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Understanding CGRP and Cardiovascular Risk

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Book cover Calcitonin Gene-Related Peptide (CGRP) Mechanisms

Part of the book series: Handbook of Experimental Pharmacology ((HEP,volume 255))

Abstract

Increasing knowledge about the role of calcitonin gene-related peptide (CGRP) in migraine pathophysiology has led to the development of antibodies against this peptide or its receptor. However, CGRP is widely expressed throughout the body, participating not only in pathophysiological conditions but also in several physiological processes and homeostatic responses during pathophysiological events. Therefore, in this chapter, the risks of long-term blockade of the CGRP pathway will be discussed, with focus on the cardiovascular system, as this peptide has been described to have a protective role during ischemic events, and migraine patients present a higher risk of stroke and myocardial infarction.

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References

  • Al-Rubaiee M, Gangula PR, Millis RM, Walker RK, Umoh NA, Cousins VM, Jeffress MA, Haddad GE (2013) Inotropic and lusitropic effects of calcitonin gene-related peptide in the heart. Am J Physiol Heart Circ Physiol 304:H1525–H1537

    Article  CAS  Google Scholar 

  • Aubdool AA, Thakore P, Argunhan F, Smillie SJ, Schnelle M, Srivastava S, Alawi KM, Wilde E, Mitchell J, Farrell-Dillon K, Richards DA, Maltese G, Siow RC, Nandi M, Clark JE, Shah AM, Sams A, Brain SD (2017) A novel alphacalcitonin gene-related peptide analogue protects against end-organ damage in experimental hypertension, cardiac hypertrophy, and heart failure. Circulation 136:367–383

    Article  CAS  Google Scholar 

  • Avilés-Rosas VH, Rivera-Mancilla E, Marichal-Cancino BA, Manrique-Maldonado G, Altamirano-Espinoza AH, Maassen Van Den Brink A, Villalón CM (2017) Olcegepant blocks neurogenic and non-neurogenic CGRPergic vasodepressor responses and facilitates noradrenergic vasopressor responses in pithed rats. Br J Pharmacol 174:2001–2014

    Article  Google Scholar 

  • Buse DC, Loder EW, Gorman JA, Stewart WF, Reed ML, Fanning KM, Serrano D, Lipton RB (2013) Sex differences in the prevalence, symptoms, and associated features of migraine, probable migraine and other severe headache: results of the American Migraine Prevalence and Prevention (AMPP) Study. Headache 53:1278–1299

    Article  Google Scholar 

  • Bushnell C, McCullough LD, Awad IA, Chireau MV, Fedder WN, Furie KL, Howard VJ, Lichtman JH, Lisabeth LD, Piña IL, Reeves MJ, Rexrode KM, Saposnik G, Singh V, Towfighi A, Vaccarino V, Walters MR (2014) Guidelines for the prevention of stroke in women. Stroke 45:1545–1588

    Article  Google Scholar 

  • Chai W, Mehrotra S, Jan Danser AH, Schoemaker RG (2006) The role of calcitonin gene-related peptide (CGRP) in ischemic preconditioning in isolated rat hearts. Eur J Pharmacol 531:246–253

    Article  CAS  Google Scholar 

  • Chan KY, Edvinsson L, Eftekhari S, Kimblad PO, Kane SA, Lynch J, Hargreaves RJ, de Vries R, Garrelds IM, van den Bogaerdt AJ, Danser AH, Maassenvandenbrink A (2010) Characterization of the calcitonin gene-related peptide receptor antagonist telcagepant (MK-0974) in human isolated coronary arteries. J Pharmacol Exp Ther 334:746–752

    Article  CAS  Google Scholar 

  • Chang CL, Donaghy M, Poulter N (1999) Migraine and stroke in young women: case-control study. Br Med J 318:13–18

    Article  CAS  Google Scholar 

  • Deen M, Correnti E, Kamm K, Kelderman T, Papetti L, Rubio-Beltran E, Vigneri S, Edvinsson L, Maassen Van Den Brink A, European Headache Federation School of Advanced Studies (2017) Blocking CGRP in migraine patients – a review of pros and cons. J Headache Pain 18:96

    Article  Google Scholar 

  • Depre C, Antalik L, Starling A, Koren M, Eisele O, Lenz RA, Mikol DD (2018) A randomized, double-blind, placebo-controlled study to evaluate the effect of erenumab on exercise time during a treadmill test in patients with stable angina. Headache 58:715–723

