www.revportcardiol.org
Revista
Portuguesa
de
Cardiologia
Portuguese
Journal
of
Cardiology
ORIGINAL
ARTICLE
The
Portuguese
Registry
of
Hypertrophic
Cardiomyopathy:
Overall
results
Nuno
Cardim
a,∗,
Dulce
Brito
b,
Luís
Rocha
Lopes
c,d,
António
Freitas
e,
Carla
Araújo
f,
Adriana
Belo
g,
Lino
Gonc
¸alves
h,
Jorge
Mimoso
i,
Iacopo
Olivotto
j,m,
Perry
Elliott
k,m,
Hugo
Madeira
l,
on
behalf
of
the
participating
centres
1aHospitaldaLuz,Lisboa,Portugal;FaculdadedeCiênciasMédicas,UniversidadeNovadeLisboa,Lisboa,Portugal
bHospitaldeSantaMaria,CentroHospitalarLisboaNorte(CHLN),CentroCardiovasculardaUniversidadedeLisboa(CCUL),
FaculdadedeMedicina,UniversidadedeLisboa,Lisboa,Portugal
cBartsHeartCentre,BartsHealthNHSTrust;InstituteofCardiovascularScience,UniversityCollegeLondon,UnitedKingdom
dCentroCardiovasculardaUniversidadedeLisboa,Lisboa,Portugal
eHospitalFernandodaFonseca,Amadora-Sintra,Portugal
fCentroHospitalardeTrás-os-MonteseAltoDouro,EPE,HospitaldeSãoPedro,VilaReal,Portugal;EpidemiologyResearchUnit
(EPIUnit),InstitutodeSaúdePública,UniversidadeofPorto(ISPUP),Porto,Portugal
gSociedadePortuguesadeCardiologia,DepartamentodeBioestatística,Coimbra,Portugal
hCentroHospitalareUniversitáriodeCoimbra-HospitalGeral;FaculdadedeMedicinadaUniversidadedeCoimbra,Coimbra,
Portugal
iCentroHospitalardoAlgarve,Faro,Portugal jCareggiUniversityHospital,Florence,Italy
kBartsHeartCentre,BartsHealthNHSTrust/InstituteofCardiovascularScience,UniversityCollegeLondon,UnitedKingdom
lCentroCardiovasculardaUniversidadedeLisboa,Lisboa,Portugal
mMemberoftheScientificCommitteeofPRo-HCM
Received17July2017;accepted8August2017
KEYWORDS Hypertrophic cardiomyopathy; Registry; Leftventricular hypertrophy; Outcome Abstract
Introduction:WereporttheresultsofthePortugueseRegistryofHypertrophicCardiomyopathy, aninitiativethatreflectsthecurrentspectrumofcardiologycentersthroughouttheterritory ofPortugal.
Methods:Adirectinvitationtoparticipatewassenttocardiologydepartments.Baselineand outcomedatawerecollected.
Results:A total of29 centers participatedand 1042patients were recruited. Four centers recruited49%ofthepatients,ofwhom59%weremale,andmeanageatdiagnosiswas53±16 years.Hypertrophiccardiomyopathy(HCM)wasidentifiedasfamilialin33%.Themajorreason for diagnosis wassymptoms(53%).HCMwasobstructivein35%ofcasesandgenetictesting
∗Correspondingauthor.
E-mailaddress:cardimnuno@gmail.com(N.Cardim).
1 ListofparticipatingcentersandprincipalinvestigatorsareprovidedinAppendixA.
https://doi.org/10.1016/j.repc.2017.08.005
wasperformedin51%.Invasiveseptalreductiontherapywasofferedto8%(23%of obstruc-tivepatients).Most patients(84%) hadanestimatedfive-year riskofsudden deathof<6%. Thirteenpercentreceivedanimplantablecardioverter-defibrillator.Afteramedianfollow-up of3.3years(interquartilerange[P25-P75]1.3-6.5years),31%wereasymptomatic.All-cause mortality was 1.19%/year andcardiovascular mortality0.65%/year. The incidence of heart failure-relateddeathwas0.25%/year,ofsuddencardiacdeath0.22%/yearandofstroke-related death0.04%/year.Heartfailure-relateddeathplushearttransplantationoccurredin0.27%/year andsuddencardiacdeathplusequivalentsoccurredin0.53%/year.
Conclusions:Contemporary HCM inPortugal ischaracterized by relatively advancedage at diagnosis,andahighproportionofinvasivetreatmentofobstructiveforms.Long-termmortality islow;heartfailureisthemostcommoncauseofdeathfollowed bysuddencardiacdeath. However, theburdenofmorbidity remainsconsiderable,emphasizingthe needfor disease-specifictreatmentsthatimpactthenaturalhistoryofthedisease.
