Dyslipoproteinemia and Atherosclerosis

Daniel W. Stock MD

Founding Diplomate, American Board of Clinical Lipidology

Member, National Lipid Association and Midwest Lipid Association

Former Adjunct Clinical ProfessorIndiana University School of Medicine

Disclosures

Speakers Bureau: Liposcience Inc.Lilly Pharmaceuticals Inc.Warner-Chilcott Inc.

•Framingham showed ↑’ing risk with ↑’ing LDL and ↓’ing HDL cholesterol

CAD status

LDL-C HDL-C AMCE ∆

4S 2º 188 46 34%

LIPID 2º 150 36 34%

CARE 2º 139 39 22%

WOSCOPS 1º 193 44 31%

AFCAPS/TexCAPS 1º 150 36 37%

ASCOT-LLA 1º 131 50 36%

HPS 1º& 2º NA NA 17%

JUPITER 1º 108 49 44%

VA-HIT 2º 112 32 22%

Lipid Analysis Shortcomings

• 50% of Framingham AMCE patients had LDL <130 mg/dl

• 75% of Framingham AMCE patients < 55 yo had LDL <130 mg/dl

• Majority of lipid trial patients did not benefit from therapy

• On-treatment lipids did not predict clinical outcome

• Forces the treatment of low-risk individuals in order to protect high-risk individuals

Beta HCG level

5 50 500 5000 500,000

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total cholesterol

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LDL Cholesterol

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“Lipids” and Atherosclerosis

• Atherosclerosis occurs because of abnormal lipoproteins and/or lipoprotein kinetics, not abnormal lipid levels.

“… all abnormalities in plasma lipid concentrations, or dyslipidemia, can be translated into dyslipoproteinemia.”

“… the shift of emphasis to lipoproteins offers distinct advantages in the recognition and management of such disorders.”

Fredrickson et al., NEJM 1967; 276: 148

Total Cholesterol (+)

VLDL-C + LDL-C + HDL-C(+) (+) (-)

IDL LDL

+ + + + + + + + + + - - - + +

Association with CHD: Positive (+) or Negative (-)

Lipoprotein Particles

NON-POLARLIPID CORE

Cholesterol EsterTriglyceride

POLAR SURFACE COAT

Phospholipid

Free cholesterol

Apolipoprotein

Apolipoprotein

Apolipoprotein

At the same LDL cholesterol, with small versus large size LDL Particles

Up to 70%More Particles

Small LDL

Large LDL

CholesterolBalance

100 mg/dL 100 mg/dL

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

Among Individuals At The Same LDL-C Level, The Number of LDL Particles Vary

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

At the same LDL cholesterol, with the same size LDL Particles (at any triglyceride level)

Up to 40%More Particles

Less Cholesterol Carried Per Particle

Normal Cholesterol Carried Per Particle

100 mg/dL 100 mg/dL

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

Among Individuals At The Same LDL-C Level, The Number of LDL Particles Vary

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

CholesterolBalance

LDL-C often fails to reflect the number of LDL particles and the CHD risk they confer

The number of LDL particles (LDL-P™) varies widely among patients with similar LDL-C values. In this analysis, patients with an LDL-C between 95 mg/dL and 105 mg/dL have highly variable LDL particles, and thus variable CHD risk.

Otvos JD, Jayarajah E, Cromwell, WC. AJC 2002;90(8A):22i-29i

LDL-C Often Fails to Reflect the Number of LDL Particles

• LDL particles can be large or small, and the amount of cholesterol contained within these particles varies widely.

Otvos JD, Jayarajah E, Cromwell, WC. AJC 2002;90(8A):22i-29i

Enhanced Macrophage Uptake

– Modified / retained lipoproteins

Enhanced Macrophage Uptake

– Modified / retained lipoproteins

Particle Movement

– Gradient driven

Particle Movement

– Gradient driven

Oxidative Modification Oxidative Modification

Adhesion molecules MCP-1

Colony-stimulatingfactors

Tissue factorPAI-1

Endothelial cellsEndothelial cells

MonocyteMonocyte

Particle Retention

– Lipoprotein particle binding to proteoglycans

Particle Retention

– Lipoprotein particle binding to proteoglycans

Mildly modified LDL

Extensively modified LDL

Pathophysiology of AtherosclerosisPathophysiology of Atherosclerosis

“The rate of passive diffusion is increased when the circulating levels of LDL are elevated.”

