newcastle mitochondrial disease guidelines
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NewcastleMitochondrialDiseaseGuidelines CardiacInvolvementinAdultMitochondrialDisease:ScreeningandInitialManagementJune2010
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ContentsIntroduction 3Patient‐centeredCare 4Keyprioritiesforimplementation 51. GuidanceforCardiacScreening 6
1.1. Standard12‐leadECGs 61.2. Trans‐thoracicechocardiograms 61.3. Holter(24‐hour)monitoring 61.4. Cardiacmagneticresonanceimaging 7
2. GuidanceforClinicalManagement 8
2.1. Cardiologyreferral 82.2. Conventionalcardiacriskfactors 82.3. Hypertrophicremodelling 82.4. Conductionblockandpacemakerimplantation 82.5. Pre‐excitationsyndromes 92.6. Atrialfibrillation 92.7. Implantablecardioverter‐defibrillators(ICDs) 102.8. Leftventricularsystolicdysfunction 11 2.9. Pre‐operativeassessment 11
3. Notesonthescopeofthisguidance 13
4. Implementation 145. Researchrecommendations 15
5.1. Naturalhistorystudies 155.2. Energy‐sparingmedicationsinhypertrophicremodelling 15 5.3. Cardiacmagneticresonanceimaging/spectroscopy 15 5.4. Exerciseandmitochondrialdisease/cardiomyopathy 15
6. Updatingtheguideline 15
AppendixA:TheGuidelineDevelopmentGroup 16AppendixB:Screening/managementalgorithm 17References 18
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IntroductionMitochondrialdiseaseclinicallyaffectsaminimum9.2/100,000oftheadultpopulationwithafurther16.5/100,000atriskofdevelopingdisease.Cardiacinvolvementinmitochondrialdiseaseiscommonandcanincludebothconductionabnormalitiesandcardiomyopathy.Evidenceexistsforalinkbetweengeneticdefectandthetypeofcardiacinvolvementwith,forexample,heartblockfrequentlypresentinpatientswithlarge‐scalemtDNAdeletions;hypertrophiccardiomyopathyinpatientswithmtDNApointmutationsandventricularpre‐excitationinpatientswithtwoofthemostprevalentpathogenicmtDNAmutations(m.3243A>G/m.8344A>G).Importantlycardiacinvolvementinmitochondrialdiseaseisoftentreatable,yetnoguidelinesexist.Treatmentismorelikelytobeeffectiveifinitiatedearlyandforthisreasonitisimportanttoscreenallpatientswithmitochondrialdiseaseatthepointofdiagnosis.Cardiacdiseaseinpatientswithmitochondrialdiseasemayprogressinsidiouslyandrarelycausessymptomsuntiladvancedinseverity.Morbidityandmortalitymaythereforebeavoidedifcardiacinvolvementisdetectedearlierthroughtheimplementationoforganisedscreeningprograms.Pacemakerimplantationinpatientswithatrio‐ventricularblockmaypreventsuddencardiacdeath,whiletheuseofangiotensinconvertingenzyme(ACE)inhibitorsinsomepatientsmaypreventearlyhypertrophicremodelling.Leftventricularsystolicanddiastolicdysfunctionarebothpotentcontributorstotheoccurrenceofatrialfibrillationinavarietyofclinicalcontexts.Additionally,hypertrophiedhearts,suchasareseeninsomepatientswithmitochondrialdisease,toleratetheabruptonsetofarapidheartratepoorly.Beta‐adrenergicreceptorantagonists(betablockers)orcalciumchannelblockerscanhelptheheartfunctionbetterinpathologicalhypertrophybyslowingheartrateandimprovingdiastolicfilling.Indirectlythiscandelaytheonsetof,orprevent,atrialfibrillation–aconsequenceofleftventriculardiastolicdysfunction.Addressingcardiacandrespiratoryinvolvementinotherprogressivegeneticconditions(egDuchenneandBeckermusculardystrophy)hasbeenshowntoprovidesignificantbenefitsintermsofmorbidity,mortality,andqualityoflife,andislikelytooffersimilarbenefitsinpatientswithmitochondrialdisease.Thisis
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bestcoordinatedthroughaspecialistmitochondrialcentre,withsubsequentcareprovidedeithercentrallyorlocallydependingonindividualcircumstancesandpatientpreference.Patient‐centredCare
