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