Bioenergetic Abnormalities Associated with Severe Left Ventricular Hypertrophy

Abstract Transmurally localized 31P-nuclear magnetic resonance spectroscopy (NMR) was used to study the effect of severe pressure overload left ventricular hypertrophy (LVH) on myocardial high energy phosphate content. Studies were performed on 8 normal dogs and 12 dogs with severe left ventricular hypertrophy produced by banding the ascending aorta at 8 wk of age. Spatially localized 31P-NMR spectroscopy provided measurements of the transmural distribution of myocardial ATP, phosphocreatine (CP), and inorganic phosphate (Pi); spectra were calibrated from measurements of ATP content in myocardial biopsies using HPLC. Blood flow was measured with microspheres. In hypertrophied hearts during basal conditions, ATP was decreased by 42%, CP by 58%, and the CP/ATP ratio by 32% in comparison with normal. Increasing myocardial blood flow with adenosine did not correct these abnormalities, indicating that they were not the result of persistent hypoperfusion. Atrial pacing at 200 and 240 beats per min caused no change in high energy phosphate content in normal hearts but resulted in further CP depletion with Pi accumulation in the inner left ventricular layers of the hypertrophied hearts. These changes were correlated with redistribution of blood flow away from the subendocardium in LVH hearts. These findings demonstrate that high energy phosphate levels and the CP/ATP ratio are significantly decreased in severe LVH. These abnormalities are proportional to the degree of hypertrophy but are not the result of persistent abnormalities of myocardial perfusion. In contrast, depletion of CP and accumulation of Pi during tachycardia in LVH are closely related to the pacing-induced perfusion abnormalities and likely reflect subendocardial ischemia. (J. Clin. Invest. 1993. 92:993-100

Coordination Polymers Based on [Cp*FeACHTUNGTRENUNG(h5-P5)]:\ud MAS NMR Studies

Slow diffusion reactions of the pentaphosphaferrocene ['CP AST'FE'('eta POT. 5-'P IND. 5')] ('CP AST'='eta POT. 5'- 'C IND. 5''ME IND. 5'. (1)) with 'CU'X (X='CL', 'BR', I) in different stoichiometric ratios and solvent mixtures result in the formation of one- and two-dimensional polymeric compounds 2-6 with molecular formula '[{'CU'('mü'-X)}-{'CP AST''FE'('mü IND.3','eta POT. 5':'eta POT. 1':'eta POT. 1'-'P IND. 5')}] IND. n' (X='CL' (2a), I (2'c)), '[{'CU'('mü'-I)}-{'CP AST''FE'('mü IND.3','eta POT. 5':'eta POT. 1':'eta POT. 1'-'P IND. 5')}] IND. n'(3), '[{'CU'('mü'-X)}-{'CP AST''FE'('mü IND.4','eta POT. 5':'eta POT. 1':'eta POT. 1'-'P IND. 5')}] IND. n' (X='CL' (4a), 'BR' (4b), I (4c), 'BR' (4'b), I (4'c)), '[{'CU IND.3''('mü'-I) IND. 2'('mü IND. 3'-I)}- {'CP AST''FE'('mü IND. 5','eta POT. 5':'eta POT. 1':'eta POT. 1':'eta POT. 1''P IND. 5')}] IND n' (5) and '[{'CU IND. 4''('mü'-X) IND. 4'(C'H IND. 3'CN)}- {'CP AST''FE'('mü IND. 7','eta POT. 5':'eta POT. 2':'eta POT. 1':'eta POT 1':'eta POT. 1'-'P IND. 5')}] IND n'(X='CL' (6a), 'BR' (6b)), respectively. The polymeric compounds have been characterised by single-crystal X-ray diffraction analyses and, for selected examples, by magic angle spinning (MAS) NMR spectroscopy. The solidstate structures demonstrate the versatile coordination modes of the cyclo-'P IND. 5' ligand of 1, extending from two to five coordinating phosphorus atoms in either 'sigma' or 'sigma'-and-'pi' fashion. In compounds 2a, 2'c and 3, two phosphorus atoms of 1 coordinate to copper atoms in a 1,2 coordination mode (2a, 2'c) and an unprecedented 1,3 coordination mode (3) to form one-dimensional polymers. Compounds 4a-c, 4'b, 4'c and 5 represent two-dimensional coordination polymers. In compounds 4, three phosphorus atoms coordinate to copper atoms in a 1,2,4 coordination mode, whereas in 5 the cyclo-'P IND. 5' ligand binds in an unprecedented 1,2,3,4 coordination mode. The crystal structures of 6a,b display a tilted tube, in which all P atoms of the cyclo-'P IND. 5' ligand are coordinated to copper atoms in 'sigma'- and 'pi'-bonding modes.Deutsche Forschungsgemeinschaft (projects Sche 384/26- 1 and Ec168/10, “Supramolecular Aggregations

