Scientific Sessions 2008 of the American Heart Association (AHA

Transcription

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HJERTEFORUM NR 1 - 2009; VOL 22
Scientific Sessions 2008
of the American Heart Association (AHA)
AHA 2008 og lipider
Leiv Ose, Lipidkinikken, Rikshospitalet
Størst oppmerksomhet var det knyttet til JUPITER-studien innenfor lipidfeltet på American
Heart Associations (AHAs) årlige møte i år.
Resultatene bidro til at både media og fagfolk
kalte det en ny ”landmark study”. At resultatet
ikke ville bli negativt antok man i det studien
var avbrutt etter 1,9 år. Den var planlagt å vare i
4 år. Dette var en studie som inkluderte ca. 200
pasienter fra Norge og fra forskjellige sentra i
USA, Canada og Europa. Det var en dobbeltblind randomisert studie som inkluderte 17 802
friske menn og kvinner som skulle få enten
rosuvastatin 20 mg eller placebo. Deltagerne
skulle ha alder over 50 år for menn og 60 år for
kvinner og være hjertefriske. Dette var primært
en statinstudie, og forutsetningen for inklusjon
var at LDL-kolesterol skulle være lavere enn
3,4 mmol/l og at CRP var høyere enn 2,0 mg/
dl. Alder var i snitt 66 år, blodtrykk 134/80,
41 % hadde metabolsk syndrom, 71 % var av
kaukasisk rase, 17 % var røkere, CRP var 4,4
(2,8 -7,1), LDL-kolesterol 2,8 mmol/l, HDLkolesterol 1,3 mmol/l , triglyserider 1,3 mmol/l,
totalkolesterol 4,8 mmol/l , blodsukker 54 og
HBA1c% 5,7. LDL-kolesterol i rosuvastatingruppen falt til 1,4 mmol/l målt etter 12 og 48
mnd., mens LDL-kolesterol forble uforandret i
placebogruppen. CRP falt til 2,2 etter 12 mnd.
og var nede på 1,8 etter 48 mnd. i behandlingsgruppen. I placebogruppen falt CRP til 3,5 etter
12 mnd. og forble så uforandret. Triglyserider
falt med 17 % i behandlingsgruppen. Etter 1,9
år med oppfølging så man at det primære sammensatte endepunkt ble redusert med 44 %.
Denne reduksjonen ble sett i nesten alle individuelle endepunkt inkludert 55 % reduksjon
av ikke-fatalt hjerteinfarkt, en 48 % reduksjon
i ikke-fatalt slag og en 48 % samlet reduksjon
i risikoen for harde kardiale endepunkt (hjerteinfarkt, slag og død av kardiovaskulær årsak).
Alle funn var høygradig signifikante. Det var
ingen forskjell mellom menn og kvinner, alder
over og under 65 år, røker eller ikke-røker, hypertensjon eller ikke-hypertensjon, BMI over 30
eller under 25, metabolsk syndrom eller ikke,
uavhengig også om det forelå en Framingham
risiko-score over eller under 10 %. Rosuvastatin
viste seg å være sikker, uten forskjell i bivirkninger som myopati, kreft eller kreftdødsfall.
Nyre- og leverfunksjon forble uforandret, og det
var ingen forskjell i blodsukker, HbA1c eller
glukosuri, men en signifikant insidensøkning av
lege-rapportert diabetes. Det ble også rapportert
om en signifikant 20 % reduksjon av total mortalitet (p=0,02).
Denne studien vil måtte få implikasjoner for
preventiv kardiologi. Jeg oppfatter dette som en
statinstudie hvor deltagerne hadde en risikomarkør eller indikator. CRP er et uttrykk for inflammasjon og er satt i sammenheng med hjerte- og
karsykdom i flere studier. Det kan godt være at
hvis man hadde valgt andre inflammasjonmarkører, ville man ha fått tilsvarende resultat. En
CRP-reduksjon finner vi ved alle statiner, men
rosuvastatin er det kraftigste statinet på markedet i dag og gir også en markert CRP-reduksjon.
Studien ble slått stort opp i USA TODAY
og New York Times. I Norge ble den slått opp
i Dagbladet og ble senere også omtalt i Dagens
Medisin. Som vanlig rapporteres det at Per Fuggeli og Steinar Westin har motforestillinger mot
studien og eventuelle konsekvenser av studien,
men det er jo ikke overraskende.
SEARCH-studien ledet av Oxford-gruppen
var også imøtesett med interesse. Et av hovedmålene var å se om 20 mot 80 mg simvastatin ga signifikant bedre endepunktresultat med
hensyn til kardiovaskulære hendelser og derfor
om den ytterligere reduksjon av LDL-kolesterol
resulterte i signifikant bedring hos ca. 12 000
overlevende etter hjerteinfarkt. Å gå fra 20 til
80 mg simvastatin ga en ytterligere reduksjon
på 0,35 mmol/l og dette resulterte i en ikke-signifikant reduksjon av kardiale hendelser med 6
%. Oxford-gruppen rapporterte tidlig at 80 mg
simvastatin ga økede problemer med myopati
og rabdomyolyse. Det var signifikant mer tilfeller av myopati med 80 mg mot 20 mg (53 vs.
3). Dette gjør at vi må trekke den konklusjon
av 80 mg simvastatin ikke lenger bør anbefales. Jeg vil i framtiden anbefale å gå rett på 40
mg og så legge til Ezetrol (ezetimibe). Dette
illustrerer igjen at SLVs anbefaling om å gå til
høyeste tolererbare dose av simvastatin før man
kan skifte til atorvastatin var feil og bør endres.
Det er altså meningen at pasienten skal risikere
myopati før atorvastatin kan tas i bruk? Bivirkninger kommer vel ikke i løpet av de første uker
eller måneder? I SEARCH-studien ble det også
undersøkt på om 2 mg folsyre og 1 mg vitamin
B 12 reduserte risikoen for hjertesykdom. Det
ble funnet en signifikant reduksjon av homocystein ved bruk av folsyre. Folsyre og B12 var
ikke skadelig på noen måte, men hadde ingen
virkning på hjerte-/karsykdom.
Physicians Health Study II, som var en forlengelse av den store studien som hadde amerikanske leger og helsearbeidere som deltagere,
hadde nå ferdigbehandlet sine data etter 8 år.
Studien hadde en 2 x 2 x 2 x 2 faktorialt design,
og 14 641 friske menn ble randomisert. Det var
vitamin C og vitamin E som ble testet ut: igjen
ingen effekt på hjerte-/karsykdom. Det står
nå klart at de aktuelle vitaminer ikke har noen
plass i forebyggelsen av hjerte-/karsykdommer.
Mitt råd vil være å glemme vitamin C, E og
folsyre. Homocystein bør også ”begraves”. Om
våre helsekostkjeder tar budskapet er tvilsomt
så lenge det er penger å tjene, men Mattilsynet
må ta tak i dette uføret igjen. Ved årets AHA var
det flere studier som viste at omega 3 og fet fisk
hadde positive kardiale virkninger, men igjen
spør jeg - hvorfor må omega 3 tilsettes juice,
smør etc? Tran eller produkter med fancy smak
for barn (om nødvendig) er da bra fortsatt?
Observasjoner i SEAS og SEARCH ble
diskutert inngående på en av hovedsesjonene.
Konklusjonen fra den uavhengige og frittalende
Oxford-gruppen med Rory Collins og Sir Richard Peto i spissen avviser at ezetimibe fører til
kreft, men andre hevdet i diskusjonen at man
skulle ha et våkent øye fortsatt for mulige negative virkninger av medikamentet. Det var ingen
som anbefalte å gjøre endringer i bruken av
ezetimibe (Ezetrol), hvis ytterligere reduksjon
av LDL-kolesterol var ønskelig, dvs. at behandlingsmålet ikke var nådd.
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AHA 2008. Hjertesvikt.
Lars Gullestad, Hjertemedisinsk avdeling, Rikshospitalet
Det ble lagt frem flere spennende studier innenfor hjertesvikt, og enkelte vil ha betydning for
klinisk praksis.
Morbidity and mortality outcomes from aerobic exercise training in heart failure: Results
from the Heart Failure and A Controlled Trial
Investigating the Outcomes of exercise training (HF-ACTION) study.
Fysisk trening bedrer utholdenhet, livskvalitet
og er assosiert med reduksjon av risikofaktorer og kardiale biomarkører hos pasienter etter
hjerteinfarkt. Mindre studier og meta-analyser
tyder også på at trening har en gunstig effekt på
dødelighet hos pasienter med hjertesvikt, men
hittil er det ikke utført større prospektive studier
som har testet om fysisk trening øker overlevelsen. HF-ACTION studien ble gjennomført for å
avklare om trening har effekt på dødelighet hos
pasienter med hjertesvikt og om slik trening er
sikker. 2331 pasienter med hjertesvikt, NYHA
klasse II-IV, EF < 35 % og som stod på optimal
medisinsk behandling ble randomisert til trening eller standard oppfølging. Standard oppfølging bestod av optimalisering av medikamentell
behandling, generelle råd om livsstil inkludert
trening og telefonoppfølging. Treningsgruppen
fikk i tillegg et strukturert supervisert treningsopplegg på treningsstudio (i alt 36 ganger, 3
ganger/uke à 30 min med puls omkring 70 % av
maks) og etter dette instrukser om hjemmetrening (5 ganger i uken à 40 minutter med puls
omkring 50-60 % av maks.). De fikk tredemølle
eller sykkel for dette formål. Gjennomsnittsalder var 59 år, 30 % kvinner, BMI 30 kg/m2 og
gjennomsnittlig var EF 25 %. Den medikamentelle behandling var god; 90 % brukte ACEhemmere eller ARB, 95 % betablokker og 43 %
aldosteronblokker. 40 % hadde ICD. Compliance i treningsgruppen mht. gjennomføring av trening ble redusert med tiden og var ca 50 % av
forventet ved slutten. Trening medførte økning
av den fysiske prestasjonsøkning, men økningen
var moderat: 6 min gangtest økte med 20 m vs
5 m i kontrollgruppen, og maksimal VO2 økte
med 0,5 ml/kg/min vs. 0,2 ml/kg/min i kontroll-
gruppen. Etter 2,5 år var det en ikke-signifikant
tendens til reduksjon av det primære endepunkt
død og hospitaliseringer med 7 % (HR 0,93,
95 % KI 0,84-1,02). Etter justering for basale faktorer var endringen signifikant på 11 %
(p<0,01), og det sekundære endepunkt med
kardiovaskulære dødsfall og hospitalisering for
hjertesvikt med 15 % (p<0,001). Antall alvorlige hendelser (SAE) var lik i de 2 gruppene.
I en substudie ble effekten av trening på
helsestatus vurdert med Kansas City Cardiomyopathy livskvalitetskjema (KCCQ). Dette
er et validert skjema med 23 spørsmål og en
skala som går fra 0-100. Gjennomsnittlig fant
man en moderat bedret effekt i treningsgruppen
(gjennomsnittlig økning 5 poeng) vs. kontrollgruppen (gjennomsnittsøkning 3 poeng). Totalt
sett hadde 54 % en bedring på 5 poeng eller
mer (ansett som klinisk signifikant bedring) vs.
28 % i kontrollgruppen.
Studien viser således at fysisk trening hos
pasienter med hjertesvikt er sikker og at den er
assosiert med en moderat, men ikke signifikant
reduksjon av dødelighet og kliniske hendelser. I
tillegg bedres livskvalitet. Studien føyer seg inn
i vår viten om trening som en viktig komponent
av livsstilsendringer og kan generelt anbefales.
Hvorvidt høyintensitetsintervalltrening kan gi
en bedre gevinst gjenstår å vise selv om foreløpige resultater, bl.a. fra Norge, er lovende. En
utfordring fremover blir å finne ut hvordan man
kan få pasientene til å følge opp trening over
lengre tid.
The I-Preserve Trial: A randomized doubleblind placebo-controlled trial of Irbesartan in
the treatment of heart failure in patients with
preserved ejection fraction.
ACE-hemmere og angiotensin II-blokkere
(ARB) har dokumentert effekt ved hjertesvikt
og redusert EF, mens verdien ved hjertesvikt og
preservert EF (HFpEF) ikke er avklart. Tidligere studier med ARB hos pas med HFpEF med
candesartan- (CHARM) og perindopril- (PEPCHF) studiene viste en ikke-signifikant bedring
av kliniske endepunkt med disse medikamen-
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tene. I I-Preserve-studien ble 4128 pasienter
> 60 år med symptomer og tegn på hjertesvikt
og EF > 45 % randomisert til irbesartan eller
placebo. Pasientene i NYHA-gruppe II måtte i
tillegg ha vært hospitalisert for hjertesvikt siste
6 mnd., og det skulle være objektive tegn på
myokarddysfunksjon ved røntgen, EKG eller
ekkokardiografi. Det primære endepunkt var
død eller kardiovaskulære hospitaliseringer,
mens sekundære endepunkter var kardiovaskulær død, død eller hospitalisering for hjertesvikt, kardiovaskulær død + hjerteinfarkt + slag,
livskvalitet eller en reduksjon av BNP. Gjennomsnittsdosen av irbesartan var 275 mg/dag.
Populasjonen var typisk for slike pasienter med
alder 72 år og 60 % var kvinner. Hypertensjon
var hyppigste etiologiske faktor for hjertesvikt
med 64 %, mens 25 % hadde utspring i koronarsykdom. Medikasjon ved studiestart inkluderte
diuretikum hos 83 % (53 % loop diuretikum),
betablokkere hos 59 %, kalsium-kanal-blokkere
40 %, spironolakton 15 % og ACE-hemmere
25 %. Etter en oppfølgingstid på 4,5 år var det
ingen forskjell i det primære endepunkt død
eller kardiovaskulære hospitalisering på 742
(36 %) ved irbesartan vs. 763 (37 %) ved placebo (HR 0,95, 95 % KI 0,86-1,05). Man så
heller ikke effekt på noen av de sekundære endepunktene.
Studien viste således ingen effekt verken på
det primære eller noen av de sekundære endepunktene av angiotensin II-blokkeren irbesartan
på toppen av annen medikamentell behandling
hos pasienter med HFpEF. Det er således intet
rasjonale for å gi ARB til sviktpasienter med diastolisk dysfunksjon. Det er heller ingen andre
medikamenter som har hatt klinisk signifikant
effekt i denne pasientgruppen. Dette tyder på at
vår grunnleggende forståelse av de basale patofysiologiske forhold ved diastolisk dysfunksjon
er mangelfull.
The effect of subcutaneuous treatment with
interferon-beta-1b over 24 weeks on safety,
virus elimination and clinical outcome in patients with chronic viral cardiomyopathy (BICC
study).
Idiopatisk dilatert kardiomyopati (CMP) er en
vanlig årsak til hjertesvikt og er hyppigste årsak
til hjertetransplantasjon. Med PCR-teknikk har
man funnet viralt genom hos ca. 50 % av pasientene i myokardbiopsier. Tidligere studier
har vist at dette, spesielt persisterende virus,
er assosiert med en forverret prognose. Medikamentell behandling som tar sikte på å fjerne
virus, kan derfor være et terapeutisk alternativ.
BICC studien, som var en fase II studie, ville
teste hypotesen om at interferon b (INFB-1b)
ville eliminere virus og være assosiert med bedring av kliniske symptomer. 336 pasienter med
CMP ble diagnostisert med biopsitaking fra
myokard. Av disse var 143 positive for adeno-,
entero- eller parvovirus B19. De ble randomisert til 3 grupper med injeksjon av INFB-1b 4 x
106 IU pr injeksjon eller 8 x 106 IU pr injeksjon
eller placebo gitt hver annen dag. Etter 24 uker
med behandling ble biopsi gjentatt. Det primære
endepunkt var eliminasjon av virus, mens sekundære endepunkt var flere kliniske parametre
som NYHA-klasse, livskvalitet, 6 min. gangtest og antall uventede hendelser. Den spontane
viruseliminering (placebo) var ca. 18 %. Graden
av eliminasjon av virus ble doblet ved INFB1b, dvs. 35 % (p<0.05) (høyest for entero- og
adenovirus, mens parvovirus B19 i mindre grad
ble eliminert). Fjerning av virus var assosiert
med en signifikant bedring av NYHA-klasse og
livskvalitet, mens 6 min gangdistanse ikke ble
påvirket.
