Abnormal myocardial phosphorus-31 nuclear magnetic resonance spectroscopy in women with chest pain but normal coronary angiograms.

BACKGROUND: After hospitalization for chest pain, women are more likely than men to have normal coronary-artery angiograms. In such women, myocardial ischemia in the absence of clinically significant coronary-artery obstruction has long been suspected. Most methods for the detection of the metabolic effects of myocardial ischemia are highly invasive. Phosphorus-31 nuclear magnetic resonance (31P-NMR) spectroscopy is a noninvasive technique that can directly measure high-energy phosphates in the myocardium and identify metabolic evidence of ischemia. METHODS: We enrolled 35 women who were hospitalized for chest pain but who had no angiographically significant coronary-artery obstructions and 12 age- and weight-matched control women with no evidence of heart disease. Myocardial high-energy phosphates were measured with 31P-NMR spectroscopy at 1.5 tesla before, during, and after isometric handgrip exercise at a level that was 30 percent of the maximal voluntary grip strength. We measured the change in the ratio of phosphocreatine to ATP during exercise. RESULTS: Seven (20 percent) of the 35 women with chest pain and no angiographically significant stenosis had decreases in the phosphocreatine:ATP ratio during exercise that were more than 2 SD below the mean value in the control subjects without chest pain. There were no significant differences between the two groups with respect to hemodynamic variables at rest and during exercise, risk factors for ischemic heart disease, findings on magnetic resonance imaging and radionuclide perfusion studies of the heart, or changes in brachial flow during the infusion of acetylcholine. CONCLUSIONS: Our results provide direct evidence of an abnormal metabolic response to handgrip exercise in at least some women with chest pain consistent with the occurrence of myocardial ischemia but no angiographically significant coronary stenoses. The most likely cause is microvascular coronary artery disease.

31P-magnetic resonance spectroscopy studies of cardiac transplant patients at rest.

Studies in animal models and patients have suggested that 31P-magnetic resonance spectroscopy (MRS) may be useful in diagnosing transplant rejection, but such studies often are confounded by the late inclusion of patients after transplantation. The present study examined the utility of 31P-MRS in the diagnosis of acute allograft rejection during the first posttransplant month. Thirteen recent heart transplant recipients underwent 57 resting 31P-MRS studies within 24 hr of a biopsy. Subjects lay supine with a 10-cm surface coil placed over the heart. A 1-dimensionsal chemical shift imaging protocol was used to collect spectral information. Spectra from the heart were weighted for distance from the coil and summed before analysis. ANOVA and Duncan's multiple range test were used to analyze the data comparing phosphocreatine (PCr)/ATP ratios with biopsy scores. Transplant patients had significantly lower myocardial PCr/ATP ratios when compared with a normal control group (1.27 +/- 0.27 versus 1.61 +/- 0.22, p < 0.001). However, when the patient group was classified by biopsy score, the expected order of score, 0 > 1 > 2 > 3, was not obtained. Rather, the order was 2 > 0 > 1 > 3. Although the difference between scores 2 and 3 was significant (1.46 versus 1.14, alpha = 0.05 level), the lower three groups were statistically indistinguishable. In addition, the PCr/ ATP ratios were not predictive of future biopsies. Although significantly lower than normal control subjects, resting myocardial PCr/ATP ratios of transplant subjects are not useful in assessing thelevel of rejection. It is suggested that the measurement may be more predictive in mildly exercised myocardium.

Reproducibility of human cardiac 31P-NMR spectroscopy.

The reproducibility of the phosphocreatine to adenosine triphosphate ratio (PCr/ATP) was assessed from cardiac phosphorus-31 (31P) NMR spectra of the human left ventricle acquired with three different localization techniques. Cardiac 31P-NMR spectra (n = 68) were obtained at rest from 16 healthy subjects with three-dimensional (3D) image selected in vivo spectroscopy (ISIS), 1D spectroscopic imaging (SI), or with a combination of 2D ISIS and the 1D SI technique (ISIS + SI). The average PCr/ATP ratios were 1.41 +/- 0.20 for ISIS + SI and 1.31 +/- 0.19 for ISIS and were in the lower range of values obtained in previous studies, mainly because of a lower saturation correction factor for the cardiac PCr/ATP ratio. The SI experiment yielded an average PCr/ATP value of 0.98 +/- 0.20, significantly lower as compared to the correct values obtained with ISIS + SI and ISIS (p < 0.001), underscoring the need for 3D localization to avoid contamination of the NMR signal by liver tissue. Intersubject standard deviations of the PCr/ATP ratio were comparable to values reported previously. For all three localization techniques the absolute intra-examination differences in PCr/ATP (0.06 for ISIS to 0.15 for ISIS + SI) were significantly smaller (p approximately 0.03) than inter-examination differences (0.24 for ISIS to 0.29 for ISIS + SI). Therefore, consecutive acquisition of cardiac 31P-NMR spectra from the same patient during a single examination, e.g. under various cardiac loading conditions, appears to be a reliable approach for metabolic evaluation of heart disease.