©2017SociedadePortuguesadeCardiologia.PublishedbyElsevier Espa˜na, S.L.U.Allrights reserved. PALAVRAS-CHAVE Miocardiopatia hipertrófica; Registo; Hipertrofia ventricularesquerda; Prognóstico
RegistoPortuguêsdeMiocardiopatiaHipertrófica:resultadosglobais Resumo
Objetivo:Apresentac¸ãodosresultadosdoRegistoPortuguêsdeMiocardiopatiaHipertrófica. Metodologia:ConvitediretoaosdiferentescentrosdecardiologiadePortugal,comanálisede dadosbasaisedeseguimento.
Resultados: Foram 29 os centros participantes e 1042 doentes incluídos. Quatro centros incluíram49%dosdoentes,59%dosexomasculino,idademédiadediagnóstico53±16anos. Adoenc¸afoiconsideradafamiliarem 33%eapresenc¸adesintomasfoiaprincipalcausade diagnóstico(53%).Amiocardiopatiahipertróficafoiobstrutivaem35%.Oestudogenéticofoi efetuadoem51%.Oitoporcentodosdoentesfizeramterapêuticainvasivadereduc¸ãoseptal (23%dosdoentescomobstruc¸ão).Amaioriadosdoentes(84%)apresentavaumriscoestimadode mortesúbitaaos5anos<6%.Em13%foicolocadodesfibrilhadorcardioversorimplantável.Após umseguimentode3,3anos,intervalointerquartil(P25-P75)1,3---6,5anos,31%estavam assin-tomáticos.Amortalidadetotalfoide1,19%/anoeacardiovascularde0,65%/ano.Aincidência demorteporinsuficiênciacardiacafoide0,25%/ano,ademortesúbitade0,22%/anoeade morteporacidentevascularcerebalde0,04%/ano.Amortalidadeporinsuficiênciacardíacae transplantecardíacofoide0,27%/anoeademortesúbitaeequivalentesde0,53%/ano. Conclusões:AmiocardiopatiahipertróficaemPortugalapresentaidadedediagnósticoelevada eéfrequenteotratamentoinvasivodeformasobstrutivas.Amortalidadeébaixa,ainsuficiência cardíacaéaprincipalcausademorte,seguidapelamortesúbita.Adoenc¸aapresentaelevada morbilidade,realc¸aanecessidadedodesenvolvimentodetratamentosespecíficoscomimpacto nasuahistórianatural.
©2017SociedadePortuguesadeCardiologia.PublicadoporElsevierEspa˜na,S.L.U.Todosos direitosreservados.
Listofabbreviations AF atrialfibrillation ASA alcoholseptalablation CMR cardiacmagneticresonance CRF casereportform
HCM hypertrophiccardiomyopathy HF heartfailure
ICD implantablecardioverter-defibrillator IVS interventricularseptum
LVH leftventricularhypertrophy
PRo-HCM PortugueseRegistryofHypertrophic Cardiomyopathy
SCD suddencardiacdeath TIA transientischemicattack
Introduction
Hypertrophiccardiomyopathy (HCM) representsan impor-tant health burden as a cause of sudden cardiac death (SCD),heartfailure(HF),atrialfibrillation(AF)andstroke. HCM shares many disadvantages of rare diseases, includ-inglimitedrecognition,lackofprospectivestudiesassessing treatment,andlittleordelayedaccesstoadvanced treat-mentoptionswithoutenjoyingtheirregulatorybenefits.1---4
Randomized clinical trialsareinfrequentin HCM and rec-ommendations are largely based on expert consensus.1---4
Additionally,themajorityofstudiesstilloriginatefrom ter-tiaryreferralcenters,andlittleisknownabouttheclinical profileandmanagementofthediseaseatanationwidelevel. Therealimpactofgeneticsandimagingtechniqueson ear-lierandwider recognitionofHCM, aswell asof advanced treatment options on outcomes, is also unknown. It is of paramount importance to capture these changes and to provideanswerstothesequestions.1,2,5
Accordingly,theimportanceofclinicalregistriesofHCM is increasing, since they provide the bestsource of real-worlddatainspecificcountriesandgeographicalregions.
Assuming a prevalence of 1:5005 for HCM in general
and of 1:3200 for ‘clinical HCM’6 (patients who come to
medicalattention),thenumberofpatientswithHCMin Por-tugal (population about 10 million) is respectively around 200007and3000.6However,fewstudieshaveaddressedthis
population.8,9Besidesitsrelevancetonationalcardiologists,
the Portuguese HCM population represents an interesting samplebecauseofthecountry’srelativelysmallsize, homo-geneouspopulationandhighpenetrationofhealthcare.
The Portuguese Registry of Hypertrophic Cardiomyopa-thy(PRo-HCM)wasinstitutedtocollectinformationonthe actualsituationofHCMinPortugal.Itspecificallyassessed epidemiological, sociodemographic and clinical data, cur-rent standards for diagnosis, treatment, follow-up, and outcomes.Anotheraimwastodevelopareliablesourceof informationforhealthprofessionals,patientsandfamilies, onappropriateness,effectivenessandqualityofcare.
