Special Issue Article
Conventional vascular risk factors: Their role in the association between migraine and cardiovascular diseases
Cephalalgia 2015, Vol. 35(2) 146–164 ! International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0333102414559551 cep.sagepub.com
Simona Sacco, Francesca Pistoia, Diana Degan and Antonio Carolei Abstract Introduction: Migraine, in particular migraine with aura, has been found to be associated with cardiovascular disease. However, the role of conventional vascular risk factors in the association is still debated. The aim of the present review is to address the association between migraine and conventional cardiovascular risk factors as well as to address their possible role in the association between migraine and cardiovascular disease. Methods: Data for this review were obtained through searches in multiple sources up to May 2014 using the terms ‘‘migraine’’ OR ‘‘headache’’ in combination with all the vascular risk factors of interest. Results: Data about the possible association between migraine and high blood pressure values are heterogeneous, hindering any final conclusion. Data addressing the possible association between migraine and diabetes mellitus indicate the lack of any association or in some cases a negative association between the two conditions. The body of evidence on the role of dyslipidemia in migraineurs is relatively homogeneous and, with few exceptions, reports an association between migraine and an unfavorable lipid profile; however, the difference in lipid levels between migraineurs and non-migraineurs is small and its clinical implication unclear. Regarding obesity, a trend has been observed of increased risk of migraine with increasing obesity, especially in young patients, albeit in the midst of conflicting data. Evidence about the association between cigarette smoking and migraine mostly indicates that migraineurs are more commonly smokers than non-migraineurs. On the other hand, the majority of the available studies report less alcohol use in migraineurs than in non-migraineurs. Finally, many of the available studies suggest a more frequent family history of cardiovascular disease in migraineurs as compared to non-migraineurs. Since most of the studies that supported the association between migraine and cardiovascular disease adjusted the analyses for the presence of several vascular risk factors, they cannot entirely explain this association. Conclusions: Based on the available reported data, it seems unlikely that the higher risk of cardiovascular disease in migraineurs is mediated by any single vascular risk factor. For this reason the role of specific interactions among risk factors with the contribution of genetic, environmental, personality and psychological factors should be appropriately investigated. Keywords Migraine, vascular disease, arterial hypertension, diabetes mellitus, dyslipidemia, cigarette smoking, alcohol, cardiovascular disease Date received: 29 March 2014; revised: 12 September 2014; accepted: 17 September 2014
Introduction Migraine, in particular migraine with aura (MA), has been found to be associated with cardiovascular disease (CVD) (1–19). Mechanisms underlying the hypothesized causal relationship between migraine and CVD have not yet been established. It is improbable that CVD occurs exclusively through the conventional
Institute of Neurology, Department of Applied Clinical Sciences and Biotechnology, University of L’Aquila, Italy Corresponding author: Simona Sacco, Department of Neurology, University of L’Aquila, Piazzale Salvatore Tommasi, 1, L’Aquila 67100, Italy. Email: [email protected]
147
Sacco et al. mechanisms commonly recognized in the general population (e.g. atherosclerosis and small vessel disease); migraine-specific mechanisms are probably involved. Additionally, whether ischemic stroke and ischemic heart disease share common mechanisms in migraineurs is still unproven. Several studies have addressed the burden of conventional vascular risk factors (RFs) in migraineurs. However, in some areas results from the available studies are conflicting and definitive conclusions cannot be drawn. In this review we will examine the association between migraine and conventional vascular RFs such as arterial hypertension, diabetes mellitus (DM), dyslipidemia, obesity, cigarette smoking, alcohol consumption, and family history of CVD; additionally we will briefly address their possible role in the association between migraine and CVD.
