1. 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 Professor
Indiana University School of Medicine

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

3. Framingham showed ↑’ing risk with ↑’ing LDL and ↓’ing HDL cholesterol
CAD status
LDL-C
HDL-C
AMCE ∆ 4S 2º
188 46
34%
LIPID
150 36
CARE
139 39
22%
WOSCOPS 1º
193 44
31%
AFCAPS/TexCAPS
37%
ASCOT-LLA
131 50
36%
HPS
1º& 2º NA
17%
JUPITER
108 49
44%
VA-HIT
112 32

4. 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

5. Number of patients 5 50
500
5000
500,000
Beta HCG level

7. Number of patients
LDL Cholesterol

8. “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.”
SLIDE 7
The second fundamental concept is that cholesterol and triglyceride values have utility in that they serve as surrogate markers for the lipoproteins in which they are carried.
Since the 1960’s it has been understood that lipoproteins are central to cholesterol and triglyceride transport. As such, Fredrickson noted that abnormal lipid concentrations could be translated into dyslipoproteinemias, or abnormal levels of lipoproteins responsible for cholesterol and triglyceride transport.
Given the more central relationship of lipoproteins to atherosclerosis, Fredrickson further noted that shifting emphasis from lipids to lipoproteins offered “… distinct advantages in recognition and management of such disorders .”
Fredrickson et al., NEJM 1967; 276: 148

9. Total Cholesterol (+) VLDL-C + LDL-C + HDL-C
(+) (+) (-)
SLIDE 6
Each major class of plasma lipoprotein (VLDL, LDL, HDL) comprises subclass particles of varying size. This would have no impact on risk assessment if not for the fact that some subclasses differ in their associations with CHD.
High concentrations of large VLDL, small LDL, and IDL are associated with enhanced risk (as indicated by the bigger plus signs). And not all HDL subclasses appear to be protective (negative association with CHD); the two smallest subclasses appear to have a positive association with CHD (ie., there is “bad” good cholesterol!).
The relative proportions of the subclasses in each lipoprotein class vary widely from person to person for metabolic reasons. As a result, people with the same levels of LDL and HDL cholesterol can have very different risks. For example, at a given level of LDL cholesterol, a person with mostly small, dense LDL particles has a 3 to 5-fold greater risk of CHD than someone with large LDL.
Lipoprotein subclass information, which would improve diagnosis and treatment of CHD risk, has been unavailable to clinicians for analytical reasons. Subfractionation of lipoproteins is far more difficult and time-consuming than simple fractionation of LDL and HDL, requiring methods such as density gradient ultracentrifugation and gradient gel electrophoresis
IDL LDL
Association with CHD: Positive (+) or Negative (-)

10. Lipoprotein Particles
Apolipoprotein
Apolipoprotein
POLAR
SURFACE COAT
Phospholipid
Free cholesterol
NON-POLAR
LIPID CORE
Cholesterol Ester
Triglyceride
Because cholesterol and triglycerides are hydrophobic lipids that are insoluable in plasma, intravascular transport cannot occur with these lipids in their free state. Consequently, cholesterol esters and triglycerides are packaged into spherical lipoprotein particles that span a wide range of particle size and density.
Lipoprotein particles are configured so that the outer surface is polar and the inner core is non-polar. The surface of lipoprotein particles is composed of a phospholipid monolayer, non-esterified cholesterol, and various apolipoproteins. The core of lipoprotein particles contains variable amounts of cholesterol ester and triglycerides.
Apolipoprotein 10

11. Among Individuals At The Same LDL-C Level, The Number of LDL Particles Vary
At the same LDL cholesterol, with small versus large size LDL Particles
Up to 70%
More Particles
Cholesterol
Balance
100 mg/dL
100 mg/dL
Because of variability in the amount of cholesterol carried inside LDL particles, LDL-C often does not reflect accurately LDL-P. Two processes are primarily responsible for this phenomenon.
First, small sized LDL particles carry less cholesterol per particle than large sized particles. For LDL particles differing by 3 nm in diameter, there is approximately 40% less core cholesterol in the smaller versus larger particle. Thus, the person with the smaller LDL particles will require almost 70% more particles to carry the same amount of LDLC than the person with the larger particles.
Otvos JD, et al. Am J Cardiol 2002;90(suppl):22i-29i
Cromwell WC, et al. J Clin Lipidology. 2007;1(6):
Large LDL
Small LDL
Otvos JD, et al. Am J Cardiol 2002;90(suppl):22i-29i
Cromwell WC, et al. J Clin Lipidology. 2007;1(6): 11

