Elevated plasma dimethylglycine predicts ...

Elevated plasma dimethylglycine predicts cardiovascular risk only when plasma methylmalonic acid is also high Vegard Lysne Gard Frodahl Tveitevåg Svingen Elin Strand Per Magne Ueland Eva Ringdal Pedersen Ottar Nygård

Elevated plasma dimethylglycine (DMG) and increased cardiovascular risk SAP

AMI

Hazard ratio

Total mortality

Cardiovascular mortality

Plasma dimethylglycine, µmol/L Svingen, GFT. et al. Arterioscler Thromb Vasc Biol. 2013. Svingen, GFT. et al. Eur j prev cardiol. 2014

PPARα activation and elevated plasma DMG

÷

Met

DMG

Hcy

Betaine

Sarcosine

÷

Glycine

Serine

PPARα ↑

Choline

Sheikh, K. et al. Am J Physiol Endocrinol Metab(2007). Chu, R. et al. Mol Cell Biol(2004). Wrzesinski, K. et al. J Proteomics.(2013)

PPARα activation increases both DMG and methylmalonic acid (MMA) GASTRIC

PPAR 2014

TTA PPARγ (Roziglitazone)

4

PPARα (WY 14.643)

3 Standardized mean 2 difference

1 0 -1

Control group

DMG

MMA

DMG

Control group

MMA

MMA, DMG and risk

DMG ↑

Risk ↑

?

PPARα ↑

MMA ↑

MMA, DMG and risk

Population

Groups

End points

4154 patients with suspected stable angina pectoris, median follow-up 4.7y

Plasma MMA and DMG above/below median

• Acute myocardial infarction • Cardiovascular mortality • Total mortality

Incidence & mortality rates Low MMA

High MMA

Total population

Low DMG

High DMG

Low DMG

High DMG

n

4154

1360

960

720

1114

MMA (pmol/L)

160

130

140

210

210

DMG (µmol/L)

4.1

3.3

5.0

3.5

5.0

n = 343 (8.2 %)

(5.6 %)

(7.2 %)

(6.1 %)

(13.8 %)

(1.8 %)

(2.4 %)

(3.5 %)

(8.4 %)

(4.1 %)

(5.3 %)

(7.5 %)

(13 %)

Acute myocardial infarction

Cardiovascular mortality Total mortality

n = 306 (7.4 %)

The risk is confined to those with high MMA / high DMG Low MMA / Low DMG Low MMA / High DMG Acute myocardial infarction

High MMA / Low DMG

High MMA / High DMG

***

Cardiovascular mortality

*** Total mortality

* 1

2

* p < 0.05, *** p < 0.001

*** 3

4

5

Adjusted for age, gender, diabetes, hypertension and smoking.

So, what is different about this group? Low MMA

High MMA

Total population

Low DMG

High DMG

Low DMG

High DMG

p*

Male

72 %

73.5 %

74.5%

69.2 %

69.7 %

0.018

Age

61.7 (10.4)

58.9 (9.1)

61.0 (9.4)

64.1 (9.2)

66.3 (9.7)