Studien viste således at INFB-1b økte graden av eliminering av virus i myokard og at
dette var assosiert med klinisk bedring. Imidlertid hadde behandlingen hos over 50 % ingen effekt, spesielt hos pasienter med parvovirus B19.
Riktig seleksjon av pasienter blir derfor viktig i
fremtiden. Resultatene er oppmuntrende og gir
grunnlag for en større fase III-studie med kliniske endepunkter inkludert overlevelse.
Midregional pro-Adrenomedullin (MRproADM) vs BNP and NT-proBNP as prognosticator in heart failure patients: Results
from the BACH multinational trial.
Både BNP og NT-proBNP har vært hyppig
brukt for å stille diagnose og for å estimere
prognose ved hjertesvikt. Det har vært reist
spørsmål om andre biomarkører kan være til
ytterligere hjelp enten alene eller sammen med
BNP/NT-proBNP. Adrenomedullin er et protein
med vasodilaterende egenskaper og er viktig for
mikrosirkulasjon og endotelfunksjon. Proteinet har imidlertid en halveringstid på kun 22
min., mens MR-proADM er mer stabilt, med en
lengre halveringstid. Hensikten med BACH-
studien var å teste om MR-proADM kunne
være en bedre prediktor for død hos pasienter
med akutt dyspnoe. 1641 pasienter i USA, Europa og New Zealand med akutt dyspnoe ble
inkludert i undersøkelsen. Akutt hjertesvikt var
årsak til sykehushenvendelsen hos 568 pasienter, mens ikke-kardiale årsaker forelå hos 1073.
Gjennomsnittsalder var 64 år, 36 % hadde kjent
hjertesvikt, 19 % tidligere hjerteinfarkt og 29 %
diabetes mellitus. Det ble tatt blod til analyse på
BNP, NT-proBNP og MR-proADM for å teste
den prediktive verdien for 90 dagers dødelig-
het. Studien viste at MR-proADM økte den
prediktive verdi for 90 dagers dødelighet (AUC
0,735) sammenlignet med BNP (AUC 0,608)
og NT-proBNP (AUC 0,636). Pasientene med
MR-proADM i den høyeste kvartilen hadde en
betydelig overdødelighet sammenlignet med
de andre pasientene. Bestemmelse av MRproADM økte den prediktive verdi for dødelighet uansett årsak til dyspnoe og kan således
være en markør på generell sykdom. Hvorvidt
måling av MR-proADM vil endre klinisk praksis er imidlertid usikkert.
AHA – 2008. Cytokiner og hjertesvikt
Maria Vistnes og Geir Christensen, Institutt for eksperimentell
medisinsk forskning, Oslo universitetssykehus
og Senter for hjertesviktforskning, Universitetet i Oslo
På årets vitenskapelige sesjoner var flere sesjoner viet cytokiners rolle ved hjertesvikt. Den
store bredden og dybden i presentasjonene
viste at det foregår mye og god forskning på
dette feltet. I foredragene kom det klart frem at
hjertesvikt er forbundet med endringer i flere
cytokinsystemer, både lokalt i myokard og i
blod. Mye tyder på at økt produksjon av cytokiner kan betraktes som en adaptiv respons på
økt belastning av myokard, men på lengre sikt
kan cytokinene virke profibrotiske og proapoptotiske og derved påvirke både remodellering
og hjertefunksjon negativt. Dersom man ønsker
å benytte cytokiner som behandlingsstrategi
ved hjertesvikt, er ikke bare valg av terapeutisk angrepspunkt sentralt, men tidspunkt for
start av behandling er sannsynligvis også viktig.
Imidlertid ble det på møtet lagt vekt på at vår
kunnskap om den patogenetiske betydningen
av hvert enkelt cytokinsystem må bli bedre for
å kunne utnytte dem som terapeutiske angrepspunkter og for å finne rett tidspunkt for slik
behandling. Av stor interesse i denne sammenheng var sesjonen ”Innate Immunity and Heart
Failure”, der fem inviterte forskere la frem en
grundig oppdatering på hva som var nytt om cytokiner og hjertesvikt det siste året.
En av disse foreleserne var Douglas Mann
fra Baylor College of Medicine i Houston,
Texas. Han tok for seg kliniske studier publisert
i 2008 som har studert antiinflammasjonsbehandling hos hjertesviktpasienter. Mange kjenner Douglas Mann som mannen bak de kliniske
studiene med etanercept. Etanercept er en rekombinant human TNF-reseptor bestående av to
TNF-reseptor type II som binder seg til løselig
(sirkulerende) TNF, og som derved inaktiverer
TNF ved å hindre det i å binde seg til reseptorer
på celleoverflaten. Behandling med etanercept
har gitt klinisk bedring hos pasienter med blant
annet reumatoid artritt og psoriasis. Uttestingen av dette medikamentet ved hjertesvikt ble
som kjent gjort i to studier; RENAISSANCE og
RECOVER, og totalmaterialet ble analysert i
RENEWAL (Randomized EtaNErcept Worldwide evALuation). Fra eksperimentelle studier
var det svært gode holdepunkter for at dette
skulle være en god behandlingsstrategi. Men til
tross for høye forhåpninger ga etanercept ingen
reduksjon i mortalitet, snarere en tendens til å
forverre tilstanden, og entusiasmen knyttet til
anti-TNF-behandling kjølnet.
Douglas Mann har etter publisering av studiene spurt seg om hvorfor disse store kliniske
studiene ikke ga de positive resultatene man
forventet ut i fra prekliniske studier. I foredraget
”Cytokines in Heart Failure” presenterte Mann
oppsiktsvekkende resultater fra dette arbeidet
som til dels kan forklare hvorfor ikke etanercept
ga positive resultater i de kliniske studiene, men
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som også understreker at måten man angriper et
cytokinsystem på er av stor betydning.
Manns eksperimenter viser at etanercept,
som antas å virke som en antagonist, faktisk
kan fungere som en stimulerende agonist. Hos
hjertesviktpasienter som mottok etanercept,
observerte man høyere plasmakonsentrasjoner
av TNF enn i placebogruppen, noe som ville
vært uproblematisk dersom TNF forble bundet til etanercept og dermed ikke var biologisk
aktivt. Men Mann har nå vist at “on-off rate”
når det gjelder TNFs binding til etanercept er
overraskende høy ved romtemperatur, slik at
etanercept synes å stabilisere TNF i en biologisk
aktiv form i plasma. Som følge av dette øker
bioaktiviteten av TNF i hjertesviktpasienter som
mottar etanercept. TNFs bioaktivitet er størst
ved bestemte konsentrasjoner av etanercept og
TNF, og Mann har vist i eksperimentelle studier
at ved høye konsentrasjoner av TNF skal det
lavere konsentrasjon av etanercept til for å nå
denne toppen og dermed øke TNFs bioaktivitet
betraktelig. Disse funnene kan forklare hvorfor
etanercept har fungert dårlig som behandling av
hjertesviktpasienter med høye konsentrasjoner
av TNF, mens effekten av etanercept er gunstigere i pasienter med reumatoid artritt som har
lavere TNF-konsentrasjoner i utgangspunktet.
Det ble også presentert andre studier rettet
mot inflammasjon ved hjertesvikt. I ACCLAIM
har man forsøkt å redusere inflammasjonen ved
å benytte Celacade. Prinsippet er at man oksiderer pasientens eget blod ex vivo, for deretter å
tilbakeføre det intramuskulært. Under oksideringen vil apoptotiske mekanismer oppreguleres, noe som kroppen tolker som et potensielt
tilhelingssignal og dermed demper inflammasjonen. Hjertesviktpasientene i studien mottok
behandlingen åtte ganger over 600 dager. Totalt
sett var det ingen reduksjon i mortalitet i gruppen som mottok Celacade i forhold til kontrollgruppe. Det ble imidlertid funnet en signifikant
reduksjon i mortalitet hos pasientene med NYHA-klasse II og i en gruppe av pasienter med
dilatert kardiomyopati uten tidligere hjerteinfarkt. Det er derfor mulig at denne terapien kan
benyttes til pasienter med dilatert kardiomyopati. Studien ble nylig publisert i Lancet.
I GISSI-HF, som også nylig ble publisert
i Lancet, mottok en gruppe 1 gram n-3 flerumettede fettsyrer (PUFA) og en gruppe 10 mg
rosuvastatin. De inkluderte tilhørte enten NY-
HA-klasse II-IV eller hadde ejeksjonsfraksjon
over 40 %, men hadde da vært sykehusinnlagt
på grunn av hjertesvikt siste året. Det teoretiske
rasjonale bak å gi n-3 flerumettede fettsyrer til
hjertesviktpasienter er at de konkurrerer med
n-6 flerumettede fettsyrer i dannelsen av eikosanoider, og eikosanoidene som da blir dannet
virker mer antiinflammatoriske. I gruppen som
mottok PUFA fant man en reduksjon i relativ
risiko for myokardinfarkt på 9 %. Resultatene
kan betraktes som lovende til tross beskjeden
risikoreduksjon, siden PUFA evnet å vise effekt
i tillegg til annen hjertesviktbehandling som pasientene mottok.
I gruppen som mottok rosuvastatin, var det
ikke positiv effekt på de to primære endepunktene som var død eller hospitalisering av kardiovaskulære årsaker. Rosuvastatin kan virke
antiinflammatorisk ved å blokkere prenylerte
proteiner, som igjen blokkerer AT1-reseptor og
NADPH-oksidase, men stimulerer eNOS. Den
antiinflammatoriske effekten av rosuvastatin
er likevel støttet i en annen studie, JUPITER,
som nylig er publisert i New England Medical
Journal og ble presentert på møtet av studiens
førsteforfatter Paul Ridker. I JUPITER er menn
og kvinner med økte nivåer av høysensitivitets
C-reaktivt protein (hs-CRP), men uten hyperlipidemi inkludert. I intervensjonsgruppen, som
fikk 20 mg rosuvastatin daglig, var insidensen
av hjerteinfarkt og slag signifikant redusert.
Både nivået av kolesterol og hs-CRP var redusert i denne gruppen. Resultatene indikerer at
hemming av inflammasjon hos pasienter kan
bidra til å forhindre alvorlige kardiovaskulære
hendelser.
Mann avsluttet sin presentasjon ved å sitere en indianer med navnet Nobody fra filmen
”Dead Man”. Indianeren Nobody sier “One
must go without food and water, then the secret
spirits will recognize those who fast”. Mann har
vel etter flere år med stor innsats på feltet inflammasjon og hjertesvikt en følelse av å ha gått
uten ”food and water”, i denne sammenheng
positive effekter på primære endepunkt. Men
samtidig har ”the secret spirits” lært ham mye
om cytokiner og hjertesvikt som han oppsummerte slik: ”Vår evne til å overføre antiinflammatoriske strategier ”from bench to bedside” i
kliniske fase III-studier har så langt ikke vært
vellykkede. Det er uvisst om dette skyldes
problemer med dagens antiinflammatoriske be-
handlingstrategier, uegnet seleksjon av pasienter
eller gale hypoteser. De kliniske studiene fra det
siste året viser uansett at bedre forståelse av de
basale mekanismer i immunresponsen ved hjertesvikt er nødvendig før oppstart av nye kliniske
studier”.
AHA 2008. Ekko/billeddiagnostikk
Ola Gjesdal, Hjertemedisinsk avdeling, Rikshospitalet.
American Heart Associations kongress i New
Orléans presenterte i år mer enn 4000 abstrakter, og billeddiagnostikk sto for en stor andel av
disse. Ekkokardiografi var hovedmetode i over
500 abstrakter. CT var benyttet i mer enn 500
arbeider, og det var nesten 200 arbeider som
omhandlet MR. Totalt var det 300 arbeider som
vurderte deformasjon målt med en eller flere av
disse metodene.
Vurdering av venstre ventrikkels funksjon
er viktig i den ekkokardiografiske evalueringen,
og de etablerte metodene (vurdering av venstre
ventrikkels ejeksjonsfraksjon og wall motion
score index) har flere svakheter. De siste årene
har de fleste leverandører av ultralydutstyr
kommet med doppleruavhengige metoder for
evaluering av deformasjonen i venstre ventrikkels myokard, og dette gjenspeilte seg også i abstraktene. Disse metodene (eks: Vector Velocity
Imaging (VVI), Speckle Tracking Echocardiography (STE)) baserer seg på at naturlige akustiske markører (Speckles, “de hvite flekkene”) i
vevet automatisk følges gjennom hjertesyklus.
Deformasjon kan derved uttrykkes på samme
måte som ved vevsdopplerbaserte metoder, men
metodene er i mindre grad vinkelavhengige
og også mer intuitive i bruk. Metodene benytter seg av vanlige gråtonebilder, og analysene
krever derfor ikke spesialopptak. I likhet med
vevsdopplerbaserte metoder kan deformasjonen
uttrykkes ved tøyning (strain), strain rate, hastighet eller forflytning (displacement), men man
kan også evaluere venstre ventrikkels rotasjon
og vridning (twist).
Langt de fleste ekkorelaterte abstraktene på
årets møte benyttet STE i evalueringen av venstre ventrikkels funksjon, og flere hadde benyttet “global strain”, som er gjennomsnittet av de
segmentale strainverdiene og slik sett uttrykker venstre ventrikkels funksjon. Enkelte hadde
også benyttet metoden på høyre ventrikkel eller
på atriene og karstrukturer.
To av temaene som fikk stor oppmerksomhet i år, var klaffelidelser og resynkroniseringsterapi. Ved patologi i mitral- eller
aortaklaffen er det vesentlig at operativt inngrep
blir utført før venstre ventrikkel skades permanent. Utfordringen ligger i at endringene i
volum- og trykkbelastning som følge av stenose
eller lekkasje initialt kompenseres av endringer
i myokards kontraksjon. På grunn av kompensasjonen vil eksempelvis venstre ventrikkels ejeksjonsfraksjon opprettholdes i lang tid, og skaden
på myokard kan derfor være permanent på operasjonstidspunktet dersom man baserer seg på
konvensjonelle mål. To studier som så på dette,
var fra Marcinac et al (London, AI) og Delgado
et al (Leiden, AS). Begge fant at deformasjon
målt ved strain eller strain rate var nedsatt pre
operativt til tross for bevart ejeksjonsfraksjon,
og antydet at redusert deformasjon er et bedre
mål for bestemmelse av operasjonstidspunkt.
Operasjon endret deformasjonen i normal retning: den økte ved aortastenose, mens den avtok
noe etter klaffekirurgi ved aortainsuffisiens.
Det var heller ikke på dette møtet mye nytt
mht. nytten av ekkokardiografi for påvisning
av dyssynkroni og prediksjon av CRT-effekt.
Et stort antall indekser benytter differansen i
tid mellom den maksimale deformasjonen, hastigheten eller deformasjonshastigheten mellom
det tidligst og det senest aktiverte segmentet. Et
godt abstrakt i denne kategorien var arbeidet til
Miyazaki (Mayo Clinic) hvor langaksestrain ble
målt med STE i 16 segmenter før og 6 måneder
etter CRT hos 91 pasienter. Som tidligere vist
ga resynkronisering kortere tidsintervall mellom
maksimal kontraksjon i tidlig og sent aktiverte segmenter. Det nye var at dette i hovedsak
skyldtes at maksimal kontraksjon i de tidligst
aktiverte segmentene ble forsinket, og i mindre
91
grad at de senest aktiverte segmentene nådde
maksimal kontraksjon tidligere. Dette skjer
fordi septum etter resynkronisering kontraherer
samtidig med lateralveggen og derved mot et
høyere veggstress, noe som gir en langsommere
kontraksjon.
Direkte påvisning av infarktstørrelse har
tradisjonelt bare vært mulig med kontrast-MR.
Det er kjent at CT har høy negativ prediksjonsevne for koronare stenoser, og mye tyder nå på
at man også kan visualisere arr i myokard med
kontrast-CT. Nytt er det også at ekkokardiografi
kan påvise arrvev. En spennende studie kom fra
Montant et al (Brussel) som hadde sammenliknet infarktstørrelse målt med 3D kontrastekko
og kontrast-MR hos 50 postinfarktpasienter.
Metodene samsvarte svært godt, og ultralyd
kan dermed få en fremtidig rolle for direkte
påvisning av infarktstørrelse og ikke bare ved
indirekte påvisning av nedsatt kontraksjon som
i dag.
