Www.drsarma.in 1 Welcome. Dr.Sarma@works 2 CD ROM Available The contents of my today’s...

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1

Welcome

Dr.Sarma@works

2

CD ROM Available

The contents of my today’s presentations

are made available in a CD-ROM format

This CD, in addition, contains my talks on

Asthma, COPD, Hypertension, ECG, CAD

Dyslipidemias, Diabetes, Osteoporosis…

Dr.Sarma@works

3

Knowledge that isn’t implemented never works

Knowledge that isn’t implemented never works

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Coronary Artery Disease in Indians

(C A D I)

Coronary Artery Disease in Indians

(C A D I)

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Coronary Heart Disease in IndiansIs it different from CAD elsewhere ?

Should we test it differently ?

What should be our strategy ?

Dr. Sarma V.S.N. Rachakonda M.D., (Med) M.Sc., (Canada)

Consultant Physician & Chest Specialist

visit us at: www.drsarma.in

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http://www.ispub.com/ijc/vol1n2/cadi.xml

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A must read book

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Lets learn what we are !!

1. Meraa Bhaarat Mahaan

2. The Volcano

3. The Tsunami

4. Mirrors of CV Health

5. Who loads the Gun ?

6. What pulls the triggers ?

7. Our Treasure in Tummy

8. Influence of Affluence

9. Good, Bad, Ugly & Deadly

10. Why not count the boats ?

11. How to count the risks ?

12. The Missing Links !!

13. Our Women are Men

14. Our Novelty of risk factors

15. Fuel on Fire / Fire on Fuel?

16. Is it the End of the Road?

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2. The Volcano

3. The Tsunami














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Meraa Bhaarat Mahaan

• We have glorious culture, traditions and values

• Excellent present prosperity

• Enviable future projections too

• Innumerable great achievements in all fields

• In spite of our three Ps (population, poverty, politicians)

• We are proud to be the children of our mother land

• For a glimpse of the glory of our Bhaarat please visit

• http://chyk.net/Indian_culture.power.asp for a slide show

With highest reverence and salutations to Mother India….

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With Great Reverence

• Saare jehan se achchaa …….Hindustan hamara…

• Saare jehan se oonchaa …….T2DM hamara hamara…

• Saare jehan se oonchaa …….CADI hamara hamara…

• 2 to 6 fold higher CAD than people of other ethnicity

• Indians have the highest among the highest CAD rates

• Irrespective of gender, region, religion, SES

• Same is true of immigrant Indians all over the globe

• CAD risk is considerable even in vegetarian Indians

• Indian CAD is 10 years younger, Often silent MI

• Triple vessel disease, SD, MACE are more in Indians

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CADI is ‘Malignant’

• CADI strikes early !

• CADI strikes hard !!

• CADI strikes almost any one !!!

• CADI strikes unexpectedly !!!!

• Conventional RF can’t explain it away

• CADI is malignant in its onslaught.

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CAD Mortality

Age Adjusted mortality for 100,000 population per year in 35-74 age.

INDIA

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CAD in Indians

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CAD in Asian Indians

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MI in Singapore - Ethnicity

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CAD in California - Ethnicity

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CAD Deaths – 7 Countries study

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2. The Volcano

3. The Tsunami














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The Volcano

• We are in the middle of the wave of CAD epidemic

• This CADI epidemic will peak by 2015

• 50% deaths in India will be CVD deaths.

• CADI will overtake Infectious diseases.

• By 2015 CADI will be six times more than the West

• CADI will be 20 times more than the Chinese, although

• Our culture shuns smoking, 50% are vegetarians and

• We lack many of the classic risk factors for CAD

• Remember CADI is preventable, predictable & curable

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The Quotes

• “Genetics loads the gun, environment pulls the trigger. Even if you have a loaded gun, you don’t pull the trigger, no harm is done."

Dr.Enas A Enas

Director, CADI Research Foundation

• “Just being an Indian places you at higher risk for heart disease than having high cholesterol & being a smoker”

Dr. H. Robert Superko

Director, Berkeley Heart Lab

• “A lot of people, they just look healthy, they feel healthy, they don’t get tested for heart disease. By the time some of them find out they have CAD, they’re either in an ambulance or a hospital bed”

Dr.A.K. Rao

National Asian Indian Heart Disease Program

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The Berkeley Study

• 25 % of the MIs occur below 40 yrs, unheard of any where

• In the young Indians (< 30 yrs), CAD mortality is three fold higher than Whites in UK and ten fold higher than Chinese.

• Sadly many of the Indians are dying young !!

• Indians have higher prevalence of thrombotic risk factors

• The conventional risk factors become doubly dangerous

• Even pre-menopausal women showed multi vessel CADI

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UK Indian Study

Age-specific death rates form CAD in UK Indians and general population per 100,000/yr

Balrajan et al, I Heart J 1999

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CADI Strikes the Young

Enas A Enas et al, I Heart J 2001

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1110.99.7

6.55.5

4

0

2

4

6

8

10

12

(1) 1960; 30-70 years

(2) 1962; 30-70 years

(3) 1968; >30years

(4) 1990; 25-64 years

(5) 1994; 35-64 years

(6) 2001>20 years

Year

Pre

vale

nce

%

1. Agra; 3. N India; 4. Delhi; 6. Chennai Indian Heart J 2002; 54: 103

We have worsened !!

