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CLINICAL RESEARCH: HEART RHYTHM DISORDER

Combined Metabolomic and Proteomic Analysis of Human Atrial Fibrillation

Manuel Mayr, MD, PhD^_*,1,_*, Shamil Yusuf, MRCP^,1,_**, Graeme Weir, MB, Yuen-Li Chung, PhD, Ursula Mayr, MD^_*, Xiaoke Yin, PhD^_*, Christophe Ladroue, PhD^||, Basetti Madhu, MSc, PhD^¶, Neil Roberts, MB, Ayesha De Souza, PhD, Salim Fredericks, PhD, Marion Stubbs, DPhil^¶, John R. Griffiths, MB, BS, DPhil^¶, Marjan Jahangiri, MD, MRCS, Qingbo Xu, MD, PhD^_* and A. John Camm, MD, FRCP, FACC

^_* Cardiovascular Division, King’s College, London, United Kingdom
Department of Cardiac and Vascular Sciences, St. George’s, University of London, London, United Kingdom
Department of Cardiac Surgery, St. George’s, University of London, London, United Kingdom
Department of Basic Medical Sciences, St. George’s, University of London, London, United Kingdom
^|| Department of Informatics, University of Sussex, Brighton, United Kingdom
^¶ Cancer Research UK Cambridge Research Institute, Cambridge, United Kingdom.

Manuscript received December 29, 2006; revised manuscript received July 12, 2007, accepted September 7, 2007.

^_* Reprint requests and correspondence: Dr. Manuel Mayr, Cardiovascular Division, King’s College, University of London, 125 Coldharbour Lane, London SE5 9NU, United Kingdom (Email: manuel.mayr{at}kcl.ac.uk).

^_** Dr. Shamil Yusuf, Department of Cardiac and Vascular Sciences, St. George’s, University of London, Cranmer Terrace, London SW17 0RE, United Kingdom. (Email: s.yusuf{at}sgul.ac.uk).

Objectives: 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.

Abbreviations and Acronyms   AF = atrial fibrillation   CABG = coronary artery bypass grafting   CRP = C-reactive protein   MALDI = matrix-assisted laser-desorption ionization   NMR = nuclear magnetic resonance   PCA = principal component analysis   SR = sinus rhythm

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