Authors: Claudio Tana, Dilara Onan, Roberta Messina, Marta Waliszewska-Prosół, David Garcia-Azorin, Luis Leal-Vega, Maria Begoña Coco-Martin, Raffaele Ornello, Bianca Raffaelli, Marcio Nattan Portes Souza, William Wells-Gatnik, Paolo Martelletti
Categories: Review, Migraine, Cardiovascular disease, Aura, Depression, CGRP-targeted therapy, Medication overuse headache
Source: Neurology and Therapy
Authors: Claudio Tana, Dilara Onan, Roberta Messina, Marta Waliszewska-Prosół, David Garcia-Azorin, Luis Leal-Vega, Maria Begoña Coco-Martin, Raffaele Ornello, Bianca Raffaelli, Marcio Nattan Portes Souza, William Wells-Gatnik, Paolo Martelletti
Migraine, particularly with aura, has been consistently associated with an increased risk of cardiovascular disease, including ischemic stroke and myocardial infarction. Shared pathophysiological mechanisms such as endothelial dysfunction, platelet aggregation, systemic inflammation, and autonomic imbalance suggest that migraine may act as an early clinical marker of systemic vascular vulnerability. Psychiatric comorbidities, frequently present in chronic migraine, further compound disability and may contribute to long-term cardiovascular risk. This narrative review discusses the evolving understanding of migraine as a multisystem disorder, emphasizing its vascular and neuropsychiatric dimensions. Emerging data on calcitonin gene-related peptide (CGRP)-targeting monoclonal antibodies highlight their efficacy not only in reducing headache burden but also their favorable cardiovascular safety profile. Moreover, preliminary evidence suggests these agents may have a positive effect on mood symptoms in patients with comorbid depression and anxiety. Recognizing migraine as a condition that intersects neurological, cardiovascular, and psychiatric pathways may support earlier risk stratification and guide integrated treatment approaches in complex patient populations.
Migraine, particularly with aura, is associated with an increased risk of cardiovascular disease, including ischemic stroke and myocardial infarction.Shared mechanisms such as endothelial dysfunction, inflammation, platelet activation, and autonomic imbalance may underlie the link between migraine and vascular events.Psychiatric comorbidities, including anxiety and depression, are common in patients with chronic migraine and may further increase systemic vulnerability.CGRP-targeting monoclonal antibodies are effective in reducing migraine frequency, have shown a favorable cardiovascular safety profile, and may also improve mood symptoms, making them suitable for patients with migraine, medication overuse, and psychiatric comorbidities.Viewing migraine as a multisystem disorder may lead to better risk stratification and more integrated, multidisciplinary care strategies.
Migraine has long been considered a debilitating neurological disorder primarily affecting daily life, productivity, and overall well-being. Characterized by recurrent attacks of moderate to severe head pain, which is often accompanied by nausea, photophobia, and phonophobia, migraine significantly impacts patients’ physical, emotional, and social functioning. During the disease course, the episodic nature of the migraine may evolve into chronicity, leading to an even greater burden [1].
According to the Global Burden of Disease Study, migraine ranks among the top causes of years lived with disability (DALYs) worldwide, underscoring its far-reaching consequences beyond mere pain [2] Moreover, the unpredictability of attacks often results in anticipatory anxiety and social withdrawal, contributing to a vicious cycle of psychological impairment and reduced quality of life. In an occupational context, migraine is a leading cause of absenteeism and presenteeism, causing notable economic repercussions. However, despite its significant prevalence and disabling nature, migraine remains underdiagnosed and undertreated, especially in marginalized populations [3].
In recent years, emerging research has unveiled a deeper connection between migraine and cardiovascular disease (CVD), shifting the perception of migraine from an isolated neurological event to a potential marker of systemic vascular dysfunction. This association is particularly significant in patients with migraine with aura (MwA), who exhibit an increased risk of ischemic stroke, myocardial infarction (MI), and other cardiovascular complications. Novel insights regarding the interplay between migraine and CVD suggest that endothelial dysfunction, neurovascular dysregulation, platelet hyperactivity, and systemic inflammation may contribute to the overlapping pathophysiological mechanisms of these conditions. Additionally, genetic predisposition and sex-related hormonal influences further complicate the risk profile, making this a highly individualized and evolving area of study [4].
This narrative review focuses on the epidemiological, clinical, and mechanistic links between migraine and CVD, highlighting gaps in current knowledge and discussing the implications on the diagnosis, prevention, and management of these frequently comorbid conditions. Understanding this association is crucial for developing personalized risk stratification strategies, optimizing cardiovascular screening in patients with migraine, and identifying therapeutic interventions that balance neurological and cardiovascular health.
This narrative review is based on a targeted literature search conducted in PubMed and Scopus databases up to April 2025. The search strategy included combinations of the following migraine, aura, CVD, MI, stroke, calcitonin gene-related peptide (CGRP), atherosclerosis, endothelial dysfunction, and comorbidity. Articles were included if they were peer-reviewed, published in English, and focused on adult populations. Both original studies and relevant reviews were considered.
Two authors (C.T. and D.O.) independently screened the titles and abstracts, followed by full-text reviews of eligible papers. Any disagreement was resolved through discussion. References from key papers were also manually checked to identify additional relevant studies. This process aimed to ensure a comprehensive and unbiased selection of literature.
This article is a narrative review of previously published literature. No new studies involving human participants or animals were conducted by the authors. Ethical approval and informed consent were therefore not required.
Stroke is the ninth leading contributor to DALYs among individuals aged 25–49, with a burden that is increasing progressively with age. In the 50–74 age group, it rises to the second leading cause of DALYs, and represents the second leading cause of death in the world [5]. While previous research has demonstrated a positive association between migraine and stroke, the substantial global burden, both in terms of disability and mortality, has motivated ongoing investigation into the potential overlapping mechanisms underlying these two conditions. Notably, individuals with MwA are at significantly greater risk of ischemic stroke. In this population, it is estimated that the risk of stroke is approximately doubled when compared to those without aura [6]. The risk of ischemic stroke is further elevated in patients with migraine with frequent attacks. This is particularly apparent among women under the age of 45, those who use estrogen-containing oral contraceptives, and individuals who smoke [7].
The association between migraine and hemorrhagic stroke remains controversial. A recent meta-analysis examining data from 1600 individuals with hemorrhagic stroke reported an increased risk among female patients with migraine under the age of 45 (RR 1.55, 95% CI 1.16–2.07; P = 0.003) and among patients with any type of migraine (RR 1.57, 95% CI 1.10–2.24; P = 0.012). However, no significant association was found between MwA and the risk of hemorrhagic stroke [8]. Conversely, another meta-analysis including 654 patients found no association between migraine and hemorrhagic stroke, further highlighting the inconsistency of current evidence and the need for larger, well-controlled prospective studies [9]. In a recent meta-analysis, a positive association between migraine and the risk of hemorrhagic stroke was observed using a fixed-effect model; however, this association did not remain statistically significant under the random-effects model. Moreover, the analysis revealed substantial heterogeneity across studies, suggesting variability in study populations or methodologies, greatly limiting the generalizability of these findings [10].
While some studies suggest that migraine may be considered an independent risk factor for stroke in young women, this remains a topic of ongoing debate due to conflicting findings across the literature. It has also been emphasized that this risk appears to decline with age, possibly as a result of hormonal changes and the shifting vascular profile associated with the menopausal transition [11, 12].
In summary, the variability in findings based on factors such as sex, age, smoking status, and oral contraceptive use, particularly in relation to the type of stroke, highlights the complexity of the association between migraine and cerebrovascular events, and underscores the need for further high-quality research to clarify these interactions.
Although the underlying mechanisms remain incompletely understood, cortical spreading depression (CSD) is considered a key pathophysiological process potentially linking MwA to ischemic stroke. Endothelial dysfunction, manifested through impaired vasodilation and vasoconstriction, along with platelet activation, elevated levels of fibrinogen, D-dimer, and von Willebrand factor, and a dysregulated coagulation cascade, may all contribute to oxidative stress, which is attributed to both conditions. Furthermore, the prevalence of patent foramen ovale (PFO) has been reported to range from 19% to 77.9% in patients with MwA, and from 11% to 34.1% in those without aura. This elevated prevalence in MwA supports a possible mechanistic link between PFO, migraine, and the increased risk of stroke [13].
The genetic basis of migraine and its vascular comorbidities is also a subject of ongoing investigation. The association between MwA and ischemic stroke should be considered particularly in the context of hereditary vascular disorders, where specific gene mutations may contribute to both conditions. For instance, in cases of cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) attributed to mutations in the* NOTCH3* gene, a MwA-like headache is often one of the earliest clinical manifestations that commonly precedes recurrent ischemic events [14]. Similarly, polymorphisms in the* MTHFR* gene, which are associated with elevated homocysteine levels, have been implicated in both increased stroke risk and migraine pathogenesis. Mutations affecting coagulation factors, such as those involved in prothrombin or factor V Leiden pathways, may also predispose individuals to thromboembolic events and have been explored as shared risk factors in patients experiencing MwA [15]. These examples highlight the importance of considering migraine not merely as a benign episodic disorder but, in some cases, as a marker of underlying genetic vulnerability to cerebrovascular disease [7, 16].
Recent epidemiological studies have indicated that coronary artery disease (CAD) and migraine may share common and overlapping vascular mechanisms [17]. In a population-based study by Bigal et al. some authors found that MwA was significantly associated with increased prevalence of major cardiovascular events, including angina, MI, and stroke, even after adjusting for traditional risk factors. In contrast, migraine without aura was not independently associated with elevated cardiovascular risk. These findings reinforce the notion that MwA represents a distinct vascular risk phenotype, underscoring the importance of cardiovascular screening and prevention strategies in this patient subgroup [17]. Underlying mechanisms may include endothelial dysfunction, systemic inflammation, altered platelet reactivity, and genetic predisposition that may contribute to both migraine pathophysiology and atherosclerotic processes. Such shared pathways reinforce the need to consider migraine, particularly MwA, as a potential marker of broader vascular risk [18]. In a cohort study involving 585 individuals, migraine was found to be highly prevalent among patients with acute coronary syndrome due to spontaneous coronary artery dissection (SCAD), with a reported lifetime prevalence of 42%, particularly among women. These patients frequently reported additional comorbidities, including chest pain, arterial aneurysms, and depression. On the basis of these findings, vascular screening and advanced imaging techniques are recommended in individuals presenting with both migraine and CAD, especially when SCAD is suspected, to identify underlying vascular abnormalities and guide appropriate management [19].
