Circulating microRNAs in heart failure

Eline Lizet Vegter

Circulating microRNAs in heart failure

Vertaalde titel van de bijdrage: Circulerende microRNAs in hartfalen

Eline Lizet Vegter

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Hartfalen is een ernstige aandoening waarbij de pompfunctie van het hart tekort schiet en kent helaas een slechte prognose. De ontwikkeling van nieuwe medicamenten is daarom zeer gewenst en meer informatie over onderliggende epigenetische processen zou kunnen leiden tot nieuwe aangrijpingspunten voor therapie. MicroRNAs (miRNAs) zijn kleine stukjes RNA welke niet coderen voor eiwitten maar in staat zijn de genexpressie te beïnvloeden. In verschillende aandoeningen, waaronder hartfalen, blijken miRNAs een grote rol te spelen. MiRNAs oefenen hun functie intracellulair uit, maar zijn ook aanwezig in circulerend bloed en andere lichaamsvloeistoffen, waardoor ze mogelijk als potentiele biomarkers zouden kunnen fungeren. Echter, hun rol en functie in de circulatie van hartfalen patiënten is nog niet bekend. In dit proefschrift hebben we een profiel van consistent verlaagde miRNA waarden geïdentificeerd in de circulatie van patiënten met acuut hartfalen. Een daling tijdens de eerste dagen van opname was geassocieerd met een verhoogde kans op sterfte. Tevens laten we zien dat deze miRNAs geassocieerd zijn aan andere, aan hartfalen gerelateerde biomarkers en onderliggende cardiovasculaire mechanismen. Hierbij bleek dat deze relaties afhankelijk zijn van de ziektestatus van de patiënt en het tijdspunt van meten. Ook vonden we associaties tussen lage miRNA waarden en de aanwezigheid van atherosclerose en gerelateerde ziekteprocessen zoals inflammatie, angiogenese en endotheel dysfunctie, en laten we zien dat deze miRNA waarden gerelateerd zijn aan de volume status van hartfalen patiënten. Daarnaast constateren we dat de eerder gevonden resultaten in hartfalen patiënten niet rechtstreeks te vertalen zijn naar diermodellen met hartfalen.

Vertaalde titel van de bijdrage	Circulerende microRNAs in hartfalen
Originele taal-2	English
Kwalificatie	Doctor of Philosophy
Toekennende instantie	Rijksuniversiteit Groningen
Begeleider(s)/adviseur	Voors, Adriaan, Supervisor van der Meer, Peter, Co-supervisor
Datum van toekenning	18-okt.-2017
Plaats van publicatie	[Groningen]
Uitgever	Rijksuniversiteit Groningen
Gedrukte ISBN's	978-94-9268-392-2
Status	Published - 2017

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Title and contentsFinal publisher's version, 276 KB
Chapter 1Final publisher's version, 614 KB
Chapter 2Final publisher's version, 2,57 MB
Chapter 3Final publisher's version, 1,81 MB
Chapter 4Final publisher's version, 3,7 MB
Chapter 5Final publisher's version, 524 KB
Chapter 6Final publisher's version, 1,21 MB
Chapter 7Final publisher's version, 1,21 MB
Chapter 8Final publisher's version, 578 KB
AppendicesFinal publisher's version, 648 KB
Complete thesisFinal publisher's version, 10,7 MB
PropositionsFinal publisher's version, 53,1 KB

