DETECTIVE : DR.S.ARUNVHF.

Indians have been reported to have the highest incidence

of CAD. (Enas E, et al. Dyslipidemia among Indo-Asians Strategies for Identification an Management. Br J Diabetes Vasc Dis 2005;5:81-90.)

The prevalence rate is almost 80-120 per 1000 population.

CAD also occurs more prematurely, often affecting people under the age of 40 years.

ATHEROSCLEROSIS OVERVIEW

THE USUAL SUSPECTS…Non-Modifiable Risk Factors Family History

– Twice the risk of MI if one first-degree relative with MI– Triple the risk of MI if 2+ first-degree relatives with MI– Risk is strongest if MI occurred at age 55 or less

Advancing Age– Risk of CAD Increases as we get older

Gender– Men are at risk at an earlier age than women– Women’s risk of heart disease increases after menopause

and soon equals men’s

THE USUAL SUSPECTS….

Modifiable risk factors:• High blood cholesterol levels (specifically, low-density

lipoprotein cholesterol [LDL-C])• High blood pressure• Cigarette smoking• Diabetes mellitus• Obesity• Lack of physical activity• Metabolic syndrome• Mental stress and depression

HYPERCHOLERTEROLEMIATotal Cholesterol Distribution:

CHD vs Non-CHD Population

Castelli WP. Atherosclerosis. 1996;124(suppl):S1-S9.1996 Reprinted with permission from Elsevier Science.

35% of CHD Occurs in People with TC<200 mg/dL

150 200

Total Cholesterol (mg/dL)

250 300

No CHD

CHD

Framingham Heart Study—26-Year Follow-up

1.20

1.100

1.063

1.019

1.006

0.95

5 10 20 40 60 80 1000

ChylomicronRemnants

VLDL

LDL-R

HDL2

HDL3DL3

Particle Size (nm)

Den

sity

(g/

ml)

Chylomicron

VLDLRemnants

Lipoprotein Particles

Lp(a)

IDL

Only these lipoprotein particles found in plaque at biopsy.

1.050

Lipid Atherogenesis

HDL

Liver

Advancedfibrocalcific

lesion

Oxidativemodification

of LDL

LDL+

VLDL

Cholesterolexcreted

Endothelialinjury

Adherenceof platelets

Releaseof PDGF

High plasmaLDL

LDL infiltrationinto intima

+Macrophages

Foam cells

Fatty streak

LCATAPO-A1

Othergrowthfactors

Rationale for therapeutic lowering of Apo B lipoproteins: decrease the probability of inflammatory response to retention

Tabas I et al. Circulation. 2007;116:1832-1844.Williams KJ et al. Arterioscler Thromb Vasc Biol. 1995;15:551-561.Hoshiga M et al. Circ Res. 1995;77:1129-1135.Williams KJ et al. Arterioscler Thromb Vasc Biol. 2005;25:1536-1540.

Merrilees MJ et al. J Vasc Res. 1993;30:293-302.Nakata A et al. Circulation.1996;94:2778-2786.Steinberg D et al. N Engl J Med. 1989;320:915-924.

High Plasma Apo B Lipoprotein Levels Promote Atherogenesis

BloodApo B lipoproteinparticles

ModificationMacrophage

Monocytes bind toadhesion molecules

Smooth muscle

Foam cell

Inflammatory response

Very–low-density lipoprotein (VLDL)• Made in the liver• Triglycerides (TG) >> cholesterol esters (CE)• Carries lipids from the liver to peripheral tissues

HDL

LDL

IDL

VLDL

Athe

roge

nic

Lipo

prot

eins

Non

-HD

L; A

po B

-100

—co

ntai

ning

Intermediate-density lipoprotein (IDL)• Formed from VLDL due to lipase removal of TG• Also known as a VLDL remnant

Low-density lipoprotein (LDL) • Formed from IDL due to lipase removal of TG• CE >> TG

High-density lipoprotein (HDL)• Removes cholesterol from peripheral tissues

Lp(a)

Lipoprotein (a) • Formed from LDL w/addition of apolipoprotein A • Atherogenic and prothrombotic

Non-HDL Includes All Atherogenic Lipoprotein Classes

Low HDL-C Levels Increase CHD Risk Even When Total-C Is Normal

Risk of CHD by HDL-C and Total-C levels; aged 48–83 yCastelli WP et al. JAMA 1986;256:2835–2838

0

2

4

6

8

10

12

14

< 40 40–49 50–59 60< 200

230–259200–229

260

HDL-C (mg/dL) Tota

l-C (m

g/dL

)

14-y

inci

dence

ra

tes

(%)

for

CH

D 11.24

11.91

12.50

11.91

6.56

4.67

9.05

5.53

4.85

4.153.77

2.782.06

3.83

10.7

6.6

HDL-C Risk Factor vs Risk Marker?

