Metabolic Flux as a Predictor of Heart Failure Prognosis
2014; Lippincott Williams & Wilkins; Volume: 114; Issue: 8 Linguagem: Inglês
10.1161/circresaha.114.303551
ISSN1524-4571
AutoresCraig A. Lygate, Stefan Neubauer,
Tópico(s)Cardiovascular and exercise physiology
ResumoHomeCirculation ResearchVol. 114, No. 8Metabolic Flux as a Predictor of Heart Failure Prognosis Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBMetabolic Flux as a Predictor of Heart Failure Prognosis Craig A. Lygate and Stefan Neubauer Craig A. LygateCraig A. Lygate From the Division of Cardiovascular Medicine, Radcliffe Department of Medicine, British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, United Kingdom. and Stefan NeubauerStefan Neubauer From the Division of Cardiovascular Medicine, Radcliffe Department of Medicine, British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, United Kingdom. Originally published11 Apr 2014https://doi.org/10.1161/CIRCRESAHA.114.303551Circulation Research. 2014;114:1228–1230IntroductionMetabolic Rates of ATP Transfer Through Creatine Kinase (CK Flux) Predict Clinical Heart Failure Events and DeathBottomley et al8Sci Transl Med. 2013;5:215re3.doi:10.1126/scitranslmed.3007328.The creatine kinase (CK) system is thought to play an integral role in maintaining levels of chemical energy in the form of ATP, which is essential for normal cardiac function. In the failing heart, it has long been established that multiple components of CK energy metabolism are commonly impaired and that these correlate with disease severity. A recent study published in Science Translational Medicine adds significantly to this body of evidence by demonstrating that the rate of ATP transfer via CK, measured noninvasively by magnetic resonance spectroscopy, is an independent predictor of adverse clinical outcome in patients with nonischemic cardiomyopathy. This finding invites speculation on the future role of metabolic imaging for risk stratification in patients with heart failure. The authors further assert an implied causal role for energetics in disease progression. Although this is not supported by recent findings in loss-of-function mouse models, there is, nonetheless, a strong argument for the development of novel metabolic therapies for the failing heart.The only established role for creatine kinase is to catalyze the reversible transfer of a high-energy phosphate moiety between ATP and creatine: Cr+ATP↔PCr+ADP+H+. This initial reaction takes place at the mitochondria to create phosphocreatine (PCr), which accumulates to high levels and is readily diffusible to sites of utilization. At times of increased energy demand, PCr is available for rapid regeneration of ATP under the control of CK. Thus, the CK system is recognized to have both energy storage and energy transfer roles, whereas compartmentalization via specific CK isoforms enables buffering of local reactant concentrations in a thermodynamically favorable way.1Evidence for an impaired CK system in the human failing heart dates as far back as 1939 with the observation that total creatine levels are reduced by 30%.2 Since then, numerous animal and human studies have established firmly that a reduction in both creatine and CK enzymatic activity are a hallmark of the failing heart, regardless of pathogenesis.1,3 During the 1980s, advances in 31P MRS enabled noninvasive measurement of high-energy phosphate metabolites in the living human heart for the first time.4 The Figure shows stylized cardiac 31P spectra illustrating the typically large PCr peak and 3 smaller peaks representing the phosphate groups of ATP. Absolute concentrations are difficult to obtain and for this reason it is common to report the PCr/ATP ratio as a measure of relative abundance (value ≈1.8 in the normal heart). This ratio is a relatively robust marker of energetic status because it reflects loss of total creatine and the equilibrium constant for the CK reaction favors ATP synthesis by 100-fold, such that ATP levels are maintained near normal in all but the most advanced stages of heart failure.3 A fall in PCr/ATP, therefore, mostly reflects a fall in PCr levels. Clearly, however, there may be a pseudonormalization of PCr/ATP under circumstances where ATP becomes depleted. A series of studies in the 1990s showed that PCr/ATP was significantly reduced in patients with dilated cardiomyopathy and correlated with traditional measures of heart failure severity such as New York Heart Association class and ejection fraction.5,6 Furthermore, patients that responded to medical treatment also showed an improvement in PCr/ATP,5 and in a prospective study, PCr/ATP was shown to be an excellent prognostic indicator of mortality.7Download figureDownload PowerPointFigure. 