Hormonal fluctuations are considered one of the potential risk factors contributing to the association between migraine and CVD in women. Estrogen has been implicated in modulating vascular tone, endothelial function, and coagulation pathways, all of which may influence the pathophysiological link between migraine and vascular events. The increased risk observed in women, especially during periods of hormonal variability such as menstruation, pregnancy, or hormonal contraceptive use, supports the hypothesis of a hormonally mediated mechanism [20]. Migraine attacks are closely tied to hormonal shifts during the menstrual cycle, with estrogen withdrawal recognized as a principal trigger. This hormonal decline alters vascular tone and endothelial responsiveness, contributing to the development of hormonally mediated migraine. The use of estrogen-containing oral contraceptives may further elevate vascular risk, particularly in women with MwA that smoke. Additionally, declining estrogen levels in the postmenopausal state have been linked to an increased risk of vascular complications [21]. Notably, hormonal withdrawal has been identified as a possible trigger for chest pain and coronary events, including SCAD, especially in the postpartum period or after abrupt hormonal change [19, 22].
The relationship between migraine and MI remains controversial, with conflicting results reported in the literature. In an Australian cohort study involving 3654 individuals, both women and men diagnosed with migraine were found to have approximately twice the likelihood of a prior MI compared to individuals without a migraine diagnosis. These findings suggest a possible association between migraine and CAD, though the underlying mechanisms and causal direction remain unclear [23]. Similarly, in a large US study including 79,588 individuals with a physician-confirmed diagnosis of migraine, the risk of chest pain suggestive of MI was found to be nearly twice as high compared to individuals without a migraine diagnosis. These findings, consistent across different populations, support the hypothesis that migraine, particularly when diagnosed clinically, may be associated with an increased burden of CAD. However, further research is needed to clarify whether this association is causal or mediated by shared vascular or inflammatory mechanisms [24]. Not all studies have confirmed a clear association between migraine and MI. Some findings suggest that patients with migraine do not differ significantly from non-migraineurs in terms of objective MI risk. In a large prospective cohort study with a follow-up period of 6.1 years for 39,876 female healthcare workers and 12.9 years for 22,071 male physicians, no increased risk of MI or angina pectoris was observed in individuals who self-reported a history of migraine, in either gender [25].
In contrast, individuals with migraine appear to report symptoms consistent with angina pectoris more frequently, which may reflect increased pain sensitivity, heightened cardiovascular awareness, or functional coronary abnormalities rather than true obstructive CAD [24]. Patients with migraine are known to have a lower pain threshold, which may contribute to a heightened perception of chest discomfort. This suggests that symptoms resembling angina pectoris in patients with migraine could, in some cases, be related to altered pain processing rather than underlying CAD. The overlap between migraine-related sensory hypersensitivity and cardiovascular symptomatology highlights the need for careful clinical evaluation to distinguish true ischemic events from benign migraine-associated chest pain [19, 24]. Further supporting this complexity, two case–control studies have reported a high prevalence of migraine among individuals who experienced MI despite having angiographically normal coronary arteries. These findings suggest that mechanisms other than atherosclerotic obstruction, such as coronary vasospasm, microvascular dysfunction, or heightened autonomic reactivity, may underlie both migraine and certain forms of myocardial injury. These findings reinforce the importance of considering migraine as a potential marker of vascular vulnerability, even in the absence of traditional obstructive coronary pathology [26, 27].
Patients often present to emergency departments with headaches accompanied by elevated blood pressure. Whether high blood pressure represents a symptom of migraine or a highly associated independent disorder remains a matter of debate [26]. This issue becomes particularly relevant in patients with MwA, where vascular dysfunction due to endothelial impairment is frequently observed [26, 27]. In such cases, the presence of hypertension may reflect a shared pathophysiological mechanism, making the migraine–hypertension relationship a compelling area for cardiovascular research [28, 29]. A more comprehensive understanding of this association could improve clinical assessment and guide preventive strategies for patients with migraine with comorbid hypertension. However, the existing literature presents inconsistent findings [28]. For instance, the 10-year follow-up results of the National Health and Nutrition Examination Survey (NHANES I) showed that individuals with hypertension had a higher risk of experiencing migraine, suggesting a potential bidirectional link [28, 29].
Additionally, results from population-based studies conducted in Austria and Taiwan demonstrated that hypertension is more prevalent among individuals with migraine compared to healthy controls [30–32]. In support of this association, a prospective study with a 5-year follow-up reported that migraine was associated with an approximately 1.42-fold increased risk of developing hypertension. This further reinforces the notion that migraine may not only coexist with hypertension but possibly contributes to its onset, particularly in individuals with vascular vulnerability [33].
In a study involving 15,176 hypertensive patients with a mean follow-up period of 12.2 years, the risk of persistent or worsening hypertension was found to be 9% higher in women with MwA compared to controls. Interestingly, the risk was even higher (21%) in women with migraine without aura, and 15% higher in those with any history of migraine. The migraine and hypertension relationship, therefore, may not be limited to aura-specific mechanisms and migraine, regardless of subtype, could represent a marker of increased vascular reactivity or dysregulation in women [34]. Conversely, in a population-based study, patients with migraine were found to have higher diastolic blood pressure but lower systolic blood pressure compared to control subjects. Despite these differences in blood pressure parameters, no significant association was observed between migraine and the overall presence of hypertension [35].
Of significant interest, in two separate population-based studies involving 1174 and 1373 participants, respectively, high blood pressure was not associated with headache complaints. On the contrary, individuals with migraine were found to have lower blood pressure compared to controls [36–38]. A large cohort study of Polish patients with migraine showed that low blood pressure was found in 26.9% of the group of 1679 patients with migraine [36]. These findings challenge the assumption of a direct positive association between migraine and hypertension, and further emphasize the heterogeneity of results in the literature [37, 38]. Furthermore, the discrepancies observed across study results may be attributed to several methodological limitations, including heterogeneity in the diagnostic criteria used for both migraine and hypertension. Additionally, confounding variables such as age, medication use, and comorbidities may not have been adequately controlled for in some analyses. Another key limitation is the lack of consistent stratification by migraine subtype; many studies focus exclusively on patients with MwA, thereby limiting the generalizability of the findings to other migraine populations, such as those with migraine without aura or chronic migraine (CM) [39].
It has been suggested that hypertension could be involved in the chronification of migraine. However, this hypothesis remains to be fully validated [40]. Although findings in the literature remain inconsistent, it is crucial that patients with migraine, particularly those with evidence of endothelial dysfunction or comorbid hypertension, undergo careful cardiovascular risk assessment. Individualized management of blood pressure should be considered part of a comprehensive approach to care. Moreover, the use of certain antihypertensive agents as migraine prophylactic therapies, such as beta-blockers or calcium channel blockers, may offer dual reducing migraine frequency and severity while simultaneously lowering arterial stiffness and blood pressure. These therapeutic overlaps further support the hypothesis of a bidirectional relationship between migraine and hypertension, with shared vascular mechanisms potentially underlying both conditions [39, 41, 42].
Recent epidemiological studies have indicated that individuals with migraine may have an increased risk of atrial fibrillation [43]. As previously discussed, MwA is considered a risk factor for CVD and stroke. Given that atrial fibrillation significantly increases the risk of thromboembolic events, particularly ischemic stroke, the potential association between migraine and atrial fibrillation becomes especially relevant. Understanding this link may help identify those with migraine, especially those with aura, who could benefit from closer cardiovascular surveillance and early detection of arrhythmias that may otherwise go unnoticed [44]. Gollion et al. reported that, among young adults with ischemic stroke, the risk of atrial fibrillation was five times higher in those with MwA compared to those with migraine without aura [45]. The increased risk of atrial fibrillation in patients with migraine with aura has also been confirmed in long-term population-based studies, including a 20-year follow-up study in the USA [43], in a 19-year follow-up study in Denmark [46], and in a recent Korean study [47].
The Korean study demonstrated that migraine with severe aura increased the risk of atrial fibrillation in women by 48% compared to controls. However, no such association was observed in men. Additionally, migraine without severe aura was associated with a more modest yet notable long-term increase in atrial fibrillation, ranging from 16 to 21% in both women and men. These findings suggest that both migraine severity and sex may modulate the relationship between migraine and atrial arrhythmias, with potential implications for personalized risk assessment and monitoring strategies [47]. Interestingly, a recent study utilizing artificial intelligence (AI)-based prediction models found that patients with MwA had a higher predicted risk of atrial fibrillation compared to those without aura, particularly in women and in early disease stages. Moreover, MwA was identified as an independent risk factor for atrial fibrillation in individuals under the age of 55. These findings further support the growing body of evidence linking MwA to early-onset atrial arrhythmias and suggest that advanced computational approaches may help refine cardiovascular risk stratification in this population [48].
Emerging evidence has also suggested a possible bidirectional association between MwA and atrial fibrillation. It is hypothesized that atrial fibrillation itself may contribute to the onset of migraine attacks through mechanisms such as cerebral hypoperfusion or embolic phenomena. Clarifying this two-way interaction could have important implications for both prevention and treatment strategies in affected patients [49–51]. Another proposed explanation for the association between migraine and atrial fibrillation is the role of autonomic dysfunction. During a migraine attack, particularly with aura, autonomic imbalance may contribute to the initiation of atrial fibrillation. Conversely, embolic events occurring secondary to atrial fibrillation may trigger CSD, a key mechanism underlying the aura phase of migraine.
In addition to cerebral hypoperfusion and autonomic dysfunction, several alternative pathophysiological mechanisms have been explored, including endothelial impairment, CSD, chronic low-grade inflammation, and oxidative stress. Supporting the clinical relevance of these factors, a recent systematic review recommended that individuals with a long-standing history of migraine, especially with aura, should undergo screening for atrial fibrillation, particularly in the context of stroke prevention strategies [49]. Despite several studies suggesting a bidirectional link, the evidence remains inconsistent. A recent large-scale, 9-year follow-up study based on the Trøndelag Health Study (HUNT) found no increased risk of atrial fibrillation in individuals with migraine at baseline. In fact, migraine was associated with a lower risk of atrial fibrillation in participants over the age of 55 [44].
This opposing trend has been confirmed in other studies suggesting a lower prevalence of atrial fibrillation among individuals with migraine, regardless of aura status, compared to those without migraine. For instance, De Giuli et al. found a reduced frequency of cardiac sources of cerebral embolism, including atrial fibrillation, in patients with migraine. This suggests that other mechanisms, such as the presence of a PFO, may play a more prominent role in the pathogenesis of cerebral embolism among patients with migraine. Given the well-documented association between MwA and PFO, it is plausible that paradoxical embolism through intracardiac right-to-left shunt may contribute to stroke risk in this population, rather than classical arrhythmogenic sources such as atrial fibrillation [51]. Similarly, Lantz et al. reported a lower prevalence of migraine headache in an in-patient stroke population with documented atrial fibrillation, further supporting the observation that migraine, particularly in hospitalized stroke patients, may be less frequently associated with arrhythmogenic mechanisms compared to other sources of cerebral ischemia. This finding contributes to the ongoing debate regarding the strength and directionality of the association between migraine and atrial fibrillation, especially in the context of secondary stroke prevention [52].