At ultralyd også har et potensial for terapi
og ikke bare for diagnostikk, viste Juffermans et
al (Amsterdam) i en preklinisk studie. Ultralydpulser kan sprenge mikrobobler som inneholder medikament eller gener, og dersom dette
koordineres med administrasjonen av kontrast,
kan de benyttes til å administrere medikamentet
lokalt. Opptak av medikament i cellene skyltes
en blanding av endocytose og spontan poredannelse som følge av ultralydstimulus.
Det var også mange spennende norske bidrag innen billeddiagnostikk; disse er gjengitt
senere i dette nummeret av Hjerteforum.
Nytt innenfor antitrombotisk behandling
ved akutt koronarsyndrom
Frederic Kontny
Svært lite nytt innenfor dette temaet ble presentert ved denne kongressen. Den eneste aktuelle
”late breaking clinical trials”-presentasjonen var
ATLAS – TIMI-46-studien. Dette er en fase II–
studie av den selektive, orale, direkte faktor Xahemmeren rivaroxaban. Vel 3400 ACS-pasienter
stabilisert 1-7 dager etter den akutte hendelsen
ble gitt ASA alene (n = 761) eller ASA + klopidogrel (n = 2730) (avhengig av behandlende
leges preferanse) og deretter randomisert til placebo eller rivaroxaban for 6 mnd. i følgende doseringer: 5 mg, 10 mg eller 10 mg x 1 per dag,
eller 2,5 mg, 5 mg eller 10 mg x 2 per dag.
Det primære endepunktet var å finne den
optimale dosering av rivaroxaban for bruk i en
fase III-studie. Ved siden av TIMI ”major”- og
”minor”-blødninger, ble også et mer sensitivt mål for blødning brukt: ”blødninger som
tiltrengte medisinsk tilsyn”. Dette kunne være
småblødninger (for eksempel neseblødninger).
Som ventet var det en dose-avhengig økning
i blødninger assosiert med rivaroxaban – fra
6,1 % i 5 mg–gruppen til 15,3 % i 20 mg–gruppen. I gruppen av pasienter som ble gitt både
ASA og klopidogrel, forekom TIMI major-blødning hos 1,2 % i rivaroxaban-gruppen og 0,2 %
i placebo-gruppen (p = 0,03), mens tilsvarende
blødningsforekomst hos kun ASA-behandlete
var 1,2 % og 0 % (ns).
De to gruppene som ble gitt henholdsvis
ASA alene og ASA i kombinasjon med klopidogrel inneholdt ganske forskjellige pasienter. De
som kun fikk ASA, var eldre, flere hadde diabetes og/eller tidligere myokardinfarkt og færre
fikk utført PCI. Følgelig var forekomsten av
effekt-endepunktet død/myokardinfarkt/hjerneslag forskjellig i disse to strata: 11,9 % i ASAgruppen og 3,8 % i ASA + klopidogrel-gruppen.
Rivaroxaban (2,5 og 5 mg x 2 pr. dag; aktuelle doser for fase III) var assosiert med en
absolutt risikoreduksjon i forekomst av dette
endepunktet på 5,3 % (HR 0,54; p=0,08) hos
pasientene med dobbel platehemming, og 1,8 %
(HR 0,55; p=0,09) hos ASA-behandlete.
Kommentar: Flere FXa-hemmere har vært/
er gjenstand for klinisk utprøving hos pasienter med ACS, og selv om resultatene fra en fase
II-studie på dette preparatet er interessante gjenstår det å se resultat fra en fase III-studie. Det er
verdt å merke seg at trippel anti-trombotisk behandling i denne studien ikke var forbundet med
øket forekomst av alvorlige blødninger sam-
93
94
menlignet med rivaroxaban og ASA. For øvrig
er effekten av trippel antitrombotisk behandling
som konsept allerede demonstrert i tidligere
studier (ESTEEM) og videre klinisk utprøving
langs denne linjen synes formålstjenelig.
AHA 2008. Nytt innenfor invasiv kardiologi
Vernon Bonarjee, Hjerteavdelingen,
Stavanger Universitetssjukehus
Ved AHA sin kongress i New Orléans var det en
egen Late Braking trials-sesjon som omhandlet
resultater fra studier innenfor invasiv kardiologi. Et kort referat fra studiene er gjengitt nedenfor.
ATLAS ACS-TIMI 46 - Dr. Michael Gibson fra Beth Israel sykehuset i Boston presenterte resultatene fra denne studien. Dette var en
randomisert dobbelblindet fase II -studie med
rivaroxaban, en oral faktor Xa-hemmer, ved
akutt koronarsyndrom (STEMI eller NSTEMI/
UAP). 3491 pasienter ble randomisert innen 7
dager etter symptomdebut. Primært siktemål var
å kartlegge tolerabel dose (sikkerhet), og det sekundære siktemål var å se på effekten av rivaroxaban ved denne dosen. Pasienter ble stratifisert
i forhold til bruk av klopidogrel (761 pas. med
kun ASA og 2730 pasienter med ASA + klopidogrel). Sikkerheten ble målt etter TIMI-blødningskriterier. Primært endepunkt for effekt var
en kombinasjon av død, hjerteinfarkt, slag og
ny revaskularisering. Sekundært endepunkt for
effekt var død, hjerteinfarkt og slag. Begge stratifiseringsgruppene ble delt i 3 like deler som
fikk enten placebo eller rivaroxaban fra 5 til 20
mg eller fra 2,5 til 10 mg i 6 måneder.
Resultatene viste flere tilfeller av mindre
blødninger med rivaroxaban, men ingen forskjell i større blødninger. Blødningsfaren var
doserelatert. Det var færre primære effektendepunkter med behandling, men dette var ikke
statistisk signifikant (HR 0,79, p=0,10). Det var
derimot signifikant færre sekundær endepunkter
(HR 0,69, p = 0,028) med rivaroxaban. Det var
mindre hendelser i gruppen som fikk en kombinasjon av ASA og klopidogrel i forhold til ASA
alene, men effekt av rivaroxaban var lik i disse
2 gruppene. Ut i fra resultatene går man nå videre med en ny studie, ATLAS 2- TIMI 51, der
en ser på effekten av 2,5 og 5 mg rivaroxaban
ved akutt koronarsyndrom på kardiovaskulær
død, hjerteinfarkt og slag.
Mass-DAC register - Dr. Laura Mauri
fra Brigham and Women’s sykehuset i Boston presenterte denne studien basert på registerdata fra alle ikke-føderale sykehus i staten
Massachusetts. Prevalens av iskemisk hjertesykdom er høyere blant diabetikere, og de har
oftere restenose, infarkt og hjertedød etter PCI
sammenliknet med ikke-diabetikere. Målsettingen var å undersøke om medikamentavgivende stenter (DES) var forbundet med høyere
mortalitet blant diabetikere og om bruk av DES
førte til færre revaskulariseringer av behandlet
åre (TVR) sammenliknet med ren metall-stent
(BMS). Prospektiv data ble samlet mellom april
2003 og september 2004. Kliniske og prosedyrerelaterte data ble samlet i en statlig database
(Mass-DAC). Disse data ble slått sammen med
data fra sykehusutskrivelser. Informasjon om
mortalitet ble hentet fra flere kilder inkludert
”Social Security Website”. Pasienter fra andre
stater ble ekskludert.
Pasienter måtte få enten DES eller BMS, og
de som fikk begge typer, ble ekskludert. I denne
perioden ble 21045 pasienter behandlet, hvorav
6008 var diabetikere. Av disse kunne 5051
(3341 med DES og 1710 med BMS) være med i
studien. Det var flere forskjeller i utgangsvariabler mellom pasienter som fikk DES og BMS.
Etter planen ble det utført en ”propensity matching”, dvs. en utvelgelse av pasienter i henhold
til 67 variabler for å få 2 sammenliknbare grupper. Primær endepunkt var å se på forskjell i
mortalitet, nye infarkter og TVR i disse 2 gruppene i løpet av 3 års observasjon.
Etter matching var det 1476 pasienter i
begge grupper, og her var det ingen forskjell i
utgangskriterier. Resultatene viste 3,2 % lavere
mortalitet (-6,0- -0,4, p=0,02), 3,0 % færre nye
infarkter (-5,6 - -0,5, p= 0,02) og 5,4 % færre
TVR (-8,3 - -2,4, p<0.001) i DES-gruppen sammenliknet med BMS-gruppen. Studien konkluderte med at bruk av DES resulterte i færre
reinfarkter, færre TVR og redusert mortalitet
sammenliknet med BMS blant pasienter med
diabetes mellitus. Resultatene er publisert i Circulation 2008;118.
TIMACS- Tidligere studier og metaanalyser har vist at invasiv strategi er bedre enn konservativ behandling hos høyrisikopasienter med
akutt koronarsyndrom. Tidspunkt for intervensjon har variert mellom studiene, og optimalt
tidspunkt for intervensjon er fortsatt uavklart.
Dette var bakgrunnen for ”Timing of Intervantion in Patients with Acute Coronary Syndrome”
(TIMACS)-studien som ble presentert av dr.
Mehta fra Hamilton, Canada.
3031 pasienter med ustabil angina eller
NSTEMI bla randomisert til tidlig invasiv
strategi (<24 timer) eller forsinket invasiv behandling (>36 timer). Pasienter måtte ha 2 av 3
inklusjonskriterier: alder >60 år, iskemi på EKG
eller forhøyelse av biomarkører. 1633 pasienter var med i OASIS 5-studien, og de fikk enten
fondaparinux eller enoxaparin som antikoagulasjon. Resten (1398 pasienter) kunne få heparin,
LMWH, fondaparinux eller bivalirudin. Alle
fikk ASA og klopidogrel. GP IIb/IIIa-hemmere
ble gitt etter behov. Primært endepunkt var en
kombinasjon av død, nye hjerteinfarkt og slag
innen 180 dager. Sekundære endepunkter var:
a) død, nytt hjerteinfarkt eller refraktær iskemi,
b) død, nytt hjerteinfarkt, refraktær iskemi, ny
revaskularisering eller slag og c) slag. Dette var
en multinasjonal studie med sentra fra alle kontinenter unntatt Afrika. Randomisering varierte
mellom 1:1, 1.2 og 2.1. Fordelingen ble 1593 i
tidlig gruppe og 1438 i forsinket gruppe. Gruppene var godt balansert.
Det var en del overkryssing der 12 % av
pasienter i tidlig gruppe fikk forsinket behandling og 25 % i den andre gruppen ble behandlet
tidlig. I tidlig gruppe ble 97,6 % og i forsinket gruppe ble 95,5 % angiografert. Tidlig
angiografi ble utført etter 14 (13-21) timer og
forsinket behandling etter 50 (41-81) timer. Behandling besto av PCI i hhv. 59,6 % og 55,0 %
og bypass-kirurgi i hhv. 14,7 % og 13,6 %.
Resultatene viste færre primær endepunkter med tidlig intervensjon, men forskjellen var
ikke statistisk signifikant. Forskjellen i sekundær endepunkt a og b var derimot signifikant
pga. en markert forskjell i innsidens av refraktær iskemi. Det var ingen forskjell i død, slag
eller nye hjerteinfarkt. Subgruppeanalyser viste
at pasienter med høyest risiko hadde en klar fordel av tidlig behandling.
Studien ble gjennomgått av dr. Deepak
Bhatt fra Boston. Han mente at studien var godt
planlagt. Resultatene pekte i retning av at tidlig
behandling var fordelaktig, men studien hadde
ikke styrke nok til å gi et svar på problemstillingen. Lengre observasjonstid ville sannsynligvis
vært nødvendig for å vise forskjeller i mortalitet. Resultatene viste i alle fall ingen fordeler
ved å vente med invasiv behandling.
Den siste studien som ble presentert var
”Tailored Clopidogrel Loading Dose According to Platelet reactivity Monitoring to
prevent Stent Thrombosis.” Studien var fra
Marseille i Frankrike og ble presentert av Dr.
Bonello. Det finnes stor individuell variasjon
på effekt av ladningsdosen av klopidogrel. Effekt av klopidogrel på blodplater kan måles ved
hjelp av vasodilatator-stimulert fosfoprotein
(VASP)-indeks. Tilstrekkelig effekt defineres som VASP-indeks < 50 %. I denne studien
ble pasienter som skulle til PCI pga. NSTEMI,
UAP eller stabil angina randomisert til en kontrollgruppe (n=215) og en testgruppe (n=214)
der PCI først ble utført etter påvist VASP-indeks
<50 %. Alle fikk 250 mg ASA og 600 mg klopidogrel. Testgruppen fikk ytterligere 600 mg
klopidogrel med 24 timer mellomrom (maks.
2400 mg) inntil VASP-indeks var < 50 %. I
testgruppen hadde 83 pasienter VASP-indeks >
50 % etter første dose. Etter annen dose var det
fortsatt 40 pasienter som måtte få dose nr 3. Av
disse var det 17 pasienter som måtte få dose nr
4 før PCI. Etter PCI fikk alle 160 mg ASA og
75 mg klopidogrel daglig. Sikker stenttrombose
var primært endepunkt. Sekundært endepunkt
var MACE, inkludert kardiovaskulær død, hjerteinfarkt, TVR og blødninger. Gruppene var
godt balansert.
Resultatene viste 2 akutte og 8 subakutte
stenttromboser i kontrollgruppen mot kun 1
subakutt stenttrombose i testgruppen (p=0,01).
Alle trombosene oppsto innen 7 dager etter PCI.
Det var 19 MACE-tilfeller i kontrollgruppen,
inkludert 10 hjerteinfarkt mot kun 1 hjerteinfarkt i testgruppen (p<0 001). Det var ingen
forskjeller i forekomst av blødninger. Studien
konkluderte med at stenttromboser og hendelser etter PCI kunne reduseres ved å kontrollere
platereaktivitet. Dette styrker indikasjonen for
95
96
måling av klopidogrels effekt på platereaktivitet
før PCI.
Det bør nevnes at forfatterne har publisert data fra et mindre antall pasienter (164 til
sammen) i J Am Coll Cardiol 2008;51:1404-11,
med tilsvarende resultater.
Nytt om hypertensjon
Eva Gerdts
Universitetet i Bergen og Haukeland universitetssykehus
Resistent hypertensjon
Resistent hypertensjon er i likhet med hypertensjon et økende helseproblem i verden. Resistent
hypertensjon defineres som blodtrykk (BT) over
behandlingsmål (systolisk BT >140 mmHg og/
eller diastolisk BT >90 mmHg hos ikke-diabetikere eller systolisk BT >130 mmHg og/eller
diastolisk BT >85 mmHg hos diabetikere) til
tross for kombinasjonsbehandling med 3 blodtrykkssenkende medikamenter hvorav et diuretikum. Data fra ALLHAT-studien viste forekomst
av resistent hypertensjon på 40 % etter 3 års
behandling, men mye av dette var forårsaket
av restriksjoner i bruk av effektiv diuretikabehandling på bakgrunn av studiens randomiserte
medikasjon. Andre identifiserte prediktorer for
resistent hypertensjon er kvinnekjønn, afrikansk
rase, fedme, type II-diabetes, øket serum-kreatinin og venstre ventrikkelhypertrofi på EKG (1).
Disse prediktorene kan enkelt identifiseres ved
kontroll av hypertonikere og krever er mer intensivt behandlings- og kontrollopplegg.
Blant pasienter med resistent hypertensjon
er det høy forekomst av reversible årsaker til
hypertensjon – sekundær hypertensjon.
Sekundære årsaker til resistent
hypertensjon:
• Obstruktiv søvnapné – viktigste årsak til
resistent hypertensjon både hos kvinner og
menn
• Primær hyperaldosteronisme – 22 % hadde
dette i en serie fra Ullevål universitetssykehus
• Parenkymatøs nyresykdom
• Nyrearteriestenose
Andre reversible årsaker til resistent hypertensjon:
• Dårlig compliance – pasienten tar ikke medisinene som er forskrevet
Høyt Na-inntak
Fedme
Høyt alkoholinntak
Fysisk inaktivitet
Unøyaktig blodtrykksmåling – viktig at
pasienter sitter og hviler i 5 minutter før måling og at cuff-størrelsen er adekvat
• Inntak av homeopatisk medisin – spesielt
ephedra som finnes i mange urteblandinger
Til tross for økende forekomst av resistent hypertensjon er ifølge NHANES epidemiologiske
data fra USA 57 % av ikke-diabetiske hypertonikerne kontrollert, hvilket er en betydelig
bedring fra siste registrering. Men bare 25 % av
hypertonikere med diabetes er kontrollert. En
hovedårsak her er kombinert fedme og diabetes.
