Legeforeningen - Heart Failure 2010...engangsdose ved perkutan intrakoronar infusjon. Pasienter (n=39) med hjertesvikt, både iskemisk og non-iskemisk kardio-myopati, i NYHA-funksjonsklasse

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Heart Failure 2010Den årlige Heart Failure-kongressen som arrangeres av Heart Failure Association of the European Society of Cardiology, ble i år avviklet i Berlin 29. mai-1. juni. Denne gjenforente tyske hovedstaden var et hyggelig møte selv om selve kongressenteret ikke var av de mest moderne med bl.a. litt kummerlige forhold for poster-presentasjonene, i tillegg til at været var vått og kaldt de siste 2 dagene. Kongressen dekket de fleste emner innen hjertesvikt fra basal- og translasjonsforskning til epidemio-logi, diagnostisering inkludert ”imaging” og biomarkører, monitorering, risikostratifisering og behandling, både med medikamenter, ”devicer” og kirurgi. Neste Heart Failure-kongress vil bli arrangert i Göteborg i mai 2010. Årets kongress hadde 3319 deltagere som var reduksjon i forhold til fjordårets kongress i Nice der det var 3800 deltagere. I år var det 1097 innsendte abstracts som var en 18 % økning i forhold til i fjor. Det var også i år som i fjor god deltagelse fra Norge, og det var også en del norske abstrakter. Vinneren av Young Investigator Award for basalfors-kning var også fra Norge, Ida G. Lunde fra Institutt for eksperimentell medisinsk forskning, Oslo universitetssykehus, Ullevål.

Her presenteres studiene fra Late Breaking Trials, et kort referat fra et foredrag som omhandlet hva kardiologer bør vite om fettvev samt de norske abstrakter.

Erik Øie, stedlig redaktør

late Breaking trialsLinn E. Fosshaug og Erik Øie, Medisinsk avdeling, Diakonhjemmet sykehus og Institutt

for indremedisinsk forskning, Oslo universitetssykehus, Rikshospitalet

BeneFiCialPresentert av Adriaan Voors (Groningen, Nederland)

Advanced glycation end-products (AGE) er glykosylerte proteiner som akkumulerer i kroppen ved økende alder. Økt AGE-akkumulering er rapportert hos pasienter med diabetes og nyresvikt. Det er foreslått at AGE kan bidra til utvikling og progresjon av hjertesvikt, hovedsakelig pga. dannelse av kryssbindinger i ekstra-cellulær matriks som kan føre til stivere kar og hjertemuskel, men også pga. en direkte effekt på AGE-reseptorer. Mindre studier har indikert at behandling med AGE-kryssbindingsbryteren alagebrium kan

ha gunstige effekter på diastolisk funksjon hos pasienter med hjertesvikt. Formålet til BENEFICIAL var å undersøke effekten av alagebrium på arbeidskapasitet og hjertefunksjon hos pasienter med kronisk hjertesvikt med redusert systolisk funksjon. 100 pasienter med ejeksjonsfraksjon (EF) < 45 % (gjennomsnittlig 33 %) ble rekruttert og randomisert til placebo eller alagebrium 400 mg x 1 eller placebo i 36 uker. Det primære endepunktet var bedring i aeorbisk kapasitet (VO2-max). Resultatene viste ingen gunstig effekt på VO2-max (heller en sterk trend mot forverrelse, p=0,06) og ellers ingen signifikante endringer i diasto-lisk funksjon (E/E’), EF, nivå av AGE i vev og væsker, pro-BNP, NYHA-funksjonsklasse

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og livskvalitet. Konklusjonen er derfor at alagebrium skuffende nok ikke har gunstig effekt hos pasienter med kronisk hjerte-svikt, men at medikamentet var sikkert og veltolerert. Ved baseline var pasientene som ble behandlet med alagebrium, litt eldre og hadde høyere nivåer av proBNP. Dette kan ha influert på resultatene.

CuPiDPresentert av Barry Greenberg (San Diego, USA)

Endringer av kalsiumbalansen i sar-koplasmatisk retikulum gir nedsatt kontrak-tilitet og relaksasjon i myokard. Forstyrrelser i kalsiumbalansen antas å være relatert til nedregulering av sarkoplasmatisk retikulum Ca2+-ATPase (SERCA2a) ved hjertesvikt. CUPID er en fase-II-studie der formålet var å kartlegge effekten og sikkerheten av genterapi med SERCA2a (Mydicar®) hos pasienter med alvorlig hjertesvikt. SERCA2a ble administrert ved å bruke en rekombinant adeno-assosiert viral vektor og gitt som en engangsdose ved perkutan intrakoronar infusjon. Pasienter (n=39) med hjertesvikt, både iskemisk og non-iskemisk kardio-myopati, i NYHA-funksjonsklasse III-IV med EF < 35 % og VO2-max > 20 ml//kg/min, med ICD implantert < 6 mnd. siden og stabil hjertesvikt siste 30 dager ble inklu-dert i studien. Pasientene ble randomisert til placebo (n=14) eller lav- (n=8), mid-dels- (n=8) eller høydosebehandling (n=9) med Mydicar® og fulgt i 12 måneder. Det var imidlertid resultatene etter 6 måneders oppfølging som ble presentert på konfe-ransen. Endepunkt var symptomatiske og funksjonelle mål samt EF, ende-systolisk volum og pro-BNP. Resultatene indikerte at genterapi med Mydicar® er sikkert og at høydosebehandling er assosiert med redusert risiko for multiple kardiovaskulære hendelser som forverret hjertesvikt, hjerte-infarkt, utstyrsimplantasjon, transplantasjon og død samt bedring i funksjonell kapasitet, pro-BNP og hjertefunksjon. Merkelig nok var det for flere av effektmålene ingen dose-avhengighet som man skulle forvente, altså at økende mengde virusoverført SERCA2a ville gi økende effekter eller i det minste lik effekt som indikasjon på at en var kommet til toppen av dose-respons-kurven. Man så ingen tendens til negative effekter av

medikamentet etter 6 måneder. Disse pre-liminære resultatene støtter videre studier med genterapi med SERCA2a hos pasienter med alvorlig hjertesvikt. CUPID er imidlertid en liten fase-II-studie med foreløpig kun 6 måneders oppfølging. Selv om resultatene etter 12 måneder også skulle vise seg å være gunstige, bør man avvente en større fase-III-studie før man kan snakke om et mulig nytt behandlingsprinsipp ved alvorlig hjertesvikt.

triDent-1Presentert av William T. Abraham (Colum-bus, USA)

Renal dysfunksjon er vanlig hos pasienter som legges inn for akutt dekom-pensert hjertesvikt og er assosiert med dårlig prognose. Stimulering av adenosin A1-reseptorene i nyrene fører til kontraksjon i afferent arteriole som igjen gir redusert glomerulær filtrasjons-hastighet (GFR) og økt natrium-reabsorpsjon i proksimale tubuli. Behandling med adenosin A1-resep-tor-antagonsiter kan derfor tenkes å være gunstig hos pasienter med nedsatt nyre-funksjon. Preliminære studier med adenosin A1-reseptor-antagonisten rolofyllin har vist lovende resultater, mens resultatene fra den store PROTECT-studien som ble presentert på ESC-kongressen i 2009, viste kun en lett bedring av symptomer i tillegg til at det var en trend mot forverret nyrefunksjon og ingen bedring i morbiditet og mortalitet hos hjertesviktpasienter behandlet med rolofyllin. TRIDENT-1 er en multisenter, dob-beltblind, placebokontrollert fase-III-studie som hadde som formål å kartlegge sikkerhet og effektivitet av behandling med adenosin A1-reseptor-antagonisten tonapofylline (BG9928) ved akutt dekompensert hjerte-svikt og nedsatt nyrefunksjon. Pasientene skulle ha kliniske tegn til overvæsking i form av dyspné, ødemer, økt intravenøst trykk, stuvning eller forøket pro-BNP. De inklu-derte pasientene ble randomisert til placebo eller 3 ulike dosenivåer av medikamentet (hhv. 0,03, 0,15 eller 0,30 mg/kg) gitt hver 12. time i opp til 5 dager. Gruppene ble sam-tidig behandlet med furosemid 40 mg i.v. Det var planlagt inklusjon av 600 pasienter, men inklusjonen ble stoppet av Data Safety and Monitoring Commitee. Da var til sammen 420 pasienter inkludert. Resultatene viste at


tonapofyllin ikke hadde signifikant effekt på endring i kroppsvekt eller hospitaliserings-lengde. En doselineær subjektiv bedring av dyspné ble observert etter 24 timer. Imidlertid så man en trend mot forverring av nyresvikt med økende behandlingsdose, dog ikke signifikant. Én prosent av pasientene som ble behandlet med tonapofyllin, fikk krampeanfall under behandling (tilsvarende det som ble sett i PROTECT-studien), men ingen pasienter fikk slag (som tidligere vist ved rolofyllin). Man valgte derfor å avslutte studien. Siden det ikke er funnet noen klar behandlingseffekt i tillegg til den økte risi-koen for kramper, vil det sannsynligvis ikke bli gjennomført nye studier med intravenøs behandling med adenosin A1-reseptor-antagonsiter. Hvorvidt perorale adenosin A1-reseptor-antagonsiter som foreløpig ikke har vist økt krampetendens, vil bli testet i større pasientstudier, er uvisst på bakgrunn av PROTECT og TRIDENT-1.

rFa-HFPresentert av Michael McDonald (Glasgow, UK)