As summarized in Table 1, a wide range of clinical and observational studies have explored the association between migraine and various cardiovascular outcomes. While some studies consistently report an increased risk of ischemic stroke, MI, hypertension, and atrial fibrillation, others yield conflicting or null results. This heterogeneity may reflect differences in study design, population characteristics, diagnostic criteria, and migraine subtypes, highlighting the need for more standardized and longitudinal research.Table 1Summary of key clinical and observational studies evaluating the association between migraine and cardiovascular riskStudyDesignPopulationKey findingsOutcomeSubgroupsFollow-upSignificanceSchürks et al. 2009 (BMJ) [6]Meta-analysisMultiple studies; migraine vs. non-migraineMigraine with aura doubles ischemic stroke riskIschemic strokeMigraine with auraMultiple studies (varied)Statistically significant (p < 0.05)Sacco et al. 2013 (Stroke) [8]Meta-analysis1600 patients with hemorrhagic stroke↑ Hemorrhagic stroke in young women with migraineHemorrhagic strokeWomen < 45 with auraCross-sectional analysisSignificant (p = 0.003)Hu et al. 2017 (Neurol Sci) [9]Meta-analysis3371 patients with stroke No association with hemorrhagic strokeHemorrhagic strokeGeneral migraine populationMeta-analysis (no direct follow-up)Not significantTa-Thi et al. 2021 (Sustainability [10])Bayesian meta-analysisVarious cohort studies↑ Risk in fixed model only; random model not sigHemorrhagic strokeWomen < 45Meta-analysis (varied)Only fixed model significantBigal et al. 2010 (Neurology [17])Case–control study6102 patients with migraine and 5243 controlsIncreased CVD risk both with migraine with and without auraMI, stroke, and claudicationMigraine without and with aura5 yearsStatistically significantMitchell et al. 1998 (Aust NZ J Med) [23]Cohort study3654 AustraliansMigraineurs ~ 2 × MI history vs. controlsMIMen and womenNot reportedStatistically significantSternfeld et al. 1995 (Neurology) [24]Cohort study79,588 Americans↑ Chest pain in migraineursMIPhysician-diagnosed migraineNot specifiedStatistically significantCook et al. 2002 (Headache) [25]Prospective cohort study61,947 healthcare workersNo ↑ MI/angina risk in either sexMI and angina pectorisMen and women6.1 years (women), 12.9 years (men)Not significantRist et al. 2018 (Cephalalgia) [34]Prospective cohort study15,176 hypertensive womenMigraine with/without aura ↑ hypertension riskHypertensionAura and no aura12.2 yearsSignificant in all female groupsGiri et al. 2024 (Cephalalgia) [44]Prospective cohort studyTrøndelag populationNo AF risk in > 55-year-olds; ↓ AF risk overallAF> 55 years9 yearsNot significant overall; inverse trendGollion et al. 2021 (Cephalalgia) [45]Case–control studyYoung adults with ischemic stroke5 × ↑ AF risk in migraine with aura vs. without auraAF in patients with strokeMigraine with aura vs. without auraCross-sectional at stroke presentationStatistically significant (p < 0.05)Rhee et al. 2022 (Korean NHIS study) [47]Nationwide cohort studyKorean adults with migraineSevere aura ↑ AF risk in women by 48%; mild aura ↑ AF risk in men and women by 16–21%Incident AFAura severity, sex-stratifiedLongitudinal (mean not reported)Statistically significant (p < 0.01 in women with severe aura)De Giuli et al. 2021 (Eur J Neurol) [51]Observational studyMigraineurs with cerebral embolism↓ AF and embolic sources in migraineursCardiac embolic sources incl. AFAura and no auraCross-sectionalStatistically significantLantz et al. 2015 (Acta Neurol Scand) [52]Observational studyIn-patient stroke population↓ Migraine prevalence in patients with AF-strokeMigraine prevalence in AF strokePatients with AF-strokeCross-sectionalStatistically significantThis table outlines the methodological features, population subgroups, and cardiovascular outcomes assessed, including MI, ischemic stroke, hemorrhagic stroke, hypertension, and AF, as well as the follow-up duration and statistical significance. The heterogeneity among studies reflects differences in study design, population characteristics, migraine subtype definitions (with or without aura), and outcome assessment methodsAF atrial fibrillation,* MI* myocardial infarction
Identifying migraine in patients with high risk cardiovascular disease is crucial given the well-established association between migraine, particularly MwA, and CVD. The complex relationship between migraine and cardiovascular risk profiles requires a comprehensive approach that incorporates clinical assessment, cardiovascular risk prediction tools, and vascular imaging [53, 54]. The European Systematic Coronary Risk Evaluation 2 (SCORE2) and the Framingham Risk Score (FRS) are widely recognized cardiovascular risk assessment tools designed to estimate an individual’s risk of developing cardiovascular events. SCORE2 is specifically tailored to the European population, incorporating factors such as age, sex, cholesterol levels, smoking status, systolic blood pressure, and diabetes status to stratify individuals into various risk categories. The SCORE2 estimates the 10-year risk of first-onset fatal and nonfatal CVD [55]. Similarly, the FRS considers age, gender, cholesterol measurements, systolic blood pressure, treatment for hypertension, smoking status, and presence of diabetes to provide a quantifiable risk of developing coronary heart disease or other cardiovascular events over a decade [56].
Several studies employing the SCORE2 and FRS have demonstrated a complex association between migraine and cardiovascular health, with significant variation depending on migraine status (active or in remission) and the presence of aura. An early large-scale population-based study showed higher FRS in individuals with migraine, especially those with aura, compared to non-migraine controls [57]. The Nord-Trøndelag Health Study (HUNT) further corroborated these findings, noting elevated FRS in those with migraine compared to non-headache controls. Elevated cardiovascular risk was significantly influenced by lifestyle factors such as smoking, increased body mass index (BMI), and decreased physical activity in patients experiencing migraine without aura and those with alternate headache disorders. However, in individuals experiencing MwA, elevated cardiovascular risk persisted independently of these lifestyle factors, suggesting distinct and possibly intrinsic pathophysiological mechanisms underlying their increased cardiovascular vulnerability [58].
More recent studies have shown that women with elevated FRS were more likely to report a past history of migraine, but were less likely to experience active or new-onset migraine symptoms, particularly among older individuals [59, 60]. Similarly, a recent study employing SCORE2 demonstrated that individuals, particularly women with higher cardiovascular risk scores, frequently reported a history of migraine but exhibited a decreased likelihood of having active or incident migraine episodes [55, 61]. This inverse association underscores a paradoxical nature of the relationship between migraine and cardiovascular health, indicating that higher cardiovascular risk profiles could be inversely associated with ongoing migraine activity. Collectively, these findings emphasize the complex and bidirectional interplay between cardiovascular risk factors and migraine status.
Insulin resistance and metabolic syndrome are among the clinical factors that deserve particular attention and further investigation in patients with CVD, given their role in elevating vascular risk and their established association with migraine. Metabolic syndrome comprises a cluster of conditions including abdominal obesity, dyslipidemia, hyperglycemia, and insulin resistance, collectively increasing the risk of CVD and diabetes mellitus [62]. Several observational studies reported a high prevalence of metabolic syndrome in patients with migraine, particularly among those with aura, who additionally demonstrate higher rates of obesity and dyslipidemia compared to migraine-free individuals [63].
Insulin resistance has also been associated with migraine, as demonstrated by higher insulin levels and elevated homeostasis model assessment-insulin resistance scores in individuals with migraine compared to healthy controls. Notably, individuals with both migraine and insulin resistance experienced more severe attacks, characterized by greater pain intensity, longer duration, and increased disability, compared to those without insulin resistance. These findings suggest a contributory role of metabolic dysfunction in determining migraine severity [64]. Mechanistically, impaired glucose metabolism and insulin dysregulation may provoke migraine episodes by altering neuronal and cerebrovascular function. Clinical and experimental studies propose glucose hypometabolism and mitochondrial dysfunction as factors contributing to migraine pathogenesis through enhanced cortical hyperexcitability and susceptibility to CSD [65]. Moreover, adipose tissue dysfunction may further contribute to migraine through inflammatory signaling molecules including adiponectin and CGRP, recognized mediators of nociception and vascular modulation [65, 66]. In contrast, alternate studies have failed to demonstrate a significant association between migraine, insulin resistance, and metabolic syndrome [67, 68]. Nevertheless, many studies assessing the relationship between migraine and metabolic syndrome lack robust statistical estimates, limiting definitive conclusions [63].
Ultrasonographic imaging has become instrumental in evaluating the relationship between migraine and vascular health by assessing markers such as carotid intima-media thickness (CIMT) and arterial stiffness. CIMT, a non-invasive measure of subclinical atherosclerosis, has shown variable associations with migraine. Several studies have reported increased CIMT in individuals with migraine compared to controls, regardless of aura status, suggesting an elevated subclinical atherosclerotic burden [69]. However, other studies have presented more nuanced findings. Some suggest that MwA is specifically associated with diffuse carotid thickening, whereas migraine without aura may be linked to a lower risk of carotid plaques and arterial stiffening, potentially reflecting distinct pathophysiological mechanisms between migraine subtypes [70]. In contrast, additional studies have found no significant differences in atherosclerotic markers, including CIMT and arterial stiffness, between individuals with and without migraine, suggesting that migraine may not universally contribute to atherosclerotic processes [71, 72].
Another widely debated issue is whether cardiovascular risk factors contribute to the presence of white matter hyperintensities (WMHs), which are frequently observed in patients with migraine undergoing magnetic resonance imaging of the brain. WMHs are small, non-specific areas of increased signal intensity on T2-weighted and FLAIR sequences, typically located in the deep, subcortical, or periventricular white matter. While some studies have reported a higher prevalence of WMHs in individuals with migraine, particularly those with aura [73, 74], other investigations have not established significant differences compared to control populations [75, 76]. The specificity of these findings to migraine, as well as the factors influencing their occurrence, remains uncertain. Conflicting results have been reported regarding the influence of clinical and demographic variables such as headache laterality, aura characteristics, attack frequency, age, disease duration, and sex. Moreover, WMHs are frequently observed in older individuals, those with cardiovascular comorbidities, and patients affected by other primary headache disorders, such as tension-type headache [77, 78]. The pathophysiological mechanisms underlying WMHs in migraine remain incompletely understood. Proposed hypotheses include repeated episodes of CSD resulting in transient cerebral hypoperfusion, blood–brain barrier disruption, endothelial dysfunction, and neurogenic inflammation [79, 80]. Additional theories suggest that vascular abnormalities, whether related to systemic atherosclerotic risk factors or structural cardiac anomalies, may contribute to WMH development [81]. In particular, PFO and atrial septal defects have been associated with a higher prevalence of WMHs in individuals with migraine, especially those with aura. However, conflicting data regarding this association have also been reported [82, 83].
