The Ludwigshafen Risk and The Ludwigshafen Risk and Cardiovascular Health Study: LDLCardiovascular Health Study: LDL TGTGCardiovascular Health Study: LDLCardiovascular Health Study: LDL--TGTG►►739 subjects with stable angiographic CAD and 570 739 subjects with stable angiographic CAD and 570 matched control subjects in which CAD had been ruled out matched control subjects in which CAD had been ruled out by angiography and not taking lipid medicationby angiography and not taking lipid medication

►►Th i ti fTh i ti f LDL t i l idLDL t i l id (LDL(LDL TG ) ( ddTG ) ( dd►►The association of The association of LDL triglycerides LDL triglycerides (LDL(LDL--TGs) (odds TGs) (odds ratio [OR], 1.30; 95% CI, 1.19 to 1.43; P< 0.001) with CAD ratio [OR], 1.30; 95% CI, 1.19 to 1.43; P< 0.001) with CAD was stronger than that of LDLwas stronger than that of LDL--C (OR, 1.10; 95% CI, 1.00 to C (OR, 1.10; 95% CI, 1.00 to 1.21; P=0.047).1.21; P=0.047).

►►In subjects with high LDLIn subjects with high LDL--TG, LDLs were depleted of TG, LDLs were depleted of cholesteryl esters (CEs), and VLDLs, IDLs, and dense cholesteryl esters (CEs), and VLDLs, IDLs, and dense LDLs were significantly elevated.LDLs were significantly elevated.

►►Th di ti l f LDLTh di ti l f LDL TG f CADTG f CAD►►The predictive value of LDLThe predictive value of LDL--TG for CAD was TG for CAD was independent of LDLindependent of LDL--C.C.

Marz W et al. Circulation. 2004;110:3068-3074

LDL Particle CompositionLDL Particle CompositionLDL Particle CE/TG composition differences

Cholesteryl Ester (CE)

Normal Ratio Low Ratio

Triglycerides

Normal CE/TG ↓ CE/TG Free Cholesterol

Normal CE/TG ratio is 4.0

↓ratio

The Ludwigshafen Risk and The Ludwigshafen Risk and Cardiovascular Health StudyCardiovascular Health StudyCardiovascular Health StudyCardiovascular Health Study

Median (25th and 75th percentile)LDL-C & LDL-TG and ApoB

Median (25th and 75th percentile) concentrations of apoB in lipoprotein

subfractions in 114 patients with elevated fasting glucose, impaired glucose

tolerance, or T2DM having LDL-TG ≤ 54.4 /dL ( 57 i l ) LDL TG ≥ 54 430

35

Apolipoprotein B (mg/dL)

LDL-TG ≤ 54 mg/dLLDL-TG ≥ 54 mg/dL

mg/dL (n57, circles) or LDL-TG ≥ 54.4 mg/dL (n57, squares). *P0.05

(Mann-Whitney U test).20

25

30

***

g

Subjects with LDLSubjects with LDL--TGs above theTGs above the

5

10

15 ****

**

Subjects with LDLSubjects with LDL TGs above the TGs above the median had significantly higher median had significantly higher

concentrations of VLDL, IDL, and concentrations of VLDL, IDL, and dense LDL dense LDL (LDL(LDL--5 and LDL5 and LDL--6). 6).

0

5

VLDLIDL

LDL-1 LDL-3 LDL-5LDL-2 LDL 4 LDL-6

In contrast, buoyant LDL (LDLIn contrast, buoyant LDL (LDL--1 1 and LDLand LDL--2) and intermediate LDL 2) and intermediate LDL

(LDL(LDL--3 and LDL3 and LDL--4) were not 4) were not differentdifferent

Marz W et al. Circulation. 2004;110:3068-3074

IDL LDL-2 LDL-4 LDL-6 differentdifferent

The Ludwigshafen Risk and The Ludwigshafen Risk and Cardiovascular Health StudyCardiovascular Health StudyCardiovascular Health StudyCardiovascular Health Study

LDL-TG and Inflammatory Markers

2 0

2.2 * *1.41.6 * *

Unadjusted Unadjusted for CAD, sex, age, smoking, BMI, MS/DM, HTN

1.6

1.8

2.0**

0.8

1.0

1.2 * ** *

-CR

P (m

g/L)

SAA

(mg/

L)

1.2

1.4

11 2 3 4 2 3 4 1 2 3 4 1 2 3 40.4

0.6hs- S

*P< 0.05

Estimated marginal means (95% CI) of concentrations of CRP & SAA by quartiles of LDL-C and LDL-TG.

