A higher prevalence of migraine in patients with cardiac syndrome x compared to patients with cardiovascular disease and healthy control

A higher prevalence of migraine in patients with cardiac syndrome x compared to patients with cardiovascular disease and healthy control | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article A higher prevalence of migraine in patients with cardiac syndrome x compared to patients with cardiovascular disease and healthy control Mehran Movahednia, Elham Ouspid, Shahin Abbaszadeh, Massomeh Mahmoodi, and 2 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4019762/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background Cardiac syndrome X(CSX), is a type of ischemic heart disease, that is characterized by angina-like chest pain, without any evidence of significant coronary vascular abnormalities. Some evidence has revealed a significant association between migraines, particularly migraine with aura, with cardiovascular diseases (CVDs). In this case-control study, the prevalence of migraine and the role associated risk factors were compared between the patients with CSX, CVD, and healthy control individuals. Methods The patients with CSX (n = 70), CAD (n = 70), and healthy individuals (n = 70) were enrolled in this study. For each enrolled subject, demographic and clinical data were collected. The prevalence of migraine and associated risk factors were determined in each group. Results The prevalence of migraine in the CSX group (40%) was significantly higher compared to those of CVD (24%) (p = 0.047) and healthy controls groups (21%) (p = 0.017). In the control subjects, but not in the CVD and CSX groups, the female gender was a significant risk factor for migraine. The prevalence of migraine with aura was significantly higher in patients with CSX (20%) compared to patients with CVD (8%) (p = 0.045). The family history of migraine was significantly higher in patients with CSX (57.0%) compared to patients with CVD (31.0%) and the control group (35.7%) (p = 0.004). Conclusions The results of this study revealed a significantly higher prevalence of migraine in patients with CSX. The findings also showed a familial aggregation of migraine in the patients with CSX, suggesting a role of genetic factors in predisposing CSX patients to migraine. Migraine Cardiac syndrome X Cardiovascular diseases Risk factors Introduction Migraine is a prevalent debilitating neurovascular disorder, affecting more than 1 billion people globally. Migraine attack usually consists of four different phases including prodrome, aura, headache, and postdrome phases. The headache phase is associated with several symptoms including photophobia, nausea, vomiting, and fatigue which disturb daily activities and reduce the quality of life of migraineurs ( 1 ). The burden of migraine, however, is not restricted to the headache phase and patients may suffer from several symptoms such as hypersensitivity, phonophobia, photophobia, and vestibular disorders in the interictal phase, the phase between migraine attacks ( 2 , 3 ). Although the exact molecular and cellular mechanisms underlying migraine pathogenesis are not completely understood, several reasonable explanations have been proposed. At the molecular level, the critical role of calcitonin-gene-related peptides (CGRPs) in the pathogenesis of migraine has been documented and CGRP receptor antagonists and monoclonal antibodies against CGRP or its receptors have revealed substantial efficacy in the treatment of migraine attacks ( 4 ). In addition to CGRP receptors, numerous studies have indicated the high efficacy and safety of 5-HT 1F receptor agonists such as Lasmiditan in the treatment of migraine ( 5 ). At the cellular level, prior studies have described the role of mitochondrial dysfunction in the pathogenesis of migraine. The correlation of migraine with mitochondrial genome polymorphisms and biomarkers of oxidative stress are amongst the evidence that indicates the possible contribution of mitochondrial dysfunction to migraine pathology ( 6 ). A wide range of risk factors has been identified for migraine. Multiple investigations have concluded the important role of genetic factors in migraine development including familial aggregation of migraine, a high concordance rate of migraine in monozygotic twins, and the association between several genetic polymorphisms with the increased risk of migraine ( 7 ). The association of migraine with demographic characteristics such as sex and age have also been described. Women are at a higher risk of migraine development than men which could be related to differences in sex hormone fluctuations or psychological factors. Although migraine can occur at any age, their prevalence rate exhibits an age-dependent manner, increases from early life to middle age, and then gradually declines ( 8 ). Clinical and experimental data have revealed the association of migraine with numerous comorbidities including cardiovascular, psychiatric, neurologic, as well as inflammatory disorders. The association with these comorbidities complicates the diagnosis, increases the risk of progression to chronic migraine, limits treatment options, and lowers the quality of life of migraineurs. Therefore, understanding migraine comorbidities is very important because it can help to determine possible common or overlapping pathological mechanisms of diseases and can lead to the development of new diagnostic and therapeutic strategies ( 9 ). A growing body of evidence has revealed a significant association between migraines, particularly migraine with aura, with cardiovascular diseases (CVDs) such as ischemic heart disease, myocardial infarction, angina, and arrhythmia ( 10 ). Because alteration in blood flow is involved in the pathogenesis of migraines and CVDs, this association can be described by inadequate blood flow to the heart or brain due to genetic factors, endothelial dysfunction, and coagulation abnormalities ( 11 ). Cardiac syndrome X (CSX), is a type of ischemic heart disease, that is characterized by angina-like chest pain, and ST segment depression during exercise, without any evidence of significant coronary vascular abnormalities at coronary angiography ( 12 ). CSX is more prevalent in postmenopausal women. Although the potential risk factors for CSX have not yet been fully elucidated, several mechanisms may involve including microvascular abnormalities ( 13 ) and mitochondrial dysfunction. Because these abnormalities have been proposed in the etiology of migraine, we have suggested a link between migraine and CSX in our previous study ( 14 ). In this study, we have extended our previous study to a larger population of CSX patients. Furthermore, the association of several risk factors, notably sex and familial aggregation are evaluated. Patients and Methods Patient population This case-control study was performed from March to October 2021. Adult patients, aged between 18–70 years old, with a history of angina chest pain, abnormal cardiac tests including exercise test, SPECT MPI, and normal angiography results were classified in the CSX group (n = 70), and if showed more than 50% coronary artery involvement in angiography were categorized in CAD group (n = 70). Seventy healthy individuals without any history of previous illness, with a normal ECG, were randomly selected as the control group. Severe valvular heart diseases, previous coronary artery diseases, diabetes mellitus, congenital heart disease, hypertension, and cardiomyopathy were exclusion criteria for the control and CSX groups. The patients with a history of severe anxiety, depression, and headache that unrelated to migraine were excluded from the study. The study protocol was approved by the Ethics Committee