Figure 1.
Onset of infection in sepsis leads to an up-regulation of inducible nitric oxide synthase (NOS) in response to lipopolysaccharide and pro-inflammatory cytokines. This consequently increases nitric oxide (NO) production, which has a multitude of effects on endothelial, vascular, and immune function. Asymmetric dimethylarginine (ADMA) is produced by the methylation of arginine residues on proteins by the enzyme protein-arginine methyltransferase (PRMT) and metabolized by dimethylarginine dimethylaminohydrolase (DDAH). ADMA competitively inhibits NOS, thereby limiting NO production.
Table 1.
Hemodynamic Shock Types.
Figure 2.
Schematic representation of DDAH2 gene (adopted from www.ncbi.nlm.nih.gov/gene/23564), including the upstream promoter, the ATG translation start site, and the −871 6g/7g and −449 G/C polymorphisms. Exons are numbered 1–7. Exon 1 is non-coding, but this area and intron 1 appear to contain a second promoter region.
Figure 3.
Patient screening and study enrollment.
Flow diagram of patient screening and enrollment.
Table 2.
Patient Characteristics.
Table 3.
DDAH2 Genotype Frequencies.
Figure 4.
Relationship between plasma ADMA concentration and the DDAH2 −449G/C genotype in septic patients.
Plasma ADMA concentrations differed according to −449G/C genotype on day 1 but not day 3. ADMA was highest in septic patients with −449CC homozygous genotype, intermediate in −449GC heterozygotes, and lowest in the GG homozygotes on day 1 (p = 0.01, panel A). While a similar trend in plasma ADMA was observed on day 3, the difference was not significant (p = 0.33, panel B).
Table 4.
ADMA, type of shock, and vasoactive infusion requirements in septic patientsa.
Figure 5.
All of the septic shock patients with the −449CC homozygous genotype exhibited “warm” shock. While day 1 plasma ADMA concentration did not differ between “warm” and “cold” shock (p = 0.42), when compared with −449CC homozygous patients with shock, ADMA was significantly lower in those with the −449G allele for “cold” shock (p = 0.02) and trended lower for “warm” shock (p = 0.09).