Prevalence of CAD in India from 1960 - 2001

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CADI Research Foundation

Enas A Enas et al A Heart J 2001

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2. The Volcano

3. The Tsunami














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CAD Tsunami in India

• “There is a CAD tsunami in India”

• The immediate step is awareness of CADI

• Awareness among doctors is crucial

• Then, we need to educate the population at large

• Second step is employing preventive strategies

• The key to tackling this Tsunami lies in prevention

PadmaShri Prof. Ashok Seth

Intervention Cardiologist, AIIMS

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Key Points

• Risk for CAD begins in early childhood

• Plaque build up develops later in life due to RF

• CAD is not an unavoidable consequence for all

• Risky blood paves the way for plaque build up

• Small, soft, inflamed, lipid rich plaque ruptures

• 75% of MI occur in people with < 25% stenosis

• Only 1/3 have advanced warning as chest pain

• Half of SDs occur in so called “Healthy” persons

• 2/3 of these SDs occur before they reach hospital

• Don’t wait. Begin heart healthy life style now!

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SHARE and CUPS

1. The Chennai Urban Population Study (CUPS)

• Prevalence of CAD to be 11%

• 10 folds increase in the last 40 years

2. The Study of Health Assessment and Risk in Ethnic groups (SHARE) in Canada

• CAD prevalence in migrant Indians to be 10.7 %, in Europeans 4.9 % and in Chinese 1.9 % .

3. Analysis of 1.2 m deaths from 1979 to 1993, in Canada

• Mortality in Canadian SA men & women 42% and 29%

• In European men and women 29% and 18%

• In Chinese men and women 18% and 11%

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2. The Volcano

3. The Tsunami














[email protected]@works

The Progressive Development of Cardiovascular DiseaseThe Progressive Development of Cardiovascular Disease

End stage Heart DiseaseEnd stage Heart Disease

Congestive Heart FailureCongestive Heart Failure

Ventricular DilationVentricular Dilation

RemodelingRemodeling

Arrhythmia & Muscle LossArrhythmia & Muscle Loss

Myocardial InfarctionMyocardial Infarction

Myocardial IschemiaMyocardial Ischemia

CADCAD

AtherosclerosisAtherosclerosis

Endothelial DysfunctionEndothelial Dysfunction

Risk FactorsRisk Factors

Coronary ThrombosisCoronary Thrombosis

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Mirrors of CV Health

• Diabetes Mellitus (DM = CAD)• Hypertension, Isolated Systolic Hypertension• Pulse Pressure, Mean Arterial Pressure (MAP)• Metabolic syndrome• Left Ventricular Hypertrophy• ABI (Ankle Brachial Index)• Micro albuminuria (MAU)• Intermittent claudication• Erectile Dysfunction (ED)• Retinopathy

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Dushta Chatushtayam

HY

PE

RT

EN

SIO

N DIA

BE

TE

S

↑ CHOLESTEROL

SMOKING

HEART ATTACK

Only 35%- 50% of the angiographically proved CADI is accounted for by these BIG FOUR

38

HT – CV Mortality

Kannel WB Euro Heart J 1992;13(Suppl G):34-42.

29

14

65

35

0

10

20

30

40

50

60

70

Men Women

Age

-Adj

uste

d R

ate/

1000

NormotensiveHypertensive

The Framingham Heart Study

Risk Ratio 2.2 2.5

39

Adapted from MacMahon S, Rodgers A. Clin Exper Hypertension 1993;15(6):967-978.

0

100

200

300

400

500

600

Stroke CHD VascularDeaths

Treatment of HT – CV Mortality

5 Randomized Trials in 12,483 Elderly Hypertensives

% Reduction in odds: 19%p<0.05

34%p<0.001

23%p<0.001

346383

288

438 Treatment

Control

Tot

al N

umbe

r of

In

divi

dual

s A

ffec

ted

438494

Overall BP DifferenceSystolic: 15 mm HgDiastolic: 6 mm Hg

40

CVE and LVH

The Framingham Heart Study

Cupples LA, D’Agostino RB. NIH Publication No 87-2703, Feb 1987.

2315

10 8

69

55

32

42

0

10

20

30

40

50

60

70

80

Men Women Men Women

Age

-Adj

uste

d R

ate/

1000

No LVHLVH

Risk Ratio 3.2 5.33.73.0CHD Stroke

41

DM and CVE : LIFE study

Increased Risk of Primary Endpoint

23

46

0

10

20

30

40

50

60

Primary EndpointRat

e pe

r 10

00 P

atie

nt-Y

ears

Non-DiabeticDiabetic

2530

0

10

20

30

40

50

60

Primary EndpointRat

e pe

r 10

00 P

atie

nt-Y

ears

Non-ISHISH(n=1195)

(n=7998)

(n=1326)

(n=7867)

Relative Risk: 2.0 1.2

42

DM and CAD - CUPS

Mohan V et al CUPS…

43

HT and CAD in CUPS

Mohan V et al CUPS…

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How important is the CAG ?