The observed discrepancies among studies evaluating the association between migraine and cardiovascular risk factors may be influenced by differences in the populations examined, variability in methodologies, or differing criteria used to define migraine activity. Larger, standardized, longitudinal studies are essential to clarify these complex relationships, accurately identify patient subgroups at higher cardiovascular risk, and develop targeted preventive strategies. Integrating systematic cardiovascular evaluations, including clinical risk assessments using validated tools such as SCORE2 and FRS, alongside imaging markers for subclinical vascular disease, should become standard practice when managing patients with migraine, especially those with aura [55, 60].
A recent population-based study added valuable insight into the relationship between modifiable and non-modifiable risk factors of migraine by utilizing data from the well-established Rotterdam Study cohort. The authors’ findings highlight that the association between migraine and CVD does not appear to follow a traditional risk factor model. This observation supports the hypothesis that migraine may reflect a distinct vascular phenotype that is not adequately captured by standard cardiovascular risk assessment tools [84]. Among modifiable risk factors, the consumption of tobacco, whether through smoking or alternative methods, is a well-established risk factor for the development of multiple chronic diseases, but the exact relationship between nicotine dependence and primary headaches remains unknown [85–87]. Currently, population-based data from headache diaries are extremely limited and no controlled trials exist to confirm a cause-and-effect relationship between tobacco use and headache of any type [88]. Of the available data, a longitudinal study of 980 individuals found that smoking in childhood or adolescence was not a risk factor for the development of migraine in adolescence or adulthood [89].
While the effects of smoking on migraine attack frequency and migraine pain intensity remain poorly defined, many patients with migraine believe that smoking triggers or exacerbates their condition. In an English study involving 100 patients with migraine, 20% reported habitual smoking. Of those that smoked, half believed that smoking increased the intensity of migraine pain. However, fewer reported smoking as a trigger of migraine attacks [90]. Furthermore, among 58 Spanish medical students with migraine, those that smoked reported a higher rate of suffering ≥ 1 monthly migraine attacks when compared to those that did not smoke (77% versus 56%) [91]. In recent studies, it has been shown that heavy secondhand smoke (SHS) exposure is associated with severe headache or migraine in adults who have never smoked, with the effect of exposure varying depending on BMI and level of physical activity. A study including 4560 participants (median age, 43 years; 60% female; 71.5% white) from the National Health and Nutrition Examination Survey demonstrated that heavy SHS exposure (serum cotinine between 1 to 10 ng/mL) had a significant positive association with severe headaches or migraine in never-smoking adults. Additionally, in participants who were sedentary and those with a BMI < 25, significant associations between SHS and severe headache or migraine were observed [92].
Migraine and smoking are independently associated with an increased risk of stroke, and the risk of stroke appears to be greater in those with migraine who smoke compared to non-smokers [93]. A meta-analysis investigating the relationship between stroke and migraine showed that smoking was associated with a nine-fold increased risk of stroke among people with migraine (RR 9.03, 95% CI 4.2–19.34) [6].
Dyslipidemia is the most common risk factor for CVD. In studies on lipid levels in those with migraine, a correlation between plasma lipid levels and both the risk and severity of migraine has been demonstrated [94]. The available evidence suggests that individuals with migraine and normal body weight may present with subtle lipid profile alterations, particularly involving elevated total cholesterol (TC) levels. This trend appears to be independent of migraine subtype, whether with or without aura, although other lipid parameters generally remain within normal ranges [95, 96]. In those with migraine, it has been observed that triglyceride levels generally remain within normal ranges, while levels of high-density lipoprotein (HDL) cholesterol tend to be reduced, unlike the typical pattern of dyslipidemia seen in obesity. Additionally, elevated levels of oxidized low-density lipoprotein (LDL) have been associated with an increased risk of migraine and are considered a potential risk factor, independent of BMI [95, 97].
The Genetic Epidemiology of Migraine Study, which was conducted on a group of 5755 people aged 20–65, including 620 patients with migraine, indicated the presence of an unfavorable lipid profile in patients with MwA, including an increased concentration of TC ≥ 240 mg/dl, and a TC/HDL ratio of more than 5.0 [57]. In addition to gender, age, systolic blood pressure, and smoking, TC is a factor used to assess the risk of cardiovascular death within 10 years. Therefore, an abnormal TC value in those with migraine leads to an increased 10-year risk of cardiovascular death [98].
In addition to the increased cardiovascular risk in those with migraine, abnormal lipid profiles have been directly linked to an increased frequency of headache episodes. Furthermore, cholesterol-lowering drugs (statins) may be effective in the prevention of migraine [98, 99]. While the mechanism in which statins function in the preventative treatment of migraine is poorly understood, it is likely related to a pleiotropic effect, including their protective function on the vascular endothelium, stabilization of atherosclerotic plaque, and anti-inflammatory effect. Consequently, a holistic approach to treatment, including appropriate lipid-lowering therapy, is of great value when approaching patients with migraine.
The link between migraine and diabetes mellitus (DM) is also unclear. A recent meta-analysis showed that DM was negatively associated with the occurrence of migraine, whereas migraine was positively associated with the occurrence of DM. However, as most of the results indicated a low or very low level of evidence, they should be interpreted with caution [100]. Furthermore, a clear relationship between DM and migraine is likely complicated and potentially obfuscated by various pathophysiological factors and frequent use of multiple medications in those with DM.
Regardless of age and sex, alcohol use is a major risk factor for CVD. The belief that mild to moderate alcohol intake can lower blood pressure is not supported by scientific research [101]. Alcohol is considered a trigger of migraine attacks and an inverse relationship between alcohol consumption and migraine may be related to reverse causality [89]. A recent meta-analysis that included 126,173 participants with migraine reported that the risk of migraine in those that drink alcohol is approximately 1.5 times lower than in the group of non-drinkers (RR 0.71, 95% CI 0.57–0.89). The explanation of this phenomenon may indicate that migraine leads to alcohol avoidance, rather than alcohol having any protective role against migraine [102].
Diet is thought to play a contributory role in modulating the risk of various chronic diseases, including migraine, although the underlying mechanisms pertaining to this relationship remain complex and incompletely understood [103]. Numerous studies have investigated the impact of specific nutrients and dietary patterns on the frequency and intensity of migraine attacks, although findings remain heterogeneous and oftentimes inconclusive [104, 105]. However, few studies have comprehensively evaluated the overall impact of dietary patterns on migraine risk and treatment response. Recent studies have consistently shown a significant relationship between poor diet and migraine prevalence [103].
The Healthy Eating Index-2015 defines high-quality diets as those that are associated with higher intake of nutrient-dense foods, including fruits, vegetables, whole grains, dairy products, sources of total protein and healthy fatty acids [106]. It also emphasizes the reduction of sodium intake, refined grains, added sugars, and saturated fats. In addition to providing essential nutrients, a healthy diet is associated with a reduction in the severity of migraine attacks [107]. Additionally, a diet rich in fiber may help reduce inflammation by modulating the rate of glucose absorption, altering the intestinal microflora, and reducing the production of inflammatory cytokines [108].
Sleep is essential for maintaining the body’s homeostasis and optimal physical and mental health. Both sleep quality and quantity can be affected by multiple factors such as noise, artificial light, temperature, or the use of electronic devices (smartphones, laptops) prior to sleep [109]. A lack of circadian rhythm stability (intercontinental travel, shift work), sleep deprivation, and poor sleep quality lead to an increased risk of CVD, obesity, and hypertension [110].
A growing body of evidence suggests a close relationship between sleep disturbances and migraine [111]. However, defining the exact relationship between these factors remains complex, as changes in sleep can be a triggering factor, a cure, or a symptom of migraine [111, 112]. Despite this link, there remain few objective studies investigating sleep architecture with polysomnography (PSG) in those with migraine [113]. The relationship between obstructive sleep apnea (OSA), a major risk factor for developing hypertension, and headache, is also unclear. A recent meta-analysis of 15,402 patients showed that the prevalence of headache in OSA was 33%, with 16% reporting migraine. The results of this study suggest that OSA did not increase the risk of headache [114].
Physical activity is a proven strategy for the prevention of CVD and boasts effectiveness in the treatment of many disorders of chronic pain [115]. In patients with migraine, exercise has been shown to maintain a stable body weight and improve self-esteem, which is associated with an alleviation of disease symptoms. On the other hand, for some patients, exercise is a trigger of their migraine attacks, oftentimes leading to avoidance of physical activity throughout the interictal period [116, 117].
Large population studies have shown that a low level of physical activity is associated with a higher incidence of migraine and other headaches. Conversely, a higher level of physical activity is associated with a reduction in the frequency and disability associated with migraine [118, 119]. Scientific studies in this field show encouraging results, demonstrating that accessibility to aerobic training has positive therapeutic results in patients with migraine [115]. Above all, without significant expense to the patient, physical exercise can reduce migraine severity, reduce body weight, improve symptomatology of comorbid mental illnesses, and improve outcomes in conditions that often coexist with migraine [120].
The influence of social determinants of health, particularly socioeconomic status (SES), on the risk of chronic diseases is increasingly recognized and supported by a growing body of evidence. Low SES has been linked to increased cardiovascular risk that is equivalent to traditional risk factors [121]. This is likely due to the combination of biological, psychosocial, and behavioral risk factors, which are more prevalent in disadvantaged individuals [122].
Non-communicable diseases are the leading cause of death, and people living in low-income and lower-middle-income countries (LLMICs) are 1–5 times more likely to die prematurely from a non-communicable disease than those living in high-income countries [123]. Lifestyle patterns vary considerably across SES and cultural contexts. While some high-SES groups may adopt behaviors such as increased consumption of processed foods or reduced physical activity, evidence on these associations remains mixed and context dependent [124]. Together, these factors play a significant role in the course of chronic diseases, including migraine. Furthermore, a global problem in LLMICs is the lack of, or limited access to, adequate healthcare and medical specialists. This translates into a lack of screening programs and access to optimal treatments that prevent severe complications [125].
