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1、Archives of Cardiovascular Disease 116(2023)590596Disponible en ligne surScienceDGuidelinesPharmacological coronary spasm provocative testing in clinicalpractice:A French Coronary Atheroma and Interventional CardiologyGroup(GACI)position paper Fabien Picarda,1,Julien Adjedjb,Jean-Philippe Colletc,Er

2、ic Van Belled,Jacques Monsegue,Bernard Karsentyf,Patrick Dupouyg,Marine Quilloth,Guillaume Bonneti,Alexandre Gautierj,Guillaume Caylak,Hakim Benamerl,m,naDepartment of Cardiology,Cochin Hospital,Hpitaux Universitaire Paris Centre,APHP,75014 Paris,FrancebDepartment of Cardiology,Institut Arnault-Tzan

3、ck,06700 Saint-Laurent-du-Var,FrancecSorbonne Universit,ACTION Study Group,INSERM UMRS 1166,Institut de Cardiologie,APHP,75013 Paris,FrancedCHU Lille,Department of Cardiology,Department of Interventional Cardiology for Coronary,Valves and Structural Heart Diseases,Institut Coeur Poumon,INSERM U1011,

4、Institut Pasteur de Lille,EGID,Universit de Lille,59000 Lille,FranceeDepartment of Interventional Cardiology,Institut Cardio-Vasculaire,Groupe Hospitalier Mutualiste Grenoble,38000 Grenoble,FrancefHpital priv Saint-Martin,ELSAN,33600 Pessac,FrancegPle Cardio-Vasculaire Interventionnel,Clinique les F

5、ontaines,77000 Melun,FrancehDepartment of Interventional Cardiology,Centre Hospitalier Henri-Duffaut,84000 Avignon,FranceiHaut-Lvque Cardiology Hospital,Bordeaux University,33600 Pessac,FrancejDepartment of Cardiology,Hpital Bichat,APHP,75018 Paris,FrancekCardiology Department,Nmes University Hospit

6、al,Montpellier University,30900 Nmes,FrancelICPS Jacques Cartier,Ramsay Gnrale de Sant,91300 Massy,FrancemICV-GVM La Roseraie,93300 Aubervilliers,FrancenHpital Foch,92150 Suresnes,Francea r t i c l e i n f oArticle history:Received 28 August 2023Received in revised form 3 October 2023Accepted 4 Octo

7、ber 2023Available online 13 October 2023Keywords:Coronary spasmVasospastic anginaProvocative testingErgonovinePrinzmetal anginaa b s t r a c tVasospastic angina,also described as Prinzmetal angina,was rst described as a variant form of anginaat rest with transient ST-segment elevation;it is common a

8、nd present in many clinical scenarios,includ-ing chronic and acute coronary syndromes,sudden cardiac death,arrhythmia and syncope.However,vasospastic angina remains underdiagnosed,and provocative tests are rarely performed.The gold-standard diagnostic approach uses invasive coronary angiography to i

9、nduce coronary spasm usingergonovine,methylergonovine or acetylcholine as provocative stimuli.The lack of uniform protocoldecreases the use and performance of these tests,accounting for vasospastic angina underestimation.This position paper from the French Coronary Atheroma and Interventional Cardio

10、logy Group(GACI)aims to review the indications for provocative tests,the testing conditions,drug protocols and positivitycriteria.2023 Elsevier Masson SAS.All rights reserved.Tweet:New position paper of the GACI on coronary spasm provocative test.This article addresses indications,testing conditions

11、,drug protocols and positivitycriteria for coronary spasm testing in the cath-lab.Corresponding author.Cardiology Department,Cochin Hospital,Hpitaux Uni-versitaire Paris Centre,APHP,27,rue du Faubourg-Saint-Jacques,75014 Paris,France.E-mail address:Fabien.picardaphp.fr(F.Picard).1Twitter handle:pica

12、rd fabien.1.AbbreviationsCOVADIS Coronary Vasomotor Disorders International StudyESC European Society of CardiologyLCA left coronary arteryRCA right coronary arteryTIMI Thrombolysis in Myocardial InfarctionVSA vasospastic anginahttps:/doi.org/10.1016/j.acvd.2023.10.0021875-2136/2023 Elsevier Masson

13、SAS.All rights reserved.F.Picard,J.Adjedj,J.-P.Collet et al.Archives of Cardiovascular Disease 116(2023)5905962.IntroductionMore than 60 years ago,Prinzmetal rst described a vari-ant of angina occurring at rest associated with electrocardiogrammodications.This condition,called vasospastic angina(VSA

14、),isa heterogeneous phenomenon that can occur in patients withor without coronary atherosclerosis,can be focal or diffuse andcan affect epicardial or microvasculature coronary arteries.VSA iscaused by an intrinsic anomaly of coronary vasomotricity,whichmay be responsible for resting chest pain with

15、concomitant elec-trocardiogram changes,such as transient ST-segment elevation;itcan classically result in angina or myocardial infarction with noobstructive coronary arteries 13.Many centres have been unwilling to perform routine provoca-tive testing for multiple reasons,including longer procedural