Atrieflimmer er vanlig hos pasienter med hjertesvikt og er assosiert med dårli-gere prognose. Radiofrekvensablasjon (RFA) kan som kjent føre til gjenopprettelse av sinusrytme hos mange pasienter. Formålet med RFA-HF-studien var å sammenligne effekten av RFA med optimal medikamentell hjertesviktbehandling hos pasienter med persisterende atrieflimmer, hjertesvikt og alvorlig venstre ventrikkel-dysfunksjon. I denne lille studien ble til sammen 41 pasienter i NYHA-funksjonsklasse II-IV og EF < 35 % randomisert til RFA (n=22) eller medisinsk behandling (n=19). Av de 22 pasientene som ble abladert, oppnådde man sinusrytme hos kun 10 pasienter (6 pasienter krevde 2 ablasjoner). Det primære endepunktet var venstre ventrikkels EF vurdert med MR etter 6 måneder. Det ble funnet en ikke-signifikant trend mot bedring i EF vurdert med MR (+4,5 % vs. +2,8 %). Når EF ble vurdert med radionukleotid ven-trikulografi, så man imidlertid en signifikant bedring hos gruppen som var abladert (+8,2 % vs. +1,4 %, p=0.03). Utgangs-EF ble målt svært forskjellig ved undersøkelse med MR og radionukleotid ventrikulografien, og dette kan ha hatt betydning for utfallet. Hos

pasientene som hadde oppnådd sinusrytme, var det signifikant bedring i EF vurdert ved MR (p=0.008). Dog må det understrekes at dette var en post hoc-analyse og at videre forskning må gjøres før man kan konkludere ytterligere. Det var dessuten høy komplika-sjonsrate i RFA-gruppen (14,8 %; 1 hjerne-slag, 2 hjertetamponader og 1 hospitalise-ring pga. hjertesvikt). Denne studien er for liten til å trekke konklusjoner vedrørende RFA-behandling av hjertesviktpasienter med atrieflimmer. Antall pasienter som oppnådde sinusrytme, var skuffende lavt og komplikasjonsraten overraskende høy.

Fair-HF renal function analysisPresentert av Piotr Ponikowski (Wroclaw, Polen)

FAIR-HF-studien som ble publisert i New England Journal of Medicine i 2009, viste at pasienter med kronisk hjertesvikt og jernmangel som fikk intravenøs injeksjon av jern, fikk bedret helsestatus og NYHA-funk-sjonsklasse. I denne post hoc-substudien av FAIR-HF var formålet å undersøke om intravenøs administrasjon av jern hos kro-niske hjertesviktpasienter med jernmangel også kunne ha positiv effekt på glomerulær filtrasjonsrate (GFR). Det er kjent at pasien-ter med nyresvikt har et forverrer forløpet av hjertesvikt. Dagens hjertesviktbehandling har enten ingen effekt på nyrefunksjonen eller forverrer nyrefunksjonen. Pasienter i NYHA-funksjonsklasse II-III med EF < 40 %, hemoglobin 9,5-13 g/dl og lave ferritin-nivåer ble inkludert. Pasientene ble rando-misert til i.v. jern/carboxymaltose 200 mg ukentlig i starten og deretter hver 4. uke i 24 uker (n=304) eller placebo (n=155). Studien viste at jernbehandling hadde en gunstig effekt på nyrefunksjonen med en mode-rat stigning i estimert GFR, uavhengig av utgangsverdiene. I tillegg var det gunstige effekter på symptomer, NYHA-funksjons-klasse og livskvalitet. Detter er spennende data som kan medføre at vi i fremtiden vil behandle hjertesviktpasienter med jernman-gel med jerntilskudd. Det trengs imidlertid flere og større studier før slik behandling kan anbefales. Det bør også undersøkes om peroralt jerntilskudd har tilsvarende gunstig effekt som intravenøs behandling, noe som vil forenkle behandlingen betydelig.


MaDit-Crt echocardiography studyPresentert av Scott D. Solomon (Boston, USA)

Kardial resynkroniseringsterapi (CRT) er godt dokumentert som effektiv behandling ved hjertesvikt og QRS-bredde > 120 ms hos pasienter med EF < 35 % i NYHA-funksjonsklasse III-IV. MADIT-CRT-studien hadde som formål å kartlegge effekten av CRT-behandling hos hjertesvikt-pasienter med EF < 30 % og breddeforø-ket QRS (> 130 ms.), men med kun milde symptomer (NYHA-funksjonsklasse I- II). MADIT-CRT ble publisert i New England Journal of Medicine i 2009 og viste 41 % reduksjon i risiko for hjertesvikt-hendelser. På årets Heart Failure-kongress ble data fra MADIT-CRT Echocardiography Study pre-sentert. De primære endepunkter i denne ekkokardiografiske substudien var død (uavhengig av årsak) og hjertesvikthendel-ser relatert til ekkokardiografiske funn av endret hjertestørrelse og funksjon. 1820 pasienter ble inkludert i hovedstudien, og de ble randomisert 3:2 til CRT-ICD eller ICD alene. I denne substudien ble pasienter som fikk utført ekkokardiografi ved studiestart og etter 1 år, inkludert (n=749 i CRT-ICD-gruppen og n=623 i ICD-alene-gruppen). Venstre ventrikkels volum ble estimert med Simpsons metode i apikalt vindu. Hos CRT-pasientene observerte man en 21 % reduksjon av endediastolisk volum (EDV) sammenlignet med en 5,9 % reduksjon i EDV hos ICD-pasientene (p<0,0001). Esti-mert EF økte med 11 % hos CRT-pasientene, mens ICD-pasientene kun hadde en 3 % bedring (p<0,0001). Reduksjon i ventrikkel-størrelse var signifikant prediktiv for redu-sert risiko for det primære endepunktet død og hjertesvikthendelser og for total-morta-litet. Disse dataene viser at hjertesviktpa-sienter med betydelig redusert EF, dvs. < 30 %, og grenblokksmønster med QRS-bredde >130 ms, men som har lite symptomer pga. optimal medikamentell behandling, også har nytte av CRT-behandling, og at dette i alle fall delvis skyldes revers remodellering av venstre ventrikkel. Pasientgruppen som tilfredsstiller inklusjonskriteriene i MADIT-CRT, er stor. I Norge ligger vi dårlig an når det gjelder å implantere biventrikulære pacemakere på pasienter i NYHA-funk-

sjonsklasse III-IV som etter internasjonale retningslinjer bør få CRT-behandling. Hvis nye internasjonale retningslinjer for CRT-behandling også inkluderer hjertesviktpa-sienter i NYHA-funksjonsklasse I-II, vil vi i Norge få enda større problemer med å følge anbefalingene, og vi risikerer å bli enda mer latterliggjort på internasjonale møter der implantasjonsraten for biventrikulære pacemakere i forskjellige land blir diskutert, enn vi blir i dag.

CHaMPiOnPresentert av William T. Abrahamolumbus, USA) og Philip B. Adamsin (Oklahoma City, USA)

CardioMEMS er en liten innretning som kan implanteres ved høyre hjerte-kateterisering i arteria pulmonalis for å overvåke forandringer i pulmonalarterie-trykk. Formålet med CHAMPION-studien var å evaluere sikkerheten og effektiviteten av CardioMEMS, og målet var å redu-sere hjertesviktrelaterte innleggelser hos behandlingsgruppen (invasiv trykkmåling og standard hjertesviktbehandling) sammen-lignet med kontrollgruppen (kun standard hjertesviktbehandling). Pasienter i NYHA-funksjonsklasse III (n=550) som hadde stabil hjertesviktmedikasjon og fravær av hjertesvikthendelse siste 12 måneder samt kroppsmasse-indeks < 35, ble inkludert og randomisert til behandling basert på tradi-sjonelle data alene eller behandling basert på hemodynamiske data fra trykksensoren i tillegg til tradisjonelle data. Gjennomsnittlig tid for implantasjon av pulmonalarterie-sensoren var 7 minutter. Måltrykket i arteria pulmonalis var systolisk 15-35 mmHg, diastolisk 8-20 mmHg og middeltrykk 10-25 mmHg. Det primære sikkerthetsen-depunktet var fravær av utstyrsrelaterte komplikasjoner eller sensor-svikt, mens det primære effektivites-endepunktetet var antall hjertesviktrelaterte innleggelser over en periode på 6 måneder. Det ble observert 8 utstyrsrelaterte feil, men ikke registrerte trykksensor-svikt, noe som tilfredsstilte de predefinerte sikkerhetsendepunktene. Man observerte en 30 % reduksjon i hjertesvikt-hendelser ved studiens slutt i trykksensor-gruppen sammenlignet med pasientene i kontroll-gruppen (p <0,022). Flere sekundære endepunkter som bedring


i middeltrykk i arteria pulmonalis, dager i live og utenfor sykehus samt livskvalitet, ble observert i trykksensor-gruppen. Dette er lovende resultater fra en relativ stor studie som tidligere liknende studier ikke har vist like klart.