Figure 1 illustrates the associations between migraine and both neurovascular and cardiovascular conditions, highlighting potential risk modifiers such as age, sex, aura status, hormonal influences, and comorbidities.Fig. 1Reported associations between migraine and neuro- or cardiovascular diseases with their potential risk modifiers. Solid lines indicate associations supported by consistent evidence, such as the link between migraine with aura and ischemic stroke, while dashed lines represent relationships that remain controversial or insufficiently substantiated in the literature, including those with atrial fibrillation and hemorrhagic stroke. This visual framework underscores the complexity of migraine as a systemic disorder with multifaceted vascular implications. Figure 1 is original and was created with BioRender.com. Agreement number for ML286AME6W
The association between migraine and CVD suggests the possibility of shared pathogenic mechanisms, with genetics emerging as a critical area of research. Advances in genome-wide association studies (GWAS) and Mendelian randomization (MR) techniques have provided insights into the genetic overlap between these conditions, revealing both shared risk loci and divergent effects. A landmark study by Winsvold et al. investigating the genetic overlap between migraine and CAD using data from two large-scale GWAS of CAD (C4D: 15,420 cases, 15,062 controls; CARDIoGRAM: 22,233 cases, 64,762 controls) and one GWAS of migraine (22,120 cases, 91,284 controls) found a significant enrichment of genetic variants associated with CAD as a function of their association with migraine. Furthermore, these findings were replicated across two independent GWAS of CAD [126].
Notably, one shared risk locus in the* PHACTR1* (phosphatase and actin regulator 1) gene was identified with high statistical significance. PHACTR1 is expressed in both vascular and brain tissue, where it regulates endothelial function and synaptic activity, suggesting a plausible biological link between migraine and CAD. In addition, other loci, such as* KCNK5* (potassium channel K subfamily member 5) and* AS3MT* (arsenite methyltransferase), demonstrated signs suggestive of shared risk. KCNK5 regulates potassium channels implicated in vascular tone and neuronal excitability, further aligning with the vascular hypothesis of migraine pathogenesis [126].
Using a genomic approach focusing on common variants, Malik et al. also found a shared genetic basis for migraine and ischemic stroke, particularly through common variants that influence vascular function. Specifically, two loci with significant pleiotropy were rs9349379 in* PHACTR1*, associated with migraine and large artery ischemic stroke, and rs1058587in* GPD1L* (glycerol-3-phosphate dehydrogenase 1 like), associated with migraine and cardioembolic stroke. Additional loci with suggestive overlap were rs12134493 in* TSPAN2* (tetraspanin-2) and rs11172113 in* LRP1* (low-density lipoprotein receptor-related protein 1), both of which are implicated in vascular function. These findings support a vascular mechanism in migraine-related stroke risk and demonstrate the utility of GWAS analyses for uncovering shared genetics [127].
Vascular and endothelial dysfunction are increasingly recognized as pivotal mechanisms linking migraine and CVD. These processes involve impaired regulation of vascular tone, endothelial injury, and prothrombotic states, which may be exacerbated by shared genetic and environmental factors. The vascular hypothesis of migraine postulates that endothelial dysfunction contributes to abnormal cerebral blood flow (CBF), particularly during CSD, a wave of neuronal depolarization associated with aura and pain [128]. For example, González-Quintanilla et al. found a reduction in flow-mediated dilation (FMD) in patients with CM compared to both patients with episodic migraine and healthy controls [129]. This aligns with earlier work by Vanmolkot et al. who reported decreased FMD in patients with new-onset migraine compared to controls [130]. Furthermore, endothelial dysfunction is a hallmark of atherosclerosis, a primary driver of CVD. In this sense, Shimbo et al. showed that lower levels of FMD predicted the incidence of cardiovascular events at 36 months. Genetic variants, such as those in* PHACTR1*, regulate endothelial function and may underlie these shared phenotypes [131].
Inflammation is a key factor in both migraine and CVD, acting as a common thread linking these clinical entities. In migraine, neurogenic inflammation is involved, especially through activation of the trigeminovascular system, which releases pro-inflammatory peptides such as CGRP and substance P. These neuropeptides lead to vasodilation, plasma extravasation, and degranulation of mast cells in the meninges. This inflammatory cascade sensitizes pain pathways and contributes to migraine attacks [132]. Likewise, in CVD (particularly atherosclerosis), chronic inflammation drives endothelial dysfunction and plaque formation [133]. These two conditions feature elevated levels of systemic inflammatory markers, like C-reactive protein (CRP), suggesting a shared inflammatory burden [134]. On the other hand, oxidative stress arises from an imbalance between the production of reactive oxygen species (ROS) and antioxidant defenses. In migraine, excessive production of ROS in the brain is thought to lower the threshold for CSD [135] and damage endothelial cells, impairing CBF regulation and exacerbating migraine susceptibility. In CVD, oxidative stress accelerates atherosclerosis by oxidative modification of LDL, forming foam cells that promote plaque instability [136]. ROS also reduce the bioavailability of nitric oxide (NO), which plays a critical role in protecting the vascular endothelium from damage. Endothelial dysfunction is therefore a common feature driven by inflammation and oxidative stress in both migraine and CVD [136].
At present, there is no specific management strategy for individuals with migraine and cardiovascular comorbidities. Primary and secondary cardiovascular prevention in individuals with migraine follows the same principles and guidelines that apply to the general population. However, the interaction between some cardiovascular drugs and migraine itself or its treatment should be considered, including the well-known interaction between anti-seizure medications such as topiramate or valproate and anticoagulant drugs prescribed to individuals with atrial fibrillation [137].
Moreover, cardiovascular risk directly associated with medications for the acute and preventive treatment of migraine should be considered. Among acute treatments, triptans can increase the risk for ischemic stroke and ischemic heart disease [138] and are therefore contraindicated in patients with a history of those ischemic events; non-steroidal anti-inflammatory drugs also carry a slightly increased risk for CVD, while acetaminophen (paracetamol) and lasmiditan are not associated vascular risk [54]; gepants were tested for cardiovascular safety without showing relevant concerns [139]. Among preventive treatments, anti-seizure medications and onabotulinumtoxinA are those with the highest cardiovascular safety [54]. Some other medications used for migraine prevention, such as beta-blockers or calcium channel blockers, can interact with treatments for secondary cardiovascular prevention, including antihypertensives, antiarrhythmics, and drugs for heart failure [140].
Given the established association between migraine, particularly MwA, and an increased risk of ischemic stroke and other vascular events, the potential role of antithrombotic therapy in migraine management remains an area of ongoing investigation. To date, the therapeutic benefit of antithrombotic drugs in migraine prevention remains controversial, and available evidence is inconclusive.
A recent systematic review identified 12 randomized controlled trials (RCTs) and eight observational studies evaluating antithrombotic drugs in migraine prevention, including aspirin, clopidogrel, dipyridamole, warfarin, and direct oral anticoagulants [141]. However, high heterogeneity in study populations, outcome measures, and trial designs has prevented definitive conclusions regarding their efficacy.
Among these agents, low-dose aspirin has been the most extensively studied for its potential role in reducing stroke risk in patients with migraine with additional vascular risk factors. While some evidence suggests positive trends in reducing migraine frequency [142, 143], there is insufficient evidence to support its routine use for migraine prevention in individuals without additional cardiovascular risk factors, especially considering the increased risk of gastrointestinal bleeding.
Other antiplatelet agents, such as clopidogrel and dipyridamole, have also been explored for migraine prevention, though the available data remain inconclusive [141]. An RCT evaluating clopidogrel at a daily dose of 75 mg in patients with migraine found no significant reduction in headache days or disability compared to placebo [144]. In contrast, a small study investigating dual antiplatelet therapy with aspirin and dipyridamole vs. placebo showed an improvement in reducing migraine frequency and severity [145].
The role of anticoagulation in migraine prevention remains uncertain. Some observational studies have reported a higher prevalence of migraine in individuals with inherited thrombophilic disorders, such as factor V Leiden and prothrombin gene mutations, raising the question of whether targeted anticoagulation could benefit select subgroups [146]. However, RCTs evaluating direct oral anticoagulants for migraine prevention are lacking. Some retrospective reports suggest that vitamin K antagonists, such as warfarin, may reduce migraine burden in patients with known prothrombotic conditions. However, these findings remain anecdotal and must be weighed against the significant bleeding risks associated with long-term anticoagulation [141].
The relationship between migraine and cardiovascular health is particularly relevant in patients with a PFO, a congenital cardiac defect that may allow paradoxical embolism [147]. This has led to investigations questioning whether PFO closure could reduce migraine frequency. Clinical trials evaluating PFO closure in migraine have failed to meet their primary endpoints. However, some studies have suggested a tendency toward improvement in aura symptoms following PFO closure [148–150]. Current guidelines do not recommend routine PFO closure solely for migraine prevention, though further research is warranted to identify patients who may benefit from this intervention. Subgroup analyses suggest that those with frequent aura and large PFOs may be more likely to experience symptom improvement, but these findings require confirmation in larger studies. Given the complex interplay between migraine and vascular health, further large-scale studies are needed to determine whether specific migraine subgroups may benefit from antithrombotic strategies.