Imaging of Glucose Metabolism by 13C-MRI Distinguishes Pancreatic Cancer Subtypes in Mice

Metabolic differences among and within tumors can be an important determinant in cancer treatment outcome. However, methods for determining these differences non-invasively in vivo is lacking. Using pancreatic ductal adenocarcinoma as a model, we demonstrate that tumor xenografts with a similar genetic background can be distinguished by their differing rates of the metabolism of 13C labeled glucose tracers, which can be imaged without hyperpolarization by using newly developed techniques for noise suppression. Using this method, cancer subtypes that appeared to have similar metabolic profiles based on steady state metabolic measurement can be distinguished from each other. The metabolic maps from 13C-glucose imaging localized lactate production and overall glucose metabolism to different regions of some tumors. Such tumor heterogeneity would not be not detectable in FDG-PET

Dynamic Imaging of Glucose and Lactate Metabolism by C-13-MRS without Hyperpolarization

Abstract Metabolic reprogramming is one of the defining features of cancer and abnormal metabolism is associated with many other pathologies. Molecular imaging techniques capable of detecting such changes have become essential for cancer diagnosis, treatment planning, and surveillance. In particular, 18F-FDG (fluorodeoxyglucose) PET has emerged as an essential imaging modality for cancer because of its unique ability to detect a disturbed molecular pathway through measurements of glucose uptake. However, FDG-PET has limitations that restrict its usefulness in certain situations and the information gained is limited to glucose uptake only.13C magnetic resonance spectroscopy theoretically has certain advantages over FDG-PET, but its inherent low sensitivity has restricted its use mostly to single voxel measurements unless dissolution dynamic nuclear polarization (dDNP) is used to increase the signal, which brings additional complications for clinical use. We show here a new method of imaging glucose metabolism in vivo by MRI chemical shift imaging (CSI) experiments that relies on a simple, but robust and efficient, post-processing procedure by the higher dimensional analog of singular value decomposition, tensor decomposition. Using this procedure, we achieve an order of magnitude increase in signal to noise in both dDNP and non-hyperpolarized non-localized experiments without sacrificing accuracy. In CSI experiments an approximately 30-fold increase was observed, enough that the glucose to lactate conversion indicative of the Warburg effect can be imaged without hyper-polarization with a time resolution of 12s and an overall spatial resolution that compares favorably to 18F-FDG PET

Laminar differences in functional oxygen metabolism in monkey visual cortex measured with calibrated fMRI

Summary: Blood-oxygenation-level-dependent functional magnetic resonance imaging (BOLD fMRI) of cortical layers relies on the hemodynamic response and is biased toward large veins on the cortical surface. Functional changes in the cerebral metabolic rate of oxygen (ΔCMRO2) may reflect neural cortical function better than BOLD fMRI, but it is unknown whether the calibrated BOLD model for functional CMRO2 measurement remains valid at high resolution. Here, we measure laminar ΔCMRO2 elicited by visual stimulation in macaque primary visual cortex (V1) and find that ΔCMRO2 peaks in the middle of the cortex, in agreement with autoradiographic measures of metabolism. ΔCMRO2 values in gray matter are similar as found previously. Reductions in CMRO2 are associated with veins at the cortical surface, suggesting that techniques for vein removal may improve the accuracy of the model at very high resolution. However, our results show feasibility of laminar ΔCMRO2 measurement, providing a physiologically meaningful metric of laminar functional metabolism

Functional MRI Evidence for LTP-Induced Neural Network Reorganization

The hippocampal formation is a region of the forebrain that is important for memory and spatial navigation [1] and [2]. On the basis of a vast amount of literature, the hippocampus is linked with long-term potentiation (LTP), the increased synaptic strength following repeated stimulation of the hippocampal neurons [3] and [4]. LTP is considered to be the experimental demonstration of Hebb‘s postulate on synaptic strength and learning [5], and it is the dominant model of an experience-dependent modification of brain circuits. Yet, despite the importance of this phenomenon for brain physiology and behavior, little is known about how experimentally measured regional synaptic modifications alter the activity of global, widespread networks. Here, we use simultaneous fMRI, microstimulation, and electrophysiology [6], [7] and [8] to unveil global changes in brain activity due to local hippocampal plasticity. Our findings offer the first evidence of an LTP-induced network reorganization that includes increased interhemispheric communication and recruitment of limbic and neocortical circuits after changes in synaptic strength within the hippocampus