MusiCPresentert av Inder Anand (Edina, USA)

Effektiv monitorering av væs-kestatus vil kunne hjelpe til å predikere utvikling av akutt hjertesvikt. Vektmåling som brukes i dag, mangler tilstrekkelig sensitivitet og spesifisitet. MUSIC-studien hadde som formål å validere en algoritme som var ment for å forutsi akutt dekom-pensert hjertesvikt. Et apparat ble festet på brystveggen, og denne registrerte EKG, puls, aktivitet, kroppsstilling, respirasjons-frekvens, thoraximpedans (væskestatus) og kroppstemperatur. Inklusjonskriteriene var NYHA-funksjonsklasse III-IV, EF < 40 % og nylig dekompensert hjertesvikt. 100 pasienter ble inkludert og fulgt i 90 dager. Man definerte væskeindeks som endring av bioimpedans fra utgangsverdi, og man fant at væskeindeks hadde en sensitivitet på 78 % og spesifisitet 58 % for å forutsi akutte hjertesviktrelaterte hendelser. Ved å kombinere de ulike parametere oppnådde man en sensitivitet på 63 % og spesifisitet på 90 %. Det ble funnet at enkelte pasi-entgrupper ikke var egnet for apparatet (overvektige og eldre). Funnene i denne studien er lovende. Det manglet imidlertid mye data (fra hele 9 av 21 pasienter som utviklet akutt dekompensert hjertesvikt) som gjør at kostnad-nytte-effekten ikke blir så gunstig. Nye studier er derfor påkrevet for å trekke endelige konklusjoner. Mangel på nye effektive medikamenter i behandlin-gen av pasienter med hjertesvikt har ført til fokus på forskjellige utstyr som hjelpemid-del for bedret behandling. Biventrikulær pacemaker er foreløpig eneste utstyr (hvis en ikke regner med LVAD) som er aktuelt for selekterte pasienter med kronisk hjerte-svikt, men slik behandling har til gjengjeld vist svært gunstig effekt. Utstyret brukt i denne studien hadde den fordelen at den ikke trengte invasiv implantasjon, men kun ble klistret på thorax-veggen.

Phrenic nerve stimulation studyPresentert av Piotr Ponikowski (Wroclaw, Polen)

Sentral søvnapné har høy prevalens hos hjertesviktpasienter og er assosiert med økt sympatisk stimulering og dermed sannsynlig økt risiko for arytmi, iskemi og trykkforandringer intrathorakalt. Det er 2 hovedtyper av pusteproblemer under søvn: Obstruktiv søvnapné der lungefunksjonen er normal, men de øvre luftveier kollapser periodevis under søvn, og sentral søvnapné der normal respirasjonskontroll er forstyrret under søvn. Stimulering av nervus phrenicus kan modulere kontraksjonen av diafragma og dermed påvirke pustemønsteret. Ved å stimulere n. phrenicus under episoder med sentral søvnapné kan man få initiert respira-sjon eller økt inspirasjonstiden. Formålet med denne studien var å evaluere effekten og sikkerheten ved unilateral transvenøs stimulering av n. phrenicus hos pasienter med hjertesvikt og sentral søvnapné. Man inkluderte 13 pasienter med dokumenterte sentrale apnéperioder og klinisk stabil hjer-tesvikt. En temporær ledning ble plassert transvenøst nær n. phrenicus. Pasientene fikk én natt med nervestimulering og én kontrollnatt uten stimulering. Stimulering av n. phrenicus virket å være trygt og godt tolerert. Det var ingen uheldige effekter på søvnen eller luftveis-tonus og ingen ner-vestimulerings-assosierte arytmier. Det ble funnet 91 % reduksjon i sentral søvnapné-indeks, 55 % bedring av oksygeneringsni-våer, 51 % mindre nattlige oppvåkninger og 49 % reduksjon i apné-hyponé-indeks (p=0,001 for alle endringene). Dette er interessante funn. Studien er riktignok svært liten, men bør stimulere til gjennomføring av større studier for å kartlegge effekten på livskvalitet og på harde endepunkter.

Handheld BnP-studyPresentert av Christine Angermann (Würz-burg, Tyskland)Det er godt kjent at hjertesvikt ofte er vanskelig å diagnostisere i primærhelse-tjenesten. I denne studien var formålet å undersøke om håndholdt ekkokardiografi og måling av BNP kan øke allmennpraktikerens treffsikkerhet ved diagnostikk av hjertesvikt. Pasienter fra primærhelsetjenesten med antatt hjertesvikt grunnet symptomer ble


randomisert til 4 forskjellige screenings-metoder: Symptomer og kliniske tegn alene (kontrollgruppen n=208), symptomer, kliniske tegn og håndholdt ekkokardio-grafi (n=212), symptomer, kliniske tegn og BNP (n=221) og symptomer, klinisk tegn, håndholdt ekkokardiografi og BNP (n=211). Etter diagnostikk hos allmennpraktiker ble pasientene henvist til diagnostikk hos kar-diolog. 44 % av pasientene fikk diagnosen hjertesvikt hos kardiolog (26 % systolisk hjertesvikt og 74 % hjertesvikt med pre-servert systolisk funksjon). Resultatene fra de forskjellige screening-gruppene viste at bruk av BNP og håndholdt ekkokardiografi ikke økte allmennpraktikerens treffsikkerhet med hensyn på diagnosen. Allmennprak-tikeren stilte såkalt korrekt diagnose, dvs. samme diagnose som kardiologen, hos ca. 60 % av pasientene uavhengig av scree-nings-metode. Riktignok økte spesifisiteten signifikant, men sensitiviteten ble redusert, spesielt ved bruk av alle fire modaliteter, slik at hyppigheten av korrekt diagnose forble uendret. Likevel ga både ekkokardiografi og BNP god prognostisk informasjon, hvilket hjalp allmennpraktikeren å bedre identifi-sere pasientene som trengte videre opp-følging. Resultatene er noe overraskende. Det er mulig at allmennpraktikerne ikke var trent godt nok til å bruke et håndholdt ekkoapparat og til å utføre BNP-anlyser. En annen mulighet er at kardiologene ikke alltid stilte korrekt diagnose. Det er også mulig at grenseverdiene for BNP-nivåene i diagnos-tikken av hjertesvikt var for høye (< 100 pg/ml som diagnostisk rule-out og > 400 pg/ml som diagnostisk rule-in). Den kanskje viktigste grunnen til de skuffende resulta-tene er at mange av pasientene som kar-diologene ga diagnosen hjertesvikt, hadde preservert systolisk funksjon, en tilstand der det er mindre stigning i BNP-verdiene og vanskeligere å stille diagnosen hjertesvikt ekkokardiografisk.

DuelPresentert av Vyacheslav Mareev (Moskva, USA)

Diuretikabehandling gis som oftest til pasienter med akutt hjertesvikt selv om det finnes begrensede data fra randomi-serte og kontrollerte studier som støtter slik behandling. Formålet med DUEL-studien var

å sammenligne effektiviteten og sikkerheten av peroral lavintensitetsterapi med torase-mid og furosemid hos pasienter med akutt hjertesvikt. Man inkluderte 470 pasienter fra 30 sentra i Russland i NYHA-funksjons-klasse II-IV innlagt pga. akutt dekompensert hjertesvikt. Alle pasientene brukte loop-diu-retika regelmessig før innleggelsen. Pasien-ter med nyoppstått akutt hjertesvikt ble ikke inkludert. Pasientene ble randomisert 2:1 til behandling med peroral torasemid 20 mg daglig (n=316) og furosemid 80 mg daglig (n=154). Behandlingen kunne opptitreres og forandres til intravenøs administrasjon ved behov. Det primære endepunktet var tid til kompensert hjertesvikt, basert på vekt og symptomer. Gjennomsnittlig tid til kompen-sert hjertesvikt var 7 dager for pasienter i torasemid-gruppen og 11 dager for pasien-ter i furosemid-gruppen. Pasientene som var randomisert til torasemid hadde også større bedring av symptomer (p =0,03) og lavere hyppighet av bivirkninger på dag 3. Dog må det legges til at forskjellene til dels kan forklares ut i fra doseforskjeller. I tillegg førte lavdose diuretikabehandling til relativt lange sykehusinnleggelser. Studien gir ingen svar på om hva som er optimal diuretikabehandling ved akutt dekompen-sert hjertesvikt siden det ikke ble gjort sam-menligninger med intravenøs behandling og høydosebehandling.


G. Jondeau fra Frankrike holdt et foredrag som omhandlet hva kardiologer trenger å vite om fettvev. Det er kjent at mortaliteten ved hjertesykdom har sunket med over 60 % de siste 40 år, mens mortaliteten ved hjertesvikt har vært nærmest uendret. I tillegg er fedme et økende problem i verden i dag. Studier viser at overvekt er en viktig risikofaktor for utvikling av hjertesvikt, og Jondeau ga en rask innføring i fettve-vets ulike egenskaper og betydning ved hjertesvikt.

Som vist i Framinghamstudien, fremgikk det også av Jondeaus foredrag at økende kroppsmasse-index (BMI) er en risikofaktor for utvikling av kronisk hjerte-svikt, samtidig som BMI paradoksalt nok virker beskyttende dersom man allerede har utviklet hjertesvikt.

Det er velkjent at cytokiner har betydning ved utvikling av hjertesvikt og at fettvev er et organ som produserer en rekke cytokiner. I denne forbindelse ble forskjellene mellom subkutant og visceralt fett diskutert. Jondeau viste til at visce-ralt fett er en viktig kilde til produksjon av inflammatoriske cytokiner som TNF-α og IL-6, som bl. a. kan føre til insulinresistens. Subkutant fett derimot er sannsynligvis mindre viktig når det gjelder syntese av inflammatoriske mediatorer. Et eksempel på at visceralt fettvev i mange sammenhenger er viktigere enn subkutant fettvev er data som viser at reduksjon i subkutant fett ved fettsuging ikke fører til endringer i insulin-resistens, mens tilsvarende naturlig vekttap gir betydelig bedring av samme parametere. Ved diettindusert fedme ser man en økning av andelen makrofager i visceralt fett fra ca 5 % til inntil 60 % som kan forklare denne sammenhengen. Interessant nok tyder tidligere studier på at epikardielt fettvev har samme egenskaper som visceralt fett, og dette styrker hypotesen om at fettvev har betydning ved forskjellige kardiovaskulære tilstander.

Jondeau diskuterte også adipo(cyto)kiners betydning for utvikling av hjertesvikt, med adiponektin som eksempel. Adiponek-tin syntetiseres i adipocytter og er inverst assosiert med økende BMI hos friske. Man har sett at forhøyede nivåer av adiponektin kan være en prediktor for mortalitet hos hjertesviktpasienter, kanskje fordi det er et uttrykk for kakeksi.

