Oxidative stress and increased formation of vasoconstricting F2-isoprostanes in patients with reversible cerebral vasoconstriction syndrome

doi:10.1016/j.freeradbiomed.2013.04.022

Free Radical Biology and Medicine

Volume 61, August 2013, Pages 243-248

https://doi.org/10.1016/j.freeradbiomed.2013.04.022 Get rights and content

Highlights

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Urine 8-iso-prostaglandin F_2α is elevated in patients with RCVS.
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8-Iso-prostaglandin F_2α is correlated with severity of vasoconstriction.
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Temporal trends of 8-iso-prostaglandin F_2α and vasoconstriction are similar.
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Oxidative stress is potentially implicated in the pathogenesis of RCVS.

Abstract

The pathophysiology of reversible cerebral vasoconstriction syndrome (RCVS) is unknown. Oxidative stress is detrimental to endothelial function and vascular reactivity. We hypothesized that the oxidative stress marker 8-iso-prostaglandin F_2α, which is also a potent vasoconstrictor, might contribute to the pathogenesis of RCVS. Recruited participants included 103 RCVS patients, 53 patients with primary headache with acute severe attacks, and 54 healthy controls. Subjects recruited prior to 2009 were discovery cohort, whereas those after 2009, replication cohort. Urine samples were obtained from all patients at registration and from 79 patients with RCVS again at remission stage. Urine 8-iso-prostaglandin F_2α was analyzed by liquid chromatography-tandem mass spectrometry. Patients with RCVS received magnetic resonance angiography and transcranial color-coded sonography. In RCVS patients, the urine 8-iso-prostaglandin F_2α level was higher than that in the other groups in discovery, replication, and combined cohorts (RCVS, 0.29±0.18; primary headache with acute severe attacks, 0.21±0.19; control, 0.18±0.09 ng/mg creatinine; P<0.001), and it was positively correlated with the flow velocities of major intracranial arteries, especially within the first week of disease onset (middle cerebral artery, Spearman's correlation coefficient [r_s]=0.580, P=0.002; anterior cerebral artery, r_s=0.472, P=0.042; posterior cerebral artery, r_s=0.457, P=0.022; basilar artery, r_s= 0.530, P=0.002). The 8-iso-prostaglandin F_2α level decreased from the ictalto remission stage in RCVS patients (0.31±0.21 vs 0.16±0.10 ng/mg creatinine, P<0.001). 8-Iso-prostaglandin F_2α was higher in patients with RCVS and correlated with the severity of vasoconstrictions. Further studies are required to explore its potential pathogenic role.