• 2/3 of ACS result from CA stenosis of < 50%

• < 15% MI result from CA stenosis of < 75%

• CAG may give a false sense of security

• In asymptomatic subjects CAG not indicated

• Instead focus on conventional and novel RF

• In ACS, CAG is a must to plan Rx. strategy

• The nature of the plaque determines occlusion

• Lipid rich, soft plaques are rupture vulnerable

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2. The Volcano

3. The Tsunami














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Who Loads the Gun ?

• Genetics loads the gun

• Indian CAD Gun is heavily loaded

• CADI is a combination of Nature and Nurture

• Genetically high Lp(a) levels

• Genetic predisposition to DM, IRS, TNFr2

• Atherogenic Lipoprotein Phenotype (ALP)

• Genetically low HDL 2b sub fraction

• Genetically more of LDL Phenotype B

• Elevated Homocysteine in Indians (tHCy)

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2. The Volcano

3. The Tsunami














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CAD Prediction in 21st Century

Cardiovascular RiskCardiovascular RiskCardiovascular RiskCardiovascular Risk

LipidsLipidsHTNHTN

DiabetesDiabetes

LipidsLipidsHTNHTN

DiabetesDiabetesBehavioralBehavioralBehavioralBehavioral HemostaticHemostatic

ThromboticThromboticHemostaticHemostaticThromboticThrombotic InflammatoryInflammatoryInflammatoryInflammatory GeneticGeneticGeneticGenetic

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What Pulls the Trigger ?

• CADI is a combination of Nature and Nurture

• Sedentary life style, Affluence, Urbanization

• ↑CHO, Crunchy, munchy, fatty food habits

• Minimal or non eating of fruits, nuts, vegetables

• ↓Fiber, Over boiling, Reuse of oil, ↑Fast foods

• Central adiposity, Visceral fat, IRS

• Carelessness about risk assessment

• Emphasis on treatment rather than prevention

• Device ridden, Intervention oriented approach

• Extremely important, often forgotten factor - Stress

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2. The Volcano

3. The Tsunami



6. Who pulls the triggers ?











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Intra abdominal fat

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Normal Central Adiposity

Courtesy of Wilfred Y. Fujimoto, MD.

The Treasure in Tummy

Courtesy of Wilfred Y. Fujimoto, MD.

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• Insulin resistance – Hyperinsulinemia• Hyperglycemia – IFG, IGT, DMII• Pro-inflammatory state (↑CRP)• Pro-coagulant changes (↑PAI-1, ↑Fibrinogen)• Dyslipidemia (↑TG, ↓HDL)• Premature atherosclerosis, IHD, CAD • Type 2 diabetes• Hypertension, ED• Prevalence of 17 to 25% in Indians > 30%

Metabolic Syndrome

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Our cut off values !

1. BMI < 23, WC Normal - Good

2. BMI > 23, WC Normal - Bad

3. BMI < 23, WC Increased - Worse

4. BMI > 23, WC Increased - Worst

For Indians• BMI < 23 Normal• BMI of 23 to 24.9 Over weight• BMI of > 25 Obesity

Central adiposity causes ↑IL6, which ↑hepatic hs-CRP

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Metabolic Syndrome

InsulinInsulin

ResistanceResistance

Hyper-Hyper-

insulinaemiainsulinaemia

HypertensionMicroalbuminuria

Centralobesity

Triglycerides

HDLcholesterol

Small dense LDL

Hyperuricemia

Prothrombotic state (fibrinogen,Factor VIIa,

fibrinolytic activity)

Impaired Glucose Tolerance

Type 2 DiabetesDiabetes Care 1998;21(2):310–314.

Williams G, Pickup JC. Handbook of Diabetes. 2nd Edition, Blackwell Science. 1999.

200% CVD Risk

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Risk Factor Defining Level

Abdominal Obesity Waist Circumference

Men >90 cm (>36 in)

Women >80 cm (>32 in)

Triglycerides >150 mg/dl

HDL cholesterol

Men <40 mg/dl

Women <50 mg/dl

Blood pressure >130/>85 mmHg

Fasting glucose >110 mg/dl

Metabolic Syndrome, Syndrome X, Deadly Quartet, Reaven’s Syndrome

NCEP guidelines 2001 (WHO Modified for Indians)

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Acanthosis Nigricans

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Plasma Insulin Levels in Asian Indians & Europeans Mohan et al 1986

Plasma Insulin Levels in Asian Indians & Europeans Mohan et al 1986

Basal Insulin Levels (Micro u/ml)

Indians Europeans P value

Non diabetics 16.7 ± 3.0 6.9 ± 0.9 < 0.01

Diabetics 18.0 ± 5.0 11.5 ± 0.9 < 0.05

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2. The Volcano

3. The Tsunami














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The Thrifty Genes

The human race adapted over millions of years to living in a world of scarcity, where it paid to eat everything good tasting

in sight when you could find it.