I diagnostikk av resistent hypertensjon er
det viktig først å supplere med en 24 timers
blodtrykksmåling for å utelukke white-coat hypertensjon. Videre er resistent hypertensjon assosiert med høy forekomst av endeorganskade,
særlig i nyrer og hjerte, samt øket risiko for død
og kardiovaskulære hendelser. I en subanalyse
fra ALLHAT-studien viser prospektive data fra
dem som etter 2 års behandling hadde resistent
hypertensjon at de hadde 37 % øket mortalitet og 60 % høyere forekomst av ikke-fatale
kardiovaskulære hendelser som hjerteinfarkt,
hjerneslag og hjertesvikt i løpet av resten av
oppfølgingstiden i studien (2).
Mange pasienter med resistent hypertensjon
kan effektivt behandles med mer adekvat diuretika-dosering eller saltrestriksjon. Det er viktig
å merke seg at serum-aldosteron øker proporsjonalt med visceralt fett hos pasienter med lavrenin-hypertensjon. Dette utgjør en stor del av
pasienter med essensiell hypertensjon, og tillegg
av en aldosteronhemmer hos disse pasientene
er meget effektivt så sant nyrene tåler kombina•
•
•
•
•
sjon med ACE-hemmer eller angiotensin-reseptorblokker.
Litteratur:
1.
2.
Cushman WC, Ford CE, Cutler JA, Margolis
KL, Davis BR, Grimm RH, Black HR, Hamilton BP, Holland J, Nwachuku C, Papademetriou
V, Probstfield J, Wright JT Jr, Alderman MH,
Weiss RJ, Piller L, Bettencourt J, Walsh SM;
ALLHAT Collaborative Research Group. Success and predictors of blood pressure control in
diverse North American settings: the antihypertensive and lipid-lowering treatment to prevent
heart attack trial (ALLHAT). J Clin Hypertens
(Greenwich). 2002;4:393-404.
Eide IK, Torjesen PA, Drolsum A, Babovic A,
Lilledahl NP: Low-renin status in therapy-resist-
ant hypertension: a clue to efficient treatment. J
Hypertens 2004;22:2217-26
3.
Calhoun DA, Jones D, Textor S, Goff DC,
Murphy TP, Toto RD, White A, Cushman WC,
White W, Sica D, Ferdinand K, Giles TD,
Falkner B, Carey RM. Resistant hypertension:
diagnosis, evaluation, and treatment. A scientific
statement from the American Heart Association
Professional Education Committee of the Council for High Blood Pressure Research. Hypertension. 2008;51:1403-19. Epub 2008 Apr 7.
4.
Cushman WC. The burden of uncontrolled
hypertension: morbidity and mortality associated with disease progression. J Clin Hypertens
(Greenwich). 2003;5(3 Suppl 2):14-22.
Norske abstrakter presentert på AHA
AHJ, Volume 118, Issue 18 Supplement; October 28, 2008 / Abstracts From Scientific Sessions 2008
6208 The Association Of
Metabolic Clustering And
Physical Activity With
Cardiovascular Mortality: The
Hunt Study In Norway
Arnt E Tjønna; Tom I Nilsen; Stig A
Slørdahl; Lars Vatten Ulrik Wisløff.
NTNU, Trondheim, Norway
The importance of physical-activity status in predicting premature cardiovascular death has mainly
been reported in studies of asymptomatic populations. Whether physical activity compensates
for the adverse effect of multiple cardiovascular
risk factors is not well understood. The present
study determined whether the positive association of a clustering of cardiovascular risk factors (CRF) with mortality could be weakened by
exercise training in 49791 individuals who were
free from known cardiovascular disease, and in
3751 individuals with CRF, at the beginning of
follow-up between 1984 and 1986. We used the
Cox proportional hazards model to estimate hazard
ratios (HR) of cardiovascular death. People with
CRF had a HR for cardiovascular mortality of 1.38
(95% CI, 1.28–1.48) compared to those without CRF. The effect of CRF was stronger among
women than men. In people with CRF, there was a
reduction in the risk of cardiovascular death with
increased training. In the most physically active
people with CRF, the reduction was 24% (HR,
0.76, 95% CI, 0.61–0.95) compared to the inactive
with CRF. Compared to inactive healthy people,
we observed a HR of 1.41 (95% CI, 1.16–1.70) in
inactive people with CRF, whereas high physical activity in healthy people yielded a HR of 0.81
(95% CI, 0.72–0.92). HR associated high physical
activity and CRF was 1.03 (95% CI, 0.82–1.29).
We demonstrate that individuals with CRF are
at greater risk of premature cardiovascular death
compared to people without CRF, and that the risk
of people with CRF who were most physical active
appear to be comparable to that of inactive individuals without CRF.
P160 Teaching Hospital
Employees Basic Life Support
using MiniAnne and a
24-minute Self-instruction
Video
Conrad A Bjørshol1; Eldar Søreide1; Leif
Moen1; Linda Sivertsen1; June Glomsaker1 Kjetil Sunde2. 1 Stavanger Univ
Hosp, Stavanger, Norway, 2 Ulleval
Univ Hosp, Oslo, Norway
Introduction Personal resuscitation manikins
with self-instruction video have been shown to be
as effective as traditional CPR courses in teaching lay people basic life support (BLS). In order to
improve in-hospital skills and self confidence in
BLS, we introduced a campaign consisting of this
concept in a university hospital.
97
98
Material and methods All 5,400 employees at
Stavanger University Hospital received a personal
resuscitation manikin (MiniAnne, Laerdal Medical,
Stavanger, Norway) with a 24-min self-instruction
video. In addition to recommended home training,
video-facilitated training with the same system
was offered on an hourly basis for nine days in a
hospital meeting room. Prior to this all participants
judged their own BLS self confidence (on a scale
from 1 to 5, 1=very poor, 5=very good). In addition, randomly chosen employees, evenly distributed between the different departments, were asked
to perform BLS on a MiniAnne equipped with a
counting device measuring the number of correct
chest compressions and mouth-to-mouth ventilations (MTMV) during the first two minutes. Their
skills were reassessed six months later. Finally, all
employees judged their BLS self confidence nine
months after the campaign was initiated. Results
were analyzed using the Wilcoxon signed rank test,
Mann-Whitney U test and students t-test, as appropriate, and presented as median with inter-quartile
range.
Results The number of correct chest compressions
increased from 60 (5–102) pre-course (n=59) to
119 (75–150) at the six-month follow up (n=39),
p<0.0005. There was no difference in the number
of correct MTMV with 3 (0–8) vs 4 (0–7), respectively, p=0.23. The self-reported confidence
in BLS skills increased from 3.1 prior to MiniAnne introduction (n=3,466) to 3.8 (n=1,399) nine
months later, p=0.031.
Conclusion This in-hospital BLS campaign including a personal resuscitation manikin and a
self-instruction video, increased the number of
correctly performed chest compressions and lead
to higher self confidence in BLS skills. Such a
campaign has the potential to increase and improve
BLS performance for in-hospital cardiac arrests.
13 A Prospective Randomized
Controlled Trial on the
Effects of Intravenous Drug
Administration on Survival to
Hospital Discharge after Out-ofhospital Cardiac Arrest
Theresa M Olasveengen1; Kjetil
Sunde2; Jon Thowsen3; Petter Andreas
Steen4 Lars Wik5. 1 Institute for Experimental Med Rsch and Dept of Anaesthesiology, Ulleval Univ Hosp, Oslo,
Norway, 2 Institute for Experimental
Med Rsch and Dept of Anaesthesiolo-
gy, Ulleval Univ Hosp, Oslo, Norway, 3
Div of PreHosp Medicine, Ulleval Univ
Hosp, Oslo, Norway, 4 Univ of Oslo,
Faculty Div UUH, and Div of PreHosp
Medicine and Institute for Experimental Med Rsch, Ulleval Univ Hosp, Oslo,
Norway, 5 The National Competence
Cntr for Emergency Medicine and Institute for Experimental Med Rsch, Ulleval Univ Hosp, Oslo, Norway
Background: Intravenous (IV) epinephrine,
atropine and amiodarone are included in CPR
guidelines despite lacking evidence for increased
survival to hospital discharge, and epinephrine has
been associated with decreased survival in epidemiologic studies. Our hypothesis was that IV access and drug administration remove focus from
the all important chest compressions, and consequently lead to more chest compression pauses (increased hands-off fraction) and subsequent adverse
outcome.
Materials and methods: Patients with non-ambulance witnessed adult out-of-hospital cardiac
arrest of all causes (except trauma, anaphylactic
shock and asthma induced) in the Oslo and Follo
EMS between May 2003 and April 2008 were
randomized to receive either standard ACLS (IV
group) or ACLS without IV Access (No-IV group).
Ambulance run sheets, Utstein forms, Hospital
records and continuous ECGs with impedance signals were reviewed. Quality of CPR and clinical
outcome was compared between the two groups
using Chi square and t-tests as appropriate. Values
are given as percentages or means ± standard deviation.
Results: Resuscitation was attempted in 1112
patients of whom 835 were included in the study.
There were 415 patients in the IV group and 420
patients in the No-IV group. Utstein variables
known to affect survival were equally distributed
between the two groups. The CPR quality parameters were adequate, and did not differ between the
IV group and the No-IV group with hands-off fractions 0.18±0.11 and 0.17±0.11, compression rates
118±11 and 116±10, and ventilation rates 11±4 and
11±4, respectively. There were 10.6% surviving to
hospital discharge in the IV group and 9.0% in the
No-IV group (p=0.523).
Conclusion: Quality of CPR was adequate and
comparable for both randomization groups. There
was no difference in survival to hospital discharge
between the IV group and No-IV group.
P148 Patients Presenting with
Initial Non-shockable Rhythms
after Cardiac Arrest Do Not
Have Inferior Outcome If
They Progress to a Shockable
Rhythm
Theresa M Olasveengen1; Martin Samdal2; Petter Andreas Steen3; Lars Wik4
Kjetil Sunde5. 1 Institute for Experimental Med Rsch and Dept of Anaesthesiology, Ulleval Univ Hosp, Oslo,
Norway, 2 Faculty of Medicine, Univ
of Oslo, Oslo, Norway, 3 Univ of Oslo,
Faculty Div UUH, and Div of PreHosp
Medicine and Institute for Experimental Med Rsch, Ulleval Univ Hosp, Oslo,
Norway, 4 The National Competence
Cntr for Emergency Medicine and Institute for Experimental Med Rsch,
Ulleval Univ Hosp, Oslo, Norway, 5 Institute for Experimental Med Rsch and
Dept of Anaesthesiology, Ulleval Univ
Hosp, Oslo, Norway
Background: Cardiac arrest patients presenting
with initial non-shockable rhythms have previously been reported to have inferior outcome if they
progress to a shockable rhythm. We wanted to confirm this observation in our prospectively collected
database, and assess whether differences in CPR
quality could help explain any such difference in
outcome.
Materials and methods: All out-of-hospital cardiac arrest cases in the Oslo EMS between May
2003 and April 2008 were retrospectively studied,
and cases with initial asystole or pulseless Electrical Activity (PEA) were selected. Ambulance
run sheets, Utstein forms, Hospital records and
continuous ECGs were reviewed. Quality of CPR
and outcome were compared for patients who progressed to a shockable rhythm and patients who
remained in non-shockable rhythms.
Results: There were 738 cases with initial nonshockable rhythms; 508 (69%) with asystole and
230 (31%) with PEA. One hundred and fourteen
(16%) patients progressed to a shockable rhythm,
while 622 (85%) remained in a non-shockable
rhythm during the entire resuscitation effort (two
unknown). There were no significant demographic differences between the shockable and
non-shockable group. Hands-off ratio was higher
in the shockable than the non-shockable group,
0.20±0.12 vs. 0.16±0.10 (p<0.001) with no sig-
nificant difference in compression and ventilation rates (118±9 vs. 116±10 and 11±4 vs. 11±4,
respectively. Seven patients (6.1%) survived to
hospital discharge in the shockable group and 15
(2.4%) in the non-shockable group (p=0.064).
Conclusion: Patients presenting with non-shockable rhythms who progress to a shockable rhythm
do not have inferior outcome compared to the patients who remain in non-shockable rhythms during the resuscitation effort. This occurred despite
more pauses in chest compressions in the shockable group, probably related to defibrillation attempts.
P59 Effect Of Implementation
Of The 2005 Resuscitation
Guidelines On Quality Of
Cardiopulmonary Resuscitation
(CPR) And Survival
Theresa M Olasveengen1; Eystein Vik2;
Petter Andreas Steen3; Lars Wik4 Kjetil
Sunde5. 1 Institute for Experimental
Med Rsch and Dept of Anaesthesiology, Ulleval Univ Hosp, Oslo, Norway,
2
Faculty of Medicine, Univ of Oslo,
Oslo, Norway, 3 Univ of Oslo, Faculty
Div UUH, and Div of PreHosp Medicine
and Institute for Experimental Med
Rsch, Ulleval Univ Hosp, Oslo, Norway, 4 The National Competence Cntr
for Emergency Medicine and Institute
for Experimental Med Rsch, Ulleval
Univ Hosp, Oslo, Norway, 5 Institute
for Experimental Med Rsch and Dept
of Anaesthesiology, Ulleval Univ Hosp,
Oslo, Norway
Background: ACLS providers have been shown
to deliver inadequate CPR with long intervals
without chest compressions. Several changes made
to the 2005 CPR Guidelines were intended to reduce these intervals. We have evaluated if quality
of CPR performed by the Oslo Emergency Medical
System (EMS) improved after implementation of
the 2005 CPR guidelines, and if any such improvement would result in increased survival.
Materials and methods: Retrospective, observational study of all consecutive adult cardiac arrest
patients treated during a two year period before
(May 2003–April 2005) and after (January 2006–
December 2007) implementation of the 2005
CPR guidelines. CPR quality was assessed from
continuous electronic recordings from LIFEPACK
12 defibrillators where ventilations and chest com-
99
100
pressions were identified from typical transthoracic impedance changes. Ambulance run sheets,
Utstein forms and hospital records were evaluated in order to assess outcome. Values are given
as median (95% confidence intervals) or mean ±
standard deviation and differences analysed using
unpaired Student’s t-test or Chi square as appropriate.
Results: Resuscitation was attempted in 435 patients before and 481 patients after implementation of the 2005 Guidelines. ECGs usable for CPR
quality evaluation were obtained in 64% and 76%
of the cases, respectively. Pre-shock pauses decreased from median 17 (15, 20) to 5 seconds (4,
10) (p<0.001), overall hands-off ratios decreased
from 0.23±0.13 to 0.14±0.09 (p<0.001), compression rates from 120±9 to 115±10 (p<0.001) and
ventilation rates from 12±4 to 10±4 (p<0.001),
from the first to the last period, respectively. Overall survival to hospital discharge was 10.3% and
13.1% (p=0.235).
Conclusion: Quality of CPR improved after implementation of the 2005 Guidelines with a trend
towards improved survival to hospital discharge.
P104 Socio-Emotional Stressors
Increase Ventilation Rate During
Advanced Cardial Life Support
in a Manikin Model
Kjell I Øvergård1; Cato A Bjørkli1;
Conrad Bjørshol2; Helge Myklebust3
Thomas Hoff4. 1 Univ of Oslo, Oslo,
Norway, 2 Stavanger Univ Hosp, Stavanger, Norway, 3 Laerdal Med Corp,
Stavanger, Norway, 4 Univ of Oslo,
Oslo, Norway
Background: Studies suggest that trained medical
personnel deliver manual ventilations at excessive
rates while performing advanced cardiac life support (ACLS). Excessive ventilation rates may contribute to increased mortality among these patients.
We seek to uncover the root causes of hyperventilation during ACLS.
Hypothesis: We hypothesized that the presence
of socio-emotional stressors would increase the
ventilation rate during simulated cardiac arrest in a
manikin model.
Method: A within-subject study involved two
conditions presented in randomized order. Ten students at the University of Oslo participated in the
study. In one condition all participants ventilated
a standard intubated manikin while being alone in
the room. Another condition involved in addition
the presence of six more people and a telephone
conversation with a simulated 911 dispatcher. All
participants were instructed to ventilate the manikin ten times per minute in both conditions. Ventilation rate was measured by the interval between
the initiation of each ventilation event (Inter-Response-Interval; IRI).
