HEART FAILURE 2017 PARIS 29. APRIL 2. MAI 2017

HEART FAILURE 2017 PARIS 29. APRIL 2. MAI 2017 Årets europeiske hjertesviktkongress befestet sin rolle som verdens største og mest betydningsfulle hjertesviktmøte. I fire dager satte rundt 5000 deltagere fra mer enn 100 land hverandre stevne i Paris. Antallet abstrakter og andre presentasjoner var rekordhøyt med over 2000 innlegg. Kongressen var bygget opp på tradisjonelt vis, men med et stadig økt fokus på omsetting av resultater fra studier til klinisk praksis. Dette ble blant annet ivaretatt under titler som Workshops, Hands On Tutorials og Guidelines in Daily Practise. Yngre leger, sykepleiere og forskere ble spesielt tilgodesett i egne sesjoner og arrangementer, i tråd med årets motto: «Rendez-vous with the future». Naturlige høydepunkter i kongressen var tre sesjoner med ferske resultater fra nyere studier, Late Breaking Trials. Noen av disse studiene er referert her, sammen med andre aktuelle tema og norske abstraktbidrag. Rune Mo Stedlig redaktør for Hjerteforum (her foran Triumfbuen) 117 hjerteforum N 4/ 2017/ vol 30

BROMOKRITIN TIL PASIENTER MED POSTPARTUM-KARDIOMYOPATI Efraim Bulut, Medisinsk avdeling, Haraldsplass Diakonale Sykehus En studie, presentert på Heart Failure 2017, indikerer at bromokriptin til behandling av peripatrum-kardiomyopati (PPCM) ser ut til å være forbundet med betydelig forbedret funksjon av venstre ventrikkel (LV) og lavere morbiditet. Bare en uke med bromokriptinbehandling synes å være tilstrekkelig, men pasienter som er kritisk syke, bør motta en høyere initial dose av behandlingen. Denne multisenter proof-of-conceptstudien inkluderte 63 PPCM-pasienter med venstre ventrikkels ejeksjonsfraksjon (LVEF) < 35 % til kortvarig (2,5 mg daglig i en uke) eller langvarig (5 mg daglig i 6 uker etterfulgt av 2,5 mg daglig i to uker) behandling med bromokriptin i tillegg til standard hjertesviktterapi. Det primære endepunktet var endring i LVEF etter seks måneder. Studien ble ledet av professorene Denise Hilfiker-Kleiner og Johann Bauersachs fra Hannover. De konkluderte med at bromokriptinbehandling både i én og åtte uker så ut til å være trygt ved behandlingen av PPCM og at terapien var assosiert med betydelig forbedret venstre ventrikkelfunksjon, uten forskjell mellom gruppene. Sammenligninger med tilsvarende pasientkohorter som ikke er behandlet med bromokriptin, indikerer resultatene gunstig effekt av å legge til bromokriptin i minst én uke i tillegg til vanlig hjertesviktbehandling. Bauersachs og Hilfiker-Kleiner uttalte: «Hittil finnes det ingen terapi som spesifikt retter seg mot patofysiologien til PPCM. Der er økende evidens for at prolaktin, og spesielt den spaltede angiostatiske formen 16kd prolaktin, spiller en aktiv rolle i sykdomsutviklingen». De sa videre: «Selv om vår studie omfattet 63 pasienter og er den største randomiserte studien så langt for pasienter med denne relativt sjeldne sykdommen, er det nødvendig med flere data for å bekrefte effekten av bromokriptin. Det verdensomspennende PPCM-registeret organisert av EUROBservational Research Programmet fra HFA/ESC vil gi mer kunnskap om denne sykdommen. «Det ser også ut til at en kort lavdose bromokriptinbehandling er tilstrekkelig i de fleste former for PPCM. Men vår egen erfaring tyder på at kritisk syke pasienter (det vil si de som har en LVEF < 25 % og er i kardiogent sjokk) kan ha nytte av en langvarig behandling med høyere startdose av bromokriptin. Denne hypotesen må testes i et prospektivt randomisert studie». OM IVABRADIN VED HJERTESVIKT MED BEVART EJEKSJONSFRAKSJON, TAKOTSUBO-SYNDROMET OG HJERTESVIKT OG ATRIEFLIMMER Rune Mo, Klinikk for hjertemedisin, St. Olavs hospital Ivabradin ved hjertesvikt med bevart ejeksjonsfraksjon Dokumentasjonen for behandling av hjertesvikt med bevart ejeksjonsfraksjon (HFpEF) er begrenset. I en venstre ventrikkel med forstyrret diastolisk fylning kan redusert hjertefrekvens ha gunstig hemodynamisk effekt. EDIFY-studien (The preserved left ventricular ejection fraction chronic heart hjerteforum N 4/ 2017 / vol 30 118

Failure with ivabradine study) analyserte effekten av sinusknutehemmeren ivabradin ved HFpEF. Resultatene ble fremlagt i en Late Breaking Trials-sesjon. Samtidig med den orale presentasjonen ble EDIFY-studien gjort tilgjengelig elektronisk (Komajda, M. et al. Effect of ivabradine in patients with heart failure with preserved ejection fraction: the EDIFY randomized placebo-controlled trial. Eur Heart J 30. april 2017, DOI: 10.1002/ ejhf.876). Studien omfattet 179 pasienter med hjertesvikt i NYHA-klasse II-III, LVEF > 45 %, sinusrytme 70/min, og NT-proBNP 220 pg/ml eller BNP 80 pg/ml. Pasientene ble randomisert til ivabradin opp til 7,5 mg to ganger daglig eller til placebo. Etter 8 måneders oppfølging var pulsen signifikant lavere i ivabradin-gruppen enn hos pasienter som fikk placebo. Det var imidlertid ingen forskjell mellom gruppene i de primære endepunktene, et ekkokardiografisk fylningsmål (E/e -ratio), i NTproBNP eller i 6 minutters gangdistanse. Redusert hjertefrekvens var heller ikke assosiert med effekter på sekundære endepunkter (dimensjoner av venstre ventrikkel og atrium, EF og dopplerparametre). Studien ga ikke holdepunkter for uheldige effekter av ivabradin. Pulsreduksjon ved ivabradin ga altså ikke positiv effekt på hemodynamiske parametre eller funksjonsnivå hos pasienter med HFpEF. Førsteforfatter Michael Komajda fra Paris fremmet tanken om at pulsreduksjon ikke vil gi gunstig effekt hvis det allerede foreligger fibrose i myokard. Uavhengig av det konkluderer studien med at ivabradin ikke har noen plass i behandlingen av pasienter med HFpEF. Takotsubo-syndromet En egen sesjon var satt av til takotsubosyndrom. Ordstyrer Alexander Lyon fra Storbritannia oppfordret til å bruke begrepet takotsubo-syndrom og ikke takotsubokardiomyopati. Primært takotsubo-syndrom med en fysisk eller psykisk trigger skilles fra sekundært takotsubo-syndrom ved andre medisinske tilstander. Grunnleggende vil et takotsubo-syndrom presenteres med circumferensiell dysfunksjon av venstre eller høyre ventrikkel uten at det affiserte området tilsvarer et koronart perfusjonsområde. På samme måte vil koronar angiografi ikke kunne påvise en typisk culprit-lesjon. NTpro- BNP vil være sterkt forhøyet, mens troponin T- nivåer vil være lavt i forhold til utbredelsen av hypo- eller akinesi. Det vil kunne påvises forskjellige forandringer i EKG. Elmir Omerovic fra Sverige foretok en historisk gjennomgang med utgangspunkt i Cannons presentasjon av voodo-død i 1942, broken heart syndrome ved Parkes i 1969, før Seto så beskrev takotsubosyndromet i 1990. Mye er fortsatt uklart vedrørende anatomi, fysiologi, etiologi, og mekanismer for reversibilitet. Samtidig er interessen for Takotsubo-syndromet åpenbart stigende med et høyt antall publikasjoner. I det svenske SCAAR-registrert er også antallet pasienter med takotsubosyndrom sterkt økende. I følge Omerovic er takotsubo-syndrom den vanligste form av ikke-iskemisk kardiomyopati i den svenske befolkningen. De svenske tallene støttes av amerikanske data som viser en tredobling av pasienter innlagt med primært eller sekundært takotsubo-syndrom i perioden 2007-2012 (Khera et al. Trends in hospitalization for takotsubo cardiomyopathy in the United States. Am Heart J 2016; 172: 53-63). Det økende antall pasienter kan være betinget av økt oppmerksomhet om tilstanden. Omerovic åpnet også for en reelt økt insidens med en mulig kobling til allment økt stressnivå og engstelse i befolkningen. Ghadri fra Sveits redegjorde for takotsubo-syndrom som årsak til akutt hjertesvikt og som differensialdiagnose til akutte koronarsyndromer. Det kliniske bildet kan også omfatte mitralinsuffisiens, venstre ventrikkelobstruksjon og intraventrikulær trombe. Typisk klinisk presentasjon er brystsmerter, tungpustethet, sjokk og/ eller død. I forhold til lokalisering skiller vi mellom en apikal, midtventrikulær, basal eller fokal presentasjon. Utbredelsen av kontraktilitetsforstyrrelser passer ikke med påviste koronare lesjoner. Det er likevel viktig å merke seg at en betydelig andel, opptil 15 %, av pasienter med takotsubo samtidig har koronarsykdom. Takotsubo-syndrom er ingen ufarlig tilstand. I henhold til data fra SWEDEHEART er mortaliteten sammenlignbart med et ST- elevasjonsinfarkt. Med tanke på behandling vil lavmolekylært heparin kunne være indisert. Ved hjertesvikt gis standard hjertesviktbehandling. Betablokker er indisert ved obstruksjon av venstre 119 hjerteforum N 4/ 2017/ vol 30