31P spectra from a normal ex vivo rat heart during a saturation transfer experiment. Selective irradiation at the frequency corresponding to the γ-ATP peak (small arrow) effectively renders this phosphate group NMR-invisible. Under the action of creatine kinase (CK), this invisible phosphate group is interconverted to phosphocreatine (PCr), but remains NMR-invisible. The observed result is a reduction in the visible PCr peak. The extent of this reduction reflects the rate of phosphotransfer via CK, that is, CK flux. Adapted from Lygate et al16 with permission.The latest report by Bottomley et al8 is a welcome and logical progression of this approach and builds on earlier studies from the same group to establish 31P MRS methods to measure CK flux in the human heart.9–11 Acquiring these measurements is a major technical challenge, but the basic concept is simple enough12 (Figure). There are several reasons why flux might be superior to measuring metabolite levels. First, it avoids the problem of PCr/ATP pseudonormalization described above. Second, flux through CK is arguably more sensitive with a wider dynamic range, because it reflects both changes in metabolites and in CK activity. Third, it has been argued that CK is part of a near-equilibrium enzymatic network, where changes in flux may occur in the absence of altered metabolite levels.13 However, it should be noted that there is a certain ambiguity to what exactly CK flux represents because it is not uni-directional, but rather an average flux for all NMR-visible CK reactions within the volume of interest, and in common with metabolite quantification there is no distinction between different cellular compartments.12Having previously established that CK flux is impaired in patients with heart failure,9 Bottomley et al8 report on a prospective nonrandomized study in 58 patients with nonischemic cardiomyopathy and 17 healthy volunteers. All were confirmed to be free of coronary artery disease and had been clinically stable for ≥2 weeks before a single 31P MRS examination to obtain a 1-dimensional (1D) data set from the anterior myocardium. Follow-up was for a median 4.7 years (up to 8.2 years) with death and hospitalization as end points. The take-home finding is that CK flux, but not metabolite levels or PCr/ATP, was an independent predictor of all cause and cardiovascular mortality.Clearly this is a promising initial finding, which needs to be repeated in a larger and more diverse cohort. For example, it is important to know whether reduced CK flux is selective for heart failure. The authors have shown previously that CK flux is reduced in ischemic myocardium commensurate with the extent of infarct transmurality,10 and have excluded coronary artery disease in this study. What other comorbidities may affect CK flux? The PCr/ATP ratio has been shown to be reduced in hypertension, diabetes mellitus, obesity, valve disease, and inherited heart muscle diseases, such as hypertrophic cardiomyopathy.14 Although not studied to date, it is likely that CK flux will also be decreased in these conditions. Furthermore, are these findings true for all ages and ethnicities? It is a limitation that this study examines a single time point, when change in flux over time may be an even better prognostic indicator. This would also answer the question of whether CK flux is a marker for therapeutic efficacy, that is, does CK flux increase when New York Heart Association class improves as previously shown for PCr/ATP ratio.5 Comparison with established prognostic indicators would be advantageous, for example, does CK flux correlate with ejection fraction or New York Heart Association class in these patients? How does it compare with plasma brain natriuretic peptide levels, which are, after all, much quicker and simpler to measure as a supplementary prognostic indicator?The current technology has methodological limitations relying as it does on a single 1D slice from the anterior myocardium. This risks signal contamination from the intercostal muscles and necessarily assumes that energetic changes are homogeneous throughout the myocardium. As discussed, this is not true for ischemic heart disease, and patients with anterior myocardial infarction would not be suitable for assessing heart failure prognosis using this approach. However, it is surely only a matter of time before 2D- and 3D-chemical shift imaging approaches become available for CK flux measurement and circumvent this problem. As with PCr/ATP ratio in the 1990s there remain major practical barriers to adoption of CK flux as a routine prognostic marker, not least is access to an MR system with specialized phosphorus coils and technical expertise. This makes it expensive and time consuming, with the average scan in this study taking 70 minutes, which may be too long for many patients to endure. Again, we