of Bandar-Abbas University of Medical Sciences. The protocol was explained to the patients and written informed consent was obtained from all the patients. For each enrolled subject, demographic and clinical data were collected. The presence of migraine in the subjects and their parents, siblings, and children was evaluated using a Migraine Screen Questionnaire (MS-Q) based on the International Headache Society (IHS) criteria ( 15 ). Statistical analysis: SPSS software (Version 15) was used to analyze the data. Continuous variables were presented as mean ± standard deviation (SD) and categorical variables were presented as frequency. The Chi-square test was used to compare qualitative variables between groups. Mann-Whitney and One-way ANOVA tests were used to compare continuous variables between groups. Binary logistic regression was used to determine the significant associations between the risk factors and migraine. A p-value less than 0.05 was considered a significant difference. Results Table 1 shows various clinical and demographic characteristics of the healthy patients enrolled in this study. The mean age and BMI were not significantly different among the studied groups. The prevalence of migraine in all studied subjects was 34.3% (n = 60) of which 61.7% of the subjects (n = 37) were female and 38.3% were male (n = 23) (p = 0.035). The prevalence of migraine in the CSX group was 40% which was significantly higher compared to those of CVD (24%) (p = 0.047) and healthy controls groups (21%) (p = 0.017). In the control subjects with migraine, the number of female subjects (n = 13; 86.7%) was significantly higher than males with migraine (n = 2; 13.3%) (p = 0.002), however, in the CVD and CSX groups the frequencies of males and females with migraine were not significantly different. The prevalence of migraine with aura was significantly higher in patients with CSX (20%) compared to patients with CVD (8%) (p = 0.045). Family history of migraine was observed in 40(57.0%) patients with CXS which was significantly higher compared to patients with CVD (31.0%) and the control group (35.7%) (p = 0.004). Table 2 reveals and compares various characteristics between patients with (n = 60) and without migraine(n = 150). No significant difference was observed in the mean age and BMI of the subjects with and without migraine. Significant higher percentages of family history of migraine and female sex were observed in the patients with migraine compared to those in subjects without migraine. The prevalence of obesity and smoking was not significantly different among subjects with and without migraine. The results of logistic regression models are summarized in Table 3 . The data showed that family history was the only significant predictor of migraine in all cases (OR 4.88, 95% CI: 2.56–9.30; p < 0.0001). In the control group, predictors of migraine included female sex (OR 7.25, 95% CI: 1.43–36.70; p < 0.017) and family history (OR 4.08, 95% CI: 1.11–14.95; p < 0.034). Furthermore, the data showed that family history was the only predictor of migraine in the CVD (OR 7.00, 95% CI: 2.11–23.13; p < 0.01) and CSX group none of the evaluated factors were a predictor of migraine. Table 1 Comparison of various characteristics between patients and control group Variables Control(a) CVD(b) CSX(c) p values a vs b a vs c b vs c Age (years); (mean ± SD) 50.2 ± 10.0 51.2 ± 9.0 51.5 ± 8.0 0.529 0.410 0.846 BMI (kg/m 2 ); (mean ± SD) 25.0 ± 3.9 26.2 ± 4.4 26.5 ± 5.3 0.0.08 0.120 0.846 Obesity (BMI ≥ 30); n (%) 6(8.6) 12(17.1) 16(22.9) 0.130 0.02 0.398 Female Sex; n (%) 36(51.4) 35(50.0) 36(51.4) 0.866 0.866 1.0 Smoking; n (%) 7( 10 ) 35(50.0) 36(51.4) < 0.001 < 0.001 0.866 Migraine; n (%) 15(21.0) 17(24.0) 28(40) 0.687 0.017 0.047 Migraine with aura; n (%) 9( 13 ) 6( 8 ) 14( 20 ) 0.412 0.254 0.045 Family history; n (%) 25(35.7) 22(31.0) 40(57.0) 0.591 0.011 0.002 Abdominal pain in their children; n (%) 8(11.4) 8(11.4) 15(21.4) 0.919 0.137 0.172 BMI: Body Mass Index, CVD: Cardiovascular disease, CSX: Cardiac syndrome X, n: number Table 2 Comparison of various characteristics between subjects with and without migraine Variables Subjects with migraine (n = 60) Subjects without migraine (n = 150) p values Age (years); (mean ± SD) 50.3 ± 8.7 51.3 ± 9.2 0.508 BMI (kg/m 2 ); (mean ± SD) 25.8 ± 4.0 25.9 ± 4.8 0.989 Obesity (BMI ≥ 30); n (%) 7(11.7) 27(18.0) 0.320 Female Sex; n (%) 37(61.6) 70(46.6) 0.035 Smoking; n (%) 25(41.6) 53(35.3) 0.241 Family history; n (%) 41(68.3) 46(30.7) P < 0.001 BMI: Body Mass Index, n: number Table 3 Predictors of migraine in the logistic regression model Group Predictors OR CI (95%) P value All case Family history YES 4.879 2.56–9.30 < 0.0001 NO - - - Control sex Female 7.254 1.43–36.70 0.017 Male - - - Family history YES 4.080 1.11–14.95 0.034 NO - - - CVD Family history YES 7.000 2.12–23.15 0.001 NO - - - CSX Family history YES 2.750 0.99–7.62 0.052 NO - - - CVD: Cardiovascular disease, CSX: Cardiac syndrome X. Discussion A growing number of studies have revealed mitochondrial deficits in the brain and muscles of migraineurs ( 6 ). Mitochondrial dysfunction is also considered a feature of patients with CSX(Hsiu-Bao); therefore, it is speculated that this common feature, mitochondrial dysfunction, can lead to comorbidity between migraine and CSX. The results of the present study displayed a higher prevalence of migraine in the patients with CSX compared to healthy control and the patients with CVD. Furthermore, a higher frequency of family history of migraine was observed in the patients with CSX compared to CVD and healthy control, suggesting a possible role of genetic factors in predisposing CSX patients to migraine. Several studies have indicated comorbidity between migraine, particularly migraine with aura, and CVD. Although the exact mechanism is not clearly understood, changes in blood flow led to insufficient blood flow to the heart and brain a common feature of CVD and migraine ( 11 , 16 ). However, our data revealed that the prevalence of migraine in the patients with CVD was not significantly different from that observed in the healthy control group. Similarly, Nemati et al showed the same prevalence of migraine in CVD patients and healthy control subjects ( 14 ). They also demonstrated a higher significant prevalence of migraine in patients with CSX (60%) compared to that of the healthy group (22%) and concluded that CSX may be a manifestation of migraine. Their finding is consistent with the results of our study which showed a higher prevalence of migraine in CSX patients (40%) compared to the control group (21%). Several mechanisms can explain the association of CSX and migraine. Vasospasm, endothelial abnormalities, and mitochondrial dysfunction are among possible mechanisms that may connect CSX to migraine ( 14 ). Several epidemiological investigations have shown a higher prevalence of migraines in women compared to men ( 17 , 18 ). In addition, sex-related differences in migraine attacks have been confirmed by the findings of structural and functional brain MRIs ( 19 ). Several possible mechanisms include fluctuation in the circulating level of estrogen, genetic factors, as well as sex differences in the exposure and response to the environmental stressor may involve in this issue ( 18 , 20 ). When we analyzed the control group, the results of binary regression demonstrated female sex is a predicting factor for migraine which is in line with several previous studies ( 18 ). However, this result did not observe in the patients with CVD and CSX, suggesting that gender does not play a role in increasing the prevalence of migraine in the patient with CSX. Due to the association of obesity with vascular endothelium damage ( 21 ) and the role of