ventrikkels utløpstraktus, men synes ikke å bedre langtidsprognosen. Dobbel platehemming er kun aktuelt ved samtidig koronarsykdom, så også statiner. ACE-hemmere og angiotensin 2-reseptorblokkere kan bedre prognosen på lang sikt. Hjertesvikt og atrieflimmer En Guidelines in daily practice-sesjon omhandlet atrieflimmer og hjertesvikt. Kotecha fra Storbritannia introduserte dette klinisk viktige temaet, der rundt en tredjedel av pasienter med hjertesvikt har atrieflimmer og vise versa. Samtidig atrieflimmer og hjertesvikt kan vanskeliggjøre klinisk vurdering, ekkokardiografi, så vel som tolking av økte verdier for natriuretiske peptider. Behandlingsmessig vil fokus måtte rettes parallelt mot atrieflimmer og hjertesvikt. Linde fra Sverige anbefalte i tråd med aktuelle retningslinjer elektrokonvertering av atrieflimmer hos hemodynamisk kompromitterte pasienter, alternativt rytmekontroll med amiodaron eller frekvenskontroll med digoxin. Generelt vil rytmekontroll hos pasienter med hjertesvikt ivaretas ved elektrokonvertering, amiodaron eller ablasjon. Flere studier på ablasjon er underveis (f.eks. CASTLE-AF, RAFT-AF og AMICA) og vil kunne bedre grunnlaget for behandlingsvalg i pasientgruppen. Hos hemodynamisk stabile pasienter vil førstevalg for frekvenskontroll fortsatt være betablokker. Hvis det likevel er aktuelt å bruke digoxin hos pasienter med hjertesvikt og redusert EF, er det viktig å ta med resultater fra DIGstudien. Her er mortaliteten lavest ved en serumkonsentrasjon på 0,5-0,7 ng/ml og en tydelig økning av mortalitet ved konsentrasjoner over 1,5-2,0 ng/ml (Adams et al. Eur J Heart Fail 2016; 18: 1072 1081). Linde refererte også arbeider som tyder på at målfrekvens for atrieflimmer hos hjertesviktpasienter bør ligge i området 70-90 slag/min (Mareev et al. Clin Ther 2015; 37:2215-24) eller 60-100 slag/min (Li et al. Circ Heart Fail 2015;8:871-879). Cleland fra Storbritannia refererte en metaanalyse av 11 placebokontrollerte betablokkerstudier på hjertesvikt (Kotecha et al. J Am Coll Cardiol 2017; 69: 2885-96). Her ble sammenhengen mellom hjertefrekvens og mortalitet studert hos pasienter med redusert EF ved henholdsvis sinusrytme og atrieflimmer. Høy hjertefrekvens ved inklusjon var relatert til mortalitet hos pasienter i sinusrytme (HR 1,11 per 10 slag/min; 95 % KI 1,07-1,15; p < 0,0001), men ikke hos pasienter i atrieflimmer (HR 1,03 per 10 slag/ min; 95 % KI 0,97-1,08; p = 0,38). Betablokkere ga lavere mortalitet for pasienter i sinusrytme (HR 0,73, 95 % KI 0,67-0,79; p < 0,001), uavhengig av hjertefrekvens ved inklusjon. I kontrast til dette hadde betablokker ingen effekt på mortalitet hos pasienter med atrieflimmer (HR 0,96, 95 % KI 0,81-1,12; p = 0,58). Redusert hjertefrekvens under behandling var assosiert med bedret prognose for pasienter i sinusrytme (HR 1,16 per 10 slag/min økt hjertefrekvens, 95 % KI 1,11-1,22; p < 0,0001), men ikke for pasienter i atrieflimmer. Resultatene må sees i lys av at hjertefrekvensen ble analysert i tre lave frekvenskategorier, henholdsvis < 70, 70-90 og > 90 slag/min. Cleland drøftet på generelt grunnlag at for lav hjertefrekvens hos pasienter i atrieflimmer vil kunne bidra til pauser som i sin tur kan legge til rette for ventrikulære arytmier. Manglende mortalitetsgevinst av betablokkade er, sammen med optimal målfrekvens, effekten av ablasjon og kardial resynkroniseringsterapi, områder som fortsatt er uavklart i den store gruppen av pasienter med atrieflimmer og hjertesvikt. 121 hjerteforum N 4/ 2017/ vol 30

LATE BREAKING TRIALS, SØVNAPNÉ, DIABETES MELLITUS OG HJERTESVIKT SAMT FREMTIDSVYER Lars Gullestad, Kardiologisk avdeling, Oslo universitetssykehus, Rikshospitalet. RELAX-AHF-2: Serelaxin ved akutt hjertesvikt (presentert av J.R. Teerlink and M. Metra) Relaxin er et naturlig forekommende peptid som finnes både hos kvinner og menn. Hos kvinner øker hormonet betydelig gjennom svangerskapet og bidrar til den termodynamiske adaptasjon som finner sted. Serelaxin er en rekombinant peptid av det humane relaxin-2-hormonet som ved infusjon gir vasodilatasjon og reduserer derfor pre- og afterload og beder nyregjennomblødning. I tillegg reduseres oksidativt stress og inflammasjon, og stoffet virker inn på remodellering etter hjerteinfarkt og ved hjertesvikt i eksperimentelle modeller. I RELAX-AHF-studien ble 1161 pasienter med akutt hjertesvikt randomisert til serelaxin eller placebo som en 48 timers infusjon. Serelaxin reduserte det primære endepunkt dyspné (19 % økning av «VAS AUC» frem til dag 5). I tillegg reduserte serelaxin forverring av hjertesvikt i forbindelse med sykehusinnleggelsen med 47 % og reduserte nivået av pro-bnp. I tillegg så man en signifikant reduksjon av kardiovaskulær død (HR 0,64, p=0,028) og total død (HR 0,83, p=0,02) i løpet av 180 dager. Dette var bakgrunnen for å starte RELAX-AHF-2, der man ville teste hypotesen om at serelaxin kunne redusere endeorganskade og bedre symptomer som igjen ville resultere i redusert forekomst av forverret hjertesvikt (WHF) og kardiovaskulær død. Totalt ble 6600 pasienter med akutt hjertesvikt (dyspné, øket BNP/proBNP, persisterende symptomer) randomisert til infusjon med serelaxin (30 µg/kg/dag) eller placebo for 48 timer. Det primære endepunkt var kardiovaskulær død frem til 180 dager og forverret hjertesvikt under det primære sykehusoppholdet. Sekundære endepunkter inkluderte totaldød, varighet av sykehusopphold og et sammensatt endepunkt av kardiovaskulær død og hospitalisering grunnet forverret hjertesvikt. Hovedresultater: 1) Kardiovaskulær død ved 180 dager: serelaxin (285 av 3274, 8,7 %) vs. placebo (290 av 3271, 8,9 %) (HR 0,98, 95 % KI: 0,83-1,15, p=0,38), 2) forverret hjertesvikt til dag 5: serelaxin 6,9 %, placebo: 7,7 % (HR 0,89, 95 % KI: 0,75-1,07 (ns)), 3) total død inntil 180 dager: 11,2 % med serelaxin vs. 11,9 % med placebo (HR 0,94, 95 % KI: 0,81-1,08, p=0,39), 4) kardiovaskulær død eller rehospitalisering av hjertesvikt: serelaxin 24,3 % vs. 24,9 % (HR 0,97, 95 % KI: 0,88-1,07, p=0,27) og 5) varighet av sykehusopphold: serelaxin: 6,8 dager vs. placebo: 6,9 (ns). Det var ingen forskjell i sikkerhet eller bivirkninger. RELAX-AHF-2-studien er således å betrakte som en nøytral studie, og på tross av effekt på dyspné og BNP/proBNP kunne man ikke vise effekt på harde endepunkt. Serelaxin vil således ikke bli brukt i rutinen ved akutt hjertesvikt, og minner oss om viktigheten av å kjøre store, vel designede studier med tilstrekkelig antall pasienter for å svare på viktige kliniske problemstillinger på tross av lovende og ofte uventede resultat i mindre studier. Hvorvidt serelaxin kan få en plass hos utvalgte pasienter, gjenstår å analysere. Studien er ennå ikke publisert. Det natriuretiske peptidet ularatide ved akutt hjertesvikt The effect of ularatide on the clinical course and cardiovascular mortality in acutely decompensated heart failure depend on the eligibility of patients for the trial: deep dive results of the TRUE-AHF Trial (presentert av M. Packer). Bakgrunnen for TRUE-HFstudien er at pasienter med akutt hjertesvikt ofte har væske- og saltretensjon samt vasokonstriksjon som gir øket belastning på hjertet og mikronekrose som manifesters med økt nivå av BNP/proBNP og troponiner. Dette hjerteforum N 4/ 2017 / vol 30 122

