(Stroke. 2000;31:3079-d.)
© 2000 American Heart Association, Inc.
Letters to the Editor |
Adrenomedullin in Patients With Cerebral Vasospasm After Aneurysmal Subarachnoid Hemorrhage
Department of Neurosurgery, Emergency and Critical Care Medical Center, Nara Prefectual Nara Hospital
Department of Emergency and Critical Care Medicine, Nara Medical University
Department of Neurosurgery, Nara Medical University, Nara, Japan
National Cardiovascular Center Research Institute, Osaka, Japan
First Department of Internal Medicine, Miyazaki Medical College, Miyazaki, Japan
Key Words: vasospasm • peptides • subarachnoid hemorrhage
To the Editor:
Cerebral vasospasm leading to delayed brain ischemia is a major cause of death in patients who initially survive subarachnoid hemorrhage (SAH).1 2 Because of this, the prediction and treatment of vasospasm are critical in the management of SAH patients. Recent studies published in Stroke have reported that several factors, including age <50 years,3 hyperglycemia,3 the duration of unconsciousness after SAH,4 and the plasma level of brain natriuretic peptide,5 could be predictors for the development of cerebral vasospasm after SAH. We suggest adrenomedullin as another possible marker of symptomatic vasospasm.
In a human pheochromocytoma, we discovered adrenomedullin, which proved to be a vasorelaxant peptide of 52 amino acids.6 Adrenomedullin is a ubiquitous peptide that is also found in plasma and cerebrospinal fluid (CSF).7 The adrenomedullin gene is highly expressed in vascular endothelial and vascular smooth muscle cells.7 This peptide regulates the vascular tonus and growth of vascular cells as an autocrine and/or paracrine vasoactive hormone.6 7
Several factors, such as endothelin, inflammatory cytokines, and oxygen free radicals, which seemingly play a role in vasospasm,2 8 9 stimulate the adrenomedullin production from vascular cells.7 10 Additionally, adrenomedullin in the central nervous system (CNS) is involved in controlling brain function,7 and its mRNA and peptide are upregulated in the ischemic cerebral cortex of rodents.7 Therefore, if adrenomedullin plays a role in the pathological processes of cerebral vasospasm and subsequent brain ischemia in SAH patients, the CSF concentrations of adrenomedullin would be expected to change in relation to the vasospasm and brain ischemia.
We investigated plasma and ventricular CSF concentrations of adrenomedullin by radioimmunoassay in 14 aneurysmal SAH patients (3 men and 11 women, mean age 62.0 [SD 7.3] years) in the early period (1 to 3 days after SAH, before vasospasm) and late period (7 to 9 days, development and progression of vasospasm). The 14 patients, who had no preexisting neurological diseases or other chronic disorders, underwent aneurysm clipping within 48 hours after admission. At the time of surgery, each patient had a Glasgow Coma Scale score11 exceeding 10. The plasma adrenomedullin concentration was also measured in 13 healthy control subjects (7 men and 6 women, mean age 32.2 [SD 6.6] years). Brain ischemia due to vasospasm was estimated by repeated neurological examinations and transcranial Doppler sonography and was confirmed by cerebral angiography and single-photon emission CT. We analyzed the adrenomedullin levels of plasma and CSF, comparing them to the presence of symptomatic vasospasm, with nonparametric statistical techniques.
Plasma concentrations of adrenomedullin in the healthy controls averaged 5.05 [SEM 0.21] fmol/mL. In both early and late periods, the 4 patients with no vasospasm (NV) and the 10 patients with vasospasm (V) had significantly higher plasma concentrations of adrenomedullin than the healthy controls (in the NV group, P<0.001 for both periods; V group, P=0.001 and P<0.001 for early and late periods, respectively; Mann-Whitney U test). However, the plasma adrenomedullin concentration did not differ significantly between the 2 groups of NV and V in any period. In the NV and V groups, the plasma adrenomedullin levels did not change significantly over time.
Unlike the plasma levels, the CSF adrenomedullin levels were
significantly greater in the V group than in the NV group in the early
and late periods (Table
). Furthermore,
only in the V group did the CSF concentration of adrenomedullin
increase significantly in the late period compared with the early
period (31.06 [SEM 7.52] and 11.02 [SEM 1.63], respectively;
P=0.009). There was no statistically significant correlation
between plasma and CSF adrenomedullin concentrations for the V group in
the early or late periods.
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The patients with symptomatic vasospasm had significantly higher CSF levels of adrenomedullin than those without vasospasm from the prevasospasm period after SAH. In addition, the CSF adrenomedullin concentration increased with time in response to brain ischemia, and the increase was unrelated to the plasma concentrations. We speculate that the production sites of CSF adrenomedullin in these patients could be ischemic neurons,7 reactive astrocytes,7 infiltrating inflammatory cells in the ischemic brain,7 and/or cerebral vascular cells under oxidative stress.7 The CNS adrenomedullin may play a modulatory role in the cerebral vasospasm and subsequent brain ischemia after SAH. We suggest that CSF adrenomedullin can be a sensitive marker for symptomatic vasospasm.
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