Egne data som ble presentert som abstrakt på kongressen, tyder på at fettsyrer som bl.a. syntetiseres i fettvev, kan være viktig ved hjertesvikt. Våre data viser at det er betydelige endringer i fettsyrenivåene i plasma ved hjertesvikt med reduserte nivåer av n-3 (omega-3) og n-6 flerumettede fettsyrer, reduserte nivåer av flere oksiderte langkjedete mettede fettsyrer og en økning i nivåene av enumettede fettsyrer. Disse end-ringene var signifikant assosiert med funk-sjonsklasse, redusert hjertefunksjon (redu-sert cardiac index og økte plasmanivåer av Nt-proBNP) og økt systemisk inflammasjon (økte plasmanivåer av CRP). Våre data viser også at lave nivåer av den n-3 flerumettede fettsyren C20:4n-3 og spesielt høye nivåer av den enumettede fettsyren C18:1n-7 er signifikant assosiert med mortalitet pga. progresjon av hjertesviktmortalitet i denne HF populasjonen.

Tidligere studier har vist at behand-ling med Omacor® som inneholder n-3 flerumettede fettsyrer (hovedsakelig eicosa-pentaensyre (EPA) og docosahexaensyre (DHA)), signifikant reduserte risikoen for død etter hjerteinfarkt (GISSI-Prevenzione) og død samt hospitalisering pga. hjertesvikt hos pasienter med hjertesvikt (GISSI-HF). Videre studier vil vise om også andre fettsyrer enn EPA og DHA har gunstig og kanskje gunstigere effekt som behandling ved hjertesvikt.

all a CarDiOlOgist neeDs tO knOw aBOut Fat tissue

Linn E. Fosshaug og Erik Øie, Medisinsk avdeling, Diakonhjemmet sykehus og Institutt for indremedisinsk forskning, Oslo universitetssykehus, Rikshospitalet


Vinner aV HelMut

Drexler YOung inVestigatOr

awarD in BasiC sCienCe 2010

Ida Gjervold Lunde fra Institutt for ekspe-rimentell medisinsk forskning ved Oslo Universitetssykehus, Ullevål, vant årets ”Helmut Drexler Young Investigator Award in Basic Science” for studien Phosphorylation of syndecan-4 regulates activation of the pro-hypertrophic calcineurin-NFAT signalling path-way in the myocardium der dataene tyder på en viktig rolle for fosforylering av synde-can-4 og syndecan-4-calcineurin-interak-sjon ved utvikling av myokardhypertrofi.

Under følger abstraktet:

Phosphorylation of syndecan-4 regulates activation of the pro-hypertrophic calcineurin-NFAT signalling pathway in the myocardiumI.G. Lunde, A.V. Finsen, H.O. Jarstadmarken, I. Sjaastad, A. Hasic, H. Kvaloy, T. Tonnesen, S.A. Wilcox-Adelman, C.R. Carlson, G. Chris-tensen. Institute for Experimental Medical Research, Ullevaal University Hospital, Oslo, Norway; University of Oslo, Faculty Division Rikshospitalet University Hospital, Depart-ment of Cardiology, Oslo, Norway; Department of Cardiothoracic Surgery, Ullevaal University Hospital, Oslo, Norway; Boston Biomedical Research Institute, Watertown, Massachu-setts, USABackground: Myocardial hypertrophy and subsequent heart failure develop in response to pressure overload. However, the signalling


processes involved are poorly understood. We have previously linked syndecan-4, a transmem-brane proteoglycan localized to focal adhesions and costameres in cardiomyocytes, to develop-ment of pathological myocardial hypertrophy. In brief, mice lacking syndecan-4 do not develop concentric hypertrophy after aortic banding. In the present study we demonstrate a crucial role for phosphorylation of syndecan-4 in regulating the central pro-hypertrophic calcineurin-Nuclear Factor of Activated T-cell (NFAT) signalling path-way in the myocardium. Methods/Results: In vitro pull-down experiments showed that recombinant calcineurin binds directly to syndecan-4 and to a lesser extent to syndecan-2. Immunoprecipitations showed that the association between endogenous calcineurin, its activator calmodulin and syndecan-4 was stronger in pressure-overloaded murine hearts, compared to sham-operated controls. The syn-decan-4 cytoplasmic domain is 28 amino acids long and composed of three regions; C1 and C2 are conserved between the four syndecans, while the V-region is specific for each of them. In vitro pull-down and peptide array experiments sho-wed that calcineurin interacts with the V-region of syndecan-4 through its autoinhibitory domain. Phosphorylation of serine 179 (pS179) in C1 has previously been shown to be important for

protein interactions. We demonstrate that pS179 is reduced in patients with aortic stenosis and in pressure-overloaded murine hearts, compared to controls. More calcineurin immunoprecipi-tated with non-phosphorylated syndecan-4 than with the phosphorylated, indicating that reduced pS179 in syndecan-4 is involved in the hypertrophic response. Similarly, pull-down with pS179 or peptides mimicking constitutively phosphorylated S179 (S179D/E) resulted in reduced binding of calcineurin. Finally, activation of NFATc4 occurred in HEK293 cells transfected with a mutant mimicking minimally phosphory-lated S179 (S179A) whereas S179D/E mutations did not. Conclusions: In a pressure-overloaded heart, serine 179 in syndecan-4 is dephosphorylated and calcineurin binds to the intracellular V-region through its autoinhibitory domain. Our results indicate that increased binding of calcineurin to syndecan-4 results in activation of NFATc4, a well-known pro-hypertrophic transcription factor. Conclusively, these data suggest a crucial role for phosphorylation of syndecan-4 and the syndecan-4-calcineurin interaction in develop-ment of myocardial hypertrophy.


anDre nOrske aBstrakter På Heart Failure 2010

188 Circulating secreted frizz-led related protein 3 (sFRP3) predicts outcome in patients with chronic heart failureET. Askevold 1; CP. Dahl 1; K. Broch 1; S. Aak-hus1; A. Yndestad 2; L. Gullestad 1; P. Aukrust2; T. Ueland2. 1University of Oslo, Faculty Division Rikshospitalet University Hospital, Department of Cardiology, Oslo, Norway; 2University of Oslo, Rikshospitalet Univer-sity Hospital, Research Institute for Internal Medicine, Oslo, NorwayBackground: Reactivation of Wnt-signalling in cardiac remodelling has been shown in expe-rimental models. Interruption of this signalling attenuates the hypertrophic response to pressure overload. We hypothesized that serum levels of sFRP3, a soluble inhibitor of the Wnt-signalling pathway, could provide prognostic information in patients with chronic heart failure (HF).Methods: We included 182 patients with chronic HF in NYHA class II-IV. During a mean follow-up of 37 (+17) months, 53 patients died or underwent heart transplantation (HTx). Soluble inhibitors of the Wnt pathway, secreted frizzled-related protein 3 (sFRP3), Wnt inhibitory factor 1 (WIF-1) and dickkopf-1 (DKK-1), were measured by ELISA technique.Results: HF patients had elevated levels of sFRP3 compared to controls (p<0.01). sFRP3 was posi-tively correlated to left ventricular end diastolic volume (r=0.27, p<0.001) and systolic volume (r=0.21, p<0.02). Increased sFRP3 (above median 180 pg/mL) was strongly associated with increased mortality/HTx [HR 2.20 (1.23-3.94), p=0.007], even after multivariate analysis (p=0.022).Conclusion: Serum levels of sFRP3 are elevated in HF patients and are related to cardiac dimension

and systolic function. High levels of sFRP3 predict a poor outcome.

190 Degradation of type I col-lagen is increased in patients with symptomatic heart failure following myocardial infarctionC. Manhenke 1; S. Orn 1; I. Squire 2; K. Dickstein 1. 1Stavanger University Hospital & Institute of Medicine, University of Bergen, Stavanger, Norway; 2University of Leicester, Leicester, United KingdomBackground: We assessed the time profiles of circulating markers of collagen turnover (CTO) following acute myocardial infarction (MI) in patients with and without symptoms (Figure 1) of heart failure during 2 years follow-upMethods: Plasma levels of N-terminal fragment of type I collagen (PINP), carboxyterminal telopeptide of type I collagen (ICTP), N-terminal fragment of type III collagen (PIIINP), matrix metalloproteinase-1(MMP-1) and tissue inhibitor of MMP-1 (TIMP-1) were assessed in 233 pati-ents following acute MI. The CTO markers were assessed prior to treatment by either captopril or losartaan, at a median of 3 days following MI, and at 1 month, 1 year and 2 years following MI.Results: With the exception of PIIINP, all markers demonstrated significant time dependent changes following MI (p<0.001). In patients with symptoms of heart failure, the levels of type I collagen degradation marker (ICTP) were significantly elevated at one (p = 0.005) and two years (p = 0.007) (Figure). The synthesis markers of type I and type III collagens (PINP and PIIINP respectively) showed a non-significant increase between one and two years in patients with symptoms of heart failure. In contrast, in patients without symptoms of heart failure there was a non-significant decrease in these variables during the same time-period.


Conclusions: This study provides evidence for a persistently increased collagen type I degra-dation in patients with heart failure symptoms during long-term follow up after MI.

