31P-MR spectroscopy in human end-stage heart failure during therapy with recombinant human growth hormone

4. Conclusions Evaluation of the myocardial energy metabolism in human endstage heart failure is noninvasively feasible by using³¹P-MR spectroscopy. The investigations were well tolerated by all patients. The PCr/ATP ratio is significantly diminished in patients with dilated cardiomyopathy. In this study a part of the patients showed a significant increase in the PCr/ATP ratio. A possible explanation for this fact could be the enhancement of muscle structures induced by growth hormone therapy, which could be proven using MR tomography by an increase in myocardial muscle mass. A further point is the improvement or increase in the myocardial energy metabolism and an improvement of the PCr/APT ratio. A final assessment of this issue will be possible in summer 1998 after unblinding the study population. Further studies will have to show whether the increase of the PCr/ATP ratio after r-HGH treatment will be a good predictor for a possible increase of myocardial contractility. Furthermore, long-term studies with a high number of patients are necessary to investigate the effects on the survival prognosis of this new substance.     

Whither human cardiac spectroscopy?

Human cardiac magnetic resonance (MR) spectroscopy is presently comprised, almost exclusively, of phosphorus (³¹P) studies. These provide access to supply-side energy metabolism in the anterior myocardium of patients with hypertrophy, with cardiomyopathies including heart failure, with heart transplants, and with ischemic disease and myocardial infarction. A link between reduced phosphocreatine (PCr) to adenosine triphosphate (ATP) ratios and heart failure has been identified which might assist diagnosis in the presence of other confounding factors. PCr/ATP is often reduced in transplanted hearts for reasons not understood, but the ratio is presently an unreliable predictor of significant histological rejection for many patients. Myocardial infarction may reduce overall metabolite levels. In reversible myocardial ischemia,³¹P exercise stress-testing can produce reversible PCr/ATP reductions, at least in anterior disease: these seem to be specific for ischemic disease and may be helpful, especially if new technologies such as phased detector arrays and Overhauser enhancement can provide access to more of the heart. Human cardiac spectroscopy with nuclei other than³¹P may potentially access citric acid cycle metabolites, oxymyoglobin and deoxymyoglobin, and creatine levels, which may also be altered in heart failure.     

(31)P-MR Spectroscopy for the evaluation of energy metabolism in intact residual myocardium after acute myocardial infarction in humans

Objective experimental studies have demonstrated that acute myocardial infarction (MI) alters energy metabolism even in non-infarcted adjacent tissue. In patients with subacute MI, the influence of the regional ischemie insult on energy metabolism of intact septal myocardium was analyzed using³¹P-Magnetic resonance spectroscopy (MRS). Patients and Methods in eight patients with wall motion abnormalities in the anterior wall³¹P-spectra were obtained from non-infarcted adjacent scptal myocardium, as well as infarcted anterior myocardium (voxel size 25 ccm each) 29 ±8 days after MI using a 3D-CSI technique. Additionally, cardiac function was analyzed using breath-hold cine MRI. MR1 was repeated 6 months after revascularization to assess viability of infarcted segments. Eight age-matched healthy volunteers served as control group. Results according to follow-up MRI 4/8 patients showed regional wall motion recovery. Here, PCr/ATP-ratios were not significantly reduced in intact septal myocardium as well as infarcted anterior myocardium compared to healthy volunteers (1.28 ±0.10 and 1.14 ±0.09 vs. 1.45 ±0.29). No recovery of regional function was detected in 4/8 patients with —therefore—non-viable anterior myocardium. PCr/ATP-ratios were significantly reduced in intact and infarcted myocardium compared with healthy volunteers as well as to patients with wall motion recovery (0.77 ±0.17 and 0.49 ±0.23;P < 0.05). Discussion these preliminary results indicate that energy metabolism is reduced in patients with persisting wall motion abnormalities after myocardial infarction and revascularization in ischemically injured as well as in adjacent non-injured myocardium.     