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Evolution ?

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Is this the way ?

Urban Children on an average watch TV for 2-2.5 hrs. in a day

Fast and Fatty Foods

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Childhood Obesity

“Fat pre-teens have arteries of middle-

aged smoker”

Sharon Kirkey CanWest Med University

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Television watching became even more convenient with Sony’s introduction of a new remote controlled remote control – Tokyo News line

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This how we walk the dog !

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Influence of Affluence

• Rapid Urbanization

• Rural to Urban Migration

• Brain drain to affluent countries

• Mechanization and lack of hard physical work

• Poor physical activity and sedentary life style

• Couch potatoes and Mouse potatoes !!

• Increase in calorific and fatty food

• Psychological stress of the affluent way of life

• Childhood and Adolescent Obesity

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With in no time !!

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2. The Volcano

3. The Tsunami














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Lipoproteins - Boats

ECTG

Apoprotein boat

Apo A I and A II for HDL Apo B100 for LDLApo B100+C+E – VLDL, IDL Apo B100+Apo(a) – Lp(a)

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Good, Bad, Ugly & Deadly

CTG

B 100 + E +C

CTG

B 100

CTG

A I, A II

HDL LDL

VLDL

CTG

B 100+ (a)

Lp(a)TG

GOOD BAD

UGLY DEADLY

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Apolipoprotein B

Apolipoprotein BApolipoprotein B

Non-HDL-CNon-HDL-CMeasurementsMeasurements

TG-rich lipoproteinsTG-rich lipoproteins

VLDLVLDL VLDLRVLDLR IDLIDL LDLLDL SDLSDL

All are the terrorists

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Apolipoproteins A1, A2

CE

A-I

CE

A-I

CE

A-II A-II

HDL 1 HDL 2 HDL 3

APO A I Atheroprotective

Alcohol increases Athero-neutral

The soldiers

The soldier-like

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Blood Lipids

• Total Cholesterol < 200 • ‘Good’ Cholesterol

– HDL 1, HDL 2, HDL 3 > 50• ‘Bad’ Cholesterols (Non HDLc) < 150

– LDLc, IDLc, SDL < 100– VLDLc, VLDLr < 30– Lp(a) < 20

HDL 1 and HDL 2 are protective HDL 3 Neutral

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Typical Lipid Profile in Rural China

• Total Cholesterol 127 • ‘Good’ Cholesterol

– HDL 1, HDL 2, HDL 3 44• ‘Bad’ Cholesterols (Non HDLc) 83

– LDLc, IDLc, SDL 53– VLDLc, VLDLr 20

– Lp(a) 10Highly anti atherogenic lipid profile

In some communities with TC of 80 mg CAD is virtually nil

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2. The Volcano

3. The Tsunami














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Better Count the Boats

• Instead of measuring Good, Bad, Ugly & Deadly

• Better count Apo B boats carrying the terrorists

• Count Apo A1 boats carrying the soldiers

• Apo A2 carries soldier-like (scouts) people

• Express the ratio of Apo B ÷ Apo A1

• It indicates the ratio of terrorists to soldiers

• Apo B includes LDL, VLDL (TG), sLDL, Lp(a)

• Apo A1 includes only HDL1 and HDL2

• This is the approach used in Interheart study

• It is available, not very expensive, ratio < 2 good

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Inter Heart Study

Apo B / Apo A1 Ratio No evidence of threshold

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The Interheart Study

• Dyslipidemia

• Current smoking

• Diabetes

• Hypertension

• Abdominal obesity (waist circumference)

• Psychosocial (stress, depression)

• Lack of daily fruit and vegetables in diet

• Lack of exercise

• Alcohol

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Inter Heart Study

• Nine simple and modifiable risk factors are strongly associated with acute MI worldwide.

• These 9 risk factors account for >90% of the PAR globally and in most regions.

• Abnormal ApoB-ApoA1 ratio and smoking are the 2 most important risk factors and account for over two thirds of the PAR.

• Implementing preventive strategies would prevent the majority of premature CHD worldwide.

