© 2010 CV Health: Three Ways to ‘kNOw’ Kathleen O’Neil-Smith, MD Malden, MA

© 2010

CV Health: Three Ways to ‘kNOw’

Kathleen O’Neil-Smith, MDMalden, MA

© 2010© 2010 2

Learning Objectives:

• Know Your Number– LDL-Particle # VS. LDL-Cholesterol as a

determinant of risk and treatment

• ‘No’ Inflammation– hs-CRP and JUPITER– LpPLA2 is a marker of vascular inflammation

• Know degree of Insulin Resistance– Lipid Metabolism in insulin resistance– Relationship between inflammation and insulin

resistance

© 2010© 2010 3


© 2010© 2010 4

Coronary Heart Diseasein the United States

• CHD is the single largest killer of men and women

• Each year 1.1 million people experience an MI

• 12 million have history of MI and/or angina

• 53.3 million adults have elevated LDL-C and warrant intervention

• By age 60, every 5th man and 17th woman develops CHD

• 1999 estimated direct and indirect costs of heart disease are $99.8 billion

© 2010© 2010 5

Heart Disease = Leading Cause of Death, Stroke = 2nd/3rd Leading

Cause of Death

631,636

559,888

137,119 121,599

72,449

0

200,000

400,000

600,000

800,000

1,000,000

HeartDisease

Cancer Stroke Accidents Diabetes

National Center for Health Statistics 2006.

315,000

82,00071,000 65,000

41,000

0

50,000

100,000

150,000

200,000

250,000

300,000

350,000

HeartDisease

Stroke LungCancer

COPD Breast Cancer

National Heart, Lung and Blood Institute, 2006

Total Leading Causesof Death in the US

Leading Causes of Death for American Women

© 2010© 2010 6

© 2010© 2010 7

Sub-fractionation improves detection of people at

cardiovascular riskThese 30

patients would not have been identified as

being at increased

CardioVascular risk.

Superko,HR Am J Cardiol 2001;88:260-64

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Traditional Risk Factors»Lipid Markers»~55 % of CAD

Cardiovascular Profile»Lipid Markers»Inflammatory Risk Markers»>70 % of CAD

Advanced Cardiovascular Profile»Advanced Lipid Profile w/ fractionation»Risk Markers of Inflammation»Insulin Resistance

>84 % of CAD

© 2010© 2010 9

Current guidelines for lipid management

LDL Cholesterol: The Primary Target of Therapy

JAMA, May 16, 2001

© 2010© 2010 10

Limitations of LDL in Predicting CHD

Framingham Heart Study - 26 year follow-up

• 50% of persons who develop CAD are missed with the routine lipid panel

• 80% of MI patient population have similar cholesterol levels as those who did not have an MI1

Elevated LDL-cholesterol is only one lipid abnormality associated with CHD2

• As little as 25% of premature CHD is attributable to elevated LDL-C values

1Castelli W, Atherosclerosis 1996; 124: S1-S92Genest J Jr, et al. J Am Coll Cardiol 1992;19:792-802

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HDL

LDL

Standard Lipid Profile

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Patients with smaller LDL size have greater CHD risk at any given level

of LDL-C.

Patients with smaller LDL size have greater CHD risk at any given level

of LDL-C.

CholesterolBalance

130 mg/dL 130 mg/dL

Large LDL(Pattern A)

Small LDL(Pattern B)

Higher riskLower risk

© 2010© 2010 13

Patients with greater LDL-P have greater CHD risk at any given level

of LDL-C.

Patients with greater LDL-P have greater CHD risk at any given level

of LDL-C.

