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Abstract

Background

Individuals with migraine present ictal elevation of endothelin-1 levels. Migraine can be subclassified into episodic migraine and chronic migraine. Apart from the inconsistent reports on interictal endothelin-1 levels, most studies did not distinguish between episodic migraine and chronic migraine.

Methods

We measured plasma endothelin-1 levels in participants with episodic migraine (n = 87), with chronic migraine (n = 88), and controls (n = 50).

Results

Interictal endothelin-1 levels were not significantly different among participants with episodic migraine, those with chronic migraine, and controls (pg/ml, median and interquartile range, 10.19 [7.76–13.69] vs. 9.25 [6.91–10.73] vs. 9.46 [7.00–14.19], p = 0.131). After excluding participants with fibromyalgia (n = 50) and medication-overuse headache (n = 21), endothelin-1 levels were still similar among groups (10.51 [7.96–14.10] vs. 9.24 [6.96–10.81] vs. 9.46 [7.00–14.19], p = 0.230). Endothelin-1 levels did not significantly differ among participants with migraine with aura, those with migraine without aura, and controls (9.36 [4.26–13.35] vs. 9.50 [7.23–13.02] vs. 9.46 [7.00–14.19], p = 0.975). There was no significant association of endothelin-1 with headache intensity (mild, 8.99 [8.99–8.99] vs. moderate, 8.71 [6.85–12.15] vs. severe, 9.55 [7.23–13.13], p = 0.517) or headache frequency per month (exponential and 95% confidence interval, 0.709 [0.296–1.698], p = 0.440) in participants with episodic migraine and chronic migraine.

Conclusions

Interictal plasma endothelin-1 level is an unlikely marker for episodic migraine and chronic migraine.

Keywords

Endothelium headache migraine vascular human biomarker

Introduction

Endothelin-1 (ET-1) is a peptide comprising 21 amino acid residues derived from the endothelium (1). Previous studies have proposed a possible link between ET-1 and migraine. Specifically, increased ET-1 levels have been noted during the ictal phase of migraine. Moreover, they induce cortical spreading depression in rats (2 –7), considered an underlying mechanism for migraine with aura.

Chronic migraine (CM) and episodic migraine (EM) are subtypes of migraine. CM is defined as headaches occurring ≥15 days/month and migraine features presenting ≥8 days/month (8). Headache is a key symptom of migraine attacks, but in CM it often persists without the typical attacks. Therefore, the interictal period in CM has been defined differently from that in EM (9). Compared with EM, CM presents with more comorbidities, lower prevalence, and increased pain.

Moreover, some biomarker studies on CM and EM have reported contrasting findings (9,10), while previous studies on ET-1 levels in migraine did not differentiate between CM and EM. Furthermore, there have been inconsistent reports regarding interictal ET-1 levels (2,4 –7). We aimed to compare the interictal ET-1 levels in participants with CM with those in participants with EM and healthy controls.

Methods

Participants

We recruited female participants with EM and CM aged 19–65 years, who visited an outpatient clinic of the department of neurology of a tertiary university hospital. The inclusion criteria were: a) female individuals aged 19–65 years, meeting the criteria of EM (code 1.1 or 1.2) or CM (code 1.3) in the third edition of the International Classification of Headache Disorders (ICHD-3) (8); b) ≥48 h after cessation of headache attacks for EM and mild or lower headache intensity for CM; c) If individuals with EM or CM were receiving preventive medications, we only enrolled individuals who maintained the types and dosages of preventive medications for ≥1 month; and d) full understanding of the study protocol. The exclusion criteria were: a) secondary headache(s) other than medication overuse-headache (MOH, code 8.2), diagnosed based on the diagnostic criteria of the ICHD-3; b) chronic pain conditions other than fibromyalgia (FM), diagnosed according to the 2016 American College of Rheumatology (ACR) criteria (11); and c) current medical and psychiatric treatment other than antihypertensive medications.

Healthy controls were recruited through advertisement and considered eligible if they did not experience headaches and migraine attacks anytime during the previous year and their lifetime, respectively.

