References — 110

List of abbreviations — 124

Authors affiliations — 126

Nederlandse samenvat-ting — 127

Curriculum Vitae — 131

List of publications — 133

Dankwoord — 134

110

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List of abbreviations

3’UTR 3’ untranslated region ANF/ANP atrial natriuretic factorANGII angiotensin II BNP brain natriuretic peptide CaM calmodulinCaMK calmodulin dependent protein kinaseCVD cardiovascular diseaseDIO1 deiodinase type IDIO2 deiodinase type IIDIO3 deiodinase type IIIDLK1 delta-like homologue 1 ERK extracellular signal-regulated kinaseET-1 endothelin-1FLUC firefly luciferaseFS fractional shortening GPCR g-coupled receptorGSK-3β glycogen synthase kinase 3βHDAC4 histone deacetylase 4HIF-1α hypoxia-inducible factor-1α HO hypothyroidHOT3 hyperthyroidHPRT hypoxanthine-guanine- phosphoribosyl-

transferase IGF-1 insulin growth factor 1IGF-R1 insulin growth factor receptor 1JAK/STAT janus kinase/signal transducer

and activator of transcriptionJNKs c-jun N-terminal kinasesLAD left anterior descending coronary arteryLV left ventricleMAPK mitogen-activated protein kinasesMCT8 monocarboxylate transporter 8MEF2 myocyte enhancer factor 2MI myocardial infarction miRNA microRNAmTOR mammalian target of rapamycinMyh6/MHCα myosin heavy chain αMyh7/MHCβ myosin heavy chain βNE norepinephrineNFAT nuclear factor of activated T-cells

transcription factorNTIS non-thyroidal illness syndromePAH pulmonary arterial hypertension PDK1 phosphoinositide-dependent protein

kinase 1PI3K phospho-inositide 3-kinase PKA protein kinase APKC protein kinase CPLC phospholipase CPTU propylthiouracilRAAS renin-angiotensin-aldosteron systemRLUC renilla luciferaserT3 3,3’,5’-triiodothyronine RV right ventricleSECIS selenocysteine insertion sequenceSERCA2A sarcoplasmic reticulum

Ca2+-ATPase SHH sonic hedgehog T2 3,3’-diiodothyronine

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T3 3,5,3’-triiodothyronine T4 thyroxineTGFβ transforming growth factor β TH thyroid hormoneTHRAP1 thyroid hormone receptor associated

protein 1TR thyroid hormone receptorTRE thyroid hormone responsive elementTSH thyroid stimulating hormone

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Author affiliations

Ellen Dirkx Department of Cardiology, CARIM School for Cardiovascular Diseases, Faculty of Health, Medicine and Life Sciences, Maastricht University, The Netherlands (current affiliation: Department of Molecular Medicine, International Centre of Engineering and Biotechnology (ICGEB), Trieste, Italy.

Diederik W.D. Kuster Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.

Alain van Mil Division of Heart and Lungs, Department of Cardiology, University Medical Center Utrecht, Utrecht, the Netherlands.

Joyce Mulders Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.

Alice Muller Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.

Cees B.M. Oudejans Department of Clinical Chemistry, VU University Medical Center, Amsterdam, The Netherlands.

Walter J. Paulus Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.

Christine J. Pol Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands (current affiliation: Temple University School of Medicine, Department of Pharmacology, Center for Translational Medicine, Philadelphia, USA).

Warner S. Simonides Department of Physio-logy, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.

Marian J. Zuidwijk Department of Physiology, Institute for Cardiovascular Research, VU University Medical Center, Amsterdam, The Netherlands.