• Low HDL-C predicts high CVD Risk• High HDL-C predicts anti-atherogenic effects:

– Anti-inflammatory– Antioxidant– Antithrombotic– Pro-endothelial

• But clinical trials of HDL-C-raising agents so far have failed to prove CVD benefit—suggesting that HDL-C may be only a risk marker

• Triglyceride-rich lipoproteins carry cholesterol and promote atherosclerosis*

• Very–low-density lipoprotein (VLDL) is precursor to low-density lipoprotein (LDL)

• Hypertriglyceridemia (HTG) drives– Cholesterol esters enrichment of VLDL (more atherogenic)– ↓ LDL size (small, dense LDL are more atherogenic)*– ↓ LDL-C (small, dense LDL carry less cholesterol)*– ↓ High-density lipoprotein (HDL) size (small, dense HDL are unstable)

• HTG is linked to other proatherogenic states*– Insulin resistance– Proinflammatory state– Prothrombotic state– Prooxidative state– Endothelial dysfunction

*Reasons why non–HDL-C is stronger than LDL-C as predictor of cardiovascular disease

THEN CAME Hypertriglyceridemia…..

Apolipoprotein B

LDL=130 mg/dL

Fewer Particles More Particles

Cholesterolester

More apolipoprotein B

Otvos JD, et al. Am J Cardiol. 2002;90:22i-29i.

Correlates with: TC 198 mg/dL

LDL-C 130 mg/dLTG 90 mg/dLHDL-C 50 mg/dL

Non–HDL-C148 mg/dL

Correlates with: TC 210 mg/dL

LDL-C 130 mg/dLTG 250 mg/dLHDL-C 30 mg/dL

Non–HDL-C180 mg/dLTC=total cholesterol, LDL-C=low-density lipoprotein cholesterol, TG=triglycerides, HDL-C=high-density lipoprotein cholesterol

Elevated Triglycerides Are Associated With Increased Small, Dense LDL Particles

Cholesterol per particle, BUT

Subendothelial penetration

Subendothelial binding

Oxidized/modified

LDL-receptor clearance

LDL=low-density lipoprotein

Why Is Small, Dense LDL More Atherogenic?

TG Metabolism in CHD: Studies in the Postprandial State

400

300

200

100

0

TG

(m

g/d

L)

UncorrectedCorrected for Fasting

TG Level*

Hours after Test Meal

300

200

100

0

Patsch JR et al. Arterioscler Thromb 1992;12:1336-1345.

0 2 4 6 8 0 2 4 6 8

CHD Case

s

Controls

Controls

Error bars = SEM

CHD Case

s

Lp(a) in Atherogenesis: Another Culprit?

• Identical to LDL particle except for addition of apo(a)

• Plasma concentration predictive of atherosclerotic disease in many epidemiologic studies, although not all

• Accumulates in atherosclerotic plaque

• Binds apo B-containing lipoproteins and proteoglycans

• Taken up by foam cell precursors

• May interfere with thrombolysis

Maher VMG et al. JAMA. 1995;274:1771-1774.Stein JH, Rosenson RS. Arch Intern Med. 1997;157:1170-1176.

LDL cholesterol lowering* - First choice: HMG CoA reductase inhibitor (statin)

- Second choice: Bile acid binding resin or fenofibrate HDL cholesterol raising - Behavior interventions such as weight loss, increased physical

activity and smoking cessation

- Glycemic control

- Difficult except with nicotinic acid, which is relatively contraindicated, or fibrates

Triglyceride lowering - Glycemic control first priority

- Fibric acid derivative (gemfibrozil, fenofibrate)

- Statins are moderately effective at high dose in hypertriglyceridemic subjects who also have high LDL cholesterol

Order of Priorities for Treatment of Dyslipidemia in Adults

DIABETES MELLITUS

QUESTION !!!!!PATIENT A ( 48 YRS)

• T2DM – 10 YRS• ON OHA’S• METFORMIN 1G• GLIPIZIDE 5 MG• HBA1C – 10.2 %

PATIENT B ( 35 YRS)

• T2DM 5 YRS• ON SC.INSULIN• METFORMIN 500 MG• HBA1C 4.6 %

WHO IS MORE PRONE TO MACROANGIOPATHY WITH OTHER SIMILAR RISK FACTORS????

