Health Practice
Circulation January 28, 2003Circulation January 28, 2003
“Measurement of hs-CRP is an independent marker of risk“Measurement of hs-CRP is an independent marker of riskand may be used at the discretion of the physician as partand may be used at the discretion of the physician as part
of global coronary risk assessment in adults without knownof global coronary risk assessment in adults without knowncardiovascular disease. Weight of evidence favors use cardiovascular disease. Weight of evidence favors use particularly among those judged at intermediate risk byparticularly among those judged at intermediate risk by
global risk assessment”.global risk assessment”.
1 mg/L 3 mg/L 10 mg/L
LowRisk
ModerateRisk
HighRisk
Acute Phase ResponseIgnore Value, Repeat Test in 3 weeks
>100 mg/L
Ridker PM. Circulation 2003;107:363-9
0.0
1.0
2.0
3.0
4.0
5.0
High Medium Low Low
Medium
High
Total Cholesterol:HDL RatioTotal Cholesterol:HDL RatioRidker et al, Circulation. 1998;97:2007–2011.
hs-CRPhs-CRP
Rela
tive
Risk
Rela
tive
Risk
0
5
10
15
20
25
Visser M et al. JAMA 1999;282:2131-2135.
Normal
Perc
ent w
ith C
RP
0.22
mg/
dL
Overweight Obese
31
• 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
Apolipoprotein BApolipoprotein BNon-HDL-CNon-HDL-CMeasurementsMeasurements
TG-rich lipoproteinsTG-rich lipoproteins
VLDLVLDL VLDLRVLDLR IDLIDL LDLLDL SDLSDL
Cholesterol lipoproteinsCholesterol lipoproteins
Feingold KR et al. Arterioscler Thromb. 1992;12:1496-1502.Lamarche B et al. Circulation. 1997;95:69-75.
• 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
O2 Endothelial Cells and H2O2 Vascular Smooth Muscle
Endothelial Dysfunction
Apoptosis
VasoconstrictionLeukocyteadhesion
Lipiddeposition
ThrombosisVSMCgrowth
HypertensionSmokingDiabetes LDL Homocysteine Estrogen
deficiency
37
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
NormalModerateIntermediateSevere
05 – 1011 – 3031 – 100> 100
43
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
44
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)
• 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
Eastman RC, Keen H. Lancet 1997;350 Suppl 1:29-32.
Microalbuminuria
10
8
6
4
2
0
10.02
Smoking Hypertension
CHD Odds Ratio
6.52
Cholesterol
2.323.20
Normal < 10 mm
This case 26 mm
The Framingham Heart Study
Cupples LA, D’Agostino RB. NIH Publication No 87-2703, Feb 1987.
Risk Ratio 3.2 5.33.73.0CHD Stroke
Rader, NEJM 2000; 343: 1181.
Circulation 2008, 108: 250-252
Blankenberg, S. et al. Circulation 2010;121:2388-2397
Copyright ©2010 American Heart AssociationBlankenberg, S. et al. Circulation 2010;121:2388-2397
Fully adjusted HRs of biomarkers for incident cardiovascular events
• 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
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