Methods
Registrydesignandmethodology
ThePRo-HCMregistrywasconceivedbytheWorkingGroup on Myocardial and Pericardial Diseases of the Portuguese Society ofCardiology, directedbyan executive anda sci-entificcommittee,andmanagedinthePortugueseNational CenterforDataCollectioninCardiology(CNCDC).Thisstudy wasformulatedandconductedincompliancewiththe prin-ciplesofthedeclarationof Helsinki,andapprovedby the National Center for Data Protection. It was an observa-tional,multicenter,voluntary,non-mandatorystudy,witha two-yearenrollment period(April 2013-April2015), retro-spectivebutincludingaprospectiveupdate.
Adirectinvitationwasmadetocardiologydepartments nationwide,centralandregional,publicandprivate, aca-demicandnon-academic,coveringruralandurban,coastal andinlandareas.Additionally, theregistrywasadvertised in the Portuguese Journal of Cardiology, meetings and newsletters. If theinvitation was accepted, the principal
investigatorreceived detailedinstructions, acenter iden-tification number and a unique username and password to gain access to the electronic case report form (CRF) (http://www.spc.pt/RegistosMiocardiopatia/Public/Login. aspx?ReturnUrl=%2fRegistosMiocardiopatia%2f). The CRF contained seven sections: (1) patient identification and demographic/epidemiological data; (2) past history and baselineclinical data;(3)mortalityandrisk stratification; (4)diagnostic tests;(5) genetictesting, familyscreening, and genetic counseling; (6) treatment; (7) last assess-ment (clinical course, follow-up, and outcomes). In the diagnostic tests section the investigators were asked to enter the exams performed at the time of first assess-ment,includingelectrocardiogram(ECG),echocardiogram, ambulatory ECG, exercise test, exercise echocardiogram, cardiacmagnetic resonance(CMR), andcardiaccomputed tomography.
Centerswereaskedtoincludeallpatientswitha diagno-sisofHCMfollowedatthecentercurrentlyorinthepast(no retrospectivetimelimit),includingthosealreadydeceased at thetime of enrollment. Written informedconsent was obtainedfromlivingpatientsandfromaproxyofdeceased patients.
Inclusion criteria were age >18 years at the time of enrollment, and unexplained left ventricular hypertrophy (LVH):wallthickness≥15mmbyimagingtechniques(in first-degreerelatives10 ≥14mm in theinferiorinterventricular
septum(IVS)orlateralwallor≥13mmintheanteriorIVS orinferiorwall).
Exclusion criteria were secondary LVH (grade ≥2 hypertension11),moderateorsevereaorticstenosis,12
previ-ouslydiagnosedcardiacorsystemicdisease,andmetabolic ormulti-organsyndromeassociatedwithLVH.
Afterthe inclusion period,extra timewasprovided to complete the CRFs and to clean the database. The final dateofregistryclosurewasDecember31,2015.CRFswere reviewed to confirm consistency of data. Whenever nec-essary,querieswere senttoinvestigators.In theeventof repeatedpatients(sameinitials,genderandbirthdate),the onewiththelongerfollow-uptimewasincluded.
Definitions
Throughoutthe study,most data arerelative tothe time offirstvisit.Whenclinicallyrelevant, dataatthetimeof diagnosisofHCMarealsoshown.
Follow-uptimewasdefinedastimefrominitial assess-mentatthecentertolastassessmentordeath.
Suddencardiacdeath(SCD)wasdefinedasunexpected death occurring within one hour of symptom onset in patientswho had previously experienceda relatively sta-bleoruneventfulclinicalcourse.Resuscitationfromcardiac arrestorappropriateimplantablecardioverter-defibrillator (ICD)therapies forprimarypreventionwereconsidered as equivalentsofSCD.
HF-related death was defined as that occurring in the context of progressive cardiac decompensation, with declineinleftventricularfunction.13Hearttransplantation
wasconsideredasequivalenttoHF-relateddeath.
Stroke-relateddeathsinthesettingofparoxysmal, per-sistentorpermanentAFwereclassifiedasAF-strokerelated
Viana do Castelo Vila Real Braga Porto Viseu Aveiro Guarda Castelo Branco Coimbra Leiria PORTUGAL Santarem Lisbon Portalegre Evora Setubal Beja Faro Madeira Azores Braganca 45.0% 40.0% 35.0% 30.0% 25.0% 20.0% 15.0% 10.0% 5.0% 0.0%
North Central Lisbon South + Islands Central; 7.7%
North; 31.8%
Lisbon; 40.1%
PRo-HCM
South + Islands; 20.4%
PRo-HCM: no. of patients per center
180 160 140 120 100 80 60 40 20 0 C1 C2 C3 C4 C5 C6 C7 C8 C9 C10C11 C12C13C14C15C16 C17C18C19 C20 C21 C22C23 C24 C25 C26 C27 C28 C29 53 45 7 7 10 3 4 7 7 6 3 9 38 21 1 36 104 70 55 144 99 79 14 14 2 27 167 1 9
Figure1 ParticipatingcentersinthePro-HCMregistry:distributionbyregionsandbycenter.Left:participatingcenters(n=29); topright:distributionofthe1042patientsbyregionsofPortugal:theLisbonregionincludedthehighestnumberofpatientsand thecentralregionofPortugalthelowest;bottomright:notetheheterogeneityintermsofpatientsenrolledpercenter.
deaths.Stroke-relateddeathsintheabsenceofdocumented AFwerenotincludedinthisgroup.