Functional and metabolic consequences of aortic valve replacement

4. Conclusions Severe aortic valve stenosis leads to a decreased myocardial PCr/ATP, and to impairment of LV diastolic function. Following aortic valve replacement, myocardial PCr/ATP normalizes completely, whereas LV diastolic function improves significantly. Moreover, there is an association between altered myocardial HEP metabolism and impaired LV diastolic function.     

Glycolytic atp production estimated from31p magnetic resonance spectroscopy measurements during ischemic exercisein vivo

In an oxygen-depleted muscle, glycolytically produced ATP is inversely related to the ([ATP] + creatine phosphate [PCr]) decrease because ATP, PCr, and glycolysis are virtually the only energy sources under these conditions. In particular, the onset of glycolysis or any appreciable increase in the rate of glycolytic ATP production will lead to a slower rate of ([ATP] + [PCr]) breakdown at a given energy consumption. To quantify this relationship, endurance athletes performed isometric foot plantar flexion (20% of a test force [TF],n=10; 50% TF,n=5) during local arterial occlusion. Parameters of energy metabolism were measured with³¹P magnetic resonance spectroscopy (³¹P-MRS). During exercise, [PCr] decreased to 80±10 (20% TF) and 11±4% (50% TF) of its resting concentration, and pH dropped from 7.04 0.01 to 6.98±0.10 (20% TF) and from 7.03±0.02 to 6.70 0.10 (50% TF). In both experiments, two phases of ([ATP] + [PCr]) decrease were observed: an initial faster decrease was followed by a slower decline. The latter phase started at about the time when the pH began to drop. The difference between a line extrapolated from the slope of the initial phase and the measured ([ATP] + [PCr]) decrease was used as an estimate for glycolytically produced ATP. This estimate and pH were significantly correlated withr=–0.97 (20% TF) andr=–0.99 (50% TF). These results indicate that glycolytically produced ATP can be estimated from the ([ATP] + [PCr]) decrease during exercise.     

Assessment of left ventricular wall motion in normal and diseased hearts with velocity-encoded magnetic resonance

We present a noninvasive MR technique to assess the regional myocardial wall motion quantitatively. The method uses a phase-contrast sequence in conjunction with a masking program allowing for exact myocardial wall demarcation. Five healthy volunteers, aged 24 to 36 years, were studied to evaluate normal heart motion. These data served as a normal reference to myocardial motion patterns determined in five patients, aged 51 to 73 years, with known coronary artery disease induced wall motion abnormalities. Tangential motion in normal subjects showed a clockwise rotation at the cardiac base and counterclockwise rotation at the apex. The maximal radial velocity was 30.45±5.9 mm/s^–1. Dyskinetic myocardial motion could be differentiated from normal ventricular motion: The number of hypomotile segments as well as hypokinetic and paradox phases determined with this method correlated well with patients' ejection fractions (r ²=0.95). This preliminary study demonstrates the ability of velocity-encoded MR to characterize myocardial motion and differentiate normal from dyskinetic heart motility.Address for correspondence: Division of Nuclear Medicine, Department of Radiology, University Hospital Zurich, Rämistrasse 100, CH-8091 Zürich, Switzerland. Additional reprints of this chapter may be obtained from the Reprints Department, Chapman & Hall, One Penn Plaza, New York, NY 10119.     

Physiological constraints on changes in pH and phosphorus metabolite concentrations in ischemically exercising muscle: implications for metabolic control and for the interpretation of31P-magnetic resonance spectroscopic studies

Relationships between pH and the concentrations of phosphocreatine (PCr), inorganic phosphate (Pi), and lactate during ischemic exercise depend on passive buffering, proton consumption as a consequence of net PCr breakdown, the control of glycogenolysis, (particularly in relation to the concentration of Pi, a substrate of glycogen phosphorylase that is produced by net PCr breakdown), and the creatine kinase equilibrium. The author analyzes the implications of these relationships for the interpretation of³¹P-magnetic resonance spectroscopic data and for the control of glycogenolysis. For realistic adenosine diphosphate (ADP) concentrations, given the constraints of the creatine kinase equilibrium, the pH must be near-linear with lactate, with an apparent buffer capacity (i.e., the ratio of lactate accumulation to pH change) that is nearly twice the true buffer capacity (i.e., the ratio of net proton loading to pH change). The implications for glycogenolytic control depend on adenosine triphosphate (ATP) turnover, but an upper limit of activation of glycogen phosphorylase (i.e., the amount of thea form) that would permit no increase in ADP concentration can be calculated. Phosphorylase activation during ischemic exercise seems approximately proportional to the power output, consistent with calcium stimulation of phosphorylaseb kinase. In simulations, ADP concentration is highly sensitive to this proportionality, as (unlike in purely oxidative exercise) ADP concentration is not known to participate in any closed feedback loops in ischemic exercise.     