YusufS et al. Lancet. 2004;364:937-52.PAR = population attributable risk Apo= apolipoprotein

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Inter Heart Study

Multiplicative effect of risk

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2. The Volcano

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CAD in Asian Indians - RF

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Total Cholesterol and CAD

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

150 200

Total Cholesterol (mg/dL)

250 300

No CHD

CHD

Framingham Heart Study—26-Year Follow-up

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

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CADI Urban v/s Rural

Urban Delhi Rural HaryanaRisk Factor Female Male Female Male

n=1594 n=1456 n=1417 n=1070

Smoking 2.6 28.7 25.3 54.7

BMI >25 Kg/m2 48.6 35.5 11.4 7.9

“Apple” shape obesity 39.1 70.9 22.1 42.3

Hypertension 29.0 25.5 10.8 14.0

Diabetes 11.2 10.9 2.6 2.9

Cholesterol >200* 39.7 36.8 16.3 16.3

HDL Cholesterol <40* 59.9 38.7 55.9 45.6

Triglycerides >150* 39.7 45.2 29.9 33.0

*mg/dl Sethi K.K. Coronary Artery Disease in Indians, 1998

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Lp(a) in Young Indian Patients with Angiographically Proven CHD

Parameter % Patients

Total cholesterol >200 mg/dl 54.3

Triglyceride >200 mg/dl 56.1

HDL <35 mg/dl 59.6

Lp(a) >30 mg/dl 61.4

n=57; age <40 yrsMishra et al (Cuttack)

Indian Heart J 2001; 53: Abst 60

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CAD Deaths - Cholesterol

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CADI v/s FHS study

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RF in CAD – PROCAM Study

Odds Ratio for CAD when LP(a) > 20 mg

Coronary heart disease and HDL-CFramingham Heart Study

Gordon, Castelli et al. Am J Med 1977; 62: 707–714


0

50

100

150

200

Rat

e/10

00

<25 25–34 35–44 45–54 55–64 65–74 75+

HDL-C (mg/dl)

Women

Men

Relative risks of MI

3.21

3.78

1.00

2.41 Low HDL cholesterol<47 mg/dl

High HDL cholesterol47 mg/dl

Low total cholesterol<212 mg/dl

High total cholesterol212 mg/dl

Stampfer, Sacks et al. N Engl J Med 1991; 325: 373–381Stampfer, Sacks et al. N Engl J Med 1991; 325: 373–381

The Physicians Health Study

HDL-C vs LDL-C as a predictor of CHD risk

*Men aged 50–70 Gordon, Castelli et al. Am J Med 1977; 62: 707–714


100 mg/dl 160 mg/dl 220 mg/dl0

0.5

1

1.5

2

2.5

3

Risk of CAD over 4years of follow-up*

LDL-C

85 mg/dl

65 mg/dl

45 mg/dl

25 mg/dl

CHD RR

HDL-C

HDL-C is strongly predictive despite desirable TC

Miller, Circulation 1992; 86: 1165–1170Miller, Circulation 1992; 86: 1165–1170

0

10

20

30

40

50

60

70

80

HDL-C levels

Developingsubsequent CAD

events (%)75%

<35 mg/dl

45%

>35 mg/dl

Perc

enta

ge

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RF for CV Events

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

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Indian Dyslipidemia

• High Triglyceride levels

• Low levels of HDL

• High levels of small dense LDL

• Atherogenic lipoprotein phenotype (ALP)

• Moderately increase in LDL levels

Asian J Diabetol Jan-Mar 2002:15-18Lipid Disorders:Implications & Management Ed. Tripathy & Das, 2002Sethi K.K. Coronary Artery Disease in Indians, 1998

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Missing Links

• 35% to 50% of CADI only have the BIG FOUR

• Many CADI have no traditional risk factors.

• Low HDL by itself is Dyslipidemia in Indians

• Many have normal LDL but low HDL

• 30% to 50% may not have BIG four and ↓HDL

• High Lp(a), MS, ↑TG, tHCy account for most

• sLDL, ↑Fibrinogen, Inflammation, Infection

• Elevated Homocysteine in Indians (tHCy)

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Lipoprotein(a) or Lp(a)

• Similar to LDL molecule• A single apo-A is attached by a disulfide

bond to apo-B 100• Primary determinant is genetic• Normal value 20 mg %, > 30 mg high risk• It competes with plasminogen because of its

structural similarity and so interferes with plasmin synthesis and thrombolytic pathway

• Nicotinic acid, Statins, Fibrate noeffect• TRUFA ↑Lp(a) and n-3 fattys (Omega) ↓Lp(a)

Meta analysis of 27 prospective studies, 5436 CHD cases, F/u of 10 yrs

People with Lp(a) levels in the top third of baseline measurement are at about 70% increased risk of CHD compared with those in the bottom third.

Circulation, 2000, 102: 1082-1085

Serum Lp(a) is an independent risk factor for CAD in NIDDM patients in south India

Diabetes care, 1998, 21, 1819-1823

Meta analysis of 27 prospective studies, 5436 CHD cases, F/u of 10 yrs

People with Lp(a) levels in the top third of baseline measurement are at about 70% increased risk of CHD compared with those in the bottom third.

