BackgroundAlterations in cardiac metabolism accompany many diseases of the heart. The advent of cardiac hyperpolarized magnetic resonance spectroscopy (MRS), via dynamic nuclear polarization (DNP), has enabled a greater understanding of the in vivo metabolic changes that occur as a consequence of myocardial infarction, hypertrophy and diabetes. However, all cardiac studies performed to date have focused on rats and larger animals, whereas more information could be gained through the study of transgenic mouse models of heart disease. Translation from the rat to the mouse is challenging, due in part to the reduced heart size (1/10th) and the increased heart rate (50%) in the mouse compared to the rat.Methods and ResultsIn this study, we have investigated the in vivo metabolism of [1-13C]pyruvate in the mouse heart. To demonstrate the sensitivity of the method to detect alterations in pyruvate dehydrogenase (PDH) flux, two well characterised methods of PDH modulation were performed; overnight fasting and infusion of sodium dichloroacetate (DCA). Fasting resulted in an 85% reduction in PDH flux, whilst DCA infusion increased PDH flux by 123%. A comparison of three commonly used control mouse strains was performed revealing significant metabolic differences between strains.ConclusionsWe have successfully demonstrated a hyperpolarized DNP protocol to investigate in vivo alterations within the diseased mouse heart. This technique offers a significant advantage over existing in vitro techniques as it reduces animal numbers and decreases biological variability. Thus [1-13C]pyruvate can be used to provide an in vivo cardiac metabolic profile of transgenic mice.
Objective: To establish the analytical performance of a heart fatty acid binding protein (HFABP) method suitable for routine clinical use and examine its role for the diagnosis of myocardial ischemia and myocardial infarction. Methods: Analyses of HFABP were performed on an Advia 2400 (Siemens Healthcare Diagnostics). Imprecision, limit of detection (LOD), limit of blank (LOB), and linearity were assessed using standard methods. Stability was assessed at 4°C, −20°C, and with 3 repeated freeze-thaw cycles. Clinical diagnostic performance was assessed using chest pain in patients, with a final diagnosis according to the universal definition of myocardial infarction with cardiac troponin I (cTnI) measured on the Siemens Advia Centaur (cTnI Ultra method, 99th percentile 50 ng/L, 10% CV 30 ng/L). Ischemia was detected using sampling pre-and postangioplasty. Results: LOD and analytical imprecision exceeded the manufacturer's specification (LOD 1.128 μg/L, 20% CV 1.3 μg/L, 10% CV 2.75 μg/L). Clinical diagnostic efficiency was less than cTnI. Addition of HFABP to cTnI produced a modest increase in diagnostic sensitivity at a cost of significant loss of specificity. Conclusions: Although the test had excellent analytical performance, it did not contribute to the clinical diagnosis of patients with chest pain. HFABP appears to be a marker of myocardial infarction not myocardial ischemia. IMPACT STATEMENT In this study, the performance characteristics of a fully automated assay for heart fatty acid binding protein (HFABP) were confirmed against the manufacturer's specification. The clinical role was examined for the early diagnosis of acute myocardial infarction (AMI) in patients presenting with chest pain and in patients undergoing percutaneous intervention as a model of myocardial ischemia. The assay met performance specifications. HFABP is a marker of myocardial necrosis, not myocardial ischemia, and does improve early sensitivity for detection of AMI but results in a significant loss of diagnostic specificity when combined with cardiac troponin measurement.
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