Increased cardiac Pi/PCr in the diabetic heart observed using phosphorus magnetic resonance spectroscopy at 7T.

Phosphorus magnetic resonance spectroscopy (31P-MRS) has previously demonstrated decreased energy reserves in the form of phosphocreatine to adenosine-tri-phosphate ratio (PCr/ATP) in the hearts of patients with type 2 diabetes (T2DM). Recent 31P-MRS techniques using 7T systems, e.g. long mixing time stimulated echo acquisition mode (STEAM), allow deeper insight into cardiac metabolism through assessment of inorganic phosphate (Pi) content and myocardial pH, which play pivotal roles in energy production in the heart. Therefore, we aimed to further explore the cardiac metabolic phenotype in T2DM using STEAM at 7T. Seventeen patients with T2DM and twenty-three healthy controls were recruited and their cardiac PCr/ATP, Pi/PCr and pH were assessed at 7T. Diastolic function of all patients with T2DM was assessed using echocardiography to investigate the relationship between diastolic dysfunction and cardiac metabolism. Mirroring the decreased PCr/ATP (1.70±0.31 vs. 2.07±0.39; p<0.01), the cardiac Pi/PCr was increased (0.13±0.07 vs. 0.10±0.03; p = 0.02) in T2DM patients in comparison to healthy controls. Myocardial pH was not significantly different between the groups (7.14±0.12 vs. 7.10±0.12; p = 0.31). There was a negative correlation between PCr/ATP and diastolic function (R2 = 0.33; p = 0.02) in T2DM. No correlation was observed between diastolic function and Pi/PCr and (R2 = 0.16; p = 0.21). In addition, we did not observe any correlation between cardiac PCr/ATP and Pi/PCr (p = 0.19). Using STEAM 31P-MRS at 7T we have for the first time explored Pi/PCr in the diabetic human heart and found it increased when compared to healthy controls. The lack of correlation between measured PCr/ATP and Pi/PCr suggests that independent mechanisms might contribute to these perturbations.

L-Carnitine Stimulates In Vivo Carbohydrate Metabolism in the Type 1 Diabetic Heart as Demonstrated by Hyperpolarized MRI.

The diabetic heart is energetically and metabolically abnormal, with increased fatty acid oxidation and decreased glucose oxidation. One factor contributing to the metabolic dysfunction in diabetes may be abnormal handling of acetyl and acyl groups by the mitochondria. L-carnitine is responsible for their transfer across the mitochondrial membrane, therefore, supplementation with L-carnitine may provide a route to improve the metabolic state of the diabetic heart. The primary aim of this study was to use hyperpolarized magnetic resonance imaging (MRI) to investigate the effects of L-carnitine supplementation on the in vivo metabolism of [1-13C]pyruvate in diabetes. Male Wistar rats were injected with either vehicle or streptozotocin (55 mg/kg) to induce type-1 diabetes. Three weeks of daily i.p. treatment with either saline or L-carnitine (3 g/kg/day) was subsequently undertaken. In vivo cardiac function and metabolism were assessed with CINE and hyperpolarized MRI, respectively. L-carnitine supplementation prevented the progression of hyperglycemia, which was observed in untreated streptozotocin injected animals and led to reductions in plasma triglyceride and ß-hydroxybutyrate concentrations. Hyperpolarized MRI revealed that L-carnitine treatment elevated pyruvate dehydrogenase flux by 3-fold in the diabetic animals, potentially through increased buffering of excess acetyl-CoA units in the mitochondria. Improved functional recovery following ischemia was also observed in the L-carnitine treated diabetic animals.

Weighted averaging in spectroscopic studies improves statistical power.

PURPOSE: In vivo MRS is often characterized by a spectral signal-to-noise ratio (SNR) that varies highly between experiments. A common design for spectroscopic studies is to compare the ratio of two spectral peak amplitudes between groups, e.g. individual PCr/γ-ATP ratios in 31 P-MRS. The uncertainty on this ratio is often neglected. We wished to explore this assumption. THEORY: The canonical theory for the propagation of uncertainty on the ratio of two spectral peaks and its incorporation in the Frequentist hypothesis testing framework by weighted averaging is presented. METHODS: Two retrospective re-analyses of studies comparing spectral peak ratios and one prospective simulation were performed using both the weighted and unweighted methods. RESULTS: It was found that propagating uncertainty correctly improved statistical power in all cases considered, which could be used to reduce the number of subjects required to perform an MR study. CONCLUSION: The variability of in vivo spectroscopy data is often accounted for by requiring it to meet an SNR threshold. A theoretically sound propagation of the variable uncertainty caused by quantifying spectra of differing SNR is therefore likely to improve the power of in vivo spectroscopy studies. Magn Reson Med 78:2082-2094, 2017. © 2017 The Authors Magnetic Resonance in Medicine published by Wiley Periodicals, Inc. on behalf of International Society for Magnetic Resonance in Medicine. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.