endothelial dysfunction in the pathogenesis of CSX ( 22 ), it has been postulated that obesity may play a role in the development of CSX. In the present study, no significant difference was observed in the BMI of patients with CSX and healthy control individuals, however, the prevalence of obesity (BMI ≥ 30) was significantly higher in the patients with CSX compared to the control group and Chi-square test revealed that obesity was associated with the increased risk of CSX (odd ratio = 2,95% CI (0.953–4.233). On the other hand, obesity is also considered a risk factor for the development and exacerbation of migraine ( 23 ). However, in the present study no significant association was observed between BMI and migraine, and the prevalence of obesity (BMI ≥ 30) was not significantly different in the patients with CSX compared to the control group. Therefore, a higher prevalence of migraine in patients with CSX could not be described as a higher prevalence of obesity in CSX patients. The essential role of genetic factors in the development of migraine have been indicated by numerous studies ( 24 , 25 ), and heritability of 42% has been estimated for migraine ( 26 ). The familial aggregation of migraine as well as familial early age onset and severity of migraines are also confirmed by polygenic risk scores analyses ( 27 , 28 ). Furthermore, genome-wide association (GWS) studies have identified the association of migraine with more than thirty distinct genomic loci, suggesting the polygenic nature of migraine ( 29 ). The results of the present study showed a higher familial history of migraine in the CSX group which suggests the possible role of genetic factors in predisposing CSX patients to migraine. Conclusions The results of this study revealed a significantly higher prevalence of migraine in patients with CSX. The findings also showed a remarkable familial aggregation of migraine in the patients with CSX, suggesting a role of genetic factors in predisposing CSX patients to migraine and also common pathology of both conditions. Due to the Covid19 pandemic a relatively low number of patients and healthy control enrolled in the present study; therefore, further studies with larger populations of CSX patients are needed to confirm the results of this study. In addition, GWS studies are warranted to determine the possible genetic loci that predispose CSX patients to migraine. Declarations Ethical Approval: The study received ethics approval from the Ethics Committee of Hormozgan University of Medical Sciences (No: 94-96/374). Informed consent was obtained from all individual participants included in the study. Consent for publication : Not Applicable Data availability: The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request. Competing Interests: The authors declare that they have no competing interests. Funding: The present study was funded by the Hormozgan University of Medical Sciences, Iran Author Contributions: M.M, E.O and A.GH contributed to the study design and supervision. M.M performed the statistical analysis. M.M, E.O, F.D and A.GH wrote the manuscript. A.GH and SH.A revised the manuscript. All authors read and approved the final manuscript. Acknowledgments: The authors of this article would like to express their deepest gratitude to the Vice-Chancellor of Research and Technology of Hormozgan University of Medical Sciences for the technical and financial support for this study. References Vincent M, Viktrup L, Nicholson RA, Ossipov MH, Vargas BB. The not so hidden impact of interictal burden in migraine: A narrative review. Frontiers in neurology. 2022;13:1032103. Nascimento TD, Kim DJ, Chrabol C, Lim M, Hu XS, DaSilva AF. Management of Episodic Migraine with Neuromodulation: A Case Report. 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Gormley P, Kurki MI, Hiekkala ME, Veerapen K, Häppölä P, Mitchell AA, et al. Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families. Neuron. 2018;98(4):743-53.e4. de Boer I, van den Maagdenberg A, Terwindt GM. Advance in genetics of migraine. Current opinion in neurology. 2019;32(3):413-21. Chasman DI, Schürks M, Anttila V, de Vries B, Schminke U, Launer LJ, et al. Genome-wide association study reveals three susceptibility loci for common migraine in the general population. Nature genetics. 2011;43(7):695-8. Additional Declarations No competing interests reported. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-4019762","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Research Article","associatedPublications":[],"authors":[{"id":276725304,"identity":"0e6689b2-9841-49e9-a563-429fd0132a7e","order_by":0,"name":"Mehran Movahednia","email":"","orcid":"","institution":"1.\tCardiovascular Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran","correspondingAuthor":false,"prefix":"","firstName":"Mehran","middleName":"","lastName":"Movahednia","suffix":""},{"id":276725305,"identity":"f19c1838-de62-42c1-ac92-183b5fdb0cf7","order_by":1,"name":"Elham Ouspid","email":"","orcid":"","institution":"1.\tCardiovascular Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran","correspondingAuthor":false,"prefix":"","firstName":"Elham","middleName":"","lastName":"Ouspid","suffix":""},{"id":276725306,"identity":"7f090388-fbf5-4bf7-926b-3ffa2a40504b","order_by":2,"name":"Shahin Abbaszadeh","email":"","orcid":"","institution":"1.\tCardiovascular Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran","correspondingAuthor":false,"prefix":"","firstName":"Shahin","middleName":"","lastName":"Abbaszadeh","suffix":""},{"id":276725307,"identity":"5426f771-fe75-4edd-b6f0-e31cf6091544","order_by":3,"name":"Massomeh Mahmoodi","email":"","orcid":"","institution":"1.\tCardiovascular Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran","correspondingAuthor":false,"prefix":"","firstName":"Massomeh","middleName":"","lastName":"Mahmoodi","suffix":""},{"id":276725308,"identity":"f4f74e0a-6884-4ab2-b3aa-544b4d2ce042","order_by":4,"name":"Farideh Dastsouz","email":"","orcid":"","institution":"1.\tCardiovascular Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran","correspondingAuthor":false,"prefix":"","firstName":"Farideh","middleName":"","lastName":"Dastsouz","suffix":""},{"id":276725309,"identity":"34d6908a-eead-419f-ab41-42fce6944c3d","order_by":5,"name":"Atefeh Ghareghani","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA8UlEQVRIiWNgGAWjYJCCD4wNNswMEswHGBgbiFHPxsA4g7EhjZ1Bgi2BJC2H+RkkeAyI08I/v/lgw8cdadLy0T3fJH7usJFjYD98dAM+LRLH2BIbZ56xMTa8c3abZO+ZNGMGnrS0G3itOcZj/pi3LS3ZcEbuNgnetsOJDRI8Zni1yB/j/9j8t+1w/cYZOc8k/xKjxeAYD2MzY9thZnmJHDZpomwxPJZm2NjblsZsIJFmbC3blmbMRsgvcocPP2z42WbDLD8j+eHNt202cvzsh4/h9z7chQcYWCRADDailIOAfAMD8weiVY+CUTAKRsGIAgB+V09GhRBMwQAAAABJRU5ErkJggg==","orcid":"","institution":"1.