er assosiert med forverret prognose etter utskriving i form av død og hospitalisering. Ularitide er et natriuretisk peptid som gir doseavhengig hemodynamiske effekter hos pasienter med akutt hjertesvikt. Det er også utført en mindre studie med peptidet, SIRIUS II, der ularitide var assosiert med lavere 30 dagers mortalitet. Det var imidlertid få dødsfall, og for å få et endelig svar designet man en stor randomisert studie, TRUE-AHF. I TRUE-AHF studien ville man teste hypotesen om at dersom man kunne motvirke den ugunstige hemodynamiske situasjon ville man kunne bedre prognose. Studien hadde to primære endepunkt: langtids kardiovaskulær dødelighet og klinisk utkomme den første tiden. Dette er den første studien ved akutt hjertesvikt der kardiovaskulær død er et primært utkomme og baserer seg på funn i RELAX-HF studien der det var færre dødsfall med serelaxin enn placebo (et sekundært endepunkt). Det andre primære endepunkt i studien var kort tids klinisk forløp lagt opp som et sammensatt endepunkt av a) endring av symptomer og b) forekomst av forverret hjertesvikt, som ses hos 5-30 %. Innføring. Dette ble satt sammen på en hierarkisk måte og omsatt til et tall. 2157 pasienter med akutt hjertesvikt ble randomisert til infusjon av ularitide (det natriuretiske peptid: 15 ng/kg/ min) eller placebo, og dette ble gitt etter en median tid på 6,1 timer (dvs. relativt raskt). Hovedresultater: Ularitide ga en forventet effekt på hemodynamikken med et fall av systolisk blodtrykk og en 47 % større reduksjon av NT-proBNP over 48 timer. Videre så man en økning av hemoglobin og kreatinin og et fall av leverenzymer med ularitide. Dog var det ingen forskjell mellom gruppene i troponinutslipp. Videre resulterte ularitide i signifikant færre hjertesvikthendelser under hospitaliseringsperioden, spesielt i infusjonsperioden, en effekt som tapte seg etter at infusjonsperioden var over. Derimot var det ingen effekt av ularitide på de primære endepunktene, kardiovaskulær død opp til 34 måneder (HR 1,03, 95 % KI: 0,85-1,25, p=0,75) eller på et klinisk sammensatt endepunkt. Så på tross av en gunstig initial hemodynamisk effekt og et bedret korttidsforløp så man ingen effekt på kardiovaskulær død under oppfølging. For bedre å skjønne diskrepansen mellom bedret hemodynamisk effekt og manglende effekt på klinisk sammensatt endepunkter og kardiovaskulær død har man gjort subanalyser over inkluderbare vs. ikke-inkluderbare pasienter. Dette ble presentert på denne kongressen. For å være inkluderbar (og for å se på en effekt på dyspné) var kravet at pasientene skulle ha vedvarende dyspné på tross av diuretika og være stabile i 2 timer uten endring av medikasjon med et stabilt blodtrykk. Når man gjennomgikk dette, viste det seg at 358 (17 %) av pasientene ikke fylte kravene til inklusjon, mens 1799 (83 %) var inkluderbare. Videre analyser viste da også at ularitide bedret dyspné hos inkluderbare, men ikke hos ikke-inkluderbare pasienter. Kardiovaskulær død ble imidlertid ikke influert. Analysene viser således betydning av å følge oppsatte inklusjonskriterier og hvordan studieresultater kan påvirkes dersom dette ikke er tilfelle. Alle studiestedene hvor dette (feil inklusjon) fant sted («study sites of consern») befant seg i Øst Europa. Søvnapné En egen sesjon «Sleep disordered breathing and heart failure -Time to rethink» ble holdt. Martin Cowie som ledet SERVE-HF studien, holdt et innlegg om «Randomized trials in heart failure and sleep apnea». Søvnapné (SA) er vanlig ved hjertesvikt (40-75 %) og av de tre typene, sentral søvnapné (CSA), obstruktiv søvnapné (OSA) og kompleks/blandet form som er en kombinasjon av de to første, er CSA den vanligste ved hjertesvikt og er mer uttalt jo verre hjertesvikten er. Det er mange flotte teorier for hvilke patofysiologiske konsekvenser SA vil ha, og observasjonelle studier har tydet på at behandling av SA vil kunne bedre prognose hos pasienter som både har SA og hjertesvikt. De tre randomiserte studiene som er gjort (CANPAP, SERVE-HF og CAT-HF) viser derimot ingen tydelig effekt på verken kardiovaskulær død eller hospitalisering for forverret hjertesvikt. SERVE viste endog en statistisk negativ effekt. Spørsmålet er hva som ligger bak en nøytral og negativ effekt. I SERVE-HF-studien har man generert en stor database, og det vil nå komme subanalyser som prøver å identifisere mekanistiske faktorer. På denne konfe- 123 hjerteforum N 4/ 2017/ vol 30

ransen refererte Cowie til en subanalyse på plutselig død. Dette forekom hyppigst hos dem med dårligst venstre ventrikkelfunksjon (EF < 30 %), gjennom hele døgnet (dvs. ikke bare ved pustestopp om natten), døden inntraff uten forvarsel og ICD ga ingen beskyttelse. Risikoen ved bruk av maskebehandling var spesielt stor for plutselig død (HR 5,21 (2,1-12,8). Mekanismen for dette er ukjent. Flere subanalyser vil komme. Diabetes mellitus og hjertesvikt Det siste året har det vært stor oppmerksomhet rundt betydning av SGLT 2-hemmere ved diabetes mellitus etter resultatene av EMPA-REG OUTCOME-studien ble presentert (New Engl J Med 2015). På denne kongressen var det flere satellittsymposier der betydning av hjertesvikt ved diabetes mellitus ble belyst. Generelt vil pasienter med diabetes mellitus type 2 utgjøre 25-40 % av pasienter med hjertesvikt, og blant pasienter med diabetes mellitus type 2 over 65 år er forekomsten av hjertesvikt 20-25 %. Tilstedeværelse av hjertesvikt ved diabetes mellitus type 2 innebærer en forverret prognose. Hos pasienter med diabetes mellitus type 2 og hjertesvikt bør man optimalisere hjertesviktbehandling. «Tradisjonelle» medikamentgrupper som ACE-hemmere/angiotensin II-reseptorblokker, betablokkere og aldosteronblokkere har like god effekt hos pasienter med diabetes mellitus som dem uten, men den absolutte gevinsten er større hos dem med diabetes mellitus pga. økt risiko. Noen diabeteslegemidler (glitazoner, saxagliptin, alogliptin) øker risikoen for hjertesvikthendelser hos pasienter med diabetes mellitus og bør unngås, mens SGLT 2-hemmere er assosiert med redusert risiko. Nylig publiserte studier med glukagon-liknende peptid (GLP-1)-analog, liraglutid (LEADER-studien, New Engl J Med 2016;375:311), viste effekt på kardiovaskulær dødelighet hos pasienter med diabetes mellitus type 2, mens effekten på hjertesvikthospitalisering ikke var signifikant. En bekymring med disse medikamentene er øket hjertefrekvens som i seg selv er forbundet med en forverret prognose. Vil vi kunne fjerne eller kurere hjertesvikt? I forbindelse med et symposium: The 50th anniversary of heart transplantation, ga E. Braunwald en forelesning der han endret tittel til: «Will we be able to abolish heart failure?». Han tok utgangspunkt i 10 observasjoner: 1. Arteriosklerotisk sykdom er årsak til minst 75 % av hjertesvikttilfellene i den vestlige verden 2. LDL-kolesterol er viktigste risikofaktor for utvikling av arteriosklerose 3. Statiner har primær- og sekundærpreventiv effekt på utvikling av koronarsykdom, men ingen dokumentert effekt ved hjertesvikt 4. Både primær- og sekundærprevensjon starter sent (> 45 års alder) på et stadium der arteriosklerose er avansert 5. Langtidsbehandling med statiner er vanskelig pga. dårlig etterlevelse (bruk av statiner i primærprevensjon er 50 % etter 1 år, 20 % etter 3 år) 6. Vi trenger metoder for å redusere LDLkolesterol over lang tid 7. Betydning av PCSK9 er validert som prinsipp 8. Blokade av PCSK9 gir øket LDL-reseptortetthet og redusert LDL-nivå 9. PCSK9-hemmer med humane antistoff krever injeksjon hver 2.-4. uke og er dyrt. Alternativ kan man blokkere syntese av RNA. Inclisiran er en langtidsvirkende blokker av RNA (RNAi) som hemmer syntese av PCSK9 med varighet opp til ett år (Fitsgerald N Eng J Med 2017;376: 41). Resultatet er oppregulering av LDL-reseptor med påfølgende reduksjon av LDL-kolesterol. 10. Gitt terapeutisk sikkerhet vil 1 dose hvert år med start fra 30 års alder gi en LDL-verdi rundt 60 mg/dl (1,55 mmol/l som vil hindre utvikling av arteriosklerose og hjertesvikt. Skulle man kommentere dette måtte det være hvorfor vente til 30 år. Vi vet fra IVUS-analyser av donorhjerter ved hjertetransplanta- hjerteforum N 4/ 2017 / vol 30 124