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Nederlandse samenvatting

Chronisch hartfalen, als gevolg van cardio-vasculaire ziekten, wordt gekarakteriseerd door een verslechterde pompfunctie van het hart met als gevolg dat bloed minder efficiënt door het lichaam kan worden gepompt. Er ontstaan hierbij klachten zoals vermoeidheid, kort ademigheid en oedeemvorming, met multi- orgaanfalen of hartritmestoornissen als belangrijkste doodsoorzaak. Ondanks de groeiende kennis slaagt men met de huidige therapieën er niet in om chronisch hartfalen te genezen, maar is enkel in staat de sympto-men te bestrijden. De wereldwijd stijgende prevalentie van chronisch hartfalen gaat hand in hand met de stijgende aantallen mensen met bekende, onafhankelijke risicofactoren voor hartfalen zoals: obesitas, diabetes, hypertensie of een lichamelijk inactieve levensstijl. Aangezien de kans op het ontwikkelen van hartfalen op een latere leeftijd toeneemt, zal het aantal patiën-ten met chronisch hartfalen verder stijgen in een wereld waarin de levens verwachting nog steeds toeneemt. Momenteel wordt geschat dat 23 miljoen mensen zijn aangedaan door chronisch hartfalen, waarbij de mortaliteit ten gevolge van ischemische hartziekten het hoogst is. Wereldwijd sterven elk jaar 7 miljoen mensen aan ischemie- gerelateerde hartziekten, waaronder een hartinfarct. Berekeningen voor-spellen dat in 2020 dit aantal zal stijgen tot 9 miljoen mensen. In Nederland is van 1 op de 4 mensen die overlijdt, de oorzaak gerelateerd aan cardiovasculaire ziekten. In 2012 overleden 6195 mensen aan een acuut hartinfarct en nog eens 3525 mensen ten gevolge van chronisch hartfalen veroorzaakt door ischemische hart-ziekten. Deze laatste groep bevat een groei-end aantal patiënten dat een hartinfarct heeft overleefd dankzij verbeterde behandelingen. Hoewel het hart de capaciteit heeft om te compenseren voor het verlies van pompfunctie na een infarct, schiet deze adaptatie veelal tekort, met chronisch hartfalen als gevolg. Het proces van adaptatie is het onderwerp van de studies die beschreven zijn in dit proefschrift. De adaptatie van het hart (remodellering) als gevolg van ischemische hartziekten, en met name volgend op een hartinfarct, is gedefinieerd als de moleculaire, cellulaire en structurele veranderingen die er op gericht zijn om de toegenomen wandspanning en afgeno-men cardiac output te normaliseren. Deze remodelering van zowel het geïnfarceerde als het niet geïnfarceerde (gespaarde) myocard is onderdeel van een scala aan compensatoire mechanismen, waaronder het verhogen van contractiliteit van het hart d.m.v. het Frank- Starling mechanisme, de activatie van het

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sympathisch zenuwstelsel en het renine- angiotensine-aldosteronsysteem, en de ver-hoogde afgifte van natriuretische peptides. Vergroting van de hartspiercellen van het gespaarde myocard (hypertrofie) is de belangrijkste ultieme respons van het over-belaste hart, waarbij diverse factoren en signaal-transductieroutes betrokken zijn. Hoewel hypertrofie initieel adaptief is, wordt het bij blijvende overbelasting van het hart een bepalende factor in de ontwikkeling van hartfalen. Er wordt dan ook gesproken van pathologische hypertrofie, in tegenstelling tot fysiologische hypertrofie, bijvoorbeeld als gevolg van training. Sinds 2006 is bekend dat korte, niet voor eiwit coderende RNA frag-menten, zogenaamde microRNAs (miRNAs), nauw betrokken zijn bij de regulatie van gen-expressie, ook in het hart. Door te binden aan een complementaire sequentie geloka-liseerd op de 3’UTR van messenger RNA (mRNA) kan een miRNA de expressie van het desbetreffende mRNA beïnvloeden door te interfereren met de translatie naar eiwit. Diverse miRNAs zijn reeds geïdentificeerd die een cruciale rol spelen bij de veranderingen in cardiale gen-expressie die ten grondslag liggen aan adaptatie maar ook aan de ont-wikkeling van pathologische hypertrofie. De morfologie, contractie-eigenschappen en metabolisme van het hart worden in sterke mate bepaald door het niveau van schildklier-hormoon. Stijging van dit niveau bij hyper-thyreoïdie leidt tot een hogere hartfrequentie en belasting van het hart, met fysiologische hypertrofie als gevolg. Of schildklierhormoon-signaaltransductie een rol speelt bij patholo-gische hypertrofie als gevolg van o.a. een hartinfarct, is onderwerp van discussie. Over-eenkomstige expressiepatronen van cardiale genen bij een tekort aan schildklierhormoon (hypothyreoïdie) en bij hartfalen, suggereren dat er een verband bestaat tussen een ver-laagde schildklierhormoonactiviteit in het hart en het ontwikkelen van chronisch hartfalen. De schildklier produceert overwegend het inactieve pro-hormoon thyroxine (T4) en in geringe mate het actieve hormoon triiodo-thyronine (T3). Dejodases, een groep van drie selonoproteïnen spelen een belangrijke rol bij het activeren en inactiveren van schildklier-hormonen. Het overgrote deel van perifeer T3 is het resultaat van de conversie van T4 naar T3 door dejodase type I en II (respectievelijk Dio1 en Dio2) in o.a. de lever, vetweefsel en in geringe mate de skeletspieren. Dejodase type III (Dio3), dat verantwoordelijk is voor de inactivatie van T3, komt met name tot