Thromboembolic events, defined as stroke, transient ischemicattack(TIA)orsystemicperipheralembolism,were recorded.14
The classification of identified genetic variants was assigned to the investigators, as pathogenic/probably pathogenic, of unknown significance or benign/probably benign, according to current knowledge of their pathogenicity,15,16 as provided by genetic laboratories
(thesedatawerenotcentrallyreviewedorcorrectedbythe coordinatorsof theregistry).A geneticstudy wasdefined asnegativeifnopathogenic/probablypathogenicmutation wasdetectedandasinprogressifnoresultwasprovidedat inclusion.
Statisticalanalysis
Continuousvariableswereexpressedasmeanandstandard deviationorasmedianandinterquartilerange(IQR) (P25-P75).Categoricalvariablesweregivenastotalnumberand percentages.Chi-squareorFishertestswereusedfor com-parisons of categoricalvariables and Student’s t tests for continuousvariables.SurvivalwasassessedbyCox propor-tionalhazardregression.Survivalcurveswereconstructed according to the Kaplan-Meier method, and comparisons wereperformedusingthelog-rank test.Allp-valueswere two-sidedandconsideredsignificantwhen<0.05.All analy-seswereperformedusingSPSS19.0®.
Results
Ofthe62institutionscontacted,37accepted,andthefinal numberofparticipatingcenterswas29(Figure1).Thetotal numberofpatientswas1042.Figureswerecomparedwith othernationalregistries17,18(Table1).
Baselineassessment
Almost half of the patients (n=514, 49%) came from the fourmajorcenterswithspecificinterestinHCM(theother 25centersenrolled528patients,51%)(Figure1).TheLisbon regionincludedthelargestnumber,followedbytheNorth region,theSouthandIslands,andtheCentralregion.Ofthe 29centers,onlythreeincludedmorethan100patientsand eightmorethan50 patients.Twenty-onecentersincluded fewerthan50patientseach,13centersfewerthan10and sixcentersfewerthanfive.
The patient cohort showed a slight preponderance of males. Mean age at diagnosis was 53±16years and more thanonequarterwerediagnosedovertheageof65years. The diseasewasclassifiedasfamilialinonethird. Atfirst consultationmostpatientsweresymptomatic19(Table2).
Diagnostictests
The ECG was abnormal in 964 individuals (93%). AF was recordedin117(11%).
Table1 Comparisonbetweenpopulationsofnationalregistriesofhypertrophiccardiomyopathy.
Portugueseregistry(PRo-HCM) Italianregistry17 Frenchregistry18
Registryperiod 2013-2015 2000-2002 2005-2015
Countrypopulation 10million 50million 66million
Patientsinregistry 1042 1677 1401
EstimatedprevalenceofHCMbasedontheCARDIAstudy:1:5005
HCMpatients 20000 100000 132000
Patientsincludedinregistry 5% 2% 1%
Estimatedprevalenceof‘clinical’HCM:1:32006
Patientswith‘clinical’ HCM 3125 16000 18750
Patientsincludedinregistry 33% 10% 7%
HCM:hypertrophiccardiomyopathy.
Table2 Summaryofbaselinecharacteristicsand diagnos-tictests. n % HCMpatients 1042 Male/female 613/429 59/41 Ageatdiagnosis 53±16(9-88) Diagnosis>50years 605 58 Diagnosis>65years 281 27 Familial/sporadic 347/559 33/54 Non-obstructiveHCM 613 59 ObstructiveHCM 365 35
Reasonfordiagnosis
Symptoms 551 53 Incidental 319 31 Familyscreening 129 12 Symptomsatfirstconsultation Asymptomatic 311 30 Symptomatic 715 69 Dyspnea 328 32 Angina 241 23 Palpitations 189 18 Syncope 95 9 NYHAI/II/III/IV 146/792/94/10 14/76/9/1 Imagingmethodofdiagnosis
Echocardiography 932 89 CMR/CCT 110 11 Holter 867 83 Exercisetest 437 42 Exerciseechocardiography 175 17 CMR 475 46 CA 122 12 EMB 12 1 Genetictest 528 51
CA:cardiacangiography;CCT:cardiaccomputed tomography;
CMR:cardiacmagneticresonance;EMB:endomyocardialbiopsy;
HCM:hypertrophiccardiomyopathy;NYHA:NewYorkHeart
Asso-ciationfunctionalclass.
Echocardiographicassessmentatenrollmentshowedthat HCMwasnon-obstructive(instantaneouspeakDoppler intra-ventricular pressure gradient <30 mmHg) in 613 (59% of patients)andobstructivein365(35%)(Table2).Ofthese,
323(88%)hadobstructionatrestand42(12%)had exercise-inducedobstructiononly,duringexerciseechocardiography. Obstructionwasattheleftventricularoutflowtractin89%. Anapicalaneurysmwaspresentin23patients(2%).