sjon at mange har avanserte plakk, og autopsistudier fra soldater i 20-årene under krig viser arteriosklerose i varierende grad. Kanskje dette kan bli neste gave til konfirmasjonen? Årets ESC-HF-kongress ga viktig lærdom. Nøytrale og negative studier utfordrer vår tradisjonelle tankebane og tvinger oss til å tenke utenfor boksen. I tillegg viser de betydning av adekvate randomiserte klinisk kontrollerte studier. ABSTRAKTER MED NORSKE BIDRAG PRESENTERT VED HEART FAILURE 2017 NADPH oxidase-4 promotes adaptive cardiac remodelling in the chronically stressed heart by driving protein O-GlcNAcylation and enhancing cardiac fatty acid oxidation A A Adam Abner Nabeebaccus 1 ; A Zoccarato 1 ; A D Hafstad 2 ; C X S Santos 1 ; E Aasum 2 ; A C Brewer 1 ; M Zhang 1 ; J West 3 ; J Griffin 3 ; T Eykyn 1 ; M Mayr 1 ; A M Shah 1. 1 King s College London, Cardiovascular Division, London, United Kingdom; 2 University of Tromsø, Tromsø, Norway; 3 University of Cambridge, Department of Biochemistry, Cambridge, United Kingdom. Funding Acknowledgements: Medical Research Council, UK (MRC, UK); British Heart Foundation, UK (BHF, UK). Background: Reactive oxygen species (ROS) production contributes to both adaptive and maladaptive remodelling pathways in the heart and is involved in the pathophysiology of cardiac hypertrophy and failure. NADPH oxidase-4 (Nox4), a specialised ROS-generating enzyme has beneficial effects by promoting adaptive remodelling during pressure-overload cardiac hypertrophy. Purpose: To understand how Nox4, a ROS-generating enzyme promotes adaptive cardiac remodelling to achieve beneficial effects in the chronically stressed heart. Methods and Results: An unbiased global overview of putative Nox4-mediated changes, from cardiac-specific Nox4 transgenic (TG) and wild-type (WT) mouse hearts was first characterised through a 2D-DIGE proteomics approach. The proteome of TG hearts demonstrated a significant over-representation of changes in protein levels of enzymes involved in glucose and fatty acid utilisation. Targeted LC-MS approaches identified a differential accumulation of glycolytic intermediates in the proximal part of glycolysis both in unstressed and pressure-overloaded TG hearts. To specifically quantify glucose uptake, glycolysis, glucose oxidation and fatty acid oxidation rates, ex vivo working heart studies were conducted. TG hearts had a marked increase cf. WT in palmitate oxidation rate in the unstressed as well as pressure-overloaded heart (3.6 fold increase; n=6/group; p=0.01). Glucose uptake was unaltered, but glycolysis and oxidation rates were decreased, suggesting diversion of glucose away from oxidation. Importantly, an increase in palmitate oxidation was not detrimental either for in vivo cardiac energetics (31P-NMR) or contractile function during pressure-overload hypertrophy. We found that activity of the hexosamine biosynthesis pathway (HBP), an alternative route for glucose metabolism, was increased in TG hearts as assessed by the O-GlcNAc post-translational modification of cardiac proteins by N-acetylglucosamine, the end-product of HBP. O-GlcNAc levels were 2.4 fold higher in TG cf. WT (n=4/group; p=0.02). In cultured cardiomyocytes, endogenous Nox4 induced similar changes in HBP and palmitate oxidation (extracellular flux analysis), and it was found that changes in O-GlcNAcylation regulated fatty acid oxidation. Mechanistically, the rate-limiting enzyme of HBP - Gfat1 was specifically upregulated by Nox4 and we could also demonstrate that the O-GlcNAcylation of Cd36 (the main fatty acid uptake protein in the heart) was dependent on Nox4, providing a potential reason for increased FAO. Conclusion: These results show that Nox4 reprograms substrate utilisation in the heart by directing glucose towards the HBP and inducing a linked increase in fatty acid oxidation. These data identify a novel redox mechanism that drives beneficial metabolic reprogramming in the heart. In particular the results suggest that increasing fatty acid oxidation in the chronically stressed heart may be a beneficial therapeutic strategy. 125 hjerteforum N 4/ 2017/ vol 30

Value of cardiac work estimation in the prediction of response to cardiac resynchronization therapy E Galli1; C Leclercq1; A Hubert1; O Smiseth2; A Bernard3; E Samset2; A Hernandez4. 1University Hospital of Rennes, Cardiology, Rennes, France; 2University of Oslo, Oslo, Norway; 3University Hospital of Tours, Tours, France; 4Laboratory Signal Processing and Image, Rennes, France. Background: Cardiac resynchronization therapy (CRT) in heart failure is limited by still too many non-responders. Purpose: to evaluate if the estimation of cardiac performance by pressure-strain loops (PSLs) analysis is useful for the selection of CRT candidates. Methods: 97 patients undergoing CRT (ejection fraction: 27±6%, QRS duration: 164±18 ms) according to current guidelines were studied before and after a median 6-month follow-up (FU). Conventional dyssynchrony parameter were evaluated, and left ventricular (LV) global longitudinal strain (GLS) was used to estimate LV positive work (PosW) and negative work (NegW) by PSLs. Results: At FU, positive response to CRT (CRT+) was defined as 15% reduction in LV end-systolic volume and was observed in 63 (65%) patients. In a multivariate regression model (Basal model, c2=27.9) including clinical, electrocardiographic, echocardiographic data and classic dyssynchrony parameters, non-ischemic etiology (OR 3.16, p=0.036), septal flash (OR 4.20, p=0.009) and LV end-systolic diameter (OR 0.92, p=0.016) emerged as significant predictor of CRT+. The addition of both PosW and NegW at the Basal model caused a significant increment in model power (c2=47.5, p1057 mmhg/% (OR 7.9, p=0.003) and NegW >384 (OR 13.89, p=0.006) remained the only predictors of CRT+. The combination of PosW >1057 mmhg/% and NegW >384 mmhg/% showed an excellent specificity (100%), positive predictive value (100%) and accuracy (89%) for the identification of CRT +. Conclusions: the estimation of cardiac work by PSL curves appears to be a novel and very promising tool to identify CRT responders, even when compared with more traditional indexes of cardiac dyssynchrony. Further studies on larger series should be designed to confirm these results. How do cardiologists and nurses think about telemonitoring in patients with heart failure? A survey in Lithuania and Norway E Lycholip1; IT Aamodt2; I Lie2; J Celutkiene1; A Stromberg3; T Jaarsma4 1Vilnius University, Clinic of Cardiac and Vascular diseases, Centre of Cardiology and Angiology, Vilnius, Lithuania; 2University of Oslo, Oslo University Hospital, Department of Cardiothoracic surgery, Oslo, Norway; 3Linkoping University, Department of Medical and Health Sciences, Linkoping, Sweden; 4Linkoping University, Department of Social- and Welfare studies, Norrkoping, Linkoping, Sweden. Background: Currently there is still lack of evidence that telemonitoring in heart failure (HF) patients is an effective way to early notice and react to the patient s deterioration when at home, to reduce the frequency of hospitalisations. Meanwhile these systems are implemented in several parts of Europe. Little is known about the opinion of cardiologists and cardiac nurses regarding the suitability and relevance of telemonitoring in Norway and Lithuania. Purpose: To describe health care professionals (HCP) perceptions of the feasibility and relevance of telemonitoring in patients with HF in Lithuania and Norway. Methods: The survey was performed nationwide in two Nordic Baltic countries enrolling cardiologists and cardiac nurses working with HF patients in 47 hospitals in Lithuania and 60 hospitals in Norway. Validated translations from English to Lithuanian and Norwegian of a previously developed validated questionnaire were used. Data were collected between September and December 2016. Results: Responses from 541 HCP (n=315 in Lithuania [135 cardiologists, 173 nurses] and n=226 in Norway [62 cardiologists, 157 nurses]) were analysed. Educational degree of respondents included 12% and 9% doctoral, 36% and 11% master and 21% and 67% bachelor in Lithuania and Norway, respectively. Almost all participants use e-mail and Internet, while 72% and 93% in Lithuania and Norway, respectively, use e-mail in their mobile phones. More than one fifth of respondents in both countries were familiar with TM. The majority of the cardiologists and nurses in both Nordic Baltic countries consider the outpatient clinic and home visits most often as good ways to follow-up patients after discharge. In total 49% and 58% of the participants in Lithuania and Norway answered that internet-based monitoring was a good way of follow up. Substantial proportion of respondents reported telemonitoring as a relevant (55 and 58%) or very relevant measure (14 and 20%) and frequently named daily feedback to the patient as feasible (22 and 47%). hjerteforum N 4/ 2017 / vol 30 126

Conclusion: Modern digital technologies are widely used by health care professionals in Lithuania and Norway. A substantial proportion of cardiologists and nurses are familiar with telemonitoring and believe that daily feedback to the patients is feasible. However, the majority of HC providers in both Lithuania and Norway see a large role for outpatient clinics, GP s and home visits by nurse. High rates of left ventricular systolic dysfunction in patients with diabetes in Malawi, Africa CJ Watson1; M Chisale2; H Lee3; J Wu3; J O donoghue4; A Cheung1; M Ledwidge5; K Mcdonald6; J Chipolombwe2; J Gallagher5 1Queen s University of Belfast, Belfast, United Kingdom; 2Mzuzu Central Hospital, Mzuzu, Malawi; 3Luke International Norway, Mzuzu, Malawi; 4Imperial College London, London, United Kingdom; 5University College Dublin, Dublin, Ireland; 6Heart Failure Unit, St Vincent s University Hospital, Dublin, Ireland. Background: It is estimated that 415 million people worldwide suffer from diabetes with more than 80% living in low and middle-income countries (LMIC). Sub-Saharan Africa (SSA) will see an 81% rise in incidence of diabetes by 2030, with a predicted 68% increase in hypertension over a similar period. Ventricular dysfunction and heart failure are major complications of diabetes and is involved in the pathogenesis and prognosis of the disease. Limited data is available on heart failure and diabetes in SSA populations. The aim of this project was to investigate the prevalence of left ventricular systolic dysfunction in a cohort of people with diabetes attending a hospital clinic in Malawi, Africa. Methods: Ninety-five consecutive consenting patients attending a Diabetes Outpatient Clinic were recruited to the MTIMA pilot study. Anthropometric and medication data was collected. Point of care testing for blood glucose, glycated HbA1c, and lipids were conducted. All patients underwent echocardiography. Results: Echocardiography analysis revealed a high rate of left ventricular systolic dysfunction in patients with diabetes in Malawi, with 35% having an ejection fraction less than 50%. The mean age of the study population was 58 years (range 35-85), and 38% were male. The mean time since initial diagnosis was 6 years (range 0-45 years). Mean BMI was 27, with 24% of the cohort having a BMI >30. Mean HbA1c was 68mmol/mol (range 28-129mmol/mol), with 59% of the patients above IDF HbA1c target for limited care in LMIC. Mean reported lipid data for this cohort was; total cholesterol (4.48mmol/l), LDL (2.71 mmol/l), HDL (0.98 mmol/l), triglycerides (1.79 mmol/l). Blood pressure control was sub-optimal, mean SBP/DBP 147mmHg (96-216) / 86mmHg (54-124), with 79% patients above the IDF blood pressure target for limited care in LMIC. Discussion: Patient recruitment into this observational study is ongoing with the aim to report of additional heart failure related features in patients with diabetes in Malawi, including profiling of cardiac biomarkers. Atrial and ventricular cellular Ca signaling at different stages in a rat model of heart failure with preserved ejection fraction F Felix Hohendanner1; D Bode1; U Primessnig1; T Guthof1; S Jeuthe1; V Adams2; N Rolim3; U Wisloff3; P Burkert1; F Heinzel1 1Charite - Campus Virchow-Klinikum (CVK), Berlin, Germany; 2University of Leipzig, Leipzig, Germany; 3Norwegian University of Science and Technology, Trondheim, Norway. Funding Acknowledgements: BIH (Clinical Scientist); OptimEx HF with preserved ejection fraction (HFPEF) constitutes about 50% of HF patients who present symptoms for HF, but normal or near-normal systolic function. No standardized treatment has shown to improve prognosis, and the underlying pathomechanisms are not resolved and may differ with etiology. We postulated that alterations in atrial and ventricular function in vivo are associated with phenotype and disease stage-dependent alterations in cardiomyocyte Ca signaling. We examined in vivo function and cardiomyocyte Ca transients (Fluo4-AM, field stim) in a clinically relevant rat model of metabolic risk factors and HFPEF. ZSF-1+/- (lean, hypertension; Ln) and ZSF-1+/+ (metabolic syndrome, HFPEF; Ob) rats fed with high fat diet at 21 weeks were compared to another series examined at 28 weeks and to wildtype (CTRL). Results: At 21 weeks, in vivo measurements showed unaltered ejection fraction, LV mass and relaxation in Ln. In Ob ventricular ejection fraction was also preserved, but ventricular relaxation was impaired and LV mass and E/e increased, as in HFpEF. This was paralleled by an unchanged cytosolic Ca2+ transient (CaT) peak amplitude (Fpeak), and unchanged SR Ca2+ content in cardiomyocytes isolated from the left ventricle. Diastolic decay of the cytosolic CaT was unchanged in Ln, but significantly slowed in Ob. At 28 weeks, even though in vivo data indicated an HFPEF phenotype in Ob, cardiomyocyte CaT showed significantly reduced Fpeak and SR Ca2+ content indicating that cellular changes in obesity-related HFPEF are highly stage-dependent. Left atrial size was increased and atrial emptying fraction was reduced vs. CTRL already at 21 weeks in Ob but not in Ln. Interestingly, 127 hjerteforum N 4/ 2017/ vol 30

