CGRP and migraine from a cardiovascular point of view: what do we expect from blocking CGRP?

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Abstract

Calcitonin gene-related peptide (CGRP) is a neuropeptide with a pivotal role in the pathophysiology of migraine. Blockade of CGRP is a new therapeutic target for patients with migraine. CGRP and its receptors are distributed not only in the central and peripheral nervous system but also in the cardiovascular system, both in blood vessels and in the heart. We reviewed the current evidence on the role of CGRP in the cardiovascular system in order to understand the possible short- and long-term effect of CGRP blockade with monoclonal antibodies in migraineurs.

In physiological conditions, CGRP has important vasodilating effects and is thought to protect organs from ischemia. Despite the aforementioned cardiovascular implication, preventive treatment with CGRP antibodies has shown no relevant cardiovascular side effects. Results from long-term trials and from real life are now needed.

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Pathophysiology of Migraine: A Disorder of Sensory Processing.

Peter J Goadsby, Philip Holland, Margarida Martins-Oliveira … (2017)

Plaguing humans for more than two millennia, manifest on every continent studied, and with more than one billion patients having an attack in any year, migraine stands as the sixth most common cause of disability on the planet. The pathophysiology of migraine has emerged from a historical consideration of the "humors" through mid-20th century distraction of the now defunct Vascular Theory to a clear place as a neurological disorder. It could be said there are three questions: why, how, and when? Why: migraine is largely accepted to be an inherited tendency for the brain to lose control of its inputs. How: the now classical trigeminal durovascular afferent pathway has been explored in laboratory and clinic; interrogated with immunohistochemistry to functional brain imaging to offer a roadmap of the attack. When: migraine attacks emerge due to a disorder of brain sensory processing that itself likely cycles, influenced by genetics and the environment. In the first, premonitory, phase that precedes headache, brain stem and diencephalic systems modulating afferent signals, light-photophobia or sound-phonophobia, begin to dysfunction and eventually to evolve to the pain phase and with time the resolution or postdromal phase. Understanding the biology of migraine through careful bench-based research has led to major classes of therapeutics being identified: triptans, serotonin 5-HT1B/1D receptor agonists; gepants, calcitonin gene-related peptide (CGRP) receptor antagonists; ditans, 5-HT1F receptor agonists, CGRP mechanisms monoclonal antibodies; and glurants, mGlu5 modulators; with the promise of more to come. Investment in understanding migraine has been very successful and leaves us at a new dawn, able to transform its impact on a global scale, as well as understand fundamental aspects of human biology.

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Migraine and cardiovascular disease: systematic review and meta-analysis

Markus Schürks, Pamela M Rist, Marcelo E. Bigal … (2009)

Objective To evaluate the association between migraine and cardiovascular disease, including stroke, myocardial infarction, and death due to cardiovascular disease. Design Systematic review and meta-analysis. Data sources Electronic databases (PubMed, Embase, Cochrane Library) and reference lists of included studies and reviews published until January 2009. Selection criteria Case-control and cohort studies investigating the association between any migraine or specific migraine subtypes and cardiovascular disease. Review methods Two investigators independently assessed eligibility of identified studies in a two step approach. Disagreements were resolved by consensus. Studies were grouped according to a priori categories on migraine and cardiovascular disease. Data extraction Two investigators extracted data. Pooled relative risks and 95% confidence intervals were calculated. Results Studies were heterogeneous for participant characteristics and definition of cardiovascular disease. Nine studies investigated the association between any migraine and ischaemic stroke (pooled relative risk 1.73, 95% confidence interval 1.31 to 2.29). Additional analyses indicated a significantly higher risk among people who had migraine with aura (2.16, 1.53 to 3.03) compared with people who had migraine without aura (1.23, 0.90 to 1.69; meta-regression for aura status P=0.02). Furthermore, results suggested a greater risk among women (2.08, 1.13 to 3.84) compared with men (1.37, 0.89 to 2.11). Age less than 45 years, smoking, and oral contraceptive use further increased the risk. Eight studies investigated the association between migraine and myocardial infarction (1.12, 0.95 to 1.32) and five between migraine and death due to cardiovascular disease (1.03, 0.79 to 1.34). Only one study investigated the association between women who had migraine with aura and myocardial infarction and death due to cardiovascular disease, showing a twofold increased risk. Conclusion Migraine is associated with a twofold increased risk of ischaemic stroke, which is only apparent among people who have migraine with aura. Our results also suggest a higher risk among women and risk was further magnified for people with migraine who were aged less than 45, smokers, and women who used oral contraceptives. We did not find an overall association between any migraine and myocardial infarction or death due to cardiovascular disease. Too few studies are available to reliably evaluate the impact of modifying factors, such as migraine aura, on these associations.

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Vascular actions of calcitonin gene-related peptide and adrenomedullin.