expressie tijdens de foetale ontwikkeling, maar in veel geringere mate in adulte weefsels. Lokale activatie en inactivatie van schildklier-hormonen is een belangrijk aspect van de normale fysiologie. Studies die hebben aan-getoond dat Dio3 opnieuw tot expressie komt in falende hart suggereren dat deze activiteit verantwoordelijk is voor de lokale inactivatie van T3 als onderdeel van de adaptatie van het hart volgend op een hartinfarct. Het opnieuw tot expressie komen van diverse foetale genen is een karakteristiek onderdeel van het proces van adaptatie en het ontwikkelen van hartfalen. Schildklierhormoonactie vindt hoofdzakelijk plaats op het niveau van de regulatie van gen- expressie, welke verloopt via de binding van T3 aan schildklierhormoonreceptoren op het DNA. Ondanks het grote belang van schildklier-hormoon voor cardiale gen-expressie en het grote aantal studies naar de rol van miRNAs in het gezonde en het falende hart is weinig bekend over de effecten van T3 op miRNA expressie in het hart. Het werk beschreven in dit proefschrift is uitgevoerd om meer inzicht te krijgen in de relatie tussen schildklierhormoon-actie en miRNAs in het hart en de mogelijke rol hiervan in de ontwikkeling van pathologische hypertrofie als gevolg van een hartinfarct.

Om in hoofdstuk 2 de vraag te kunnen beantwoorden of er in het hart T3-responsieve miRNAs aanwezig zijn, zijn hypothyreote muizen 3 dagen met T3 behandeld. Door kort te behandelen is getracht inzicht te krijgen in juist die miRNAs die het meest T3-gevoelig zijn. Dit resulteerde in een miRNA profiel van 52 gereguleerde miRNAs, waaronder drie miRNAs waarvan reeds is vastgesteld dat deze T3- gevoelig zijn. In overeen stemming met de door T3 geïnduceerde fysiologische hyper-trofie van het hart, voorspelde in silico analyse dat een klein deel van de gereguleerde miRNAs deze vorm van hypertrofie stimuleert. Opmer-kelijk is dat het merendeel van de gereguleerde miRNAs juist pathologische groei van het hart onderdrukt. Het doorgronden van de rol van T3-gereguleerde miRNAs kan nieuwe inzichten opleveren in de mechanismen betrokken bij hartfalen en daardoor uitzicht bieden op betere behandelmethoden. Omdat deze analyse berust op computervoorspellingen is het noodzakelijk te onderzoeken of deze T3-gereguleerde miRNAs daadwerkelijk pathologische hyper-trofie kunnen onderdrukken in bijvoorbeeld een diermodel voor hartinfarct of overbelasting.