Circulation, 2000, 102: 1082-1085

Serum Lp(a) is an independent risk factor for CAD in NIDDM patients in south India

Diabetes care, 1998, 21, 1819-1823

Association of Lp(a) to CADAssociation of Lp(a) to CAD

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Multiplicative with Lp(a)

• 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

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CAD & Lp(a) – PROCAM Study

Odds Ratio for CAD LP(a) levels, TC/HDL

Hypertriglyceridemia and CHD Risk: Associated Abnormalities

Hypertriglyceridemia and CHD Risk: Associated Abnormalities

Atherogenic lipoprotein profile or Phenotype B Generation of small, dense LDL-C Association with low HDL-C

Increased coagulability plasminogen activator inhibitor (PAI-1) factor VIIc activation of prothrombin to thrombin Elevated levels of fibrinogen

Atherogenic lipoprotein profile or Phenotype B Generation of small, dense LDL-C Association with low HDL-C


The Netherlands J Med , 2000, 56:110-118

This ALP is present and seen in Insulin resistant individuals Diabetics

More prevalent in India

This ALP is present and seen in Insulin resistant individuals Diabetics

More prevalent in India

0

10

20

30

40

50

60

70

80

90

100

20 40 60 80 100 120 140 160 180 200 220 240 260 280 300 500

Phenotype A

Phenotype B

% Cumulativefrequency

TG (mg/dL)

Cumulative Distribution of Adjusted Plasma TG Levels – LDL Phenotypes A and B

Cumulative Distribution of Adjusted Plasma TG Levels – LDL Phenotypes A and B

Austin M et al. Circulation. 1990;82:495-506.

20 25 30 35 40 45 50 55 60 65 70 75 80

Phenotype A

Phenotype B

% Cumulativefrequency

HDL-C (mg/dL)

100

90

80

70

60

50

40

30

20

Cumulative Distribution of Adjusted HDL – LDL Phenotypes A and B

Cumulative Distribution of Adjusted HDL – LDL Phenotypes A and B

Austin M et al. Circulation. 1990;82:495-506.

When Tg >200 mg/dl, LDL particles will be small and dense in 90% patients

When Tg <90 mg/dl, almost all particles will be large and fluffy

The frequency of phenotype B is increased 2 fold in patients with type 2 diabetes

ALP is associated with 3-4 fold increase in the risk of CAD

When Tg >200 mg/dl, LDL particles will be small and dense in 90% patients

When Tg <90 mg/dl, almost all particles will be large and fluffy

The frequency of phenotype B is increased 2 fold in patients with type 2 diabetes

ALP is associated with 3-4 fold increase in the risk of CAD

Am J Cardiol, 1998, 82: 67U-73U

Atherogenecity of small and dense LDLAtherogenecity of small and dense LDL Generates free radicals Increased trans endothelial filteration susceptibility to oxidation Reduced affinity for the LDL receptor Increased binding to intimal proteoglycan Formation of proaggregatory /vasoconstrictor

mediators.Br J Clin Pharmacol, 48: 125-133, 1999

Associated with impaired invivo endothelial function independent of HDL, LDL, Tg.

Circulation, 2000, 102: 716-721

Generates free radicals Increased trans endothelial filteration susceptibility to oxidation Reduced affinity for the LDL receptor Increased binding to intimal proteoglycan Formation of proaggregatory /vasoconstrictor

mediators.Br J Clin Pharmacol, 48: 125-133, 1999

Associated with impaired invivo endothelial function independent of HDL, LDL, Tg.

Circulation, 2000, 102: 716-721

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2. The Volcano

3. The Tsunami














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Indian Women are Men !!

• Who said there is gender discrimination in India?

• Indian women compete with men in CAD rates

• Women CADI is one of the highest on the globe

• Pre-menopausal women enjoy protection, but

• This estrogen related protection is annulled– If the women has Lp(a) > 30 mg%– If she has developed T2DM, IGT, IFG, PCOS– If she has central adiposity (who is non cylindrical?)– If she is a smoker (in rural India women smoke more)

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2. The Volcano

3. The Tsunami














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Novel independent CHD risk factors

1. Micro Albuminuria - MAU

2. hs-CRP

3. Homocysteine (tHCy)

4. Fibrinogen

5. Erectile Dysfunction (ED)

Low intake of Zinc

Low intake of Potassium

CADI risk

enhancers

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Micro Albuminuria (MAU)

• MAU: 30-300mg albumin in urine over 24 hrs

• Occurs in DM and HT

• Not detected on ‘protein’ dipstick

• 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

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MAU – CVD risk factors

2.23.3

5.3

2.2

4.9

10.5

1 1.5 2.51

2.24.8

0

2

4

6

8

10

12

< 140 140-160 > 160 < 5.2 5.2-7.0 >7.0

2

12.5

12.1

0

1

2

3

4

5

6

F M - +Relative risk of

CHD

Gender Smoking

SBP (mmHg) Total Cholesterol (mmol/L)

Borch-Johnson K et al. 1999 (MONICA Study)

5.65.1

1.4

Normoalbuminuria

Microalbuminuria

Micro

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hs-CRP and CAD

PP<0.001<0.001

PP<0.001<0.001

PP=0.03=0.03

Quartile of hs-CRPQuartile of hs-CRP

P P Trend <0.001Trend <0.001

Re

lati

ve

Ris

k o

f M

IR

ela

tiv

e R

isk

of

MI

0

1

2

3

1 2 3 4

Ridker et al, N Engl J Med. 1997;336:973–979.

