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

2. Learning Objectives: Know Your Number ‘No’ Inflammation
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

3. Learning Objectives:

4. Coronary Heart Disease in 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
© Dr. Mary James and GSDL 2003

5. Heart Disease = Leading Cause of Death, Stroke = 2nd/3rd Leading Cause of Death
Total Leading Causes of Death in the US
Leading Causes of Death for American Women
315,000
82,000
71,000
65,000
41,000
50,000
100,000
150,000
200,000
250,000
300,000
350,000
Heart
Disease
Stroke
Lung Cancer
COPD
Breast Cancer
National Center for Health Statistics 2006.
National Heart, Lung and Blood Institute, 2006 5

7. Sub-fractionation improves detection of people at cardiovascular risk
These 30 patients would not have been identified as being at increased CardioVascular risk.
Superko,HR Am J Cardiol 2001;88:260-64
© Dr. Mary James and GSDL 2003

8. >84 % of CAD >70 % of CAD Lipid Markers ~55 % of CAD
Traditional Risk Factors
Lipid Markers
~55 % of CAD
Cardiovascular Profile
Inflammatory Risk Markers
>70 % of CAD
Advanced Cardiovascular Profile
Advanced Lipid Profile w/ fractionation
Risk Markers of Inflammation
Insulin Resistance
>84 % of CAD
© Dr. Mary James and GSDL 2003

9. Current guidelines for lipid management
LDL Cholesterol: The Primary Target of Therapy
JAMA, May 16, 2001
© Dr. Mary James and GSDL 2003

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
In Framingham, 50% of patients with normal routine lipid panels still develop CAD
LDL-cholesterol levels fail to differentiate populations of individuals with and without CHD. As seen in the Framingham Heart Study, 26 year follow-up data reveals that LDL-cholesterol levels were the same in 80 percent of patients who experienced a myocardial infarction (MI) versus those who did not experience an event.
This limitation is more acute in patients with premature CHD. Due to the presence of non-LDL lipoprotein abnormalities, only some of which are associated with LDL-cholesterol elevations, as few as 25 percent of premature CHD patients have LDL-cholesterol elevations over 130 mg/dl.
1Castelli W, Atherosclerosis 1996; 124: S1-S9
2Genest J Jr, et al. J Am Coll Cardiol 1992;19:
© Dr. Mary James and GSDL 2003

11. Standard Lipid Profile
LDL
HDL
© Dr. Mary James and GSDL 2003

12. Patients with smaller LDL size have greater CHD risk at any given level of LDL-C.
Lower risk
Higher risk
Cholesterol
Balance
130 mg/dL
But I want to introduce another aspect of the characteristics of people with small, dense LDL. At any given level of LDL cholesterol, if you have smaller LDL particles, by definition you have more of them. These are containers for cholesterol. The smaller the container, the less cholesterol it carries. So this relationship always holds.
And so the question needs to be asked, and it was introduced in the previous talk: Is the greater risk associated with small, dense LDL actually caused by the size of LDL or is LDL size simply a marker for the fact that these folks have more LDL particles and it’s the greater number of LDL particles that’s responsible for the higher risk. So that’s really the key point where there is disagreement.
Large LDL
(Pattern A)
Small LDL
(Pattern B)

13. Patients with greater LDL-P have greater CHD risk at any given level of LDL-C.
Lower risk
Higher risk
Cholesterol
Balance
130 mg/dL
But I want to introduce another aspect of the characteristics of people with small, dense LDL. At any given level of LDL cholesterol, if you have smaller LDL particles, by definition you have more of them. These are containers for cholesterol. The smaller the container, the less cholesterol it carries. So this relationship always holds.
And so the question needs to be asked, and it was introduced in the previous talk: Is the greater risk associated with small, dense LDL actually caused by the size of LDL or is LDL size simply a marker for the fact that these folks have more LDL particles and it’s the greater number of LDL particles that’s responsible for the higher risk. So that’s really the key point where there is disagreement.
Large LDL
(Pattern A)
Small LDL
(Pattern B)