In hoofdstuk 3 is de hypothese getest dat T3-gereguleerde miRNAs betrokken zijn bij het remodeleren van het gespaarde myocard

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na een hartinfarct. De differentiële expressie van zowel reeds bekende door T3-gereguleerde miRNAs, te weten miR-206, 208a en 208b, als een aantal in hoofdstuk 2 geïdentificeerde miRNAs zijn in lijn met de in eerdere studies gesuggereerde verlaagde T3 niveaus in het gespaarde myocard. Opmerkelijk was de verhoogde expressie van miRNAs behorend tot een groot miRNA-cluster stroomopwaarts van het eveneens geïnduceerde Dio3. Het is aangetoond dat de activatie van deze zoge-noemde ‘genomic imprinted DLK1-DIO3 region’ een rol speelt bij de proliferatie en differentiatie van cellen. Aangezien een hypothyreoot milieu een voorwaarde is voor verschillende cellen om te kunnen prolifereren, suggereert dit dat de verhoogde expressie van Dio3 een rol speelt in dit proces. De gepresenteerde data tonen voor het eerst aan dat proliferatie van bestaande hartspiercellen wordt geïnitieerd in het adulte hart volgend op een infarct, maar bekend is dat er geen nieuwe cardiomyocyten gevormd worden. Blijkbaar ontbreken factoren die nood -zakelijk zijn om het proces van proliferatie te voltooien. Identificatie van die factoren kan een belangrijke stap zijn in de ontwikkeling van nieuwe therapie.

Ondanks dat verschillende onderzoeksgroepen hebben gesuggereerd dat re-expressie van het foetale gen Dio3 een rol speelt in het ontwik-kelen van hartfalen, blijft het mechanisme dat ten grondslag ligt aan de regulatie van Dio3 in het volwassen hart onduidelijk. In hoofdstuk 4 testten wij de hypothese dat Dio3 expressie gereguleerd wordt door miRNAs. Uit in silico analyse bleek dat van alle gereguleerde miRNAs in het remodelerende hart, miR-214 een potentiële kandidaat is voor regulatie van Dio3 door te binden aan een geconserveerde regio in het SECIS-element [zie hoofdstuk 1]. In vitro experimenten hebben aangetoond dat miR-214 inderdaad Dio3 expressie kan onder-drukken. Opmerkelijk is dat zowel Dio3 als miR-214 verhoogd tot expressie komen na een hartinfarct, waarmee deze miRNA juist Dio3 expressie zou remmen in plaats van stimuleren. Immunohistochemie op opeen-volgende parrafinecoupes heeft aangetoond dat Dio3 en miR-214 in hetzelfde gebied tot expressie komen in het hart. Dit suggereert dat Dio3 en miR-214 afzonderlijk worden gereguleerd of aan elkaar gerelateerd zijn via een gedeelde signaaltransductieroute. Deze laatste mogelijkheid werd gesuggereerd door resultaten van expressieanalyses op verschil-lende tijdspunten na het induceren van een infarct in het muizenhart. Deze analyses hebben uitgewezen dat Dio3 expressie en

activiteit voorafgaat aan miR-214 expressie. Tevens is gebleken dat miR-214 expressie in het muizen hart onderdrukt wordt na een korte behandeling met T3. De gepresenteerde data suggereren dat Dio3 expressie onder controle staat van o.a. miR-214 middels een negatieve terugkoppeling. Een dergelijk mechanisme zou er op gericht kunnen zijn te voorkomen dat lokale T3 levels verder reduceren met als gevolg een verdere reductie van de pomp-functie van het reeds falende hart.

