J Thromb Thrombolysis DOI 10.1007/s11239-014-1079-0
Epidemiological association between migraine and lipoprotein(a): a systematic review Camilla Mattiuzzi • Gianfranco Cervellin Giuseppe Lippi
•
Ó Springer Science+Business Media New York 2014
Abstract Migraine is a relatively frequent and disabling condition, which poses a large clinical and economical burden on human society. Since there is now emerging evidence that the risk of cardiovascular diseases may be significantly increased in patients with migraine, and that lipoprotein(a) is a powerful, independent cardiovascular risk factor, we performed an electronic searched on Medline, Scopus and Web of Science using the keywords ‘‘migraine’’ and ‘‘lipoprotein(a)’’ or ‘‘apolipoprotein(a)’’ or ‘‘Lp(a)’’ or ‘‘apo(a)’’, with no language or date restriction. The electronic search produced four cross-sectional studies which reported original data about the epidemiological association between lipoprotein(a) and migraine, and used standardized criteria for diagnosing migraine. In only one out of the four studies the concentration of lipoprotein(a) was found to be higher in migraineurs than in controls, whereas in the remaining three investigations lipoprotein(a) levels were found to be virtually identical between cases and controls. This analysis suggests that if any epidemiological and clinical link exists between
C. Mattiuzzi Service of Clinical Governance, General Hospital of Trento, Trento, Italy G. Cervellin Emergency Department, Academic Hospital of Parma, Parma, Italy G. Lippi Laboratory of Clinical Chemistry and Hematology, Academic Hospital of Parma, Parma, Italy G. Lippi (&) U.O. Diagnostica Ematochimica, Azienda OspedalieroUniversitaria di Parma, Via Gramsci, 14, 43126 Parma, Italy e-mail: [email protected]; [email protected]
migraine and cardiovascular disease, a direct involvement of lipoprotein(a) seems unlikely according to the available epidemiological evidence. Keywords Migraine Headache Lipoprotein(a) Lp(a) Cardiovascular disease
Introduction Migraine is a relatively frequent and disabling condition, which poses a large clinical and economical burden on human society. It has been estimated that the overall frequency of migraine attacks approximates 12 % in adults, with a prevalence that is nearly threefold higher in women than in men [1]. Based on ictal disability, this condition is ranked seventh highest among specific causes of disability in the general population [2]. According to the Headache Classification Committee of the International Headache Society (IHS), migraine is a primary form of headache which typically manifests as pain localized above the orbitomeatal line and that can be classified in two forms, i.e., migraine with or without aura [3]. Clinically, migraine is characterized by recurrent attacks of headache and various combinations of symptoms related to the gastrointestinal and autonomic nervous system. There is now emerging evidence that the risk of cardiovascular disease may be significantly increased in patients with migraine. Schu¨rks et al. [4] performed a systematic review and meta-analysis on Medline, Embase and Cochrane Library, to identify case–control and cohort studies exploring the potential association between migraine and cardiovascular disease. The pooled analysis of the nine studies investigating the relationship between migraine and ischemic stroke found a significant increased risk of this
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condition in migraineur patients, with a relative risk (RR) of 1.73 (95 % CI 1.31–2.29; p = 0.004). The RR was also found to be higher in women (2.08; 95 % CI 1.13–3.84, p = 0.01) than in men (1.37; 95 % CI 0.89–2.11; p = 0.10). As regards the eight studies exploring the association between migraine and myocardial infarction, migraineur patients displayed a significant RR of this condition (1.12; 95 % CI 0.95–1.32; p = 0.02), which seemed to be more significant in women (RR 1.14; p = 0.03) than in men (RR 1.15; p = 0.07). As regards studies on specific gender differences, Kurth et al. [5] performed a prospective investigation on 27,840 women (5,125 with active migraine at baseline) aged [45 years, who were followed up for a mean period of 10 years. When compared with non-migraineurs, women with a history of migraine had multivariable-adjusted hazard ratios (HRs) of 2.15 (95 % CI 1.58–2.92; p \ 0.001) for cardiovascular disease, 1.91 (95 % CI 1.17–3.10; p = 0.01) for ischemic stroke, and 2.08 (95 % CI 1.30–3.31; p = 0.02) for myocardial infarction. As regards the male gender, the same authors performed