OnambulatoryHolterECGmonitoring,AFwaspresentin 118patients(11%).Anexercisetestwascarriedoutinless thanhalfofthepopulationandexerciseechocardiography inapproximatelyonefifth(Table2).
CMRwasperformedinalmosthalfofthecohort.Its incre-mentalvalueoverechocardiographywastheassessmentof fibrosis(59%), diagnosisin false-negativeechocardiograms (6%)anddetectionofmassiveLVH(4%).
Riskstratificationforsuddencardiacdeath atbaseline(atthetimeofthefirstvisit)
BasedontheAmericanHeartAssociationmodelforSCD2,20
(SupplementaryTable1),halfofthepatientshadnorisk fac-tors,onethirdhadoneriskfactor and15%morethanone riskfactor.Ourdataalsoshowedthataccordingtothe Euro-peanSocietyofCardiology SCDriskscore,1,21 themajority
ofpatientshadafive-yearrisklowerthan4%. Genetictesting
Intotal,51%ofthepatientshadundergonegenetictesting andin40%oftheseapathogenic/probablypathogenic muta-tionwasfound(Table3).Inthisgroup,whenthecausative genemutationwasreported,thetwomostfrequentgenes
wereMYBPC3andMYH7.
Treatment
Most patients (n=909; 87%) received medical treatment (Table4).Septalreductiontherapywasperformedin8%of thecohort, 23%of theobstructive group.Cardiac surgery wasperformed2.6timesmorefrequentlythanASA.Surgery wasperformedin11centers(ofthese,onlytwoperformed morethan10surgeries).ASAwasperformedinfourcenters (onlyonereached10procedures).
AnICD wasimplantedin 13%of thepopulation,mainly forprimaryprevention.Apacemakerwasimplantedin9%, usuallyforconductiondisorders.
Table3 Resultsofgenetictesting.15,16
n %
HCMpatientstested 528 51
Positive 210 40
VUS 40 8
Pathogenic/probablypathogenicmutationa 210
MYBPC3 99 49 MYH7 56 28 TNNT2 25 12 TNNI3 10 5 TPM1 8 4 CRSP3 8 4 MYL3 2 1 MYL2 1 0.5
CRSP3: muscle LIM protein; HCM: hypertrophic cardiomyopa-thy;MYBPC3:cardiacmyosin-bindingproteinC;MYH7:myosin heavychain;MYL2:regulatorymyosinlightchain;MYL3: essen-tialmyosinlightchain;TNNI3:cardiactroponinI;TNNT2:cardiac troponinT;TPM1:tropomyosin;VUS:variantsofunknown signif-icance.
aRawdataderivedfromCRFdata,insertedbythe
investiga-torsasreportedbythegeneticlaboratoryandnotconfirmedby thecoordinatorsoftheregistry,includingtheattributed classi-ficationof‘pathogenic/probablypathogenicmutation’.
Table4 TreatmentinthePRo-HCMregistry.
n % Beta-blockers 768 74 CCBs 262 25 Disopyramide 19 2 Amiodarone 151 15 Anticoagulants 276 27 VKAs 208 75 NOACs 60 22 ACEIs 226 22 ARBs 178 17 Diuretics 252 24 Nitrates 24 2 ASA 23 2 Surgery 61 6 ICD 140 13 Primaryprevention 123 88 Secondaryprevention 15 11 Pacemaker 92 9 Bradyarrhythmia 64 70 Gradientreduction 19 21
ACEIs: angiotensin-converting enzyme inhibitors; ARBs:
angiotensin receptor blockers; ASA: alcohol septal ablation;
CCBs:calciumchannelblockers;ICD:implantablecardioverter
defibrillator:NOACs:neworalanticoagulants;VKAs:vitaminK
antagonists.
Follow-up,morbidityandmortality
Meanfollow-upwas5.3±6.1years,median3.3 years(IQR [P25-P75]1.3-6.5years).Atlastassessment,mostpatients weresymptomatic(Figure2),usuallywithmildtomoderate
symptoms. A small number (n=42, 4%) developed systolic dysfunction.
All-cause mortality was 6.2% (Table 5). Cardiovascular mortalitywas3.4%,mostfrequentlyduetoHF,followedby SCDandbystroke-relateddeath.
In univariate analysis, 16 of the predefined variables weresignificantlyrelatedtomortality.Multivariateanalysis showed four major risk indicators of cardiovascular mor-tality: late diagnosis (>60 years), family history of SCD, progressivesystolicdysfunctionandobstructiveHCM (Sup-plementaryTable2).
Of the 12 patients with SCD, seven were between 40 and65 yearsold,threewere olderthan65, andonlytwo were aged under 40 years. In a number of patients SCD was aborted by appropriate ICD shocks in the setting of primary prevention or documented successful in- and/or out-of-hospitalresuscitation.Therefore,actualplusaborted SCDoccurredin29patients.
