Unraveling the paradox: cardiovascular risk profiling in migraine– a correspondence

Abstract

We read with great interest the recent publication by Marston and colleagues in Nature Medicine, entitled “Endothelial cell-related genetic variants identify LDL cholesterol-sensitive individuals who derive greater benefit from aggressive lipid lowering” (issue 31, March 2025, pages 963–969). Among their compelling findings, the association between the endothelial cell-specific polygenic risk score (EC-PRS) – which consists of SNPs associated with coronary artery disease – and a reduced risk of migraine headaches stood out, although not being the study’s primary aim. Migraine imposes a substantial individual and socioeconomic burden worldwide. Beyond its neurological manifestations as a primary headache disorder, migraine has increasingly been recognized as an independent and underappreciated cardiovascular risk factor, linked to major cardiovascular and cerebrovascular events. However, the biological underpinnings of this association remain poorly understood, particularly since they do not appear to be mediated through traditional or atherosclerotic pathways, and they are not associated with established cardiovascular risk factors. In this Correspondence, we build upon the findings of Marston et al. and contextualize them within the broader framework of migraine as a neurovascular disorder. Drawing from translational evidence, we propose a conceptual model that integrates findings regarding EC-PRS into the complex biological interplay linking migraine and cardiovascular disease, including coronary artery disease. In doing so, we aim to advance our understanding of migraine not only as a neurological disorder but as a marker of vascular vulnerability with implications for future research regarding personalized cardiovascular prevention, including statin therapy.

Main Text

With great interest, we have read the paper entitled “Endothelial cell-related genetic variants identify LDL cholesterol-sensitive individuals who derive greater benefit from aggressive lipid lowering” by Marston and colleagues, recently published in Nature Medicine [1]. In this genome-wide association study, the authors investigated the modifying role of low-density lipoprotein cholesterol (LDL-C) levels on the association between single nucleotide polymorphisms that are linked to endothelial cell (EC) function and incident coronary artery disease. The study demonstrates that the EC-specific polygenic risk score (EC-PRS), comprising 35 single nucleotide polymorphisms, is an independent risk predictor of the development of coronary artery disease. This risk was modified by LDL-C levels, while the cardiovascular preventive benefit of LDL-C lowering therapies (i.e., statins and PCSK9 inhibitors) was the largest among individuals with higher EC-PRS.

Interestingly, the EC-PRS was associated with a decreased risk of migraine headaches (OR per 1 SD increase = 0.94 (95% CI 0.92–0.96)). Besides being classified as the number one disabling disorder in women under the age of fifty [2], migraine – especially with aura symptoms – is an underappreciated cardiovascular risk factor associated with major cardiovascular and cerebrovascular events, including ischaemic and hemorrhagic stroke as well as myocardial infarction [3]. Notably, the incidence rate of migraine with aura for cardiovascular events has been demonstrated to be higher than that of obesity, high triglycerides, and even LDL-C [4]. Paradoxically, in contrast to the majority of such traditional cardiovascular risk factors, migraine is not associated with large-vessel atherosclerosis [5]. Women with a history of migraine and symptoms of suspected cardiac ischaemia even showed lower angiographic coronary severity scores, and less severe angiographic coronary artery disease [6]. In addition, while most traditional cardiovascular risk factors, such as hyperlipidemia, diabetes mellitus, and obesity, are comorbid, especially with increasing age, such overlap has not been consistently observed with migraine [7]. Migraine could, therefore, rather be considered a “non-atherosclerotic” or “non-traditional” cardiovascular risk factor, whose association with cardiovascular disease might be mediated by alternative biological pathways.

One such proposed pathway is endothelial dysfunction, which involves oxidative stress and inflammation. Marston and colleagues mention two vasodilatory and vasoconstrictive mediators herein, namely nitric oxide and endothelin-1, that have opposite pathophysiological effects in coronary artery disease and migraine [1]. While endothelin-1 might indeed be involved in the acute phase of migraine attacks, in the aura phase in particular [8], data on the association between endothelial dysfunction and migraine in general are yet inconsistent and inconclusive [9]. Aside from methodological heterogeneity between studies, a more plausible explanation may be that endothelial dysfunction represents an early stage of atherosclerosis – a process that is not expected to be particularly more present among migraine patients based on previous clinical data on vascular calcifications and atherosclerosis. Whether this also explains the finding that EC-PRS was associated with a decreased risk of migraine headaches by Marston and colleagues [1] remains to be demonstrated.