a prospective study of 20,084 men (1449 with migraine) aged 40–84 years, who were followed up for a mean period of 15.7 years [6]. When compared with non-migraineurs, men with a history of migraine had multivariable-adjusted HRs of 1.24 (95 % CI 1.06–1.46; p = 0.008) for cardiovascular disease, 1.12 (95 % CI 0.84–1.50; p = 0.43) for ischemic stroke, and 1.42 (95 % CI 1.15–1.77; p \ 0.001) for myocardial infarction. Among the various risk factor for cardiovascular disease, several lines of evidence now attest that lipoprotein(a) (Lp(a)), a genetic variant of low density lipoproteins (LDLs), exhibits a robust and specific association with this condition. In particular, a meta-analysis of scientific literature published by the European Atherosclerosis Society Consensus Panel, has recently reported that increased Lp(a) levels were significantly predictors of both ischemic heart disease (30 studies and 106,645 subjects; RR 1.13; 95 % CI 1.09–1.18) and ischemic stroke (13 studies and 69,539 subjects; RR 1.10; 95 % CI 1.02–1.19) [7]. It was hence concluded that Lp(a) should be routinely screened in all patients at intermediate or high risk of cardiovascular disease, who present with (i) premature cardiovascular disease; (ii) familial hypercholesterolemia, (iii) family history of premature cardiovascular disease and/or elevated Lp(a), (iv) recurrent cardiovascular disease despite hypocholesterolemic treatment, (v) C3 % 10 year risk of fatal cardiovascular disease, and (vi) C10 % 10 year risk of fatal and/or non-fatal coronary heart disease. These indications have been then reiterated in subsequent recommendations [8, 9]. The combined evidence that migraine is significantly associated with cardiovascular disease [10, 11], and that Lp(a) is a powerful risk factor for cardiovascular disease,
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prompted us to explore whether any epidemiological association may exist between Lp(a) and migraine. This is particularly relevant in the era of personalized medicine, when drug development is increasingly driven by biomarkers derived from phenotypic screening [12].
Search criteria With the aim to review clinical and epidemiological evidence about the association between Lp(a) and migraine, we performed an electronic searched on medline, scopus and web of science (i.e., the mostly accessed biomedical research platforms) [13], using the keywords ‘‘migraine’’ and ‘‘lipoprotein(a)’’ or ‘‘apolipoprotein(a)’’ or ‘‘Lp(a)’’ or ‘‘apo(a)’’, with no language or date restriction. The references of retrieved articles were also searched for identifying additional articles about this topic. Only those articles using standardized criteria for diagnosing migraine (i.e., those of the IHS) [3], and reporting original data about the epidemiological association between migraine and Lp(a) were finally included in our systematic review. The methodological quality of the included studies was assessed by QUADAS (quality assessment for studies of diagnostic accuracy, an evidence-based quality assessment tool for use in systematic reviews of diagnostic accuracy studies, maximum score 14) by G.L. and C.M. Potential discrepancies were resolved by consensus and, where necessary, the third author (G.C.) was consulted. When each specific criterion was fulfilled, a score of 1 was given, 0 if a criterion was unclear, and -1 if a criterion was not achieved. Heterogeneity across studies was also estimated by Chi-square based statistics and I-square test, where thresholds of 25, 50 and 75 % designate low, moderate, and high heterogeneity.
Overview on epidemiological data The electronic search performed according to the previously defined criteria identified 52 items after elimination of duplicates across the three biomedical research platforms. After careful reading of title, abstract and full text (when available), we excluded 48 articles, which did not report original data about the epidemiological association between Lp(a) and migraine, or failed to use standardized criteria for diagnosing migraine. Therefore, four clinical studies were finally included in this systematic review (Table 1) [14–17]. The inter-study variability was however high, and largely attributable to heterogeneity, especially for sample size (Chi-squared 431.5; DF 4; I-squared 99.1 %; p \ 0.001), gender (Chi squared 70.0; DF 4;
Lipoprotein(a) and migraine Table 1 Synthesis of published studies that have investigated the clinical and epidemiological association between lipoprotein(a) (Lp(a)) and migraine Authors
Study population
Outcome
QUADAS score
Reference
