Dyslipoproteinemia and Atherosclerosis

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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

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Disclosures
Speakers Bureau Liposcience Inc. Lilly
Pharmaceuticals Inc. Warner-Chilcott Inc.
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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
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Lipid Analysis Shortcomings

• 50 of Framingham AMCE patients had LDL lt130
  mg/dl

• 75 of Framingham AMCE patients lt 55 yo had LDL
  lt130 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

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Number of patients
500,000
5
50
500
5000
Beta HCG level
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Number of patients
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
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Total Cholesterol ()
Association with CHD Positive () or Negative
(-)
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Lipoprotein Particles
Apolipoprotein
Apolipoprotein
NON-POLAR LIPID CORE Cholesterol
Ester Triglyceride
Apolipoprotein
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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
100 mg/dL
100 mg/dL
Large LDL
Small LDL
Otvos JD, et al. Am J Cardiol 200290(suppl)22i-2
9i
Cromwell WC, et al. J Clin Lipidology.
20071(6)583-592.
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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)
Normal Cholesterol Carried Per Particle
Less Cholesterol Carried Per Particle
Cholesterol Balance
Otvos JD, et al. Am J Cardiol 200290(suppl)22i-2
9i
Cromwell WC, et al. J Clin Lipidology.
20071(6)583-592.
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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
200290(8A)22i-29i
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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
200290(8A)22i-29i
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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

• Enhanced
• Macrophage Uptake
• Modified / retained lipoproteins

• Oxidative Modification

• Particle Retention
• Lipoprotein particle
• binding to proteoglycans

1 Weissberg PL, Rudd JH. Textbook of
Cardiovascular Medicine 2nd ed. 2002. p. 6.
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Alternative Measures of LDL as Predictors of CHD
Events in VA-HIT
plt0.001
Odds Ratio per 1-SD Increment of on-trial value
p0.17
p0.25
p0.31
LDL-C
Non-HDL-C
ApoB
LDL-P
Adjusted for treatment, age, hypertension, smoking
, BMI, and diabetes
Circulation 20061131556-63
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Alternative Measures of HDL as Predictors of CHD
Events in VA-HIT
plt0.001
Odds Ratio per 1-SD Decrement of on-trial value
p0.18
p0.42
HDL-C
ApoA-1
HDL-P
Adjusted for treatment, age, hypertension, smoking
, BMI, and diabetes
Circulation 20061131556-63
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Fig. 2 Survival Curves for Framingham Subjects
with Concordant LDL-C and LDL-P
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Fig. 2 Survival Curves for Framingham Subjects
with Discordant LDL-C and LDL-P
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Fig. 2 Survival Curves for Framingham Subjects
with Concordant and Discordant LDL-C and LDL-P
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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 Womens Health Study
LDL pattern not an independent predictor of risk after NMR LDL-P adjustment Framing. Offspring Study VA-HIT Womens Health Study MESA
Independent of sex, age, smoking status and
BP Superior predictor to and independent of
apo B-100
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NMR HDL-P vs. HDL-C
NMR HDL-P better risk predictor than HDL-C Framing. Offspring Study PLAC-1 VA-HIT MESA Womens 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
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Treatment Summary
Large VLDL-P
HDL-P
LDL Size
Small LDL-P
LDL-P
any
?
? or ?
??? or ?
???
Statins
any
?
? or ?
?? or ?
??
Ezetimibe
any
???
???
???
??
Niacin
Only ?
?
?
??
??
BAS
Only ??
??
??
??
??
Fibrates/ pioglitazone
Only ??
?
?
??
?
?-3 FA
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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 19.8 Pattern B
20.5-18.0 Large HDL-P 6.8 (50th) Large VLDL-P
0.1
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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 20.9 Pattern A
23.0-20.6 Large HDL-P 9.0 (75th) Large VLDL-P
0.2
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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 21.6 Pattern A
23.0-20.6 Large HDL-P 9.3 (80th) Large VLDL-P
0.7 (20th)
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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 (lt 2nd) HDL-C 42
(28th) TG 33 Non HDL-C 76 (lt 2nd)
LDL-P 808 (3rd) HDL-P 26.2 (21st) Small LDL-P
508 LDL Particle Size 21.1 Pattern A
23.0-20.6 Large HDL-P 8.3 (78th) Large VLDL-P
0.0 (5th)
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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 21.1 Pattern A
23.0-20.6 Large HDL-P 12.4 (95th) Large VLDL-P
0.1 (10th)

• Carotid U/S No demostrable plaque either
  carotid artery

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Patient Fancher

• 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 21.1 Pattern A
20.5-18.0 Large HDL-P 5.4 (60th) Large VLDL-P
5.9
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Patient Chew

• 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

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 20.4 Pattern B
20.5-18.0 Large HDL-P 12.3 (95th) Large
VLDL-P 13.7
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Patient Chew

• 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

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 20.45 Pattern B
20.5-18.0 Large HDL-P 7.2 (60th) Large VLDL-P
2.6
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Patient Jones

• 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 20.7 Pattern A 23.0 -
20.6 Large HDL-P 6.8 (50th) Large VLDL-P 0.1
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Patient Jones

• 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

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 20.9 Pattern A 23.0 - 20.6 Large HDL-P
10.1 (90th) Large VLDL-P 0.2