Thisguidelineoffersexpertconsensusadviceonthecareofpatientswithmitochondrialdisease.Thecareofthesepatientsandtheirtreatmentshouldtakeintoaccountpatients’needsandpreferences.Peoplewithmitochondrialdiseaseshouldhavetheopportunitytomakeinformeddecisionsabouttheircareandtreatment,inpartnershipwiththeirhealthcareprofessionals.Ifpatientsdonothavethecapacitytomakedecisions,healthcareprofessionalsshouldfollowtheDepartmentofHealthguidelines–‘Referenceguidetoconsentforexaminationortreatment’(2001),availablefromwww.dh.gov.uk.HealthcareprofessionalsshouldalsofollowthecodeofpracticeaccompanyingtheMentalCapacityAct(asummaryofthiscodeisavailablefromwww.dca.gov.uk/menincap/bill‐summary.htm).Goodcommunicationbetweenhealthcareprofessionalsandpatientsisessential.Itshouldbesupportedbythebestavailableinformationtailoredtothepatients’needs.Treatmentandcare,andtheinformationpatientsaregivenaboutit,shouldbeculturallyappropriate.Itshouldalsobeaccessibletopeoplewithadditionalneedssuchasphysical,sensoryorlearningdisabilities,andtopeoplewhodonotspeakorreadEnglish.Ifthepatientagrees,familiesandcarersshouldhavetheopportunitytobeinvolvedindecisionsabouttreatmentandcare.Familiesandcarersshouldalsobegiventheinformationandsupporttheyneed.
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KeyPrioritiesforImplementationInviewofthediversephenotypesofmitochondrialdisease,werecommendthatallpatientsdiagnosedwithmitochondrialdiseaseshouldhaveaminimumcardiovascularassessmentatbaseline.Thisguidancealsoappliestothoseasymptomaticcarriersdeemedtobeatsignificantriskofdevelopingdisease.Thisshouldincludeaclinicalassessment(cardiovascularhistoryandexamination),standard12‐leadelectrocardiogram(ECG)andtransthoracicechocardiogram.Furtherinvestigationandfollow‐upshouldbebasedontheinitialevaluationandthelikelihoodofcardiacinvolvement,ifknown,forthespecificgeneticsub‐type.Allpatientsshouldhaveaccesstoaspecialistwithexperienceofthemanagementofcardiacinvolvementinmitochondrialdisease.Thisdocumentisintendedforguidanceonly,andshouldnotreplacepatient‐specificmanagementplansinfluencedbyotherfactorssuchaspatientpreferenceandpragmatism.
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GuidanceforCardiacScreeninginPatientswithMitochondrialDisease
1.1. Standard12‐leadECGsarerecommendedforpatientsasfollows:
1.1.1. Allpatients,atthetimeofdiagnosis.
1.1.2. Allpatients,atanintervalof12‐months(orearlierifachangein
clinicalstatusordevelopmentofsymptomssuggestiveofcardiac
involvement).
1.1.3. Extensionofthis12‐monthintervalshouldbeconsideredonlyafter
discussionwithaclinicianexperiencedinthemanagementofcardiac
involvementinmitochondrialdisease.
1.2. Trans‐thoracicechocardiogramsarerecommendedforpatientsas
follows:
1.2.1. Allpatientsatthetimeofdiagnosis.
1.2.2. Allpatientsatanintervalof12‐months(orearlierifachangein
clinicalstatusordevelopmentofsymptomssuggestiveofcardiac
involvement).
1.2.3. Extensionofthis12‐monthintervalshouldbeconsideredonlyafter
discussionwithaclinicianexperiencedinthemanagementofthe
cardiacmanifestationsofmitochondrialdisease.Itisusuallyacceptable
toextendtheintervalto3yearsiftheECGandechocardiogramhave
remainedwithinnormallimitsoverasimilarperiod.
1.3. Holter(24‐hour)ECGmonitoringisrecommendedforpatientsasfollows:
1.3.1. Allpatientsathigh‐riskofpre‐excitationsyndrome/conduction
diseaseatdiagnosis,evenifasymptomatic(e.g.atrio‐ventricularblock
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inpatientswithsinglelargescaledeletionorventricularpre‐excitation
inpatientswithm.8344A>Gorm.3243A>G).
1.3.2. AllpatientswithseverelyimpairedLVsystolicfunction(LVEF<35%)
toidentifyasymptomaticventriculararrhythmiasofprognostic
importance(ienon‐sustainedventriculartachycardia,NSVT).