Methods Data for this review were obtained through searches in Embase, Google Scholar, ISI Web of Science, and Medline from their first availability up to May 2014. The search terms included ‘‘migraine’’ OR ‘‘headache’’ AND (‘‘arterial hypertension,’’ ‘‘diabetes mellitus,’’ ‘‘dyslipidemia,’’ ‘‘hypercholesterolemia,’’ ‘‘obesity,’’ ‘‘body mass index,’’ ‘‘cigarette smoking,’’ ‘‘alcohol,’’ ‘‘history of cardiovascular disease’’). We also searched reference lists and papers cited in the identified articles. We considered only studies addressing, as their primary or secondary aim, the difference in the distribution of vascular RFs between migraineurs and nonmigraineurs. We excluded studies using as the reference group participants with non-migraine headache, not defining migraine or the RF of interest, performed on individuals with metabolic disease only, or not adopting a matching procedure or adjusted analyses to account for possible confounders. When studies provided more than one adjusted model, we used the one including the largest number of factors. Where a cohort study analyzed the association between migraine and the RF of interest considering only baseline data, we have reported the study as cross-sectional in our results. We reviewed only studies published in English.
Results Blood pressure (BP) Several studies have attempted to investigate the association between migraine and BP values, with contradictory results (details on sample size, demographic characteristics of included participants, and findings are shown in Table 1) (6,20–32). An association between headache, including migraine, and high BP values has been found by some studies (6,23–26,30).
Other studies have pointed to the lack of a clear association between migraine and increased BP values (20– 22,28) and some have demonstrated an inverse relationship between migraine and high BP values (20,21,27,29,31,32). The Genetic Epidemiology of Migraine (GEM), a large, well-conducted cross-sectional study, reported that individuals with migraine had a 1.64 increase in the risk of presenting a history of physician-diagnosed hypertension (25). This finding was consistent both in patients with MA and with migraine without aura (MO). In line with this observation, the National Health and Nutrition Examination Survey (NHANES), a prospective cohort study involving 12,220 participants, reported an increased risk of migraine in individuals with arterial hypertension; no details were provided regarding MA or MO (24). The prospective cohort Bruneck study also indicated, in an analysis of cross-sectional data, that hypertension was more common in migraineurs than in controls (26). Additionally, two cross-sectional studies in Taiwan using administrative coding data supported this same observation (6,30). In line with those findings, a casecontrol study on Japanese patients, showed higher values for both systolic BP (SBP) and diastolic BP (DBP) in migraineurs as compared to non-migraineurs, regardless of migraine subtype (23). On the other hand, some studies did not find a clear association between the presence of hypertension and migraine, or indeed indicated the presence of an inverse relationship (Table 1). Several reports from the NordTrøndelag Health (HUNT) Study, a prospective cohort study involving a large number of participants from adolescence to adulthood, indicated in cross-sectional analyses that individuals with hypertension or high BP values were not at increased risk of migraine (22,27,28). Similarly, a cross-sectional population-based study, the Sao˜ Paulo Ageing & Health (SPAH) Study, did not find an increased risk of hypertension in migraineurs but suggested the presence of an inverse association in women (20). This last finding is in line with those reported by the large cross-sectional Reykjavik Study (21), by cross-sectional data from the prospective Epidemiology of Vascular Aging (EVA) Study (29), and by some reports from a cross-sectional Brazilian study (31) and from the HUNT-2 study (32) suggesting a decreased risk of migraine associated with high BP values (31) or lower mean BP values in migraineurs (32).
Diabetes Mellitus (DM) Studies addressing the association between migraine and DM (details on sample size, demographic characteristics of included participants, and findings are
221 subjects; 111 migraineurs
125,550 subjects; 20,925 migraineurs 12,220 subjects; 1,109 migraineurs
Case-control
Crosssectional*
Cohort, prospective
Schwaiger, 2008; Bruneck Study (26)
Crosssectional*
574 subjects; 111 migraineurs
Cross-sectional 5,755 subjects; 620 migraineurs
20
22,685 subjects; 1,648 migraineurs
Cohort, prospective
Hagen, 2002; Nord-Trøndelag Health Study (HUNT) study (22) Ikeda, 2012 (23)
Kuo, 2013; Taiwan National Health Insurance Research Database (6) Merikangas, 1997; National Health and Nutrition Examination Survey (NHANES) (24) Scher, 2005; Genetic Epidemiology of Migraine (GEM) study (25)
19–87
21,537 subjects; 2,116 migraineurs
Crosssectional*
Gudmundsson, 2005; Reykjavik Study (21)
55–94
20–65
25–74
18
NR
65
Sample size (n)
Cross-sectional 1,450 subjects; 165 migraineurs
Design
29
52
60
70
69
NR
52
78 migraineurs 56 non-migraineurs
Age range (years) Women (%)
Bensen˜or, 2011; Sao˜ Paulo Ageing & Health Study (SPAH) (20)
Study (first author, year; acronym)
Table 1. Summary of selected studies addressing the relationship between migraine and blood pressure.