LDL-TGLDL-CLDL-TGLDL-C

CRP, SAA, fibrinogen, and ILCRP, SAA, fibrinogen, and IL--6 increased in parallel to LDL6 increased in parallel to LDL--TG. TG. This relationship was independent of This relationship was independent of

Marz W et al. Circulation. 2004;110:3068-3074

conventional coronary risk factors. In contrast, SAA, fibrinogen, and ILconventional coronary risk factors. In contrast, SAA, fibrinogen, and IL--6 were not different across the quartiles of 6 were not different across the quartiles of LDLLDL--C, and CRP was significantly lower even in the highest quartile of LDLC, and CRP was significantly lower even in the highest quartile of LDL--C compared with the lowest quartileC compared with the lowest quartile

The Ludwigshafen Risk and The Ludwigshafen Risk and Cardiovascular Health Study: LDLCardiovascular Health Study: LDL TGTGCardiovascular Health Study: LDLCardiovascular Health Study: LDL--TGTG

ORs (95% CI) for angiographic ORs (95% CI) for angiographic CAD by sensitive CRP and LDLCAD by sensitive CRP and LDL--CRP LDL-TG

LDL-TG and Inflammatory MarkersCAD by sensitive CRP and LDLCAD by sensitive CRP and LDL--

TG. CRP and LDLTG. CRP and LDL--TG were TG were broken down into tertiles, and broken down into tertiles, and ORs were calculated for each ORs were calculated for each resulting layer in reference to resulting layer in reference to 3rd Tertile

2nd Tertile1st Tertile

C LDL TG1.001.061.051.711.65

p = 0.045

group with both CRP and LDLgroup with both CRP and LDL--TG in their lowest tertiles.TG in their lowest tertiles.

3rd Tertile

2nd Tertile

1st Tertile

2nd Tertile

1.501.271.721.782 30 p = 0 00

p = 0.021p = 0.032

These findings suggestThese findings suggest3rd Tertile

2nd Tertile

1st Tertile

3rd Tertile

2.302.17

1.471.112.11

p = 0.00p = 0.005

p = 0.0020 073

These findings suggest These findings suggest that that LDLLDL--TGTG, although , although

positively related to positively related to systemic markers of systemic markers of i fl tii fl ti ii

1.00.0 2.0 3.0 4.0 5.0 Odds ratio

3rd Tertile1.653.212.47

p = 0.073p = 0.000p = 0.001

inflammation, inflammation, is an is an independent risk factor independent risk factor

of CADof CAD..

Marz W et al. Circulation. 2004;110:3068-3074

UnadjustedUnadjusted for CAD, sex, age, smoking, BMI, MS/DM, HTN

The Ludwigshafen Risk and The Ludwigshafen Risk and Cardiovascular Health Study: LDLCardiovascular Health Study: LDL TGTGCardiovascular Health Study: LDLCardiovascular Health Study: LDL--TGTG

Alt ti f LDL t b li h t i dAlt ti f LDL t b li h t i d►►Alterations of LDL metabolism characterized Alterations of LDL metabolism characterized by high LDLby high LDL--TG are related to CAD, systemic TG are related to CAD, systemic lowlow--grade inflammation and vascular damagegrade inflammation and vascular damagelowlow--grade inflammation, and vascular damage. grade inflammation, and vascular damage.

►►High LDLHigh LDL--TGs are indicative of CETGs are indicative of CE--depleted depleted LDL l t d IDL d d LDLLDL l t d IDL d d LDLLDL, elevated IDL, and dense LDL.LDL, elevated IDL, and dense LDL.

►►LDLLDL--TG may better reflect the atherogenic TG may better reflect the atherogenic potential of LDL than LDLpotential of LDL than LDL--C.C.

Marz W et al. Circulation. 2004;110:3068-3074

The Ludwigshafen Risk and The Ludwigshafen Risk and Cardiovascular Health Study: LDLCardiovascular Health Study: LDL TGTGCardiovascular Health Study: LDLCardiovascular Health Study: LDL--TGTG

In conclusionIn conclusion, we show that disorders of LDL , we show that disorders of LDL metabolism characterized by elevated LDLmetabolism characterized by elevated LDL--TG TG

rather than by elevated LDLrather than by elevated LDL--C may incite C may incite or or promote vascular inflammation. promote vascular inflammation.

The determination of LDLThe determination of LDL--TG would thus TG would thus add add to LDLto LDL--C in predicting CAD. C in predicting CAD.

Marz W et al. Circulation. 2004;110:3068-3074