\tCardiovascular Research Center, Hormozgan University of Medical Sciences, Bandar Abbas, Iran","correspondingAuthor":true,"prefix":"","firstName":"Atefeh","middleName":"","lastName":"Ghareghani","suffix":""}],"badges":[],"createdAt":"2024-03-06 07:21:07","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-4019762/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-4019762/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":61788196,"identity":"2cf4a117-20a7-487f-b7f2-bb8aa512697c","added_by":"auto","created_at":"2024-08-05 15:04:18","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":579262,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-4019762/v1/b87de72f-ece1-4ba2-b537-e616ec7dc020.pdf"}],"financialInterests":"No competing interests reported.","formattedTitle":"A higher prevalence of migraine in patients with cardiac syndrome x compared to patients with cardiovascular disease and healthy control","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMigraine is a prevalent debilitating neurovascular disorder, affecting more than 1\u0026nbsp;billion people globally. Migraine attack usually consists of four different phases including prodrome, aura, headache, and postdrome phases. The headache phase is associated with several symptoms including photophobia, nausea, vomiting, and fatigue which disturb daily activities and reduce the quality of life of migraineurs (\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e). The burden of migraine, however, is not restricted to the headache phase and patients may suffer from several symptoms such as hypersensitivity, phonophobia, photophobia, and vestibular disorders in the interictal phase, the phase between migraine attacks (\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e, \u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e). Although the exact molecular and cellular mechanisms underlying migraine pathogenesis are not completely understood, several reasonable explanations have been proposed. At the molecular level, the critical role of calcitonin-gene-related peptides (CGRPs) in the pathogenesis of migraine has been documented and CGRP receptor antagonists and monoclonal antibodies against CGRP or its receptors have revealed substantial efficacy in the treatment of migraine attacks (\u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e). In addition to CGRP receptors, numerous studies have indicated the high efficacy and safety of 5-HT\u003csub\u003e1F\u003c/sub\u003e receptor agonists such as Lasmiditan in the treatment of migraine (\u003cspan citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e). At the cellular level, prior studies have described the role of mitochondrial dysfunction in the pathogenesis of migraine. The correlation of migraine with mitochondrial genome polymorphisms and biomarkers of oxidative stress are amongst the evidence that indicates the possible contribution of mitochondrial dysfunction to migraine pathology (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). A wide range of risk factors has been identified for migraine. Multiple investigations have concluded the important role of genetic factors in migraine development including familial aggregation of migraine, a high concordance rate of migraine in monozygotic twins, and the association between several genetic polymorphisms with the increased risk of migraine (\u003cspan citationid=\"CR7\" class=\"CitationRef\"\u003e7\u003c/span\u003e). The association of migraine with demographic characteristics such as sex and age have also been described. Women are at a higher risk of migraine development than men which could be related to differences in sex hormone fluctuations or psychological factors. Although migraine can occur at any age, their prevalence rate exhibits an age-dependent manner, increases from early life to middle age, and then gradually declines (\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e). Clinical and experimental data have revealed the association of migraine with numerous comorbidities including cardiovascular, psychiatric, neurologic, as well as inflammatory disorders. The association with these comorbidities complicates the diagnosis, increases the risk of progression to chronic migraine, limits treatment options, and lowers the quality of life of migraineurs. Therefore, understanding migraine comorbidities is very important because it can help to determine possible common or overlapping pathological mechanisms of diseases and can lead to the development of new diagnostic and therapeutic strategies (\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e). A growing body of evidence has revealed a significant association between migraines, particularly migraine with aura, with cardiovascular diseases (CVDs) such as ischemic heart disease, myocardial infarction, angina, and arrhythmia (\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e). Because alteration in blood flow is involved in the pathogenesis of migraines and CVDs, this association can be described by inadequate blood flow to the heart or brain due to genetic factors, endothelial dysfunction, and coagulation abnormalities (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e). Cardiac syndrome X (CSX), is a type of ischemic heart disease, that is characterized by angina-like chest pain, and ST segment depression during exercise, without any evidence of significant coronary vascular abnormalities at coronary angiography (\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e). CSX is more prevalent in postmenopausal women. Although the potential risk factors for CSX have not yet been fully elucidated, several mechanisms may involve including microvascular abnormalities (\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e) and mitochondrial dysfunction. Because these abnormalities have been proposed in the etiology of migraine, we have suggested a link between migraine and CSX in our previous study (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). In this study, we have extended our previous study to a larger population of CSX patients. Furthermore, the association of several risk factors, notably sex and familial aggregation are evaluated.\u003c/p\u003e"},{"header":"Patients and Methods","content":"\u003cdiv id=\"Sec3\" class=\"Section2\"\u003e \u003ch2\u003ePatient population\u003c/h2\u003e \u003cp\u003eThis case-control study was performed from March to October 2021. Adult patients, aged between 18\u0026ndash;70 years old, with a history of angina chest pain, abnormal cardiac tests including exercise test, SPECT MPI, and normal angiography results were classified in the CSX group (n\u0026thinsp;=\u0026thinsp;70), and if showed more than 50% coronary artery involvement in angiography were categorized in CAD group (n\u0026thinsp;=\u0026thinsp;70). Seventy healthy individuals without any history of previous illness, with a normal ECG, were randomly selected as the control group. Severe valvular heart diseases, previous coronary artery diseases, diabetes mellitus, congenital heart disease, hypertension, and cardiomyopathy were exclusion criteria for the control and CSX groups. The patients with a history of severe anxiety, depression, and headache that unrelated to migraine were excluded from the study. The study protocol was approved by the Ethics Committee of Bandar-Abbas University of Medical Sciences. The protocol was explained to the patients and written informed consent was obtained from all the patients. For each enrolled subject, demographic and clinical data were collected. The presence of migraine in the subjects and their parents, siblings, and children was evaluated using a Migraine Screen Questionnaire (MS-Q) based on the International Headache Society (IHS) criteria (\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e).\u003c/p\u003e \u003c/div\u003e \u003cdiv id=\"Sec4\" class=\"Section2\"\u003e \u003ch2\u003eStatistical analysis:\u003c/h2\u003e \u003cp\u003eSPSS software (Version 15) was used to analyze the data. Continuous variables were presented as mean\u0026thinsp;\u0026plusmn;\u0026thinsp;standard deviation (SD) and categorical variables were presented as frequency. The Chi-square test was used to compare qualitative variables between groups. Mann-Whitney and One-way ANOVA tests were used to compare continuous variables between groups. Binary logistic regression was used to determine the significant associations between the risk factors and migraine. A p-value less than 0.05 was considered a significant difference.