    Article  Google Scholar 

  • Doods H, Hallermayer G, Wu D, Entzeroth M, Rudolf K, Engel W, Eberlein W (2000) Pharmacological profile of BIBN4096BS, the first selective small molecule CGRP antagonist. Br J Pharmacol 129:420–423

    Article  CAS  Google Scholar 

  • Edvinsson L (2017) The trigeminovascular pathway: role of CGRP and CGRP receptors in migraine. Headache 57(Suppl 2):47–55

    Article  Google Scholar 

  • Edvinsson L, Linde M (2010) New drugs in migraine treatment and prophylaxis: telcagepant and topiramate. Lancet 376:645–655

    Article  CAS  Google Scholar 

  • Edvinsson L, Delgado-Zygmunt T, Ekman R, Jansen I, Svendgaard NA, Uddman R (1990) Involvement of perivascular sensory fibers in the pathophysiology of cerebral vasospasm following subarachnoid hemorrhage. J Cereb Blood Flow Metab 10:602–607

    Article  CAS  Google Scholar 

  • Edvinsson L, Mulder H, Goadsby PJ, Uddman R (1998) Calcitonin gene-related peptide and nitric oxide in the trigeminal ganglion: cerebral vasodilatation from trigeminal nerve stimulation involves mainly calcitonin gene-related peptide. J Auton Nerv Syst 70:15–22

    Article  CAS  Google Scholar 

  • Etminan M, Takkouche B, Isorna FC, Samii A (2005) Risk of ischaemic stroke in people with migraine: systematic review and meta-analysis of observational studies. Br Med J 330:63

    Article  Google Scholar 

  • Gangula PRR, Wimalawansa SJ, Yallampalli C (2002) Sex steroid hormones enhance hypotensive effects of calcitonin gene-related peptide in aged female rats. Biol Reprod 67:1881–1887

    Article  CAS  Google Scholar 

  • Gao Y, Song J, Chen H, Cao C, Lee C (2015) TRPV1 activation is involved in the cardioprotection of remote limb ischemic postconditioning in ischemia-reperfusion injury rats. Biochem Biophys Res Commun 463:1034–1039

    Article  CAS  Google Scholar 

  • Gennari C, Fischer JA (1985) Cardiovascular action of calcitonin gene-related peptide in humans. Calcif Tissue Int 37:581–584

    Article  CAS  Google Scholar 

  • Gennari C, Nami R, Agnusdei D, Fischer JA (1990) Improved cardiac performance with human calcitonin gene related peptide in patients with congestive heart failure. Cardiovasc Res 24:239–241

    Article  CAS  Google Scholar 

  • Goadsby PJ, Lipton RB, Ferrari MD (2002) Migraine – current understanding and treatment. N Engl J Med 346:257–270

    Article  CAS  Google Scholar 

  • Gulbenkian S, Opgaard OS, Ekman R, Andrade NC, Wharton J, Polak JM, Queiroz e Melo J, Edvinsson L (1993) Peptidergic innervation of human epicardial coronary arteries. Circ Res 73:579–588

    Article  CAS  Google Scholar 

  • Holland PR, Goadsby PJ (2018) Targeted CGRP small molecule antagonists for acute migraine therapy. Neurotherapeutics 15:304–312

    Article  CAS  Google Scholar 

  • Homma S, Kimura T, Sakai S, Yanagi K-I, Miyauchi Y, Aonuma K, Miyauchi T (2014) Calcitonin gene-related peptide protects the myocardium from ischemia induced by endothelin-1: intravital microscopic observation and 31P-MR spectroscopic studies. Life Sci 118:248–254

    Article  CAS  Google Scholar 

  • Humphries KH, Pu A, Gao M, Carere RG, Pilote L (2008) Angina with “normal” coronary arteries: sex differences in outcomes. Am Heart J 155:375–381

    Article  Google Scholar 

  • Inoue T, Shimizu H, Kaminuma T, Tajima M, Watabe K, Yoshimoto T (1996) Prevention of cerebral vasospasm by calcitonin gene-related peptide slow-release tablet after subarachnoid hemorrhage in monkeys. Neurosurgery 39:984–990

    CAS  PubMed  Google Scholar 

  • Jianping L, Kevin AC, Donald JD, Scott CS (2013) Renal protective effects of α-calcitonin gene-related peptide in deoxycorticosterone-salt hypertension. Am J Physiol Renal Physiol 304:F1000–F1008

