Sequence Variation in the DDAH1 Gene Predisposes for Delayed Cerebral Ischemia in Subarachnoidal Hemorrhage.

Juliane Hannemann,Tabea Brüning,Rainer Böger,Julia Zummack,Daniel Appel,Miriam Seeberger-Steinmeister

doi:10.3390/jcm9123900

Abstract

Delayed cerebral ischemia (DCI) often causes poor long-term neurological outcome after subarachnoidal hemorrhage (SAH). Asymmetric dimethylarginine (ADMA) inhibits nitric oxide synthase (NOS) and is associated with DCI after SAH. We studied single nucleotide polymorphisms (SNPs) in the NOS3, DDAH1, DDAH2, PRMT1, and AGXT2 genes that are part of the L-arginine–ADMA–NO pathway, and their association with DCI. We measured L-arginine, ADMA and symmetric dimethylarginine (SDMA) in plasma and cerebrospinal fluid (CSF) of 51 SAH patients at admission; follow-up was until 30 days post-discharge. The primary outcome was the incidence of DCI, defined as new infarctions on cranial computed tomography, which occurred in 18 of 51 patients. Clinical scores did not significantly differ in patients with or without DCI. However, DCI patients had higher plasma ADMA and SDMA levels and higher CSF SDMA levels at admission. DDAH1 SNPs were associated with plasma ADMA, whilst AGXT2 SNPs were associated with plasma SDMA. Carriers of the minor allele of DDAH1 rs233112 had a significantly increased relative risk of DCI (Relative Risk = 2.61 (1.25–5.43), p = 0.002). We conclude that the DDAH1 gene is associated with ADMA concentration and the incidence of DCI in SAH patients, suggesting a pathophysiological link between gene, biomarker, and clinical outcome in patients with SAH.

Highlights

Subarachnoidal hemorrhage (SAH) is a major neurosurgical emergency
We demonstrated in a previous study that higher levels of the endogenous inhibitor of nitric oxide (NO) synthase (NOS), Asymmetric dimethylarginine (ADMA), and its congener, symmetric dimethylarginine (SDMA), are markers of delayed cerebral ischemia (DCI) and poor neurological outcome in SAH patients [10]
We found a significantly poorer survival rate in patients with external ventricular drain (EVD) (Relative Risk (RR), 3.897, p = 0.039), but no significant associations of EVD with the incidence of DCI (RR, 1.271, p = 0.286) nor vasospasm (RR, 1.542, p = 0.305)

Summary

Introduction

Subarachnoidal hemorrhage (SAH) is a major neurosurgical emergency. Vasospasm and cerebral ischemia often occur with some delay during intensive care unit (ICU) treatment of SAH; delayed cerebral ischemia (DCI) is associated with poor clinical outcome [1]. Various strategies to restore pulmonary NO levels, e.g., the use of inhaled NO [7], exogenous NO donors, or phosphodiesterase-5 (PDE5) inhibitors, have been shown to mitigate the risk of cerebral vasospasm and ischemia after SAH. One experimental study in haptoglobin 2-2 transgenic mice tested the effects of L-citrulline that is converted to L-arginine after absorption, and found improved cerebral perfusion and neurological outcome [8]. Restoring eNOS substrate concentration has been shown to be effective only when this enzyme is blocked by a competitive inhibitor [9]. We demonstrated in a previous study that higher levels of the endogenous inhibitor of NO synthase (NOS), ADMA, and its congener, symmetric dimethylarginine (SDMA), are markers of DCI and poor neurological outcome in SAH patients [10]

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