1

Enhanced Endothelial Dysfunction

Enhanced Endothelial Dysfunction

1 Weissberg PL, Rudd JH. Textbook of Cardiovascular Medicine 2nd ed. 2002. p. 6.

Od

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-SD

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1.2

1.3

LDL-C Non-HDL-C

ApoB LDL-P

p<0.001

Alternative Measures of LDL as Predictors of CHD Events in VA-HIT

Adjusted for treatment, age, hypertension,smoking, BMI, and diabetes

p=0.31

p=0.17p=0.25

Circulation 2006;113:1556-63

Adjusted for treatment, age, hypertension,smoking, BMI, and diabetes

1

1.1

1.2

1.3

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HDL-C ApoA-1 HDL-P

p<0.001

p=0.18

p=0.42

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Alternative Measures of HDL as Predictors of CHD Events in VA-HIT

Circulation 2006;113:1556-63

0.74

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Low LDL-P & Low LDL-C(n=1,249)

High LDL-P & High LDL-C (n=1,251)

Fig. 2 Survival Curves for Framingham Subjects withConcordant LDL-C and LDL-P

Fig. 2 Survival Curves for Framingham Subjects withDiscordant LDL-C and LDL-P

0.74

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Low LDL-CHigh LDL-P

(n=282)

High LDL-CLow LDL-P

(n=284)

0.74

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Low LDL-CHigh LDL-P

(n=282)

High LDL-CLow LDL-P

(n=284)

Low LDL-P & Low LDL-C(n=1,249)

High LDL-P & High LDL-C (n=1,251)

Fig. 2 Survival Curves for Framingham Subjects withConcordant and Discordant LDL-C and LDL-P

NMR LDL-P significantly better risk predictor than all lipid panel parameters

Framing. Offspring Study*†

Cardiovascular Health Study*

VA-HIT*†

PLAC-1*

Healthy Women Study*

MESA*†

NMR LDL-P significantly better risk predictor than all lipid panel parameters except TC/HDL-C

Women’s Health Study*†

LDL pattern not an independent predictor of risk after NMR LDL-P adjustment

Framing. Offspring Study*†

VA-HIT*†

Women’s Health Study*†

MESA*†

NMR LDL-P vs. Lipids

* Independent of sex, age, smoking status and BP† Superior predictor to and independent of apo B-100

NMR HDL-P better risk predictor than HDL-C

Framing. Offspring Study*†

PLAC-1*

VA-HIT*†

MESA*†

Women’s Health Study*†

NMR HDL-P better predictor of therapy response that HDL-C

PLAC-1*

VA-HIT*†

NMR HDL-P vs. HDL-C

* Independent of sex, age, smoking status and BP, and all lipid panel parameters† Superior predictor to and independent of apo B-100

Treatment Summary

Only BAS

Only Ω-3 FA

Only Fibrates/

pioglitazone

any?Niacin

any or or Ezetimibe

any or or Statins

Large

VLDL-P

HDL-PLDL

Size

Small

LDL-P

LDL-P

Patient Bradley

TC = 145LDL-C = 93 (15th)HDL-C = 39 (20th)TG = 66Non HDL-C = 106 (10th)

• 65 YO WM, 71” tall 198#, BP 110/70m, never smoker, neg FHx of premature atherosclerosis, Dx of BPH, Dyslipoproteinemia, Atrial fibrillation, ED

• Lipoprotein Therapy: Pravastatin 20 MG QD

LDL-P = 1560 (60th)HDL-P = 28.7 (40th)Small LDL-P = 1369LDL Particle Size = 19.8 Pattern B = 20.5-18.0Large HDL-P = 6.8 (50th)Large VLDL-P = 0.1

Patient Bradley

TC = 123LDL-C = 68 (3rd)HDL-C = 42 (25th)TG = 63Non HDL-C = 81 (2nd)

LDL-P = 1045 (20th)HDL-P = 27.7 (38th)Small LDL-P = 722LDL Particle Size = 20.9 Pattern A = 23.0-20.6Large HDL-P = 9.0 (75th) Large VLDL-P = 0.2

• 65 YO WM, 71” tall 198#, BP 110/70m, never smoker, neg FHx of premature atherosclerosis, Dx of BPH, Dyslipoproteinemia, Atrial fibrillation, ED

• Changed from pravastatin to rosuvastatin 10 MG QD.

Patient Gregory

TC = 199LDL-C = 132 (50th)HDL-C = 54 (75th)TG = 67Non HDL-C = 145 (40th)

• 43 YO WM, 68” tall 155#, BP 110/80m, never smoker, non-drinker, regular exercise,+ FHx of premature atherosclerosis, No medical diagnoses.

• Lipoprotein Therapy: None

LDL-P = 1147 (30th)HDL-P = 25.0 (18th)Small LDL-P = 517LDL Particle Size = 21.6 Pattern A = 23.0-20.6Large HDL-P = 9.3 (80th)Large VLDL-P = 0.7 (20th)

• CXR: Mild Aortic Calcification• Carotid U/S: minimal non-calcifying plaque L CCA and bilat ICA

Patient Gregory

TC = 118LDL-C = 69 (< 2nd)HDL-C = 42 (28th)TG = 33Non HDL-C = 76 (< 2nd)

• 43 YO WM, 68” tall 155#, BP 110/80m, never smoker, non-drinker, regular exercise,+ FHx of premature atherosclerosis, No medical diagnoses.