PATIENT B MORE PRONE THAN PATIENT A. TIGHT BS CONTROL USUALLY WILL LEAD TO

HIGH GLYCEMIC VARIABILITY AND THUS MORE OXIDATIVE STRESS.

SMOKING

SMOKING

• Smoking has adverse hemostatic and inflammatory effects, including increased levels of CRP, soluble ICAM-1, fibrinogen, and homocysteine.

• Cessation of cigarette consumption overwhelmingly remains the single most important intervention in preventive cardiology.

• Smoking predicts better outcome following various reperfusion strategies (the so-called “smoker's paradox”) --- smokers are likely to undergo such procedures at a much younger age and hence have on average lower comorbidity

ROLE OF DIET

Malnutrition is caused by an unbalanced diet. Most people think of malnutrition as deficiency. However the biggest form of malnutrition in the developed

world is obesity

Malnutrition

OBESITY

SUBSTANCES NORMAL WEIGHT OVERWEIGHT

Leptin Low High

Adiponectin High Low

TNF-alpha Low Very High

IL-6 Low Very High

Angiotensin Low High

Plasminogen activator inhibitor

High Increased

Resistin Low High

PHYSICAL INACTIVITY

THE REAL NIGHTMARE

Moderate physical activity at least 30-60 minutes 5 days a week or longer will help to raise HDL-C, lower total and LDL-C, lower TG, lower glucose, insulin, and blood pressure levels.

HYPERTENSION

Stress

Psychosocial factors associated with CAD risk:– Type A personality

– Hostility/Anger

– Depression/Anxiety

3 to 4 times increased risk of death in first year following MI

Stress

Influence CAD risk via 2 main mechanisms: Catacholamine release

– increased BP– increased HR– vasoconstriction

– increased O2 demand

Decreased adherence to lifestyle modification recommendations

UNUSUAL SUSPECTS.. Nontraditional factors that are associated with increased risk

of CVD, but a causal link has not yet been proved with certainty

– Poor oral health– Dietary trans fat intake– Homocysteine– Lipoprotein A– Infectious agents

– Adhesion molecules– Cytokines– Fibrogen– High sensitive C-

reactive protein

HYPERHOMOCYSTINEMIA Homocysteine is a non-protein-forming, sulfur-

containing amino acid. It is an intermediary amino acid, which is formed

exclusively by demethylation of methionine, during conversion of methionine to cysteine.

There is no naturally occuring dietary source of

homocysteine.

(Ref :Clinical Biochemistry 36 (2003) 431–441)

METABOLISM OF HOMOCYSTEINE : (Ref :Clinical Biochemistry 36 (2003) 431–441)

CAUSES OF HYPERHOMOCYSTEINEMIA :

Genetic enzyme deficiency – 5-Methyltetrahydrofolate reductase Cystathionine B-synthase Methionine synthase

Vitamin deficiency – Vitamin B12 Vitamin B6 Folate (Ref : ARCH INTERN MED/ VOL 158, JUNE 22, 1998)

cont..

Chronic medical disorders – Chronic renal failure Systemic lupus erythematosus Psoriasis Hypothyroidism Acute-phase response to systemic illness

Demographic – Increasing age Male

(Ref : ARCH INTERN MED/ VOL 158, JUNE 22, 1998)

cont…

Drugs – Methotrexate

Antiepileptics ( phenytoin and carbamazepine) Nicotinic acid Thizide diuretics Nitrous oxide Fibrates MetFormin TObacco use/smoking (Ref : ARCH INTERN MED/ VOL 158, JUNE 22, 1998)

MECHANISM OF INJURY :

HYPERHOMOCYSTEINEMIA IN INDIANS : Indian studies examining the prevalence of

hyperhomocysteinemia in the community have reported a much higher incidence of 52 to 84% vs 5 to 7 % rate worldwide.

The mean homocysteine levels too are quiet high among indians varying from 19.5 to 23.2 micromols/L vs 4.4 to 10.8 micromols/L in worldwide.

(Wadia R, et al. Hyperhomocysteinemia and Vitamin B12 Deficiency in Ischaemic Strokes in India, Ann Ind Acad Neurol 2004;7:387-92.

Refsum H, et al. Hyperhomocysteinemia and elevated methylmalonic acid indicate a high prevalence of cobalamin deficiency in Asian Indians. Am J Clin Nutr 2001;74:233-41.)