Results: The participants had a higher ventilation
rate during exposure to socio-emotional stressors (Mean IRI = 5.55, SD =2.57) than during the
alone condition (Mean IRI = 7.28, SD = 2.51; t(9)
= –3.205, 95% CI –2.95, –.51; Cohen’s d = 1.04;
p = .011). Five participants ventilated much faster
than the recommended rate of 10 bpm during the
socio-emotional scenario (range 11.5–22 bpm for
these four people). Only two persons ventilated
faster than the recommended rate of 10 bpm in the
alone condition.
Conclusions: Socio-emotional pressure increases
ventilation rate during advanced cardiac life support in a manikin model. This may have consequences for the organization and training of ACLS
providers.
576 The Prognostic Value of the
Long Pentraxin 3 as Compared
to B-Type Natriuretic Peptide
and High-Sensitive C-Reactive
Protein, and their Combination,
as a Prognostic Marker of
Mortality in Acute Chest Pain
Patients
Trygve Brügger-Andersen1; Volker Pönitz1; Frederic Kontny2; Harry
Staines3; Heidi Grundt4; Kyoko Miyamoto5; Chihiro Miyazawa5; Tadashi
Matsuura5; Mina Sagara5 Dennis W.T.
Nilsen6. 1 UiB, Stavanger Univ Hosp,
Stavanger, Norway, 2 Dept of Cardiology, Volvat Med Cntr, Oslo, Norway,
Sigma Statistical Services, Balmullo,
United Kingdom, 4 UiB, Stavanger Univ
Hosp, Stavanger, Norway, 5 Perseus
Proteomics Inc., Tokyo, Japan, 6 UiB,
Stavanger Univ Hosp, Stavanger, Norway
Elevated plasma levels of long pentraxin 3
(PTX3), high-sensitive C-reactive protein (hsCRP)
and B-type natriuretic peptide (BNP) are found in
acute coronary syndromes (ACS). The aim of this
study was to assess the prognostic value of PTX3
as compared to BNP and hsCRP, and their combi-
nation, as a prognostic marker of mortality in acute
chest pain patients. PTX3 was measured in EDTA
plasma with a new, high-sensitive ELISA method
(PPMX, Tokyo, Japan). BNP was analysed in
EDTA plasma using the Microparticle Enzyme Immunoassay (MEIA) Abbott AxSYM®. HsCRP was
measured with the use of an immunoturbidimetric
assay (Tinaquant® C-reactive protein (latex) high
sensitive assay, Roche Diagnostics). The blood
samples were taken on admission in 795 patients.
The patients were followed for 24 months concerning mortality. For statistical analysis, the study cohort was divided into quartiles (Q1–4) according to
PTX3 levels. A multiple logistic regression was fitted which included standard risk measures. At 24
months follow-up, 121 of the 784 patients included
in the model had died. The odds ratio for comparing Q4 versus Q1 for PTX3, BNP and hsCRP
were 4.34, 3.35 and 0.52 (p=0.001, p=0.024 and
p=0.096), respectively, and the combination of
PTX3 and BNP showed an incremental prognostic
value (figure). PTX3 is a new independent marker
that strongly predicts long-term all-cause mortality
in patients with acute chest pain and the combination of this marker with BNP adds substantially to
the prognostic value as compared to either marker
alone.
cludes C-reactive protein (CRP). Unlike CRP,
PTX3 is produced by the major cell types involved
in atherosclerotic lesions in response to inflammatory stimuli. Increased PTX3 levels are found
in acute coronary syndromes (ACS). Its role in
long-term prediction of clinical outcome is, however, unknown. The aim of the current study was
to assess the predictive value of PTX3 concerning all-cause mortality in patients hospitalized
for acute chest pain. Plasma PTX3 was measured
with a new, high-sensitive ELISA method (PPMX,
Tokyo, Japan) in blood samples taken on admission in 784 patients admitted for acute chest pain
suggestive of ACS. The patients were followed for
24 months concerning clinical outcome. For statistical analysis, the study cohort was divided into
quartiles according to PTX3 levels. A multiple logistic regression model was fitted to include standard risk measures. At 24 months follow-up 121
patients had died. By logistic regression, the odds
Odds Ratio for death among patients with highest
PTX3 levels was 3.13 as compared to those with
lowest levels (p=0.007) (table). Long Pentraxin 3
is a new, independent marker that strongly predicts
long-term all-cause mortality in patients with acute
chest pain.
577
Long Pentraxin 3: A New,
Independent Marker of
Mortality in Acute Chest Pain
Frederic Kontny1; Trygve Brügger-Andersen2; Harry Staines3; Heidi Grundt4;
Kyoko Miyamoto5; Chihiro Miyazawa5;
Tadashi Matsuura5; Mina Sagara5 Dennis W Nilsen6. 1 Volvat Med Cntr, Oslo,
Norway, 2 Volker Pönitz Stavanger
Univ Hosp, Stavanger, Norway, 3
Sigma Statistical Services, London,
United Kingdom, 4 Stavanger Univ
Hosp, Stavanger, Norway, 5 Perseus
Proteomics Inc., Tokyo, Japan, 6 Stavanger Univ Hosp, Stavanger, Norway
Long Pentraxin 3 (PTX3) is a newly identified
member of the Pentraxin protein family that in-
101
4305 Long-term Follow-up Of
Left Ventricular Function After
Acute Myocardial Infarction
Treated With Intracoronary
Injection Of Autologous Bone
Marrow Cells. The ASTAMI
Study
Jan Otto Beitnes1; Einar Hopp1; Ketil
Lunde1; Hans-Jørgen Smith1; Svein
Solheim2; Harald Arnesen2; Kolbjørn
Forfang3; Jan E Brinchmann3 Svend
Aakhus3. 1 Rikshospitalet Univ Hosp,
Oslo, Norway, 2 Ullevål Univ Hosp,
Oslo, Norway, 3 Rikshospitalet Univ
Hosp, Oslo, Norway
102
Background: Long-term effects of cardiac autologous cell therapy are not well known. We performed a 3 year follow-up of the ASTAMI study.
Patients with acute ST-elevation anterior wall
myocardial infarctions were initially randomized to
either intracoronary injection of autologous mononuclear bone marrow cells (mBMCs) (n=50) or
control (n=50). At 6 months, LV ejection fraction
improved in both groups, with no significant difference between groups.
Methods: All eligible patients underwent MRI
with a 1,5 T scanner (Siemens) 2–3 weeks, 6
months and mean(SD) 3,2 (0,2) years after myocardial infarction and stem cell injection. Infarct
size was determined from gadolinium late-enhancement MR images. All images were analyzed
by experienced observers blinded for treatment assignment. Left ventricular volumes were calculated by the area-length method.
Results: There was no significant difference in
EDV, ESV or LVEF between baseline and 3 years
in neither group. Infarction volume was reduced at
3 years in both groups (p<0,001). No significant
effects of mBMC treatment could be identified on
LV volumes, LVEF or infarct size. Thus intracoronary injection of mBMCs in acute myocardial infarction does not improve global LV function over a
3 year follow-up. Left ventricular function after
mBMC-treatment
5307 Cardiomyocyte Sodium
Accumulation Promotes
Diastolic Dysfunction in Serca2
Knockout Mice
William Louch1; Karina Hougen1; Magnus Aronsen1; Halvor K Mork1; Ivar
Sjaastad2; Kristin B Andersson2; Geir
Christensen3 Ole M Sejersted3. 1 Univ
of Oslo, Oslo, Norway, 2 Ullevaal Univ
Hosp, Oslo, Norway, 3 Univ of Oslo
and Ullevaal Univ Hosp, Oslo, Norway
Terminal decompensation during heart failure
involves deterioration of diastolic function. We
investigated the mechanisms underlying this functional decline in mice with cardiomyocyte-specific, conditional excision of the Serca2 gene (KO).
At 4 weeks following gene deletion, SERCA lev-
els in KO cardiomyocytes were reduced by more
than 95% from flox-flox (FF) controls. Surprisingly, echocardiographic measurements indicated
only moderate impairment of in vivo function, as
systolic and diastolic tissue velocities were 62%
and 72% of FF values, respectively. Diastolic heart
failure developed in KO between 6 and 7 weeks,
as diastolic tissue velocity rapidly declined to 51%
of FF values. We compared cardiomyocyte contractions and Ca2+ cycling at the 4 and 7 week time
points. In KO cells, contractions were reduced between 4 and 7 weeks (from 40% to 14% of FF values), and the rate of relaxation was slowed (from
11% to 3% of FF values). Similar alterations were
observed in Ca2+ transients. Sarcoplasmic reticulum (SR) Ca2+ content was markedly reduced in
4-week KO, although a minute thapsigargin-sensitive SR Ca2+ release could be induced. SR content
was further decreased in 7-week KO and SR Ca2+
release was not detectable, although Western blots
showed no difference in SERCA levels between 4
and 7 week KO. Ca2+ influx via Ca2+ channels was
enhanced in KO (integrated current ~200% of FF)
at both time points. However, greater NCX-mediated Ca2+ extrusion in 4-week KO was partially
reversed in 7-week KO due to elevation in cytosolic [Na+] (34 mM vs 25 mM in FF). Normalizing cytosolic [Na+] using patch clamp increased
the rate of decline of the Ca2+ transient in 7-week
KO to 4-week KO values. Thus, KO mice
compensate for loss of SR function by
increasing trans-sarcolemmal Ca2+ flux.
However, in the longer term, cytosolic Na+
accumulation impairs NCX-mediated Ca2+
extrusion, which promotes development of
diastolic heart failure.
5324 Endurance Training
Abolish Arrhythmogenic
Calcium Leak In
Cardiomyocytes From Mice
With Transgenic Overexpression Of CamkiidC
Morten A Hoydal1; Tomas O Stolen1;
Joan H Brown2; Lars S Maier3; Godfrey L Smith4 Ulrik Wisloff5. 1 Faculty
of Medicine, NTNU, Trondheim, Norway, 2 Univ of California, San Diego,
San Diego, CA, 3 Heart Cntr Goettingen, Goettingen, Norway, 4 Univ of
Glasgow, Glasgow, United Kingdom, 5
Faculty of Medicine, NTNU, Trondheim,
Norway
Background The cytosolic calcium/calmodulindependent protein kinase IId (CaMKIIdC) phosphorylates several central proteins related to Ca2+
handling. Transgenic (TG) over-expression of
CaMKIIdC causes depressed cardiac function,
altered Ca2+ handling and increased diastolic sarcoplamic reticulum (SR) Ca2+ leak. The later may
be a central trigger for delayed after depolarisation
and ventricular arrhythmias in heart failure. Endurance training increases also the activity of CaMKIIdC in healthy mice, but in contrast to individuals
with heart disease, this improves cardiac performance. We hypothesised that endurance training improves Ca2+ handling and reduces diastolic SR Ca2+
leak in TG mice with over-expression of CaMKIIdC and heart failure.
Methods We compared TG mice exhibiting a
3-fold increase in CaMKIIdC activity (n=8), with
wild type (WT) controls (n=8). Four CaMKIIdC
TG mice underwent high intensity endurance training 5 days per week over 12 weeks. Ca2+ handling
and diastolic SR Ca2+ leak were measured in Fura2AM loaded cardiomyocytes.
Results CaMKIIdC TG mice had decreased cardiomyocyte shortening (3.3±1.8% in TG vs.
6.2±1.2% in WT, P<0.01). Ca2+ transient amplitude
were lower (Fura-2AM ratio in TG was 0.09±0.03
vs. 0.18±0.02 in WT, P<0.01) and time to 50%
twitch Ca2+ release was slower (25±2ms in TG vs.
15±1ms in WT, P<0.05). SR Ca2+ leak over the
RyR was significantly larger in TG mice (19±3%
of total SR Ca2+ vs. 5±2% in WT, P<0.01). Endurance training restored cardiomyocyte shortening
(5.9±1.3% in TG trained) to levels of WT control.
Ca2+ amplitude was also significantly increased
(Fura-2AM ratio 0.15±0.02 in TG trained). Endurance training reduced diastolic SR Ca2+ leak to levels of WT control (4±2%, P<0.01). After inhibition
of CaMKIIdC, by autocamtide-2-related inhibitory
peptide, the increased SR Ca2+ leak in sedentary
TG was abolished, while trained TG and WT control mice remained unaffected. The protein kinase
inhibitor A, H89, did not affect SR Ca2+ leak in any
groups.
Conclusion Endurance training improved cardiomyocyte function and Ca2+ handling in mice
with TG over-expression of CaMKIIdC. Increased
diastolic SR Ca2+ leak, that may trigger ventricular arrhythmias, was completely abolished after
endurance training.
4732 Determinants of Left
Ventricular Early Diastolic
Lengthening Velocities
103
Espen W Remme1; Anders Opdahl2
Otto A Smiseth3. 1 Rikshospitalet Univ
Hosp, Oslo, Norway, 2 Rikshospitalet
Univ Hosp and Univ of Oslo, Oslo,
Norway, 3 Rikshospitalet Univ Hosp,
Oslo, Norway
The proposed determinants of the LV wall early
diastolic lengthening velocity (E’) are: relaxation
rate of active fiber stress (tau), LV pressure during
early filling, restoring forces, and passive elastic
wall stiffness. In experimental and clinical studies
the individual determinants are difficult to alter
and investigate separately due to their inter-dependency. The purpose of this study was to develop a mathematical model that provided a physical
basis for the determinants and to validate their individual effect on E’. The LV wall was represented
by a lumped parameter model consisting of two
elements in parallel (Fig. a): one representing the
active fiber stress (Sa) and the other the passive
elastic stress (Sp) represented by an elastic spring
with stiffness K and resting length L0. The sum of
active and passive wall stresses was set to equal
LV pressure (LVP). Active stress was prescribed
to decay exponentially. E’ was assessed during a
simulation with baseline model parameter values
and a higher value of each parameter in turn. At
baseline E’ was 6.2 cm/s. E’ was decreased to 4.1
cm/s and delayed by prolonging relaxation from
tau = 40 to 60 ms (Fig. b). Increasing LVP during
early filling by 5 mmHg increased E’ to 10.6 cm/s
(Fig. c). Decreasing restoring forces by increasing
end systolic length from 57 to 60 mm decreased
E’ to 2.6 cm/s (Fig. d). Increasing passive stiffness
from K=1500 to 3000 mmHg/m decreased E’ to
5.1 cm/s (Fig. e). The mathematical model validated former experimental results and confirmed
that E’ increases with shortening of tau, increase of
diastolic LVP, decreased end systolic length, and
decreased passive stiffness.
2822 A Novel Method for
Assessing Left Ventricular
Dyssynchrony
Kristoffer Russell1; Anders Opdahl1;
Espen W Remme1; Ola Gjesdal1; Helge
Skulstad1; Erik Kongsgård2; Thor Edvardsen3 Otto A Smiseth3. 1 Institut for
surgial Rsch, Oslo, Norway, 2 Riks
hospitalet Univ Hosp, Oslo, Norway, 3
Institut for surgial Rsch, Oslo, Norway
Background: The search for better echocardiographic markers of dyssynchrony has been hampered by the lack of a precise reference method
104
for timing LV electromechanical activation. In the
present study we propose a new method for defining onset of regional mechanical activation (OMA)
and validate its ability to reflect onset of electrical
activation as defined by regional intramyocardial
ECG (IM-ECG).
Methods: In 12 anesthetized dogs with LV micromanometers we measured segment length in each
LV wall by sonomicrometry and speckle tracking echocardiography (STE) (n=10) and electrical activation as onset of R in regional IM-ECG.
OMA was defined as the time when the myocardial
pressure-segment length coordinate deviated from
its passive-elastic curve (Fig 1). Timing was calculated relative to onset of R in ECG at baseline,
caval constriction (n=7), during LBBB (n=5) and
during LAD-occlusion (n=8).
Results: During all interventions we observed a
small and essentially constant delay of OMA by
sonomicrometry relative to electrical activation
(14±8 (mean±SD).There was a close correlation
between timing of electrical activation and OMA;
R=0.88 and R=77, for sonomicrometry and STE,
respectively, while correlation was moderate between electrical activation and time to peak S.
Main results are displayed in Figures 2 and 3.