Plasma collection

We obtained 10 mL blood samples from the right antecubital vein between 9:00 and 12:00 a.m. after the participants had rested for ≥15 min. After centrifugation at 3000 rpm for 15 min at 4°C, the plasma was harvested and stored at −70°C until use.

ET-1 measurement

Plasma ET-1 levels were quantified using an enzyme-linked immunosorbent assay (ELISA) kit (ab133030) (Abcam, Cambridge, UK) following manufacturer’s instructions. The ELISA kit had a minimum detection limit of 0.41 pg/ml. The estimated inter-assay and intra-assay precision was ≤0.1% and ≤0.3% coefficient of variation, respectively.

Sample size

The sample size was computed based on a previous study on interictal ET-1 levels in individuals with transformed migraine (TM) and controls (6). The ratio of patients with TM to controls was 1:2. To assume a 5% significance level and 80% power, the sample sizes of the disease and control groups were calculated as 18 and 9, respectively. We targeted to enrol 80 participants in the EM and CM groups to assess the association of ET-1 levels with clinical characteristics. Accordingly, we targeted to enrol 40 healthy individuals in the control group.

Assessment of anxiety, depression, FM and MOH

Anxiety was evaluated using the Generalized Anxiety Disorder-7 (GAD-7) questionnaire (12), with a GAD-7 score ≥7 indicating anxiety. We used the Patient Health Questionnaire-9 (PHQ-9) to evaluate depression (13), with a PHQ-9 score ≥10 indicating depression. The GAD-7 and PHQ-9 were validated in the Korean language (12,13). FM and MOH were diagnosed based on the 2016 ACR criteria and MOH diagnostic criteria of ICHD-3, respectively (8,11).

Assessment of diagnosis of hypertension, antihypertensive medication use, alcohol drinking and smoking

Diagnosis of hypertension and antihypertensive medication use were assessed by asking participants questions. If a participant positively responded to questions regarding diagnosis of hypertension and taking antihypertensive medications, the participant was classified as having a diagnosis of hypertension and taking antihypertensive medications, respectively. Alcohol drinking was evaluated by asking the participants and categorized as no drinking, drinking <1 time per week and drinking ≥1 time per week. Smoking was assessed by asking participants a question and was divided into no current smoking and current smoking.

Statistical analyses

The Shapiro–Wilk test was used to assess the normality of the data distribution. After normality was confirmed, an independent t-test or analysis of variance was used to compare continuous variables. If normality was not confirmed, the Mann–Whitney U test or Kruskal–Wallis test was utilized, with values being expressed as medians (interquartile ranges). Post-hoc analyses were conducted using Bonferroni’s method. The chi-square test was used to compare categorical variables. Poisson regression analysis was used to evaluate the association of ET-1 levels with the monthly headache frequency, the severity of anxiety (GAD-7 score), and depression (PHQ-9 score). A two-tailed p < 0.05 was considered statistically significant. IBM SPSS software version 23.0 for Windows (IBM Corp., Armonk, NY, USA) was used in all statistical analyses.

Ethical approval

This study was reviewed and approved by the Institutional Review Board of Severance Hospital, Yonsei University (approval No. 2018–2711-004). The design and all aspects of this study followed the principles of the Declaration of Helsinki. Participants provided written informed consent before participation.

Results

Demographic and clinical characteristics of participants

We enrolled 87, 88, and 50 female individuals in the EM, CM, and control groups, respectively. Table 1 summarizes the participants’ demographic and clinical characteristics. There were no significant differences in age and body mass index among participants with EM, those with CM, and controls. Among 175 participants with EM or CM, nine were classified as having migraine with aura.

Table 1.

Demographic and clinical characteristics of the included participants with episodic migraine, chronic migraine, and healthy controls.