CaT amplitude in isolated atrial myocytes was increased in both Ln and Ob (2.3±0.2 vs 2.9±0.2 and 2.8±0.2; n=22, 22 and 26 cells; p<0.05). Moreover, time to 50% of maximal Ca release (TF50) was significantly increased in atrial Ln but not in Ob, suggesting a lower number of recruited Ca release sites in Ln. Sodium Calcium exchanger (NCX) and SR Ca ATPase (SERCA) activity, as assessed by application of caffeine were not significantly altered in Ln or Ob. Ca spark frequency after 3 Hz stimulation was significantly increased in Ln (to 1.9±0.4 vs. 1.0±0.2 and 0.7±0.2 Sparks/100μm/sec in ZSF-obese and WT in n=7, 18 and 11 cells resp.; p<0.05) but unchanged in Ob. Tetracaine-dependent SR Ca leak, however, was significantly increased in Ln and Ob suggesting increased spark-independent SR Ca leak in Ob. Summary: Ventricular diastolic dysfunction in obesity-related HFPEF is associated with altered Ca signaling during excitation-contraction coupling with a time-dependent worsening of the CaT. However, in vivo atrial function deteriorates at early states of remodeling despite increased cardiomyocyte CaT amplitudes. In addition, our data suggest underlying altered local control of Ca in atrial cardiomyocytes from obesity-related HFPEF vs lean rats with metabolic risk factors. Right ventricular histological and molecular alterations in a rat model of HFpEF: effects of exercise training L Rosenbusch1; C Besler1; S T Bowen1; K Rommel1; T Fischer1; M Von Roeder1; N Rolim2; U Wisloff2; A Linke1; G Schuler1; V Volker Adams1; P Lurz1. 1University Leipzig, Heart Center, Leipzig, Germany; 2Norwegian University of Science and Technology, Trondheim, Norway. Funding Acknowledgements: European Commission: Framework 7 (EU 602405-2) Aims: Heart failure with preserved ejection fraction (HFpEF) remains a major diagnostic and therapeutic challenge in clinical cardiology. Recent studies suggest that HFpEF is a biventricular disorder with patients also demonstrating impairments of systolic and diastolic function of the right ventricle (RV). However, the underlying mechanisms of impaired RV function in HFpEF are to be characterized. The present study aimed to investigate histological and molecular changes of the RV in a rat model of HFpEF, and to characterize whether exercise training has any impact on these alterations. Methods: RVs were obtained from obese diabetic Zucker fatty / spontaneously hypertensive heart failure F1 hybrid (ZSF1-obese) rat or ZSF1-lean rats as control group at 20 weeks of age. In a separate group of experiments, ZSF1-obese rats were randomly assigned to either a moderate continuous exercise training or sedentary lifestyle for 8 weeks until the age of 28 weeks. Excised RVs were stained for fibrosis. mrna expression of TNFa, IL-6 and IL-1b was analyzed by PCR. Quantification of protein carbonylation was used as a measure of reactive oxygen species burden. Expression of pro- and anti-inflammatory enzymes was examined, and TNFa-related profibrotic signaling pathways were characterized. Results: At the age of 20 weeks, ZSF1-obese rats exhibited signs of HFpEF when compared to the lean counterparts, as evidenced by increased E/e (16.0±2.0 vs. 22.5±1.0), preserved left ventricular ejection fraction (73±2 vs. 71±3%) and reduced exercise capacity, as determined by VO2max (41.4±1.1 vs. 47.8±2.8 ml/kg/min). ZSF1-obese rats displayed a profound increase in RV fibrosis as compared to ZSF-1 lean rats. TNFa levels were higher in RV from ZSF1-obese rats when compared to ZSF-1 lean rats, whereas no change was observed for IL-6 and IL-1 b. Catalase expression was increased in ZSF1-obese rats, suggesting an augmented reactive oxygen species burden in the RVs. Expression of the NADPH oxidase Nox2 homologue did not differ between both groups. At 28 weeks, differences in RV fibrosis between ZSF-1 obese and lean rats persisted. Notably, exercise training led to a decrease in RV fibrosis in ZSF-1 obese rats (11% vs. 8% as compared to sedentary ZSF-1 obese rats, P<0.05), whereas fibrosis in ZSF-1 lean rats was not significantly altered. The favourable effect of exercise training on RV fibrosis in ZSF-1 obese rats was accompanied by decrease in TNFa levels and reactive oxygen species. Conclusion: The present study is the first to characterize morphological changes of the RV in an in vivo model of HFpEF. The data suggest that inflammation, reactive oxygen species and fibrosis are major characteristics of the RV in HFpEF, and can be reversed by exercise training. The underlying mechanisms are part of ongoing investigations and likely provide important novel insights into the pathophysiology of the disease and potential novel treatment targets for patients with HFpEF. Effects of telemonitoring and disease management on self-care, anxiety and depression: results from the IN TOUCH study E Edita Lycholip1; IT Aamodt2; I Lie2; H Hillege3; I Kraai3; A De Vries3; J Celutkiene4; A Stromberg5; T Jaarsma6. 1Vilnius University, Clinic of Cardiac and Vascular diseases, Vilnius, Lithuania; 2University of Oslo, Oslo University Hospital, Department of Cardiothoracic surgery, Oslo, Norway; 3University Medical Center Groningen, University hjerteforum N 4/ 2017 / vol 30 128

