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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‐

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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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