In hoofdstuk 5 is de expressie van DIO3 bestu-deerd in hartweefsel van o.a. patiënten waarvan bekend is dat zij leden aan ischemische hart-ziekten. Expressieniveaus werden bestudeerd met behulp van immunohisto chemische analyse van weefsel microarrays. Deze arrays zijn opgebouwd uit linkerventrikelweefsel van geëxplanteerde harten van patiënten met eindstadium hartfalen en donorharten. Analyse wees uit dat er sig nificant meer DIO3 expressie aanwezig is in weefsel afkomstig van patiënten. Deze data komen overeen met de verhoogde DIO3 mRNA expressie gemeten in weefsel afkomstig uit dezelfde patiëntengroep in ver gelijking met donoren. Een belangrijke waar-neming was dat, net zoals in eerdere immuno-histochemische analyses in de muis, er geen DIO3 expressie werd aangetoond in andere cellen dan cardiomyocyten. Ondanks de signi-ficante inductie van DIO3 was het niet mogelijk om DIO3 activiteit te meten. Een mogelijke verklaring is dat de humane biopten meer dan vier jaar zijn opgeslagen in vloeibare stikstof waarbij de activiteit van DIO3 is gedaald tot onder de detectiegrens van de huidige assay. In vergelijking, de analyse van Dio3 activiteit in vers geprepareerde muizenharten, die ver-gelijkbare intensiteit vertoonden als de humane weefsel microarrays, resulteerde in waarden net boven de detectielimiet. Eerdere activiteitsmetingen hebben aangetoond dat foetaal humaan myocardium DIO3 activiteit bevat, maar dat dit nagenoeg verdwijnt in de neonatale periode, zoals ook vastgesteld in knaagdieren. Dit wordt ondersteund door de reciproke expressie van de T3-gereguleerde genen MYH6 en MYH7. De inductie van DIO3 in patiënten met ischemisch hartfalen suggereert dat de verstoorde cardiale T3-signaaltransduc-tie zoals is waargenomen in diermodellen ook plaatsvindt in de mens.

Als laatste worden in hoofdstuk 6 de bevin-dingen bediscussieerd en de implicaties voor mogelijke therapieën besproken. Al een geruime tijd bestaat interesse in het gebruik van schildklierhormoon als therapie om het

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falende hart te genezen. De aanwijzingen dat DIO3 opnieuw tot expressie komt in het volwassen falende hart heeft deze interesse verder aangewakkerd. Voor het therapeutisch gebruik van zowel schildklierhormoon als miRNAs zal het moment van toedienen en de conditie van het hart van cruciaal belang zijn. Zo wordt gesuggereerd dat de lokale reductie van T3, als gevolg van een hartinfarct, initieel een adaptieve reactie is van het hart om energie te besparen en pas in een later stadium nega-tieve consequenties heeft voor contractiliteit. Behandeling met schildklierhormoon zal dan alleen zinvol zijn in dit latere stadium van remodelering. Daarentegen suggereren de data gepresenteerd in hoofdstuk 2 dat lokale reductie van T3 bijdraagt aan pathologische remodelering door het opheffen van de inhibi-tie door anti-pathologische miRNAs. Dit laatste suggereert dat een vroege behandeling met schildklierhormoon juist gunstige effecten zal hebben op het falende hart.

Het doel van deze studie was om meer inzicht te krijgen in de relatie tussen schild-klier hormoonactie en miRNAs in het hart. Gebaseerd op de verkregen data en de beschikbare literatuur kan worden geconclu-deerd dat deze relatie substantieel is en dat schildklierhormoonactie en T3-responsieve miRNAs in het gezonde en het falende hart een belangrijke, tot nu toe onbekende, rol lijken te spelen. Ondanks de groeiende hoeveelheid kennis met betrekking tot het ontstaan van hartfalen, blijft het ontwikkelen van effectieve therapieën voor alsnog een enorme uitdaging. De data beschreven in dit proefschrift pleiten voor meer onderzoek naar de rol van schildklier hormoonactie in het falende hart, alsook naar de mogelijk-heden om hartspecifieke verhoging van schildklierhormoonactie als therapie toe te passen.

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Curriculum vitae Rob Janssen was born on January 6th 1981 in Nieuwegein, The Netherlands. After completing his secondary education at the Olympus College in Arnhem, he started the study Technical microbiology at Rijn IJssel College in Arnhem and successively enrolled the study Biomedical Laboratory research at Hogeschool van Arnhem en Nijmegen in Nijmegen, The Netherlands. This resulted in 2005 in a position as a research technician at the Department of Physiology at the Radboud University in Nijmegen. In 2007 he enrolled in the master Biomedical Sciences – Human pathobiology at the Radboud University in Nijmegen. As part of his studies he performed internships at the Department for Biophysics and Physiology at Weill Cornell medical college in New York, USA, and Human Genetics at the Radboud University in Nijmegen. After success-ful completing this study in 2010, he started as a Ph.D. student at the Department of Physi-ology at the VU University Medical Center in Amsterdam, The Netherlands. His research, supervised by dr. Warner S. Simonides, dr. Alice Muller, and prof. dr. Walter J. Paulus, concentrated on thyroid hormone metabolism and microRNAs in the heart. Since December 2014 he started as a junior Postdoc at the Department of Anatomy, Embryology and Physiology at the Amsterdam Medical Center in Amsterdam.