Cine-MRI assessment of cardiac function in mice anesthetized with ketamine/xylazine and isoflurane

Since small-animal MRI generally requires anesthesia, the effect of the anesthetic regimen on the explored organ(s) has to be taken into account for study interpretation. In this work, we assess the influence of ketamine/xylazine and isoflurane anesthesia on left-ventricular (LV) function in the mouse in vivo by cine-MRI. Three groups of animals were anesthetized with ketamine/xylazine (n = 13) and two different concentrations of isoflurane (1.25%, n = 12 and 2.00%, n = 12) delivered in O₂/N₂O mix. Long- and short-axis cine-MRI was performed to measure end-diastolic volume, stroke volume, ejection fraction and LV wall thickness. Ketamine/xylazine significantly reduced heart rate, cardiac output and wall thickness, but increased stroke volume and end-diastolic volume compared with both isoflurane groups. No differences across all groups were observed in ejection fraction or systolic wall thickening. Breath rate under isoflurane was significantly lower and concentration dependent, whereas heart function was independent of concentration in all measured parameters. These findings are in agreement with echocardiography and catheterization studies. Isoflurane is advantageous for MR studies because it better maintains cardiac function. Taking into account previously obtained myocardial perfusion measurements, isoflurane concentration should, however, be maintained at the minimum required for a stable sleep even if cardiac function is unaffected by higher isoflurane concentrations.     

23Na microscopy of the mouse heart in vivo using density-weighted chemical shift imaging

The mouse has become an important animal model for human cardiac disease, and the development of techniques for non-invasive imaging of the mouse heart in vivo is, therefore, of great potential interest. Previous magnetic resonance imaging studies have concentrated on pathologically induced changes in cardiac structure and dynamics by acquiring proton images. Further information can be gained by studying cardiac function and physiology using other nuclei, for example, sodium. Sodium imaging of such a small structure presents considerable technical challenges. In this work we show the first sodium images of the mouse heart, with an isotropic spatial resolution of 1 × 1 × 1 mm, acquired in a time of 1.5 h. The ventricles, septum and myocardium are readily distinguishable in these images, which were acquired through the combination of 3D density-weighted chemical shift imaging, optimized instrumentation, and a high magnetic field strength (17.6 T). Measurements of the myocardial:blood sodium concentration in the left and right ventricles agree well with theoretical values.     

High-resolution MR imaging in mice

6. Conclusions Due to its high temporal and spatial resolution, the described MR technique is able to face the requirements of the small sized, fast beating mouse heart, resulting in time-resolved visualization of the cardiac morphology and function in great detail. This allows for accurate and reproducible quantification of LV performance including wall motion and contraction-relaxation dynamics. Hence, MRI offers the non-invasive investigation of physiological and pathophysiological changes of cardiac function over time, both under acute and chronic myocardial stress. Applied in models of cardiac failure, the MR method should aid understanding the mechanisms of LV remodeling after myocardial infarction and LV hypertrophy due to pressure overload in gene-targeted mouse models.     