Theincidenceofall-causeandcardiovascularmortality was1.19%/yearand0.65%/year,respectively;theincidence ofHF-relateddeathwashigherthanthatofSCD,andthe lat-terwashigherthanthatofstroke.However,theincidenceof SCDdeathplusequivalentswashigherthantheincidenceof HFdeath,withorwithoutequivalents(Table5andFigure3). Thromboembolic events occurred in 65 patients (6%) (stroken=52,TIAn=11,peripheralembolismn=2).Ofthese, halfhaddocumentedAF.
Compared with low-volume centers (<15 patients included, n=16), high-volume(>100patients,n=3) centers hadyoungerpatientsandmorefamilialHCMandperformed moregenetictesting,familyscreeningandexclusionof phe-nocopies(SupplementaryTable3).Additionally,despitethe highernumberofdiagnostictestsandofdrugprescriptions ofhigh-volumecenters,nomajordifferencesinoutcomes werefound.
Discussion
The PRo-HCM registry provides a detailed contemporary assessment of the clinical profile, management strategies and outcomes of HCM in Portugal. While most data are consistent with the existing literature,17,18,22 the present
findings show elements of novelty and some differences from the guidelines.1,2 Our results are important at both
nationalandinternationallevel,asseveralcountries, world-wide,mayfacesimilarconditionsinthemanagementofthe disease.
Epidemiologicalandsociodemographicdata
Thetotalnumberofpatientsincludedrepresentsabout5% of the estimated prevalence in Portugal,5,7 but up toone
third of the Portuguese population with ‘clinical’ HCM.6
Accordingly, this is, toour knowledge, the most compre-hensivenationalHCMregistrypublished.17,18,22Thisnational
effortprovidescredibilitytoourdataasrepresentativeof the realPortuguese scenario. The distribution of patients betweenreferral andcommunity-based centers(four cen-tersincludedhalfofthepatientsand25centerstheother half) shows that a significant number of patients are fol-lowed in non-referral centers.Of note, however, wasthe
Population 600 550 500 450 400 350 300 250 200 150 100 50 0 Asymptomatic Symptomatic 327 578 600 500 400 300 200 100 0
Mild/Moderate Severe Undetermined 15 41 522 Symptomatic patients 327 578
Figure2 Follow-updata:symptomsatlastassessment.Atthelastassessmentmostpatientsweresymptomatic(left),andthe majorityhadmildtomoderatesymptoms(right).
Table5 MortalityinthePRo-HCMregistry.
n Mortalityrate
Totalmortality 65 1.19%/year
CVmortality 36 0.65%/year
HF-relateddeath 14 0.25%/year
SCD 12 0.22%/year
Stroke-relateddeath 2 0.04%/year
Other 8 0.15%/year
SCDequivalents 17 0.31%/year
SCDdeathplusequivalents 29 0.53%/year
HFequivalents 1 0.02%/year
HFdeathplusequivalents 15 0.27%/year
CV: cardiovascular; HF: heart failure; SCD: sudden cardiac
death.
lowproportionofreportedfamilialHCM,probablyreflecting alowrateofsystematicfamilyscreeningprogramsand/or areferralcenterbiasinanotherregistry.22
Baselineassessment
Over a decade since the publication of another national registry,17 theclinical spectrumof HCM appearsvery
sim-ilar, suggesting that its clinical profile is not undergoing majorchangesintheWesternworld.Themajordifference istheolderageatdiagnosis,withmorethanonefourthof patients diagnosed over the age of 65 years. This finding mayreflectdelayeddiseasepenetrance,lackofsystematic familyscreening,and---potentially---anincreased diagnos-tic yield in older patients.1,2 By contrast,the association
foundinourcohortofalowrateoffamilialHCM,laterage ofpresentation,andlowriskprofile,maymoreclosely mir-rorthereal-worlddiseasescenario,reflectingtheinclusion oftheseunselectedlower-riskHCMpatientsinthecohort. Recentreportshaveinfactidentifiedalower-riskcohortof HCM patients, withlater onsetand lowerrate of familial disease,23,24whichmayexplainourfindings.
Theproportionofobstructiveformsinourcohort,about one third, basically reflects patients with obstruction at rest,andisconsistentwiththeexistingliteratureforresting
obstruction.1,2Accordingly,duetothelowrateofexercise
echocardiographyperformed,25 many patients with labile
obstructionwereprobablynotdetectedandwereclassified asnon-obstructive,whichatfirstsightsuggestsadeviation fromthe guidelines. However,as the recommendations1,2
fortheuseofexerciseechocardiographyinnon-obstructive HCMatrest arerelatively recent,someofthesepatients, assessed earlier, have not undergone exercise echocar-diography and were diagnosed as non-obstructive in this observationalstudy.