Kurth et al., 2008
27,626 women (5,087 with migraine)
OR 1.04 (95 % CI 0.91–1.20; p = 0.68)
11
[14]
Cinzia et al., 2009
250 subjects (197 females and 53 males; 138 with migraine)
OR 3.88 (95 % CI 1.59–9.51; p = 0.003) in females
11
[15]
12
[16]
8
[17]
OR 2.23 (95 % CI 0.40–12.33; p = 0.30) in males Gruber et al., 2010
104 normal weight subjects (80 females and 24 males; 43 with migraine) and 32 obese subjects (15 males and 17 females; 17 with migraine)
No significant difference of Lp(a) levels between cases and controls (p = ns)
Teber et al., 2011
126 children (62 females and 64 males; 63 with migraine)
OR 3.48 (95 % CI 1.05–11.50; p = 0.04)
OR odds ratio; QUADAS quality assessment for studies of diagnostic accuracy
I-squared 94.3 %; p \ 0.001) and age (Chi squared 214.8; DF 4; I-squared 98.1 %; p \ 0.001). The first study exploring the epidemiological association between Lp(a) and migraine was published by Kurth et al.[14] in 2008. The authors performed a large crosssectional investigation including 27,626 women aged C45 years (5,087 with history of migraine), who had blood samples available for assessment of a broad range of cardiovascular risk factors, including Lp(a). The plasma concentration of Lp(a) was found to be virtually identical between patients with or without history of migraine (238 vs. 239 mg/L; p = 0.81). Accordingly, the multivariableadjusted odds ratio (OR) for association between Lp(a) and migraine status did not achieve statistical significance in the entire cohort of patients (1.02; 95 % CI 0.94–1.10; p = 0.68), and nor in migraineur patients with (1.04; 95 % CI 0.91–1.20) and without aura (1.00; 95 % CI 0.89–1.12; p = 0.93 for trend). Cinzia et al. [15] measured the plasma levels of Lp(a) in 138 patients with migraine (mean age 38 ± 13 years; 110 females and 28 males), referred to an italian headache service, as well as in 112 healthy subjects (87 females and 25 males). Although the median concentration of plasma Lp(a) was found to be virtually identical between cases and controls (104 mg/L; range 1–2110 vs. 103 mg/L; range 9–695 mg/L; p = 0.80), it was however observed that the rate of patients with values [300 mg/L was more than twofold higher in cases than in controls (33/138 vs. 11/112; p = 0.004). It was hence estimated that abnormal levels of plasma Lp(a) were significant predictors of migraine in multivariate analysis after adjustment for age, gender, hypertension and smoking habit, displaying an OR of 3.40 (95 % CI 1.57–7.55; p = 0.002). Interestingly, this association remained significant in the female (OR 3.88; 95 %
CI 1.59–9.51; p = 0.003), but not in the male gender (OR 2.23; 95 % CI 0.40–12.33; p = 0.30). Gruber et al. [16] measured plasma Lp(a) in 61 normal weight patients with migraine (19 males and 42 females; mean age 35 ± 9 years) assessed in a german department of neurology, as well as in 43 normal weight controls (5 males and 38 females; mean age 36 ± 11 years). The concentration of Lp(a) was found to be virtually identical between cases and controls (176 ± 171 vs. 182 ± 179 mg/L; p = ns). In the same study, Lp(a) was also measured in 15 obese migraine patients (9 males and 4 females; mean age 40 ± 9 years) and in 17 obese controls (mean age 36 ± 11 years; 6 males and 11 females). The concentration of Lp(a) was found to slightly but not significantly higher in cases than in controls (207 ± 258 vs. 134 ± 92 mg/L; p = ns). Teber et al. [17] assessed the plasma levels of Lp(a) in 63 children aged between 4 and 18 years (33 males and 30 females subjects), who were referred to a turkish pediatric neurology department with a final diagnosis of migraine (18 with aura and 45 without aura). The plasma concentration of Lp(a) was also measured in 63 age-matched healthy control subjects. In children with migraine, the median concentration of Lp(a) was nearly 60 % higher than in the control population (776 mg/L; range 20–593 vs. 494 mg/L; range 20–453 mg/L; p = 0.001). The rate of patients with values [300 mg/L was also marginally but significantly higher in children with migraine than in the non-pain control population (12/63 vs. 4/63; p = 0.032). It was finally observed that abnormal Lp(a) levels were significant predictor of migraine in multivariate analysis after adjustment for age and gender, with an OR of 3.48 (95 % CI 1.05–11.50; p = 0.04).
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The data published in these studies could not be metaanalyzed, since the outcome would have been dramatically biased by the larger study of Kurth et al. [14], which included more than 98 % of the overall sample size.