Pyruvate dehydrogenase as a therapeutic target for obesity cardiomyopathy.

INTRODUCTION: Obesity cardiomyopathy is a major public health problem with few specific therapeutic options. Abnormal cardiac substrate metabolism with reduced pyruvate dehydrogenase (PDH) activity is associated with energetic and functional cardiac impairment and may be a therapeutic target. AREAS COVERED: This review summarizes the changes to cardiac substrate and high energy phosphorus metabolism that occur in obesity and describes the links between abnormal metabolism and impairment of cardiac function. The available evidence for the currently available pharmacological options for selective metabolic therapy in obesity cardiomyopathy is reviewed. EXPERT OPINION: Pharmacological restoration of PDH activity is in general associated with favourable effects upon cardiac substrate metabolism and function in both animal models and small scale human studies, supporting a potential role as a therapeutic target.

Short-term consumption of a high-fat diet impairs whole-body efficiency and cognitive function in sedentary men.

We recently showed that a short-term high-fat diet blunted exercise performance in rats, accompanied by increased uncoupling protein levels and greater respiratory uncoupling. In this study, we investigated the effects of a similar diet on physical and cognitive performance in humans. Twenty sedentary men were assessed when consuming a standardized, nutritionally balanced diet (control) and after 7 d of consuming a diet comprising 74% kcal from fat. Efficiency was measured during a standardized exercise task, and cognition was assessed using a computerized assessment battery. Skeletal muscle mitochondrial function was measured using (31)P magnetic resonance spectroscopy. The diet increased mean ± se plasma free fatty acids by 44% (0.32±0.03 vs. 0.46±0.05 mM; P<0.05) and decreased whole-body efficiency by 3% (21±1 vs. 18±1%; P<0.05), although muscle uncoupling protein (UCP3) content and maximal mitochondrial function were unchanged. High-fat diet consumption also increased subjects' simple reaction times (P<0.01) and decreased power of attention (P<0.01). Thus, we have shown that a high-fat diet blunts whole-body efficiency and cognition in sedentary men. We suggest that this effect may be due to increased respiratory uncoupling.

A comparison of cardiac (31)P MRS at 1.5 and 3 T.

(31)P MRS was evaluated on normal volunteers at 1.5 and 3 T, and the signal-to-noise ratio (SNR) of the two field strengths was calculated. The in vivo spin-lattice, T(1), relaxation times for PCr and gamma-ATP, which are essential for correcting for the effects of radiofrequency saturation on the PCr/ATP ratio, were determined at 3 T. The T(1) values for six volunteers were 3.8 +/- 0.7 s for PCr (mean +/- SD) and 2.4 +/- 1.1 s for gamma-ATP, which are similar to reported values at 1.5 T, allowing us to use protocols developed at 1.5 T at the new clinical field strength of 3 T. Direct comparison between 1.5 T and 3 T in the same 10 subjects, using coils of identical geometry and identical pulse sequences gave a mean SNR for PCr at 3 T which was 206 +/- 94% of that at 1.5 T. The linewidth for PCr increased from 13 +/- 6 Hz at 1.5 T to 22 +/- 12 Hz at 3 T. The coefficient of variation in the measurement of PCr/ATP, based on the Cramer-Rao lower bounds, was reduced from 32 +/- 25% at 1.5 T to 18 +/- 13% at 3 T. Thus, (31)P MRS at 3 T is greatly improved by the increase in SNR compared with acquisitions at 1.5 T because of the higher field strength.

Ultrashort TE chemical shift imaging (UTE-CSI).

A fundamental modification to the conventional chemical shift imaging (CSI) method is described that improves the imaging of species with short T2's (i.e., less than approximately 2 ms). This approach minimizes the delay before each k-space point is collected. This results in different time delays, T(d), for different free induction decay (FID) acquisitions in k-space. On a clinical 1.5 T system this yields an effective delay due to transmit/receive switching of 70 micros and an echo time (TE) from the center of the excitation pulse to the center of k-space of 170 micros, as compared with 1-2 ms for conventional CSI techniques. Using this method, the signal decay before acquisition is greatly reduced, thus enabling imaging of species with very short T2)(e.g., 200 micros) and increasing the signal-to-noise ratio (SNR) of species with intermediate T2. Increases in the SNR of the short T2 components of 23Na in the heart, and 31P acquisitions of bone are about 27% and 400%, respectively, compared to an optimized conventional CSI approach. The imperfections of this approach are also described, and the magnitude of the resultant image artifacts is quantified for different practical imaging situations. These artifacts were not found to be significant in the described applications. This new method allows us to obtain information on short T2 components without degrading the image quality from long T2 components.