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RR of CAD - hs-CRP+TC:HDL

0.0

1.0

2.0

3.0

4.0

5.0

High Medium Low Low

Medium

High

Total Cholesterol:HDL RatioTotal Cholesterol:HDL Ratio hs-CRP

hs-CRP

Rel

ativ

e R

isk

Rel

ativ

e R

isk

Ridker et al, Circulation. 1998;97:2007–2011.

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hs-CRP interpretation

1 mg/L 3 mg/L 10 mg/L

LowRisk

ModerateRisk

HighRisk

Acute Phase ResponseIgnore Value, Repeat Test in 3

weeks

>100 mg/L

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Homocysti(e)ne

• 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

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Hyper-homocyst(e)inemia

Blood Homocyst(e)ine Levels

Classification Values in mmol/LNormalModerateIntermediateSevere

05 – 1011 – 30

31 – 100 > 100

Fibrinogen as a risk factorFibrinogen as a risk factor

A meta analysis of 12 population based study

and 6 studies in patients with pre existing

vascular disease suggest a strong

association between fibrinogen levels and

CAD risk as well as the role for fibrinogen in

predicting outcome of patients with CADI.

A meta analysis of 12 population based study

and 6 studies in patients with pre existing

vascular disease suggest a strong

association between fibrinogen levels and

CAD risk as well as the role for fibrinogen in

predicting outcome of patients with CADI.

IHJ, March-Aapril, 2000, 52: 221-225IHJ, March-Aapril, 2000, 52: 221-225

Role of fibrinogen in CAD patientsRole of fibrinogen in CAD patients In Indian population, elevated plasma fibrinogen levels

and abdominal obesity appear to be significantly associated with CAD

In Indian population, elevated plasma fibrinogen levels and abdominal obesity appear to be significantly associated with CAD

Parameters Cases ControlsParameters Cases Controls

Tc mg/dl 198 172

HDL mg/dl 25 26

Tg mg/dl 144 129

Fibrinogen mg/dl 420 305

Tc mg/dl 198 172

HDL mg/dl 25 26

Tg mg/dl 144 129

Fibrinogen mg/dl 420 305

IHJ, 1999, 51, 499-502IHJ, 1999, 51, 499-502

Hypertriglyceridemia and CHD RiskAssociated Abnormalities

Hypertriglyceridemia and CHD RiskAssociated Abnormalities



The Netherlands J Med , 2000, 56:110-118

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ED = ED

• Erectile Dysfunction = Endothelial Dysfunction

• Marker of CV Health and CVD

• Due poor NO balance at the endothelium

• Penis is the barometer of cardiovascular health

• Close questioning is essential to uncover it

• Data suggests that is more so in South Asians

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2. The Volcano

3. The Tsunami














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Atherothrombosis

Vulnerable (high risk) Plaque

+Vulnerable (high risk) Blood

=High risk (vulnerable) Patient

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“Vulnerable (hyper reactive) Blood”

Classic

• Diabetes, Smoking, Hyperlipidemia

• Inflammation/ Apoptosis/ Infection? Cathecholamines

• Fibrinogen Lp(a) Homocysteinemia

• Factor V Leiden, Platelet- Polymorph Shear rate

• Genetic Protein deficiencies (AT III, Prot C or S)

• Hypercoagulable state (↑FVII, ↑F1.2, ↑FPA)

• Hypofibrinolytic state (↑PAI-1, ↓t-PA, ↓u-PA)

Not so classic

• Depression, Circulating TF activity, Stress

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Atherothrombosis

Progression of Atherosclerosis Atherothrombosis

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Atherothrombosis

Plaque Erosion Plaque Rupture

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The Vulnerable plaque

A mild to moderate atherosclerotic plaque is more likely to rupture & trigger thrombosis (MI or Stroke) than a severe plaque.

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FoamFoamCells Cells

FattyFattyStreak Streak

IntermediateIntermediateLesion Lesion AtheromaAtheroma

FibrousFibrousPlaquePlaque

ComplicatedComplicatedLesion/ RuptureLesion/ Rupture

Adapted from Pepine CJ. Am J Cardiol. 1998;82(suppl 104).

