Combined metabolomic and proteomic analysis of human atrial fibrillation.
OBJECTIVE
We sought to decipher metabolic processes servicing the increased energy demand during persistent atrial fibrillation (AF) and to ascertain whether metabolic derangements might instigate this arrhythmia.


BACKGROUND
Whereas electrical, structural, and contractile remodeling processes are well-recognized contributors to the self-perpetuating nature of AF, the impact of cardiac metabolism upon the persistence/initiation of this resilient arrhythmia has not been explored in detail.


METHODS
Human atrial appendage tissues from matched cohorts in sinus rhythm (SR), from those who developed AF post-operatively, and from patients in persistent AF undergoing cardiac surgery were analyzed using a combined metabolomic and proteomic approach.


RESULTS
High-resolution proton nuclear magnetic resonance (NMR) spectroscopy of cardiac tissue from patients in persistent AF revealed a rise in beta-hydroxybutyrate, the major substrate in ketone body metabolism, along with an increase in ketogenic amino acids and glycine. These metabolomic findings were substantiated by proteomic experiments demonstrating differential expression of 3-oxoacid transferase, the key enzyme for ketolytic energy production. Notably, compared with the SR cohort, the group susceptible to post-operative AF showed a discordant regulation of energy metabolites. Combined principal component and linear discriminant analyses of metabolic profiles from proton NMR spectroscopy correctly classified more than 80% of patients at risk of AF at the time of coronary artery bypass grafting.


CONCLUSIONS
The present study characterized the metabolic adaptation to persistent AF, unraveling a potential role for ketone bodies, and demonstrated that discordant metabolic alterations are evident in individuals susceptible to post-operative AF.
Mayr
Manuel
M
Cardiovascular Division, King's College, London, United Kingdom. manuel.mayr@kcl.ac.uk
Yusuf
Shamil
S
Weir
Graeme
G
Chung
Yuen-Li
YL
Mayr
Ursula
U
Yin
Xiaoke
X
Ladroue
Christophe
C
Madhu
Basetti
B
Roberts
Neil
N
De Souza
Ayesha
A
Fredericks
Salim
S
Stubbs
Marion
M
Griffiths
John R
JR
Jahangiri
Marjan
M
Xu
Qingbo
Q
Camm
A John
AJ
D020155:3-Hydroxybutyric Acid / Q000378:metabolism*; D001281:Atrial Fibrillation / Q000209:etiology / Q000378:metabolism*; D015256:Coenzyme A-Transferases / Q000378:metabolism*; D001026:Coronary Artery Bypass; D003327:Coronary Disease / Q000150:complications / Q000378:metabolism / Q000601:surgery; D006801:Humans; D007657:Ketone Bodies / Q000378:metabolism*; D009682:Magnetic Resonance Spectroscopy; D009206:Myocardium / Q000201:enzymology / Q000378:metabolism*; D011183:Postoperative Complications / Q000209:etiology / Q000378:metabolism; D040901:Proteomics
D007657:Ketone Bodies; D015256:Coenzyme A-Transferases; C021460:3-ketoacid CoA-transferase; D020155:3-Hydroxybutyric Acid