14. At The Same LDL-C Level, Number of LDL Particles Varies
Up to 70%
More Particles
Cholesterol
Balance
100 mg/dL
Large LDL
Small LDL
Two patients with 100 mg/dL LDL-cholesterol. The patient on the left has fewer particles because more cholesterol is being carried in each particle, and they are cholesterol enriched. The patient on the right has more particles because they are cholesterol depleted

15. Carotid Atherosclerosis in MESA*
LDL-C <100 mg/dL (n=1,425)
Carotid IMT (microns) Q1
<1055 Q2 Q3 Q4
>1545
n=32
Concordant
with LDL-C
n=153
n=352
n=888
Why do I say that? This slide shows the adjusted IMT values of these different groups of individuals, all with low LDL-C - the green concordant group and the yellow and red discordant groups. These are increasing quartiles of LDL particle number. The concordant group (green) with the lowest LDL-P has the lowest carotid IMT. When LDL particle number is higher (Q2) the atherosclerosis is higher. When LDL particle number is much higher (Q3 and Q4), the atherosclerosis is much higher. Note that these are analyses adjusted not only for non-lipid variables, but also for HDL-C and TG. So despite the fact you might expect the cardiovascular disease risk, or the atherosclerosis in this case, to be greater among those with lower LDL size, lower HDL-C and higher triglycerides, these data show that at least a portion of the reason for the higher atherosclerosis in these low LDL-C individuals is their increased LDL particle number.
LDL Particle Number

16. Carotid Atherosclerosis in MESA*
LDL-C = mg/dL (n=1,362)
n=143
Concordant
with LDL-C
n=371
Carotid IMT (microns)
n=499
n=349
So let’s look at what the carotid atherosclerosis of these groups tells us. Here’s the concordant group in yellow. When LDL-P is lower (green), completely independent of everything else, atherosclerosis is lower. When LDL-P is higher (red), atherosclerosis is clearly higher – and there is a strong, almost linear, graded relationship with atherosclerosis, independent of other lipid and non-lipid risk factors. To me, this data is very informative and has important implications for the management of LDL-related CVD risk. Q1
<1055 Q2 Q3 Q4
>1545
LDL Particle Number

17. Weight of Evidence
LDL-C levels have long been the guideline directed focus and goal for the treatment of atherosclerosis in order to reduce risk of CVD. There is ongoing evidence that shows many patients who have reached target LDL-C levels have a high residual risk for CVD, due to an increased concentration of atherogenic low density lipoproteins (LDL-P).
The next part of the presentation will review the data from some of these studies.

19. CHD Event Associations of LDL-P versus LDL-C
Framingham Offspring Study (n=3,066)
Event-Free Survival
Concordant
Discordant
Years of Follow-up
Cromwell WC et al. J Clin Lipidology 2007;1(6):

20. CHD Event Associations of LDL-P versus LDL-C
Framingham Offspring Study (n=3,066)
Better survival
Lower risk
Worse survival
Higher risk
Low LDL-C
Low LDL-P
(n=1,249)
High LDL-C
High LDL-P
(n=1,251)
Event-Free Survival
Concordant
Discordant
Years of Follow-up
Cromwell WC et al. J Clin Lipidology 2007;1(6):

21. CHD Event Associations of LDL-P versus LDL-C
Framingham Offspring Study (n=3,066)
Years of Follow-up
Event-Free Survival
Low LDL-C
High LDL-P
(n=282)
High LDL-C
Low LDL-P
(n=284)
Better survival
Lower risk
Worse survival
Higher risk
(n=1,249)
(n=1,251)
Concordant
Discordant
Cromwell WC et al. J Clin Lipidology 2007;1(6):

22. ADA and ACC Consensus Statement In Patients at Risk
Summary
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:
Thomas Dayspring MD

23. ADA and ACC Consensus Statement In Patients at Risk
Summary
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.”
Brunzell JD, Davidson M, Furberg CD et al. Diabetes Care 2008;31:
Thomas Dayspring MD