Hospital Groningen, Groningen, Netherlands; 4Vilnius University, Clinic of Cardiac and Vascular diseases, Centre of Cardiology and Angiology, Vilnius, Lithuania; 5Linkoping University, Department of Medical and Health Sciences, Linkoping, Sweden; 6Linkoping University, Department of Social- and Welfare studies, Norrkoping, Linkoping, Sweden Introduction: Self-care, depression and anxiety are important patient reported outcomes (PRO s) for heart failure (HF) patients and these PRO s might be effected by disease management and/ or telemonitoring. Previously no influence of the intervention on the primary outcomes (mortality, HF-readmission and health-related quality of life) in the IN TOUCH study was reported. However, patient-reported self-care, anxiety and depression were not analysed yet. Aim: To assess whether telemonitoring (TM) and an Information Communication Technology guided disease management system (ICTguided-DMS) had effect on self-care behavior, anxiety and depression and to investigate factors contributing to changes in self-care. Methods: In the IN TOUCH study 177 patients were randomized to ICT-guided-DMS or to TM +ICT-guided-DMS with a follow-up of nine months. Current analysis included 118 participants who filled the 9-item European Self-care Questionnaire (EHFScBS_9) and Hospital Anxiety and Depression scale (HADs) (mean age 69± 11.5 years; 70% male; 81% in NYHA class III IV; mean left ventricular ejection fraction [LVEF] 27.2± 9.9%). Chi-square, Student s t test, Wilcoxon and Mann Whitney tests were used. The association of study co-variates including age, quality of life evaluated by Minnesota Living with HF Questionnaire (MLHFQ), NYHA functional class, NT-proBNP level, LVEF, HADs score with the changes in self-care was assessed using multivariable stepwise logistic regression analysis. Results: The baseline level of self-care was significantly lower in the ICT-guided-DMS group (n=60) compared to TM +ICT-guided-DMS group (n=58, p=0.023) as assessed by the total score of EHFScBS_9. In the course of intervention self-care behavior significantly improved in the ICT-guided-DMS group (p<0.01), but not in TM +ICT-guided-DMS group. ICT-guided-DMS significantly improved the consulting behavior subscore (p<0.05). During the trial the prevalence of depression and anxiety decreased from 33.8% to 26.3% and from 25.4% to 22.9% respectively. Level of anxiety significantly decreased in the whole study group (p<0.05), without statistical significance in the separate intervention groups. Self-care behavior worsened in 46 participants (19 in ICT-guided-DMS and 27 in TM +ICTguided-DMS group [p=0.210]). The following baseline factors were significantly associated with decreasing self-care behavior from baseline to the end of study: physical subscale of MLHFQ (OR 1.76, 95% CI 1.143 2.712, per 10 points, p<0.05), LVEF (OR 0.75, 95% CI 0.587 0.959, per 5%, p<0.05), NYHA class (OR 0.251, 95% CI 0.089 0.711, III versus II class, p<0.05). Conclusions: ICT guided disease management may improve patients self-care, specifically in the subscale consulting behavior, and reduce anxiety, both with and without telemonitoring. Worse physical aspect of quality of life, lower ejection fraction and lower NYHA class were factors associated with poorer self-care. Increases in natriuretic peptides precede heart failure hospitalization in patients with a recent coronary event and type 2 diabetes B Claggett1; E Wolsk2; MA Pfeffer1; R Diaz3; K Dickstein4; HC Gerstein5; LV Kober2; FC Lawson6; EF Lewis1; AP Maggioni7; JJV Mcmurray8; JL Probstfield9; MC Riddle10; SD Solomon1; J-C Tardif11. 1Brigham and Women s Hospital, Cardiology, Boston, United States of America; 2Rigshospitalet - Copenhagen University Hospital, Copenhagen, Denmark; 3Estudios Cardiologicos Latinoamerica (ECLA), Rosario, Argentina; 4Stavanger University Hospital, Stavanger, Norway; 5McMaster University, Hamilton, Canada; 6Sanofi US, Bridgewater, NJ, United States of America; 7Research Center of the Italian Association of Hospital Cardiologists, Florence, Italy; 8University of Glasgow, Glasgow, United Kingdom; 9University of Washington, Seattle, United States of America; 10Oregon Health & Science University, Portland, United States of America; 11Montreal Heart Institute, Montreal, Canada Funding Acknowledgements: Sanofi Background: Natriuretic peptides (NP) are used clinically to aid in the diagnosis of heart failure (HF) and considered for monitoring clinical status in patients with this syndrome. The timing of any such changes prior to a HF hospitalization (HFH) remains less well explored. We implemented a novel statistical approach to better characterize temporal changes of NP prior to HFH. Methods: B-type natriuretic peptide (BNP) and N-terminal prohormone B-type natriuretic peptide (NT-proBNP) were measured in 5450 patients with type 2 diabetes and a recent coronary event in the ELIXA trial (NCT01147250). Measurements were done at baseline and at weeks 24, 76, and 108; patients were included in the present analysis if they had measurements at both baseline and 24 weeks with no intervening HFH. To characterize potentially non-linear temporal changes in NP levels preceding adjudicated HFH, we utilized all measurements available prior to HFH in a post-hoc, retrospective repeated- 129 hjerteforum N 4/ 2017/ vol 30

measures analysis using restricted cubic splines, with non-hfh patients as a control group. NP values are summarized using geometric means at various time points prior to HFH. Results: During a median follow-up of 26 months, 151 patients (3%) experienced HFH. Patients who experienced HFH had higher baseline NP levels compared to patients without HFH (BNP [234 pg/ml vs. 101 pg/ml, p<0.001]; NT-proBNP [862 pg/ml vs 304 pg/ml; p<0.001]). Geometric mean levels of patients who did not experience HFH declined slowly with time (Figure). In those who experienced a HFH, NP levels remained relatively constant until about 6 months prior to HFH, and subsequently increased approximately two-fold by the time of HFH (BNP: 478 pg/ml, NT-proBNP: 2059 pg/ml) [Figure]. Conclusion: In patients with type 2 diabetes and a recent coronary event, a novel analysis revealed that, while elevated NP levels are associated with future HFH in general, more dramatic increases in NP levels typically precede HFH by about 6 months, suggesting that detectable cardiac deterioration accelerates prior to HFH. Figure: Geometric mean concentrations (±95% CI) of BNP (panel A) and NT-proBNP (panel B) before HFH blue line, compared with patients with no HFH black line (no HFH: n=5299, HFH: n=151). High serum bilirubin is associated with short-term mortality following a myocardial infarction complicated by heart failure and/or left ventricular systolic dysfunction Z Frikha1; JP Ferreira1; E Bozec1; JJ Mcmurray2; B Pitt3; K Dickstein4; P Rossignol1; F Zannad1; N Girerd1 1INSERM, Centre d Investigations Cliniques 9501, Université de Lorraine, CHU de Nancy, Institut Lorrain du cœur et des vaisseaux, Nancy, France and INI-CRCT F-CRIN Network, Vandoeuvre-les- Nancy, France; 2University of Glasgow, BHF Cardiovascular Research Centre, Glasgow, United Kingdom; 3University of Michigan, School of Medicine, Ann Arbor, United States of America; 4Stavanger University Hospital, Department of Cardiology, Stavanger, Norway Objectives: Higher serum bilirubin has been associated with poorer prognosis in patients with heart failure (HF). We examined the association between serum bilirubin and clinical outcomes in patients with clinical signs of HF and/or left ventricular systolic dysfunction following acute myocardial infarction (MI). Methods: 7467 patients from the High-Risk MI Database Initiative (which merged the datasets of the CAPRICORN, EPHESUS, OPTIMAAL and VALIANT trials) with an available baseline total bilirubin concentration were studied. The association between baseline bilirubin concentration and cardiovascular mortality, hospitalization for HF and all-cause mortality was assessed using Cox proportional hazards models. Results: The mean baseline total bilirubin concentration was 12±7 μmol/l and was above the normal range (>17.1 μmol/l) 1053 (14.1%) patients. In multivariable analysis, with adjustment for baseline characteristics (demographic, co-morbidity, Killip score, left ventricular ejection fraction and laboratory variables), patients with bilirubin >17.1 μmol/l were at significantly higher risk for 90-day cardiovascular mortality (HR=1.45, CI=1.14 1.86, p=0.003), cardiovascular mortality or hospitalization for HF (HR=1.26, CI=1.05 1.51, p=0.02) and all-cause mortality (HR=1.51, CI=1.20-1.91, p<0.001). The addition of bilirubin in the survival model was associated with a significant improvement in reclassification to predict cardiovascular mortality (continuous net reclassification improvement=6.4%, CI=0.7%-9.6%, p=0.04). Conclusions: In MI patients complicated with HF and/or systolic dysfunction, bilirubin concentration is an independent predictor of mortality and improves risk stratification. This low-cost routinely available biomarker may improve risk assessment in this population. Effectiveness of the heartfailurematters.org website in patients with stable HF KP Wagenaar1; KP Dickstein2; BD Broekhuizen1; T Jaarsma3; AW Hoes1; F H Frans Hendrik Rutten1 1University Medical Center Utrecht, Julius Centre for Health Sciences and Primary Care, Utrecht, Netherlands; 2University of Bergen, Cardiology, Bergen, Norway; 3Linkoping University Hospital, Cardiology, Linkoping, Sweden. On behalf of: e-vita heart failure study group. Funding Acknowledgements: Unrestricted grant from «Care Within Reach» Background: The ESC/HFA website heartfailurematters.org (HFM website) is widely used, but its effectiveness has never been formally evaluated. Aim: To assess the effect on self-care of the HFM website on top of usual care provided by heart failure (HF) nurses in outpatient clinics. Methods: In a randomized controlled we compared usual care + HFM website to usual care in stable HF patients from nine Dutch HF outpatient clinics. The primary outcome was self-care measured with the European Heart Failure Self-care Behaviour Scale (EHFScB scale). Secondary outcomes were health status, and cost-effectiveness. hjerteforum N 4/ 2017 / vol 30 130