Conclusion Lp(a) has recently emerged as an independent risk factor for a variety of cardiovascular disorders, including acute coronary syndrome, ischemic stroke and peripheral artery occlusive disease [18]. The leading biological hallmark of this lipoprotein is the presence of a single copy of the highly polymorphic and glycosylated apolipoprotein(a), which is covalently linked to apolipoprotein B100, the main protein moiety of LDLs. This biochemical association confers a high cardiovascular potential to this lipoprotein, which hence displays both atherogenic and antifibrinolytic properties [19]. Since several cross-sectional and prospective studies have reported that the concentration of Lp(a) is independently associated with cardiovascular disease, while others investigations have found that the risk of cardiovascular disease is increased in patients with migraine, it seems reasonable to hypothesize that at least part of the cardiovascular risk in migraineur patients may be attributable to Lp(a). There are in fact several aspects that may link Lp(a) biology with the pathogenesis of migraine. First, migraine has a strong inflammatory component, and several proinflammatory biomarkers are involved in the process of nerve endings sensitization, thus lowering the individual threshold of pain [20]. Accordingly, Lp(a) is an acute phase reactant, and its concentration is frequently increased in patients with inflammatory disorders [21, 22]. Then, vasoconstriction of cerebral arteries with subsequent decreased cerebral blood flow is the leading trigger of a migraine attack [23]. In this regard, increased Lp(a) levels are associated with selective impairment of vasodilator capacity of receptor-mediated endothelial stimuli [24]. Finally, migraine is associated with a prothrombotic state [25], wherein Lp(a) exerts powerful prothrombotic/antithrombolytic effects [26]. It is hence reasonable to hypothesize that increased levels of Lp(a) may enhance vasoconstriction of cerebral blood vessels, amplify a pre-existing prothrombotic state and increase the local inflammatory response, thus ultimately triggering migraine or worsening its symptoms. Despite the limited number of studies available in the current scientific literature, the results of this systematic review are consistent with the lack of a significant epidemiological association between Lp(a) and migraine. More specifically, two studies failed to find any significant difference in the rate of abnormal Lp(a) values in migraine patients and in controls [14, 17], one of them reported a
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marginal statistical significance [17], whereas the remaining concluded that increased Lp(a) levels are associated with migraine in females but not in males [15] (Table 1). The most plausible explanation for the different outcomes is probably attributable to the large inter-study heterogeneity as regards sex prevalence, mean age and especially sample size (all p \ 0.001). In conclusion, our analysis suggests that if any epidemiological and clinical link exists between migraine and cardiovascular disease, a direct involvement of plasma Lp(a) seems less plausible according to the recent and limited evidence, so that further studies are needed to support or definitely rule out this association, and especially verify the potential role of Lp(a) in the brain environment.
References 1. Bigal ME, Lipton RB (2009) The epidemiology, burden, and comorbidities of migraine. Neurol Clin 27:321–334 2. Steiner TJ, Stovner LJ, Birbeck GL (2013) Migraine: the seventh disabler. Headache 53:227–229 3. Headache Classification Committee of the International Headache Society (IHS) (2013) The international classification of headache disorders, 3rd edition (beta version). Cephalalgia 33:629–808 4. Schu¨rks M, Rist PM, Bigal ME, Buring JE, Lipton RB, Kurth T (2009) Migraine and cardiovascular disease: systematic review and meta-analysis. BMJ 339:b3914 5. Kurth T, Gaziano JM, Cook NR, Logroscino G, Diener HC, Buring JE (2006) Migraine and risk of cardiovascular disease in women. JAMA 296:283–291 6. Kurth T, Gaziano JM, Cook NR, Bubes V, Logroscino G, Diener HC, Buring JE (2007) Migraine and risk of cardiovascular disease in men. Arch Intern Med 167:795–801 7. Nordestgaard BG, Chapman MJ, Ray K, Bore´n J, Andreotti F, Watts GF, Ginsberg H, Amarenco P, Catapano A, Descamps OS, Fisher E, Kovanen PT, Kuivenhoven JA, Lesnik P, Masana L, Reiner Z, Taskinen MR, Tokgo¨zoglu L, Tybjærg-Hansen A, European Atherosclerosis Society Consensus Panel (2010) Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J 31:2844–2853 8. Lippi G, Franchini M, Targher G (2011) Screening and therapeutic management of lipoprotein(a) excess: review of the epidemiological evidence, guidelines and recommendations. Clin Chim Acta 412:797–801 9. Goldstein LB, Bushnell CD, Adams RJ, Appel LJ, Braun LT, Chaturvedi S, Creager MA, Culebras A, Eckel RH, Hart RG, Hinchey JA, Howard VJ, Jauch