An important consideration herein is the distinction between absolute plasma levels of mediators and their actual biological activity, which depends on their binding to specific receptors and subsequent activation leading to vasodilation or vasoconstriction. Thus, measurements of plasma concentrations do not inherently capture the effects of receptor (de)sensitization and, therefore, cannot be assumed to represent true biological activity in migraine patients. Taking this into account, we have applied a novel and non-invasive technique that induces local thermal hyperaemia of the skin of the forearm to study microvascular activity [10]. By applying blocking compounds, we differentiated between i) endothelium-dependent responses and ii) endothelium-independent responses. The first mechanism captures the contribution of nitric oxide bioavailability or endothelial dysfunction, while the latter captures the contribution of neuropeptide activity – a second proposed pathway that might be involved in the association between migraine and cardiovascular disease. Among middle-aged women, comparable in age to the cohort studied by Marston and colleagues [1] and with presumed elevated cardiovascular risk due to polycystic ovary syndrome, we observed no significant differences in endothelium-dependent vascular responses between those with and without migraine. However, neuropeptide action was observed to be lower compared with those without migraine [10]. While larger studies are warranted to replicate these findings, also in younger women and men, the absence of lower endothelium-dependent responses among migraine patients is consistent with data by Marston and colleagues [1].

Biology, however, unfolds with far greater complexity (Fig. 1). First, while calcitonin gene-related peptide (CGRP) is a key vasodilatory neuropeptide in migraine pathophysiology, serving as a target of novel antimigraine therapies and a protective molecule under ischaemic circumstances, other neuropeptides – some exerting opposing effects – have also been implicated [11, 12]. Second, studies on lipid profiling and serum lipids are conflicting regarding the involvement of LDL-C in migraine [13, 14]. This is further complicated by the presence of aura – a factor not accounted for separately by Marston and colleagues [1] – and the migraine activity status. While we assume that Marston and colleagues [1] studied prevalent migraine in their analyses, we have shown that higher cardiovascular risk score categories were observed among women with a migraine history but not with active migraine at baseline or incident migraine [15]. Thus, migraine activity status influences cardiovascular risk status — and potentially lipid profiles — independent of age. Further research is warranted to understand the association between EC-PRS and the influence of different migraine activity statuses while accounting for the potentially modifying influence of lipids. This is also relevant when considering statin therapy in migraine, given the possible association between the expression of the HMG-CoA reductase gene and an increased migraine risk, especially with aura – as evaluated in a recent systematic review and meta-analysis [16]. A recent Mendelian randomization study also demonstrated significant associations between lipid-modifying drug target genes and a lower risk of migraine, in particular with the enhancement of LPL (lipoprotein lipase) and inhibition of HMGCR (3-hydroxy-3-methylglutaryl-CoA reductase) [17]. While larger randomized studies are warranted, the potential efficacy of statins in reducing migraine frequency and triptan usage presents a promising novel (and relatively low-cost) adjunct preventive therapeutic option in the headache field. Importantly, since their effectiveness seems to vary based on lifestyle factors (such as smoking and alcohol use) and comorbid conditions, further research is warranted to better integrate these therapies into individualized treatment strategies [18]. Furthermore, the exact biological actions of these therapies in migraine patients – both, with and without hypercholesterolemia – represents an important area for further research. These actions include the role of neuropeptides involved in migraine pathophysiology and microvascular function, such as CGRP, but also pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) [19].

Fig. 1

– A hypothesized overview of biological mechanisms involved in the association between the EC-specific polygenic risk score, migraine, and coronary artery disease. Green arrows and lines represent stimulatory or upregulated effects, while red arrows and lines indicate inhibitory or downregulated effects. Please note that this is a simplified model and does not capture the full complexity of the interactions and (causal) effects involved. Image was created using BioRender

In summary, the study by Marston and colleagues provides a clinically relevant tool to select individuals who would benefit most from lipid lowering therapy, and adds a meaningful piece to the intricate puzzle of migraine-related cardiovascular risk — even though this was not the study’s primary aim. These findings will, hopefully, pave the way for research on improving cardiovascular risk assessment – and, eventually, personalized treatment, including statin use – in migraine patients.