Training–  Cardiac Function and Adaptation

(PhD-training course organized by the Dutch Heart Foundation), Papendal, The Netherlands (2012)

–  Vascular Biology (PhD-training course organized by the Dutch Heart Foundation), Papendal, The Netherlands (2014)

Teaching–  Supervisor of the course ‘Cardiovascular

(patho)physiology’ for bachelor students of Medicine, Department of Physiology, VU University Medical Center, Amsterdam, The Netherlands (2012, 2013).

Oral Presentations–  Annual symposium of the Dutch thyroid

club (2011)–  European Thyroid Association annual

meeting (2012)–  European Thyroid Association annual

meeting (2013)–  European Society of Cardiology – Heart

Failure (2014)

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Poster Presentations–  Annual VUmc Science Exchange day (2012)–  Annual VUmc Science Exchange day (2013)–  Annual VUmc Science Exchange day (2014)–  American Heart Association (2014)

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List of publications

Full PapersTiel Groenestege WM, Thébault S, van der

Wijst J, van den Berg D, Janssen R, Tejpar S, van den Heuvel LP, van Cutsem E, Hoenderop JG, Knoers NV, Bindels RJ. Impaired basolateral sorting of pro-EGF causes isolated recessive renal hypo-magnesemia. J. Clin. Invest. 117:2260 – 2267 (2007).

Janssen R, Zuidwijk M, Muller A, Mulders J, Oudejans CBM, Simonides WS. Cardiac expression of deiodinase type 3 (Dio3) follow-ing myocardial infarction is associated with the induction of a pluripotency microRNA signature from the Dlk1-Dio3 genomic region. Endocri nology. 154(6):1973–1978 (2013).

Janssen R, Zuidwijk MJ, Kuster DWD, Muller A, Simonides WS. Thyroid hormone-regulated cardiac microRNAs are predicted to suppress pathological hypertrophic signaling. Frontiers Endocrinology, 5:171 (2014).

Oudejans CBM, Michel OJ, Janssen R, Habets R, Poutsma A, Sistermans EA, Weiss MM, Incarnato D, Oliviero S, Kleiverda G, van Dijk M, Arngrímsson R. Susceptibility allele- specific loss of miR-1324-mediated silencing of the INO80B chromatin-assembly complex gene in pre-eclampsia. Hum. Mol. Genet. 24 (1): 118-127 (2015).

Janssen R, Zuidwijk MJ, Muller A, van Mil A, Dirkx E, Oudejans CBM, Paulus WJ, Simonides WS. MicroRNA 214 is a potential regulator of thyroid hormone levels in the mouse heart following myocardial iInfarction, by targeting the thyroid-hormone inactivating enzyme deiodinase type III. Frontiers Endocrinology, 7:22 (2016).

AbstractsJanssen R, Zuidwijk MJ, Mulders J, Muller A,

Oudejans CBM, Simonides WS. ETA: Eur Thyroid J;1(suppl 1):1–74, OP5 (2012).

Janssen R, Zuidwijk MJ, Muller A, Oudejans CBM, Simonides WS. ETA: Eur Thyroid J ;2(suppl 1):75–194, OP13 (2013).

Janssen R, Zuidwijk MJ, Muller A, van Mil A, Dirkx E, Oudejans CBM, Simonides WS. ESC: European Journal of Heart Failure, 16: 210–214, 1048 (2014).

Janssen R, Zuidwijk MJ, Kuster DWD, Muller A, Simonides WS. AHA: Circulation. 130: A17690 (2014).