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

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Presentation on theme: "© 2010 CV Health: Three Ways to ‘kNOw’ Kathleen O’Neil-Smith, MD Malden, MA."— Presentation transcript:

1 © 2010 CV Health: Three Ways to ‘kNOw’ Kathleen O’Neil-Smith, MD Malden, MA

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

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

5 © Heart Disease = Leading Cause of Death, Stroke = 2 nd /3rd Leading Cause of Death National Center for Health Statistics ,000 82,000 71,000 65,000 41, , , , , , , ,000 Heart Disease StrokeLung Cancer COPDBreast Cancer National Heart, Lung and Blood Institute, 2006 Total Leading Causes of Death in the US Leading Causes of Death for American Women

6 ©

7 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

8 © 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

9 © Current guidelines for lipid management LDL Cholesterol: The Primary Target of Therapy JAMA, May 16, 2001

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 MI 1 Elevated LDL-cholesterol is only one lipid abnormality associated with CHD 2 As little as 25% of premature CHD is attributable to elevated LDL-C values 1 Castelli W, Atherosclerosis 1996; 124: S1-S9 2 Genest J Jr, et al. J Am Coll Cardiol 1992;19:

11 © HDL LDL Standard Lipid Profile

12 © Patients with smaller LDL size have greater CHD risk at any given level of LDL-C. Cholesterol Balance 130 mg/dL Large LDL (Pattern A) Small LDL (Pattern B) Higher risk Lower risk

13 © Patients with greater LDL-P have greater CHD risk at any given level of LDL-C. Cholesterol Balance 130 mg/dL Large LDL (Pattern A) Small LDL (Pattern B) Higher risk Lower risk

14 © Up to 70% More Particles Small LDL Large LDL Cholesterol Balance 100 mg/dL At The Same LDL-C Level, Number of LDL Particles Varies

15 © Carotid IMT (microns) Q1 <1055 Q Q Q4 >1545 Carotid Atherosclerosis in MESA* LDL-C <100 mg/dL (n=1,425) LDL Particle Number n=888 n=352 n=153 n=32 Concordant with LDL-C

16 © Carotid IMT (microns) Q1 <1055 Q Q Q4 >1545 LDL Particle Number n=349 n=499 n =371 n=143 Carotid Atherosclerosis in MESA* LDL-C = mg/dL (n=1,362) Concordant with LDL-C

17 © Weight of Evidence

18 ©

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

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

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

22 © 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: SummarySummary

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:

24 © LDL Lowering Drugs Reduce LDL-P

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

27 ©

28 © 2008 © 2010 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

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

32 © Kuller MRFIT 1996 CHD death Ridker PHS 1997 MI Ridker PHS 1997 Stroke Tracy CHS/RHPP 1997 CHD Ridker PHS 1998,2001 PAD Ridker WHS 1998,2000,2002 CVD Koenig MONICA 1999 CHD Roivainen HELSINKI 2000 CHD Mendall CAERPHILLY 2000 CHD Danesh BRITAIN 2000 CHD Gussekloo LEIDEN 2001 Fatal Stroke Lowe SPEEDWELL 2001 CHD Packard WOSCOPS 2001 CV Events Ridker AFCAPS 2001 CV Events Rost FHS 2001 Stroke Pradhan WHI 2002 MI, CVD death Albert PHS 2002 Sudden Death Relative Risk (upper versus lower quartile) Ridker PM. Circulation 2003;107: hs-CRP = Risk Factor for CVD

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, % decrease in CDA end-points 20% decrease in ‘all cause’ mortality! 40% of participants had insulin resistance...

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 to plaque rupture at sites of only moderate stenosis. Lp-PLA2

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

36 © Unadjusted Adjusted for age Multivariable DM, smoking adjustment* CRP ≤ 3 mg/L Lp-PLA 2 < ng/mL N=447 CRP > 3 mg/L Lp-PLA 2 < ng/mL N=176 CRP ≤ 3 mg/L Lp-PLA 2 ≥ ng/mL N=203 CRP > 3 mg/L Lp-PLA 2 ≥ ng/mL N=108 Additive Effect of CRP and Lp-PLA 2 in Coronary Risk Prediction: MONICA Hazard Ratio (95% CI) Koenig et al. (AHA 2003)

37 © Summary and Conclusions  Lp-PLA 2 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-PLA 2 were independently associated with incident CHD in multivariable analysis including CRP (ARIC)  Lp-PLA 2 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)

38 ©

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]

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

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

43 © Obesity Trends* Among U.S. Adults BRFSS, 2006 (*BMI ≥30, or ~ 30 lbs. overweight for 5’ 4” person) No Data <10% 10%–14% 15%–19% 20%–24% 25%–29% ≥30%

44 © High Glycemic Diet Genetic propensity Insulin Resistance Elevated fasting and postprandial Insulin & glucose blood levels Visceral Adiposity Lack of Exercise Smoking Chronic Stress Inflammation Antecedents, Triggers and Mediators

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

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

47 © Dyslipidemia Hyperglycemia Hypertension Insulin Resistance Abdominal Obesity Oxidative Stress (free radicals) Inflammation LDL oxidation Plaque formation Atherosclerosis Increased coagulation Heart Disease Diabetes Mellitus

48 ©

49 ©

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

51 ©

52 © Lipid Markers Independent Risk Factors Insulin Resistance Score by Lipid Fractionation

53 © Lipid Markers Independent Risk Factors Insulin Resistance Score by Lipid Fractionation

54 © Lipid Markers Independent Risk Factors 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

56 ©

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.

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!

60 © Learning Objectives: 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


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