    Article  Google Scholar 

  • Juul R, Edvinsson L, Gisvold SE, Ekman R, Brubakk AO, Fredriksen TA (1990) Calcitonin gene-related peptide-LI in subarachnoid haemorrhage in man. Signs of activation of the trigemino-cerebrovascular system? Br J Neurosurg 4:171–179

    Article  CAS  Google Scholar 

  • Juul R, Aakhus S, Björnstad K, Gisvold SE, Brubakk AO, Edvinsson L (1994) Calcitonin gene-related peptide (human α-CGRP) counteracts vasoconstriction in human subarachnoid haemorrhage. Neurosci Lett 170:67–70

    Article  CAS  Google Scholar 

  • Kaski JC, Collins P, Nihoyannopoulos P, Maseri A, Poole-Wilson PA, Rosano GMC (1995) Cardiac syndrome X: clinical characteristics and left ventricular function: long-term follow-up study. J Am Coll Cardiol 25:807–814

    Article  CAS  Google Scholar 

  • Keith IM, Tjen-A-Looi S, Kraiczi H, Ekman R (2000) Three-week neonatal hypoxia reduces blood CGRP and causes persistent pulmonary hypertension in rats. Am J Physiol Heart Circ Physiol 279:H1571–H1578

    Article  CAS  Google Scholar 

  • Kurth T, Schürks M, Logroscino G, Buring JE (2009) Migraine frequency and risk of cardiovascular disease in women. Neurology 73:581–588

    Article  Google Scholar 

  • Labastida-Ramirez A, Rubio-Beltran E, Villalon CM, MaassenVanDenBrink A (2017) Gender aspects of CGRP in migraine. Cephalalgia 333102417739584

    Google Scholar 

  • Lei J, Zhu F, Zhang Y, Duan L, Lei H, Huang W (2016) Transient receptor potential vanilloid subtype 1 inhibits inflammation and apoptosis via the release of calcitonin gene-related peptide in the heart after myocardial infarction. Cardiology 134:436–443

    Article  CAS  Google Scholar 

  • Lindstedt IH, Edvinsson ML, Evinsson L (2006) Reduced responsiveness of cutaneous microcirculation in essential hypertension – a pilot study. Blood Press 15:275–280

    Article  Google Scholar 

  • Liu Z, Liu Q, Cai H, Xu C, Liu G, Li Z (2011) Calcitonin gene-related peptide prevents blood–brain barrier injury and brain edema induced by focal cerebral ischemia reperfusion. Regul Pept 171:19–25

    Article  CAS  Google Scholar 

  • Maassen van den Brink A, Rubio-Beltrán E, Duncker D, Villalón CM (2018) Is CGRP receptor blockade cardiovascularly safe? Appropriate studies are needed. Headache 58:1257–1258

    Article  CAS  Google Scholar 

  • MaassenVanDenBrink A, Meijer J, Villalón CM, Ferrari MD (2016) Wiping out CGRP: potential cardiovascular risks. Trends Pharmacol Sci 37:779–788

    Article  CAS  Google Scholar 

  • Mai TH, Wu J, Diedrich A, Garland EM, Robertson D (2014) Calcitonin gene-related peptide (CGRP) in autonomic cardiovascular regulation and vascular structure. J Am Soc Hypertens 8:286–296

    Article  CAS  Google Scholar 

  • McCulloch J, Uddman R, Kingman TA, Edvinsson L (1986) Calcitonin gene-related peptide: functional role in cerebrovascular regulation. Proc Natl Acad Sci 83:5731–5735

    Article  CAS  Google Scholar 

  • Mieres JH, Gulati M, Merz NB, Berman DS, Gerber TC, Hayes SN, Kramer CM, Min JK, Newby LK, Nixon JV, Srichai MB, Pellikka PA, Redberg RF, Wenger NK, Shaw LJ (2014) Role of noninvasive testing in the clinical evaluation of women with suspected ischemic heart disease. Circulation 130:350–379

    Article  Google Scholar 

  • Mitsikostas DD, Reuter U (2017) Calcitonin gene-related peptide monoclonal antibodies for migraine prevention: comparisons across randomized controlled studies. Curr Opin Neurol 30:272–280

