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Rapid Responses: Rapid Responses published:
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Stratification by Treatment Assignment
- Steven C. Vlad (9 August 2008)
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Migraine and cardiovascular risk: we should not forget oral contraceptive use in young women
- Antonio Carolei, Simona Sacco (9 August 2008)
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Migraine and Vascular Disease – another common link?
- Jecko Thachil (15 August 2008)
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Migraine, vascular risk, and cardiovascular events
- Radhakrishnan Ramaraj (16 August 2008)
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Steven C. Vlad, Instructor of Medicine Boston University School of Medicine
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This study took place in the context of a clinical trial of Vitamin E and aspirin. It would be reassuring to see that the results are robust after stratification by treatment arms, since the process of randomization should equally distribute potential confounders within these. Competing interests: None declared |
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Antonio Carolei, Professor of Neurology University of L'Aquila, Simona Sacco
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Migraine and particularly migraine with aura has been associated with an increased risk of cardiovascular events, including ischaemic stroke and coronary heart disease, mostly in women.1 A relevant point is represented by the identification of which women among the wide population of migraineurs with aura are at the highest risk to develop vascular events. Some important hints come from the study by Kurth et al.2 who investigated whether the association between migraine with aura and cardiovascular disease can be attributed to the presence of some risk factors measured by the Framingham risk score (which includes age, total cholesterol, high density lipoprotein cholesterol, smoking, and systolic blood pressure stratified by treatment for hypertension). Despite the important contribution coming from this study we think that if some of the conclusive remarks are not properly clarified, any advice may become misleading for the clinician. Actually, women included in the study were aged 45 and over while it is well known that history of migraine with aura is a risk factor for cerebral ischaemia mostly in women below the age of 45 and especially in those under 35 years of age.3,4 These data might explain why Kurth et al. found an association between active migraine with aura and ischaemic stroke in women with the lowest Framingham risk score. Moreover, the study by Kurth et al. while considering hormone therapy after menopause did not take into account the role of oral contraceptives that increased the odds ratio for ischaemic stroke when used by young women with migraine with aura and showed a greater than multiplicative effect in the presence of cigarette smoking or high blood pressure.3,4 In conclusion, Kurth et al., give important insight to a selected population of women but we would advice to reconsider what is already known on the topic3-5 and what the study adds, avoiding to otherwise neglect the increased risk of stroke in young women with migraine with aura when they use oral contraceptives and in the presence of vascular risk factors. Simona Sacco, research fellow in neurology
and Antonio Carolei, professor of neurology
Correspondence to: A Carolei a_carolei@yahoo.com We declare no competing interests. References 1. Sacco S, Cerone D, Carolei A. Comorbid neuropathologies in migraine: an update on cerebrovascular and cardiovascular aspects. J Headache Pain 2008;9:237-48. 2. Kurth T, Sch¨¹rks M, Logroscino G, Gaziano JM, Buring JE. Migraine, vascular risk, and cardiovascular events in women: prospective cohort study. BMJ 2008;337:a636. 3. Carolei A, Marini C, De Matteis G, the Italian National Research Council Study Group of Stroke in the Young. History of migraine and risk of cerebral ischaemia in young adults. Lancet 1996;347:1503¨C6. 4. Chang CL, Donaghy M, Poulter N. Migraine and stroke in young women: case-control study. The World Health Organisation Collaborative Study of Cardiovascular Disease and Steroid Hormone Contraception. BMJ 1999;318:13¨C8. 5. Carolei A, Marini C, Fieschi C, and the National Research Council Study Group. Migraine and risk of ischaemic stroke. BMJ 1994;308:343. Competing interests: None declared |
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Jecko Thachil, Research Fellow Liverpool