\u003c/p\u003e \u003c/div\u003e"},{"header":"Results","content":"\u003cp\u003eTable\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows various clinical and demographic characteristics of the healthy patients enrolled in this study. The mean age and BMI were not significantly different among the studied groups. The prevalence of migraine in all studied subjects was 34.3% (n\u0026thinsp;=\u0026thinsp;60) of which 61.7% of the subjects (n\u0026thinsp;=\u0026thinsp;37) were female and 38.3% were male (n\u0026thinsp;=\u0026thinsp;23) (p\u0026thinsp;=\u0026thinsp;0.035). The prevalence of migraine in the CSX group was 40% which was significantly higher compared to those of CVD (24%) (p\u0026thinsp;=\u0026thinsp;0.047) and healthy controls groups (21%) (p\u0026thinsp;=\u0026thinsp;0.017). In the control subjects with migraine, the number of female subjects (n\u0026thinsp;=\u0026thinsp;13; 86.7%) was significantly higher than males with migraine (n\u0026thinsp;=\u0026thinsp;2; 13.3%) (p\u0026thinsp;=\u0026thinsp;0.002), however, in the CVD and CSX groups the frequencies of males and females with migraine were not significantly different. The prevalence of migraine with aura was significantly higher in patients with CSX (20%) compared to patients with CVD (8%) (p\u0026thinsp;=\u0026thinsp;0.045). Family history of migraine was observed in 40(57.0%) patients with CXS which was significantly higher compared to patients with CVD (31.0%) and the control group (35.7%) (p\u0026thinsp;=\u0026thinsp;0.004). Table\u0026nbsp;\u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e reveals and compares various characteristics between patients with (n\u0026thinsp;=\u0026thinsp;60) and without migraine(n\u0026thinsp;=\u0026thinsp;150). No significant difference was observed in the mean age and BMI of the subjects with and without migraine. Significant higher percentages of family history of migraine and female sex were observed in the patients with migraine compared to those in subjects without migraine. The prevalence of obesity and smoking was not significantly different among subjects with and without migraine. The results of logistic regression models are summarized in Table\u0026nbsp;\u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e. The data showed that family history was the only significant predictor of migraine in all cases (OR 4.88, 95% CI: 2.56\u0026ndash;9.30; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.0001). In the control group, predictors of migraine included female sex (OR 7.25, 95% CI: 1.43\u0026ndash;36.70; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.017) and family history (OR 4.08, 95% CI: 1.11\u0026ndash;14.95; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.034). Furthermore, the data showed that family history was the only predictor of migraine in the CVD (OR 7.00, 95% CI: 2.11\u0026ndash;23.13; \u003cem\u003ep\u003c/em\u003e\u0026thinsp;\u0026lt;\u0026thinsp;0.01) and CSX group none of the evaluated factors were a predictor of migraine.\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eComparison of various characteristics between patients and control group\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"7\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c6\" colnum=\"6\"\u003e\u003c/div\u003e \u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c7\" colnum=\"7\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eControl(a)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCVD(b)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\" morerows=\"1\" rowspan=\"2\"\u003e \u003cp\u003eCSX(c)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"3\" nameend=\"c7\" namest=\"c5\"\u003e \u003cp\u003ep values\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c5\"\u003e \u003cp\u003ea vs b\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c6\"\u003e \u003cp\u003ea vs c\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c7\"\u003e \u003cp\u003eb vs c\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years); (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50.2\u0026thinsp;\u0026plusmn;\u0026thinsp;10.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51.2\u0026thinsp;\u0026plusmn;\u0026thinsp;9.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e51.5\u0026thinsp;\u0026plusmn;\u0026thinsp;8.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.529\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.410\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.846\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBMI (kg/m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e); (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.0\u0026thinsp;\u0026plusmn;\u0026thinsp;3.9\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e26.2\u0026thinsp;\u0026plusmn;\u0026thinsp;4.4\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e26.5\u0026thinsp;\u0026plusmn;\u0026thinsp;5.3\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.0.08\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.120\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.846\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eObesity (BMI\u0026thinsp;\u0026ge;\u0026thinsp;30); n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e6(8.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e12(17.1)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e16(22.9)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.130\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.02\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.398\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFemale Sex; n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e36(51.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35(50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36(51.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.866\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.866\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e1.0\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSmoking; n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7(\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e35(50.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e36(51.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.866\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMigraine; n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e15(21.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e17(24.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e28(40)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.687\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.047\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eMigraine with aura; n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e9(\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e6(\u003cspan citationid=\"CR8\" class=\"CitationRef\"\u003e8\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e14(\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.412\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.254\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.045\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFamily history; n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25(35.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e22(31.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e40(57.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.591\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.011\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.002\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAbdominal pain in their children; n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e8(11.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e8(11.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e15(21.4)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c5\"\u003e \u003cp\u003e0.919\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c6\"\u003e \u003cp\u003e0.137\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"char\" char=\".