Original ContributionOxidative stress and increased formation of vasoconstricting F2-isoprostanes in patients with reversible cerebral vasoconstriction syndrome
Graphical abstract
Introduction
Reversible cerebral vasoconstriction syndrome (RCVS) is characterized by abrupt severe headaches (thunderclap headaches) and reversible cerebral vasoconstrictions [1]. Several large-scale studies have demonstrated that RCVS is not uncommon and should be recognized early because of its substantial risk of devastating complications, such as posterior reversible encephalopathy syndrome, ischemic stroke, intracerebral hemorrhage, and cortical subarachnoid hemorrhage [2], [3], [4], [5], [6], [7]. Severe vasoconstriction, especially of the middle and posterior cerebral arteries, is associated with posterior reversible encephalopathy syndrome or ischemic stroke [3], [4].
Despite a gradual delineation of clinical features, the pathophysiology of RCVS remains elusive. Endothelial dysfunction and sympathetic overactivity might be involved in the pathogenesis of RCVS; however, direct evidence for these connections is lacking. Oxidative stress has complex interactions with endothelial dysfunction or sympathetic overactivity, is detrimental to vascular reactivity, and is associated with vasoconstriction [8], [9], [10], [11], [12].Therefore, it is likely to be associated with RCVS, and an objective measurement for oxidative stress may be useful for assessing disease severity.
F2-isoprostanes are produced in vivo by the nonenzymatic free radical peroxidation of arachidonic acid [10], [13]. Among the isoprostanes, 8-iso-prostaglandin F2α (also known as Iso-PGF2α Type-III or 15-F2t-isoprostane) is the most stable and reliable marker for oxidative stress [10], [13]. In addition, 8-iso-prostaglandin F2α has been found to be a potent vasoconstrictor in most species and vascular beds, both in vitro and in vivo [14]. In patients with aneurismal subarachnoid hemorrhage, 8-iso-prostaglandin F2α has been identified in the cerebrospinal fluid and its level is particularly high in those with delayed vasospasm [15], [16]. RCVS shares commonalities with subarachnoid hemorrhage including the presence of thunderclap headaches and cerebral vasoconstrictions, although they occur in different patterns. These similarities suggest that RCVS and subarachnoid hemorrhage might share some common pathophysiological pathways. These evidences point to a plausible hypothesis that 8-iso-prostaglandin F2α plays a role in the pathogenesis of RCVS and might correlate with disease severity. The purpose of this study was to address this hypothesis.
Section snippets
Participants and clinical settings
Consecutive patients with RCVS were recruited from the headache clinic, neurologic wards, and emergency department of Taipei Veterans General Hospital. Taipei Veterans General Hospital is a 2909-bed national medical center located in Taipei City (Capital of Taiwan) that serves both veterans and nonveteran citizens. The headache clinic, which has been in operation since 1997, has a headache patient pool of>10,000 patients, and sees an average of 30–35 RCVS patients per year (based on data from
Participants and their characteristics
The discovery cohort consisted of 51 patients with RCVS, 27 patients with primary headache with acute severe attacks, and 27 normal controls. The replication cohort included 52 patients with RCVS, 26 patients with primary headache with acute severe attacks, and 27 normal controls. Pooled together, there were 103 patients with RCVS, 53 patients with primary headache with acute severe attacks (migraine (n =41) or cluster headaches (n =12)), and 54 normal controls eligible for final analysis.
Discussion
Our study demonstrated that the urine level of 8-iso-prostaglandin F2α was significantly elevated in patients with RCVS during the ictal stage compared to those with primary headaches with acute severe attacks or normal controls, and was correlated with the severity of vasoconstriction. In addition, the urine level of 8-iso-prostaglandin F2α was decreased in the patients with RCVS as the disease was remitted. These findings suggested that oxidative stress may play a role in the pathogenesis of
Disclosure
Dr. Shih-Pin Chen received grants from the National Science Council of Taiwan and Taipei-Veterans General Hospital.
Dr. Yu-Ting Chung reports no disclosures.
Dr. Tsung-Yun Liu reports no disclosures.
Dr. Yen-Feng Wang reports no disclosures.
Dr. Jong-Ling Fuh is a member of a scientific advisory board of Elli Lilly, and has as well received research support from the Taiwan National Science Council, Taipei-Veterans General Hospital and Elli Lilly.
Dr. Shuu-Jiun Wang has served on the advisory boards
Acknowledgments
This study was supported by grants from the National Science Council of Taiwan (99-2314-B-075-036-MY3, 100-2314-B-010-019-MY2, 100-2314-B-010-018-MY3), Taipei-Veterans General Hospital (V100B-007, VGHUST101-G7-1-1, V101C-106, V101E7-003), NSC support for Center for Dynamical Biomarkers and Translational Medicine, National Central University, Taiwan (NSC 100-2911-I-008-001), Brain Research Center, National Yang-Ming University and a grant from Ministry of Education, Aim for the Top University
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