CholesterolBalance

130 mg/dL 130 mg/dL

Large LDL(Pattern A)

Small LDL(Pattern B)

Higher riskLower risk

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Up to 70%More Particles

Small LDL

Large LDL

CholesterolBalance

100 mg/dL 100 mg/dL

At The Same LDL-C Level, Number of LDL Particles

Varies

At The Same LDL-C Level, Number of LDL Particles

Varies

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Car

oti

d IM

T (

mic

ron

s)

800

850

900

950

1000

Q1

<1055

Q2

1055-1285

Q3

1285-1545

Q4

>1545

Carotid Atherosclerosis in MESA*LDL-C <100 mg/dL (n=1,425)

LDL Particle Number

n=888

n=352n=153

n=32

Concordant with LDL-C

© 2010© 2010 16

Car

oti

d IM

T (

mic

ron

s)

800

850

900

950

1000

Q1

<1055

Q2

1055-1285

Q3

1285-1545

Q4

>1545LDL Particle Number

n=349

n=499

n=371

n=143

Carotid Atherosclerosis in MESA*LDL-C = 100-130 mg/dL (n=1,362)

Concordant with LDL-C

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Weight of EvidenceWeight of Evidence

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CHD Event Associations of LDL-P versus LDL-C

Framingham Offspring Study (n=3,066)

0.74

0.76

0.78

0.80

0.82

0.84

0.86

0.88

0.90

0.92

0.94

0.96

0.98

1.00

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Years of Follow-up

Eve

nt-

Fre

e S

urv

ival

Cromwell WC et al. J Clin Lipidology 2007;1(6):583-592.

Concordant

Discordant

© 2010© 2010 20

0.74

0.76

0.78

0.80

0.82

0.84

0.86

0.88

0.90

0.92

0.94

0.96

0.98

1.00

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Years of Follow-up

Eve

nt-

Fre

e S

urv

ival

Low LDL-CLow LDL-P (n=1,249)

High LDL-CHigh LDL-P (n=1,251)

Better survivalLower risk

Worse survivalHigher risk

Concordant

Discordant




© 2010© 2010 21

0.74

0.76

0.78

0.80

0.82

0.84

0.86

0.88

0.90

0.92

0.94

0.96

0.98

1.00

0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16

Years of Follow-up

Eve

nt-

Fre

e S

urv

ival

Low LDL-CHigh LDL-P (n=282)

High LDL-CLow LDL-P (n=284)



0 . 7 4

0 . 7 6

0 . 7 8

0 . 8 0

0 . 8 2

0 . 8 4

0 . 8 6

0 . 8 8

0 . 9 0

0 . 9 2

0 . 9 4

0 . 9 6

0 . 9 8

1 . 0 0

0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 1 5 1 6

Pro

babi

lity

of E

vent

-Fre

e S

urvi

val

Years of Follow-up

0 . 7 4

0 . 7 6

0 . 7 8

0 . 8 0

0 . 8 2

0 . 8 4

0 . 8 6

0 . 8 8

0 . 9 0

0 . 9 2

0 . 9 4

0 . 9 6

0 . 9 8

1 . 0 0

0 1 2 3 4 5 6 7 8 9 1 0 1 1 1 2 1 3 1 4 1 5 1 6

Pro

babi

lity

of E

vent

-Fre

e S

urvi

val

Years of Follow-up

Low LDL-CLow LDL-P (n=1,249)

High LDL-CHigh LDL-P (n=1,251)



Low LDL-CHigh LDL-P (n=282)

High LDL-CLow LDL-P (n=284)

Concordant

Discordant




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ADA and ACC Consensus Statement In

Patients at Risk

• A more accurate way to capture the risk posed by LDL may be to measure the number of LDL particles directly using nuclear magnetic resonance (NMR)

• “Many cross-sectional and prospective studies show that LDL particle number is a better discriminator of risk than is LDL cholesterol.”

• Measurements of apoB or LDL particle number by NMR more closely quantitate the atherogenic lipoprotein load.

Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822

SummarySummary

© 2010© 2010 23

ADA and ACC Consensus Statement In

Patients at Risk

• ApoB and LDL particle number also appear to be more discriminating measures of the adequacy of LDL lowering therapy than are LDL cholesterol or non-HDL cholesterol.”

• ApoB and LDL particle concentration also appear to be more closely associated with obesity, diabetes, insulin resistance, and other markers of CMR than LDL cholesterol or non-HDL cholesterol.”