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 F_2α (also known as Iso-PGF_2α Type-III or 15-F2t-isoprostane) is the most stable and reliable marker for oxidative stress [10], [13]. In addition, 8-iso-prostaglandin F_2α 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 F_2α 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 F_2α 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 F_2α 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 F_2α 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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NEO-PUFAs are considered as biomarkers of oxidative stress (Van't Erve et al., 2017) but recent studies showed them to exert physiological functions. A remarkable point to notice about isoprostanes (IsoPs) and other NEO-PUFAs is that, they are often assumed to be inherently deleterious (Chen et al., 2013; Njie-Mbye et al., 2013; Bauer et al., 2014; Gauthier et al., 2014; Spinelli et al., 2014) particularly, F2-IsoPs from AA. However, F3-IsoPs from EPA is considered to be biologically inactive, but high consumption of fish elevated blood F3-IsoPs and suppressed F2-IsoPs leading to cardioprotection in Canadian Inuit population (Alkazemi et al., 2016).
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Reversible Cerebral Vasoconstriction Syndrome as an Unusual Complication of a Dural Arteriovenous Fistula treated with Onyx Embolization
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At a 7-month imaging follow-up, cerebral angiography showed complete obliteration of the dAVF with no signs of vasoconstriction (Figure 2E and F). The mechanism of vasoconstriction in RCVS has not been elucidated, but hypotheses suggest deregulation of the cerebral vasculature secondary to endothelial dysfunction and oxidative stress rather than structural changes in the vessels.3,7 The cause of this dynamic unbalance remains unknown, however, although several predisposing factors have been reported (Table 1).
Reversible cerebral vasoconstriction syndrome (RCVS) is a rare entity with an unknown pathophysiology. RCVS has been reported to occur more frequently in women age 20–50 years. Several causative mechanisms have been postulated involving transient deregulation of cerebral arterial tone, small vessel endothelial dysfunction, biochemical factors, hormonal deregulation, oxidative stress, and genetic predisposition. All these mechanisms and triggers are related to sympathetic overactivation, which eventually produces vasoconstriction. RCVS is distinguished by acute severe recurrent thunderclap headaches with or without other neurologic symptoms. However, the diagnosis can be challenging, requiring a high level of suspicion by the clinician, and RCVS is often underdiagnosed.
We present an unusual case of an 18-year-old female who developed RCVS after embolization of a dural arteriovenous fistula with onyx embolic material. Cerebral angiography was performed and verapamil was administered intra-arterially, resulting in a slight decrease in vasoconstriction with clinical improvement. The patient was maintained on oral verapamil during hospitalization. At a 7-month follow-up, the patient was neurologically stable, and cerebral angiography demonstrated no signs of vasoconstriction.
Endovascular procedures are a rare trigger for the development of RCVS and may be misdiagnosed. Prompt recognition of symptoms and diagnosis with treatment are necessary to reduce the risk of stroke. The management approach should be based on the premise of discontinuing precipitating drugs and administering calcium channel blocking agents.
Reversible cerebral vasoconstriction syndrome: an important and common cause of thunderclap and recurrent headaches
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It is also often associated with posterior reversible encephalopathy syndrome (PRES), suggesting the importance of endothelial dysfunction in the disease.6,13 Markers for oxidative stress have also been correlated with disease severity, notably urinary 8-iso prostaglandin F2α, which is a marker for vasoconstriction and oxidative stress that has been found to correlate with the severity of vasoconstriction.11 Importantly, histopathology in RCVS patients who have undergone biopsy show no histological changes in the cerebral vessels to suggest inflammatory or vasculitic processes.2,3.
Reversible cerebral vasoconstriction syndrome is an intracranial vascular manifestation of a wide variety of diseases. It is the second most common cause of thunderclap headache, the most common cause of recurrent severe secondary headaches, and, in patients <60 years of age, has been reported as the commonest cause of isolated convexity subarachnoid haemorrhage. Radiologically, its key feature is vasoconstriction of the intracranial vessels, a dynamic process that is typically maximal at 2 weeks, varies in its distribution over the course of the disease, and typically resolves after 3 months. It can have haemorrhagic and ischaemic complications and sometimes occurs in concert with posterior reversible encephalopathy syndrome. It also has important associations with dissection and migraine. Rarer atypical cases can present with mild headache, no headache at all, or even a comatose state. This paper provides a detailed review of this syndrome, its pathophysiology, differential diagnosis, imaging findings, and work-up. It also describes the role that high-resolution magnetic resonance imaging (MRI) techniques can have in diagnosing the disease and emphasises the central role that all radiologists have in detecting this important and underdiagnosed condition.
Isoprostanes, neuroprostanes and phytoprostanes: An overview of 25 years of research in chemistry and biology
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Since the beginning of the 1990's diverse types of metabolites originating from polyunsaturated fatty acids, formed under autooxidative conditions were discovered. Known as prostaglandin isomers (or isoprostanoids) originating from arachidonic acid, neuroprostanes from docosahexaenoic acid, and phytoprostanes from α-linolenic acid proved to be prevalent in biology. The syntheses of these compounds by organic chemists and the development of sophisticated mass spectrometry methods has boosted our understanding of the isoprostanoid biology. In recent years, it has become accepted that these molecules not only serve as markers of oxidative damage but also exhibit a wide range of bioactivities. In addition, isoprostanoids have emerged as indicators of oxidative stress in humans and their environment. This review explores in detail the isoprostanoid chemistry and biology that has been achieved in the past three decades.
Classifying oxidative stress by F<inf>2</inf>-isoprostane levels across human diseases: A meta-analysis
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The notion that oxidative stress plays a role in virtually every human disease and environmental exposure has become ingrained in everyday knowledge. However, mounting evidence regarding the lack of specificity of biomarkers traditionally used as indicators of oxidative stress in human disease and exposures now necessitates re-evaluation. To prioritize these re-evaluations, published literature was comprehensively analyzed in a meta-analysis to quantitatively classify the levels of systemic oxidative damage across human disease and in response to environmental exposures.
In this meta-analysis, the F₂-isoprostane, 8-iso-PGF_2α, was specifically chosen as the representative marker of oxidative damage. To combine published values across measurement methods and specimens, the standardized mean differences (Hedges’ g) in 8-iso-PGF_2α levels between affected and control populations were calculated.
The meta-analysis resulted in a classification of oxidative damage levels as measured by 8-iso-PGF_2α across 50 human health outcomes and exposures from 242 distinct publications. Relatively small increases in 8-iso-PGF_2α levels (g<0.8) were found in the following conditions: hypertension (g=0.4), metabolic syndrome (g=0.5), asthma (g=0.4), and tobacco smoking (g=0.7). In contrast, large increases in 8-iso-PGF_2α levels were observed in pathologies of the kidney, e.g., chronic renal insufficiency (g=1.9), obstructive sleep apnoea (g=1.1), and pre-eclampsia (g=1.1), as well as respiratory tract disorders, e.g., cystic fibrosis (g=2.3).
In conclusion, we have established a quantitative classification for the level of 8-iso-PGF_2α generation in different human pathologies and exposures based on a comprehensive meta-analysis of published data. This analysis provides knowledge on the true involvement of oxidative damage across human health outcomes as well as utilizes past research to prioritize those conditions requiring further scrutiny on the mechanisms of biomarker generation.

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Original ContributionOxidative stress and increased formation of vasoconstricting F2-isoprostanes in patients with reversible cerebral vasoconstriction syndrome

Highlights

Abstract

Graphical abstract

Introduction

Section snippets

Participants and clinical settings

Participants and their characteristics

Discussion

Disclosure

Acknowledgments

Free Radic. Biol. Med.

Free Radic. Biol. Med.

Neurosci. Lett.

Ann. Emerg. Med.

J. Lipid. Res.

Arch. Med. Res.

Kidney Int.

Prostaglandins Leukot. Essent. Fatty Acids

Biochim. Biophys. Acta.

Narrative review: reversible cerebral vasoconstriction syndromes

Ann. Intern. Med.

Recurrent primary thunderclap headache and benign CNS angiopathy: spectra of the same disorder?

Neurology

Transcranial color doppler study for reversible cerebral vasoconstriction syndromes

Ann. Neurol.

Magnetic resonance angiography in reversible cerebral vasoconstriction syndromes

Ann. Neurol.

The clinical and radiological spectrum of reversible cerebral vasoconstriction syndrome. A prospective series of 67 patients

Brain

Hemorrhagic manifestations of reversible cerebral vasoconstriction syndrome: frequency, features, and risk factors

Stroke

Reversible cerebral vasoconstriction syndromes: analysis of 139 cases

Arch. Neurol.

Original Contribution
Oxidative stress and increased formation of vasoconstricting F2-isoprostanes in patients with reversible cerebral vasoconstriction syndrome