Collaboration between headache clinicians and general practitioners, cardiologists, or other healthcare professionals dedicated to the control of cardiovascular risk is advisable to optimize management strategies in each individual. Pharmacological strategies for migraine prevention should be carefully tailored in patients with cardiovascular comorbidities. Table 2 provides a structured overview of recommended drug classes, including their dosing, cardiovascular safety considerations, and documented efficacy in migraine prevention, to guide individualized and safe therapeutic decisions.Table 2Clinical advice for migraine prevention in individuals with comorbid cardiovascular disease [39–42, 137–151]Drug classExamplesDose rangeCV considerationsEfficacy in migraine preventionBeta-blockersPropranolol, metoprololPropranolol 40–160 mg/dayFirst-line in patients with hypertension or history of MIHigh efficacy; evidence supports reduction in attack frequency and intensityACE inhibitorsLisinoprilLisinopril 10–20 mg/dayUseful in hypertensive migraineurs; monitor for cough or angioedemaModerate efficacy; shown to reduce migraine days in some trialsARBsCandesartanCandesartan 16–32 mg/dayWell tolerated; useful if ACE inhibitors not toleratedModerate efficacy; effective for patients intolerant to beta-blockersCalcium channel blockersFlunarizine, verapamilFlunarizine 5–10 mg/day; verapamil 120–240 mg/dayFlunarizine avoided in depression; verapamil for comorbid arrhythmiasModerate efficacy; flunarizine effective in episodic migraineTricyclic antidepressantsAmitriptyline, nortriptylineAmitriptyline 10–75 mg/dayCaution in patients with CV risk due to anticholinergic effectsHigh efficacy, especially with comorbid depression or insomniaAnticonvulsantsTopiramate, valproateTopiramate 50–100 mg/day; valproate 500–1000 mg/dayMonitor weight and metabolic profile (especially with valproate)Caution in patients with hypotension or bradycardia. (Topiramate may reduce blood pressure)Consider interactions in patients on polytherapyPotential interaction with anticoagulants (e.g., valproate may increase bleeding risk); monitor INR and platelet countHigh efficacy; topiramate is one of the most effective oral preventivesCGRP monoclonal antibodiesErenumab, fremanezumab, galcanezumabStandard monoclonal dose per product (monthly or quarterly)Generally safe in CV disease; long-term data still neededHigh efficacy in episodic and chronic migraine; rapid onsetBotulinum toxin type AOnabotulinumtoxinA155–195 U every 12 weeksSafe; especially useful in chronic migraine with high disabilityEffective in chronic migraine; reduces headache and migraine daysThis table summarizes the main pharmacological options for migraine prophylaxis in patients with cardiovascular comorbidities. It includes examples, dosage ranges, cardiovascular precautions, and efficacy in migraine prevention. Special attention is given to agents such as beta-blockers, ACE inhibitors, ARBs, calcium channel blockers, tricyclic antidepressants, anticonvulsants, CGRP monoclonal antibodies, and botulinum toxin type A. Notably, anticonvulsants require careful monitoring due to potential interactions with anticoagulants and effects on metabolic and hemodynamic parametersACE angiotensin-converting enzyme,* ARB* angiotensin receptor blocker, CGRP calcitonin gene-related peptide, MI myocardial infarction
Non-pharmacological measures of cardiovascular prevention include diet, exercise, and lifestyle modifications such as smoking cessation [151]. Most of these lifestyle modifications can also improve migraine, as it is shown that exercise, both aerobic and strength training, can be considered as a non-pharmacological migraine preventive treatment [152], while low carbohydrate diets can help in controlling migraine [153]. Weight loss, whether obtained through a surgical or non-surgical approach, has been shown to significantly reduce the frequency and intensity of migraine attacks. Di Vincenzo et al. emphasize that both methods are effective, with surgical interventions yielding greater and more sustained improvements. These results support weight reduction as a valuable adjunctive strategy in the management of migraine, particularly in patients with obesity [154].
In addition to pharmacological approaches, lifestyle interventions represent a key component in the management of migraine, particularly in individuals with cardiovascular comorbidities. These measures are broadly recommended to people with migraine, not only to improve headache control but also as part of primary cardiovascular prevention, given the overall increased risk of cardiovascular events observed in this population compared to those without migraine [155]. Table 3 outlines key non-pharmacological strategies, including exercise, sleep hygiene, dietary habits, and stress management, with evidence supporting their beneficial effects on migraine control and cardiovascular health.Table 3Lifestyle interventions for migraine and cardiovascular health [151–155]InterventionDescriptionEvidence in migraineRegular aerobic exerciseEngage in moderate-intensity aerobic activity (e.g., walking, cycling) 3–5 times/weekReduces frequency and intensity; improves mood and sleepSleep hygieneMaintain regular sleep–wake cycles, avoid screen time before bedAssociated with fewer migraine attacks and better recoveryDietary modificationsLimit processed foods, high-sodium intake; consider anti-inflammatory diet (e.g., Mediterranean)Certain diets linked to reduced migraine days (e.g., low tyramine, Mediterranean)Stress management techniquesPractice mindfulness, yoga, CBT, and breathing techniquesEffective in reducing migraine burden and improving quality of lifeWeight managementAim for BMI < 25; weight loss may reduce migraine frequency and CV riskObesity is a known migraine risk factor; weight loss shown to reduce attacksCaffeine regulationAvoid caffeine overuse (> 400 mg/day); abrupt withdrawal may trigger headachesCaffeine fluctuations can trigger migraine; regulation reduces variabilitySmoking cessationEliminate tobacco to reduce both migraine and cardiovascular riskLinked to lower attack frequency and improved vascular functionAlcohol moderationLimit to ≤ 1 drink/day for women and ≤ 2 for men; avoid binge drinkingAlcohol is a common trigger; moderation prevents attack onsetHydrationEnsure adequate hydration; dehydration is a common migraine triggerHydration reduces aura and dehydration-related attacksRoutine and consistency in daily habitsEstablish stable routines for meals, sleep, physical activityConsistency helps in trigger identification and migraine stabilizationThis table summarizes non-pharmacological strategies recommended for individuals with migraine, particularly those with comorbid cardiovascular disease. Each intervention is described in terms of implementation and supported by clinical or observational evidence on its impact in reducing migraine frequency, severity, or triggers
Migraine, particularly MwA, is an independent risk factor for ischemic stroke, especially in younger women [156]. The first evidence of this association dates back to the 1975 Collaborative Group for the Study of Stroke in Young Women, which reported a doubling of stroke risk in young women with migraine compared to controls [157]. Subsequent studies have confirmed this link, showing that the increased risk is primarily seen in women under 45 years of age and is not consistently observed in men.
The Women’s Health Study further revealed a paradoxical among women older than 45 years, the highest stroke risk was observed in those with the lowest FRS scores, suggesting that migraine may be a distinct, nontraditional stroke risk factor in women [158].
Given this well-established association, cardiovascular risk assessment is essential in women with migraine, particularly before considering hormonal treatments. Estrogen plays a crucial role in modulating vascular risk [159]. Combined estrogen–progestin contraceptives (CHCs) significantly increase the risk of ischemic stroke and are generally contraindicated in women with MwA. Studies have reported that women with MwA using CHCs have a six-fold increased stroke risk compared to women without migraine [160, 161]. Although modern oral contraceptives contain significantly lower doses of estrogen than those used decades ago, they still pose a significant stroke risk in women with MwA [162]. Alternative options such as progestin-only contraceptives, intrauterine devices (IUDs), or non-hormonal methods are preferable. If estrogen-containing therapies must be used, the lowest effective dose should be selected, preferably via transdermal route, which may have a lower thrombotic risk than oral formulations.
Elevated cardiovascular risk in women with migraine may be linked to vascular dysfunction. Studies have shown that women with migraine, particularly those with aura, demonstrate increased arterial stiffness, a marker of impaired vascular health [163]. In the Atherosclerosis Risk in Communities (ARIC) study, Carson et al. assessed the lifetime prevalence of migraine and other headaches lasting four or more hours among 12,750 participants. The study reported that the highest lifetime prevalence of migraine occurred among white participants, women, and younger participants. These data illustrate substantial sex and racial disparities in migraine occurrence. Although the study did not assess cardiovascular outcomes directly, it provided valuable epidemiological insight into the burden of long-duration headaches in a cohort designed to evaluate atherosclerotic risk. By integrating headache data into a cardiovascular-focused framework, the study laid important groundwork for exploring migraine as a potential systemic marker linked to vascular vulnerability. The demographic trends observed support the growing hypothesis that migraine, particularly in women, may correlate with broader patterns of cardiovascular risk [164]. Endothelial dysfunction, impaired cerebral autoregulation, and heightened procoagulant activity have been observed in women with migraine, reinforcing the need for regular cardiovascular monitoring. This should include regular blood pressure measurements, lipid profiling, and vascular health assessments to identify modifiable risk factors early [156].
Migraine in pregnancy presents additional challenges. In a systematic review, some authors reported that the majority of women with a history of migraine, particularly those with migraine without aura, often experience a significant reduction in the frequency and intensity of attacks during the second and third trimesters of pregnancy. Conversely, migraine with aura may follow a different trajectory, potentially worsening or even presenting for the first time, especially during the first trimester [165]. Women with migraine, particularly those with aura, are at higher risk of pregnancy-related hypertensive disorders, including gestational hypertension and preeclampsia [166]. Studies have reported that preeclampsia risk is two to three times higher in women with migraine. Additionally, migraine has been linked to increased peripartum cardiovascular complications. Given these risks, comprehensive cardiovascular risk assessment should be performed before conception in women with migraine. Management strategies should focus on optimizing modifiable risk factors before pregnancy, ensuring frequent blood pressure monitoring during pregnancy, and selecting migraine treatments that are safe for both mother and fetus to minimize risks.
Migraine prevalence declines with age, yet its impact remains clinically significant, particularly in relation to cardiovascular health and comorbidities [167]. While many individuals experience disease remission or a reduction in attack frequency as they age, a subset of older adults continues to suffer from migraine, sometimes presenting with atypical clinical features. Additionally, new-onset migraine in later life, particularly MwA, should always prompt a thorough evaluation for secondary causes, including cerebrovascular disease [167].
A unique diagnostic challenge in older patients is the occurrence of late-life migraine accompaniments (LLMAs), which are characterized by prolonged aura symptoms without headache [168]. These episodes can be misinterpreted as transient ischemic attacks (TIAs) or other vascular pathologies. Neuroimaging and cardiovascular risk stratification are essential for distinguishing between MwA and cerebrovascular events. Unlike classic MwA, TIAs typically have a sudden onset and are more likely to cause purely negative neurological symptoms, such as paresis or visual field deficits. Correctly differentiating these conditions is crucial to avoid misdiagnosis and ensure appropriate stroke prevention [169].
The pharmacological management of migraine in older adults presents several challenges due to polypharmacy, comorbid conditions, and age-related changes in drug metabolism. Additionally, most RCTs evaluating migraine treatments have excluded individuals over 65 years of age, making it difficult to extrapolate efficacy and safety data for this age group. Triptans are often contraindicated in older adults because of their vasoconstrictive properties, particularly in patients with uncontrolled hypertension, prior stroke, or ischemic heart disease. Nonsteroidal anti-inflammatory drugs (NSAIDs) may also pose risks due to their gastrointestinal, renal, and cardiovascular side effects, particularly in patients with chronic kidney disease or a history of gastric ulcers [167].
Given these limitations, alternative acute treatments with a safer cardiovascular profile should be considered. As previously discussed, gepants (CGRP receptor antagonists), such as rimegepant and ubrogepant, as well as neuromodulation therapies, represent promising options without vasoconstrictive effects [170, 171]. However, long-term cardiovascular safety data for CGRP blockade in older adults remains limited. Lasmiditan, a selective 5-HT1F receptor agonist, offers another acute treatment alternative, though its sedative effects require caution in older patients, particularly those at risk of falls or cognitive impairment [172].
For preventive treatment, candesartan and beta-blockers are first-line options, particularly in those with comorbid hypertension. Angiotensin-converting enzyme (ACE) inhibitors such as lisinopril may also be beneficial. Anticonvulsants, including topiramate and valproate, should be used cautiously because of their potential to cause cognitive impairment, dizziness, and an increased risk of falls. Tricyclic antidepressants (e.g., amitriptyline) and serotonin-norepinephrine reuptake inhibitors (SNRIs) such as venlafaxine may be useful but require careful dosing to minimize the risk of sedation, orthostatic hypotension, and anticholinergic side effects. OnabotulinumtoxinA (Botox) is generally well tolerated in CM prevention, although its effectiveness in older adults remains less studied [167].