Dynamic interleaved 1H/31P STEAM MRS at 3 Tesla using a pneumatic force-controlled plantar flexion exercise rig

Objective: To develop a measurement method for interleaved acquisition of ¹H and ³¹ STEAM localised spectra of exercising human calf muscle. Materials and Methods: A non-magnetic exercise rig with a pneumatic piston and sensors for force and pedal angle was constructed to enable plantar flexion measured in the 3 T MR scanner, which holds the dual tuned (¹H ,³¹P) surface coil used for signal transmission and reception. Results: ³¹ spectra acquired in interleaved mode benefit from higher Signal to noice ratio (factor of 1.34 ±0.06 for PCr) compared to standard acquisition due to the Nuclear Overhauser effect and substantial PCr/P_i changes during exercise can be observed in ³¹P spectra. ¹H spectral quality is equal to that in single mode experiments and allows Cr2 changes to be monitored. Conclusion: The feasibility of dynamic interleaved localised ¹H and ³¹P spectroscopy during plantar flexion exercise has been demonstrated using a custom-built pneumatic system for muscle activation. This opens the possibility of studying the dynamics of metabolism with multi nuclear MRS in a single run.     

fMR; methodology

Changes of myocardial oxygenation can be studied by measurements of the apparent transverse relaxation timeT ₂ ^* , which is correlated with the oxygenation state of hemoglobin. In this study, ten patients with coronary artery disease (CAD) underwent blood oxygenation level dependent (BOLD)T ₂ ^* measurements using a segmented gradient echo pulse sequence with ten echoes.T ₂ ^* measurements were performed in a single short-axis slice of the heart at rest and under pharmacological stress with dipyridamole (DIP), which increases myocardial blood flow. For comparison, all patients underwent X-ray angiography and stress-echocardiography within 4 days after the MR exam. In one patient, MR examination was repeated 10 weeks after percutaneous transluminal coronary angioplasty (PTA). In the differentialT ₂ ^* maps, expected ischemic areas of myocardium were identified in six patients. In these regions,T ₂ ^* values (30±8 ms) were significantly reduced when compared to the remaining myocardium (48±9 ms,P<0.01). In four patients, the myocardial region of interest could not be assessed owing to severe susceptibility artifacts in the ischemic region. The success of the PTA treatment could be visualized from a more homogeneous DIP induced increase inT ₂ ^* within the ischemic myocardium (from 26±1 to 29±1 ms before PTA versus 26±1 to 31±4 ms after PTA,P<0.001. This work was presented in part at the 15th Annual Meeting of the European Society for Magnetic Resonance in Medicine and Biology (Geneva 1998), at the 6th Scientific Meeting of the International Society for Magnetic Resonance in Medicine (Sydney 1998, Book of Abstracts, p. 897), and at the Annual Meeting of the German Society of Cardiology (Mannheim 1998).     

Subacute myocardial infarction: assessment by STIR T2-weighted MR imaging in comparison to regional function

Purpose Increased T2 signal intensity (SI) can be regularly observed in myocardial infarction. However, there are controversial reports about the relationship of elevated T2 SI to myocardial viability and some authors propose that high T2 SI serves as a sign of irreversible myocardial injury. This study investigates increased T2 SI compared to myocardial function in patients with reperfused subacute myocardial infarction. Preserved function was used as criterion for viability. Methods Ten healthy volunteers and 17 patients with myocardial infarction and patent inlarct related coronary artery were examined on a 1.5 T Magnetom Vision system (Siemens). For T2-weighted MR imaging a breath-hold STIR sequence with dark-blood preparation was used. Cine FLASH 2D imaging was applied to assess myocardial function. Signal-to-noise (S/N) in STIR T2 images was measured in normal and infarcted regions and subsequently identified by two independent observers. Based on a 20 segment model of the left ventricle findings were compared to regional myocardial function. Results Elevated STIR T2 SI was found in all 17 patients and observed in 27% (204/754) of segments. S/N of normal myocardium was 5.1 ±0.7 in volunteers and 4.9 ± 0.8 in patients(P=NS). Infarcted myocardium presented with significantly-increased S/N 12.8 ± 1.9 (P < 0.0001). Significant transmural elevation of T2 SI was noted in 32% of segments with preserved systolic function. Conclusion Increased STIR T2 SI can be observed transmurally in post-ischemic myocardial regions with preserved function. It therefore cannot be used as an exclusive marker for the non-viable region.     