Findings
(continued)
OR adjusted for sex, gender, socioe- Arterial hypertension more likely in migraiconomic status, smoking status, and neurs overall (OR 1.64, 95% CI 1.3–2.0), alcohol intake in MA (OR 1.73, 95% CI 1.2–2.4) and in MO (OR 1.62, 95% CI 1.3–2.0) than in non-migraineurs; high BP values (SBP 140 mmHg or DBP 90 mm Hg) at examination similar in migraineurs and non-migraineurs Adjusted for age and gender Hypertension more common in migraineurs than in non-migraineurs (72% vs 68%)
OR adjusted for age, gender, body Similar SBP (140 vs 146 mmHg) and DBP (84 mass index, smoking status, alcohol vs 86 mmHg) values, and similar prevaconsumption, monthly income lence of arterial hypertension (75% vs 80%) in migraineurs and non-migraineurs; no increased risk of hypertension in migraineurs, inverse association in women (OR 0.58, 95% CI 0.38–0.90) OR adjusted for age and year No increased risk of migraine associated entering the study with arterial hypertension in men and women. Decreased risk of migraine in women with SBP 160 mmHg (OR 0.76, 95% CI 0.62–0.92) OR adjusted for age, occupational No increased risk of migraine in women and status, and use of antihypertensive men with high (160 mmHg) SBP and medication high (90 mmHg) DBP Age and gender matching Higher SBP and DBP values in women (109 vs 107 mmHg P
Conventional vascular risk factors: Their role in the association between migraine and cardiovascular diseases
Cephalalgia 2015, Vol. 35(2) 146–164 ! International Headache Society 2014 Reprints and permissions: sagepub.co.uk/journalsPermissions.nav DOI: 10.1177/0333102414559551 cep.sagepub.com
Simona Sacco, Francesca Pistoia, Diana Degan and Antonio Carolei Abstract Introduction: Migraine, in particular migraine with aura, has been found to be associated with cardiovascular disease. However, the role of conventional vascular risk factors in the association is still debated. The aim of the present review is to address the association between migraine and conventional cardiovascular risk factors as well as to address their possible role in the association between migraine and cardiovascular disease. Methods: Data for this review were obtained through searches in multiple sources up to May 2014 using the terms ‘‘migraine’’ OR ‘‘headache’’ in combination with all the vascular risk factors of interest. Results: Data about the possible association between migraine and high blood pressure values are heterogeneous, hindering any final conclusion. Data addressing the possible association between migraine and diabetes mellitus indicate the lack of any association or in some cases a negative association between the two conditions. The body of evidence on the role of dyslipidemia in migraineurs is relatively homogeneous and, with few exceptions, reports an association between migraine and an unfavorable lipid profile; however, the difference in lipid levels between migraineurs and non-migraineurs is small and its clinical implication unclear. Regarding obesity, a trend has been observed of increased risk of migraine with increasing obesity, especially in young patients, albeit in the midst of conflicting data. Evidence about the association between cigarette smoking and migraine mostly indicates that migraineurs are more commonly smokers than non-migraineurs. On the other hand, the majority of the available studies report less alcohol use in migraineurs than in non-migraineurs. Finally, many of the available studies suggest a more frequent family history of cardiovascular disease in migraineurs as compared to non-migraineurs. Since most of the studies that supported the association between migraine and cardiovascular disease adjusted the analyses for the presence of several vascular risk factors, they cannot