SummarySummary

Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:811-822

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LDL Lowering Drugs Reduce LDL-P

LDL Lowering Drugs Reduce LDL-P

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Treatments that Change LDL-C & LDL-P Differentially Cholesterol per particle

decreases with:

• statins

• statin + ezetimibe

• estrogen replacement therapy

• anti-retrovirals (some)

• low fat, high carb diet

LDL-C More

Cholesterol per particle increases with:

• fibrates

• niacin

• glitazones

• omega 3 FAs

• exercise

• low carb diet

LDL-P More

© 2010© 2010 27

© 2008© 2010

InflammationSystemic & Vascular

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The Causes of Inflammation

• Diet– Sugar– Trans and saturated fats– Polyunsaturated omega 6 oils (except GLA)– Insufficient fruits and vegetables

• Stress• Lack of exercise• Toxins (metals, petrochemicals)• Infections – esp. dental• Obesity/ Insulin Resistance

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Hepatic Source of Inflammatory Markers: hs-CRP and Fibrinogen

Rader. N Engl J Med 2000;343:1179.

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Kuller MRFIT1996 CHD deathRidker PHS 1997 MIRidker PHS1997 StrokeTracy CHS/RHPP1997 CHDRidker PHS1998,2001 PADRidker WHS 1998,2000,2002 CVDKoenig MONICA1999 CHDRoivainen HELSINKI 2000 CHDMendall CAERPHILLY 2000 CHDDanesh BRITAIN 2000 CHDGussekloo LEIDEN 2001 Fatal StrokeLowe SPEEDWELL 2001 CHDPackard WOSCOPS 2001 CV EventsRidker AFCAPS 2001 CV EventsRost FHS 2001 StrokePradhan WHI 2002 MI, CVD death Albert PHS 2002 Sudden Death

0 1.0 2.0 3.0 4.0 5.0 6.0Relative Risk (upper versus lower quartile)

Ridker PM. Circulation 2003;107:363-369

hs-CRP = Risk Factor for CVD

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C-Reactive Protein• Marker of inflammation, infection and injury

– Aspirin’s reduction of MI risk appears to be related to CRP levels

– CRP activates complement which injures the inner layer of blood vessels constriction of vessels, arrhythmia

• Strong predictor of the risk of future MIJUPITER Study – November, 2008• 49% decrease in CDA end-points• 20% decrease in ‘all cause’ mortality!• 40% of participants had insulin resistance. . .

© 2010© 2010 34

Lipoprotein-associated phospholipase A2 (Lp-PLA2, also known as PLAC) is an enzyme produced by intimal-based macrophages and foam cells in the early stages of atherosclerotic plaque formation.

Lp-PLA2 activity promotes inflammation and plaque instability. Levels of Lp-PLA2 reflect atherosclerosis disease activity as opposed to plaque burden. This is significant because most heart attacks and sudden coronary deaths are attributable toplaque rupture at sites of only moderate stenosis.

Lp-PLA2

© 2010© 2010 35Gorelick PB, et al. Am J Card Suppl 2008.

© 2010© 2010 36

Unadjusted Adjusted for age Multivariable DM, smoking adjustment*

CRP ≤ 3 mg/L Lp-PLA2 < 290.8 ng/mL

N=447

CRP > 3 mg/LLp-PLA2 < 290.8 ng/mL

N=176

CRP ≤ 3 mg/LLp-PLA2 ≥ 290.8 ng/mL

N=203

CRP > 3 mg/LLp-PLA2 ≥ 290.8 ng/mL

N=108

Additive Effect of CRP and Lp-PLA2 in Coronary Risk Prediction: MONICA

Haza

rd R

atio

(95%

CI)

Koenig et al. (AHA 2003)

© 2010© 2010 37

Summary and Conclusions

Lp-PLA2 was the strongest predictor/biomarker of coronary events, and was independent of traditional and emerging risk factors, including CRP in hyperlipidemic individuals (WOSCOPS)

In particular, in individuals with low LDL-C (<130 mg/dL), levels of Lp-PLA2 were independently associated with incident CHD in multivariable analysis including CRP (ARIC)

Lp-PLA2 was predictive of coronary events in a population-based sample of initially healthy middle-aged men with moderately elevated total cholesterol levels during long-term FU of 14 years (MONICA cohort)

© 2010© 2010 38

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Inflammation and Insulin Resistance