1H NMR spectroscopic imaging of myocardial triglycerides in excised dog hearts subjected to 24 hours of coronary occlusion.

BACKGROUND: Myocardial ischemic insult causes depression of fatty-acid beta-oxidation and increased fatty-acid esterification with triglyceride (TG) accumulation. This accumulation has been demonstrated to occur in the territory with diminished blood flow surrounding an infarct, ie, the region at risk. To evaluate whether the extent of TG accumulation in the canine heart after 24 hours of ischemia could be detected, we applied myocardial 1H nuclear magnetic resonance (NMR) spectroscopic imaging (SI). METHODS AND RESULTS: Seven adult mongrel dogs underwent 24 hours of left anterior descending coronary artery occlusion. Postmortem, the hearts were excised and the size and location of the infarct were determined. With a Philips 1.5-T clinical NMR imaging/spectroscopic system, two-dimensional (2D) 1H NMR SI was performed. TG 1H NMR chemical shift images were reconstructed from the frequency domain spectra by numerical integration. A statistically significant (P < .05) increase in TG signal intensity was demonstrated in the region at risk compared with the nonischemic control region. There was an intermediate quantity of TG in the infarct region. Biochemical determination of tissue TG content (milligrams per gram wet weight) in the control, at-risk, and infarct regions confirmed the 1H NMR measurements. Histological evaluation with oil red O staining also demonstrated graded TG accumulation in myocytes. The highest TG levels were found in the at-risk region and the lowest levels in the control region. CONCLUSIONS: By use of 2D 1H NMR SI, the present study confirms and extends previous work that demonstrates preferential accumulation of TG in the reversibly injured myocardium after 24 hours of coronary occlusion. This study provides an important step toward the clinical application of TG imaging. When TG imaging is ultimately possible, resultant data would have diagnostic, prognostic, and therapeutic implications.

Observation of cardiac lipids in humans by localized 1H magnetic resonance spectroscopic imaging.

Different approaches are being explored for the noninvasive observation of myocardial lipids in the human heart by in vivo 1H NMR spectroscopy. One approach is to measure cardiac lipids using a combination of volume selection and 2D gradient phase encoding. From these data sets lipid images can be reconstructed. By comparing these lipid images with 1H MR scout images, it is demonstrated that these signals represent epicardial and pericardial lipid. By selecting a smaller bar-shaped volume combined with 1D phase encoding or by using single volume techniques, it is possible to avoid most of the pericardial and epicardial lipid to obtain myocardial 1H NMR spectra of the human heart showing lipid signals, as well as trimethylamine and (phospho)creatine signals. These measurements demonstrate the feasibility of obtaining 1H NMR spectra of the human myocardium.

Lactate imaging of the human brain at 1.5 T using a double-quantum filter.

The use of a double-quantum filtered 1H NMR spectroscopic imaging technique is described to detect the spatial distribution of lactate in the human brain. In two patients the feasibility of this technique is shown and compared with existing single-quantum spectroscopic imaging and single voxel techniques. Single-slice double-quantum filtered lactate images were obtained showing the lactate distribution over the entire slice in the brain. The lipid signal suppression was sufficient for the unambiguous detection of lactate. The signal loss of the lactate signal due to the incorporation of the double-quantum filter was 50-70% relative to the single-quantum signal.

Metabolic changes in reflex sympathetic dystrophy: a 31P NMR spectroscopy study.

The lower leg skeletal muscles of 11 patients affected by reflex sympathetic dystrophy were investigated at rest by 31P nuclear magnetic resonance spectroscopy at a fieldstrength of 1.5 T. The results were compared with similar investigations of unaffected lower leg muscles of patients and volunteers. A significant increase was observed for the average tissue pH of the muscles of affected legs as deduced from the chemical shift of the resonance for inorganic phosphate. The average inorganic phosphate/phosphocreatine ratio of these muscles was also increased. The impairment of high energy phosphate metabolism, as deduced from the NMR data, may be caused by cellular hypoxia or diminished oxygen utilization, which would agree with previous findings that oxygen extraction is reduced in extremities affected by reflex sympathetic dystrophy.