    Article  CAS  Google Scholar 

  • Moskowitz MA, Sakas DE, Wei EP, Kano M, Buzzi MG, Ogilvy C, Kontos HA (1989) Postocclusive cerebral hyperemia is markedly attenuated by chronic trigeminal ganglionectomy. Am J Physiol 257:H1736–H1739

    CAS  PubMed  Google Scholar 

  • Negro A, Lionetto L, Simmaco M, Martelletti P (2012) CGRP receptor antagonists: an expanding drug class for acute migraine? Expert Opin Investig Drugs 21:807–818

    Article  CAS  Google Scholar 

  • Opgaard OS, Gulbenkian S, Bergdahl A, Barroso CP, Andrade NC, Polak JM, Queiroz e Melo JQ, Edvinsson L (1995) Innervation of human epicardial coronary veins: immunohistochemistry and vasomotility. Cardiovasc Res 29:463–468

    Article  Google Scholar 

  • Russell FA, King R, Smillie SJ, Kodji X, Brain SD (2014) Calcitonin gene-related peptide: physiology and pathophysiology. Physiol Rev 94:1099

    Article  CAS  Google Scholar 

  • Sacco S, Ornello R, Ripa P, Pistoia F, Carolei A (2013) Migraine and hemorrhagic stroke: a meta-analysis. Stroke 44:3032–3038

    Article  Google Scholar 

  • Sakas DE, Moskowitz MA, Wei EP, Kontos HA, Kano M, Ogilvy CS (1989) Trigeminovascular fibers increase blood flow in cortical gray matter by axon reflex-like mechanisms during acute severe hypertension or seizures. Proc Natl Acad Sci 86:1401–1405

    Article  CAS  Google Scholar 

  • Schebesch K-M, Herbst A, Bele S, Schödel P, Brawanski A, Stoerr E-M, Lohmeier A, Kagerbauer SM, Martin J, Proescholdt M (2013) Calcitonin-gene related peptide and cerebral vasospasm. J Clin Neurosci 20:584–586

    Article  CAS  Google Scholar 

  • Scher AI, Terwindt GM, Picavet HSJ, Verschuren WMM, Ferrari MD, Launer LJ (2005) Cardiovascular risk factors and migraine: the GEM population-based study. Neurology 64:614–620

    Article  CAS  Google Scholar 

  • Schurks M, Rist PM, Bigal ME, Buring JE, Lipton RB, Kurth T (2009) Migraine and cardiovascular disease: systematic review and meta-analysis. Br Med J 339:b3914

    Article  Google Scholar 

  • Schuster NM, Vollbracht S, Rapoport AM (2015) Emerging treatments for the primary headache disorders. Neurol Sci 36(Suppl 1):109–113

    Article  Google Scholar 

  • Smillie S-J, Brain SD (2011) Calcitonin gene-related peptide (CGRP) and its role in hypertension. Neuropeptides 45:93–104

    Article  CAS  Google Scholar 

  • Smillie S-J, King R, Kodji X, Outzen E, Pozsgai G, Fernandes E, Marshall N, de Winter P, Heads Richard J, Dessapt-Baradez C, Gnudi L, Sams A, Shah Ajay M, Siow Richard C, Brain Susan D (2014) An ongoing role of α-calcitonin gene-related peptide as part of a protective network against hypertension, vascular hypertrophy, and oxidative stress. Hypertension 63:1056–1062

    Article  CAS  Google Scholar 

  • Spector JT, Kahn SR, Jones MR, Jayakumar M, Dalal D, Nazarian S (2010) Migraine headache and ischemic stroke risk: an updated meta-analysis. Am J Med 123:612–624

    Article  Google Scholar 

  • Stovner LJ, Nichols E, Steiner TJ, Abd-Allah F, Abdelalim A, Al-Raddadi RM, Ansha MG, Barac A, Bensenor IM, Doan LP, Edessa D, Endres M, Foreman KJ, Gankpe FG, Gopalkrishna G, Goulart AC, Gupta R, Hankey GJ, Hay SI, Hegazy MI, Hilawe EH, Kasaeian A, Kassa DH, Khalil I, Khang Y-H, Khubchandan J, Kim YJ, Kokubo Y, Mohammed MA, Moradi-Lakeh M, Nguyen HLT, Nirayo YL, Qorbani M, Ranta A, Roba KT, Safiri S, Santos IS, Satpathy M, Sawhney M, Shiferaw MS, Shiue I, Smith M, Szoeke CEI, Truong NT, Venketasubramanian N, Weldegwergs KG, Westerman R, Wijeratne T, Tran BX, Yonemoto N, Feigin VL, Vos T, Murray CJL (2018) Global, regional, and national burden of migraine and tension-type headache, 1990–2016: a systematic analysis for the Global Burden of Disease Study 2016. Lancet Neurol 17:954–976