\" colname=\"c7\"\u003e \u003cp\u003e0.172\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"7\"\u003eBMI: Body Mass Index, CVD: Cardiovascular disease, CSX: Cardiac syndrome X, n: number\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003eComparison of various characteristics between subjects with and without migraine\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"4\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e \u003cp\u003eVariables\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eSubjects with migraine (n\u0026thinsp;=\u0026thinsp;60)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e \u003cp\u003eSubjects without migraine (n\u0026thinsp;=\u0026thinsp;150)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e \u003cp\u003ep values\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eAge (years); (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e50.3\u0026thinsp;\u0026plusmn;\u0026thinsp;8.7\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e51.3\u0026thinsp;\u0026plusmn;\u0026thinsp;9.2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.508\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eBMI (kg/m\u003c/b\u003e\u003csup\u003e\u003cb\u003e2\u003c/b\u003e\u003c/sup\u003e\u003cb\u003e); (mean\u0026thinsp;\u0026plusmn;\u0026thinsp;SD)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25.8\u0026thinsp;\u0026plusmn;\u0026thinsp;4.0\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e25.9\u0026thinsp;\u0026plusmn;\u0026thinsp;4.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.989\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eObesity (BMI\u0026thinsp;\u0026ge;\u0026thinsp;30); n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e7(11.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e27(18.0)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.320\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFemale Sex; n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e37(61.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e70(46.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.035\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eSmoking; n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e25(41.6)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e53(35.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.241\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003e\u003cb\u003eFamily history; n (%)\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e41(68.3)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e46(30.7)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eP\u0026thinsp;\u0026lt;\u0026thinsp;0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"4\"\u003eBMI: Body Mass Index, n: number\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab3\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003eTable 3\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e \u003cp\u003e\u003cb\u003ePredictors of migraine in the logistic regression model\u003c/b\u003e\u003c/p\u003e \u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e \u003cdiv align=\"left\" class=\"colspec\" colname=\"c5\" colnum=\"5\"\u003e\u003c/div\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eGroup\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003ePredictors\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eOR\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eCI (95%)\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eP value\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003eAll case\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFamily history\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/th\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.879\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.56\u0026ndash;9.30\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e\u0026lt;\u0026thinsp;0.0001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"5\" rowspan=\"6\"\u003e \u003cp\u003e\u003cb\u003eControl\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003esex\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eFemale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.254\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.43\u0026ndash;36.70\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.017\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eMale\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eFamily history\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.080\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.11\u0026ndash;14.95\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.034\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003eCVD\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eFamily history\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e7.000\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e2.12\u0026ndash;23.15\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.001\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\" morerows=\"2\" rowspan=\"3\"\u003e \u003cp\u003e\u003cb\u003eCSX\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e\u003cb\u003eFamily history\u003c/b\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e\u0026nbsp;\u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eYES\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e2.750\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e0.99\u0026ndash;7.62\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e0.052\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eNO\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e-\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eCVD: Cardiovascular disease, CSX: Cardiac syndrome X.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eA growing number of studies have revealed mitochondrial deficits in the brain and muscles of migraineurs (\u003cspan citationid=\"CR6\" class=\"CitationRef\"\u003e6\u003c/span\u003e). Mitochondrial dysfunction is also considered a feature of patients with CSX(Hsiu-Bao); therefore, it is speculated that this common feature, mitochondrial dysfunction, can lead to comorbidity between migraine and CSX. The results of the present study displayed a higher prevalence of migraine in the patients with CSX compared to healthy control and the patients with CVD. Furthermore, a higher frequency of family history of migraine was observed in the patients with CSX compared to CVD and healthy control, suggesting a possible role of genetic factors in predisposing CSX patients to migraine. Several studies have indicated comorbidity between migraine, particularly migraine with aura, and CVD. Although the exact mechanism is not clearly understood, changes in blood flow led to insufficient blood flow to the heart and brain a common feature of CVD and migraine (\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e, \u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e). However, our data revealed that the prevalence of migraine in the patients with CVD was not significantly different from that observed in the healthy control group. Similarly, Nemati et al showed the same prevalence of migraine in CVD patients and healthy control subjects (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). They also demonstrated a higher significant prevalence of migraine in patients with CSX (60%) compared to that of the healthy group (22%) and concluded that CSX may be a manifestation of migraine. Their finding is consistent with the results of our study which showed a higher prevalence of migraine in CSX patients (40%) compared to the control group (21%). Several mechanisms can explain the association of CSX and migraine. Vasospasm, endothelial abnormalities, and mitochondrial dysfunction are among possible mechanisms that may connect CSX to migraine (\u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e). Several epidemiological investigations have shown a higher prevalence of migraines in women compared to men (\u003cspan citationid=\"CR17\" class=\"CitationRef\"\u003e17\u003c/span\u003e, \u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). In addition, sex-related differences in migraine attacks have been confirmed by the findings of structural and functional brain MRIs (\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e). Several possible mechanisms include fluctuation in the circulating level of estrogen, genetic factors, as well as sex differences in the exposure and response to the environmental stressor may involve in this issue (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e). When we analyzed the control group, the results of binary regression demonstrated female sex is a predicting factor for migraine which is in line with several previous studies (\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e). However, this result did not observe in the patients with CVD and CSX, suggesting that gender does not play a role in increasing the prevalence of migraine in the patient with CSX. Due to the association of obesity with vascular endothelium damage (\u003cspan citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e) and the role of endothelial dysfunction in the pathogenesis of CSX (\u003cspan citationid=\"CR22\" class=\"CitationRef\"\u003e22\u003c/span\u003e), it has been postulated that obesity may play a role in the development of CSX. In the present study, no significant difference was observed in the BMI of patients with CSX and healthy control individuals, however, the prevalence of obesity (BMI\u0026thinsp;\u0026ge;\u0026thinsp;30) was significantly higher in the patients with CSX compared to the control group and Chi-square test revealed that obesity was associated with the increased risk of CSX (odd ratio\u0026thinsp;=\u0026thinsp;2,95% CI (0.953\u0026ndash;4.233). On the other hand, obesity is also considered a risk factor for the development and exacerbation of migraine (\u003cspan citationid=\"CR23\" class=\"CitationRef\"\u003e23\u003c/span\u003e). However, in the present study no significant association was observed between BMI and migraine, and the prevalence of obesity (BMI\u0026thinsp;\u0026ge;\u0026thinsp;30) was not significantly different in the patients with CSX compared to the control group. Therefore, a higher prevalence of migraine in patients with CSX could not be described as a higher prevalence of obesity in CSX patients. The essential role of genetic factors in the development of migraine have been indicated by numerous studies (\u003cspan citationid=\"CR24\" class=\"CitationRef\"\u003e24\u003c/span\u003e, \u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e), and heritability of 42% has been estimated for migraine (\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e). The familial aggregation of migraine as well as familial early age onset and severity of migraines are also confirmed by polygenic risk scores analyses (\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e). Furthermore, genome-wide association (GWS) studies have identified the association of migraine with more than thirty distinct genomic loci, suggesting the polygenic nature of migraine (\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e). The results of the present study showed a higher familial history of migraine in the CSX group which suggests the possible role of genetic factors in predisposing CSX patients to migraine.\u003c/p\u003e"},{"header":"Conclusions","content":"\u003cp\u003eThe results of this study revealed a significantly higher prevalence of migraine in patients with CSX. The findings also showed a remarkable familial aggregation of migraine in the patients with CSX, suggesting a role of genetic factors in predisposing CSX patients to migraine and also common pathology of both conditions. Due to the Covid19 pandemic a relatively low number of patients and healthy control enrolled in the present study; therefore, further studies with larger populations of CSX patients are needed to confirm the results of this study. In addition, GWS studies are warranted to determine the possible genetic loci that predispose CSX patients to migraine.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthical Approval:\u0026nbsp;\u003c/strong\u003eThe study received ethics approval from the Ethics Committee of Hormozgan University of Medical Sciences (No: 94-96/374). Informed consent was obtained from all individual participants included in the study.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003cstrong\u003e\u003cspan dir=\"RTL\"\u003e:\u0026nbsp;\u003c/span\u003e\u003c/strong\u003eNot Applicable\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eData availability:\u0026nbsp;\u003c/strong\u003eThe datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting Interests:\u0026nbsp;\u003c/strong\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding:\u003c/strong\u003e The present study was funded by the Hormozgan University of Medical Sciences, Iran\u0026nbsp;\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthor Contributions:\u0026nbsp;\u003c/strong\u003eM.M, E.O\u0026nbsp;and\u0026nbsp;A.GH\u0026nbsp;contributed to the study design and supervision.\u0026nbsp;M.M\u0026nbsp;performed the statistical analysis.\u0026nbsp;M.M, E.O, F.D\u0026nbsp;and\u0026nbsp;A.GH\u0026nbsp;wrote the manuscript.\u0026nbsp;A.GH\u0026nbsp;and\u0026nbsp;SH.A\u0026nbsp;revised the manuscript. All authors read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgments:\u0026nbsp;\u003c/strong\u003eThe authors of this article would like to express their deepest gratitude to the Vice-Chancellor of Research and Technology of Hormozgan University of Medical Sciences for the technical and financial support for this study.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eVincent M, Viktrup L, Nicholson RA, Ossipov MH, Vargas BB. The not so hidden impact of interictal burden in migraine: A narrative review. Frontiers in neurology. 2022;13:1032103.\u003c/li\u003e\n\u003cli\u003eNascimento TD, Kim DJ, Chrabol C, Lim M, Hu XS, DaSilva AF. Management of Episodic Migraine with Neuromodulation: A Case Report. Dental clinics of North America. 2023;67(1):157-71.\u003c/li\u003e\n\u003cli\u003eKung D, Rodriguez G, Evans RJNC. Chronic Migraine: Diagnosis and Management. 2023;41(1):141-59.\u003c/li\u003e\n\u003cli\u003eRusso AF, Hay DL. CGRP physiology, pharmacology, and therapeutic targets: Migraine and beyond. Physiological reviews. 2022.\u003c/li\u003e\n\u003cli\u003eCapi M, De Angelis V, De Bernardini D, De Luca O, Cipolla F, Lionetto L, et al. CGRP Receptor Antagonists and 5-HT1F Receptor Agonist in the Treatment of Migraine. Journal of clinical medicine. 2021;10(7).\u003c/li\u003e\n\u003cli\u003eBohra SK, Achar RR, Chidambaram SB, Pellegrino C, Laurin J, Masoodi M, Srinivasan A. Current perspectives on mitochondrial dysfunction in migraine. The European journal of neuroscience. 2022;56(1):3738-54.\u003c/li\u003e\n\u003cli\u003eEbahimzadeh K, Gholipour M, Samadian M, Taheri M, Ghafouri-Fard S. A Comprehensive Review on the Role of Genetic Factors in the Pathogenesis of Migraine. Journal of molecular neuroscience : MN. 2021;71(10):1987-2006.\u003c/li\u003e\n\u003cli\u003eRossi MF, Tumminello A, Marconi M, Gualano MR, Santoro PE, Malorni W, Moscato U. Sex and gender differences in migraines: a narrative review. Neurological sciences : official journal of the Italian Neurological Society and of the Italian Society of Clinical Neurophysiology. 2022;43(9):5729-34.\u003c/li\u003e\n\u003cli\u003eAhmad SR, Rosendale N. Sex and Gender Considerations in Episodic Migraine. Current pain and headache reports. 2022;26(7):505-16.