Diagnostictestsandsuddencardiacdeathrisk stratificationatbaseline
Our data show a relatively limited penetration of CMR, despite the evidence of its incremental value.1---4 These
results reflect its high costs, limited availability, and relatively recent introduction in clinical practice.1---4
By contrast,despite the factors that limitthe dissemina-tionof genetictesting1,2 (price, lack of co-payment, low
availability),halfofthepatientsunderwentgeneticstudy, whichin manycases isalreadypart ofroutinepractice.26
Theproportionoftestsinwhichavariantwasfound15,16,27,28
andtherelativeprevalenceofthedisease-causinggenesis mostlysimilartowhathasbeendescribed.1,2,15,16,27,28
How-ever,accordingtotheresultsprovidedbytheinvestigators, an unexpectedly high prevalence of pathogenic/probably pathogenic mutations15,16,27,28 was found in the TPM1 and
CSRP3 genes.17 These results should be interpreted with
caution,becausetheyarederivedfromCRFrawdatathat werenotcentrallyreviewedor correctedby thePRo-HCM coordinators.
BothofthecontemporarymodelsforSCDrisk1,2,20,21show
thatourcohortwas,at baseline,alow-risk populationfor SCD,whichpartiallyexplainsthelowrateofSCDandofICD implantations.
Treatment
Invasiveseptalreductionwasofferedtoalmostonefourth of obstructive patients, including those who were mildly
Cause Cause
CV CV
HF HF
SCD SCD
Stroke Stroke
Hazard function Hazard function
0.20 0.20 0.15 0.15 0.10 0.10 0.05 0.05 0.00 0.00 0 5 10 15 20 0 5 10 15 20
Follow-up (years) Follow-up (years)
Cum ulativ e hazard Cum ulativ e hazard HF+Equiv SCD+Equiv
Figure3 Kaplan-Meier estimatesof thecumulative hazard function for mortalityduring follow-up.Left: cumulative hazard functionformortality;right:cumulativehazardfunctionformortality,includingsuddencardiacdeathandheartfailureequivalents. Seetextforexplanation.CV:cardiovascularmortality;HF:heartfailuremortality;HF+Equiv:heartfailuremortality+equivalents; Stroke:strokerelatedmortality;SCD:suddencardiacdeathmortality;SCD+Equiv:suddencardiacdeathmortality+equivalents.
symptomatic.Althoughitcannotbeexcludedthatthisrate isbiasedbythelownumberofpatientsdetectedwithlabile obstruction,itprobablyalsoresultsfromknowledgeofthe adverse long-term effects of obstruction, aswell as from thesafetyofinvasiveprocedures,whichmayimpactfuture HCMguidelines.
Ofnote, thenumberof surgicalmyectomies wasmuch higherthanthenumberofASAprocedures,whichispartially explainedbythelateintroductionofthelatterinPortugal (2009).29Thefactthatthetwoprocedureswereperformed
indifferentcentersdeservesreflection,takingintoaccount theknowneffectofexpertiseonresults.1,2
Finally,fewerthan15%ofpatientsreceivedanICDduring follow-up,reflectingthelowriskprofileofournon-selected population.
Follow-up,morbidityandmortality
Overall, our data suggest that in Portugal, in the era of betterdiagnosticandtherapeutictechniques,HCMhaslow mortalitybuthighmorbidity.
Additionally,despitegreateruseofdiagnostictestsand differencesinmedicaltreatment,outcomesofhigh-volume centersaresimilartothoseoflow-volumecenters,calling intoquestionthevalueofHCMcentersandofthe‘huband spoke’model.7
OutcomedatashowthattheSCDrateinHCMpatientsin Portugalisverylow.Eventhoughthisfindingmaybepartially explainedbylivessavedbysuccessfulresuscitationandICD implantation,theincidenceofSCDisstilllowafterincluding theseSCDequivalentsintheSCDrate.Asaconsequenceof
theefficacyofthesepreventivemeasures,HFhasbecome theleadingcauseofdeathinHCMpatientsinPortugal.
Our figures are in overall agreement with those from other groups,30 showing that overall mortality in treated
HCM in Portugal is 1.19%, similar to that of the general Portuguese population (around 1.1% year).31 Importantly,
at follow-up most patients weresymptomatic, confirming that disease morbidity representsa significant burden to patients, health care services and providers. Accordingly, the ‘‘contemporary treatable disease’’30 has became, at
least in Portugal, a‘‘contemporary chronic treatable dis-ease’’inwhich,sidebysidewithICDs,theroleofchronic medicaltreatmentisincreasing.
Limitations
Despitetheirinherentlimitations,registriesprovide realis-ticgeographicaldataondiseasecourseandmanagement.
The inclusion of mostly symptomatic patients with advanced, established disease (mainly included by HCM referral centers)is a limitation of this registry, providing abiasedviewofthedisease(selectionbias,acommon lim-itationofmanyHCMstudies).
Additionally, disease-related mortality is underesti-mated, as patients who died before diagnosis were not included. Thissurvival biaspartiallyexplainsthelow rate ofevents,especiallythelowrateofSCD.