Results: In total, 300 (150 per group) patients were included. The mean age was 66.8 (SD 11.0) years, 74.2% were male, and 78.8% was classified as NYHA I or II at baseline. Participants had on average three face-to-face contacts per year with the HF nurse. After 3 months follow-up, the mean score on the self-care scale was significantly higher in the usual care + HFM website group compared to usual care: 73.5 vs. 70.8 (difference 2.7, 95%CI 0.6 6.2). This effect attenuated during the following 9 months until no difference after one year (difference -0.6, 95%CI -3.7 3.4). Quality of life and HF knowledge had a similar pattern as was observed in self-care. The mean costs per patient were 4,865 and 5,741 per quality-adjusted life years for HFM website + usual care and usual care, respectively. The net monetary benefit was positive (larger than 0) for HFM versus usual care. Conclusion: The heartfailurematters.org website helps improve self-care in stable HF patient on the short-term when provided in addition to rather intensive usual care provided at HF outpatient clinics, but this effect seems to attenuate over time. Nevertheless, it is cost-effective considering its effects on quality-adjusted life years. Bisoprolol compared with carvedilol and metoprolol succinate in the treatment of patients with chronic heart failure H Hanna Froehlich1; L Torres1; T Taeger1; D Schellberg1; A Corletto1; S Kazmi2; K Goode2; M Grundtvig3; T Hole4; HA Katus1; JGF Cleland5; D Atar6; AL Clark2; S Agewall6; L Frankenstein1 1University Hospital of Heidelberg, Heidelberg, Germany; 2Castle Hill Hospital, Hull, United Kingdom; 3Innlandet Hospital, Lillehammer, Norway; 4Norwegian University of Science and Technology, Medical Faculty, Trondheim, Norway; 5Imperial College London, London, United Kingdom; 6Oslo University Hospital, Oslo, Norway. Funding Acknowledgements: This work was supported from the AOK within the scope of the junior researcher s academy «health care research Baden-Württemberg» (Germany) Aims: Beta-blockers are recommended for the treatment of chronic heart failure (CHF). However, it is disputed whether beta-blockers exert a class effect or whether there are differences in efficacy between agents. Methods and results: 6,010 out-patients with stable CHF and a reduced left ventricular ejection fraction prescribed either bisoprolol, carvedilol or metoprolol succinate were identified from three registries in Norway, England, and Germany. In three separate matching procedures, patients were individually matched with respect to both dose equivalents and the respective propensity scores for beta-blocker treatment. During a follow-up of 26,963 patient-years, 302 (29.5%), 637 (37.0%), and 1,232 (37.7%) patients died amongst those prescribed bisoprolol, carvedilol, and metoprolol, respectively. In univariable analysis of the general sample, bisoprolol and carvedilol were both associated with lower mortality as compared with metoprolol succinate (HR 0.80, 95% CI 0.71-0.91, p<0.01, and HR 0.86, 95% CI 0.78-0.94, p<0.01, respectively). Patients prescribed bisoprolol or carvedilol had similar mortality (HR 0.94, 95% CI 0.82-1.08, p=0.37). However, there was no significant association between beta-blocker choice and all-cause mortality in any of the matched samples (HR 0.90; 95% CI 0.76-1.06; p=0.20; HR 1.10, 95% CI 0.93-1.31, p=0.24; and HR 1.08, 95%CI 0.95-1.22, p=0.26 for bisoprolol vs. carvedilol, bisoprolol vs. metoprolol succinate, and carvedilol vs. metoprolol succinate,respectively). Results were confirmed in a number of important subgroups. Conclusion: Our results suggest that the three beta-blockers investigated have similar effects on mortality amongst patients with CHF. Predictive value of a novel 4- mir- NAs diagnostic panel after acute myocardial infarction: Independent validation from the MITO- CARE study E Eric Schordan1; S Schordan1; TS Hall2; AI Larsen3; D Erlinge4; SE Jensen5; S Halvorsen2; D Atar2; H Firat1; Y Devaux6. 1Firalis SAS, Molecular Diagnostics, Huningue, France; 2Ulleval University Hospital, Department of Cardiology B, Oslo, Norway; 3Stavanger University Hospital, Department of Cardiology, Stavanger, Norway; 4Lund University, Department of Cardiology, Lund, Sweden; 5Aalborg University Hospital, Department of Cardiology, Aalborg, Denmark; 6CRP-Sante, Cardio Vascular Research Unit, Luxembourg, Luxembourg. On behalf of: Cardiolinc network Funding Acknowledgements: Eurostars MIPROG E! 9686 Following acute myocardial infarction (AMI), a significant proportion of patients develops heart failure (HF) due to left ventricular remodelling (LVR). The early identification of patients developing LVR is essential for evidence-based intervention and pharmacological therapy. Novel biomarkers might pave the way for improved prediction approaches. Since the discovery of their stability in the bloodstream, mirnas, short oligonucleotides which down-regulate gene expression, have been extensively studied for their potential to diagnose AMI. We previously identified a panel of 4 circulating mirnas (mir-16-131 hjerteforum N 4/ 2017/ vol 30

5p/27a-3p/101-3p/150-5p) able to significantly improve the prediction of post-ami LVR by a multivariable clinical model including N-terminal pro-brain natriuretic peptide (Nt-pro-BNP). In the present study, we aimed to confirm the predictive value of the 4-miRNA panel in an independent cohort obtained from the MITOCARE study, a prospective randomized clinical trial conducted from 2011 to 2013. We enrolled 90 patients with STEMI treated by primary PCI. The HTG EdgeSeq targeting sequencing platform was used to assess the levels of mirnas in plasma samples collected 3 days after AMI. Cardiac function was assessed by echocardiography at discharge and after 1 month. Left ventricular ejection fraction (LVEF) at 1 month was used to classify patients into 3 categories: LVEF<=40 (n=14), LVEF between 41 and 50 (n=34) and LVEF>50 (n=41). Random forest model was used for predictive modelling and individual AUC, and confidence intervals (CI) were calculated for each mirna. mir-16-5p/27a-3p/101-3p/150-5p individual AUC were 0.81, 0.75, 0,84 and 0,61, respectively. The combination of the set of 4 mirnas showed an average AUC of 0.83 (CI 0.80-0.85). Combining the 4 mirnas with NT-pro-BNP resulted in an AUC of 0.87 (CI 0.75 and 0.99). In conclusion, we here confirm the independent predictive value of the 4 mirnas (mir-16-5p/27a-3p/101-3p/150-5p) for the prediction of HF development after AMI. HTG EdgeSeq technology proves to be an efficient and clinically-applicable tool to measure circulating mirnas. These results motivate the development of molecular diagnostic kits based on mirnas to aid in outcome prediction after AMI. Endothelial and muscular alterations in a cardiometabolic obese rat model of heart failure with preserved ejection fraction (HFpEF) V Volker Adams1; C Herz1; Z Schmederer1; TS Bowen1; NPL Rolim2; T Fischer1; S Werner1; A Linke1; U Wisloff2. 1University Leipzig, Heart Center, Leipzig, Germany; 2Norwegian University of Science and Technology, Trondheim, Norway. Funding Acknowledgements: EU Commission Framework 7 (EU 602405-2) Despite normal left ventricular ejection fraction patients with heart failure with preserved left ventricular ejection fraction (HFpEF) present exercise intolerance which can be attenuated by exercise training. Alterations in the peripheral skeletal muscle as well as in the vascular system have been described with conflicting results and the molecular mechanisms mediating the beneficial effects of exercise training after disease onset is still unknown. The present study, therefore, used a cardiometabolic rat model to further elucidate: 1) alterations in the skeletal muscle (EDL) and the vascular system induced by HFpEF; and 2) the effects of exercise training during secondary prevention. After 20 weeks, obese Zucker diabetic fatty/spontaneously hypertensive heart failure F1 hybrid (ZSF1) rats (n=12) were compared to their lean counterparts (n=8), with a further 3 groups of obese ZSF1 rats assessed 8 weeks later following sedentary behavior (n=15), moderate-continuous training (MCT; n=11) or high-intensity interval training (HIIT; n=11). Obese rats displayed signs of HFpEF including diastolic dysfunction, LV hypertrophy, exercise intolerance (P<0.05) and preserved LVEF. Compared to leans, obese rats showed a significantly impaired endothelial-dependent vasodilation associated with reduced enos activation (p<0.05) and a trend towards elevated expression of gp91phox (p=0.09). Exercise, independent of modality, improved endothelial function, which was associated with a reduction in gp91phox expression (r=0.42, p=0.01). Compared to controls HFpEF animals showed signs of skeletal muscle atrophy (lower muscle weight, lower CSA) and reduced maximal absolute force, but maximal specific force was elevated (p<0.05). At the molecular level a significant higher actin expression and creatine kinase activity was detected whereas xanthine oxidase activity was reduced (p<0.05). Exercise training had no significant effect. To conclude, a cardiometabolic obese model of HFpEF was associated with impaired endothelial function and still preserved specific skeletal muscle force generation. Exercise training (independent of protocol) was able to reverse these alterations in the endothelium but had no significant effect on the skeletal muscle. Serum chloride and sodium interplay in patients with acute myocardial infarction and heart failure with reduced ejection fraction: an analysis from the high-risk myocardial infarction database initiative JP Ferreira1; N Girerd1; K Duarte1; S Coiro1; JJV Mcmurray2; H Dargie2; B Pitt3; K Dickstein4; JM Testani5; F Zannad1; P Rossignol1. 1Clinical Investigation Centre Pierre Drouin (CIC-P), Nancy, France; 2Cardiovascular Research Centre of Glasgow, Glasgow, United Kingdom; 3Northwestern University, Chicago, United States of America; 4Bergen University College, Bergen, Norway; 5Yale University, New Haven, United States of America. On behalf of: High Risk MI initiative Background: Serum chloride levels were recently found to be independently associated with mortality in heart failure (HF). hjerteforum N 4/ 2017 / vol 30 132