S Brain, Alison D. Grant (2004)

This review summarizes the receptor-mediated vascular activities of calcitonin gene-related peptide (CGRP) and the structurally related peptide adrenomedullin (AM). CGRP is a 37-amino acid neuropeptide, primarily released from sensory nerves, whilst AM is produced by stimulated vascular cells, and amylin is secreted from the pancreas. They share vasodilator activity, albeit to varying extents depending on species and tissue. In particular, CGRP has potent activity in the cerebral circulation, which is possibly relevant to the pathology of migraine, whilst vascular sources of AM contribute to dysfunction in cardiovascular disease. Both peptides exhibit potent activity in microvascular beds. All three peptides can act on a family of CGRP receptors that consist of calcitonin receptor-like receptor (CL) linked to one of three receptor activity-modifying proteins (RAMPs) that are essential for functional activity. The association of CL with RAMP1 produces a CGRP receptor, with RAMP2 an AM receptor and with RAMP3 a CGRP/AM receptor. Evidence for the selective activity of the first nonpeptide CGRP antagonist BIBN4096BS for the CGRP receptor is presented. The cardiovascular activity of these peptides in a range of species and in human clinical conditions is detailed, and potential therapeutic applications based on use of antagonists and gene targeting of agonists are discussed.

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Author and article information

Contributors

Valentina Favoni:

ORCID: http://orcid.org/0000-0001-5335-2438

+390514966845 , valentina.favoni2@unibo.it

Luca Giani: giani.luca@live.it

Linda Al-Hassany: l.alhassany@erasmusmc.nl

Gian Maria Asioli: gianmaria.asioli@gmail.com

Calogera Butera: butera.carla@hsr.it

Irene de Boer: I.de_Boer.Neur@lumc.nl

Martina Guglielmetti: martiguglie85@gmail.com

Chrysoula Koniari: chrysakoniari@gmail.com

Theodoros Mavridis: mavridismdr@gmail.com

Marge Vaikjärv: marge.vaikjarv@gmail.com

Iris Verhagen: I.E.Verhagen@lumc.nl

Angela Verzina: verzinaangela@hotmail.it

Bart Zick: b.k.t.zick@lumc.nl

Paolo Martelletti: paolo.martelletti@uniroma1.it

Simona Sacco: simona.sacco@univaq.it

Journal

Journal ID (nlm-ta): J Headache Pain

Journal ID (iso-abbrev): J Headache Pain

Title: The Journal of Headache and Pain

Publisher: Springer Milan (Milan )

ISSN (Print): 1129-2369

ISSN (Electronic): 1129-2377

Publication date (Electronic): 12 March 2019

Publication date PMC-release: 12 March 2019

Publication date Collection: 2019

Volume: 20

Issue: 1

Electronic Location Identifier: 27

Affiliations

[1 ]ISNI 0000 0004 1757 1758, GRID grid.6292.f, Department of Biomedical and Neuromotor Sciences, , University of Bologna, ; Bologna, Italy

[2 ]GRID grid.492077.f, IRCCS Istituto delle Scienze Neurologiche di Bologna, ; Via Altura, 3 Pad. G, 40139 Bologna, Italy

[3 ]Ricovero Ferdinando Uboldi, Paderno Dugnano, Italy

[4 ]ISNI 000000040459992X, GRID grid.5645.2, Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, , Erasmus MC, ; Rotterdam, The Netherlands

[5 ]ISNI 0000000417581884, GRID grid.18887.3e, Dipartimento Neurologico e INSPE, , IRCCS Ospedale San Raffaele, ; Milan, Italy

[6 ]ISNI 0000000089452978, GRID grid.10419.3d, Department of Neurology, , Leiden University Medical Center, ; Leiden, The Netherlands

[7 ]GRID grid.7841.a, Department of Clinical and Molecular Medicine, , Sapienza University, ; Rome, Italy

[8 ]ISNI 0000 0004 1757 123X, GRID grid.415230.1, Regional Referral Headache Center, , Sant’Andrea Hospital, ; Rome, Italy

[9 ]ISNI 0000 0001 2097 9138, GRID grid.11450.31, Department of Clinical Pathology, , University of Sassari, ; Sassari, Italy

[10 ]ISNI 0000 0001 2155 0800, GRID grid.5216.0, 1st Neurology Department, , Aeginition Hospital, School of Medicine, National and Kapodistrian University of Athens, ; Athens, Greece

[11 ]ISNI 0000 0001 0943 7661, GRID grid.10939.32, Faculty of Medicine, , University of Tartu, ; Tartu, Estonia

[12 ]ISNI 0000 0004 1757 3630, GRID grid.9027.c, Neurology Clinic, , University of Perugia, ; Perugia, Italy

[13 ]GRID grid.411492.b, S. Maria della Misericordia Hospital, ; Perugia, Italy

[14 ]UOC Neurologia e Stroke Unit, Ospedale SS Filippo e Nicola, Avezzano, Italy

[15 ]ISNI 0000 0004 1757 2611, GRID grid.158820.6, Department of Applied Clinical Sciences and Biotechnology, , University of L’Aquila, ; L’Aquila, Italy

Author information

Valentina Favoni http://orcid.org/0000-0001-5335-2438

Article

Publisher ID: 979

DOI: 10.1186/s10194-019-0979-y

PMC ID: 6734543

PubMed ID: 30866804

SO-VID: be974685-6a31-4ba0-ac0d-a2842283560d

License:

Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made.