Creatine loading and resting skeletal muscle phosphocreatine flux: a saturation-transfer NMR study

³¹P saturation-transfer nuclear magnetic resonance spectroscopy was used to study skeletal muscle phosphocreatine (PCr) flux in healthy male volunteers. Data analysis included consideration of effects from incomplete saturation and radiofrequency spillover. Spectra were recorded from the resting gastrocnemius muscle before and after 6 days of creatine monohydrate (Cr·H₂O) intake (20 g/day). Parallel to an improved muscle performance during maximal intermittent exercise following Cr·H₂O supplementation, the concentration of PCr increased(P = 0.01) by 23% (34.9 ± 2.8 mmol/ 1 vs. 28.6 + 2.7 mmol/1), whereas other metabolites were unaffected (inorganic phosphate: 4.3± 1.4 mmol/1, free intracellular Mg²⁺: 1.1 ±0.7 mmol 1, cytosolic pH: 7.04 ± 0.02). Forward and reverse fluxes through the creatine kinase (CK) reaction did not change significantly from their baseline levels (v_for: 11.8 ± 5.4 mmol/1 per second vs. 15.3 ± 6.8 mmol 1 per second. (v_rev: 9.5 ± 3.4 mmol/1 per second vs. 10.9 ± 3.7 mmol/ 1 per second). The rate of PCr resynthesis in resting muscle is not limited by the CK reaction, which is near equilibrium. Consequently, the post-load increase in total creatine has no effect on the unidirectional CK reaction rates.     

Monitoring kidney and renal cyst volumes applying MR approaches on a rapamycin treated mouse model of ADPKD

Object  The aim of our study was to determine total cystic volume in a mouse model of PKD using MR imaging to monitor therapeutic effects in vivo. Materials and methods  We imaged eight female pcy-mice in two groups: four belonged to an untreated control group and four were treated with the anticystic agent rapamycin, which has proven to be effective in reducing cystogenesis in animal models. The mice were imaged using a 9.4 Tesla animal scanner. MRI measurements were taken at six time points during the therapy. Total renal volumes and total cyst volumes were calculated using a thresholding approach. Results  During the course of the treatment, the total cyst volume increased significantly faster than the total renal volume in the untreated group, indicating that growth of the total renal volume in the untreated group was primarily due to the growth of the cysts, rather than the parenchyma. The measured total renal volume in the control (placebo) group was significantly higher than the volume in the treated group. Conclusion  Using MRI, we were able to monitor the cystic volume in a mouse model of PKD to assess the therapeutic effect of anticystic treatment.     

Cardiovascular phenotype characterization in mice by high resolution magnetic resonance imaging

9. Conclusion Due to its high temporal and spatial resolution, magnetic resonance imaging meets the requirements for accurate and robust in vivo visualization of the murine cardiovascular system. As an intrinsically three-dimensional imaging technique, it allows for quantification of LV volumes without relying on geometric models. Therefore, MRI is uniquely suited for the investigation of morphologic and functional changes in models of heart failure. The potential application of MRI in the mouse comprises visualization of cardiovascular anatomy and pathology in newborn and adult mice, detection of LV geometric and functional changes both acutely and chronically, visualization of cardiac microstructures such as cardiac valves and coronary arteries, and characterization and quantification of arteriosclerotic plaques in major murine arteries. Furthermore, MR spectroscopy applied to the mouse heart can give important information on in vivo myocardial metabolism. Thus, we feel confident that high resolution MRI may substantially contribute to the understanding of the basic mechanisms of a variety of cardiovascular diseases.     

Relevance of the skewness index in DTI exploration of multiple sclerosis

Object  To this day, no parameter can really monitor the progression of multiple sclerosis (MS). In this study, an index the skewness (S) derived from parameters calculated in diffusion tensor imaging (DTI) has been tested on MS patients for its ability to monitor the disease course. Materials and methods  Eighteen patients underwent two examinations within 3 months consisting of a clinical evaluation (EDSS) and DTI acquisitions on a 1.5 T imager. Tensor was calculated thanks to“home-made” software. Mean diffusivity (MD) and fractional anisotropy (FA) histograms were described for normal-appearing white matter (NAWM) and gray matter (GM) of patients with S and also with usually indices peak position (pp) and peak height (ph) for the whole group of patients and for two separate groups according to their clinical status (EDSS  ≤  3 and EDSS  > 3 at month 0). Results  Although no significant clinical evolution is observed over 3 months, S in GM showed a significant shift for both MD/FA histograms towards abnormal values for the whole group of patients (p = 0.02/p = 0.04) and for the group with EDSS  ≤  3 (p = 0.04/p = 0.007), while ph and pp do not. Conclusion  S in GM could be an alternative marker to monitor the disease course before the repercussion on the clinical score.     