Cause and Effect

© 2010© 2010 41

Obesity Trends* Among U.S. AdultsBRFSS, 1986

(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)

No Data <10% 10%–14%

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No Data <10% 10%–14% > 15%

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No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

© 2010© 2010 44

High Glycemic Diet

Genetic propensity

InsulinResistance

Elevated fasting and postprandial

Insulin & glucose blood levels

Visceral Adiposity

Lack of Exercise

Smoking

Chronic Stress Inflammation

Antecedents, Triggers and Mediators

© 2010© 2010 45

Rates of CardioMetabolic Syndrome

BMI < 25 BMI 25-30 BMI >30

MEN 30% 51% 71%

WOMEN 21% 43% 65%

TOTAL 26% 46% 68%

© 2010© 2010 47

DyslipidemiaHyperglycemiaHypertension

Insulin Insulin ResistanceResistance

Abdominal Abdominal ObesityObesity

Oxidative Oxidative StressStress

(free radicals)

InflammationInflammation

LDL oxidationPlaque formationAtherosclerosis

Increased coagulation

Heart DiseaseHeart DiseaseDiabetes MellitusDiabetes Mellitus

© 2010© 2010 48

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LDL ParticleNumber (LDL-P)

LDL Size

VLDL ParticleNumber (VLDL-P)

VLDL Size

HDL ParticleNumber (HDL-P)

HDL Size

Insulin Resistance – Changes in Lipid Fractions

LargeVLDL

MediumVLDL

SmallVLDL

LargeLDL

SmallLDL

IDL LargeHDL

SmallHDL

MedHDL

Lipoprotein Subclass Particle Numbers:

© 2010© 2010 51

© 2010© 2010 52

Lipid Markers

Independent Risk Factors

Insulin Resistance Score by Lipid Fractionation

© 2010© 2010 53

Lipid Markers



© 2010© 2010 54

Lipid Markers



© 2010© 2010 55

The Clinical Approach We know the problem and the magnitude and we

see pts daily so my answer is simple: Obesity is of major concern, it increases cardiometabolic risks

We know insulin resistance is a major cause of obesity (at least 70%)

Clinical trials have proven insulin sensitivity can be improved through lifestyle modification and 5-10% reduction in body weight improves insulin sensitivity, lipid profiles, endothelial function, reduces thrombosis and inflammatory markers

There is a 3-fold increase in the odds that a patient will attempt weight loss if it is recommended by a trusted health care professional

© 2010© 2010 56

© 2010© 2010 57

ConclusionsAlthough the causes of obesity are many;

insulin resistance and the resulting hyperinsulinemia is a major cause.

Emphasis should be on early identification of those patients who are insulin resistant for aggressive targeted intervention.

Diet, lifestyle and targeted nutritional/botanical supplementation (medical nutrition) can positively effect insulin sensitivity and lead to improved outcomes.

By looking for, identifying and treating early insulin resistance the current trends of obesity can be not only treated but reversed as well.

© 2010© 2010 58

How to use Advanced CV Risk Assessment

Screening Guidelines from NCEP:– All adults > 20 years of age should be screened

with a fasting lipid panel every 5 years.– Advanced CV Risk Assessment optimizes case

identification in high risk patients– Advanced CV Risk Assessment is able to monitor

treatment response …optimizing lipid fractionation and independent factors in high risk patients.

© 2010© 2010 59

Who is HIGH RISK?

– All men >40 years old.– All women >50 years old.– Anyone with a family history of heart disease, MI, or

stroke– Anyone who is over-weight/ obese.– Anyone with hypertension, diabetes, or elevated

traditional lipid markers.– Smokers

THIS COMPRISES many patients – but it is not for

everybody!

© 2010© 2010 60


• Know Your Number– LDL-Particle # VS. LDL-Cholesterol as a

determinant of risk and treatment

• ‘No’ Inflammation– hs-CRP and JUPITER

• Know your degree of Insulin Resistance– Lipid Metabolism in insulin resistance– Relationship between inflammation and insulin

resistance

Documents

© 2010 CV Health: Three Ways to ‘kNOw’ Kathleen O’Neil-Smith, MD Malden, MA