EC, Levine SR, Meschia JF, Moore WS, Nixon JV, Pearson TA, American Heart Association Stroke Council; Council on Cardiovascular Nursing; Council on Epidemiology and Prevention; Council for High Blood Pressure Research; Council on Peripheral Vascular Disease, and Interdisciplinary Council on Quality of Care and Outcomes Research (2011) Guidelines for the primary prevention of stroke: a guideline for healthcare professionals from the American Heart Association/American Stroke Association. Stroke 42:517–584 10. Lippi G, Guidi G (1999) Biochemical risk factors and patient’s outcome: the case of lipoprotein(a). Clin Chim Acta 280:59–71 11. Malaguarnera M, Vacante M, Russo C et al (2013) Lipoprotein(a) in cardiovascular diseases. Biomed Res Int 2013:650989 12. Becker RC, Smyth S (2012) Biomarker science: on a theme of personalized medicine. J Thromb Thrombolysis 34:141–142
Lipoprotein(a) and migraine 13. Lippi G, Favalor EJ, Simundic AM (2012) Biomedical research platforms and their influence on article submissions and journal rankings: an update. Biochem Med (Zagreb) 22:7–14 14. Kurth T, Ridker PM, Buring JE (2008) Migraine and biomarkers of cardiovascular disease in women. Cephalalgia 28:49–56 15. Cinzia F, Daniela P, Elena S, Francesco S, Emilia A, Sandra F, Graziano A, Domenico P, Rosanna A (2009) Lipoprotein(a) [Lp(a)]: a possible link between migraine and stroke. Transl Res 153:44–47 16. Gruber HJ, Bernecker C, Pailer S, Lechner A, Horejsi R, Mo¨ller R, Fazekas F, Truschnig-Wilders M (2010) Lipid profile in normal weight migraineurs — evidence for cardiovascular risk. Eur J Neurol 17:419–425 ¨ , Yılmaz A, Aksoy E, Akar N, Deda G (2011) 17. Teber S, Bektas O Lipoprotein a levels in pediatric migraine. Pediatr Neurol 45:225–228 18. Berthold HK, Gouni-Berthold I (2013) Hyperlipoproteinemia(a): clinical significance and treatment options. Atheroscler Suppl 14:1–5 19. Lippi G, Guidi G (2003) Lipoprotein(a): an emerging cardiovascular risk factor. Crit Rev Clin Lab Sci 40:1–42 20. Eising E, Datson AN, van den Maagdenberg AM, Ferrari MD (2013) Epigenetic mechanisms in migraine: a promising avenue. BMC Med 11:26
21. Hoover-Plow J, Hart E, Gong Y, Shchurin A, Schneeman T (2009) A physiological function for apolipoprotein(a): a natural regulator of the inflammatory response. Exp Biol Med (Maywood) 234:28–34 22. Lippi G, Targher G, Franchini M, Guidi GC (2009) Biochemical correlates of lipoprotein(a) in a general adult population. Possible implications for cardiovascular risk assessment. J Thromb Thrombolysis 27:44–47 23. Goadsby PJ (2007) Cortical spreading depression—better understanding and more questions. Focus on ‘‘distinct vascular conduction with cortical spreading depression’’. J Neurophysiol 97:3827 24. Schachinger V, Halle M, Minners J, Berg A, Zeiher AM (1997) Lipoprotein(a) selectively impairs receptor-mediated endothelial vasodilator function of the human coronary circulation. J Am Coll Cardiol 30:927–934 25. Bigal ME, Lipton RB (2008) Putative mechanisms of the relationship between obesity and migraine progression. Curr Pain Headache Rep 12:207–212 26. Spence JD, Koschinsky M (2012) Mechanisms of lipoprotein(a) pathogenicity: prothrombotic, proatherosclerotic, or both? Arterioscler Thromb Vasc Biol 32:1550–1551
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Epidemiological association between migraine and lipoprotein(a): a systematic review Camilla Mattiuzzi • Gianfranco Cervellin Giuseppe Lippi
•
Ó Springer Science+Business Media New York 2014
Abstract Migraine is a relatively frequent and disabling condition, which poses a large clinical and economical burden on human society. Since there is now emerging evidence that the risk of cardiovascular diseases may be significantly increased in patients with migraine, and that lipoprotein(a) is a powerful, independent cardiovascular risk factor, we performed an electronic searched on Medline, Scopus and Web of Science using the keywords ‘‘migraine’’ and ‘‘lipoprotein(a)’’ or ‘‘apolipoprotein(a)’’ or ‘‘Lp(a)’’ or ‘‘apo(a)’’, with no language or date restriction. The electronic search produced four cross-sectional studies which reported original data about the epidemiological association between lipoprotein(a) and migraine, and used standardized criteria for diagnosing migraine. In only one out of the four studies the concentration of lipoprotein(a) was found to be higher in migraineurs than in controls, whereas in the remaining three investigations lipoprotein(a) levels were found to be virtually identical between cases and controls. This analysis suggests that if any epidemiological and clinical link exists between
C. Mattiuzzi Service of Clinical Governance, General Hospital of Trento, Trento, Italy G. Cervellin Emergency Department, Academic Hospital of Parma, Parma, Italy G. Lippi Laboratory of Clinical Chemistry and Hematology, Academic Hospital of Parma, Parma, Italy G. Lippi (&) U.O. Diagnostica Ematochimica, Azienda OspedalieroUniversitaria di Parma, Via Gramsci, 14, 43126 Parma, Italy e-mail: [email protected]; [email protected]