12. Among Individuals At The Same LDL-C Level, The Number of LDL Particles Vary
At the same LDL cholesterol, with the same size LDL Particles
(at any triglyceride level)
Up to 40%
More Particles
100 mg/dL
Second, even at the same LDL particle size, the cholesterol content of LDL particles is not consistent. Due to cholesterol ester transfer protein (CETP) mediated exchange of triglycerides (TG) and cholesterol ester between cholesterol-rich (LDL and HDL) and TG-rich (VLDL, intermediate-density lipoprotein, and remnants) particles, the amount of cholesterol carried per particle is highly variable. When TG levels are elevated, or when LDL levels are decreased (even modestly), this exchange reaction results in altered LDL particles that are partially depleted in core cholesterol and enriched in core TG. When particles are partially cholesterol depleted, up to 40% more LDL particles are needed to transport the same amount of cholesterol compared to similar sized particles with the expected amount of cholesterol per particle.
Otvos JD, et al. Am J Cardiol 2002;90(suppl):22i-29i
Cromwell WC, et al. J Clin Lipidology. 2007;1(6):
Normal Cholesterol Carried Per Particle
Less Cholesterol Carried Per Particle
Cholesterol
Balance
Otvos JD, et al. Am J Cardiol 2002;90(suppl):22i-29i
Cromwell WC, et al. J Clin Lipidology. 2007;1(6): 12

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

14. 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

15. Pathophysiology of Atherosclerosis
Particle Movement
Gradient driven
Enhanced Endothelial
Dysfunction
“The rate of passive diffusion is increased when the circulating levels of LDL are elevated.” 1
Monocyte
Adhesion
molecules
MCP-1
Colony-
stimulating
factors
Tissue
factor
PAI-1
Endothelial cells
Mildly modified LDL
Extensively modified LDL
Particle Retention
Lipoprotein particle
binding to proteoglycans
Oxidative Modification
Enhanced
Macrophage Uptake
Modified / retained lipoproteins
1 Weissberg PL, Rudd JH. Textbook of Cardiovascular Medicine 2nd ed p. 6.

16. Odds Ratio per 1-SD Increment of on-trial value
Alternative Measures of LDL as Predictors of CHD Events in VA-HIT
p<0.001
Odds Ratio per 1-SD Increment of on-trial value
p=0.17
p=0.25
p=0.31
LDL-C
Non-HDL-C
ApoB
LDL-P
Adjusted for treatment, age, hypertension,
smoking, BMI, and diabetes
Circulation 2006;113:

17. Odds Ratio per 1-SD Decrement of on-trial value
Alternative Measures of HDL as Predictors of CHD Events in VA-HIT
p<0.001
Odds Ratio per 1-SD Decrement of on-trial value
p=0.18
p=0.42
HDL-C
ApoA-1
HDL-P
Adjusted for treatment, age, hypertension,
smoking, BMI, and diabetes
Circulation 2006;113:

18. Fig. 2 Survival Curves for Framingham Subjects with
Concordant LDL-C and LDL-P
Years of Follow-up
Event-Free Survival
Low LDL-P & Low LDL-C
(n=1,249)
High LDL-P & High LDL-C
(n=1,251)

19. Fig. 2 Survival Curves for Framingham Subjects with
Discordant LDL-C and LDL-P
Years of Follow-up
Event-Free Survival
Low LDL-C
High LDL-P
(n=282)
High LDL-C
Low LDL-P
(n=284)

20. Fig. 2 Survival Curves for Framingham Subjects with
Concordant and Discordant LDL-C and LDL-P
Years of Follow-up
Event-Free Survival
Low LDL-C
High LDL-P
(n=282)
High LDL-C
Low LDL-P
(n=284)
Low LDL-P & Low LDL-C
(n=1,249)
High LDL-P & High LDL-C
(n=1,251)

21. NMR LDL-P vs. Lipids
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*†
* Independent of sex, age, smoking status and BP
† Superior predictor to and independent of apo B-100

22. NMR HDL-P vs. HDL-C 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*†
* Independent of sex, age, smoking status and BP, and all lipid panel parameters
† Superior predictor to and independent of apo B-100

24. Treatment Summary LDL-P Small LDL-P LDL Size HDL-P Large VLDL-P
Statins

 or 
 or  
any
Ezetimibe 
 or 
 or  
any
Niacin 


?
any
BAS    
Only 
Fibrates/
pioglitazone    
Only 
Ω-3 FA    
Only 

26. Patient Bradley
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
TC = 145
LDL-C = 93 (15th)
HDL-C = 39 (20th)
TG = 66
Non HDL-C = 106 (10th)
LDL-P = 1560 (60th)
HDL-P = 28.7 (40th)
Small LDL-P = 1369
LDL Particle Size = Pattern B =
Large HDL-P = 6.8 (50th)
Large VLDL-P = 0.1