1.3.3. Asafirstlineinvestigationinallpatientswithveryfrequent
paroxysmalsymptomssuggestiveofcardiacinvolvement;longerterm
monitoringmaybeconsidered,includingimplantablelooprecorders.
1.4. Cardiacmagneticresonanceimaging(MRI)isrecommendedforpatients
asfollows:
1.4.1. Allpatientswithinadequateechocardiographicimages,toidentify
structuralremodellingortoquantifyabnormalitiesmoreprecisely
priortostartingorevaluatingresponsetocardio‐activetherapies.
1.4.2. Thereiscurrentlynoclearclinicalroleforcardiac31Pmagnetic
resonancespectroscopy.
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2. GuidanceforClinicalmanagementinPatientswithMitochondrialDisease
2.1. Allpatientswithsignificantcardiacinvolvementshouldbereviewedbya
cardiologistwithawarenessofthevariousmanifestationsofcardiac
involvementinmitochondrialdisease,evenifcurrentlyasymptomatic.
2.2. Conventionalcardiacriskfactorsandsymptomsshouldbeaddressed
promptlyinkeepingwithexistingguidelinesforpatientswithout
mitochondrialdisease.
2.3. Hypertrophicremodelling(leftventricularhypertrophy):
2.3.1. Treatmentwithconventionalagentssuchasbeta‐adrenergic
receptorantagonistsorcalciumchannelblockersandACEinhibitorsor
angiotensinreceptorblockersshouldbeinitiatedwithanyevidenceof
hypertrophicremodelling,regardlessofsymptomaticstatus.Doses
shouldbeoptimisedforpatients’size,weightandage.
2.3.2. Furthermanagementofthesepatientsshouldbeconsideredbya
cardiologistwithawarenessofthevariousmanifestationsofcardiac
involvementinmitochondrialdiseaseevenifcurrentlyasymptomatic.
2.4. Conductionblockandpacemakerimplantation:
2.4.1. Patientsfulfillingconventionalguidelines(EuropeanSocietyof
CardiologyorAmericanCollegeofCardiology/AmericanHeart
Association)forimplantationofpermanentpacemakersshouldbe
offeredthistherapywithoutdelay,duetotheunpredictablenatureof
progression.
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2.4.2. Permanentpacemakerimplantationmayadditionallybeconsidered
prophylacticallyforpatientswithanydegreeofatrio‐ventricular(AV)
block(includingfirst‐degreeAVblock>300ms)oranyfascicularblock
withorwithoutsymptoms,especiallyifthereisevidenceof
progressiveabnormalities.
2.5. Ventricularpre‐excitationsyndromes:
2.5.1. Allpatientswithevidenceofanaccessorypathwayshouldbeoffered
anelectrophysiologicalstudy(EPS)todefineconductionpropertiesand
whetherthepathwayandAV‐nodecansustainAV‐reentrytachycardia
(AVRT).
2.5.2. Catheterablationisindicatedforaccessorypathwayscapableof
rapidantegradeconduction(iepathwayantegradeeffectiverefractory
period<230ms)andinthoseabletosupportsustainedre‐entry
tachycardia.Theoptionofpathwayablationshouldbediscussedwith
allpatientsundergoinginvasiveEPSsincethesuccessrateofthis
procedureishigh(~95%)atverylowrisk.
2.6. Atrialfibrillation(AF):
2.6.1. Annualcardiacscreeningprovidesthebestwayofprotecting
patientswithmitochondrialdiseaseagainstthedevelopmentofAF.By
timelyidentificationandappropriatetreatmentofasymptomaticleft
ventricularsystolicand/ordiastolicdysfunction,theoccurrenceofAF
maybeminimised.
2.6.2. ThemanagementofAFinpatientswithmitochondrialdiseaseshould
beindividualisedtothepatientandinvolveacardiologistwith
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awarenessofthevariousmanifestationsofcardiacinvolvementin
mitochondrialdisease.
2.6.3. Managementmayincorporate:controlofventricularresponserate
(inpersistentorpermanentAF)withthetargetheartratesof<100
bpmatrestand<130bpmonmoderateactivity;anti‐arrhythmicdrug
therapyordirectcurrentcardioversiontorestoresinusrhythm;or
maintenanceanti‐arrhythmicdrugtherapytomaintainsinusrhythm
(inparoxysmalorpersistentAF).
