D-Dyslipidemia by Prof. Abbas Orabi | Low Density Lipoprotein | High Density Lipoprotein

DIABETIC DYSLIPIDEMIA

Abbas Orabi

Atherogenic Particles
MEASUREMENTS:
Apolipoprotein B Non-HDL-C

VLDL

VLDLR

IDL

LDL

TG-rich lipoproteins

Small, dense LDL

Pathogenesis of the atherosclerotic plaque
LDL → Ox-LDL Scavenger cells within the intima Foam cells Growth factors VSMC fibroblast

Atheromateous plaque Inflammatory cells Proteolytic enzymes Plaque Rupture Platelets aggregation Thrombus

Historical Model of Atherosclerosis
Decades Healthy Years-Months Subclinical Months-Days Symptomatic

Intima Media Lumen

Lumen narrowing

Plaque

Adapted from Nissen SE. Am J Cardiol. 2000;86:12H-17H.

Glagov’s Coronary Remodeling Hypothesis
Progression Compensatory expansion preserves lumen diameter Expansion overcome: lumen narrows

Normal Vessel

Minimal CAD

Moderate CAD

Severe CAD

CAD = Coronary Artery Disease. Reproduced with permission from Nissen SE. Am J Cardiol. 2000;86:12H-17H; Glagov S, et al. N Engl J Med. 1987;316:1371-1375.

Altered Endothelial Function
Intima Media Adventitia

Endothelial permeability

Leukocyte migration

Increased endothelial adhesiveness

Leukocyte adhesion

Reproduced with permission from Ross R. N Engl J Med. 1999;340:115-126.

Impact of LDL-C Infiltration on Coronary Artery Inflammation

-C

Reproduced with permission from Hansson GK. N Engl J Med. 2005;352:1685-1695.

Fatty Streak Formation in Atherosclerosis

Smooth-muscle migration

Foam-cell formation

Adherence and T-cell aggregation activation of platelets

Adherence and entry of leukocytes

Reproduced with permission from Ross R. N Engl J Med. 1999;340:115-126.

Formation of Complicated Atherosclerotic Plaque

Macrophage accumulation

Formation of necrotic core

Fibrous-cap formation

Reproduced with permission from Ross R. N Engl J Med. 1999;340:115-126.

Lipoprotein abnormalities in type 1 diabetes : Untreated OR poorly treated Severe Hypertriglyceridemia Due to :
 VLDL overproduction (↓ Insulin)  VLDL & chylomicrons impaired clearance (↓ LPL)

well controlled Nearly, normal lipids profile

Lipoprotein abnormalities in type 2 diabetes : LDL-cholesterol Normal or slight increase HDL-cholesterol Low

Triglyceride

Elevated

HYPERTRIGLYCERIDEMIA
The key characteristic of diabetic dyslipidemia

Causes of excess VLDL in diabetes
I Over production II Impaired clearance: *Diminished LPL activity *Abnormal VLDL: Larger More TG Apo c & Apo E *competition with chylomicron in the common metabolic pathway

TG CETP

Hepatic lipases

Small dense LDL Small dense HDL

Mechanisms of production of small (LDL) and small (HDL) in type 2 diabetes

Plasma lipoprotein profiles in type 2 diabetes :
↑ Large VLDL-1 ↓ Small VLDL-2

VLDL

LDL

↑ small LDL ↓ Large LDL

Pattern B

HDL

↓ Large HDL-2 ↑ Small HDL-3

LDL density : ↑ Small dense LDL
Small LDL is more atherogenic than large LDL due to its more susceptibility for oxidation less affinity to LDLr → increasing residence time in the plasma.

Ox-LDL :
 Ox-LDL is more atherogenic than Native LDL.  Prolonged existence in the circulation increases the likelihood of oxidation :
 Small dense LDL.  As levels of LDL-C increases so does the half life of LDL particles (Days rather than hours).  Glycated Apo B impair LDL clearance.

 HDL contains anti-oxidant enzymes (paraoxanase), so, reduced HDL may predispose to oxidation.

Atherogenicity of Ox-LDL :
 A ligand for scavenger receptors with production of “foam” cells.  Induction of programmed cell death in many cell types including VSMC, endothelial cells and macrophages.  Competitive inhibition of the binding of apoptotic bodies to macrophages, converting the normally inflammation-free clearance of apoptotic cells to a necrotic inflammatory process.

Apo B :
 An elevated apo B concentration is a common feature of diabetic dyslipidemia.  Each VLDL contains one apo B molecule.  Apo B remains associated with the particle until cleared from the circulation as IDL or LDL.  LDL account for ≈ 95% of circulating apo B.  Apo B ≈ [VLDLs, IDLs and LDLs]  Glycated apo B impairs its interaction with hepatic LDL receptor (B/E) and slows its clearance.

In the presence of LDL cholesterol – pattern B – any cholesterol measures will tend to underestimate the number of LDL particles present (small dense LDL is relatively

cholesterol depleted). Apo B ≈ LDL (small & large) + VLDL + IDL. Thus apo B level may become more widespread in clinical practice for prediction of CHD risk.

HDL in diabetes
Lower level Less formation Less survival Smaller size Cholesterol depleted (CETP) TG depleted (Hepatic lipase) PLTP Nascent

PLTP

HDL2

HDL density :
 The plasma triglyceride concentration is negatively correlated with that of large HDL2 and positively correlated with the level of small HDL3.  HDL2-relatively depleted has the greater antiatherogenic effect.  HDL3 is rapidly cleared from the circulation leading to lower serum HDL-cholesterol.

Nissen SE, JAMA 2004; 291:1071-80

Nissen SE, JAMA 2006;295:1556-65

„ASTEROID“
20 15 10 5 0 -5 -10 -15
Change in Atheroma Volume mm3

50% LDL-C reduction
n=502

-80

-70

-60

-50

-40

-30

-20

-10

0

10

20

% Change in LDL Cholesterol To reduce atheroma Both treatment groups volume: 53% LDL reduction in ASTEROID

80 mg Atorvastatin or 40 mg PATIENTSPravastatin LDL-C REDUCTION TO HALT THE NEED A 50% PROGRESSION OF ATHEROSCLEROSIS – “REVERSAL”

:To Reach Levels Below 70 mg/dl
Cholesterol Reduction 51% 53% 51%

mg 80 Atorvastatin mg 40 Rosuvastatin Ezetimibe + Standard dose statin

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