	Episodic migraine, n = 87	Chronic migraine, n = 88	Controls, n = 50	p-value
Age, median and IQR	41.500 (30.00–49.00)	43.00 (33.00–51.00)	46.00 (34.00–53.25)	0.323*
Body Mass Index, median and IQR	21.59 (19.75–23.57)	21.93 (19.94–24.56)	22.06 (20.38–23.86)	0.245*
Headache frequency per month, median and IQR	3.50 (3.00–8.00)	20.00 (17.00–30.00)		<0.001^†
Severe headache intensity, n (%)	75 (85.2)	79 (90.8)		0.256^†
Unilateral pain, n (%)	52 (59.1)	32 (36.8)		0.003^†
Pulsating quality, n (%)	86 (97.7)	86 (98.9)		1.000^†
Aggravation by movement, n (%)	67 (76.1)	73 (83.9)		0.199^†
Nausea, n (%)	83 (94.3)	82 (94.3)		0.985^†
Vomiting, n (%)	37 (42.0)	40 (46.0)		0.600^†
Photophobia, n (%)	40 (45.5)	49 (56.3)		0.150^†
Phonophobia, n (%)	36 (40.9)	57 (65.5)		<0.001
Anxiety (GAD-7 score >8), n (%)	21 (23.9)	34 (39.1)		0.030^†
Depression (PHQ-9 score >10), n (%)	13 (14.8)	48 (55.2)		<0.001^†
Fibromyalgia, n (%)	10 (11.4)	49 (56.3)		<0.001^†
Preventive medications, n (%)	21 (23.9)	33 (37.9)		0.044^†
Medication-overuse headache	1 (1.1)	19 (21.8)		<0.001^†
Migraine with aura	9 (10.2)	0 (0.0)		0.003^†
Diagnosis of hypertension	4 (4.5)	14 (16.1)	0 (0.0)	0.001*
Current antihypertensive medications	5 (5.7)	12 (13.6)	0 (0.0)	0.022*
Current smoking	6 (6.8)	8 (9.2)	0 (0.0)	0.096*
Alcohol drinking
No drinking	56 (63.6)	61 (70.1)	29 (58.0)	0.513*
<1 per week	17 (19.3)	16 (18.4)	14 (28.0)
≥1 per week	15 (17.0)	10 (11.5)	7 (14.0)

GAD-7: Generalized Anxiety Disorder-7; IQR: interquartile range; PHQ-9: Patient Health Questionnaire-9.

*Comparison among all three groups.

^†Comparison between participants with episodic and chronic migraine.

Plasma ET-1 levels

Plasma ET-1 levels of participants in the EM, CM, and control groups were 10.19 (7.76–13.69) pg/ml, 9.25 (6.91–10.73) pg/ml, and 9.46 (7.00–14.19) pg/ml, respectively (Figure 1). There were no significant differences in plasma ET-1 levels among participants with EM, those with CM, and controls (p = 0.131). After excluding participants with fibromyalgia (n = 50) and MOH (n = 21), ET-1 levels were still similar among groups (10.51 [7.96–14.10] vs. 9.24 [6.96–10.81] vs. 9.46 [7.00–14.19], p = 0.230). ET-1 levels did not significantly differ between participants with migraine with aura, those with migraine without aura, and controls (9.36 [4.26–13.35] vs. 9.50 [7.23–13.02] vs. 9.46 [7.00–14.19], p = 0.975).

Figure 1.

Box plot for endothelin-1 levels in participants with episodic migraine (n = 87), those with chronic migraine (n = 88), and healthy controls (n = 50) showing no significant among-group differences*.

Association of ET-1 with clinical characteristics, comorbidities and lifestyle factors

There was no significant difference in ET-1 levels according to clinical characteristics and comorbidities, except for the pulsating quality and phonophobia (Table 2). ET-1 levels were significantly increased in participants with photophobia and decreased in those with pulsating quality. Headache intensity did not show a significant association with ET-1 levels (mild, 8.99 [8.99–8.99] vs. moderate, 8.71 [6.85–12.15] vs. severe, 9.55 [7.23–13.13], p = 0.517).

Table 2.

Endothelin-1 levels of 175 participants with episodic and chronic migraine according to clinical characteristics and comorbidities.