2.6.4. Themostappropriateanti‐arrhythmicagentforanindividualpatient
willneedtotakeaccountoftheextentofothercardiacinvolvement(ie
severityofleftventricularsystolicordiastolicdysfunction;degreeof
leftventricularhypertrophy;comorbiditiesandinteractionswithother
medications).
2.6.5. PatientswithestablishedcardiomyopathyandAFareatriskof
thrombo‐embolicdiseaseandshouldreceiveanti‐plateletoranti‐
coagulanttherapyaccordingtoconventionalguidelinesforstroke
prevention(egCHADS2orequivalent).
2.7. Implantablecardioverter‐defibrillators(ICDs)
2.7.1. Thereisnocurrentclinicalevidencethatpatientswithmitochondrial
diseasehaveanincreasedriskofventriculartachyarrhythmia,inthe
absenceofsignificantleftventriculardysfunctionorconductionsystem
disease.
2.7.2. Conventionalguidelines(egNICETechnologyAppraisal95)forthe
implantationofICDsforbothprimaryandsecondarypreventionshould
befollowed–usingleftventricularfunction,QRSwidth+/‐Holter(24‐
11
hour)ECGrecordingandEPStoassesstheriskofventricular
tachyarrhythmia.
2.8. Leftventricularsystolicdysfunction:
2.8.1. Whilesomepatientswithmitochondrialdiseasemaypresentwith
cardiacinvolvement,otherpatientsmaydevelopleftventricular
systolicdysfunctionovertimesothatscreeninginvestigationsremaina
cornerstoneofdiseasemanagement.
2.8.2. Conventionalguidelinesforthemanagementofclinicalheartfailure
andsymptomaticleftventricularsystolicdysfunctionshouldbe
followedincludingtheuseofspecialistservices,complexdevicesand
considerationofcardiactransplantation,whereappropriate.
2.9. Pre‐operativeassessments:
2.9.1. Allpatientswithmitochondrialdiseaseshouldhaveastandard12‐
leadECGaspartofroutinepre‐operativeassessment.
2.9.2. Anup‐to‐dateechocardiogram(withinthepreceding12months)
shouldbeavailableforrevieworshouldberepeated.
2.9.3. Furtherpre‐operativeassessmentshouldbeperformedonan
individualisedbasis,consistentwithconventionalguidelines(eg
EuropeanSocietyofCardiologyorAmericanCollegeofCardiology/
AmericanHeartAssociation).
2.9.4. Liaisonwiththemitochondrialspecialistresponsibleforthepatientis
stronglyrecommendedpriortoanyintervention,unlessthiswould
incuranunacceptabledelaytotreatment.
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3. NotesonthescopeofthisguidanceTheguidelinewasdevelopedbyexpertsinmitochondrialdiseaseandcardiacdiseasebasedattheNewcastleMitochondrialCentreandtheNewcastleuponTyneHospitalsNHSFoundationTrust.Thisgroupspecifiedwhichaspectsofthescreening,diagnosisandmanagementofcardiacinvolvementinpatientswithmitochondrialdiseasewastobeincludedandexcluded.
3.1. Audience Theseguidelineareintendedforusebythefollowingpeopleor organisations:
• allhealthcareprofessionals• peoplewithmitochondrialdiseaseandtheircarers• patientsupportgroups• commissioningorganisations• serviceproviders
3.2. GuidelineLimitationsLimitationsoftheseguidelinesinclude:
• Lackofafirmevidencebaseforreference.Guidelinesinmitochondrialdiseasearecurrentlyunabletoadopttheevidence‐basedapproachusedbyorganisationssuchasNICE,andatpresentarepredominantlybasedonconsensusexpertopinion.
• Overall,theevidencereviewidentifiednorandomizedcontrolledtrialsorhighqualitycase‐controlorcohortstudies.
• Furtherstudiesareneeded(seeresearchrecommendationsbelow).• SpecialistMitochondrialCentresarelocatedinNewcastle,London,
andOxford.Thedevelopmentofthesecentresrepresentsanimportantadvanceinthecareofpatientswithmitochondrialdisease.
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4. Implementation
Integraltothisguidelineispublicationofthebenefitsofaccesstoaspecialistclinicwithexperienceinmitochondrialdisease.• Specialistmitochondrialclinicsareprovidedbyselectedcentreswiththe
supportoftheNationalCommissioningGroup.Theaccumulationofexperiencewithinthesecentres,andaccesstofocussedmulti‐disciplinaryteaminputisdesignedtoofferthebestavailablecareforpatientswithmitochondrialdisease.