Conclusions: Timing of regional LV mechanical
activation by OMA showed close correlation with
regional electrical activation over a wide range of
hemodynamic conditions and during LBBB. These
findings indicate that assessment of LV dyssynchrony by this combined invasive and non-invasive approach may be superior to conventional
echocardiographic methods.
P75 Dissemination of CPR
Skills to the Public - Can
Schoolchildren Ensure Success?
Tonje Lorem1; Aud Palm2 Lars Wik3.
1
The National Competence Cntr for
Emergency Medicine, Oslo, Norway, 2
The Norwegian Air Ambulance Foundation, Drøbak, Norway, 3 The National Competence Cntr for Emergency
Medicine, Oslo, Norway
Training a large fraction of the general population in CPR could have major public health benefit
if those most likely to witness cardiac arrest are
trained. Mass distribution of self-training manikins as a two-tiered strategy with school children
as first tier has been described as successful, but
without information on second tier age or information strategy to second tier. We studied three differ-
ent attempts at reaching older second tier persons.
In groups 1 and 2 first tier consisted of 7th graders
and in group 3 high school and medical school
students. Information about the desirable second
tier age group was given in writing prior to the distribution. In groups 1 and 3 information was only
directed towards first tier. In group 2 both first tier,
their parents and teachers were informed. The first
tier participants reported the number of second tier
trained for age-groups 12–25 years, 25–50 years,
and >50 years. Approximately 64000 (group 1),
63000 (group 2) and 81 (group 3) self-education
kits were provided with 2.7, 1.9, and 3.7 lay-rescuers trained per kit respectively (p<0.05) (Table
1). Informing also the parents of the first tier prior
to the distribution did not positively impact the
number of second tier trained lay-rescuers, but
higher age of first tier did. We speculate that 7th
graders are too young to successfully disseminate
CPR to those most likely to witness out of hospital
cardiac arrest.
Table 1. Percentage reported trained in first
and second tier divided into age-groups.
3506 Calcium Leak and
Contractility in Diabetic
Cardiomyocytes are
Normalized after Exercise
Training
Tomas Stølen1; Morten A Høydal1; Arnt
Erik Tjønna1; Ulrik Wisløff1; Godfrey L
Smith2; Ole Johan Kemi3; Terje Larsen4;
Daniele Catalucci5; Marcello Ceci6 Gianluigi Condorelli7. 1 NTNU, Trondheim, Norway, 2 Univeristy of Glasgow,
Glasgow, United Kingdom, 3 Univ of
Glasgow, Glagow, United Kingdom, 4
Univeristy of Tromsø, Tromsø, Norway,
5
I.R.C.C.S Multimedica, Milan, Italy, 6
European Brain Rsch Institute, Rome,
Italy, 7 I.R.C.C.S Multimedica, Milan,
Italy
Introduction: Patients with type 2 diabetes has
increased risk for lethal arrhythmias and sudden
cardiac death. Recently, diastolic SR Ca2+ leak has
been linked to delayed afterdepolarisation and arrhythmias. This increased SR Ca2+ leak is demon-
strated in db/db mice along side with increased risk
of arrhythmia during ischemia-reperfusion.
Method: Cardiomyocytes from high intensity
aerobic interval trained (AIT) db/db mice, sedentary db/db mice and to wild type mice (WT) were
isolated for measuring Ca2+ handling and fractional
shortening (FS), by epifluorecense, and confocal
microscopy.
Results: VO2max in AIT db/db increased more than
13% above the level of db/db sedentary and WT.
The hypertrophied myocytes in the db/db decreased by 27% (P<0.01) after AIT and were similar to WT. FS in db/db increased after AIT (from
3.5±1.6% to 7.8±1.4%, P<0.02) and were similar
to WT. AIT improved diastolic function (time to
relengthening) (P<0.01) alongside with increased
Ca2+ decay (P<0.01) and were similar to WT.
Normalised SR Ca2+ leak decreased from 13±3%
to 3±4% after AIT (P<0.01) and were similar to
WT. Ca2+ wave frequency were reduced by 74%
(P<0.05) after AIT. NCX function was increased
in db/db sedentary (P<0.05), while AIT reduced
NCX function to WT levels. SR Ca2+ leak were
normalized in the db/db sedentary when inhibiting CaMKII (P<0.01), but not after PKA inhibition. This was also confirmed by Western Blots,
showing increased phosphorylated CaMKII in db/
db sedentary (P<0.05) and reduced phosphorylated
CaMKII to WT levels after AIT. Both Ca2+ release
synchrony and to T-tubule density, which is closely
related, were reduced in sedentary db/db (P<0.05
and P<0.01, respectively) and restored to WT levels after AIT.
Conclusion: PKA phosphorylation after AIT appears as an important mechanism behind improvements in intracellular Ca2+ cycling and SR Ca2+
loading in the db/db mice, whereas CaMKII appears more important than PKA for the control
of RyR2 sensitivity and SR Ca2+ leak. This taken
together with restored T-tubule density and Ca2+ release synchrony, AIT restored FS in db/db mice.
P123 Vasopressin, but not
Norepinephrine, causes
Ventriculoarterial Mismatch
in Experimental Post Ischemic
Cardiogenic Shock
Ole-Jakob How; Assami Røsner; Petter Gjessing; Stig E Hermansen Truls
Myrmel. Univ Hosp North Norway,
Tromso, Norway
Introduction In agreement with existing guidelines, inotropic and vasopressor support is given
105
routinely in cardiogenic shock (CS). However,
there is a lack of scientific evidence supporting the
efficacy and safety of such treatment.
Hypothesis Vasoconstrictors given in cardiogenic
shock will increase the ventriculoarterial mismatch
and thus lead to reduced cardiac output
Methods In a closed chest pig model we tested
the inodilator (dobutamine, Dobut) alone and
combined with either an inoconstrictor (norepinephrine, NE) or a pure vasopressor (arginine
vasopressin, AVP). In anesthetized animals, CS
was induced by coronary microembolization under
fluoroscopic guidance. Hemodynamic indices
were obtained by Swan-Ganz catheters, left ventricular pressure-volume catheters and echocardiography, and the ventriculoarterial coupling calculated.
Results In the normal heart, Dobut (2ug/kg/min)
enhanced ventriculoarterial energy transfer, shown
as a decreased Ea/Ees (ratio of arterial and ventricular elastance), 1.0 ± 0.1 to 0.8 ± 0.1, and an
increased preload recruitable stroke work (PRSW),
53 ± 5 to 63 ± 2. This was further enhanced by NE
(100 ng/kg/min) to 0.7 ± 0.1 and 79 ± 6. In contrast, adding AVP (0.001 u/kg/min) resulted in an
increased Ea/Ees (1.0 ± 0.1) and decreased PRSW
(56 ± 8) compared to Dobut alone (a two fold
increase in systemic vascular resistance (SVR),
concomitant with no elevation in contractility). In
post ischemic CS, energy transfer from the ventricle to the arterial system (Ea/Ees 1.8 ± 0.2, PRSW
26 ± 2 and Ejection fraction 42 ± 6 %) was partly
restored by Dobut (1.4 ± 0.2, 46 ± 2 and 47 ± 6%)
unaffected by further adding NE (1.5 ± 0.2, 53 ± 2
and 45 ± 5%), but impaired after adding AVP (2.0
± 0.1, 43 ± 1 and 34 ± 4%). Consequently, Dobut
improved the shock by increasing cardiac output
(CO) and SVO2 from 74 ± 3 ml/kg and 37 ± 2% to
103 ± 8 ml/kg and 49 ± 3%. Adding NE resulted in a further improvement of CO (125 ± 9 ml/
kg) and SVO2 (59 ± 4%). In contrast AVP further
worsened the shock state by decreasing CO (70 ±
6 ml/kg) and SVO2 (45 ± 5%) compared to Dobut
alone.
Conclusion A pure afterload increasing substance
in acute ischemic hearts with cardiogenic shock
aggravate the shock state by causing a ventriculoarterial mismatch.
106
5732 Regional and Global
Myocardial Function in Patients
with Hypertensive Heart
Disease: A Two-dimensional
Ultrasound Speckle Tracking
Study
Björn Goebel ; Ola Gjesdal ; Daniela Kottke3; Christiane Schmidt-Winter3; Julia Schumm3; Thor Edvardsen4;
Hans R Figulla5 Tudor C Poerner5. 1
Univ Hosp of Jena, Jena, Germany, 2
Univ Hosp of Oslo/RisksHospet, Oslo,
Norway, 3 Univ Hosp of Jena, Jena,
Germany, 4 Univ Hosp of Oslo/RisksHospet, Oslo, Norway, 5 Univ Hosp of
Jena, Jena, Germany
1
2
Aim of the study was to asses the effect of left
ventricular hypertrophy (LVH) on regional and
global myocardial function. Sixty-eight consecutive patients with arterial hypertension and normal
coronary angiograms underwent conventional
echocardiography. According to left ventricular
mass index (LVMI) the patients were divided into
three groups: none LVH, mild-moderate LVH
(LVMI: 115–149 g/m2 for men and LVMI: 95–122
g/m2 for women) and severe LVH (LVMI > 149 g/
m2 for men and LVMI: > 122 g/m2 for women).
Two-dimensional greyscale loops were obtained
from three apical (four-chamber, two-chamber
and apical long axis) and three parasternal views
(basal, mid, apical) of the LV at a frame rate of >
70 frames/s. Using a software for two-dimensional
ultrasound speckle tracking, the absolute and the
time to peak values of systolic strain (S) and strain
rate (SRS) were extracted. For the calculation of
LV twist, rotation curves were extracted from the
basal and apical short axis view. After correcting
for heart rate and spline interpolation, LV twist was
calculated as difference between apical and basal
LV rotation curves. Results are displayed in Table
1. Patients with severe left ventricular hypertrophy
had, according to the strain rate values, a reduced
systolic function of the longitudinally and radial
directed fibers. However, LVH seemed to have no
impact on the degree of LV twist. Table 1
4235 Abnormal Myocardial
Deformation Is Associated
With Mortality Independent Of
Hypertrophy In The Absence of
Ischemia
Tony Stanton1; Charlotte Bjork Ingul2;
James L Hare3; Brian Haluska3 Thomas
H Marwick3. 1 Univ of Queensland,
Brisbane, Australia, 2 Univ of Science
& Technology, Trondheim, Norway, 3
Univ of Queensland, Brisbane, Australia
Purpose : Myocardial deformation has been
shown to identify subclinical abnormalities in
apparently normal hearts. We investigated the association of these markers with mortality after
excluding ischemia in individuals undergoing dobutamine stress echocardiography (DSE).
Methods : We studied 163 consecutive patients
with normal resting LV function and no ischemia
at DSE. Mean Bethesda scores indicated a low
ten-year risk of coronary disease (men 3.2±2.1%,
women 5.3±2.6%). Relative wall thickness (RWT)
and LVMI (indexed to height2.7) were calculated
according to ASE guidelines. Customized software
was used to measure peak systolic SR in 18 segments and mean global SR was calculated. Individuals were followed for all-cause mortality for a
mean of 5.4±1.4 years.
Results : Mean RWT 0.46±0.11 (normal <0.42)
and mean LVMI was 46.8±13.0g/m 2.7 (normal
<51g/m 2.7). RWT and LVMI were assessed in the
closest approximation to 1 standard deviation (per
change of 0.1 for RWT and 10g/m2.7 for LVMI). In
a Cox Proportional Hazards Model the strongest
predictor of all-cause mortality was peak systolic SR (HR 3.72, 95%CI 1.8 –7.65, p<0.01). RWT
(HR 1.4, 95%CI 1.0 –1.96, p<0.05) was a stronger
predictor of all-cause mortality than LVMI (HR
1.2, 95%CI 0.86 –1.96, p=NS). Kaplan Meier
curves were constructed by grouping the data into
tertiles according to peak systolic SR (p<0.01
overall).
Conclusion : Peak systolic strain rate is a significant independent predictor of all-cause
mortality, superior to LVMI and RWT.
This link between myocardial deformation
and outcome in the absence of myocardial
ischemia may be consistent with an effect
of interstitial changes on mortality. FIG
4421 Concomitant
Hydrochlorothiazide Therapy
in Hypertensive Patients is
Associated with Reduced
Cardiovascular Morbidity
and Mortality Independent
of Blood Pressure and
Electrocardiographic Left
Ventricular Hypertrophy: The
LIFE Study
Peter M Okin1; Richard B Devereux1; Darcy A Hille2; Sverre
E Kjeldsen3; Lars H Lindholm4;
Lars H Lindholm4; Jonathan M
Edelman5 Björn Dahlöf6. 1 Cornell Med Cntr, New York, NY,
2
Merck Rsch Labs, West Point,
PA, 3 Univ of Oslo, Ullevål Hosp, Oslo,
Norway, 4 Umeå Univ, Umeå, Sweden,
5
Merck & Co., Inc., North Wales, PA, 6
Sahlgrenska Univ Hosp/Östra, Göteborg, Sweden
We have previously shown that addition of hydrochlorothiazide (HCTZ) therapy in >70% of LIFE
study patients was associated with greater regression of ECG left ventricular hypertrophy (LVH),
independent of blood pressure (BP) reduction and
of the greater impact of losartan therapy on regression of LVH. Whether HCTZ therapy is associated
with improved outcomes independent of BP reduction and regression of ECG left ventricular hypertrophy (LVH) has not been examined. Outcomes
were assessed in 9,193 hypertensive patients treated in a blinded fashion with losartan or atenolol
and additional open-label HCTZ as needed according to study protocol. Patients on HCTZ at year 1
were younger, more likely to be black, were less
likely to have a history of heart failure, myocardial
infarction or ischemic heart disease, had higher
baseline systolic and diastolic BP and more severe
baseline LVH by Cornell product criteria. During
4.8±0.9 years of follow-up, use of HCTZ, treated
as a time-varying covariate was associated with
34 to 67% reductions in risk of cardiovascular
mortality, myocardial infarction, stroke, the LIFE
composite endpoint of these three events and death
from any cause after adjusting for randomized
treatment assignment (Table). In Cox multivariable
analyses adjusting for the known predictive value
of in-treatment ECG LVH by Cornell product and
Sokolow-Lyon voltage, in-treatment systolic and
diastolic pressure, randomized treatment effect,
107
age, sex, race and and other baseline risk factors,
HCTZ use remained associated with between 18
and 45% reductions in risk (table). Concomitant
HCTZ therapy is associated with lower likelihoods of CV morbidity and mortality and all-cause
mortality, independent of blood pressure lowering,
ECG LVH regression and randomized treatment
modality.
Risk of Cardiovascular Morbidity and Mortality in Relation to HCTZ Use
4692 Impact of Pressure
Recovery on Diagnosis of
Severe Aortic Stenosis in
Asymptomatic Patients. (A SEAS
Substudy)
Edda Bahlmann1; Dana Cramariuc2;
Eva Gerdts2; Christa Gohlke-Baerwolf3; Chritoph Nienaber4; Karl Heinz
Kuck5 Simon Ray6. 1 Asklepios Clinic
St. Georg, Hamburg, Germany, 2 Univ
of Bergen and Haukeland Univ Hosp,
Bergen, Norway, 3 Herz-Zentrum Bad
Krozingen, Bad Krozingen, Germany,
4
Universitaetsklinikum Rostock, Rostock, Germany, 5 Asklepios Clinic St.
Georg, Hamburg, Germany, 6 Univ
Hosps Manchester, Manchester, United
Kingdom
Background: Downstream pressure recovery (PR)
in the aorta affects transvalvular pressure gradient measurement and calculation of aortic valve
area by continuity equation in patients with aortic
stenosis (AS).
Methods: To assess the clinical importance of PR
on evaluation of severity of AS, echocardiographic
data in 1562 patients with asymptomatic aortic stenosis (mean age 67 ± 10, 39% women, 51% hypertensive) recruited in the Simvastatin Ezitimibe in
Aortic Stenosis (SEAS) study was used. The inner
diameter of the ascending aorta was measured at
annulus and at sinutubular junction. The aortic
valve area (AVAI) was calculated from annular
diameter and velocity time integrals from sub- and
transaortic flow by Doppler. PR and PR corrected
108
AVAI assessed as energy loss index (ELI) were calculated by previously published equations. Severe
aortic stenosis was defined as AVAI <0.60cm2/m2
and ELI <0.55cm 2/m2, respectively. Patients were
grouped into tertiles of peak transaortic Doppler
velocity (<2.79, 2.79 –3.32, >3.33 m/sec, respectively).