    Article  Google Scholar 

  • Tepper SJ (2018) History and review of anti-calcitonin gene-related peptide (CGRP) therapies: from translational research to treatment. Headache 58(Suppl 3):238–275

    Article  Google Scholar 

  • Tzourio C, Tehindrazanarivelo A, Iglesias S, Alperovitch A, Chedru F, d’Anglejan-Chatillon J, Bousser M-G (1995) Case-control study of migraine and risk of ischaemic stroke in young women. Br Med J 310:830–833

    Article  CAS  Google Scholar 

  • Uddman R, Edvinsson L, Ekblad E, Håkanson R, Sundler F (1986) Calcitonin gene-related peptide (CGRP): perivascular distribution and vasodilatory effects. Regul Pept 15:1–23

    Article  CAS  Google Scholar 

  • Valdemarsson S, Edvinsson L, Hedner P, Ekman R (1990) Hormonal influence on calcitonin gene-related peptide in man: effects of sex difference and contraceptive pills. Scand J Clin Lab Invest 50:385–388

    Article  CAS  Google Scholar 

  • Vanmolkot FH, Van Bortel LM, de Hoon JN (2007) Altered arterial function in migraine of recent onset. Neurology 68:1563–1570

    Article  Google Scholar 

  • Wang LH, Zhou SX, Li RC, Zheng LR, Zhu JH, Hu SJ, Sun YL (2012) Serum levels of calcitonin gene-related peptide and substance P are decreased in patients with diabetes mellitus and coronary artery disease. J Int Med Res 40:134–140

    Article  Google Scholar 

  • Wang Z, Martorell BC, Wälchli T, Vogel O, Fischer J, Born W, Vogel J (2015) Calcitonin gene-related peptide (CGRP) receptors are important to maintain cerebrovascular reactivity in chronic hypertension. PLoS One 10:e0123697

    Article  Google Scholar 

  • Wimalawansa SJ, MacIntyre I (1988) Calcitonin gene-related peptide and its specific binding sites in the cardiovascular system of rat. Int J Cardiol 20:29–37

    Article  CAS  Google Scholar 

  • Wrobel Goldberg S, Silberstein SD (2015) Targeting CGRP: a new era for migraine treatment. CNS Drugs 29:443–452

    Article  CAS  Google Scholar 

  • Yadav S, Yadav YS, Goel MM, Singh U, Natu SM, Negi MPS (2014) Calcitonin gene- and parathyroid hormone-related peptides in normotensive and preeclamptic pregnancies: a nested case-control study. Arch Gynecol Obstet 290:897–903

    Article  CAS  Google Scholar 

  • Zhang J-Y, Yan G-T, Liao J, Deng Z-H, Xue H, Wang L-H, Zhang K (2011) Leptin attenuates cerebral ischemia/reperfusion injury partially by CGRP expression. Eur J Pharmacol 671:61–69

    Article  CAS  Google Scholar 

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Authors and Affiliations

  1. Division of Vascular Medicine and Pharmacology, Department of Internal Medicine, Erasmus Medical Center, Rotterdam, The Netherlands

    Eloísa Rubio-Beltrán & Antoinette Maassen van den Brink

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  1. Eloísa Rubio-Beltrán
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  2. Antoinette Maassen van den Brink
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Correspondence to Antoinette Maassen van den Brink .

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Editors and Affiliations

  1. School of Cardiovascular Medicine & Sciences, King’s College London, London, UK

    Susan D. Brain

  2. Department of Health Sciences, University of Florence, Florence, Italy

    Pierangelo Geppetti

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Rubio-Beltrán, E., van den Brink, A.M. (2019). Understanding CGRP and Cardiovascular Risk. In: Brain, S., Geppetti, P. (eds) Calcitonin Gene-Related Peptide (CGRP) Mechanisms. Handbook of Experimental Pharmacology, vol 255. Springer, Cham. https://doi.org/10.1007/164_2019_204

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