16、time,the lack of denitive provocative spasm protocol and reporteddeaths related to provocative testing 4.Initially performedat the bedside,with intermittent electrocardiogram monitoringand administration of nitrates,catheterization laboratory-basedprovocative testing,in which short half-life provoca

17、tive drugs areadministered,has become the standard of care.Nevertheless,thedrugs and protocols available for coronary spasm diagnosis areheterogenous 5,and VSA is still a frequently overlooked diag-nosis.Timely diagnosis of VSA is mandatory to prevent furtherlife-threatening events 6,7.This position

18、 paper from the French Coronary Atheroma andInterventional Cardiology Group(GACI)aims to review the indica-tions for provocative tests,the testing conditions,drug protocolsand positivity criteria.3.Coronary vasospasm pathophysiologyCoronary spasm most often affects 50-year-old smokers,butits physiop

19、athology is multifactorial,including extrinsic(smoking)and intrinsic(genetic)factors.Several studies have highlighted therole of coronary endothelial dysfunction,coronary smooth musclehypercontractility with Rho-kinase as a key player and neurohor-monal abnormalities as triggering factors 5.The inci

20、dence ofcoronary spasm varies greatly depending on screening policies ateach centre.Approximately 10%of patients presenting with symp-toms at rest and with no evidence of obstructive coronary arterydisease display evidence of coronary artery spasm when systematicscreening is implemented 2,8.Identica

21、tion of VSA is important,as it may lead to acute coronary syndromes,ventricular arrhyth-mias,conduction disorders and sudden death 9,10.Guidelinesfrom Europe,the USA and Japan emphasize that coronary spasmprovocative testing should be applied in routine practice in patientswith angina or myocardial

22、infarction with no obstructive coronaryarteries 13.Table 1Indications for provocative coronary artery spasm testing.Strong indications ANOCA,especially if:resting angina nitrate responsive important diurnal variation in symptoms and exercise tolerance(more pronounced at night and early morning)MINOC

23、A in the absence of a culprit lesion unexplained syncope with preceding chest pain unexplained cardiac arrestGood indications Non-invasive diagnosed VSA,especially when unresponsive to medical therapyPersistent resting angina despite successful percutaneous coronary revascularizationControversial/co

24、ntraindications Acute phase of resuscitated cardiac arrestAcute phase of acute coronary syndromeSevere multivessel coronary artery disease or left main coronary artery stenosisSevere myocardial dysfunction,unless dysfunction might be a consequence of coronary spasm(controversial)No symptoms suggesti

25、ve of VSAANOCA:angina with no obstructive coronary arteries;MINOCA:myocardial infarction with no obstructive coronary arteries;VSA:vasospastic angina.4.Indications for provocative testingPatients with VSA have a higher risk of major adverse cardio-vascular events(MACE)compared with the general popul

26、ation.Identication of VSA is of utmost importance given that smok-ing cessation,calcium channel blockers and long-acting nitrateshave been demonstrated to drastically reduce symptoms and theoccurrence of subsequent cardiac events 11.If a denitive diagnosis can be made in a typical case of sponta-neo

27、us episodes of nitrate-responsive angina with either transientischaemic electrocardiogram changes or coronary artery spasm,dened as transient total or subtotal coronary artery occlusion(90%vasoconstriction),this situation is deemed very rare,andprovocative testing is necessary to rule in/out suspect

28、ed VSA.Inaddition,provocative testing should be undertaken after cardiaclife-threatening events without evident underlying cause(Table 1).Few contraindications exist,such as the acute phase of resusci-tated cardiac arrest or acute coronary syndrome,because inductionof coronary vasospasm could induce

29、 severe ventricular arrythmiaor provoke ischaemia,which can be life-threatening at the acutephase.For the same reasons and because the VSA diagnosis mightnot be retained,provocative tests should not be performed in caseof severe multivessel coronary artery disease or left main coro-nary artery steno

30、sis,as well as when the patient presents withsevere myocardial dysfunction,unless this dysfunction might bea consequence of coronary spasm(controversial).Last,patientswithout symptoms suggestive of VSA should not undergo sys-tematic provocative testing,as its performance and safety todiagnose asympt

31、omatic patients has not been evaluated.In caseof acute coronary syndrome or resuscitated cardiac arrest with noobstructive coronary artery disease or alternative cause,delayedprovocative spasm testing should be performed after the decreaseof cardiac troponin peak,although no specic data are availabl

32、e.Specic triggers of coronary artery vasospasm should be known,such as illicit drug abuse(mainly cocaine and amphetamines),med-ications(including sumatriptan and derivatives,pseudoephedrineand leukotriene modiers for asthma),systemic inammatory con-ditions,physical and mental stress,cold pressor via

33、 sympatheticactivation,hyperventilation syndrome,hormonal uctuations(e.g.variations during menstrual cycle or menopause),alcohol with-drawal,Kounis syndrome(where an allergic or hypersensitivityreaction triggers a coronary artery spasm)and hypereosinophilia(Table 2).5.Provocative testing methodsAlth