C-reactive Protein

• Circulating acute phase reactant• Many-fold increase with injury & infection• Synthesized in liver, induced primarily by

interleukin-6 (IL-6)• Stable levels in circulation, not affected by

meals, no circadian levels

Hs-CRP predicts first events

0

1

2

3

hs-CRP and Risk of Future MI in Apparently Healthy Men

Ridker PM et al. N Engl J Med 1997;336:973-979.

1<0.055

Rela

tive R

isk

of

MI

P = 0.03

Quartile of hs-CRP (range, mg/dL)

20.056–0.114

30.115–0.210

4>0.211

P < 0.001 P < 0.001

P Trend <0.001

Can intervention lower CRP levels?

Statins? YesWeight loss ??Smoking cessation??Physical activity??

No studies to date have shown CRP lowering in itself is associated with reduced event rates!

AHA/CDC Consensus Panel

Class I: NoneClass IIa:• In primary prevention, CRP measurement may be useful in

those at intermediate risk (10-20% 10-year CHD risk), to help direct further evaluation and treatment.

• In patients with stable CAD or ACS, CRP may be useful as an independent marker of recurrent events, including death, MI and restenosis following PCI.

Circulation 2003;107:499-511

Hs-CRP Recommendations

Class IIa:• Measurement should be done twice (two weeks apart) and

results averaged.• If level > 10 mg/L, test should be repeated and patient

examined for sources of infection or inflammation• Classify risk as follows:

Low < 1 mg/LAverage 1.0 – 3.0 mg/LHigh: > 3.0 mg/L

Circulation 2003;107:499-511

AHA/CDC Consensus PanelHs-CRP Recommendations

1. Screening of the population as a whole is NOT recommended

2. Application of secondary prevention measures should not depend upon hs-CRP results

3. Application of management guidelines for acute coronary syndromes should not be dependent upon hs-CRP level

4. Serial CRP levels should not be used to monitor effects of treatment

Circulation 2003;107:499-511

AHA/CDC Consensus PanelHs-CRP Recommendations

METABOLIC SYNDROME

ROLE OF INFLAMMATION

VITAMIN D DEFICIENCY

ASSOCIATED DISEASES

AUTOIMMUNE DISEASES

• TLR and cytoplasmic (inflammasome NLRP3) receptors, with their signaling pathways, participate in the development of autoimmune diseases as well as in atherosclerosis.

• When autoantibodies are present, patients with RA have an accelerated atherosclerosis in comparison to patients with RA who do not have these antibodies. Similarly, autoantibodies in SLE amplify atherosclerosis.

NOVEL ATHEROSCLEROTIC RISK FACTORS.

CAD RISK ASSESSMENT

NON INVASIVE IMAGING

• CIMT ( Carotid intima media thickness)• Aortic pulse wave velocity• F-FDG–PET/CT and DCE-CMR

internal carotid artery common carotid artery

carotid bulb

carotid dilatation

external carotid artery carotid flowdivider

Ultrasound measurement of CIMT

probe

blood flow

Wall Line Interface

Near Wall

1 Adventitia - Periadventitia

2 Media - Adventitia

3 Lumen - Intima

Far Wall

4 Lumen - Intima

5 Media-Adventitia

6 Adventitia - Periadventitia

Near and Far Wall Identification

It is common practice to call a CCA IMT >1.0mm as being abnormal, and >1.2mm as being high risk.

There is general agreement that the presence of obvious plaque indicates high risk at any age.

However, when there is only CCA IMT thickening and no plaque then the normal values need to be adjusted for age, gender and perhaps even ethnicity.

ANKLE BRACHIAL INDEX

• The ankle-brachial index is the ratio of the systolic pressure in the ankle to the systolic pressure in the arm.

“PAD patients are much more likely to die of MI than undergo amputation”

FDG – PET/CT

INVASIVE IMAGING

IVUS Technology

• Real time high resolution imaging.

• 2D tomographic assessments of vessels Also longitudinal and 3D computer asssited reconstruction.

• Allows assessment of total vessel lumen and plaque dimension in vivo.

IVUS measurements :

Nair et al Circulation. 2002 Oct 22;106(17):2200-6.

SPECIAL TECHNIQUES OF IVUS

• 1- Analysis of the backscatter IVUS radiofrequency data provided a color coded mapping based on the different backscatter signals among the tissue types (virtual histology).

- Allows examination of the different plaque

components in more details (fibrous, fibro

lipidic, calcium, lipid core.

)

INTEGRATED BACKSCATTER ANALYSIS (“VIRTUAL

HISTOLOGY”).

Gray scale IVUS vs. VH-IVUS

2- Intravascular elastography. IVUS radiofrequency acquired at different levels of intravascular pressure can measure tissue strain reflecting the mechanical properties of the vessel wall.