• CentresarecurrentlylocatedinNewcastle,LondonandOxford.TheNewcastleMitochondrialCentreiscurrentlynegotiatingprovisionofoutreachclinicsinothercentrestofacilitateeasieraccessforpatientswhodonotresidewithinareasonabledistanceoftheexistingcentres.
• Patienteducationisanimportantaspectoftheinitialconsultation,butalsoasavitalcomponentoffuturecare.Weaimtoprovideanunderstandingoftheroleofcardiacscreening,andthepotentialimpactofscreeningandearlyinterventiononprognosis.
• Accesstospecialistclinicsallowsrelevantgeneticcounsellingandfamilytracingtofacilitatetheidentificationofthoseatriskofdevelopingdisease.Thepotentialforsignificantcardiacdiseasetodevelopinasymptomaticrelativeshighlightstheimportanceofthisprogramme.
• Closeliaisonisrequiredbothwithcardiologyservicesatthespecialistcentreitself,butalsolocalcardiologyserviceswhomaybecloselyinvolvedwithfuturefollowupandmanagementofpatientswherefrequentcentralreviewisimpractical.
Robert McFarland � 2/7/10 08:28Deleted: forRareDiseases
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5. Researchrecommendations5.1. Naturalhistorystudies
Comprehensiveassessmentofalargecohortofmitochondrialdiseasepatientsfromavarietyofgenotypicandclinicalgroupsisrequiredtodocumenttheeffectsofcardiacdiseaseonmorbidityandmortality.
5.2. Energy‐sparingmedicationsinhypertrophicremodellingCurrentuseofbetaadrenergicreceptorantagonistsorcalciumchannelblockermedicationsandangiotensin‐convertingenzymeinhibitorsorangiotensinreceptorsblockersinmitochondrialdiseasepatientswithhypertrophicremodellingisempirical,basedonresultsfromanimalstudies,othergeneticallydeterminedcauses(predominantlysarcomerichypertrophiccardiomyopathy),andlargeregistriesofnon‐genetichypertrophicremodelling.Anassessmentoftheclinicalutilityofthisapproachisurgentlyneeded.
5.3. Cardiacmagneticresonanceimaging/spectroscopy(MRS)CardiacMRSrepresentsanoveltechniqueforstudyingabnormalcardiacbioenergeticsinvivo.Anassessmentoftheinteractionbetweencardiacbioenergeticsandhypertrophicremodellingisurgentlyneededandmayallowforthefutureclinicalassessmentofinterventions.
5.4. ExerciseinpatientswithmitochondrialdiseaseandcardiomyopathyCurrentlyavailableevidencewouldsupportthebenefitsofexercisetherapyinmitochondrialdiseaseandalsoinpatientswithcardiomyopathyofdifferentaetiologies.Thereishowevernocurrentevidenceofsafetyand/orbenefitofthisapproachinmitochondrialdiseasepatientswithcoexistentcardiomyopathy.
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6. Updatingtheguideline
TheNewcastleMitochondrialGuidelinesareupdatedasneededsothatrecommendationstakeintoaccountimportantnewinformation.Wecheckfornewevidenceevery2yearsafterpublication,todecidewhetherallorpartoftheguidelineshouldbeupdated.Ifimportantnewevidenceispublishedatothertimes,wemayupdatetheguidancepriortoanyscheduledchanges.
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AppendixA:TheGuidelineDevelopmentGroup DrAndrewMSchaeferConsultantNeurologistNewcastleMitochondrialCentreDrMatthewGDBatesWellcomeTrustClinicalResearchFellowNewcastleUniversityDrJohnPBourkeConsultantCardiologistandElectrophysiologistNewcastleuponTyneHospitalsNHSFoundationTrustDrRobertMcFarlandDoH/HEFCEClinicalSeniorLecturerNewcastleMitochondrialCentreProfessorDouglassMTurnbullProfessorofNeurologyNewcastleMitochondrialCentre
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AppendixB:Screening/managementalgorithm
Key: ACEi angiotensinconvertingenzymeinhibitorARB angiotensinIIreceptorblocker
CHB completeheartblockTFB trifascicularblock
SVT supra‐ventriculartachycardiaWPW Wolff‐Parkinson‐Whitesyndrome
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