Children were excluded because of important clinical differences.1,2
Futuredirections
The identification, at a national level, of discrepancies betweenourdataandtheguidelinesisanimportantfinding, warrantinga nationalefforttocorrectthem (forinstance toincludeexercise echocardiographyasastandard initial assessmentofnon-obstructiveHCMatrest,tobetterdetect labileobstruction).
Because of the large volume of data, we were unable tocover some important topics in depth. Accord-ingly, further work will be directed at comparisons between subgroups, addressing family screening, genetic testing (including founder effects, differences in pheno-type between genes, and analysis of specific mutations considered as pathogenic/probably pathogenic by the investigators), awareness of phenocopies (for instance Fabry disease), and detailed assessment of clinical HCM profiles.
Conclusions
ThePRo-HCM registryprovidescomprehensivedataonthe managementofHCMinPortugalintheeraofgenetics,CMR, ICDs andASA,andindicates theneedfor betteraccessto resourcesandsomedeviationsfromguidelines.
Contemporary HCM in Portugal is characterizedby rel-atively advanced age at diagnosis, and a high proportion of invasive treatment of obstructive forms at rest. Long-term mortality is low,and HF is the most common cause ofdeathfollowedbySCD(excludingequivalents).However, morbidityremains considerable,emphasizingthe needfor disease-specifictreatmentsthatimpactthenaturalhistory ofthedisease.
Funding
(unrestricted
grants
to
the
Portuguese
Society
of
Cardiology
for
all
myocardial
and
pericardial
disease
registries)
Gold:JabaRecordati,MerckSerono,Sanofi-Genzyme,Shire; Silver:Medinfar,Servier
IOiwassupportedbytheItalianMinistryofHealth(‘‘LVH inaorticvalvediseaseandHCM:geneticbasis,biophysical correlatesandviraltherapy models’’(RF-2013-02356787), and NET-2011-02347173 (‘‘Mechanisms and treatment of coronarymicrovasculardysfunctioninpatientswithgenetic orsecondaryLVH’’);andbyTelethonItaly(GGP13162).
Conflicts
of
interest
Theauthorshavenoconflictsofinteresttodeclare.
Acknowledgments
WearegratefultoCNCDCstaff,especiallyDr.SandraCorker, andtoInfortucanostaff.
Appendix
A.
Participating
centers
and
principal
investigators
CentroHospitalardeLeiria:JoanaCorreia;Centro Hospita-lardeLisboaNorte-HospitaldeSantaMaria:DulceBrito; CentroHospitalardeLisboaOcidental,Servic¸ode Cardiolo-gia:JoãoAbecasis; Centro Hospitalar de LisboaOcidental - Hospital São Francisco Xavier - Servic¸o de Medicina III: Cândida Fonseca; Centro Hospitalar de Trás os Montes e AltoDouro-HospitalSãoPedro:CarlaAlexandraR.Araújo; CentroHospitalardeVilaNovadeGaia/Espinho:Conceic¸ão Fonseca;Centro Hospitalar doAlgarve- Hospitalde Faro: NunoMarques;CentroHospitalardoAltoAve-Hospitalda Senhora da Oliveira: Olga Azevedo; Centro Hospitalar do BaixoVouga-HospitalInfanteD.Pedro:JoséAntónioNobre dosSantos;CentroHospitalardoOesteNorte-Centro Hos-pitalardasCaldasdaRainha:Ana FilipaPereiraRodrigues; CentroHospitalardoPorto-HospitaldeSantoAntónio: Patrí-cia Fernandes Rodrigues; Centro Hospitalar do Tâmega e Sousa- Unidade PadreAmérico: MariaConceic¸ão Queirós; CentroHospitalare UniversitáriodeCoimbra-Cardiologia B-Hospital Geral:JoanaDelgadoSilva;Centro Hospitalar TondelaViseu- Hospital deSão Teotónio:Carlos Emanuel Correia;CUFInfanteSantoHospital:PedroMatos;Hospital BeatrizÂngelo:LuísSargento;HospitaldaLuzLisboa:Nuno Cardim;HospitaldasForc¸asArmadas:SaraFerreira; Hospi-taldeBraga:NunoSalomé:HospitaldeSantaMariaMaiorde Barcelos-Servic¸oCardiologia:AlexandraSousa;Hospitalde SantoEspíritodeAngradoHeroísmo:RuteCouto;Hospital deSãoJoão:ElisabeteMartins;HospitaldoEspíritoSanto: AgostinhoCaeiro;HospitalGarciadeOrta:LuísRochaLopes; HospitalProf.DoutorFernandoFonseca:FranciscoMadeira; HospitalSAMS:BertaCarola;HPPHospitaldeCascais- Hos-pitalDr.JosédeAlmeida:Gonc¸aloProenc¸a;UnidadeLocal deSaúdedaGuarda-HospitalSousaMartins:MariaCristina Gamboa.
Appendix
B.
Supplementary
material
Supplementary material associated with this article can be found in the online version at doi:10.1016/j.repc. 2017.08.005.
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