entirely explain this association. Conclusions: Based on the available reported data, it seems unlikely that the higher risk of cardiovascular disease in migraineurs is mediated by any single vascular risk factor. For this reason the role of specific interactions among risk factors with the contribution of genetic, environmental, personality and psychological factors should be appropriately investigated. Keywords Migraine, vascular disease, arterial hypertension, diabetes mellitus, dyslipidemia, cigarette smoking, alcohol, cardiovascular disease Date received: 29 March 2014; revised: 12 September 2014; accepted: 17 September 2014
Introduction Migraine, in particular migraine with aura (MA), has been found to be associated with cardiovascular disease (CVD) (1–19). Mechanisms underlying the hypothesized causal relationship between migraine and CVD have not yet been established. It is improbable that CVD occurs exclusively through the conventional
Institute of Neurology, Department of Applied Clinical Sciences and Biotechnology, University of L’Aquila, Italy Corresponding author: Simona Sacco, Department of Neurology, University of L’Aquila, Piazzale Salvatore Tommasi, 1, L’Aquila 67100, Italy. Email: [email protected]
147
Sacco et al. mechanisms commonly recognized in the general population (e.g. atherosclerosis and small vessel disease); migraine-specific mechanisms are probably involved. Additionally, whether ischemic stroke and ischemic heart disease share common mechanisms in migraineurs is still unproven. Several studies have addressed the burden of conventional vascular risk factors (RFs) in migraineurs. However, in some areas results from the available studies are conflicting and definitive conclusions cannot be drawn. In this review we will examine the association between migraine and conventional vascular RFs such as arterial hypertension, diabetes mellitus (DM), dyslipidemia, obesity, cigarette smoking, alcohol consumption, and family history of CVD; additionally we will briefly address their possible role in the association between migraine and CVD.
Methods Data for this review were obtained through searches in Embase, Google Scholar, ISI Web of Science, and Medline from their first availability up to May 2014. The search terms included ‘‘migraine’’ OR ‘‘headache’’ AND (‘‘arterial hypertension,’’ ‘‘diabetes mellitus,’’ ‘‘dyslipidemia,’’ ‘‘hypercholesterolemia,’’ ‘‘obesity,’’ ‘‘body mass index,’’ ‘‘cigarette smoking,’’ ‘‘alcohol,’’ ‘‘history of cardiovascular disease’’). We also searched reference lists and papers cited in the identified articles. We considered only studies addressing, as their primary or secondary aim, the difference in the distribution of vascular RFs between migraineurs and nonmigraineurs. We excluded studies using as the reference group participants with non-migraine headache, not defining migraine or the RF of interest, performed on individuals with metabolic disease only, or not adopting a matching procedure or adjusted analyses to account for possible confounders. When studies provided more than one adjusted model, we used the one including the largest number of factors. Where a cohort study analyzed the association between migraine and the RF of interest considering only baseline data, we have reported the study as cross-sectional in our results. We reviewed only studies published in English.
Results Blood pressure (BP) Several studies have attempted to investigate the association between migraine and BP values, with contradictory results (details on sample size, demographic characteristics of included participants, and findings are shown in Table 1) (6,20–32). An association between headache, including migraine, and high BP values has been found by some studies (6,23–26,30).