Quantitative 31P MRS of the normal adult human brain. Assessment of interindividual differences and ageing effects.

The characteristics of the 31P MR spectra from a large central volume in the brain of 47 healthy adults (aged 25-85 years) were assessed. Spectral parameters were estimated by means of a time-domain fitting technique. Statistical uncertainties of the estimates were determined by means of the Cramer-Rao theory and minimized by introducing a priori knowledge into the fitting procedure. Age-dependency of the spectral parameters was assessed by means of linear regression. Significant differences between individuals were established for some parameters. A significant age-dependency (p < or = 0.001) of ca 20% over the age range considered was found for the intensity of the phosphocreatine resonance line.

Cardiac metabolism in patients with dilated and hypertrophic cardiomyopathy: assessment with proton-decoupled P-31 MR spectroscopy.

Proton-decoupled phosphorus-31 heart spectroscopy was performed in healthy subjects (n = 9) and patients with dilated cardiomyopathy (DCM, n = 9) or hypertrophic cardiomyopathy (HCM, n = 8). The phosphocreatine (PCr)-to-adenosine triphosphate ratio (+/- one standard deviation) after correction for blood contribution and partial saturation was significantly lower in HCM patients relative to the control subjects (1.32 +/- 0.29 vs 1.65 +/- 0.26, P < .05) but not in DCM patients (1.52 +/- 0.58 vs 1.65 +/- 0.26). The inorganic phosphate (Pi) peak was resolved only in patients with the highest spectral quality. Myocardial pH was lower in HCM patients (n = 6) relative to control subjects (n = 4) (7.07 +/- 0.07 vs 7.15 +/- 0.03, P < .05). The Pi/PCr ratio was higher in DCM (n = 3) and HCM (n = 6) patients relative to control subjects (n = 4) (0.29 +/- 0.06 and 0.20 +/- 0.04, respectively, vs 0.14 +/- 0.06; P < .05). Elevated phosphodiester signal in DCM patients correlated with 2,3-diphosphoglycerate signal (r = .94), reflecting blood pool contamination. P-31 spectroscopy enabled detection of abnormalities in cardiac metabolism and determination of pH in patients with HCM and DCM.

Application of time-domain fitting in the quantification of in vivo 1H spectroscopic imaging data sets.

Time-domain model function fitting techniques were applied to improve the reconstruction of metabolite maps from the data sets obtained from in vivo 1H spectroscopic imaging (SI) experiments. First, residual water-related signals were removed from the SI data sets by using SVD-based linear time-domain fitting based upon the HSVD (State Space) approach. Second, peak integrals of the metabolites of interest were obtained by quantifying the proton spin-echoes of the voxels by means of non-linear time-domain fitting based upon the maximum likelihood principle. Third, in order to save computational time, interpolation of the metabolite images (from size 32 x 32 to 128 x 128) was performed in the image-domain by applying one-dimensional cubic splines. It was found that the residual water signals can be almost completely removed from the SI data sets by applying the linear HSVD fitting method. Furthermore, it was found that voxel dependency of certain NMR parameters (e.g., variations of the spin-echo offset frequencies and/or phase factors) can be accounted for automatically by applying the nonlinear time-domain fitting technique. For that purpose it appeared to be essential to employ prior knowledge of the NMR spectral parameters.

1H and 31P magnetic resonance spectroscopy of the brain in degenerative cerebral disorders.

Proton and phosphorus magnetic resonance spectroscopy of the brain was performed in 35 patients with degenerative cerebral disorders: 24 patients had demyelinating (white matter) disorders and 11 patients had neuronal (gray matter) disorders. Four grades of demyelination and three grades of cerebral atrophy were distinguished by magnetic resonance imaging criteria. The spectroscopic data were compared with normal values previously obtained. With increasing degrees of demyelination, lower ratios of phosphodiesters to beta-ATP were found. This trend was statistically significant. Decreased phosphodiester-beta-ATP ratios occurred simultaneously with imaging abnormalities. The decrease in phosphodiester-beta-ATP ratio in demyelinated areas is attributed to white matter rarefaction. Increasing cerebral atrophy was accompanied by lower ratios of N-acetyl aspartate to creatine. This trend was statistically significant. The decrease in the N-acetyl aspartate-creatine ratio was demonstrated before the magnetic resonance images showed signs of cerebral atrophy in patients with neuronal disorders. As N-acetyl aspartate is located exclusively in neurons and their branches, a decrease of the N-acetyl aspartate-creatine ratio can be attributed to neuronal and axonal damage and loss.