	With relevant characteristics, median and interquartile range	Without relevant characteristics, median and interquartile range	p-value
Unilateral pain	9.52 (6.94–13.60)	9.42 (7.44–12.76)	0.748
Pulsating quality	9.45 (7.12–12.97)	14.20 (11.32–14.20)	0.047
Aggravation by routine physical activity	9.65 (7.26–13.51)	8.33 (7.01–10.73)	0.052
Severe intensity	9.55 (7.23–13.13)	8.94 (6.82–12.35)	0.329
Photophobia	9.62 (7.83–13.65)	9.32 (7.05–12.78)	0.124
Phonophobia	9.80 (8.11–13.30)	9.04 (6.58–12.79)	0.038
Nausea	9.44 (7.07–12.93)	10.48 (9.32–20.56)	0.070
Vomiting	9.51 (6.83–12.83)	9.40 (7.23–13.23)	0.970
Medication-overuse headache	9.40 (6.71–12.41)	9.44 (7.48–13.54)	0.607
Fibromyalgia	9.52 (6.75–11.94)	9.48 (7.38–13.50)	0.259
Depression (Patient Health Questionnaire-9 score ≥10)	9.80 (7.37–13.56)	9.42 (7.09–12.79)	0.371
Anxiety (Generalized Anxiety Disorder-8 score ≥7)	9.52 (7.01–12.86)	9.48 (7.28–13.15)	0.791
Migraine with aura	9.36 (4.26–13.35)	9.50 (7.23–13.02)	0.813
Diagnosis of hypertension	8.84 (6.52–9.80)	9.52 (7.21–13.12)	0.119
Current antihypertensive medications	8.84 (6.32–9.79)	9.52 (7.25–13.26)	0.049
Current smoking	11.87 (6.34–14.29)	9.45 (7.23–12.77)	0.632

Poisson regression analysis revealed no significant association of ET-1 levels with age, monthly headache frequency, severity of anxiety (GAD-7 score), and depression (PHQ-9 score) in 175 participants with EM and CM (Table 3). Among participants with EM, the severity of anxiety showed a significant positive association with ET-1 level. Age, monthly headache frequency, and severity of depression were not significantly associated with ET-1 levels. However, among participants with CM, none of the above variables, namely the severity of anxiety and depression, age, and monthly headache frequency were significantly associated with ET-1 levels.

Table 3.

Association between age, monthly headache frequency, the severity of anxiety and depression with endothelin-1 levels in participants with episodic or chronic migraine*.

	Participants with EM and CM, n = 175		Participants with EM, n = 87		Participants with CM, n = 88
	OR and 95% CI^†	p-value	OR and 95% CI^†	p-value	OR and 95% CI^†	p-value
Age	1.504 (0.500–2.218)	0.891	1.334 (0.297–5.997)	0.707	0.911 (0.703–1.180)	0.479
Monthly headache frequency	0.709 (0.296–1.698)	0.440	1.846 (0.049–69.041)	0.740	0.915 (0.537–1.558)	0.743
Severity of anxiety (GAD-7)	4.353 (0.696–27.239)	0.116	74.068 (1.158–4739.544)	0.042	1.250 (0.682–2.293)	0.471
Severity of depression (PHQ-9)	2.094 (0.420–10.404)	0.367	39.705 (0.655–2408.325)	0.079	1.175 (0.677–2.039)	0.566

*Poisson regression analysis after age adjustment.

^†Exponential and 95% confidence interval.

CM: chronic migraine; EM: episodic migraine; GAD-7: Generalized Anxiety Disorder-7; OR: odds ratio; PHQ-9: Patient Health Questionnaire-9.

ET-1 levels were not significantly different according to the diagnosis of hypertension and current smoking (Table 2). The alcohol drinking status was not significantly associated with ET-1 levels (no drinking, 9.37 [7.04–12.76] vs. <1 drink per week, 9.65 [7.72–16.52] vs. ≥1 drink per week, 10.19 [7.14–14.93], p = 0.900). Nevertheless, the ET-1 level was significantly lower in participants taking antihypertensive medications compared to participants not taking them.

Preventive medications and their association with ET-1 level

Among 175 participants with EM and CM, 54 (30.9%) used preventive medications. Categories of preventive medications are summarized in Table 4. ET-1 levels did not significantly differ according to the preventive treatment and the classes of preventive medications.

Table 4.