Recent observational studies have provided valuable insights into the efficacy and safety of anti-CGRP monoclonal antibodies (mAbs) in older adults. While RCTs have excluded individuals over 65 years, real-world evidence suggests that older patients with migraine benefit from anti-CGRP mAbs with a favorable safety and efficacy profile comparable to that observed in younger populations [173]. Importantly, no increased incidence of cardiovascular side effects has been reported in older patients receiving anti-CGRP mAbs, and these therapies have been well tolerated even in individuals with a high cardiovascular risk profile [174].
Beyond pharmacologic treatments, non-pharmacological approaches play a critical role in the management of migraine in older adults. Neuromodulation therapies, including transcranial magnetic stimulation (TMS) and vagus nerve stimulation (VNS), offer potential benefits without systemic side effects [171]. Cognitive behavioral therapy (CBT), regular sleep–wake cycles, adequate hydration, and structured physical activity can also help reduce attack frequency and severity while addressing common comorbid conditions such as depression and anxiety [167].
Given the unique challenges associated with migraine in older adults, a multidisciplinary and individualized approach is essential. Personalized treatment plans incorporating cardiovascular risk assessment, drug interaction considerations, and lifestyle modifications are key to ensuring safe and effective migraine management in this population.
Healthcare disparities significantly impact the diagnosis, treatment, and outcomes of migraine, particularly among socioeconomically disadvantaged populations and ethnic minorities [175]. Migraine is frequently underdiagnosed and undertreated in these groups, leading to inadequate management, poor health outcomes, and increased cardiovascular risk [125].
Several factors contribute to disparities in migraine care, including limited access to headache specialists, cultural differences in symptom reporting, financial constraints limiting access to advanced therapies, and implicit biases in healthcare delivery. Low-income individuals and racial/ethnic minorities are less likely to receive a migraine diagnosis, less likely to be prescribed evidence-based preventive treatments, and more likely to rely on over-the-counter (OTC) medications for symptom relief, which contributes to medication overuse headache (MOH).
Beyond direct healthcare barriers, lower SES itself is an independent risk factor for increased cardiovascular morbidity and mortality. Social determinants of health, including chronic stress, poor diet, lack of access to healthcare, and environmental exposures, contribute to higher rates of hypertension, dyslipidemia, and diabetes. Structural inequities in healthcare systems mean that these high-risk groups are often not reached by standard migraine care pathways, leading to missed opportunities for early intervention and risk mitigation [176].
Efforts to improve migraine care in underserved populations should focus on expanding access to specialized care through telemedicine, community-based educational programs, and cost-effective preventive strategies. Integrating cardiovascular screening into routine migraine care may help mitigate long-term vascular complications, particularly in high-risk individuals. Additionally, increasing awareness among healthcare providers about disparities in migraine diagnosis and treatment is crucial for ensuring more equitable access to care.
The studies discussed thus far suggest that the burden of migraine may extend beyond its clinical manifestations, potentially influencing cardiovascular risk, mental health, SES, and family well-being [177]. The interplay between psychosocial stressors and cardiovascular dysfunction can create a vicious cycle where migraine exacerbates both psychological distress and cardiac complications [178]. The recent COVID-19 pandemic has further highlighted the intricate relationship between the cardiovascular system, psychosocial discomfort, and migraine [179, 180].
Beyond biological interplay, the chronic nature of migraine leads to substantial disruptions in daily life, with long-term consequences in both personal and professional spheres. Individuals with frequent migraine attacks report higher levels of job insecurity, workplace discrimination, and reduced career progression. Collectively, these factors contribute to chronic stress and an increased allostatic load, a well-documented risk factor for cardiovascular morbidity. Financial instability due to loss of employment, reduced income, and higher out-of-pocket healthcare costs further exacerbates emotional distress which, in turn, increases an individual’s likelihood of developing hypertension, metabolic syndrome, and endothelial dysfunction [181].
The impact of migraine is not limited to the individual; family members and caregivers are also affected. Studies show that spouses and children of migraine sufferers experience higher levels of anxiety, depression, and caregiver burden, which are associated with increased rates of hypertension and dyslipidemia [182, 183]. Children of parents with CM are more likely to experience behavioral issues, academic difficulties, and emotional distress, partly due to the unpredictability of their parent’s condition and the frequent disruptions to family routine. Furthermore, parents of children with migraine without aura have significantly higher stress levels in all three dimensions of the Parenting Stress Index (PSI) compared to control parents [184]. CM is associated with higher levels of family dysfunction, marital stress, and role reversals within the household, as partners and children take on increased caregiving responsibilities. This leads to increased psychological distress in caregivers, often contributing to a higher prevalence of stress-induced hypertension, metabolic syndrome, and poor cardiovascular health in family members of migraine sufferers [185].
Caregiver burden is particularly significant in families where the primary income earner is affected by CM, as financial insecurity compounds the psychological distress experienced by the entire household. Families where one or both parents suffer from CM are at higher risk for financial strain, lower educational attainment in children, and increased reliance on public assistance programs, further highlighting the broader socioeconomic consequences of this disorder [186]. The emotional and financial toll on caregivers has been associated with poor cardiovascular health, highlighting the need for targeted interventions. Support systems, including psychosocial counseling, structured caregiver support programs, and workplace accommodations, have been proposed to mitigate these burdens and improve both patient and family well-being. Studies have suggested that family-based interventions that incorporate stress reduction techniques, financial counseling, and access to social support networks may help reduce caregiver distress and improve long-term health outcomes for both migraine sufferers and their families [187, 188].
Finally, social isolation and disease stigma associated with CM further contribute to cardiovascular risk. Patients with migraine often experience decreased social interaction, avoidant behaviors, and withdrawal from professional and personal commitments, leading to increased loneliness and higher rates of psychiatric comorbidities [189]. Social isolation itself has been shown to be an independent risk factor for hypertension, systemic inflammation, and increased mortality from CVD. For instance, a systematic review and meta-analysis found that poor social relationships were associated with a 29% increase in the risk of developing coronary heart disease and a 32% increase in the risk of stroke [190].
Moreover, disparities in healthcare access and quality further exacerbate the cardiovascular risks associated with migraine, with many patients experiencing delays in diagnosis and limited access to specialized care, particularly in underserved populations [175]. Addressing these psychosocial factors through multidisciplinary care models, mental health interventions, and social support programs is therefore essential for mitigating both migraine burden and cardiovascular complications.
Migraine is strongly associated with depression, anxiety, and chronic stress, which contribute to hypertension, endothelial dysfunction, and systemic inflammation that consequently increase the risk of MI and stroke. Studies have highlighted the bidirectional nature of this relationship, where mental health disorders can exacerbate migraine symptoms and vice versa, creating a cycle of disability and increased cardiovascular vulnerability [191, 192].
Depression in patients with migraine is particularly concerning, as studies have demonstrated a bidirectional relationship between the two conditions. The prevalence of major depressive disorder in patients with migraine is estimated at 47–50%, significantly higher than in the general population [191]. Depression has been linked to increased platelet activation, elevated levels of pro-inflammatory cytokines, and autonomic nervous system dysregulation, factors that can collectively contribute to a higher risk of atherosclerosis and cardiovascular events, as highlighted in recent research [193].
Similarly, anxiety disorders, particularly generalized anxiety disorder and panic disorder, have been linked to CM. Generalized anxiety disorder occurs in up to 50% of patients with CM, is associated with higher resting heart rates, increased blood pressure variability, and heightened sympathetic activation, all of which are associated with increased CV mortality [194]. In support of these findings, studies have reported that individuals with migraine and comorbid anxiety might have a significantly higher prevalence of hypertension and CAD, with panic disorder being particularly associated with increased nocturnal blood pressure surges. These findings suggest that stress-mediated autonomic dysfunction plays a crucial role in the cardiovascular outcomes of patients with migraine [17, 195].
Prolonged exposure to psychosocial stress in patients with migraine is linked to increased cortisol production, endothelial damage, and accelerated atherosclerosis, increasing the risk of ischemic heart disease and cerebrovascular accidents. Furthermore, patients with CM commonly exhibit high levels of CRP, interleukin-6 (IL-6), and tumor necrosis factor alpha (TNFα), all of which are biomarkers of systemic inflammation and endothelial dysfunction [196]. Additionally, stress-related hypothalamic–pituitary–adrenal (HPA) axis dysregulation has been reported in patients with migraine. HPA axis dysregulation has been associated with abnormal catecholamine release and reduced baroreceptor sensitivity, both of which contribute to arterial stiffness and impaired vasodilation, further compounding cardiovascular risk [197].
Given the strong link between migraine, mental health disorders, and cardiovascular risk, an integrated treatment approach that combines neurological, psychiatric, and cardiovascular care is essential. Screening for depression and anxiety should be standard practice in the management of migraine, particularly in patients with chronic and refractory migraine. Additionally, targeted interventions such as CBT, mindfulness-based stress reduction, and pharmacological management should be considered to reduce both psychological distress and cardiovascular morbidity in migraine sufferers [198].
Comprehensive migraine management should focus on reducing cardiovascular risk through integrated neurological, psychiatric, and cardiological interventions. Given the strong association between migraine, mental health disorders, and cardiovascular complications, a multidisciplinary approach is essential in optimizing patient outcomes.
CBT has emerged as a valuable non-pharmacological intervention for patients with migraine with high cardiovascular risk. Clinical trials have shown that CBT reduces the frequency of migraine attacks by 35–50%, improves stress resilience, and lowers cardiovascular risk by reducing sympathetic nervous system overactivation [199]. CBT has demonstrated efficacy in modifying maladaptive thought patterns, reducing emotional distress, and improving autonomic balance, which are critical in mitigating both migraine frequency and cardiovascular events. A meta-analysis investigating the role of CBT in patients with chronic pain demonstrated significant reductions in pain intensity, disability, and comorbid anxiety and depression, underscoring its potential in the holistic approach to the treatment of migraine [200].
AI is being increasingly explored as a supportive tool in delivering CBT to those with migraine and mental health conditions [201]. AI-powered digital CBT platforms and chatbot-assisted interventions have shown promise in improving adherence to behavioral therapy, personalizing cognitive restructuring exercises, and offering real-time stress management strategies. Studies have found that AI-assisted CBT interventions can enhance accessibility, particularly for patients with limited access to trained therapists, while maintaining comparable efficacy to traditional face-to-face CBT [202].