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Results from the prospective study by Kurth and colleagues indicate that women with migraine with aura are at a particularly increased risk for future cerebrovascular and cardiovascular disease [1]. Nitric oxide (NO), a ubiquitous molecule with vasodilatory and endothelial functions can be considered to be a common pathophysiological factor for migraine and vascular disease. The vascular theory of migraine suggested that the headache phase is caused by extracranial vasodilatation and the neurological symptoms are caused by intracranial vasoconstriction. Initially discovered as the endothelial relaxation factor, NO is a potent endothelial vasodilator and can cause the extracranial vasodilatation and the characteristic headache observed in migraine sufferers [2]. The activation of the NO pathway is more pronounced in migraine patients with aura and also in the luteal phase of ovarian cycle explaining the increased susceptibility to migraine attacks in perimenstrual and menstrual periods [3,4]. Also sublingual or systemic administration of glyceryl trinitrate (GTN), a supplier of NO, is able to precipitate headache attacks, whose features resemble those of the spontaneous episodes with migraine attacks [5]. The constitutive release of NO with each migraine attack depletes the enzymes involved in its synthesis and leads to a NO depleted state, especially as these enzymes have a short half life. NO is also known to inhibit platelet activation and platelet aggregation and as such, the lack of it causes platelet aggregate formation leading on to cerebrovascular and cardiovascular events [6]. This would fit in with in the hypothesis mentioned in the article that ischaemic cerebral vascular events is due to microvascular changes rather than atherosclerotic changes. Endothelial NO synthase, the principal enzyme involved in the production of NO in the vasculature, under certain pathophysiological conditions (as with risk factors for vascular disease), is upregulated and can become a source of superoxides, instead of NO [7]. This will impair endothelial progenitor cell mobilization and function, a critical factor explained by Kurth et al as a surrogate marker for the impaired vascular function. The effect of migraine with aura on the coronary arteries thus can have two mechanisms, one involving a vasculature not altered by atherosclerosis leading to angina and one involving a vasculature impaired by atherosclerosis leading to angina and myocardial infarction. It is interesting to note here that NO is helpful in relieving angina, but not beneficial in patients who suffered a myocardial infarction. In summary, NO can be considered as one of the common links between migraine and vascular disease thus explaining the increased incidence of future cerebrovascular and cardiovascular disease in women with migraine with aura. References 1. Kurth T, Schürks M, Logroscino G, Gaziano JM, Buring JE. Migraine, vascular risk, and cardiovascular events in women: prospective cohort study. BMJ. 2008 ; 337: a636. 2. Thomsen LL, Olesen J. Nitric oxide in primary headaches. Curr Opin Neurol. 2001; 14: 315-21. 3. Gallai V, Floridi A, Mazzotta G, Codini M, Tognoloni M, Vulcano MR, Sartori M, Russo S, Alberti A, Michele F, Sarchielli P. L-arginine/nitric oxide pathway activation in platelets of migraine patients with and without aura. Acta Neurol Scand. 1996; 94: 151-60. 4. Sarchielli P, Tognoloni M, Russo S, Vulcano MR, Feleppa M, Malà M, Sartori M, Gallai V. Variations in the platelet arginine/nitric oxide pathway during the ovarian cycle in females affected by menstrual migraine. Cephalalgia. 1996; 16: 468-75 5. Thomsen LL, Kruuse C, Iversen HK, Olesen J. A nitric oxide donor (nitroglycerin) triggers genuine migraine attacks. Eur J Neurol 1994; 1: 73–80. 6. Radomski MW, Palmer RM, Moncada S. An L-arginine/nitric oxide pathway present in human platelets regulates aggregation. Proc Natl Acad Sci U S A. 1990; 87: 5193-7. 7. Thum T, Fraccarollo D, Schultheiss M, Froese S, Galuppo P, Widder JD, Tsikas D, Ertl G, Bauersachs J.Endothelial nitric oxide synthase uncoupling impairs endothelial progenitor cell mobilization and function in diabetes. Diabetes. 2007; 56: 666-74. Competing interests: None declared |
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Radhakrishnan Ramaraj, Resident Physician, Department of Internal Medicine University of Arizona College of Medicine, Tucson , AZ 85724 USA
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Dear Editor, A recent study was performed to elucidate the relationship between MTHFR 677C>T polymorphism (rs1801133), migraine, and cardiovascular disease (CVD) demonstrated that carriers of the TT genotype had decreased incidence of migraine with aura and reduced risk for CVD. To the contrary they showed that migraine with aura alone doubled the risk for CVD (RR = 2.06; p < 0.0001) whereas the combination of presence of of migraine with aura and the TT genotype further increased the risk for CVD (RR = 3.66; 95p = 0.001) mostly attributed to ischemic stroke which was increased by a factor of 4. If we can identify the individuals suffering from migraine with aura who are at risk of developing ischemic events by genetic studies, then it is plausible that we can start interventions to prevent CVD at an earlier stages. References: Schürks M, Zee RY, Buring JE, Kurth T.Interrelationships among the MTHFR 677C>T polymorphism, migraine, and cardiovascular disease. Neurology. 2008;71(7):505-13. Competing interests: None declared |
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