232 Prognostic value of cardiac troponin T in patients with moderate to severe heart failure scheduled for cardiac resyn-chronization therapyM. Aarones 1; L. Gullestad 1; S. Aakhus 2; T. Ueland 3; R. Skaardal 2; H. Aass 4; HJ. Smith 5; R. Wergeland 6; P. Aukrust 3; E. Kongsgaard 2 1Oslo University Hospital, Dept. of Cardiology and University of Oslo, Oslo, Norway; 2Oslo University Hospital, Deptartment of Cardiol-ogy., Oslo, Norway; 3Research Institute of Internal Medicine, Rikshospitalet University Hospital, Oslo, Norway; 4Vestfold Hospital, Tonsberg, Norway; 5Oslo University Hospital, Department of Radiology, Oslo, Norway; 6Oslo University Hospital, Department of Medical Biochemistry, Oslo, NorwayAims: Response to cardiac resyncronization therapy (CRT) is a challenge to predict. High sensitive cardiac Troponin T (hsTnT)) might predict response to CRT and identify patients with a high risk of severe cardiovasculare events. We investigated whether baseline levels of hsTnT were associated with respons to CRT and with severe cardiovasculare events after long term follow-up.Methods: 81 consecutive patients were included according to the current guidelines for cardiac resynchronization therapy. Biochemical, func-tional, and clinical parameters were assessed at baseline and at 3, 6 and 12 months follow up (FU), and mortality / cardiac transplantation after 46+6 months FU was investigated. We also evaluated viability and left ventricular (LV) function and remodeling by cardiac magnetic resonance imaging (MRI) and echocardiography.Results: 75 patients completed 12 months FU and after a follow-up of 46+6 months a total of 15 patients died, 13 of these from cardiovascular causes and 7 underwent heart transplantation. Baseline hsTnT , 15ng/L predicted respons to CRT, and was associated with a more favourable outcome with regard to severe cardiovasculare events. Multivariate analysis found that presence of transmural scar tissue on MRI, use of statins and relatively lower ejection fraction on echoc-ardiography were independently associated with higher concentrations of troponin Tat baseline. There was a strong correlation between baseline concentrations of hsTnT and NT-proBNP.Conclusions: HsTnT levels were elevated in the majority of HF patients that were scheduled for CRT. HsTnT levels predicted response to CRT as

well long time survival. CRT is associated with a significant reduction in hsTnT concentration.

250 Very low rates of inappro-priate ICD-therapy by using optimal medical treatment and high degree of dual-chamber/biventricular ICDU. Koepp1; FT. Gjestvang 1; G. Eivindson 1; ESP. Myhre1 1Sorlandet Hospital, Kristiansand, NorwayBackground: Inappropriate ICD interventions are still challenge. Results from the main primary prophylactic ICD- trials showed a substantial amount of unnecessary shocks from 4.8% to 38% after a follow-up of 24 to 30 months. A recent report indicates a negative impact on prognosis among ICD-patients receiving inap-propriate therapy.Methods: In this study we compare rates of appropriate and inappropriate ICD interventions and rates of heart failure drugs in these trials and our consecutive registry of primary prophylactic ICD patients.Results: 106 consecutive patients were followed for an average of 24 months. The baseline rates of drugs showed that all patients received a betablocker and 98% an ACE-I or ARB. In the main trails (MADIT II, -SCD-Heft) the use of these medications were in the range of 68–70% and 68–90%. In our registry we implanted 68% CRT-D, 25% dual-chamber and only 7% single chamber devices (chronic atrial fibrillation). While MADIT II and SCD-Heft-study exclusi-vely used single-chamber ICD. In the follow-up period our patients showed a modest incidence of inappropriate ICD-intervention of 1.9% at 24 months compared to the main ICD-trials (Tab. 2). This occurred despite an programmed detection- and interventionrate of 180/min for fast VT and 220/min for VF. However, a rate of almost 20% appropriate therapies at 24 months makes a different patient selection in our registry less probably.Conclusion: These results indicate that in our hands a strict adherence to optimal medical treatment combined with a high rate of CRT are able reduce rates of inappropriate ICD-interven-tions below the landmark studies.

310 Impaired control of Ca current following SERCA knockout; arrhythmogenic implicationsHK.Mork 1; S.Richard 2; I.Sjaastad 1; KB.Andersson 1; G.Christensen 1; OM.Sejersted 1; W. Louch 1 1Institute for Experimental Medi-cal Research, Ulleval University Hospital, Uni-


versity of Oslo, Oslo, Norway; 2Inserm U-637, Cardiovascular Physiopathology - University of Montpellier, Montpellier, FrancePurpose: Altered Ca2+ handling by the sar-coplasmic reticulum (SR) and Ca2+- depen-dent arrhythmias are observed during human heart failure. We investigated the control of L-type Ca2+ current (ICa, L) when SR func-tion is reduced and the consequences for arrhythmogenesis.Methods: Experiments were performed on car-diomyocytes isolated from conditional SERCA2 KO mice (KO) which had developed heart failure 7 weeks following gene disruption. SERCA2 flox/flox (FF) mice served as controls. SR function was assessed by intracellular Ca2+ monitoring (fluo-4) during steady state and caffeine applica-tion. The whole-cell patch clamp technique was used to record ICa, L and action potentials (APs). Electrocardiogram recordings were obtained from anesthetized, self breathing animals.Results: SR Ca2+ content was reduced to 4% (P<0.05) of FF values in KO cardiomyocytes, and SR Ca2+ release did not occur on a beat-to-beat basis. Marked up-regulation of the L-type Ca2+ channel in KO (α1C subunit=178% FF, α2/delta1= 147% FF, P<0.05) were accompanied by a 40% increase in peak ICa, L (P<0.05). Loss of SR func-tion resulted in slower Ca2+ current inactivation, prolonged duration of current activation, and loss of frequency-dependent facilitation. The larger magnitude and prolonged ICa,L in KO resulted in AP prolongation, which was not observed in the presence of nifedipine or upon removal of extra-cellular Ca2+. AP prolongation was associated with prolonged QT intervals corrected for heart rate in KO mice compared to FF (5.63 ms vs 4.90 ms, P<0.05). AP prolongation is expected to be arrhythmogenic. However, incidence of early after-depolarizations in KO cardiomyocytes was not increased (FF= 2/13 cells, KO= 0/10 cells, P=NS).Conclusions: Loss of SR function resulted in greater L-type Ca2+ entry, loss of Ca2+- depen-dent inactivation, and prolonged APs. In compari-son with larger species, even the prolonged AP in failing mice is relatively brief, which may pre-clude occurrence of early after-depolarizations when SR function is impaired. However, failing APs prolong the QT interval which is expected to promote re-entrant arrhythmia.

442 Osteoprotegerin levels pre-dict mortality in symptomatic aortic stenosisT. Ueland1; P. Aukrust1; CP. Dahl1; OG. Solberg1; S. Aakhus1; L. Gullestad1 1National University Hospital, Oslo, NorwayAims: Osteoprotegerin (OPG) is a calcification-inhibitor with pleiotropic effects on the bone

metabolism,endocrine function and the immune system. To elucidate the role of OPG in the devel-opment of aortic stenosis (AS), we analyzed cir-culating levels in patients with symptomatic AS and examined the relationships to measures of AS and HF and the prognostic value of elevated OPG levels in relation toall-cause mortality.Methods and Results: We examined plasma levels in 145 patients with symptomatic severe AS and in sex- and age-matched healthy controls. We further examined their relationship to trans-valvular gradients, valve area and calcification as evaluated by backscatter analysis by echocar-diography, to measures of heart failure. Finally, we assessed the prognostic value of elevated plasma OPG in relation to all-cause mortality in these patients. We found markedly enhanced plasma levels of OPG in patients with symptoma-tic AS. Elevated OPG was poorly correlated with degree of AS but was associated with increased backscatter measurements (r=0.24,p=0.007) and deteriorating cardiac function (CO, r=-0.28, p=0.002; NT-proBNP, r=0.43, p<0.001). Further-more, OPG was predictive of all-cause mortality in patients with symptomatic AS, independent of conventional risk markers. However, the strongest risk prediction was obtained by using a combination of high OPG and high NT-proBNP (ie high NT-proBNP and high OPG).Conclusions: Circulating OPG is increased in calcific symptomatic aortic stenosis and is a strong predictor of all-cause mortality alone and in combination with NT-proBNP.

517 T-tubule proliferation in cardiomyocytes following con-ditional Serca2 knockoutF. Swift1; GF. Jolle1; KB. Andersson1; G. Chris-tensen1; OM. Sejersted1; WE. Louch1 1Institute for Experimental Medical Research, Oslo University Hospital Ulleval, Oslo, NorwayPurpose: Heart failure is associated with reduced sarco(endo)plasmic reticulum calcium ATPase (SERCA) function. Recent studies of mice with conditional cardiomyocytespecific knockout of the SERCA2 gene (KO) revealed that major reductions in SERCA and sarcoplasmic reticulum (SR) function are compensated by enhanced Ca2+ cycling over the cell membrane. These compensations maintain cardiac function at nearnormal values, at least in the short term. We hypothesize that increased transsarcolemmal Ca2+ fluxes are facilitated by alterations in sarco-lemmal morphology.Methods: Ventricular cardiomyocytes were isolated from KO hearts 7 weeks following gene disruption. SERCA2 flox-flox (FF) mice served as controls. Myocyte structure and electrophysiol-ogy were examined by standard immunocyto-chemical and patch clamp techniques.


Results: Although cardiomyocyte dimensions were unaltered in KO compared to FF control values, total surface area was increased (cell capacitance = 182 pF vs 147 pF, P<0.05). This resulted from increased t-tubule density, as revealed by confocal images of Di-8-Anepps stained myocytes. Specifically, Fourier analysis indicated a maintained organization of t-tubules which transversely spanned the cell, but an increased presence of tubules in the longitudinal direction. Immunocytochemical data showed that the newly grown longitudinal t-tubules contained Na+/Ca2+- exchangers and Ca2+ channels with co-localized ryanodine receptors in the SR. These alterations were associated with increased expression of the L-type Ca2+ channel (α1C subunit = 178% of FF values) and Na+/Ca2+-exchanger (NCX1 =216% of FF values). Peak L-type Ca2+ currents and Na+/Ca2+-exchange-mediated Ca2+ extrusion were also enhanced in KO.Conclusions: Our observations indicate that proliferation of longitudinal t-tubules facilitates trans-sarcolemmal Ca2+ flux to compensate for declining SR function following SERCA KO.