migraine and cardiovascular disease, a direct involvement of lipoprotein(a) seems unlikely according to the available epidemiological evidence. Keywords Migraine Headache Lipoprotein(a) Lp(a) Cardiovascular disease
Introduction Migraine is a relatively frequent and disabling condition, which poses a large clinical and economical burden on human society. It has been estimated that the overall frequency of migraine attacks approximates 12 % in adults, with a prevalence that is nearly threefold higher in women than in men [1]. Based on ictal disability, this condition is ranked seventh highest among specific causes of disability in the general population [2]. According to the Headache Classification Committee of the International Headache Society (IHS), migraine is a primary form of headache which typically manifests as pain localized above the orbitomeatal line and that can be classified in two forms, i.e., migraine with or without aura [3]. Clinically, migraine is characterized by recurrent attacks of headache and various combinations of symptoms related to the gastrointestinal and autonomic nervous system. There is now emerging evidence that the risk of cardiovascular disease may be significantly increased in patients with migraine. Schu¨rks et al. [4] performed a systematic review and meta-analysis on Medline, Embase and Cochrane Library, to identify case–control and cohort studies exploring the potential association between migraine and cardiovascular disease. The pooled analysis of the nine studies investigating the relationship between migraine and ischemic stroke found a significant increased risk of this
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condition in migraineur patients, with a relative risk (RR) of 1.73 (95 % CI 1.31–2.29; p = 0.004). The RR was also found to be higher in women (2.08; 95 % CI 1.13–3.84, p = 0.01) than in men (1.37; 95 % CI 0.89–2.11; p = 0.10). As regards the eight studies exploring the association between migraine and myocardial infarction, migraineur patients displayed a significant RR of this condition (1.12; 95 % CI 0.95–1.32; p = 0.02), which seemed to be more significant in women (RR 1.14; p = 0.03) than in men (RR 1.15; p = 0.07). As regards studies on specific gender differences, Kurth et al. [5] performed a prospective investigation on 27,840 women (5,125 with active migraine at baseline) aged [45 years, who were followed up for a mean period of 10 years. When compared with non-migraineurs, women with a history of migraine had multivariable-adjusted hazard ratios (HRs) of 2.15 (95 % CI 1.58–2.92; p \ 0.001) for cardiovascular disease, 1.91 (95 % CI 1.17–3.10; p = 0.01) for ischemic stroke, and 2.08 (95 % CI 1.30–3.31; p = 0.02) for myocardial infarction. As regards the male gender, the same authors performed a prospective study of 20,084 men (1449 with migraine) aged 40–84 years, who were followed up for a mean period of 15.7 years [6]. When compared with non-migraineurs, men with a history of migraine had multivariable-adjusted HRs of 1.24 (95 % CI 1.06–1.46; p = 0.008) for cardiovascular disease, 1.12 (95 % CI 0.84–1.50; p = 0.43) for ischemic stroke, and 1.42 (95 % CI 1.15–1.77; p \ 0.001) for myocardial infarction. Among the various risk factor for cardiovascular disease, several lines of evidence now attest that lipoprotein(a) (Lp(a)), a genetic variant of low density lipoproteins (LDLs), exhibits a robust and specific association with this condition. In particular, a meta-analysis of scientific literature published by the European Atherosclerosis Society Consensus Panel, has recently reported that increased Lp(a) levels were significantly predictors of both ischemic heart disease (30 studies and 106,645 subjects; RR 1.13; 95 % CI 1.09–1.18) and ischemic stroke (13 studies and 69,539 subjects; RR 1.10; 95 % CI 1.02–1.19) [7]. It was hence concluded that Lp(a) should be routinely screened in all patients at intermediate or high risk of cardiovascular disease, who present with (i) premature cardiovascular disease; (ii) familial hypercholesterolemia, (iii) family history of premature cardiovascular disease and/or elevated Lp(a), (iv) recurrent cardiovascular disease despite hypocholesterolemic treatment, (v) C3 % 10 year risk of fatal cardiovascular disease, and (vi) C10 % 10 year risk of fatal and/or non-fatal coronary heart disease. These indications have been then reiterated in subsequent recommendations [8, 9]. The combined evidence that migraine is significantly associated with cardiovascular disease [10, 11], and that Lp(a) is a powerful risk factor for cardiovascular disease,
123
prompted us to explore whether any epidemiological association may exist between Lp(a) and migraine. This is particularly relevant in the era of personalized medicine, when drug development is increasingly driven by biomarkers derived from phenotypic screening [12].