Indirect evidence for the potential ability of magnetic resonance imaging to evaluate the myocardial iron content in patients with transfusional iron overload

The purpose of this study was to evaluate the potential ability of magnetic resonance imaging (MRI) for evaluation of myocardial iron deposits. The applied MRI technique has earlier been validated for quantitative determination of the liver iron concentration. The method involves cardiac gating and may, therefore, also be used for simultaneous evaluation of myocardial iron. The tissue signal intensities were measured from spin echo images and the myocardium muscle signal intensity ratio was determined. The SI ratio was converted to tissue iron concentration values based on a modified calibration curve from the liver model. The crucial steps of the method were optimized; i.e. recognition and selection of the myocardial slice for analysis and positioning of the regions of interest (ROIs) within the myocardium and the skeletal muscle. This made the myocardial MRI measurements sufficiently reproducible. We applied this method in 41 multiply transfused patients. Our data demonstrate significant positive linear relationships between different iron store parameters and the MRI-derived myocardial iron concentration, which was significantly related to the serum ferritin concentration (ρ = 0.62.P < 0.0001) and to the MRI-determined liver iron concentration (ρ = 0.36,P = 0.02). The myocardial MRI iron concentrations demonstrated also a significant positive correlation with the number of blood units given (ρ = 0.45,P = 0.005) and the aminotransferase serum concentration (ρ = 0.54,P = 0.0008). Our data represents indirect evidence for the ability of MRI techniques based on myocardium/muscle signal intensity ratio measurements to evaluate myocardial iron overload.     

Assessment of myocardial perfusion using contrast-enhanced MR imaging: Current status and future developments

Excellent inherent tissue contrast is one of the great promises of clinical magnetic resonance (MR) imaging, but functional information is relatively limited. However, MR imaging complemented by the administration of contrast agents can provide such functional assessment. The perfusion status of the myocardium is one of the most important functional information in cardiovascular imaging. Because the clinical acceptance of a contrast agent is measured by its ability to improve patient outcome and to guide therapy, it is unlikely that detection of myocardial infarction, the final stage of ischemic heart disease, should be the target for contrast media development. It would obviously be better if occult regional myocardial perfusion deficits could be reliably detected. The current article was prepared to help the clinical radiologist to keep pace with new strategies for myocardial enhancement and their potential clinical applicability for detection of early perfusion deficits. Several techniques for noninvasive measurement of myocardial perfusion are currently evolving which have the potential to be introduced into routine MR imaging. Most investigators favor a first-pass analysis of the contrast agent bolus through the myocardium using ultrafast sequences. However, such a technique may require clinical introduction of a blood pool agent. There are good resons to favorT ₁-weighted sequences over susceptibility imaging in such first-pass studies. In the future, assessment of myocardial perfusion status using contrast-enhanced MR imaging may be done producing perfusion maps with high spatial resolution (e.g., 256×128), with sequences available on most scanners without special hardware requirements (e.g., IR-Turboflash, keyhole imaging), and requiring only a short period of time for examination (≈3 min).     

Mechanisms of31P relaxation in phosphorus metabolites

Measurements have been made of the longitudinal relaxation timeT ₁ of³¹P for the individual resonances of the metabolites AMP, ADP, ATP, P_ir and PCr (phosphocreatine) in H₂O and D₂O solutions from 5 to 60°C at various concentrations and at frequencies of 40 MHz (2.3 T) and 120 MHz (7 T). The contributions of dipolar, chemical shift anisotropy, and spin-rotation mechanisms have been separated, and activation parameters of the underlying molecular reorientations have been determined.