Other studies have pointed to the lack of a clear association between migraine and increased BP values (20– 22,28) and some have demonstrated an inverse relationship between migraine and high BP values (20,21,27,29,31,32). The Genetic Epidemiology of Migraine (GEM), a large, well-conducted cross-sectional study, reported that individuals with migraine had a 1.64 increase in the risk of presenting a history of physician-diagnosed hypertension (25). This finding was consistent both in patients with MA and with migraine without aura (MO). In line with this observation, the National Health and Nutrition Examination Survey (NHANES), a prospective cohort study involving 12,220 participants, reported an increased risk of migraine in individuals with arterial hypertension; no details were provided regarding MA or MO (24). The prospective cohort Bruneck study also indicated, in an analysis of cross-sectional data, that hypertension was more common in migraineurs than in controls (26). Additionally, two cross-sectional studies in Taiwan using administrative coding data supported this same observation (6,30). In line with those findings, a casecontrol study on Japanese patients, showed higher values for both systolic BP (SBP) and diastolic BP (DBP) in migraineurs as compared to non-migraineurs, regardless of migraine subtype (23). On the other hand, some studies did not find a clear association between the presence of hypertension and migraine, or indeed indicated the presence of an inverse relationship (Table 1). Several reports from the NordTrøndelag Health (HUNT) Study, a prospective cohort study involving a large number of participants from adolescence to adulthood, indicated in cross-sectional analyses that individuals with hypertension or high BP values were not at increased risk of migraine (22,27,28). Similarly, a cross-sectional population-based study, the Sao˜ Paulo Ageing & Health (SPAH) Study, did not find an increased risk of hypertension in migraineurs but suggested the presence of an inverse association in women (20). This last finding is in line with those reported by the large cross-sectional Reykjavik Study (21), by cross-sectional data from the prospective Epidemiology of Vascular Aging (EVA) Study (29), and by some reports from a cross-sectional Brazilian study (31) and from the HUNT-2 study (32) suggesting a decreased risk of migraine associated with high BP values (31) or lower mean BP values in migraineurs (32).
Diabetes Mellitus (DM) Studies addressing the association between migraine and DM (details on sample size, demographic characteristics of included participants, and findings are
221 subjects; 111 migraineurs
125,550 subjects; 20,925 migraineurs 12,220 subjects; 1,109 migraineurs
Case-control
Crosssectional*
Cohort, prospective
Schwaiger, 2008; Bruneck Study (26)
Crosssectional*
574 subjects; 111 migraineurs
Cross-sectional 5,755 subjects; 620 migraineurs
20
22,685 subjects; 1,648 migraineurs
Cohort, prospective
Hagen, 2002; Nord-Trøndelag Health Study (HUNT) study (22) Ikeda, 2012 (23)
Kuo, 2013; Taiwan National Health Insurance Research Database (6) Merikangas, 1997; National Health and Nutrition Examination Survey (NHANES) (24) Scher, 2005; Genetic Epidemiology of Migraine (GEM) study (25)
19–87
21,537 subjects; 2,116 migraineurs
Crosssectional*
Gudmundsson, 2005; Reykjavik Study (21)
55–94
20–65
25–74
18
NR
65
Sample size (n)
Cross-sectional 1,450 subjects; 165 migraineurs
Design
29
52
60
70
69
NR
52
78 migraineurs 56 non-migraineurs
Age range (years) Women (%)
Bensen˜or, 2011; Sao˜ Paulo Ageing & Health Study (SPAH) (20)
Study (first author, year; acronym)
Table 1. Summary of selected studies addressing the relationship between migraine and blood pressure.
Findings
(continued)
OR adjusted for sex, gender, socioe- Arterial hypertension more likely in migraiconomic status, smoking status, and neurs overall (OR 1.64, 95% CI 1.3–2.0), alcohol intake in MA (OR 1.73, 95% CI 1.2–2.4) and in MO (OR 1.62, 95% CI 1.3–2.0) than in non-migraineurs; high BP values (SBP 140 mmHg or DBP 90 mm Hg) at examination similar in migraineurs and non-migraineurs Adjusted for age and gender Hypertension more common in migraineurs than in non-migraineurs (72% vs 68%)
OR adjusted for age, gender, body Similar SBP (140 vs 146 mmHg) and DBP (84 mass index, smoking status, alcohol vs 86 mmHg) values, and similar prevaconsumption, monthly income lence of arterial hypertension (75% vs 80%) in migraineurs and non-migraineurs; no increased risk of hypertension in migraineurs, inverse association in women (OR 0.58, 95% CI 0.38–0.90) OR adjusted for age and year No increased risk of migraine associated entering the study with arterial hypertension in men and women. Decreased risk of migraine in women with SBP 160 mmHg (OR 0.76, 95% CI 0.62–0.92) OR adjusted for age, occupational No increased risk of migraine in women and status, and use of antihypertensive men with high (160 mmHg) SBP and medication high (90 mmHg) DBP Age and gender matching Higher SBP and DBP values in women (109 vs 107 mmHg P
