LONDON/CAMBRIDGE, UNITED KINGDOM. While much research has been done to analyze and describe the mechanism of the disorganized electrical activity underlying atrial fibrillation, the possibility of a dysfunctional metabolism playing a major role seems to have been overlooked. This may now change with some exciting new discoveries made by a group of researchers from the University of Cambridge and King's College, London. The researchers used two very powerful techniques (proteomics and metabolomics) to determine the impact of cardiac metabolism on the initiation and persistence of atrial fibrillation. Their paper is highly technical and to understand their findings it is necessary to bone up on a few definitions.Metabolism
is the set of chemical reactions that occur in living organisms in order to maintain life. These reactions are catalyzed and regulated by enzymes and can be divided into two major categories: - catabolism which involves the breakdown of large molecules and produces energy, and anabolism which uses energy to produce component of cells such as proteins and nucleic acids.Glycolysis
is the initial process in the breakdown (catabolism) of larger carbohydrate molecules into smaller units. It results in the production of pyrovate for the citric acid cycle (Krebs cycle, TCA cycle) of energy production and ATP (adenosine 5'-triphosphate), the body's main energy transporter.Ketone bodies
(acetoacetate, acetone, and beta-hydroxybutyrate) are produced when fatty acids are broken down in the liver and kidney to produce energy for use in the heart and brain.Proteomics
is the study of the function and structure of proteins. It uses highly sophisticated methods such as gel electrophoresis and mass spectrometry to separate and analyze the proteins and their structure.Metabolomics
is the study and identification of small-molecule metabolites generated by specific cellular processes (such as atrial fibrillation).
The British researchers compared metabolic variables in three groups of patients.
- Group SR – Patients in normal sinus rhythm prior to undergoing valve (nonrheumatic) surgery
- Group AF – Patients in permanent afib prior to undergoing valve surgery.
- Group SR-AF – Patients who developed afib after coronary artery bypass surgery.
The researchers extracted cardiac issue from all three groups during surgery and then looked for differences in protein and enzyme expression using proteomics and metabolomics. When comparing group SR with group AF they noted that heart tissue from group AF had higher levels of beta-hydroxybutyrate (a ketone body) and the ketogenic amino acids tyrosine and leucine. Group AF also had a significantly higher level of glycine and a higher fumarate/succinate ratio. Structural damage inflicted by prolonged AF was also evident as was depletion of the antioxidant protein peroxiredoxin 1 and a reduced level of ANP (atrial natriuretic peptide) precursor.
Looking at heart tissue from patients who developed afib after bypass surgery, the researchers observed that these patients had significantly reduced levels of glucose, beta-hydroxybutyrate, and acetate (a ketone body). They also noted that those who developed AF after surgery (bypass or valve) had a reduced glucose/acetate ratio and that their ratio of glycolytic end products (alanine, lactate) to lipoid metabolism end products (acetate) correlated positively with time of onset of post-operative AF (the lower the ratio, the earlier the onset of AF).
There is evidence that AF is associated with a high-energy demand and that this may explain many of the permanent changes in the atria resulting from permanent AF. There is also evidence that ketone bodies may be a main source of this energy during permanent AF.
The researchers conclude that ketone bodies play an important role in atrial fibrillation and that a discordant regulation of energy metabolites precedes the onset of AF after surgery.Mayr, M, et al. Combined metabolomic and proteomic analysis of human atrial fibrillation. Journal of the American College of Cardiology, Vol. 51, No. 5, February 5, 2008, pp. 585-94
: While these findings are most interesting and exciting, it is not at all clear how to interpret and take advantage of them. Most important, there is obviously no evidence that they apply to lone afibbers since all participants had underlying heart disease. The finding that bypass surgery patients who go into afib after their surgery are very low in ketone bodies (fatty acid breakdown products) during surgery ties in with recent findings that giving these patients fish oil supplements prior to the operation markedly reduce the risk of afib development.
The observation that valve surgery patients in permanent afib had a higher level of ketone bodies (during surgery) than did those in normal sinus rhythm support the hypothesis that the heart's energy demand is substantially increased during permanent afib and that much of this demand is met by burning fatty acids rather than glucose. This intriguing and most welcome research raises many important questions, but most of all, is hopefully the beginning of a trend to look for the causes of atrial fibrillation.