• Lipoprotein Therapy: simvastatin 20 MG QD

LDL-P = 808 (3rd)HDL-P = 26.2 (21st)Small LDL-P = 508LDL Particle Size = 21.1 Pattern A = 23.0-20.6Large HDL-P = 8.3 (78th)Large VLDL-P = 0.0 (5th)

Patient Gregory

TC = 152LDL-C = 97 (19th)HDL-C = 50 (65th)TG = 25Non HDL-C = 102 (10th)

• 43 YO WM, 68” tall 155#, BP 110/80m, never smoker, non-drinker, regular exercise,+ FHx of premature atherosclerosis, No medical diagnoses.

• Lipoprotein Therapy: lovastatin/ER niacin 1000/40 MG QD

LDL-P = 907 (7th)HDL-P = 31.0 (60th)Small LDL-P = 563LDL Particle Size = 21.1 Pattern A = 23.0-20.6Large HDL-P = 12.4 (95th)Large VLDL-P = 0.1 (10th)

• Carotid U/S: No demostrable plaque either carotid artery

Patient Fancher

TC = 187LDL-C = 84 (4th)HDL-C = 55 (52th)TG = 242Non HDL-C = 132 (30th)

LDL-P = 763 (3rd)HDL-P = 40.6 (80th)Small LDL-P = 443LDL Particle Size = 21.1 Pattern A = 20.5-18.0Large HDL-P = 5.4 (60th)Large VLDL-P = 5.9

• 53 YO WF, 64” tall, 158#, BP 120/80, Never smoker, Dx IFG (FBS 110), menopause, s/p Radical Urinary Cystectomy and continent colon reservoir for Transitional Bladder CA

• Current Meds: None

• Lipoprotein therapy: None

Patient Chew

TC = 192LDL-C = 73 (2nd)HDL-C = 58 (55th)TG = 303Non HDL-C = 134 (30th)

LDL-P = 1913 (85th)HDL-P = 39.7 (80th)Small LDL-P = 1404LDL Particle Size = 20.4 Pattern B = 20.5-18.0Large HDL-P = 12.3 (95th)Large VLDL-P = 13.7

• 46 YO WF, 67” tall, 202#, BP 120/76, no tobacco since 93, 16 pack-year hx previously, Dx of menopause, Dyslipoproteinemia, IFG, Hepatic steatosis

• Current Meds: levothyroxine 150 MCG QD, spironolactone 50 MG QD, CEE 0.625 QD, HCTZ 12.5 QD, escitalopram 20 MG QD, buproprion 150 MG QD

• Lipoprotein therapy: rosuvastatin 10 MG QD

Patient Chew

TC = 146LDL-C = 62 (1st)HDL-C = 48 (18th)TG = 181Non HDL-C = 98 (7th)

LDL-P = 1434 (50th)HDL-P = 36.2 (70th)Small LDL-P = 1103LDL Particle Size = 20.45 Pattern B = 20.5-18.0Large HDL-P = 7.2 (60th)Large VLDL-P = 2.6

• 46 YO WF, 67” tall, 202#, BP 120/76, no tobacco since 93, 16 pack-year hx previously, Dx of menopause, Dyslipoproteinemia, impaired fasting glucose, Hepatic steatosis

• Current Meds: levothyroxine 150 MCG, spironolactone 50 MG QD, CEE 0.625 QD, HCTZ 12.5 QD, lexapro 20 MG QD, buproprion 150 MG QD

• Added Omega-3 Fatty Acid Ethyl Esters 4 G QD to rosuvastatin 10 MG QD

Patient Jones

TC = 158LDL-C = 80 (5th)HDL-C = 62 (75)TG = 79Non HDL-C = 96 (5th)

LDL-P = 1459 (50th)Small LDL-P = 1067LDL Particle Size = 20.7 Pattern A = 23.0 - 20.6Large HDL-P = 6.8 (50th)Large VLDL-P = 0.1

• 60 YO BM, 72” tall, 194#, 150/70, never smoker, Dx HTN, Dyslipoproteinemia

• Current Meds: ramipril 10 MG QD, spironolactone/HCTZ 12.5/12.5 MG QD

• Lipoprotein Therapy: lovastatin/ER niacin 1000/40 MG QD

Patient Jones

TC = 135LDL-C = 86 (10th)HDL-C = 63 (75th)TG = 62Non HDL-C = 72 (1st)

LDL-P = 953 (10th)Small LDL-P = 652LDL Particle Size = 20.9 Pattern A = 23.0 - 20.6Large HDL-P = 10.1 (90th)Large VLDL-P = 0.2

• 60 YO BM, 72” tall, 194#, 150-70, never smoker, Dx HTN, Dyslipoproteinemia

• Current Meds: Altace 10 MG QD, spironolactone/HCTZ 12.5/12.5 MG QD

• Changed to rosuvastatin 10 MG QD and ER niacin 1000 MG QD