Search criteria With the aim to review clinical and epidemiological evidence about the association between Lp(a) and migraine, we performed an electronic searched on medline, scopus and web of science (i.e., the mostly accessed biomedical research platforms) [13], using the keywords ‘‘migraine’’ and ‘‘lipoprotein(a)’’ or ‘‘apolipoprotein(a)’’ or ‘‘Lp(a)’’ or ‘‘apo(a)’’, with no language or date restriction. The references of retrieved articles were also searched for identifying additional articles about this topic. Only those articles using standardized criteria for diagnosing migraine (i.e., those of the IHS) [3], and reporting original data about the epidemiological association between migraine and Lp(a) were finally included in our systematic review. The methodological quality of the included studies was assessed by QUADAS (quality assessment for studies of diagnostic accuracy, an evidence-based quality assessment tool for use in systematic reviews of diagnostic accuracy studies, maximum score 14) by G.L. and C.M. Potential discrepancies were resolved by consensus and, where necessary, the third author (G.C.) was consulted. When each specific criterion was fulfilled, a score of 1 was given, 0 if a criterion was unclear, and -1 if a criterion was not achieved. Heterogeneity across studies was also estimated by Chi-square based statistics and I-square test, where thresholds of 25, 50 and 75 % designate low, moderate, and high heterogeneity.
Overview on epidemiological data The electronic search performed according to the previously defined criteria identified 52 items after elimination of duplicates across the three biomedical research platforms. After careful reading of title, abstract and full text (when available), we excluded 48 articles, which did not report original data about the epidemiological association between Lp(a) and migraine, or failed to use standardized criteria for diagnosing migraine. Therefore, four clinical studies were finally included in this systematic review (Table 1) [14–17]. The inter-study variability was however high, and largely attributable to heterogeneity, especially for sample size (Chi-squared 431.5; DF 4; I-squared 99.1 %; p \ 0.001), gender (Chi squared 70.0; DF 4;
Lipoprotein(a) and migraine Table 1 Synthesis of published studies that have investigated the clinical and epidemiological association between lipoprotein(a) (Lp(a)) and migraine Authors
Study population
Outcome
QUADAS score
Reference
Kurth et al., 2008
27,626 women (5,087 with migraine)
OR 1.04 (95 % CI 0.91–1.20; p = 0.68)
11
[14]
Cinzia et al., 2009
250 subjects (197 females and 53 males; 138 with migraine)
OR 3.88 (95 % CI 1.59–9.51; p = 0.003) in females
11
[15]
12
[16]
8
[17]
OR 2.23 (95 % CI 0.40–12.33; p = 0.30) in males Gruber et al., 2010
104 normal weight subjects (80 females and 24 males; 43 with migraine) and 32 obese subjects (15 males and 17 females; 17 with migraine)
No significant difference of Lp(a) levels between cases and controls (p = ns)
Teber et al., 2011
126 children (62 females and 64 males; 63 with migraine)
OR 3.48 (95 % CI 1.05–11.50; p = 0.04)
OR odds ratio; QUADAS quality assessment for studies of diagnostic accuracy
I-squared 94.3 %; p \ 0.001) and age (Chi squared 214.8; DF 4; I-squared 98.1 %; p \ 0.001). The first study exploring the epidemiological association between Lp(a) and migraine was published by Kurth et al.[14] in 2008. The authors performed a large crosssectional investigation including 27,626 women aged C45 years (5,087 with history of migraine), who had blood samples available for assessment of a broad range of cardiovascular risk factors, including Lp(a). The plasma concentration of Lp(a) was found to be virtually identical between patients with or without history of migraine (238 vs. 239 mg/L; p = 0.81). Accordingly, the multivariableadjusted odds ratio (OR) for association between Lp(a) and migraine status did not achieve statistical significance in the entire cohort of patients (1.02; 95 % CI 0.94–1.10; p = 0.68), and nor in migraineur patients with (1.04; 95 % CI 0.91–1.20) and without aura (1.00; 95 % CI 0.89–1.12; p = 0.93 for trend). Cinzia et al. [15] measured the plasma levels of Lp(a) in 138 patients with migraine (mean age 38 ± 13 years; 110 females and 28 males), referred to an italian headache service, as well as in 112 healthy subjects (87 females and 25 males). Although the median concentration of plasma Lp(a) was found to be virtually identical between cases and controls (104 mg/L; range 1–2110 vs. 103 mg/L; range 9–695 mg/L; p = 0.80), it was however observed that the rate of patients with values [300 mg/L was more than twofold higher in cases than in controls (33/138 vs. 11/112; p = 0.004). It was hence estimated that abnormal levels of plasma Lp(a) were significant predictors of migraine in multivariate analysis after adjustment for age, gender, hypertension and smoking habit, displaying an OR of 3.40 (95 % CI 1.57–7.55; p = 0.002). Interestingly, this association remained significant in the female (OR 3.88; 95 %