600 Low circulating n-3 poly-unsaturated fatty acid and high monosaturated n-7 fatty acid are associated with disease severity and predict mortality in heart failureE. Øie1; T. Ueland1; CP. Dahl1; P. Bohov2; C. Berge2; A. Yndestad1; L. Gullestad1; P. Aukrust1; RK. Berge2 1Rikshospitalet University Hospital and University of Oslo, Oslo, Norway; 2Univer-sity of Bergen, Institute of Medicine, Bergen, NorwayPurpose: Free fatty acids (FFA) are the major energy sources of the heart and fatty acids (FA) are active components of biological membranes. Data indicate that FA and their composition may influence myocardial function and inflammation. This study sought to investigate whether total levels and composition of FA and FFA in plasma are altered in clinical heart failure (HF) and whether any alterations in these parameters are correlated to the severity of HF.Methods: Plasma levels of FFA and total levels and composition of FA in plasma were measured in patients with stable HF (n=183) and com-pared to healthy controls (n=20) and correlated to functional class, plasma levels of N terminal pro-B-type natriuretic peptide (Nt-proBNP) and high sensitivity C-reactive protein (hsCRP), and cardiac index (CI).Results: (i) Patients with HF had increased levels of FFA in plasma compared to controls, signifi-cantly correlated with clinical disease severity.

(ii) Patients with HF also had a decreased pro-portion in plasma of several n-3 polyunsaturated FA, an increased proportion of several monoun-saturated FA, and a decreased proportion of sev-eral readily oxidized long-chain saturated FA. (iii) These changes in FA composition were signifi-cantly associated with functional class, impaired cardiac function and enhanced systemic inflam-mation (i.e., increased hsCRP levels). (iv) Low levels of C20:4n-3 (eicosatetraenoic acid) and in particular high levels of C18:1n-7 (vaccenic acid) were significantly associated with total mortality in this HF population.Conclusions: Our data support a link between disturbed FA composition and the progression of HF, and suggest that some of these FA should be further investigated as prognostic markers in this group of patients.

914 Mechanical stress induces NFAT activity and a hypertrop-hic response in isolated cardio-myocytes from neonatal miceG. Florholmen 1; IG. Lunde 1; CR. Carlson 1; G. Christensen 1 1Oslo University Hospital, Ull-eval & University of Oslo, Oslo, NorwayPurpose: Increased mechanical stress in the myo-cardium is regarded as an important stimulus for the hypertrophic response following pressure overload in diseases such as aortic stenosis and hypertension. Activation of the calcineu-rin – nuclear factor of activated T cells (NFAT) pathway, which is central in development of pathological hypertrophy, has been observed in mice following aortic banding. However, it is not known whether increased mechanical stress per se is able to activate this pathway in cardiomyo-cytes. In this study we therefore investigated if mechanical stress activates the calcineurin – NFAT pathway and induces a hypertrophic response in cardiomyocytes isolated from neo-natal mice.Methods: Cells were isolated from 1–3 days old wild type and NFAT-luciferase reporter mice. The reporter mice have a transgen with nine copies of a NFAT binding site inserted upstream of the luciferase reporter gene. Isolated cells were plated on collagen I coated silicone membranes and exposed to cyclic stretch (10%, 1Hz) to induce mechanical stress. Luciferase activity was used as a measure of NFAT activity in cells from the reporter mice. Cyclosporin A (CsA) (500 ng/ml) was used as a calcineurin inhibitor. In wild type cells, the hypertrophic response was assessed by using 3H-leucine incorporation to measure protein synthesis.Results: Short periods (5 min – 120 minutes) or 6 and 12 hours of stretch did not increase NFAT activity compared to unstretched controls. However, following 18 and 24 hours of stretch


we observed substantially increased NFAT activity (5 + 1 fold and 12 + 1 fold, respectively). CsA pretreatment significantly reduced the stretchinduced increase in NFAT activity to 28 + 3% of values obtained in stretched cells without CsA after 24 hours. In line with activation of this pro-hypertrophic signaling pathway, we observed a significant 14 + 5% increase in 3H-leucine incorporation following 24 hours of stretch compared to unstretched controls. This increase in 3H-leucine incorporation was not observed following shorter periods of stretch (6 and 12 hours).Conclusion: We show that mechanical stress induces NFAT transcriptional activity and a hypertrophic response in cardiomyocytes as assessed by increased protein synthesis. Our results suggest that mechanical stress induces pathological hypertrophy in the myocardium by activation of the calcineurin – NFAT signaling pathway.

923 Plasma levels of Wnt inhibi-tory factor-1 (WIF-1) are eleva-ted and predict mortality in symptomatic aortic stenosisET. Askevold 1; L. Gullestad 1; S. Aakhus 1; OG. Solberg 1; P. Aukrust 2; T. Ueland 2 1University of Oslo, Faculty Division Rikshospitalet Uni-versity Hospital, Department of Cardiology, Oslo, Norway; 2University of Oslo, Rikshospi-talet University Hospital, Research Institute for Internal Medicine, Oslo, NorwayPurpose: Calcific aortic stenosis (AS) shares many histopathologic features with atherosclero-sis, including active calcification and ossification. Increasing evidence suggests an important role for Wnt-signaling in these processes. WIF-1, a secreted inhibitor of Wnt-signaling, has recently been implicated as a regulator of osteoblastic differentiation and chondrogensis in vitro, but there is still limited knowledge on the clini-cal importance of this novel Wnt inhibitor. We therefore sought to investigate a possible role for WIF-1 in AS.Methods: One-hundred and forty five patients with symptomatic AS, evaluated for aortic valve surgery, were enrolled in the study. Twenty sex-matched controls were included for comparative analyses. All patients underwent routine echo-cardiographic examinations upon inclusion, and post-hoc backscatter analyses were performed in a blinded fashion. During a mean follow up of 42 months (range 35–47) 34 patients (23%) died. Plasma WIF-1 levels were determined by ELISA technique.Results: AS patients had markedly elevated plasma WIF-1 levels compared to controls (median 114, interquartile range [86,171] pg/ml vs 58 [32,71] pg/ml, p<0.001). Plasma

WIF-1 correlated with NT-proBNP (r=0.297, p<0.001). WIF-1 showed a positive correlation with left ventricular internal dimension in systole (LVIDs), LV posterior wall diameter (LVPWd) and LV end systolic volume (LVESV) (r=0.270, 0.168 and 0.194, respectively, p<0.05 for all), while an inverse relationship was found for fractional shortening (FS) and ejection fraction (EF) (r=-0.298 and -0.201, p<0.001 and 0.018, respectively). Interestingly WIF-1 correlated with ultrasound backscatter (r=0.259, p=0.003). In survival analyses we observed a markedly reduced survival for patients with WIF-1 levels in the fourth quartile compared to the lower three quartiles (p=0.002). When entered in multi-variable analyses, WIF-1 added no significant predictive information for risk estimation beyond established risk factors. However, combining the fourth quartiles of WIF-1 and NT-proBNP proved superior to either of the parameters alone in pre-dicting all-cause mortality (Unadjusted HR=9.48, CI 4.27-21.03, p<0.001; Conditional Cox-adjusted HR 6.24, CI 2.59-14.99, p<0.001).Conclusions: Plasma levels of WIF-1 are elevated in patients with symptomatic AS. WIF-1 cor-relates with ultrasound backscatter, possibly reflecting a relationship between WIF-1 and degree of valvular calcification. In multivari-ate analyses a model of combined WIF-1 and NT-proBNP proved superior to either of the parameters alone in predicting all-cause mortal-ity in AS patients.

1089 Ankyrin B regulates Na/K-ATPase activity in mouse ven-tricular cardiomyocytesN. Tovsrud1; CR. Carlsson1; P. Wanichawan1; I. Sjaastad1; OM. Sejersted1; F. Swift1 1Institute for Experimental Medical Research, Ulleval University Hospital, University of Oslo, Oslo, NorwayPurpose: Ankyrin B is an intracellular polypeptide involved in anchoring of ion transporters, i.e. the Na/K-ATPase (NKA), in various tissue. Our hypothesis is that NKA activity is modified by the attachment to ankyrin B.Methods: Isolated ventricular cardiomyocytes were exposed to a cell permeable interaction inhibiting peptide directed against the CD2 bind-ing motif for ankyrin B on NKA. Cardiomyocytes exposed to a biologically inactive peptide served as controls. Immunoprecipitation- and pull down assays were used to validate the binding of the peptides to ankyrin B. NKA current was mea-sured during voltage clamp. The global intracel-lular cytosolic Na concentration was measured in SBFI-AM loaded myocytes as the ratio between the fluorescence recorded at 410 nm and 590 nm (excitation 340nm). As an indirect estimate of the subsarcolemmal intracellular Na con-


centration, the functional cooperation between NKA and NCX was studied using voltage clamp protocols where the two transporters were simul-taneously activated.Results: The CD2 peptide binds 39% more to ankyrin B compared to the control peptide. Expo-sure to 10 mM CD2 peptide reduces NKA current density by 19% compared to control. Neither the global intracellular cytosolic Na concentration nor the relationship between NKA activity and NCX activity, as an estimate of local Na concen-tration, were different in the two groups.Conclusions: Ankyrin B regulates NKA activity. As the local and global intracellular Na concen-tration seem unaffected, the regulatory effect is probably due to an effect on Na affinity.