34、ough consensus papers on the diagnostic criteria formicrovascular angina and VSA during provocative test have beenpublished by the Coronary Vasomotor Disorders International591F.Picard,J.Adjedj,J.-P.Collet et al.Archives of Cardiovascular Disease 116(2023)590596Table 2Specic triggers of coronary vas

35、ospasm.Hyperventilation syndrome(alkalosis)Valsalva manoeuvrePhysical and mental stressSmokingAlcohol consumption or withdrawalIllicit drug abuse(cocaine,amphetamines)Medications(triptans and derivatives,pseudoephedrine,leukotriene modiers,sympathomimetic agents adrenaline,noradrenaline,beta-blocker

36、s,parasympathomimetic agents acetylcholine,pilocarpine,ergot alkaloid ergonovine,ergotamine,5-uorouracil)Sympathetic activation(cold pressor)Kounis syndrome(allergic or hypersensitivity reaction)HypereosinophiliaTable 3Proposed provocative coronary artery spasm testing protocols.Coronary spasm provo

37、cative test conditions Continuous electrocardiogram monitoringRadial or femoral routeRadial vasodilators allowedBaseline angiogram without intracoronary nitratesDiagnostic or guiding catheters;coronary wire use is not advisedProvocative testing using either acetylcholine,ergonovine or methylergonovi

38、neControl angiography if chest pain with electrocardiogram modications or35 minutes after the last dose of provocative agentIntracoronary,intravenous or sublingual nitrates are administrated at the end of thetest,followed by control angiographyTemporary right ventricle stimulation is not mandatoryPr

39、ovocative agent Proposed dosage Proposed protocolErgonovinemaleate/methylergonovineIntravenous:400 g(nodilution)400 g ergonovine/methylergonovine intravenous bolus administration followed by LCA and RCAangiography 35 minutes after completion of the injectionbIntracoronary(LCA):100 ga100 g of intraco

40、ronaryergonovine/methylergonovine over aperiod of 3 minutes,followed by LCAangiography 35 minutes aftercompletion of the injectionbIntracoronary(RCA):100 ga100 g of intracoronaryergonovine/methylergonovine over aperiod of 3 minutes,followed by RCAangiography 35 minutes aftercompletion of the injecti

41、onbAcetylcholine Intracoronary(RCA):50100 ga50 g of intracoronary acetylcholine over a minimal period of 20 seconds,followed by RCAangiography 3 minutes after completion of the injectionb;if no spasm occurs,then administer 100 gof intracoronary acetylcholine over a minimal period of 20 seconds,follo

42、wed by RCA angiography3 minutes after completion of the injectionbIntracoronary(LCA):100200 ga100 g of intracoronary acetylcholineover a minimal period of 20 seconds,followed by LCA angiography3 minutes after completion of theinjectionb;if no spasm occurs,thenadminister 200 g of intracoronaryacetylc

43、holine over a minimal period of20 seconds,followed by LCAangiography 3 minutes aftercompletion of the injectionbLCA:left coronary artery;RCA:right coronary artery.aDiluted in 20 mL of saline solution.bIn the event of an ischaemic change on the electrocardiogram or chest symptom,perform angiography a

44、t the time of its onset.Study(COVADIS)working group 12,consensus on a standardizedprovocative protocol remains to be established.Although a largevariety of provocative test protocols exists,they are used routinelyin only a few specialized centres 13.This lack of consensus on auniform functional test

45、ing protocol hampers widespread adoptionin clinical practice.Provocative methods and agents are summa-rized in Table 3.5.1.Provocative testing conditionsElectrocardiogram monitoring is mandatory.Radial or femoralroutes can be used,and vasodilator administration is allowed toprevent radial spasm 14,1

46、5.After angiography of the left coronaryartery(LCA)and right coronary artery(RCA)with either a diagnos-tic or guiding catheter without wires,acetylcholine,ergonovineor methylergonovine is given.The intracoronary route is usedfor acetylcholine,whereas the intracoronary or intravenous routecan be used

47、 for ergonovine and methylergonovine(Table 3).Con-trol angiography should be performed immediately when chestpain with ST-segment elevation or depression occurs or within35 minutes after the last dose of provocative agent.Sublingual,intravenous or intracoronary nitrates should be then administered,i

48、rrespective of the presence of an induced spasm.A nal angiogramof the LCA and RCA is mandatory.Ergonovine and acetylcholineprovocation tests can be undertaken in an ambulatory setting14,16.Right ventricle temporary pacing is not required.592F.Picard,J.Adjedj,J.-P.Collet et al.Archives of Cardiovascu

49、lar Disease 116(2023)5905965.2.Ergonovine and methylergonovineErgonovine and its analogue methylergonovine are syntheticergot alkaloids,which act on smooth muscle,mainly by theactivation of serotoninergic receptors(5-HT2A),to produce vaso-constriction 17,18.Adverse reactions to ergot alkaloids aredi

50、verse,and include coronary vasospasm,arrhythmia,nausea,allergic reaction and ergotism.Various testing protocols usingintracoronary and intravenous administration of ergonovine andmethylergonovine have been described.For intravenous ergonovine/methylergonovine,we propose theuse of the most commonly d