- Help identify vulnerable plaque prior to rupture.

APPLICATIONS OF IVUS

• ASSESS LESION SEVERITY• ASSESS LESION MORHOLOGY• DEVICE SIZING• SAFE DELIVERY• ASSESS STENT EXPANSION AFTER PCI• ASSESS COMPLICATIONS POST PCI.

ADVANTAGE OF OCT

• CAN CLEARLY DISTINGUISH THE INTIMA FROM MEDIA.

• HIGHLY EFFICACIOUS IN MEASURING THE THICKNESS OF FIBROUS CAP

• IDENTIFY INTIMAL HYPERPLASIA WITH HIGH ACCURACY.

DISADVANTAGE OF OCT

• THE ABILITY OF LIGHT TO PENETRATE TISSUE LIMITS RESOLUTION TO BETWEEN 0.5 AND 2MM.

Electron Beam and Multidetector CT

• Much more widely available• Most coronary calcium studies use this• Multiple detectors allow increased imaging

speed• Some detectors use EKG-gating to image

diastole only (so coronary arteries are full)

• Coronary Artery Calcification (CAC) Score – Agatston Score– Based on area and density of calcified plaques– Typical report includes:

• Agatston score for each major coronary artery• Total Agatston score for the patient• Several representative images

CAC Scoring

• In multiple studies the following definitions have been used to correlate the CAC score and the coronary plaque burden:

» 0 No identifiable disease

» 1 – 99 Mild Disease

» 100 – 399 Moderate Disease

» >400 Severe Disease

Representative Images

• On CT, calcium has high attenuation values very bright!

LCA

CAC and Obstructive Disease• CAC testing has a high sensitivity and high negative predictive value

(NPV = 98%) for obstructive coronary artery disease (CAD), but limited specificity.

• Therefore, CAC testing can be used to rule out angiographically significant CAD in symptomatic patients. – CAC could be used as a filter before catheterization – patients with a negative

CAC would not continue to the cath lab.– This could save unnecessary catheterization procedures in patients presenting

to the ED with chest pain.

• Remember though, a positive CAC indicates atherosclerotic disease, and not

necessarily obstruction from stenosis.– A person with an elevated CAC score may benefit from further functional

testing to detect occult ischemia.– Functional testing is very important to determine the need for

revascularization since functionally insignificant lesions do not benefit from revascularization.

CAC Predicts Cardiac Events

• CAC is a strong independent predictor of coronary events in both symptomatic and asymptomatic persons.

• When added to the Framingham Risk Score, CAC improves the predictive value of death estimation.

ANGIOSCOPY

• DIRECT VISUALISATION OF INTRACORONARY STRUCTURES.

• The culprit lesions of ACS are sometimes detected by angioscopy even in the angiographically normal segments of coronary arteries.

• Angioscopy can further classify the culprit lesions of ACS as (1) vasospasm, (2) plaque rupture, or (3) plaque erosion

• ESPECIALLY SUITABLE FOR DETECTING PLAQUE RUPTURE,EROSION AND THROMBUS.

• Anti-vasospastic medications rather than stenting may be more suitable for the treatment of vasospasm-induced ACS.

• Percutaneous coronary intervention (PCI) of ruptured plaque rather than of erosive plaque tends to cause more distal embolization with thrombus and plaque contents. Therefore, distal protection device may be more beneficial for those cases.

INTRACORONARY THERMOGRAPHY

• INCREASED TEMPERATURE IN ATHEROSCLEROTIC PLAQUES.

• VULNERABLE PLAQUES HAVE VERY HIGH TEMPERATURE.

• CORONARY SINUS BLOOD TEMPERATURE WAS FOUND TO BE GREATER THAN RIGHT ATRIAL BLOOD TEMPERATURE IN PATIENTS WITH SIGNIFICANT CAD.

INTRAVASCULAR MRI

• BETTER SPATIAL AND TEMPORAL RESOLUTION.

Novel Invasive Imaging Modalities

WHO’S THE PRIME

CULPRIT??

WE UNDERSTOOD THE SUSPECTS!!

WE INVESTIGATED !!!

FINAL JUDGEMENT

• MAIN CULPRIT : OXIDATIVE STRESS

• ASSOCIATES : MODIFIABLE & NON- MODIFIABLE RISK FACTORS.

CONTRL DM, HT, HYPERLIPIDEMIA, MAINTAIN BODY WEIGHT

DON’T DEVELOP ANY RISK FACTORS..