Furthermore, AI-driven predictive analytics are being integrated into migraine management by analyzing patient-reported symptoms, lifestyle factors, and real-time biometrics to tailor personalized behavioral interventions. Machine learning models can help identify early warning signs of migraine exacerbations, enabling preventive strategies that incorporate CBT-based stress management techniques [203]. Additional non-pharmacological approaches, including biofeedback, mindfulness-based stress reduction, and relaxation techniques, have also demonstrated positive effects on autonomic regulation. These strategies effectively reduce blood pressure fluctuations, endothelial dysfunction, and vascular inflammation in patients with migraine at risk for CVD [204].
Given the shared pathophysiology of migraine, mental health disorders, and vascular dysfunction, several commonly prescribed medications target multiple systems simultaneously [205]. Antidepressants provide a multifaceted benefit in migraine, mental health, and CVD by modulating serotonin pathways, inflammatory markers, and autonomic function. Selective serotonin reuptake inhibitors (SSRIs) such as fluoxetine and sertraline have been shown to reduce vascular inflammation and improve endothelial function, while SNRIs like venlafaxine may improve autonomic dysfunction associated with migraine and depression. However, caution is advised when prescribing tricyclic antidepressants (TCAs) such as amitriptyline, as they may contribute to weight gain, metabolic syndrome, and QT prolongation, potentially increasing cardiovascular risk in some patients [206].
As mentioned before, beta-blockers such as propranolol, a non-selective beta-blocker, not only reduce both migraine attack frequency and hypertension but also improve symptoms of anxiety and panic disorders, making them an optimal choice in patients with comorbid cardiovascular and psychiatric conditions. However, beta-blockers should be used cautiously in patients with depression, as they have been associated with fatigue and such mood disturbances [39, 41].
Calcium channel blockers, such as verapamil, may help modulate mood stability in psychiatric disorders, showing potential benefits in patients with bipolar disorder who experience comorbid migraine, while also providing well-documented cardiovascular protection [42].
In addition to reducing migraine frequency and disability, CGRP inhibitors have shown a favorable safety profile, with no evidence of increased cardiovascular or psychiatric risk. Recent data also suggest that treatment with CGRP monoclonal antibodies may lead to improvements in depressive symptoms, further supporting their use in complex patients. Taken together, CGRP inhibitors offer a multidimensional benefit, addressing both the neurological and psychosocial burden of chronic migraine [207, 208].
Given the multifaceted nature of migraine, addressing socioeconomic, psychosocial, and cardiovascular dimensions through a multidisciplinary approach is essential to reduce long-term cardiovascular morbidity and improve patient outcomes. A patient-centered strategy that includes early cardiovascular screening, mental health support, lifestyle interventions, and targeted pharmacotherapy may enhance both migraine and cardiovascular management [3, 175].
Over the past two decades, the advancement of genomic and other “omics” technologies has paved the way for more precise and individualized cardiovascular risk stratification. Techniques such as GWAS, transcriptomics, proteomics, and metabolomics have not only broadened our understanding of disease mechanisms but also enabled the identification of polygenic risk scores and circulating biomarkers that are beginning to inform clinical decision-making. Broad implementation in clinical practice remains limited by challenges such as cost-effectiveness, clinical utility, and equitable access. However, emerging tools that combine genomic, phenotypic, and digital health data are bringing us closer to the routine use of precision medicine and offer a glimpse into a more personalized and predictive approach to disease prevention and management [209].
Emerging evidence indicates that precision medicine may help clarify the complex interplay between migraine and cardiovascular risk. Genetic studies in migraine have identified susceptibility variants not only in neuronal pathways but also in genes involved in vascular regulation, such as* MTHFR*,* NOS3*,* ACE*, and* TGFB2*, highlighting a shared molecular architecture with CVD. Pharmacogenomic research further reveals that individual variations in drug-metabolizing enzymes, transporters, and receptors can influence both migraine treatment response and cardiovascular safety profiles [15, 209].
Recent investigations have explored the role of microRNAs (miRNAs) as shared molecular regulators in migraine, atherosclerosis, and metabolic disorders such as diabetes. Specific miRNA expression profiles appear to be dysregulated in individuals with migraine, suggesting their involvement in neurovascular inflammation, endothelial dysfunction, and pain modulating pathways. In particular, certain miRNAs have been identified as modulators of vascular tone, platelet reactivity, and pro-inflammatory cytokine release. These findings raise the possibility that miRNAs could serve as both biomarkers for disease stratification and targets for precision therapy, potentially offering novel tools for early identification of high-risk patients with migraine and more personalized therapeutic approaches [210]. By integrating genomic, transcriptomic, and metabolomic data, future precision medicine approaches could help identify patients with migraine at increased cardiovascular risk, optimize treatment selection, and potentially inform preventive strategies that are tailored to each patient’s genetic and biochemical profile.
Despite robust evidence that migraine is associated with an elevated risk of CVD, current research has yet to clarify several critical aspects of this most notably, whether migraine plays a causal role in CVD or if the association arises from shared risk factors with complex temporal dynamics that remain poorly understood. In addition, the impact of migraine-specific treatments on cardiovascular outcomes is largely unknown. Certain acute therapies (e.g., frequent use of NSAIDs) might exacerbate vascular risk, but it is unclear whether effective migraine prophylaxis can reduce long-term CVD incidence [17]. Furthermore, risk stratification among migraine sufferers remains imprecise. Despite the strong association of migraine with CVD risk, adding information related to migraine status to commonly used CVD risk prediction algorithms did not substantially improve risk stratification among women [34]. Addressing these gaps will require long-term studies that track large migraine cohorts over extended periods. These large, long-term studies may enable researchers to differentiate causation from correlation, determine the cumulative vascular impact of migraine across lifespan, evaluate how interventions or changes in migraine status alter CVD outcomes, and ultimately improve risk stratification and preventive strategies for this at-risk population.
Monoclonal antibodies targeting CGRP (galcanezumab, fremanezumab, eptinezumab) or its receptor (e.g., erenumab) and small-molecule CGRP receptor antagonists (gepants such as rimegepant, atogepant, ubrogepant, and zavegepant) have been shown to effectively reduce migraine frequency in several RCTs [211]. As previously noted, initial concerns were raised about the potential cardiovascular effects of CGRP antagonism, given the peptide’s well-established role as a potent vasodilator involved in vascular homeostasis [212]. However, to date, most of these medications have shown no significant cardiovascular adverse effects. One exception was a prospective follow-up study that reported increases in both systolic and diastolic blood pressure in patients treated with erenumab, with some individuals requiring antihypertensive therapy [213]. On the other hand, a systematic review and meta-analysis did not find a significant association between erenumab and increased systemic blood pressure, although it noted a degree of evidence fragility and recommended careful consideration of the risk–benefit profile, especially in patients with multiple comorbidities [214]. Considering the physiological vasodilatory role of CGRP, it is reasonable to state that long-term studies are still needed to fully assess the risk of hypertension secondary to CGRP pathway blockade. In the meantime, monitoring blood pressure in patients receiving these treatments is considered good clinical practice [215].
Research is also being conducted on new potential therapeutic targets in migraine, including pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), amylin, adrenomedullin, nitric oxide (NO), phosphodiesterase-3 (PDE3) and phosphodiesterase-5 (PDE5), and ion channels [216].
Optimizing outcomes for patients with migraine and concomitant cardiovascular risk ideally requires an interdisciplinary approach. Integrated care models involve physicians from different specialties, including neurologists, cardiologists, and primary care providers, alongside a multidisciplinary team that includes physical therapists, psychologists, and headache nurses. In this setting, patients are more likely to receive optimal migraine-specific therapy alongside aggressive and personalized treatments for patient specific comorbidities such as hypertension, dyslipidemia, and other vascular risk factors. Simultaneously, behavioral and allied health professionals (psychologists, headache nurses, physical therapists) may help patients develop strategies to better manage stress and address psychiatric comorbidities.
Such team-based care is particularly suited to tertiary centers, since many patients with a more severe disease course present with multiple comorbid conditions (from anxiety and depression to metabolic syndrome) that can exacerbate both migraine and cardiovascular risk if left unaddressed. Early examples of multidisciplinary headache clinics and cross-referral systems indicate that this collaborative strategy can improve adherence to preventive therapies and lifestyle modifications [217]. By uniting specialties, integrated care models aim to simultaneously control migraine and mitigate long-term cardiovascular risk and optimizing healthcare resources; however, further research is needed to quantify the impact of these approaches on clinical outcomes.
As migraine, particularly MwA, is established as an independent risk factor for ischemic stroke and other cardiovascular events, contemporary guidelines call for proactive identification and management of vascular risk factors in patients with migraine. Notably, the European Society of Cardiology’s prevention guidelines recommend including MwA in the cardiovascular risk assessment, similarly to the UK’s QRISK3 calculator, which already incorporates migraine as a risk variable [54]. Patients with migraine may exhibit a higher burden of traditional risk factors (such as hypertension, hyperlipidemia, and smoking) than non-patients with migraine, which warrants systematic screening for these modifiable contributors to stroke and MI risk [55]. Clinicians treating migraine should regularly evaluate blood pressure, glycemic control, and lipid profiles. Accordingly, appropriate preventive measures should be offered (e.g., antihypertensives, statins, antithrombotics) when indicated. However, future studies are necessary to address the quantifiable impact of aggressive CVD control in patients with migraine, as well as to evaluate whether preventive treatment and reduction of migraine frequency might have any effect on CVD risk in this population [218–220].
The relationship between migraine and CVD represents a critical yet often overlooked aspect of patient care. The evidence reviewed in this paper highlights the need for a multidisciplinary approach in evaluating patients with migraine, particularly those at higher cardiovascular risk. Given the consistent, though not universal, epidemiological evidence linking migraine, particularly with aura, to an increased risk of adverse cardiovascular events, clinicians should consider a proactive yet individualized approach to the screening and management of modifiable cardiovascular risk factors in this population.
Current research underscores the role of vascular and endothelial dysfunction, inflammation, and genetic predisposition in the pathophysiology of both migraine and CVD. This growing body of evidence suggests that migraine should not be viewed solely as a neurological disorder but rather as a systemic condition with significant vascular implications.
Future research should focus on refining cardiovascular risk stratification models for patients with migraine, exploring novel therapeutic targets, and developing integrated care models that bridge neurology and cardiology. Moreover, the application of personalized medicine, including genetic profiling and biomarker identification, may revolutionize risk prediction and treatment strategies.
By promoting greater awareness of the migraine–cardiovascular connection, we can enhance early detection, reduce the burden of cardiovascular complications, and ultimately improve the long-term health outcomes of individuals affected by migraine.