Endothelin-1 levels according to class of preventive medications in participants with episodic and chronic migraine.

	Use of preventive medications, n (%)	Use of the corresponding category of preventive medications, (pg/ml)	Non-use of the corresponding category of preventive medications, (pg/ml)	p-value
All preventive medications	54 (30.9)	9.37 (7.14–11.69)	9.52 (7.18–13.54)	0.756
Antiepileptic drugs	45 (25.7)	9.51 (7.13–12.40)	9.45 (7.21–13.19)	0.866
Antidepressants	7 (4.0)	8.87 (6.75–9.92)	9.50 (7.18–13.10)	0.571
Beta blockers	14 (8.0)	9.95 (7.35–11.76)	9.45 (7.13–13.09)	0.760
Calcium channel blockers	2 (1.1)	15.36 (3.57–15.36)	9.50 (7.21–13.04)	0.983

Discussion

Our findings demonstrated no significant difference in interictal ET-1 levels among participants with EM, those with CM, and controls. Further, there was no significant association of ET-1 levels with headache frequency or intensity, and most typical headache characteristics.

Individuals with migraine present increased ictal ET-1 levels. However, only a few studies have evaluated interictal ET-1 levels in individuals with migraine and with inconsistent results. Three studies revealed no significant differences in interictal ET-1 levels between individuals with migraine and controls (4,6,7); however, two studies reported increased ET-1 levels in individuals with migraine (2,5). A small-scale study including only eight participants with TM reported significantly increased interictal ET-1 levels in individuals with TM compared with controls. However, the sample size was insufficient to evaluate between-group differences (6). Additionally, the diagnostic criteria of TM were not the same as those for CM in the ICHD-3 (8). To the best of our knowledge, this is the first study with a sufficient sample size to investigate ET-1 levels separately in individuals with EM and CM based on ICHD-3 definitions.

Although some studies suggest a role of ET-1 in the pathogenesis of migraine, other studies reported contradictory results. Cortical spreading depression (CSD) is considered a key mechanism of migraine with aura and ET-1 the most potent inducer of CSD known to date (3). A significant ET-1 release, and migraine attacks occurred after a form of sclerotherapy (14,15). In contrast, intravenous ET-1 infusion in individuals with migraine with aura failed to induce headache or aura (16). The non-significant difference in interictal ET-1 levels in participants with EM, those with CM, and controls in the present study implies that interictal ET-1 levels do not have major roles in the clinical presentation of EM and CM.

We found that interictal ET-1 levels were not increased in participants with EM and CM. This suggests that ET-1 elevation only transiently occurs during the ictal period and does not take place with mild headaches in CM. A transient ET-1 elevation during the acute migraine phase has been reported. Plasma ET-1 levels reach their highest level 2 h after the onset of attacks, with a subsequent decrease; however, an increase has been observed after up to 6 h (5,7).

ET-1 has a potent vasoconstriction effect and is involved in the development of hypertension (1). Individuals with migraine have an increased hypertension risk (17). Although the risk of hypertension in individuals with EM and CM has not been directly compared, hypertension is considered as a risk factor of the transformation from EM to CM (18). Elevated blood ET-1 level was noted in some hypertensive conditions such as pheochromocytoma and chronic kidney disease (19,20). Nevertheless, ET-1 levels in essential hypertension did not significantly differ from those in healthy controls (20). Since essential hypertension accounts for 90–95% of all hypertensive patients, the ET-1 level in most individuals with hypertension may not significantly differ compared to healthy controls (21). The present study also found that ET-1 levels did not significantly differ according to the diagnosis of hypertension in participants with EM, those with CM, and controls.

We evaluated the association of ET-1 levels with the severity of anxiety and depression as they are comorbid with both migraine and hypertension (22 –24). Anxiety and depression were more frequently associated in CM than EM and often associated with an exacerbation of clinical presentation of migraine including both EM and CM (25). We found that ET-1 levels were significantly positively associated with the severity of anxiety in participants with EM but not in CM (Table 3). The role of ET-1 levels in anxiety is not well-known but preclinical studies suggest a role in anxiety. For instance, hippocampal ET-1 decreases the excitability of pyramidal neurons and produces anxiolytic effects in mice (26). Compared with low-anxiety mice, mRNA expression of ET-1 and ET-1 B-type receptors in the amygdala were down-regulated in high-anxiety mice (27). Nevertheless, the association of plasma ET-1 and anxiety in humans has not been reported yet. Further studies focusing on the association between anxiety and ET-1 in humans are needed to verify our findings.