24. LDL Lowering Drugs Reduce LDL-P
Current lipid modifying therapies exert unique effects on lipoprotein particle number and size.
In terms of low-density lipoprotein (LDL), “statins” (HMG Co A reductase inhibitors) afford the greatest reduction in LDL particle concentration. The magnitude of particle reduction is greatest for high potency statins and least for low potency statins. Niacin primarily increases LDL particle size and secondarily reduces particle concentration. Likewise, fibrates, through their triglyceride lowering properties, primarily increase LDL particle size and have the ability to reduce LDL particle number.
High-density lipoprotein (HDL) levels are increased most significantly in response to niacin therapy, followed by fibrates and statins. The particle population enhanced to the greatest extent on all pharmacologic therapies is the cardio-protective large subclass. Recent statin trials also demonstrate that the group achieving the greatest HDL particle benefit is the group with low HDL-cholesterol levels (< 35 mg/dL) at baseline.

25. Treatment Statins lower total LDL but don’t change particle size
Niacin, fenofibrate, aspirin, exercise, and weight loss increase LDL particle size

26. 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

28. Inflammation Systemic & Vascular

29. 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

30. Inflammation
Story of Pier’s friend - tried all - stapling but no change till gluten - and inflammation

31. Hepatic Source of Inflammatory Markers: hs-CRP and Fibrinogen
Rader. N Engl J Med 2000;343:1179.

32. hs-CRP = Risk Factor for CVD
Kuller MRFIT CHD death
Ridker PHS MI
Ridker PHS Stroke
Tracy CHS/RHPP CHD
Ridker PHS1998, PAD
Ridker WHS 1998,2000, CVD
Koenig MONICA CHD
Roivainen HELSINKI CHD
Mendall CAERPHILLY CHD
Danesh BRITAIN CHD
Gussekloo LEIDEN Fatal Stroke
Lowe SPEEDWELL CHD
Packard WOSCOPS CV Events
Ridker AFCAPS CV Events
Rost FHS Stroke
Pradhan WHI MI, CVD death
Albert PHS Sudden Death
Relative Risk (upper versus lower quartile)
Ridker PM. Circulation 2003;107:

33. 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 MI
JUPITER Study – November, 2008
49% decrease in CDA end-points
20% decrease in ‘all cause’ mortality!
40% of participants had insulin resistance. . .
© Dr. Mary James and GSDL 2003

34. Lp-PLA2
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 to
plaque rupture at sites of only moderate stenosis.
The PLAC Test for Lp-PLA2 is the only FDA-cleared blood test that helps identify hidden risk for both heart attack and stroke. Early detection and more aggressive treatment can help prevent these cardiovascular events.
The PLAC Test measures Lp-PLA2 (lipoprotein-associated phospholipase A2), a vascular-specific inflammatory enzyme implicated in the formation of rupture-prone plaque. It is plaque rupture and thrombosis, not stenosis, that cause the majority of cardiac events.
50% of cardiovascular events strike in patients with unremarkable lipid levels, highlighting the prevalence of hidden cardiovascular risk.
A substantial body of evidence including over 50 studies and abstracts in peer-reviewed journals and conferences support Lp-PLA2 as a cardiovascular risk marker that provides new information, over and above traditional risk factors.
Consistent with ATP III guidelines, the PLAC Test should be used as an adjunct to traditional risk factors assessment to identify which moderate or high risk patients, as initially assessed by traditional risk factors, may actually be at higher risk.
An elevated PLAC Test may indicate a need for more aggressive therapy, including treatment to lower LDL-C goals. Lipid lowering therapies, including statins, are proven to reduce cardiovascular events regardless of baseline LDL-C levels.
The PLAC Test is the only blood test cleared by the FDA to aid in assessing risk for both coronary heart disease and ischemic stroke associated with atherosclerosis. Since LDL has proven not to be a reliable predictor of stroke, the PLAC Test addresses this unmet clinical need.
The PLAC Test is covered by Medicare at $47.43 and by a growing number of private payers. However, patients may be required to pay out-of-pocket – a small investment in their future health.