1131 The homeostatic chemo-kine CCL21 predicts mortality and may play a pathogenic role in heart failureA. Yndestad1; AV. Finsen1; T. Ueland2; C. Husberg3; K. Dickstein4; D. Hilfiker-Kleiner5; M. Lipp6; L. Gullestad7; G. Christensen3; P. Aukrust2 1Oslo University Hospital, Research Institute for Internal Medicine, Oslo, Nor-way; 2University of Oslo, Research Institute for Internal Medicine, Oslo, Norway; 3Uni-versity of Oslo, Institute for Experimental Medical Research, Oslo, Norway; 4Stavanger University Hospital, Department of Cardiol-ogy, Stavanger, Norway; 5Hannover Medical School, Department of Cardiology and Angiol-ogy, Hannover, Germany; 6Max Delbruck Cen-ter for Molecular Medicine, Berlin, Germany; 7Oslo University Hospital Rikshospitalet, Dept of Cardiology, Oslo, NorwayPurpose: Chronic heart failure (HF) is a disorder characterized by low-grade immune activation and inflammation. However, the inflamma-tory response in HF remains to be completely understood. Identification of the most important mediators of the inflammatory pathways that could be involved in the pathogenesis of HF as well as their mechanism of action are issues that need further elucidation. The chemokines CCL19 and CCL21, acting through their common recep-tor CCR7, are termed homeostatic due to their involvement in leukocyte homeostasis. Based on their essential role in concerting immunological responses and their proposed involvement in tissue remodeling, we hypothesized that these chemokines could play a pathogenic role in HF.Methods: Serum levels of CCL19 and CCL21 were analyzed in patients with HF using enzyme immunoassays. Gene expression was analyzed using real-time RT-PCR. A role for CCL19 and CCL21 was evaluated using CCR7 deficient mice and a model of postmyocardial infarction (MI) HF.

Results: Our main findings were: (i) Serum levels of CCL19 and in particular of CCL21 were mark-edly raised in patients with chronic HF (n=150) as compared with healthy controls (n=20), and a CCL21 level above median levels was inde-pendently associated with all-cause mortality (HR 3.74 [1.17-14.50], p=0.018). (ii) In patients with HF following acute MI (n=232), high versus low CCL21 levels 1 month following MI were associated with cardiovascular mortality during follow-up, even after adjustment for established risk factors (HR 3.27 [1.08-9.96], p=0.037). (iii). In humans, explanted failing LV tissue (n=29) had markedly increased expression of CCL21 as compared with non-failing myocardium (n=5). (iv) CCR72/2 mice showed markedly attenuated expression of markers of myocardial dysfunction and wall stress in post-MI HF, accompanied by increased left ventricular expression of Foxp3, a sensitive marker of regulatory T cells (Tregs), and IL-10 as compared with wild type mice.Conclusions: High serum levels of CCL21 are independently associated with mortality in chronic and acute post-MI HF. Our findings in CCR7 deficient mice may suggest that CCL21 is not only a marker, but also a mediator of myocar-dial failure, potentially involving dysregulation of Tregs within the failing myocardium.

1155 The pro-inflammatory adi-pocytokine visfatin might play a role regulating cardiac metabo-lism in human and experimen-tal aortic stenosisJL. Bjornstad1; I. Sjaastad1; S. Nygard2; AV. Finsen1; A. Hasic1; G. Christensen2; T. Tonnes-sen1 1Oslo University Hospital, Oslo, Norway; 2University of Oslo, Oslo, NorwayPurpose: The newly described adipocytokine visfatin is an insulin-mimetic factor recently reported to regulate cardiac metabolism and promote cardiomyocyte survival. In the present study we examined the expression of visfatin in aortic stenosis (AS) and after correction of the increased cardiac load in AS.Methods: To mimic aortic valve replacement (AVR) for AS, we have established a mouse model of reversible left ventricular pressure overload by banding and subsequent debanding of the ascending aorta. Cardiac dimensions and function were evaluated using echocardiography. Myocardial gene expression was analysed by RT-PCR, and Western blot was used to analyse protein levels. Serum visfatin was measured with ELISA in patients undergoing AVR for AS.Results: The mouse-model induced reversible left ventricular hypertrophy. Gene expression of vis-fatin was 0.75-fold reduced (p<0.01) after band-ing and 1.38-fold increased (p<0.001) following


debanding, both compared to sham. In accor-dance with this, banding led to 0.5-fold reduc-tion of left ventricular visfatin protein (Fig. A, * p<0.01) increasing to sham levels after deband-ing (# p,0.01). Similarly, in patients with AS serum visfatin levels were 46% reduced to from 1669 to 768 pg/ml (Fig B, * p<0.001) compared to healthy controls, returning to control levels (1592 pg/ml) two days after AVR (# p<0.001).Conclusions: The pro-inflammatory adipocy-tokine visfatin is reduced in human and experi-mental AS with rapid normalization after surgical correction of afterload. As a cardioprotective role by regulating cardiac metabolism has been described, the reduced visfatin levels might be unfavourable in pressure overload.

1173 Attenuated fatigue in slow twitch skeletal muscle during isotonic compared to isometric contractions in rats with chro-nic heart failureM. Munvkik1; PK. Lunde1; JM. Aronsen1; JAK. Birkeland1; I. Sjaastad1; OM. Sejersted1 1Insti-tute for Experimental Medical Research, Oslo University Hospital, Ulleval, Oslo, NorwayPurpose: During isometric contractions slow twitch soleus muscles (SOL) from rats with chronic heart failure (CHF) are less fatigue resistant than sham animals. However, a muscle normally shortens during activity. We examined the development of skeletal muscle fatigue fol-lowing shortening (isotonic) contractions in CHF and control.

Methods: Six weeks following coronary artery ligation, infarcted animals were classified as fail-ing (CHF) if left ventricle end diastolic pressure was .15mmHg. SHAM operated rats served as controls. SOL prepared in vivo with intact blood supply were stimulated (1s on 1s off) at 30Hz for 15min and allowed to shorten isotonically against a constant afterload. Muscle temperature was kept at 37°C. Maximum isometric force (Fmax) was measured before and after 100s and 15min of isotonic contraction.Results: Due to slowing of relaxation that sub-sided after about 200s, baseline tension between stimulations rose transiently in both groups, but significantly less in CHF than in SHAM. Isotonic shortening declined rapidly at first and then more gradually, but tended to decline less in CHF. Before isotonic contractions Fmax was not different in the groups, but during contraction there was a transient decline in SHAM, while in the CHF group Fmax tended to decline steadily. Myosin light chain 2s phosphorylation declined in both groups after 100s of isotonic contrac-tions, and remained at this level after 15min.Conclusions: Fatigue development seems to be dependent on mode of contraction. Shortening capacity and isometric relaxation rate may be better preserved in skeletal muscle from CHF rats than could be suspected from experiments using isometric contractions in the study of fatigue.

1237 The arrhythmogenic effect of beta-adrenergic stimulation is potentiated in ventricu-lar myocytes with decreased SERCA2 abundanceMK. Stokke 1; SJ. Briston 2; GF. Joelle 1; WE. Louch1; KB. Andersson 1; G. Christensen 1; DA. Eisner 2; OM. Sejersted 1; AW. Trafford 2; I. Sjaastad 1 1University of Oslo, Oslo, Norway; 2University of Manchester, Manchester, United KingdomPurpose: Ventricular arrhythmias in heart failure can be caused by delayed afterdepolarisations resulting from self-propagating Ca2+ waves in individual cardiomyocytes. We hypothesized that combined reduction in the abundance of the sarcoplasmic reticulum Ca2+ ATPase (SERCA2) and increased beta-adrenergic stimulation increases the risk for such waves compared to either of the two alone. We have used a mouse model with inducible reduction in SERCA2 to test the arrhythmogenic potential of beta-adrenergic stimulation in cardiomyocytes with reduced SERCA2.Methods: SERCA2 knockout (Serca2flox/flox Tg(aMHC-MerCreMer); KO) mice were compared with Sercaflox/flox (FF) control mice six days after induction of gene disruption. At


this time point, SERCA2 abundance is reduced by 53% without any alterations of other Ca2+ handling proteins. Cellular Ca2+ homeostasis and Ca2+ wave characteristics were investigated by whole-cell voltage clamp technique and confocal microscopy combined with Ca2+ imag-ing. Beta-adrenergic stimulation was induced by isoproterenol (100 nM). ECGs were recorded by telemetric surveillance of freely moving mice exposed to caffeine (120 mg/kg) and isoproter-enol (20 mg/kg) i.p.Results: Studies in isolated cardiomyocytes showed that in the baseline situation ([Ca2+]o=1 mM), cytosolic Ca2+ removal was slowed by 40%, SR Ca2+ content decreased by 30% and Ca2+ transient amplitude reduced by 20% in KO compared to FF. Isoproterenol increased L-type Ca2+ current integral by 24% in KO and 34% in FF, rate of the Ca2+ removal by 34% and 48%, respectively, and SR Ca2+ content by 52% and 54% (p<0.05 compared to baseline for all results). In high external Ca2+ ([Ca2+]o=10 mM), isoproterenol increased SERCA2-depen-dent Ca2+ removal by 42% in KO and 23% in FF (p<0.05 compared to baseline). Notably, the same percentage of FF cells developed waves in the presence and absence of isoproterenol (64% and 68%, respectively) while the number of KO cells with waves doubled upon isoproterenol stimulation (from 40% to 82%, p<0.05). How-ever, Ca2+ wave propagation was 19% slower in KO compared to FF (p<0.05). Telemetric ECG data supported cellular findings, since 3 of 4 KO mice developed sustained ventricular arrhyth-mias after isoproterenol stimulation, compared to 1 of 4 FF mice.Conclusions: The arrhythmogenic effect of beta-adrenergic stimulation is increased in ventricular myocytes with reduced SERCA2 abundance.