This study has some limitations. First, we evaluated the hypertension status by asking for the diagnosis of hypertension rather than measuring blood pressure. Although >75% of women with hypertension are aware of their hypertension diagnosis in Korea, some may not know about it (28). Therefore, assessing the hypertension status by asking for the diagnosis of hypertension rather than measuring blood pressure is a limitation of the present study. Second, this study enrolled only female participants in consideration of potential sex differences in ET-1 levels and to achieve the sufficient sample size. Therefore, our study did not provide information on ET-1 levels in male participants with EM, those with CM, and controls. Further studies including both male and female participants with EM and CM will allow for a better understanding of ET-1 levels in individuals with migraine. Third, although some antihypertensive medications with proven efficacy in the preventive treatment of migraine including beta blockers, angiotensin-converting enzyme inhibitors, and angiotensin receptor blockers (29) may affect the clinical presentation of migraine, we did not evaluate detailed classes of antihypertensive medications. Fourth, although we included a sufficient sample size for among-group comparisons, the sample size of some subgroup analyses could have been insufficient. Specifically, some negative results could be attributed to the small sample size.

Conclusions

In conclusion, this study is the first to investigate interictal ET-1 levels in participants with migraine by dividing them into those with EM and those with CM. However, we observed no between-group differences in interictal plasma ET-1 levels. Interictal plasma ET-1 level is an unlikely marker for EM and CM.

Article highlights

There were no significant differences in interictal plasma ET-1 levels among participants with EM, those with CM, and healthy controls.

ET-1 levels did not show a significant association with headache frequency and headache intensity in participants with migraine.

Interictal plasma ET-1 levels are unlikely to be a marker for EM and CM.

Footnotes

Acknowledgements

The authors would like to express their appreciation to the participants in this study.

Authors’ contributions

Conception and coordination of the study: CG Park and MK Chu; acquisition of data: CG Park, MK Chu, and J Kim; analysis and interpretation of data: MK Chu and J Kim; data review and statistical analysis: J Kim and CG Park; manuscript preparation: MK Chu and J Kim; critical revision of the manuscript: CG Park and MK Chu; manuscript approval: All authors.

Data accessibility

The data used in this study are available from the corresponding author on reasonable request.

Declaration of conflicting interests

The authors declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MKC was a site investigator for a multi-center trial sponsored by Novartis International AG, and Eli Lilly and Company. He has received lecture honoraria from Allergan Korea, Handok-Teva, and Eli Lilly and Company and Yuyu Pharmaceutical Company in the past 24 months. He received grants from the National Research Foundation of Korea (2019R1F1A1053841). CGP is employed by Genuv Inc. JK declares no conflicts of interest.

Funding

The authors disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: This work was supported by the National Research Foundation of Korea (NRF) grant from the Korean government (MSIT) [2019R1F1A1053841].

ORCID iD

Min Kyung Chu

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Interictal plasma endothelin-1 levels do not change in individuals with episodic and chronic migraine

Abstract

Background

Methods

Results

Conclusions

Keywords

Introduction

Methods

Participants

Plasma collection

ET-1 measurement

Sample size

Assessment of anxiety, depression, FM and MOH

Assessment of diagnosis of hypertension, antihypertensive medication use, alcohol drinking and smoking

Statistical analyses

Ethical approval

Results

Demographic and clinical characteristics of participants

Plasma ET-1 levels

Association of ET-1 with clinical characteristics, comorbidities and lifestyle factors

Preventive medications and their association with ET-1 level

Discussion

Conclusions

Article highlights

Footnotes

Acknowledgements

Authors’ contributions

Data accessibility

Declaration of conflicting interests

Funding

ORCID iD

References