Results: In the total study population, PR ranged
from 1.22–16.75 mmHg (mean 5.9±2.3), AVAI
from 0.20 –1.85 cm2/m2 (mean 0.67±0.22) and
ELI from 0.22–5.94 cm2/m2 (mean 0.89±0.45). PR
increased significantly with severity of AS (Table
1). Both AVAI and ELI decreased with increasing
peak transaortic velocity, and the overestimation of
AS severity by using unadjusted AVA was largest
in the lowest tertile (Table 1).
Conclusion: Severity of AS is often overestimated
in milder degrees of asymptomatic AS if correction
for pressure recovery is not performed. Adjustment of AVA for the effect of energy loss should
be performed routinely, and this may be especially
important for accuracy of severity assessment in
patients with relatively low transvalvular velocities.
Table 1
4730 Restoring Forces
and Lengthening Load are
Independent and Important
Determinants of Peak EarlyDiastolic Mitral Annulus Velocity
Anders Opdahl; Espen W Remme; Thomas Helle-Valle; Erik Lyseggen; Trond
Vartdal; Eirik Pettersen; Thor Edvardsen Otto A Smiseth, Rikshospitalet
Univ Hosp & Univ of Oslo, Oslo, Norway
Background: Mechanisms of early-diastolic mitral annulus velocity (E’) are poorly understood.
We investigated if restoring forces, generated by
contraction below unstressed length, and lengthening load, the expanding effect of LV pressure
during early filling, may be determinants of E’ in
addition to LV relaxation (tau).
Methods: In 15 anesthetized dogs we evaluated
LV transmural pressure-diameter loops to define
unstressed LV long-axis diameter (L0). As a reflection of restoring forces we used the difference
between minimum LV long-axis diameter and L0
(Lmin–L0). As a measure of LV lengthening load we
used LV pressure at the time of mitral valve opening (LVPMVO). E’ was measured by sonomicrometry and tissue Doppler imaging (TDI) at baseline,
during volume loading, dobutamine infusion (n=9),
and after 15 minutes and 3 hours (n=8) of LADocclusion.
Results: Changes in E’ during dobutamine and
ischemia correlated inversely with changes in tau
(R=–0.58), confirming a relationship between E’
and relaxation. Furthermore, E’ showed an even
stronger correlation with Lmin–L0 (R=–0.79, Fig 1),
suggesting a close relationship between E’ and restoring forces. During increased LVPMVO, however,
there was a marked increase in E’ which could not
be attributed to changes in tau or in Lmin–L0, but E’
correlated well with LVPMVO (R =0.78, Fig 2).
Conclusion: The present study indicates that
in the non-failing ventricle restoring forces and
lengthening load are important determinants of E’.
Furthermore, the apparent preload-dependency of
E’ is explained by the effect of lengthening load.
717 Spatial And Temporal
Nonuniformity Of The Normal
Left Ventricle During Isovolumic
Contraction And Ejection By 2D
Speckle Tracking Imaging
Anders Hodt; Marie Stugaard; Jonny
Hisdal; Einar Stranden; Dan Atar Kjetil
Steine. Aker Univ Hosp HF, Oslo, Norway
Background: The main purpose of this study was
by novel 2D speckle tracking imaging (STI) to
determine regional distribution of circumferential
shortening, rotation and torsion (twist) and their
relation to area ejection fraction (EF) during isovolumic contraction (IVC) and ejection phases in the
normal left ventricle (LV).
Methods: Twelve healthy subjects (22 ±3 years)
were included. M-mode of atrio-ventricular level
was used to describe LV longitudinal shortening,
while circumferential strain, rotation and area EF
were determined at four different LV short axis
levels (basal, papillary, sub-papillary, apical) by
STI. LV torsion was calculated as apical minus
basal rotation.
Results: See figure. During IVC, LV torsion demonstrated an “untwist pattern”, and LV shortened
more in longitudinal than in circumferential direction. During ejection, the counter clockwise rotation increased from papillary level towards apex,
–0.4 ± 3.3° and 9.6 ± 3.4° (p<0.05), respectively,
while circumferential shortening was larger in
apex than papillary level, –25.4 ± 5.0 and –19.3
± 2.4% (p<0.05), respectively. EF increased from
papillary level to apex, 52 ± 6.1 % and 65 ± 8.4 %
(p<0.05), respectively.
Conclusion: This study has showed a regional
nonuniform pattern of rotation and circumferential
shortening, with corresponding changes in regional
EF in normal LV through systole. The increased
counter clockwise rotation and circumferential
shortening towards apex during ejection may be of
mechanistic importance for distribution of blood
towards LV outflow tract. The greater extent of
longitudinal- than circumferential shortening and
untwisting suggest a LV spherical form during
IVC.
109
of TSG and was tightly coupled to septal electrical activation. These findings indicate that regional
contraction plays an active role in SF.
823 Mechanisms of Septal
Flash in Left Bundle Branch
Block
Ola Gjesdal; Espen Remme; Anders
Opdahl; Helge Skulstad; Kristoffer
Russell; Erik Kongsgård; Otto Smiseth
Thor Edvardsen. Rikshospitalet Univ
Hosp, Oslo, Norway
Objective: Septal beaking or flash (SF) is seen in
LBBB as abrupt leftward preejection displacement
of septum, and has been suggested as predictor of
successful CRT-treatment. Similar septal motion
has been observed during RV pacing and has been
attributed to end-diastolic reversal of the LV-to-RV
transseptal pressure gradient (TSG). This study explores mechanisms of SF during LBBB.
Methods: In 6 anesthetized dogs with LV and
RV micromanometers we measured myocardial
segment-lengths by sonomicrometry and M-mode
echocardiography, and intra-myocardial bipolar
ECG. LBBB was induced by RF-ablation and load
changes were performed by caval (CC) and aortic
constriction (AC). SF was defined as shown in
Figure and quantified as percent shortening of enddiastolic septal-to-lateral diameter (ED).
Results: QRS duration increased from 72 ± 2 to
122 ± 2 ms (± SEM p <0.01) after induction of
LBBB. SF was minor at baseline, but became distinct during LBBB (Table), and remained relatively constant during interventions despite marked
changes in TSG. This was confirmed by M-mode.
SF occurred after septal electrical activation, with
a relatively constant time delay (t-SF).
Conclusions: Septal flash was present in LBBB,
remained relatively constant during a wide range
Key data
P156 Health Care Professionals
in Emergency Services and
Hospitals Hesitate to Do CPR
Because of Fear of Harming The
Patient
Ewa Rosengren1; Marja Mäkinen2;
Sari Ponzer3; Jouni Kurola4; Christer Axelsson5; Lisa Kurland6; Solveig
Aune7; Leila Niemi-Murola8; Marja
Sopanen9; Erika Christensen10; silje
odegaard11 Maaret Castrén12. 1 Dep of
clinical science and education, KI SÖS,
Stockholm, Sweden, 2 Dep of Anaesthesiology and Intensive Care Medicine, Helsinki Univ, Helsinki, Finland, 3
Dep of clinical science and education,
KI SÖS, Stockholm, Sweden, 4 Dep of
Anesthesiology, Kuopio Univ, Kuopio,
Finland, 5 Gothenburg EMS, Göteborg,
Sweden, 6 Dep of Med Science, Uppsala Univ Hosp, Uppsala, Sweden, 7 Div
110
of cardiology, Sahlgrenska Univ Hosp,
Göteborg, Sweden, 8 Dep of Anaesthesiology and Intensive Care Medicine, Helsinki, Univ, Helsinki, Finland,
9
Vantaa Rescue Dept, Vantaa, Finland, 10 Unit for Med Education, Faculty of Health Sciences, Univ of Aarhus,
Aarhus, Denmark, 11 Faculty Div Ulleval Univ Hosp, Oslo, Norway, 12 Dep
of clinical science and education, KI
SÖS, Stockholm, Sweden
Introduction: Preliminary studies showed that 41,4
% of nurses in a Finnish hospital hesitate to perform defibrillation because of fear of injuring the
patient and 22,9% because the patient might die
and the nurse would feel guilty. Of 80 paramedics
in Oslo 39 % stated that deep compressions could
result in serious patient injury. These attitudes can
result in bad quality CPR starting with a delay.
Hypothesis: We assessed the hypothesis that it is
common among health care professionals to feel
that CPR might harm the patient, to hesitate to do
compressions and to hesitate to defibrillate.
Methods: Valid questionnaires were send to nurses
working in Kuopio University hospital in Finland,
Uppsala Akademiska sjukhuset, Sahlgrenska hospital, Göteborg and Södersjukhuset, Stockholm
in Sweden and to paramedics working in Vantaa
and Kuopio in Finland, Århus in Denmark and
Gothenburg in Sweden. All together 811 nurses
and 216 paramedics answered the questions about
background data and attitudes towards resuscitation, defibrillation and guidelines.
Results: Of paramedics 60% felt that deep compressions could injure the patient and 32% felt the
harm caused is bigger than the benefit of compressions. When arriving to the patient 21.5% prioritize
intubation and infusion over everything else. Of
the nurses 16% hesitate to start CPR because of
anxiety, 26% did not feel competent to defibrillate and 21% hesitate to defibrillate because they
fear to harm the patient. Still 54.2% had had CPR
training at their hospital during the last six months.
Nurses that hesitate to start resuscitation felt significantly more often that only doctors should defibrillate. This will delaye defibrillation and lives
will be lost.
Conclusion: Major changes has to be done in training programs for CPR to ensure better confidence
in performing the different tasks involved in resuscitation. Today too many health care professionals
feel that CPR might do more harm than good.
P171 Analysis of Corrected
Absolute and Relative Chest
Compression Depth during Real
In-hospital Pediatric CPR Using
Novel Forensic Engineering
Reconstruction Techniques
Dana E Niles1; Jon Nysaether2; Akira
Nishisaki3; Robert M Sutton3; Kristy
Arbogast3; Matthew R Maltese3; Benjamin S Abella4; Robert Berg5; Mark
Helfaer5 Vinay Nadkarni5. 1 Children’s
Hosp of Philadelphia, Philadelphia,
PA, 2 Laerdal Med, Stavanger, Norway, 3 Children’s Hosp of Philadelphia,
Philadelphia, PA, 4 Hosp of Univ of
Pennsylvania, Philadelphia, PA, 5 Children’s Hosp of Philadelphia, Philadelphia, PA
Introduction: AHA recommends an absolute
Chest Compression (CC) depth of 38–51mm for
adults and a relative 1/3 to 1/2Anterior-Posterior
chest Depth (APD) in children <8 years old. We
evaluated these compression parameters during
real in-hospital CPR using an FDA approved CC
sensor and novel forensic engineering reconstruction. We hypothesized that depth of CC during inhospital pediatric CPR in children >8 years would
be within the pediatric guideline target of 1/3 to
1/2AP chest depth.
Methods: With IRB approval, CC depth and force
were recorded with CC sensor during real CPR
for consecutive children >8 years in cardiac arrest. At the end of each resuscitation, patient APD
was measured. Forensic engineering reconstruction was conducted using the same bed, a weighted
manikin torso and reconstructed backboard/mattress/patient configuration. CC depth was adjusted
for mattress compression and incomplete release.
Absolute CC depth and relative CC depth in
%APD were assessed. Standard descriptive summaries (mean±SD) of compression depth were
calculated and compared with AHA 2005 pediatric
CPR guidelines for the first consecutive recorded CCs of each event, to a maximum of 500 CC/
event. Descriptive statistics, inferential statistics by
one-sample t-test were used, as appropriate.
Results: 8181 CCs from 18 CPR events (16 patients, age 15±4yrs) were recorded, reconstructed
and analyzed. Mean CC force was 32.0±7.8 kg.
Mean APD was 185±36 mm. Mean corrected absolute CC depth was 40±11 mm and mean relative
%APD was 22.7±7.2%, significantly lower than
111
33% (p<0.0001). The 10th and 90th percentiles of
relative CC depth were 13.8% and 31.0%APD,
respectively. For all CCs: 34% (2759/8181)
were 10–20%APD, 58% (4758/8181) CCs were
>20–33%APD, and only 6% (529/8181) CCs were
>33–50%APD.
Conclusions: Depth of CC delivered to in-hospital
pediatric cardiac arrest victims >8 years was less
than 1/3 relative AP chest depth for 94% of compressions. Forensic engineering techniques can be
used to evaluate the quality of CPR and assess implementation of CPR recommendations created by
consensus opinion. Supported by Laerdal Center of
Excellence and Endowed Chair Grants
=7.14 vpm, SD =1.10; t(5) =–0.20, 95% CI of mean
difference –1.83, 1.57; Cohen’s d =0.085; p =0.85).
On the average, no participants ventilated faster
than the recommended rate of 10–12 vpm during
any condition. Both the participants’ heart rate and
respiration rate were significantly different during the two conditions; mean (SD) heart rate 112
(10.7) vs. 82 (5.3) bpm (p=0.002), mean (SD) respiration rate 21.2 (5.98) vs. 14.5 (3.44) breaths per
minute (p=0.010).
Conclusions: Ventilation rates do not seem to be
elevated by physical stress of the provider. Causes
of hyperventilation should be sought elsewhere,
e.g. amongst mental stressors.
P183 Physical Stress Does Not
Increase Ventilation Rate during
Resuscitation in a Manikin
Model
2251 Chronic Aortic
Regurgitation: Early Detection
of Left Ventricular Dysfunction
by Global Systolic Strain
Joar Eilevstjønn; Jon Nysæther Helge
Myklebust. Laerdal Med AS, Stavanger, Norway
Marit Kristine Smedsrud; Eirik Pettersen; Ola Gjesdal; Kai Andersen Thor
Edvardsen. Rikshospitalet Univ Hosp,
Oslo, Norway
Background: Studies indicate that trained medical personnel often deliver manual ventilations at
excessive rates while performing advanced cardiac
life support (ACLS). Excessive ventilation rates
may contribute to increased mortality among these
patients. We seek to uncover if physical stress affects our perception of ventilation rate.
Hypothesis: We hypothesized that physical stress
would increase the ventilation rate during simulated cardiac arrest in a manikin model.
Method: Six persons at Laerdal Medical were
asked to ventilate an intubated manikin (Laerdal
ResuciAnne PC SkillReporting system) for three
minutes under two different conditions. For the
first condition the participants were asked to perform strenuous physical exercise (running up and
down a stairway for several minutes) immediately
prior to ventilating the manikin. For the second
condition all participants were allowed to rest
before performing ventilations. Participants had
to deliver ventilations at what they felt were 10
ventilations per minute (vpm). No clock or other
time keeping means were available. Heart rate and
breathing rate of the participants were measured
using ECG and trans-thoracic impedance signals
from a defibrillator (Philips HeartStart MRx).
Statistics are derived using the average rate values
from each participant.
Results: The participants did not ventilate faster
after physical stress (Mean rate =7.00 vpm, SD
=1.94) than during the condition at rest (Mean rate
Purpose This study examined whether global longitudinal systolic strain by 2-dimensional speckle
tracking echocardiography (2D-STE) could detect
early onset of myocardial dysfunction in patients
with chronic aortic regurgitation (AR).
Methods 36 patients referred to aortic valve replacement due to chronic AR were compared to
31 healthy age-matched controls. Left ventricular
(LV) global systolic strain was assessed preoperatively by 2D-STE from conventional echocardiographic apical long-axis recordings. In addition,
LV end diastolic diameter (EDD), end systolic
diameter (ESD) and ejection fraction (EF) were
measured.
Results LV dimensions were larger in the AR patients than in the normal individuals (EDD 67 ± 9
mm vs. 50 ± 5 mm (p<0.001) and ESD 45 ± 9 mm
vs. 32 ± 4 mm (p<0.001), respectively). However,
EF did not differ between the groups (58 ± 7 %
vs. 59 ± 6 %, p=ns). In contrast, global systolic
strain was markedly decreased in the AR patients
as compared to the normal subjects (–17.4 ± 3.5 %
vs. –22.1 ± 1.8 %, p<0.001).
Conclusions The study demonstrated reduced
global systolic strain along with preserved EF in
chronic AR patients. Thus, global strain seems to
detect early LV dysfunction as opposed to EF. This
might reflect that global strain is more sensitive to
identify impaired myocardial function due to the
volume load in AR. Consequently, global systolic
112
strain might represent a potential means for improved timing of valve replacement.