1281 Low rates of left ventricle lead failure by adequate lead selection in CRT-implantationU. Koepp1; FT. Gjestvang 1; G. Eivindson 1; ESP. Myhre1 1Sorlandet Hospital, Kristiansand, NorwayBackground: In most cases cardiac resynchroni-zation therapy can be obtained by implantation of a biventricular pacemaker with transvenously placed right and left ventricular (LV) leads. The LV lead is pushed through the coronary sinus into a cardiac vein. How well this lead is locked in a cardiac vein most often depends on how the last centimeters of the lead tip models when released from the introducing gear . In former stud-ies rates of LV-lead failure have been reported between 5.7 and 12.5%. To explore this challenge and to indentify possible solutions, we analyzed our single center consecutive series of LV-CRT.

Methods: In our registry from January 2002 to december 2009 we evaluated retrospectively the rate of LV-lead failure, the need for reoperation and which LV leads used.Results: through the whole period 328 attempts of LV lead placing were performed and 314 (95.7%) CRT devices was implanted. All implan-tations were carried out by the same operators with standard catheters and wires and 12 avail-able LV-leads from three manufactures (Guidant (Boston Scientific), Medtronic, St. Jude Medical). In 15 of 314 (4.8%) implanted devices LV-lead failure occurred. The rates of failure were not dif-ferent between the leads used, bedsides very low rates for the Starfix electrode (Medtronic) with active fixation (2%) and the 5 french, s-shaped Quickflex/-site-leads (0%) (St.Jude Medical). After a manual control of lead stability the initial chosen lead was changed in 53 of these 314 (16.9%) implantations, mainly to Starfix-and Quickflex/-site-leads.Conclusion: In our single center unblinded retro-spective analysis of LV- lead implantations over the last 8 years a liberal use of LV-leads from different producers have resulted in a lower rate of LV-lead failure. In our hands the 5.3-french Starfix-lead from (Medtronic) with active fixation and the S-shaped, 5-french Quickflex/-site-lead from St.Jude Medical have the lowest rate of LV-lead failure.

1339 Secretoneurin is increa-sed in the myocardium and circulation in heart failure, induces cardiomyocyte Erk1/2 and Stat3 phosphorylation, and protects against cardiomyocyte apoptosisH. Rosjo 1; M. Stridsberg 2; G. Florholmen 3; KO. Stenslokken 4; I. Sjaastad 3; C. Husberg 3; MB. Dahl 1; E. Øie 5; T. Omland 6; G. Chris-tensen 3 1Medical Division, Akershus Univer-sity Hospital, Lorenskog, Norway; 2Uppsala University, Department of Medical Sciences, Uppsala, Sweden; 3Institute for Experimental Medical Research, Oslo University Hospital, Ulleval, Oslo, Norway; 4University of Oslo, Faculty Division Ulleval University Hospital, Oslo, Norway; 5Research Institute for Internal Medicine, Oslo University Hospital, Rikshospi-tal, Oslo, Norway; 6University of Oslo, Faculty Division Akershus University Hospital, Oslo, NorwayPurpose: Secretoneurin (SN) is a peptide from the granin protein family. As the index member of the granin proteins, chromogranin A (CgA), is regulated during heart failure (HF) development, we hypothesized that SN would be increased and play a pathophysiological role in HF.


Methods: In a post-myocardial infarction (MI) HF mouse model, animals were evaluated by echocardiography before being sacrificed one week post-MI. mRNA levels were measured by qRT-PCR and SN protein levels assessed by radioimmunoassay (RIA). Localization of SN production in the myocardium was examined by immunohistochemistry. Circulating levels of SN and CgA were measured by RIA in 58 patients with chronic, stable HF recruited from an outpatient HF clinic and compared to levels in 20 age- and gender-matched healthy control subjects. Effect of SN (10 mg/ml) was examined in isolated cardiomyocytes from neonatal rats by measuring activation of intracellular signalling pathways and apoptosis.Results: Pro-SN mRNA levels were 11.5 fold upregulated in the left ventricle (LV) of HF animals compared to sham-operated animals (p<0.001). This was a greater relative increase than observed for LV BNP gene expression (5.8 fold increase). SN protein levels were also increased in the non-infarcted (35%) and infarcted region (85%) of the LV in HF animals. In contrast, there was no increase in SN levels in pulmonary tissue, spleen, liver, gastrointestinal tract and skeletal muscle during HF development. Myocardial SN production was confined to the cardiomyocytes. Patients with chronic, stable HF of mainly moderate severity had increased circulating SNlevels compared to control subjects (0.17+0.01 vs. 0.12+0.01 nmol/L, p<0.001), and-SNlevels were superior to CgA, an established HF biomarker, for diagnosing HF (ROC-AUC 0.84 vs. 0.57, p=0.001). Stimulating cardiomyocytes for 10 min with SN induced a five fold increase in Erk1/2 phosphorylation and a two fold increase in Stat3 (Tyr727) phosphorylation (p=0.04 for both). Treating cardiomyocytes with SN prior to and during 24 h of hydrogen peroxide (100 mM) exposure reduced cardiomyocyte apoptosis by 30% (p=0.005).Conclusion: SN is increased in the LV and circula-tion in HF and protects against apoptosis during cardiomyocyte stress. SN may represent both a novel endogenous protective agent in the fail-ing myocardium and a new and interesting HF biomarker.

1367 Lack of cytokine response to post-infarction heart failure and exerciseTA. Rehn1; G. Slettalokken 2; M. Munkvik 1; B. Rud 2; M. Sokjer-Pedersen 3; I. Sjaastad 1; J. Hallen 2; OM. Sejersted 1; PK. Lunde1 1Institute for Experimental Medical Research, Oslo University Hospital, Ulleval, Oslo, Norway; 2The Norwegian School of Sport Sciences, Oslo, Norway; 3Department of Cardiovascular Radiology, Oslo University Hospital, Ulleval, Oslo, NorwayPurpose: Chronic heart failure (CHF) is accom-panied by elevated plasma levels of pro-inflam-matory cytokines that seem to predict negative outcome. In the present study we examined whether skeletal muscles release cytokines to the circulation in post-infarction CHF patients and controls, and whether this is altered by training.Methods: Six post-infarction CHF patients, 8 coronary artery disease patients (CAD) and 6 healthy subjects (HS) underwent 6 weeks of unilateral endurance training of the quadriceps femoris muscle (QF). QF muscle mass and cyto-kines in mixed venous plasma were measured before and after the training period. After the training period arteriovenous concentration differences of 27 cytokines were measured over trained and untrained leg at rest, during exercise and three minutes post exercise.Results: Mixed venous plasma levels were not different between groups for any of the 27 cyto-kines before the training. The training regimen did not alter this. However, when all groups were pooled training had an independent effect on the plasma concentration of RANTES which was significantly increased (p<0.05). Arterial and venous concentrations were not significantly dif-ferent (indicating no net release) in trained and untrained leg, both at rest, during exercise as well as post exercise.Conclusions: Systemic inflammatory status is not different between stable, optimally treated post-infarction CHF patients in NYHA class II-III and controls. Skeletal muscle does not seem to con-tribute to the systemic cytokine levels in either of these groups, independent of acute exercise or training. Training even a small muscle mass seems to have beneficial effect on the RANTES plasma level.

1398 Quality of life in chronic heart failure patients from the Norwegian heart failure registryT. Hole 1; M.Grundtvig 2; L. Gullestad 3; B. Floenaes 4; A. Westheim 3 1Alesund Hospital, Alesund, Norway; 2Lillehammer Hospital, Lil-


lehammer, Norway; 3Oslo University Hospital, Oslo, Norway; 4Asker and Baerum Hospital, Oslo, NorwayPurpose: To evaluate quality of life (QOL) in outpatient heart failure (HF) patients attending multidisciplinary disease management programs at heart failure clinics in Norwegian hospitals.Methods: Data fromHF patients at 22 hospital outpatient clinics were entered in a common database; The Norwegian Heart Failure Registry. QOL assessment was done using Minnesota Liv-ing with Heart Failure Questionaire (MLHF). The assessment was optional at each hospital, and was done both at initial evaluation and 6 months after leaving the clinic.Results: A total of 1778 patients had assess-ment of QOL at baseline an 517 after 6 months. The mean age was 73 years, and 72% were men. Fortytwo% were in NYHA functional class 2 and 52% in class 3. More than 80% of the patients used diuretics, ACE inhibitor/angio-tensin receptor blocker, and betablockers. The mean (crude) MLHF score improved significantly from 2,1 (43) at initial evaluation to 1,4 (27) at 6

months after leaving the clinic (p<0.0005). All aspects of MLHF were impaired, and all improved significantly. There was a significant difference in MLHF score between different hospitals, and baseline MLHF score was significantly related to NYHA functional class, hospitalisations during the 6 months before entering the registry, brain natriuretic peptide (BNP), and inversly related to age and systolic blood pressure in multipple regression analyses. MLHF score was an inde-pendent predictor of mortality in this popula-tion together with age, reduced renal function, no ASA use, uric acid level, and mortality was inversely related to systolic blood pressure.Conclusion: Quality of life assessed with MLHF was significantly impaired in outpatient heart failure patients in Norway, and improved after follow up at outpatient HF clinics. MLHF score was significantly related to functional status, laboratory and demografic variables, and QOL was an important independent predictor of prognosis. n

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Legeforeningen - Heart Failure 2010...engangsdose ved perkutan intrakoronar infusjon. Pasienter (n=39) med hjertesvikt, både iskemisk og non-iskemisk kardio-myopati, i NYHA-funksjonsklasse