Methods and Results: We investigated the relationship between serum chloride and clinical outcomes in 7195 subjects with acute myocardial infarction (MI) complicated by reduced left ventricular function and heart failure (HF). The studied outcomes were all-cause mortality (ACM), cardiovascular mortality (CVM), and hospitalization for HF (HHF). Both chloride and sodium had a non-linear association with the studied outcomes (p <0.05 for linearity). Patients in the lowest chloride tercile (chloride 100) were older, had more comorbidities, and lower sodium levels (p <0.05 for all). Serum chloride showed a significant interaction with sodium with regard to all studied outcomes (p for interaction <0.05 for all). The lowest chloride tercile ( 100 mmol/l) was associated with increased mortality rates in the context of lower sodium ( 138 mmol/l) [adjusted HR (95%CI) for ACM =1.42 (1.14-1.77), p=0.002], whereas in the context of higher sodium levels (>141 mmol/l), the association with mortality was lost. Spline-transformed chloride and its interaction with sodium did not add significant prognostic information on top of other well established prognostic variables (p >0.05 for all outcomes). Conclusions: In post-mi with systolic dysfunction and/or HF, low serum chloride was associated with mortality (but not HHF) in the setting of lower sodium. Overall, chloride and its interaction with sodium did not add clinically relevant prognostic information on top of other well established prognostic variables. Taken together, these data support an integrated and critical consideration of chloride and sodium interplay. Role of global myocardial work in the identification of responders to CRT E Galli1; C Leclercq1; A Hubert1; A Bernard2; O Smiseth3; E Samset3; E Donal1 1University Hospital of Rennes, Cardiology, Rennes, France; 2University Hospital of Tours, Tours, France; 3University of Oslo, Oslo, Norway Background: cardiac resynchronization therapy (CRT) has a pivotal role in the management of patients with HF and wide QRS complex, but is affected by still too many non responders. Aim of the resent study is to evaluate the role cardiac work estimated by pressure-strain loops (PSLs) in predicting CRT response. Methods: 97 patients with symptomatic heart failure underwent CRT implantation according to current recommendations. Standard 2D and speckle tracking echocardiography were performed before CRTand at 6-month follow-up (FU). PSLs analysis allowed the calculation of global and regional myocardial positive (PosW) and negative work (NegW). A reduction >15% of left ventricular (LV) end-systolic volume at FU defined CRT positive response (CRT+) Results: at FU, 63 (65%) patients resulted responders to CRT. Global PosW (PosWtot), lateral wall PosW (PosWlat), global NegW (NegWtot), septal NegW (NegWsept)and lateral NegW (NegWlat) were significantly increased in CRT+. At multivariate regression analysis, no regional work parameter emerged as predictor of CRT+, PosWtot >1057 mmhg/% (OR 7.30, p=0.01) and SF (OR 7.33, p<0.0001) being the only significant predictors of CRT+. PosWtot was significantly associated to the entity of myocardial remodeling after CRT in both ischemic (r=-0.55, p<0.0001) and non-ischemic patients (r=-0.65, p<0.0001). Conclusions: patients with higher PosWtot, show a favorable response to CRT. These data support the role of residual myocardial contractility in CRT candidates and encourage further studies finalized at the assessment of the myocardial substrate of functional response in CRT candidates. Machine-learning based exploration of variability of longitudinal myocardial velocities in heart failure with preserved ejection fraction S Sanchez-Martinez1; N Duchateau2; T Erdei3; G Kunszt4; A Degiovanni5; E Carluccio6; A G Fraser3; G Piella1; B Bijnens1. 1University Pompeu Fabra, Barcelona, Spain; 2Inria, Asclepios research project, Sophia- Antipolis, France; 3Cardiff University, Wales Heart Research Institute, Cardiff, United Kingdom; 4Oslo University Hospital, Department of cardiology, Oslo, Norway; 5University of Eastern Piedmont, Department of cardiology, Novara, Italy; 6University of Perugia, Perugia, Italy. Funding Acknowledgements: EU FP7 VP2HF (no 611823), EU FP7 MEDIA (no 261409), Fundacio La Marato de TV3 (no 20154031), «La Caixa» banking foundation. Purpose: Current diagnosis of heart failure with preserved ejection fraction (HFPEF) is suboptimal since the consensus recommendations oversimplify abnormalities by only considering simplified key markers of disease, often derived from myocardial velocity patterns (e.g., E/e and E/A ratio, deceleration time). These diagnostic criteria are based on the expertise of highly trained cardiologists. However, complex mechanical interactions or subtle discriminative markers of disease could pass unnoticed even to the most expert eye. We investigate whether a comprehensive machine-learning based analysis of multiple myocardial velocity profiles, acquired 133 hjerteforum N 4/ 2017/ vol 30

during stress echocardiography, can identify characteristic patterns of cardiac (dys-)function. Methods: Longitudinal velocity traces from 33 healthy subjects (67±4 years) and 72 HFPEF (72±6 years, diagnosed according to the Consensus Statement on HFPEF, 2007) were examined. Data came from tissue Doppler acquisitions at rest and submaximal exercise at the basal septum and lateral wall of the left ventricle. Each cardiac phase was identified and used to temporally align the velocity profiles. Unsupervised machine learning (multiple kernel learning algorithm) was used to fuse the heterogeneous velocity patterns and to reduce their complexity. Agglomerative hierarchical clustering was performed on this set to identify naturally-occurring groupings within the population. The variability explained by the identified groups was reconstructed by means of advanced regression techniques. Results: The agreement between the found groups and the clinical diagnosis was high (Kappa=72.6%). In the figure, the curves range from -2 (solid line) to +2 (dotted line) standard deviations along the indicated modes of each group. The HFPEF group with respect to the healthy group showed: lower overall velocity amplitude; more pronounced diastolic fusion, especially prominent in the septal velocity at exercise; higher diastolic delay, especially in the exercise patterns; and more frequent inter-atrial contraction delay. A detailed analysis of cases classified differently by the algorithm, compared with the clinical labels, confirmed that they had subtle abnormalities that had been overlooked when applying current diagnostic criteria. Conclusion: The method proposed is automatic, objective, and independent of the diagnosis suggested by the consensus recommendations. The variability analysis of the velocities within each of the identified groups was consistent with the clinical knowledge about the HFPEF mechanical abnormalities, and revealed possible diagnostic features non-considered to date, as is the case of the delay in the atrial contraction dynamics recently suggested as an indicator of HFPEF. Furthermore, our study confirms that machine-learning based assessment of the cardiac function at exercise is helpful when characterizing the HFPEF syndrome. PI3Kgamma inhibition rescues mice from acute cardiac contractile dysfunction and sudden death caused by calcineurin inhibitors B Bernadin Ndongson Dongmo1; LR Moltzau1; KW Andressen1; M Baretta2; MV Cosson1; A Ghigo3; M Brodhun4; E Hirsch3; R Bauer2; FO Levy1. 1University of Oslo, Pharmacology, Oslo, Norway; 2University Hospital of Jena, Institute of Molecular Cell Biology, Jena, Germany; 3University of Turin, Center of Molecular Biotechnology, Turin, Italy; 4Helios-Klinikum, Pathology, Erfurt, Germany Funding Acknowledgements: The research leading to these results has received funding from the European Union Seventh Framework Programme (FP7-PEOPLE-2013-COFUND). Purpose: Calcineurin inhibitors (CNI) as cyclosporin A and tacrolimus are the most commonly used immunosuppressive drugs following solid organ transplantation and in various autoimmune diseases. But, CNI therapies are also associated with severe side effects like arterial hypertension, atherosclerosis, insulin resistance, brain, liver and renal complications, and cardio-toxicity. However, the effects of CNI on cardiac contractile function are poorly studied. In this study, we have investigated the acute effect of CNI on cardiac contractile function and the beneficial effects mediated by PI3Kg inhibition. Methods: The intact heart left ventricle contractility (Pressure-Volume-Conductance) was evaluated in mice 5h after intra-peritoneal injection of CNI in WT, PI3Kg KO (total deletion of PI3Kg), PI3Kg KD («kinase dead»; lacking PI3Kg kinase function) and in WT treated with selective inhibitor of PI3Kg. Thereafter, cardiomyocytes were studied using several biochemical approaches to investigate the beta adrenergic signaling pathway including PLB activation, camp production and phosphodiesterase (PDE) activity. Finally a long term follow up with histological studies in cardiac tissue as well as ECG using telemetry and survival analysis was performed. Results: We intriguingly found 5h after CNI injection an important reduction (<50%) of cardiac contractility (End-systolic elastance; Ees) that was confirmed in vitro with a down-regulation of beta-adrenergic signaling upon cardiomyocyte stimulation with CNI (4h). Interestingly, these effects were completely absent after the same treatment in transgenic mice and cardiomyocytes (PIKg KO, PIKg KD), and in mice and cardiomyocytes treated simultaneously with PI3Kg selective inhibitor. Following up these findings, we have also observed in cardiac sections (H&E, TUNEL) 15h after CNI, the presence of necrotic cells as well as myofibre break-up indicating a possible sign of ventricular fibrillation. Whereas the observed side effects of CNI were correlated hjerteforum N 4/ 2017 / vol 30 134

with higher mortality, the group of mice simultaneously treated with PI3Kg inhibitor interestingly exhibited a better survival rate (p<0.05). Conclusion: In this study, we observed an acute cardio-depressive effect of CNI associated with sudden death and established the rationale for PI3Kg inhibition asa potential therapeutic approach. Regulation of beta adrenoceptor evoked inotropic responses by inhibitory g protein, adenylyl cyclase isoforms 5 and 6 and phosphodiesterases MV Marie Victoire Cosson1; HG Hiis1; FO Levy1; KA Krobert1 1Oslo University Hospital, pharmacology, Oslo, Norway. Funding Acknowledgements: Nasjonalforeningen for folkehelsen. Purpose: Our data indicate that inhibitory G protein (Gi) inhibits adenylyl cyclase (AC) independently of the receptor. The two major subtypes of AC in the heart are AC5 and AC6. Compartmentalization of b1-adrenoceptor- (b1ar) versus b2ar differs depending on the subcellular localization of the AC subtypes. Deletion of AC6 impairs left ventricular responsiveness to bar ligands and it is unknown if AC5 or 6 differentially regulate b1ar- versus b2ar-mediated inotropic responses. Determine if intrinsic Gi inhibition is AC subtype selective and whether there is a differential role of AC5 and AC6 to mediate b1ar- and b2ar-evoked inotropic responses. In addition, determine if there is an interplay between Gi and phosphodiesterases 3,4 (PDE3,4). Methods: We measured b1ar- and b2ar-mediated changes in contractility in left ventricular muscle strips from wild type (WT), AC5 and AC6 knockout (KO) mice. First, with or without pertussis toxin (PTX) to inactivate Gi and/or after inhibition of PDE3 or PDE4. Results: AC6KO mice revealed increased noradrenaline potency (EC50) at the b1ar compared to WT and AC5KO. Furthermore, AC6KO mice revealed an adrenaline-evoked b2ar-inotropic response only after PDE3 or PDE4 inhibition whereas both were required in WT and AC5KO. A b2ar-mediated inotropic response was also observed after PTX treatment alone in all groups. Conclusion: Gi tonically inhibits AC since PTX enhances both b1ar- and b2ar-mediated inotropic responses despite Gi not coupling to b1ar. PDE4 seems to be the primary PDE regulating the b1ar response in all groups. Inhibiting Gi and PDE3 or PDE4 appears to synergistically enhance adrenaline-evoked b2ar-inotropic response in WT. We therefore propose that inhibiting Gi and PDEs allows camp to leak from the b2ar to the b1ar contractile compartment. 135 hjerteforum N 4/ 2017/ vol 30