CI 1.59–9.51; p = 0.003), but not in the male gender (OR 2.23; 95 % CI 0.40–12.33; p = 0.30). Gruber et al. [16] measured plasma Lp(a) in 61 normal weight patients with migraine (19 males and 42 females; mean age 35 ± 9 years) assessed in a german department of neurology, as well as in 43 normal weight controls (5 males and 38 females; mean age 36 ± 11 years). The concentration of Lp(a) was found to be virtually identical between cases and controls (176 ± 171 vs. 182 ± 179 mg/L; p = ns). In the same study, Lp(a) was also measured in 15 obese migraine patients (9 males and 4 females; mean age 40 ± 9 years) and in 17 obese controls (mean age 36 ± 11 years; 6 males and 11 females). The concentration of Lp(a) was found to slightly but not significantly higher in cases than in controls (207 ± 258 vs. 134 ± 92 mg/L; p = ns). Teber et al. [17] assessed the plasma levels of Lp(a) in 63 children aged between 4 and 18 years (33 males and 30 females subjects), who were referred to a turkish pediatric neurology department with a final diagnosis of migraine (18 with aura and 45 without aura). The plasma concentration of Lp(a) was also measured in 63 age-matched healthy control subjects. In children with migraine, the median concentration of Lp(a) was nearly 60 % higher than in the control population (776 mg/L; range 20–593 vs. 494 mg/L; range 20–453 mg/L; p = 0.001). The rate of patients with values [300 mg/L was also marginally but significantly higher in children with migraine than in the non-pain control population (12/63 vs. 4/63; p = 0.032). It was finally observed that abnormal Lp(a) levels were significant predictor of migraine in multivariate analysis after adjustment for age and gender, with an OR of 3.48 (95 % CI 1.05–11.50; p = 0.04).
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The data published in these studies could not be metaanalyzed, since the outcome would have been dramatically biased by the larger study of Kurth et al. [14], which included more than 98 % of the overall sample size.
Conclusion Lp(a) has recently emerged as an independent risk factor for a variety of cardiovascular disorders, including acute coronary syndrome, ischemic stroke and peripheral artery occlusive disease [18]. The leading biological hallmark of this lipoprotein is the presence of a single copy of the highly polymorphic and glycosylated apolipoprotein(a), which is covalently linked to apolipoprotein B100, the main protein moiety of LDLs. This biochemical association confers a high cardiovascular potential to this lipoprotein, which hence displays both atherogenic and antifibrinolytic properties [19]. Since several cross-sectional and prospective studies have reported that the concentration of Lp(a) is independently associated with cardiovascular disease, while others investigations have found that the risk of cardiovascular disease is increased in patients with migraine, it seems reasonable to hypothesize that at least part of the cardiovascular risk in migraineur patients may be attributable to Lp(a). There are in fact several aspects that may link Lp(a) biology with the pathogenesis of migraine. First, migraine has a strong inflammatory component, and several proinflammatory biomarkers are involved in the process of nerve endings sensitization, thus lowering the individual threshold of pain [20]. Accordingly, Lp(a) is an acute phase reactant, and its concentration is frequently increased in patients with inflammatory disorders [21, 22]. Then, vasoconstriction of cerebral arteries with subsequent decreased cerebral blood flow is the leading trigger of a migraine attack [23]. In this regard, increased Lp(a) levels are associated with selective impairment of vasodilator capacity of receptor-mediated endothelial stimuli [24]. Finally, migraine is associated with a prothrombotic state [25], wherein Lp(a) exerts powerful prothrombotic/antithrombolytic effects [26]. It is hence reasonable to hypothesize that increased levels of Lp(a) may enhance vasoconstriction of cerebral blood vessels, amplify a pre-existing prothrombotic state and increase the local inflammatory response, thus ultimately triggering migraine or worsening its symptoms. Despite the limited number of studies available in the current scientific literature, the results of this systematic review are consistent with the lack of a significant epidemiological association between Lp(a) and migraine. More specifically, two studies failed to find any significant difference in the rate of abnormal Lp(a) values in migraine patients and in controls [14, 17], one of them reported a
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marginal statistical significance [17], whereas the remaining concluded that increased Lp(a) levels are associated with migraine in females but not in males [15] (Table 1). The most plausible explanation for the different outcomes is probably attributable to the large inter-study heterogeneity as regards sex prevalence, mean age and especially sample size (all p \ 0.001). In conclusion, our analysis suggests that if any epidemiological and clinical link exists between migraine and cardiovascular disease, a direct involvement of plasma Lp(a) seems less plausible according to the recent and limited evidence, so that further studies are needed to support or definitely rule out this association, and especially verify the potential role of Lp(a) in the brain environment.
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