can confidently expect these barriers to diminish as the technology matures. For example, we have shown recently that, compared with 3 Tesla as used by Bottomley et al, the ultrahigh field strength of 7 Tesla improves the signal:noise ratio (SNR) of 31P MRS by a factor of 2.8, thus theoretically shortening examination time by a factor of >7 for the same signal:noise ratio.15 To our knowledge, the Bottomley group is currently the only one worldwide that has established cardiac CK flux measurements. It remains to be seen whether such measurements are reproducible between laboratories, that is, can we compare results between different centers. Given the inherent measurement errors and biological noise, a key question is whether variability is sufficiently low to detect small but physiologically significant differences. For example, if, as has been suggested, reduced CK flux occurs early in disease pathogenesis, then can it be used to predict patients who are about to develop heart failure? This kind of risk stratification is more likely to have a real impact on clinical practice than predicting poor prognosis in patients that are already diagnosed and receiving optimal therapy. A much larger prospective study in a general aging population could address this question. In the meantime, it seems likely that there will be a niche role for CK flux measurements in the assessment of new therapies specifically targeting cardiac energetics and metabolism.So what do these findings tell us about the pathophysiology of heart failure? The Bottomley study adds to a growing number of clinical studies for several decades that provide correlative evidence that energetic changes are closely related with the development of heart failure. This clearly implies, but does not prove causality, particularly since the results from mouse models have been much more equivocal. Our laboratory has shown recently that mice completely deficient in creatine and PCr do not develop more severe heart failure and have normal survival after chronic myocardial infarction.16 We have demonstrated previously similar findings in rats with pharmacological depletion of creatine and in mice with genetic deletion of CK,17,18 showing that CK deficiency is unlikely, in itself, to contribute to worsening heart failure. We would therefore argue that the issue of causality has yet to be settled, but perhaps this is a side-show that can await clarification at a later date. The more important issue is not whether CK deficiency is an underlying cause of heart failure, but more pertinently, whether augmenting the CK system (ie, supraphysiological stimulation) has therapeutic promise. An important proof-of-principle study, also from the Johns Hopkins group, recently demonstrated that the answer to this question is yes. Transgenic mice overexpressing the muscle isoform of CK in the heart maintained CK flux at higher levels in a heart failure model of pressure-overload, and this was associated with higher ejection fraction and improved survival.19 This opens a whole new and exciting avenue for future study and the ability to make noninvasive measurements of CK flux is likely to play a pivotal role. Clearly, this technology is still in its infancy but we can expect to hear a lot more from metabolic flux imaging in the years to come.Sources of FundingWork in our laboratory is funded by a grant from the British Heart Foundation (RG/13/8/30266).FootnotesThe opinions expressed in this Commentary are not necessarily those of the editors or of the American Heart Association.Commentaries serve as a forum in which experts highlight and discuss articles (published here and elsewhere) that the editors of Circulation Research feel are of particular significance to cardiovascular medicine.Commentaries are edited by Aruni Bhatnagar & Ali J. Marian.Correspondence to Craig A. Lygate, PhD, Division of Cardiovascular Medicine, Radcliffe Department of Medicine, British Heart Foundation Centre of Research Excellence, University of Oxford, Oxford, United Kingdom. E-mail [email protected]References1. Neubauer S. 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Birkedal R, Laasmaa M and Vendelin M (2014) The location of energetic compartments affects energetic communication in cardiomyocytes, Frontiers in Physiology, 10.3389/fphys.2014.00376, 5 Kapelko V (2019) Why Myocardial Relaxation Always Slows at Cardiac Pathology?, Kardiologiia, 10.18087/cardio.2019.12.n801, 59:12, (44-51) April 11, 2014Vol 114, Issue 8 Advertisement Article InformationMetrics © 2014 American Heart Association, Inc.https://doi.org/10.1161/CIRCRESAHA.114.303551PMID: 24723654 Originally publishedApril 11, 2014 PDF download Advertisement SubjectsComputerized Tomography (CT)Heart FailureMetabolism
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