Acquisition and quantitation in proton spectroscopy.

Localized proton NMR spectroscopy in the human brain is one of the more technically advanced applications of human in vivo NMR spectroscopy. Spin/echo techniques introduced reliable localization procedures, whereas the introduction of phase encoding techniques improved the spatial information content considerably. Using the sensitivity of the 1H NMR signal, a spatial resolution of 7 X 7 X 15 mm can be obtained. Chemical shift images can be reconstructed to represent the choline, creatine, N-acetyl aspartate and lactate distribution in the human brain. These low resolution images may be used as a new functional imaging modality to visualize and derive quantitative biochemical information from focal brain lesions under normal and pathological conditions.

What the clinician can learn from MR glutamine/glutamate assays.

At present in vivo NMR spectroscopic studies of brain glutamate and glutamine concentrations relative to encephalopathy have mainly been performed in hepatic encephalopathy (HE). In vivo proton NMR studies were performed in rats with hyperammonemia and acute HE due to acute liver ischemia as well as in rats with hyperammonemia due to either repeated urease i.p. injection or i.p. administration of methionine sulfoximine, a well known inhibitor of glutamine synthetase. In man, in vivo proton NMR is described in patients with chronic liver disease: cirrhosis of different etiology and associated with different degrees of HE. In the experimental models proton NMR spectroscopy of the cerebral cortex revealed an increase in glutamine concentration, a decrease in glutamate concentration and a decrease in phosphocholine compounds. In humans no clear distinction between cerebral cortex glutamate and glutamine concentration could be made by in vivo 1H NMR spectroscopy. However, the combined glutamate/glutamine peak increased in a way compatible with an increased cerebral cortex glutamine concentration during chronic HE. In the cirrhotic patients too a decrease in cerebral cortex phosphocholine compounds was observed, the explanation of which is unclear. Both the experimental work and the clinical observations support the hypothesis that impairment of the glutamate/glutamine cycle between astrocytes and neurons plays a role in the pathogenesis of hepatic encephalopathy.

In vivo monitoring of fructose metabolism in the human liver by means of 31P magnetic resonance spectroscopy.

It has been shown that fructose metabolism in the human liver can be monitored quantitatively by means of 1H image-guided 31P MRS, implemented on a clinical MR imaging system equipped with surface coils and with appropriate data processing software. Temporal resolution of the 31P MRS measurements is of the order of 2 min.

Metabolic imaging of patients with intracranial tumors: H-1 MR spectroscopic imaging and PET.

Hydrogen-1 magnetic resonance (MR) spectroscopic images of patients with intracranial tumors were obtained. Metabolite maps of N-acetyl aspartate, choline, lactate, and creatine concentrations were reconstructed with a nominal spatial resolution of 7 mm and a section thickness of 25 mm. The metabolite maps showed variations in metabolite concentrations across the tumor. In one patient, it was observed that choline concentration was increased in one part of the tumor but decreased in another part. In another patient, the concentration of N-acetyl aspartate was extremely low in one part of the tumor but only slightly increased in another part of the tumor. Lactate was observed in all patients. In one patient, a combined measurement made with positron emission tomography (PET) and MR spectroscopic imaging was performed. This demonstrated that increased lactate concentration measured with H-1 MR spectroscopic imaging corresponded topographically with increased glucose uptake measured with fluorine-18 fluoro-2-deoxyglucose PET. Combined MR spectroscopic and PET measurements provide an opportunity to investigate, in greater detail than before, glucose uptake and catabolism by intracranial tumors.

Detection of metabolic heterogeneity of human intracranial tumors in vivo by 1H NMR spectroscopic imaging.

Patients with intracranial tumors (gliomas) were examined by means of localized water-suppressed 1H NMR single volume spectroscopy and spectroscopic imaging. The 1H NMR spectra of the tumors exhibit signal intensities of the N-acetyl aspartate, choline compounds, and creatine plus phosphocreatine resonance lines that are different from the corresponding intensities observed on normal brain tissue. Also, for 6 out of the 10 patients examined so far, lactate resonance lines were detected in the tumor spectra. For one patient, abnormal 1H NMR spectra were obtained of a hemisphere which appeared normal with 1H NMR imaging. Metabolic heterogeneity of the tumorous regions could be demonstrated with 1H NMR spectroscopic imaging, using a spatial resolution in the order of 1 cm. These results suggest a spectrum of metabolic observations that may ultimately provide an important means for characterizing brain tumors.