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title = "Circulating microRNAs in heart failure",

abstract = "In this thesis we addressed the identification of a circulating miRNA signature in patients with heart failure and placed these findings in perspective by investigating several hypotheses regarding their potential role and function. These miRNAs were found in the lowest levels in patients with the most acute state of heart failure and showed an increase towards stable forms of heart failure and healthy control subjects. A further in-hospital decrease was related to an increased risk of mortality. Several associations between miRNAs and other heart failure-related biomarkers were identified in patients with worsening heart failure, and target prediction complemented by pathway analyses resulted in potential mechanisms implicated in cardiac disease. Our results indicate that miRNAs and their correlation with biomarkers are dependent on timing of measurement and clinical disease status. It was additionally shown that changes in volume status were associated with changes in circulating miRNA levels, suggesting that fluid overload contributes to downregulated miRNA levels in acute heart failure. Furthermore, these miRNAs were associated to vascular dysfunction as reflected by the presence of atherosclerosis and related disease processes including inflammation, angiogenesis and endothelial dysfunction, and also have a predictive value for the risk of cardiovascular-related rehospitalization. In our attempt to identify a suitable heart failure animal model for mechanistic miRNA studies we were not able to replicate the previously found downregulated miRNA levels. These results place emphasis on the difficulty of translation between the human heart failure setting and animal data, and underline the complex biology of circulating miRNAs.",

author = "Vegter, {Eline Lizet}",

year = "2017",

language = "English",

isbn = "978-94-9268-392-2",

publisher = "Rijksuniversiteit Groningen",

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AU - Vegter, Eline Lizet

PY - 2017

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N2 - In this thesis we addressed the identification of a circulating miRNA signature in patients with heart failure and placed these findings in perspective by investigating several hypotheses regarding their potential role and function. These miRNAs were found in the lowest levels in patients with the most acute state of heart failure and showed an increase towards stable forms of heart failure and healthy control subjects. A further in-hospital decrease was related to an increased risk of mortality. Several associations between miRNAs and other heart failure-related biomarkers were identified in patients with worsening heart failure, and target prediction complemented by pathway analyses resulted in potential mechanisms implicated in cardiac disease. Our results indicate that miRNAs and their correlation with biomarkers are dependent on timing of measurement and clinical disease status. It was additionally shown that changes in volume status were associated with changes in circulating miRNA levels, suggesting that fluid overload contributes to downregulated miRNA levels in acute heart failure. Furthermore, these miRNAs were associated to vascular dysfunction as reflected by the presence of atherosclerosis and related disease processes including inflammation, angiogenesis and endothelial dysfunction, and also have a predictive value for the risk of cardiovascular-related rehospitalization. In our attempt to identify a suitable heart failure animal model for mechanistic miRNA studies we were not able to replicate the previously found downregulated miRNA levels. These results place emphasis on the difficulty of translation between the human heart failure setting and animal data, and underline the complex biology of circulating miRNAs.

AB - In this thesis we addressed the identification of a circulating miRNA signature in patients with heart failure and placed these findings in perspective by investigating several hypotheses regarding their potential role and function. These miRNAs were found in the lowest levels in patients with the most acute state of heart failure and showed an increase towards stable forms of heart failure and healthy control subjects. A further in-hospital decrease was related to an increased risk of mortality. Several associations between miRNAs and other heart failure-related biomarkers were identified in patients with worsening heart failure, and target prediction complemented by pathway analyses resulted in potential mechanisms implicated in cardiac disease. Our results indicate that miRNAs and their correlation with biomarkers are dependent on timing of measurement and clinical disease status. It was additionally shown that changes in volume status were associated with changes in circulating miRNA levels, suggesting that fluid overload contributes to downregulated miRNA levels in acute heart failure. Furthermore, these miRNAs were associated to vascular dysfunction as reflected by the presence of atherosclerosis and related disease processes including inflammation, angiogenesis and endothelial dysfunction, and also have a predictive value for the risk of cardiovascular-related rehospitalization. In our attempt to identify a suitable heart failure animal model for mechanistic miRNA studies we were not able to replicate the previously found downregulated miRNA levels. These results place emphasis on the difficulty of translation between the human heart failure setting and animal data, and underline the complex biology of circulating miRNAs.

M3 - Thesis fully internal (DIV)

SN - 978-94-9268-392-2

PB - Rijksuniversiteit Groningen

CY - [Groningen]

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Circulating microRNAs in heart failure

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