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

36. Additive Effect of CRP and Lp-PLA2 in Coronary Risk Prediction: MONICA
CRP ≤ 3 mg/L
Lp-PLA2 < ng/mL
N=447
CRP > 3 mg/L
N=176
Lp-PLA2 ≥ ng/mL
N=203
N=108
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
6.0
Ref.
Hazard Ratio (95% CI)
Unadjusted Adjusted for age Multivariable
DM, smoking adjustment*
Koenig et al. (AHA 2003)

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)

39. Inflammation and Insulin Resistance Cause and Effect

40. NCEP/ ATP III
National Cholesterol Education Program Adult Treatment Panel III
Standard guidelines used by MDs
Focus on identifying early risk & prevention
New criteria for ‘CardioMetabolic Syndrome’
Increased waist/hip ratio
Hypertension > 130/85
Fasting Glucose >100
Elevated Triglycerides > 150
Decreased HDL < 40 [m], < 50 [f]
© Dr. Mary James and GSDL 2003

41. Obesity Trends* Among U.S. Adults BRFSS, 1986
(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)
No Data <10% %–14%

42. Obesity Trends* Among U.S. Adults BRFSS, 1996
(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)
No Data <10% %–14% > 15%

43. Obesity Trends* Among U.S. Adults BRFSS, 2006
(*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person)
We have never had an epidemic like this that we have been able to track so thoroughly and see. As I told you, this is conservative.
About 60 million adults, or 30 percent of the adult population, are now obese, which represents a doubling of the rate since 1980.
No Data <10% %–14% %–19% %–24% %–29% ≥30%

44. Antecedents, Triggers and Mediators
Genetic propensity
Inflammation
Chronic Stress
High Glycemic Diet
Visceral Adiposity
Lack of Exercise
Smoking
Insulin Resistance
Elevated fasting and postprandial
Insulin & glucose blood levels
FM approach must look at ATM’s

45. Rates of CardioMetabolic Syndrome
BMI < 25
BMI 25-30
BMI >30
MEN
30%
51%
71%
WOMEN
21%
43%
65%
TOTAL
26%
46%
68%

46. Continuum of Insulin Resistance
Wellness
Illness
Insulin Sensitive Insulin Resistance Insulin Resistance Diabetes Compensated Non-compensated
Health No Symptoms Symptoms/Pathology

47. Increased coagulation
Heart Disease
Diabetes Mellitus
Insulin Resistance
LDL oxidation
Plaque formation
Atherosclerosis
Increased coagulation
Abdominal Obesity
Dyslipidemia
Hyperglycemia
Hypertension
(This collection of factors creates the “perfect storm” in terms of disease risk.)
Throughout the course of this presentation, we’ll explore how the intimate relationships between these factors– IR, obesity, and inflammation—creates, in essence, the ‘perfect storm’ for CVD and DM.
Inflammation
Oxidative Stress
(free radicals)

50. Changes in Lipid Fractions
Insulin Resistance –
Changes in Lipid Fractions
Lipoprotein Subclass Particle Numbers:
Large
VLDL
Medium
VLDL
Small
VLDL
IDL
Large
LDL
Small
LDL
Large
HDL
Med
HDL
Small
HDL
VLDL Particle
Number (VLDL-P)
VLDL Size
LDL Particle
Number (LDL-P)
LDL Size
HDL Particle
Number (HDL-P)
HDL Size

52. Independent Risk Factors
Lipid Markers
Independent Risk Factors
71 yo Arab man on statins C
Insulin Resistance Score by Lipid Fractionation

53. Independent Risk Factors
Lipid Markers
Independent Risk Factors
49yo male on very, very low fat diet C
Insulin Resistance Score by Lipid Fractionation

54. Independent Risk Factors
Lipid Markers
Independent Risk Factors
32yo male with +FHx of MI, comes for evaluation of CHOL. MD wants LDL-C <100. C
Insulin Resistance Score by Lipid Fractionation

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

57. Conclusions
Although 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.

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.
© Dr. Mary James and GSDL 2003

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!
© Dr. Mary James and GSDL 2003

60. Learning Objectives: Know Your Number ‘No’ Inflammation
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