Broadband proton decoupled natural abundance 13C NMR spectroscopy of humans at 1.5 T.

The feasibility of broadband proton decoupled in vivo 13C NMR spectroscopy of humans at 1.5 T was explored. A dual surface coil set-up was used, comprising a circular 13C coil and a butterfly 1H decoupling coil placed at one third of its width away from the body. A calibration procedure was introduced to evaluate the specific absorption rate (SAR) in any gram of tissue for the inhomogeneous decoupling field generated by a surface coil. For the WALTZ-4 sequence it was demonstrated that broadband decoupled spectra of both subcutaneous adipose and underlying muscle or liver tissue could be obtained at 1.5 T without exceeding recommended maximum SAR values. Broadband decoupling caused an additional resolution enhancement ascribed to the removal of (1H-13C) long range couplings. Broadband proton decoupled spectra of subcutaneous adipose tissue were obtained in less than 10 min showing highly resolved and intense signals of fully relaxed carbon spin systems of triacylglycerols. Broadband proton decoupled 13C NMR spectra of calf muscle showed several resonances for metabolites resolved from triacylglycerol signals (e.g. C1-C5 of glycogen, C4 of histidine, aromatic and carbonyl carbons of aminoacids and N linked carbons of ethanolamine, choline and creatine). With an acquisition time of 20-30 min, the C1 glycogen signal was observed with a root mean square signal-to-noise ratio of about 15. Not only the glycogen C1 signal but also its C2-C6 signals could be monitored in dynamic studies. Finally broadband proton decoupled 13C spectra were obtained with signals from liver tissue (notably the carbons of glycogen).(ABSTRACT TRUNCATED AT 250 WORDS)

1H image-guided localized 31P MR spectroscopy of human brain: quantitative analysis of 31P MR spectra measured on volunteers and on intracranial tumor patients.

1H image-guided 31P MR spectra of normal human brain and of intracranial tumors have been analyzed quantitatively. Tumor types examined include prolactinoma, lymphoma, and various grade gliomas. The experimental signals were processed by means of a time-domain least-square fitting procedure, which yields the spectral parameters, as well as a prediction of the standard deviations. Significant spectral variations are observed within both populations of normal brain and of intracranial tumor 31P MR spectra. The metabolic ratios derived from the glioma 31P MR spectra and from corresponding uninfiltrated brain tissue do not differ significantly. Significant differences are, however, observed between the metabolic ratios of prolactinoma and uninfiltrated tissue 31P MR spectra. Alkaline pH values are found for the prolactinoma and the high-grade gliomas. Furthermore, spectral differences are observed between the patient's uninfiltrated tissue 31P MR spectra and those of an unmatched population of volunteers. This underscores the necessity for control measurements on the uninfiltrated tissue of the patient and for controls from a matched population of healthy individuals.

Experimental approaches to image localized human 31P NMR spectroscopy.

Experimental procedures for obtaining localized 31P NMR spectra of humans by means of the ISIS sequence are discussed in detail. The technique is optimized for use with volume coils and with surface coils in order to measure localized 31P NMR spectra of different tissues and organs. Selective frequency-modulated (FM) inversion and excitation pulses are applied for optimal inversion or excitation despite B1 inhomogeneity. Pulse imperfection may lead to spurious signal contributions from outside the selected volume; this contamination is reduced by using long pulse intervals, by properly ordering the ISIS acquisitions, and by using FM excitation pulses. Simultaneous measurement of multiple volumes was implemented by including an additional selective inversion pulse, and an extension of the ISIS addition/subtraction scheme. Localized T1 measurements with surface coils are implemented by using a B1-insensitive inversion pulse in the inversion recovery sequence. The quantitative reproducibility of localized 31P NMR spectra was verified. Absolute metabolite concentration can be determined after a suitable calibration of the 31P NMR spectrum. Localized shimming is required to obtain localized 31P NMR spectra of excellent spectral resolution. This is done by monitoring the 1H NMR signal from water by a single-shot localization technique. The techniques discussed can be applied to obtain spectra of brain, liver, heart, and other organs. 31P NMR spectra of intracranial tumors demonstrate its applicability in the examination of patients.