27. Patient Bradley
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.
TC = 123
LDL-C = 68 (3rd)
HDL-C = 42 (25th)
TG = 63
Non HDL-C = 81 (2nd)
LDL-P = 1045 (20th)
HDL-P = 27.7 (38th)
Small LDL-P = 722
LDL Particle Size = Pattern A =
Large HDL-P = 9.0 (75th)
Large VLDL-P = 0.2

28. Patient Gregory
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
TC = 199
LDL-C = 132 (50th)
HDL-C = 54 (75th)
TG = 67
Non HDL-C = 145 (40th)
CXR: Mild Aortic Calcification
Carotid U/S: minimal non-calcifying plaque L CCA and bilat ICA
LDL-P = 1147 (30th)
HDL-P = 25.0 (18th)
Small LDL-P = 517
LDL Particle Size = Pattern A =
Large HDL-P = 9.3 (80th)
Large VLDL-P = 0.7 (20th)

29. Patient Gregory
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
TC = 118
LDL-C = 69 (< 2nd)
HDL-C = 42 (28th)
TG = 33
Non HDL-C = 76 (< 2nd)
LDL-P = 808 (3rd)
HDL-P = 26.2 (21st)
Small LDL-P = 508
LDL Particle Size = Pattern A =
Large HDL-P = 8.3 (78th)
Large VLDL-P = 0.0 (5th)

30. Patient Gregory
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
TC = 152
LDL-C = 97 (19th)
HDL-C = 50 (65th)
TG = 25
Non HDL-C = 102 (10th)
LDL-P = 907 (7th)
HDL-P = 31.0 (60th)
Small LDL-P = 563
LDL Particle Size = Pattern A =
Large HDL-P = 12.4 (95th)
Large VLDL-P = 0.1 (10th)
Carotid U/S: No demostrable plaque either carotid artery

31. Patient Fancher TC = 187 LDL-C = 84 (4th) HDL-C = 55 (52th) TG = 242
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
TC = 187
LDL-C = 84 (4th)
HDL-C = 55 (52th)
TG = 242
Non HDL-C = 132 (30th)
LDL-P = 763 (3rd)
HDL-P = 40.6 (80th)
Small LDL-P = 443
LDL Particle Size = Pattern A =
Large HDL-P = 5.4 (60th)
Large VLDL-P = 5.9

32. Patient Chew TC = 192 LDL-C = 73 (2nd) HDL-C = 58 (55th) TG = 303
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 QD, HCTZ 12.5 QD, escitalopram 20 MG QD, buproprion 150 MG QD
Lipoprotein therapy: rosuvastatin 10 MG QD
TC = 192
LDL-C = 73 (2nd)
HDL-C = 58 (55th)
TG = 303
Non HDL-C = 134 (30th)
LDL-P = 1913 (85th)
HDL-P = 39.7 (80th)
Small LDL-P = 1404
LDL Particle Size = Pattern B =
Large HDL-P = 12.3 (95th)
Large VLDL-P = 13.7

33. Patient Chew TC = 146 LDL-C = 62 (1st) HDL-C = 48 (18th) TG = 181
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 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
TC = 146
LDL-C = 62 (1st)
HDL-C = 48 (18th)
TG = 181
Non HDL-C = 98 (7th)
LDL-P = 1434 (50th)
HDL-P = 36.2 (70th)
Small LDL-P = 1103
LDL Particle Size = Pattern B =
Large HDL-P = 7.2 (60th)
Large VLDL-P = 2.6

34. Patient Jones TC = 158 LDL-C = 80 (5th) HDL-C = 62 (75) TG = 79
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
TC = 158
LDL-C = 80 (5th)
HDL-C = 62 (75)
TG = 79
Non HDL-C = 96 (5th)
LDL-P = 1459 (50th)
Small LDL-P = 1067
LDL Particle Size = Pattern A =
Large HDL-P = 6.8 (50th)
Large VLDL-P = 0.1

35. Patient Jones TC = 135 LDL-C = 86 (10th) HDL-C = 63 (75th) TG = 62
60 YO BM, 72” tall, 194#, , 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
TC = 135
LDL-C = 86 (10th)
HDL-C = 63 (75th)
TG = 62
Non HDL-C = 72 (1st)
LDL-P = 953 (10th)
Small LDL-P = 652
LDL Particle Size = Pattern A =
Large HDL-P = 10.1 (90th)
Large VLDL-P = 0.2