\u003c/li\u003e\n\u003cli\u003eAmiri P, Kazeminasab S, Nejadghaderi SA, Mohammadinasab R, Pourfathi H, Araj-Khodaei M, et al. Migraine: A Review on Its History, Global Epidemiology, Risk Factors, and Comorbidities. Frontiers in neurology. 2021;12:800605.\u003c/li\u003e\n\u003cli\u003ePezzini A, Del Zotto E, Giossi A, Volonghi I, Grassi M, Padovani A. The migraine-ischemic stroke connection: potential pathogenic mechanisms. Current molecular medicine. 2009;9(2):215-26.\u003c/li\u003e\n\u003cli\u003eAgrawal S, Mehta PK, Bairey Merz CN. Cardiac Syndrome X: update 2014. Cardiology clinics. 2014;32(3):463-78.\u003c/li\u003e\n\u003cli\u003eSestito A, Lanza GA, Di Monaco A, Lamendola P, Careri G, Tarzia P, et al. Relation between cardiovascular risk factors and coronary microvascular dysfunction in cardiac syndrome X. Journal of cardiovascular medicine (Hagerstown, Md). 2011;12(5):322-7.\u003c/li\u003e\n\u003cli\u003eNemati R, Movahhednia M, Mehdizadeh S, Salimipour H, Iranpour D, Pourbehi MR, et al. Association Between Migraine Headache and Cardiac Syndrome X. Journal of the American College of Cardiology. 2016;67(17):2087-8.\u003c/li\u003e\n\u003cli\u003eL\u0026aacute;inez MJ, Dom\u0026iacute;nguez M, Rejas J, Palacios G, Arriaza E, Garcia-Garcia M, Madrigal M. Development and validation of the Migraine Screen Questionnaire (MS-Q). Headache. 2005;45(10):1328-38.\u003c/li\u003e\n\u003cli\u003eSch\u0026uuml;rks M, Rist PM, Bigal ME, Buring JE, Lipton RB, Kurth T. Migraine and cardiovascular disease: systematic review and meta-analysis. BMJ (Clinical research ed). 2009;339:b3914.\u003c/li\u003e\n\u003cli\u003eSafiri S, Pourfathi H, Eagan A, Mansournia MA, Khodayari MT, Sullman MJM, et al. Global, regional, and national burden of migraine in 204 countries and territories, 1990 to 2019. Pain. 2022;163(2):e293-e309.\u003c/li\u003e\n\u003cli\u003ePeterlin BL, Gupta S, Ward TN, Macgregor A. Sex matters: evaluating sex and gender in migraine and headache research. Headache. 2011;51(6):839-42.\u003c/li\u003e\n\u003cli\u003eMaleki N, Linnman C, Brawn J, Burstein R, Becerra L, Borsook D. Her versus his migraine: multiple sex differences in brain function and structure. Brain : a journal of neurology. 2012;135(Pt 8):2546-59.\u003c/li\u003e\n\u003cli\u003eBuse DC, Silberstein SD, Manack AN, Papapetropoulos S, Lipton RB. Psychiatric comorbidities of episodic and chronic migraine. Journal of neurology. 2013;260(8):1960-9.\u003c/li\u003e\n\u003cli\u003eOng P, Sivanathan R, Borgulya G, Bizrah M, Iqbal Y, Andoh J, et al. Obesity, inflammation and brachial artery flow-mediated dilatation: therapeutic targets in patients with microvascular angina (cardiac syndrome X). Cardiovascular drugs and therapy. 2012;26(3):239-44.\u003c/li\u003e\n\u003cli\u003eSaghari M, Assadi M, Eftekhari M, Yaghoubi M, Fard-Esfahani A, Malekzadeh J-M, et al. Frequency and severity of myocardial perfusion abnormalities using Tc-99m MIBI SPECT in cardiac syndrome X. BMC nuclear medicine. 2006;6(1):1-8.\u003c/li\u003e\n\u003cli\u003eBond DS, Roth J, Nash JM, Wing RR. Migraine and obesity: epidemiology, possible mechanisms and the potential role of weight loss treatment. Obesity Reviews. 2011;12(5):e362-e71.\u003c/li\u003e\n\u003cli\u003eNyholt DR, Anttila V, Winsvold BS, Kurth T, Stefansson H, Kallela M, et al. Concordance of genetic risk across migraine subgroups: Impact on current and future genetic association studies. Cephalalgia : an international journal of headache. 2015;35(6):489-99.\u003c/li\u003e\n\u003cli\u003eZhao H, Eising E, de Vries B, Vijfhuizen LS, Anttila V, Winsvold BS, et al. Gene-based pleiotropy across migraine with aura and migraine without aura patient groups. Cephalalgia : an international journal of headache. 2016;36(7):648-57.\u003c/li\u003e\n\u003cli\u003ePolderman TJ, Benyamin B, de Leeuw CA, Sullivan PF, van Bochoven A, Visscher PM, Posthuma D. Meta-analysis of the heritability of human traits based on fifty years of twin studies. Nature genetics. 2015;47(7):702-9.\u003c/li\u003e\n\u003cli\u003eGormley P, Kurki MI, Hiekkala ME, Veerapen K, H\u0026auml;pp\u0026ouml;l\u0026auml; P, Mitchell AA, et al. Common Variant Burden Contributes to the Familial Aggregation of Migraine in 1,589 Families. Neuron. 2018;98(4):743-53.e4.\u003c/li\u003e\n\u003cli\u003ede Boer I, van den Maagdenberg A, Terwindt GM. Advance in genetics of migraine. Current opinion in neurology. 2019;32(3):413-21.\u003c/li\u003e\n\u003cli\u003eChasman DI, Sch\u0026uuml;rks M, Anttila V, de Vries B, Schminke U, Launer LJ, et al. Genome-wide association study reveals three susceptibility loci for common migraine in the general population. Nature genetics. 2011;43(7):695-8.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"Migraine, Cardiac syndrome X, Cardiovascular diseases, Risk factors","lastPublishedDoi":"10.21203/rs.3.rs-4019762/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-4019762/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e \u003cp\u003eCardiac syndrome X(CSX), is a type of ischemic heart disease, that is characterized by angina-like chest pain, without any evidence of significant coronary vascular abnormalities. Some evidence has revealed a significant association between migraines, particularly migraine with aura, with cardiovascular diseases (CVDs). In this case-control study, the prevalence of migraine and the role associated risk factors were compared between the patients with CSX, CVD, and healthy control individuals.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e \u003cp\u003eThe patients with CSX (n\u0026thinsp;=\u0026thinsp;70), CAD (n\u0026thinsp;=\u0026thinsp;70), and healthy individuals (n\u0026thinsp;=\u0026thinsp;70) were enrolled in this study. For each enrolled subject, demographic and clinical data were collected. The prevalence of migraine and associated risk factors were determined in each group.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e \u003cp\u003eThe prevalence of migraine in the CSX group (40%) was significantly higher compared to those of CVD (24%) (p\u0026thinsp;=\u0026thinsp;0.047) and healthy controls groups (21%) (p\u0026thinsp;=\u0026thinsp;0.017). In the control subjects, but not in the CVD and CSX groups, the female gender was a significant risk factor for migraine. The prevalence of migraine with aura was significantly higher in patients with CSX (20%) compared to patients with CVD (8%) (p\u0026thinsp;=\u0026thinsp;0.045). The family history of migraine was significantly higher in patients with CSX (57.0%) compared to patients with CVD (31.0%) and the control group (35.7%) (p\u0026thinsp;=\u0026thinsp;0.004).\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e \u003cp\u003eThe results of this study revealed a significantly higher prevalence of migraine in patients with CSX. The findings also showed a familial aggregation of migraine in the patients with CSX, suggesting a role of genetic factors in predisposing CSX patients to migraine.\u003c/p\u003e","manuscriptTitle":"A higher prevalence of migraine in patients with cardiac syndrome x compared to patients with cardiovascular disease and healthy control","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2024-03-08 14:26:48","doi":"10.21203/rs.3.rs-4019762/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"c1a9d4e5-7588-4921-be28-116deefbb217","owner":[],"postedDate":"March 8th, 2024","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2024-08-05T14:56:12+00:00","versionOfRecord":[],"versionCreatedAt":"2024-03-08 14:26:48","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-4019762","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-4019762","identity":"rs-4019762","version":["v1"]},"buildId":"qtupq5eGEP_6zYnWcrvyt","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}