From FirstDecade

From ThirdDecade

From FourthDecade

Endothelial DysfunctionEndothelial Dysfunction

Atherosclerosis Time Line

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How the Occlusion develops

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Acute Risk Factors of an Arterial Pressure surge or Vasoconstriction

lead to Plaque Disruption

Acute Risk Factors of an Arterial Pressure surge or Vasoconstriction

lead to Plaque Disruption

Triggering activities of patients

Triggering activities of patients

Acute Risk Factors of a coagulability Increase or Vasoconstriction lead to

complete occlusion by Thrombus

Minor Plaque Disruption

Minor Plaque Disruption

Non-Occlusive Thrombus

Non-Occlusive Thrombus

OcclusiveThrombusOcclusiveThrombus

MI or Sudden Cardiac DeathMI or Sudden Cardiac Death

Asymptomatic Unstable Angina or

Non-Q-MIMajor Plaque

DisruptionMajor Plaque

DisruptionOcclusiveThrombusOcclusiveThrombus

Non-Vulnerable Atherosclerotic

Plaque

Non-Vulnerable Atherosclerotic

Plaque

Vulnerable Atherosclero

tic Plaque

Vulnerable Atherosclero

tic Plaque

Acute Coronary Syndrome ACS

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Tissue Factor

Juno – the two-faced God

Circulating TF

Thrombosis

Vessel wall TF

Inflammation

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Circulating TF - Cellular Sources

Sambola A. Circulation 2003; 107: 973-979

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Circulating TF and Risk Factors


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Inflammation – Thrombosis Link


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Therapeutic Target - TF

Spliced TF

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2. The Volcano

3. The Tsunami



6. Who pulls the triggers ?











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Lipid Screening - a must

1. “Screening and aggressiveness of treatment for

Lipid abnormalities lagged behind that for

hyperglycemia and hypertension, despite the

simplicity and demonstrated benefit of lipid control.

2. These disparities may reflect either a traditional

emphasis on glycemic management in diabetic

patients that outweighs emphasis on other

cardiovascular risk factors, or a slow adoption of

lipid management guidelines.”

Am J Med, June 1, 2002, Vol. 112: 603-609

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Moving Beyond LDL

1. Characteristic lipid abnormalities, such as high triglycerides and low HDL, Lp(a) with normal LDL values, are common in association with insulin resistance in South Asians.

2. Hence, European/ American recommendations on the use of statins as first-line agents may not be entirely applicable to all populations.”

3. Normal total cholesterol and normal LDL may operate as risk factors in the presence of the above RFs in South Asia populations.

Lancet 2002;360:1015-18

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Physical Activity

• Reduces all-cause mortality

• Reduces incidence and fatality of CHD

• Reduces risk of NIDDM

• Reduces BP, Improves Lipids, CCF

• Improves well being, psychological factors

• Key component in weight loss regimens

• Benefits occur at any age

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Physical Activity

• What type of activity?• How much?• How often?• At what intensity?

The answer is

The health benefits of physical activity are

proportionately related to “Exercise Volume”

Exercise Volume = Duration x Frequency x Intensity

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Take Home Points on C A D I

• High Rates – 2 to 4 fold prevalence, Incidence, Death

• Greater prematurity – 10 yrs earlier, 5 to 10 fold↑in < 40

• Greater severity – 3 vessel disease in young ♂ and ♀

• ↑prevalence of Glucose Intolerance, IRS, DM, abd. obese

• ↓prevalence of conventional RF, HT, Obesity, LDL, Smoker

• Higher rates of CAD at any given level of the big four RF

• Lower cut off values for intervention (like for diabetics)

• ↑levels of Lp(a), ApoB, ALP, sLDL, tHCy, PAI-1,↓HDL (2b)

• ↑CVD for lesser degree of atherosclerosis - ? Inflamation

• Higher % of unstable or vulnerable plaques - ? Infections

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Recommendations on Testing

1. Look for Metabolic Syndrome in every one above 20 yrs

2. Waist circumference and not BMI alone is to be recorded

3. Screen FBG and PPBG from age 20 years (earlier if F H+)

4. Lp(a) and tHCy at least once around 20 years or even early

5. If abnormal, follow up after due interventions

6. Full lipid profile at 20 yrs, Repeat every 5 yrs or 5 Kgs

7. 20% lower cut off values LDL than global guide lines

8. 10% lower cut off values for other lipids, higher for HDL

9. BMI cut off 23, IFG cut off 100 mg%, WC 90 ♂ and 85 ♀

10.Heart healthy life style and food habits form childhood itself

Enas A Enas et al, Int J Cardio, 2003

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Secondary Prevention of CAD

Where are we heading ??

Journal of internal medicine 2003:254(2):114-25

20000 B.C. 2006

Hunting-gatheringsubsistence

High level ofphysical activity

Processedfoods

Animal fatsand glucidesDietary fibre¯

Sedentary life

Paleolithic sup. age Neolithic age 19th century 21st century

Thrifty genotype Susceptibility genotype

Technology has changed a lot the way we live

But, we have not altered our lifestyle

We have to pay the very heavy price !!

What could be prevented, we treat or leave

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Should we not prevent CADI ?

- Huang Dee : Nia-Ching 2600 B.C. 1st Chinese Medical Text

Superior Doctors –

Prevent disease

Average Doctors –

Treat before its evident

Inferior Doctors –

Wait until its full blown

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150

CD ROM Available

The contents of my today’s presentations

are made available in a CD-ROM format

This CD, in addition, contains my talks on

Asthma, COPD, Hypertension, ECG, CAD

Dyslipidemias, Diabetes, Osteoporosis…

visit us at : www.drsarma.in

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151Grand Parenthood

A Place Called Love

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