2370 LDL Independent
Reduction In Cardiovascular
Morbidity And Mortality
With Rosuvastatin In Heart
Failure Patients With A
Raised C-reactive Protein: A
Retrospective Analysis Of
The Controlled Rosuvastatin
Multinational Trial In Heart
Failure (CORONA)
John McMurray1; John Kjekshus2;
Ake Hjalmarson3; Hans Wedel4; Peter
Dunselman5 Finn Waagstein6. 1 Univ
of Glasgow, Glasgow, United Kingdom, 2 Rikshospitalet Univ Hosp, Oslo,
Norway, 3 Sahlgrenska Univ Hosp,
Gothenburg, Sweden, 4 Nordic Sch of
Public Health, Gothenburg, Sweden,
5
Amphia Hosp, Netherlands, Netherlands, 6 Sahlgrenska Univ Hosptial,
Gothenburg, Sweden
Objective: The anti-inflammatory action of statins may contribute to the clinical benefits of these
drugs. Heart failure (HF) is an inflammatory state
in which the usual epidemiologic relationship between cholesterol and cardiovascular outcomes is
reversed, representing an excellent disease model
in which to test the statin anti-inflammatory hypothesis.
Methods: We carried out a retrospective subgroup
analysis of CORONA, which randomized 5011
patients with low ejection fraction HF of ischemic
etiology to placebo or rosuvastatin 10 mg daily. We
examined the effect of rosuvastatin according to
baseline plasma high-sensitivity C-reactive protein
concentration (hs-CRP) with patients divided into
two groups: < 2 mg/L (779 placebo/777 rosuvastatin) versus >/= 2 mg/L (1694 placebo/1711 rosuvastatin). Results (table): Baseline LDL was the
same in the two hsCRP groups (approx. 138 mg/
dL) and was reduced equally by 45% in each group
with rosuvastatin. In patients with a hsCRP >/= 2
mg/L, rosuvastatin treatment was associated with
nominally statistically significant reductions in
the primary outcome (cardiovascular death, myocardial infarction or stroke), all cause mortality
and the pre-specified coronary endpoint (sudden
death, fatal or nonfatal myocardial infarction, PCI
or CABG, ventricular defibrillation by an ICD,
resuscitation after cardiac arrest or hospitalization for unstable angina). Importantly, rosuvastatin
also reduced the secondary outcome of HF hospitalizations: hsCRP < 2.0 mg/L 267 placebo/264
rosuvastatin (p n.s.); hsCRP >/= 2.0 mg/L 1015
placebo/827 rosuvastatin (p = 0.0044)
Conclusions: Our findings in patients with HF support and extend previous retrospective analyses
in patients with acute and stable coronary heart
disease and add more evidence that the anti-in-
flammatory action of statins may be clinically important, not just in reducing atherosclerotic events
but also HF hospitalizations.
2387 Sex Differences in
the Relationship between
Echocardiographic Parameters
and Clinical Outcomes in
Chronic Stable Angina: Data
from the ACTION trial
Bonnie Ky1; Bridget-Anne Kirwan2;
Sophie de Brouwer2; Jacobus Lubsen3; Philip Poole-Wilson4; Jan-Erik
Otterstad5; Stephen E Kimmel6 Martin
St. John Sutton6. 1 Univ of Pennsylvania Sch of Medicine, Philadelphia, PA,
2
SOCAR Rsch, Nyon, Switzerland, 3
Erasmus Med Cntr, Rotterdam, Netherlands, 4 Imperial College London,
London, United Kingdom, 5 Vestford
Hosp, Toensberg, Norway, 6 Univ of
Pennsylvania Sch of Medicine, Philadelphia, PA
Objectives: To elucidate how the association between clinical outcomes and echocardiographic
parameters of size and function differ by sex in
chronic stable angina.
Background: Whether men and women with stable coronary disease and similar ejection fraction
(EF) have equivalent cardiac risk is unknown.
Methods: Baseline EF and end-diastolic (EDV)
and end-systolic (ESV) volumes were calculated
from 7016 patients in the ACTION study (A Coronary disease Trial Investigating Outcomes with
Nifedipine GTS). All-cause and cardiac mortality and cardiovascular events were assessed over
a mean of 4.9 years. Univariate and multivariable Cox proportional hazard models were used
to determine the interaction between gender and
echocardiographic parameters and clinical outcomes.
Results: There was significant effect modification
by sex on the association between EF < 45% and
all-cause and cardiac mortality. Relative to those
with an EF >55%, women with an EF < 45% demonstrated a greater increased risk of these two endpoints (HR 4.78, 95%CI 2.16–10.57; HR 22.44,
95%CI 3.07–164.27, respectively) as compared to
men (HR 1.99, 95%CI 1.42–2.79; HR 2.77, 95%CI
1.73– 4.43, respectively; interaction unadjusted p
= 0.03, adjusted p = 0.06 – 0.07) (Table 1). There
was also significant effect modification by gender
on the association between an EDV > 175ml and
risk of coronary procedures (unadjusted, adjusted p
= 0.02) and ESV > 100ml and risk of heart failure
(unadjusted p = 0.03, adjusted p = 0.26).
Conclusions: EF demonstrates significant effect
modification by sex on the hazard ratio for allcause and cardiac mortality. Gender also significantly modifies the relationship between EDV and
coronary procedures, and ESV with heart failure.
Men and women with chronic stable angina and
similar EF likely do not have equivalent risk. Gender-specific echocardiographic definitions may be
of incremental benefit in the identification of highrisk women.
Table 1: Unadjusted Hazard Ratios for Clinical Outcomes by Gender and Ejection Fraction
113
2413 C-reactive protein,
Vascular Cell Adhesion
Molecule and Neopterin are
Markers of Advanced Cardiac
Allograft Vasculopathy
Determined by Intravascular
Ultrasound
Satish Arora; Anne Gunther; Einar
Gude; Rune Andersen; Arne Andreassen; Pål Aukrust Lars Gullestad. Riks
hospitalet Med Cntr, Oslo, Norway
A range of inflammatory mediators are likely to
be responsible for the development of cardiac allograft vasculopathy (CAV), but a broad characterization of these markers in relation to different
intravascular ultrasound (IVUS) endpoints has
not been performed previously. Consquently, we
evaluated an extensive profile of clinical variables
and immune markers to assess the chronic inflammatory milieu associated with advanced CAV assessed by IVUS.
Methods: In total, 101 heart transplant (HTx)
recipients were included and all patients underwent IVUS examination and plasma sampling for
measurement of the following immune markers:
C-reactive protein (CRP), soluble tumor necrosis
factor receptor-1 (sTNFR-1), interleukin-6 (IL-6),
osteoprotegerin (OPG), soluble gp130, von Willebrand factor (vWf), vascular cell adhesion
molecule-1 (VCAM-1) and neopterin.
Results: Mean Percent Atheroma Volume
(PAV) was 32.4 ± 9.5%. Levels of CRP,
sTNFR-1, VCAM-1 and neopterin were
significantly higher (p < 0.05) amongst
patients with PAV < 32% (n = 50). Similar significant results were found when
using Maximal Intimal Thickness (MIT)
> 0.5 mm (n = 47) as an alternative IVUS
endpoint. Multivariate regression analysis revealed that CRP > 1.5 mg/L [adjusted
OR 4.5 (95% CI 1.7–12.4), p < 0.01], VCAM-1 >
391 ng/mL [adjusted OR 3.2 (95% CI 1.1–9.7), p =
0.04] and neopterin > 767 nmol/L [adjusted OR 3.8
(95% CI (1.2–11.7), p = 0.02] were independently
associated with PAV > 32%.
Conclusion: Advanced CAV quantified by IVUS
is associated with an inflammatory signature comprising of elevated CRP, VCAM-1 and neopterin
and reflects the multi-faceted immunological activity contributing to CAV development. Forthcoming studies should clarify if measurements of
114
these markers will allow more individualized CAV
surveillance and management of HTx recipients.
2437 The Interaction between
Left Ventricular Apical Rotation
and the Arterial Blood Pressure
in Elderly Females may Reveal
Mechanisms Involved in the
Syndrome of Diastolic Heart
Failure a Follow-Up Study
Johannes Soma; Ketil Dahl Tor-Erik
Widerøe. St Olavs Univ Hosp, Trondheim, Norway
LV apical short-axis loops were obtained with
2D echocardiography (80 – 110 frames/s) in 31
healthy females, age 69 to 84 years. Peak apical
rotation (PAR) and peak rotation velocity (PARvelocity) was assessed with speckle tracking (ST).
Ambulatory systolic (SBP) and diastolic (DBP)
blood pressures were averaged between 0600 and
2300. The difference (D) between measurements
after four years follow-up was calculated by subtracting the first from the last assessment. Apical
short-axis loops were eligible for ST in 27 subjects. SBP and DBP increased (126 ± 14 vs 133 ±
13 mm Hg, p = 0.007 and 70 ± 7 vs 73 ± 7 mm Hg,
p = 0.049) and LV end-diastolic and end-systolic
volumes decreased (84 ± 15 vs 74 ± 10 ml, p <
0.0001 and 33 ± 9 vs 25 ± 7 ml, p < 0.0001) during
follow-up. DSBP and DDBP correlated inversely
with the LV end-diastolic short-axis dimension (r
= –0.38, p = 0.03 and r = –0.43, p = 0.02). DSBP,
DDBP and DBP, correlated inversely with PAR (r
= –0.51, p = 0.007; r = –0.59, p = 0.0001 and r =
–0.47, p = 0.01). PAR correlated positively with
LV stroke volume and with body weight (p < 0.05)
and with systolic and diastolic PAR-velocity (r =
0.76, p < 0.0001 and r = 0.58, p = 0.001). Diastolic
PAR-velocity correlated with mitral E peak velocity (r = 0.48, p = 0.01). In healthy elderly females
LV peak apical rotation and peak diastolic rotation
velocity correlate with indices of LV filling and
ejection, indicating that suction, a key property
for effective early LV filling, may be preserved in
elderly subjects. Suction seems to deteriorate with
BP elevations. An age- or blood pressure related
reduction in LV end-diastolic volume may represent an additional impediment to LV filling. Both
features may contribute to the development of LV
diastolic dysfunction and to diastolic heart failure.
2642 Prevalence and
Importance of Cardiac
Arrhythmias after Acute
Ischemic Stroke
Jesper K Jensen1; James L Januzzi2;
Dan Atar3 Hans Mickley4. 1 Odense
Univ Hosp, Odense C, Denmark, 2
Massachusetts General Hosp., Massachusetts, MA, 3 Div of Cardiology, Aker
Univ Hosp and Faculty of Medicine,
Univ of Oslo, Oslo, Norway, 4 Odense
Univ Hosp, Odense C, Denmark
Although heart rhythm monitoring following acute
ischemic stroke is widely practiced, the prevalence
of arrhythmia during the acute phase of ischemic
stroke is debated. Several studies have claimed the
potential threat of QT prolongation possibly leading to Torsades de Pointes ventricular tachycardia
(VT) or ventricular fibrillation (VF). Furthermore,
knowledge of the true rate of occult atrial fibrillation (AF) among ischemic stroke patients is sparse.
224 consecutive patients with acute ischemic
stroke underwent daily 12-lead ECG during the
first 5 days after hospital admission; as well as 24
hour Holter monitoring was performed in all patients. Patients with prior AF, established ischemic
heart disease and heart failure were excluded. Patients were followed for 40 months for vital status.
The mean age of the patients was 69 years. No
patient had VT or VF. Previously unsuspected AF
could be demonstrated in only 13 of 224 patients
(6%). All 13 were detected by Holter monitoring,
while nearly half were missed by ECG. During
follow-up 53 (24 %) patients died. The presence
of AF was significantly associated with mortality (log-rank p <0.0001; Figure). In Cox analysis, patients with AF had an increased mortality
compared to patients without AF (HR=2.44; [95 %
CI, 1.00 – 6.00], P = 0.05) with adjustment for age
and stroke severity and renal failure. The fear of
serious ventricular arrhythmias in the acute phase
of ischemic stroke appears to be groundless. However, new onset AF can be demonstrated in one of
20 patients with acute ischemic stroke and seems
to be associated with an increased mortality during
long-term follow-up.
4434 Association of Elevated
Serum Glucose Levels with
Hypokalemia Independent of
Treatment in Hypertensive
Patients: Implications for
the Development of New
Diabetes
Peter M Okin1; Sverre E Kjeldsen2; Lars H Lindholm3; Björn
Dahlöf4 Richard B Devereux5. 1 Cornell Med Cntr, New York, NY, 2 Univ
of Oslo, Ullevål Hosp, Oslo, Norway,
3
Umeå Univ, Umeå, Sweden, 4 Sahlgrenska Univ Hosp/Ötra, Göteborg,
Sweden, 5 Cornell Med Cntr, New
York, NY
Thiazide diuretics can produce impaired glucose
tolerance and are associated with an increased risk
of developing diabetes. Although increased serum
glucose concentrations during thiazide therapy
have been linked to thiazide-induced hypokalemia, whether hypokalemia per se is associated with
elevations of serum glucose over time has not been
examined. Baseline and annual serum glucose
levels were examined as a function of quartiles of
serum potassium (K) levels in 6947 patients in the
LIFE study with no history of diabetes who did not
develop diabetes during the study. Patients were
randomized to losartan vs atenolol-based treatment and additional hydrochlorothiazide (HCTZ)
therapy as needed. Serum glucose was highest in
the quartile with lowest serum K at baseline and
throughout the study and decreased across quartiles of K (Table). The association between hypokalemia and elevated serum glucose was highly
significant at baseline and each year of the study
and was independent of randomized and HCTZ
treatment, serum creatinine, and of baseline levels
and changes in blood pressure and ECG left ventricular hypertrophy. Repeated measures analysis of covariance further demonstrated that serum
glucose increased over time (p<0.001) and that the
relationship of serum glucose to quartiles of K was
significant over time (p=0.001) and varied across
quartiles (p=0.003 for the interaction between glucose over time and quartiles of K). Elevated serum
glucose levels are associated with hypokalemia
115
during antihypertensive therapy, independent of
the potential impact of treatment with losartan vs
atenolol and with HCTZ and of baseline glucose
levels and other potential factors that could influence glucose levels. These findings suggest that
hypokalemia per se may be a stimulus to development of abnormal glucose tolerance and provide
insights into the relationship between antihypertensive treatment and development of diabetes.
Serum Glucose Level in Relation to the Quartile of
Serum Potassium Level
2121 Myocardial Mechanical
Dispersion Assessed by Strain
Echocardiography Identifies
High Risk Patients with Long QT
Syndrome
Kristina H Haugaa; Thor Edvardsen;
Trond P Leren; Otto A Smiseth Jan P
Amlie. Rikshospitalet Univ Hosp, Oslo,
Norway
Background: Long QT syndrome (LQTS) predisposes to life-threatening ventricular arrhythmias.
Prolonged action potentials in LQTS may cause
prolonged myocardial contraction which can be
assessed by strain echocardiography. We hypothesized that myocardial mechanical dispersion can be
assessed as heterogeneity in myocardial contraction duration and serve as a risk marker in LQTS
patients.
Methods: We included 81 mutation carriers with
genotyped LQTS and 20 healthy control subjects.
41 mutations carriers had a history of cardiac arrest
or syncope and 40 were asymptomatic. Myocardial
contraction duration was assessed as time from
Q on ECG to peak strain. Standard deviation of
contraction duration from the 6 basal LV segments
was calculated as a marker of mechanical dispersion. Figure is demonstrating homogeneous contraction duration in a healthy person compared to
mechanical dispersion in a LQTS patient.
Results: Contraction duration was prolonged
in LQTS mutation carriers compared to healthy
controls (430±50 vs. 350±30ms, p<0.001) and in
symptomatic compared to asymptomatic carriers
(440±50 vs. 410±40ms, p<0.01). Mechanical dispersion was more pronounced in symptomatic mu-
116
tation carriers compared to asymptomatic (65±22
vs. 34±18ms, p<0.001). Mechanical dispersion was
better related to severe arrhythmia than QTc (AUC
by ROC analysis 0.89 vs. 0.71).
Conclusions: Mechanical dispersion of myocardial
contraction assessed by strain echocardiography
was increased in LQTS mutation carriers and was
superior to QTc in identifying cardiac events. This
novel method can be implemented in clinical routine and may improve the management of LQTS
patients.

Scientific Sessions 2008 of the American Heart Association (AHA

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