Modeling of Survival and Frequency of Cardiovascular-Related Hospitalization in Patients with Transthyretin Amyloid Cardiomyopathy Treated with Tafamidis.

INTRODUCTION: ATTR-ACT (Tafamidis in Transthyretin Cardiomyopathy Clinical Trial) demonstrated the efficacy and safety of tafamidis in transthyretin amyloid cardiomyopathy (ATTR-CM). Model-based analyses from ATTR-ACT can examine predictor effects on dose-response/exposure-response relationships. METHODS: Parametric hazard distributions were developed for all-cause mortality and frequency of cardiovascular-related hospitalization. Time-to-event models were fitted to survival data, and repeated time-to-event models were fitted to hospitalization data. Disease-specific characteristics were assessed as baseline predictors of event hazards. RESULTS: There were 441 patients in this analysis. At month 30, 70.5% (tafamidis) and 57.1% (placebo) of patients were alive, with 154/441 deaths reported; 495 cardiovascular-related hospitalizations occurred. The cumulative risk of death was 42.1% (95% confidence interval [CI] 24.2-58.0) lower with tafamidis than with placebo, regardless of New York Heart Association (NYHA) class; significant predictors of decreased risk were genotype (wild-type), greater 6-Minute Walk Test (6MWT) distance, higher left ventricular ejection fraction (LVEF), and lower blood urea nitrogen (BUN) and N-terminal pro-B-type natriuretic peptide concentrations. The average cumulative risk of cardiovascular-related hospitalization up to 30 months was 40.8% (95% CI 31.0-49.7) lower with tafamidis in NYHA class I/II patients. Significant predictors of reduced risk were greater 6MWT distance, higher LVEF, and lower BUN and troponin I concentrations. CONCLUSIONS: Tafamidis reduced cumulative mortality and hospitalization risk versus placebo in patients with ATTR-CM. Baseline predictors of outcome were consistent with the cardiovascular nature of the disease and suggested that earlier treatment may improve outcomes. CLINICAL TRIALS. GOV IDENTIFIER: NCT01994889 (date of registration: November 26, 2013).

[Postarthroscopic glenohumeral chondrolysis--are there any causal factors? Case report]. / Die postarthroskopische glenohumerale Chondrolyse--Gibt es eine Ursache? Falldarstellung.

BACKGROUND: Postarthroscopic glenohumeral chondrolysis (PAGCL) is a rare complication of shoulder arthroscopy. PAGCL describes a chondrolysis in the shoulder joint after arthroscopy mostly affecting younger patients. The process leading to chondrolysis is not known yet. MATERIAL AND METHODS: The case report describes a patient with rapid progress of the PAGCL. A literature review with key words: PAGCL, postarthroscopic glenohumeral chondrolysis, shoulder arthroscopy AND chondrolysis, chondronecrosis AND arthroscopy was carried out. RESULTS: 16 Publications involving case reports with 96 cases were found. The mean age at operation was 28 ± 10 years (range: 13 to 61 years). The majority of patients (62%) were male. 8 diagnoses at index operation were found. 63% received intraarticular local anaesthetics (62% bupivacain, 21% bupivacain and epinephrin, 2% lidocain) through a pain pump. CONCLUSION: PAGCL is a rare and disturbing complication after shoulder arthroscopy. The majority of the patients are young and male. A relevant causal factor is an intraarticular pain pump with bupivacain. Other factors have not yet been verified. A multifactorial aetiology is likely. No specific and effective treatment regimen is described.

Quantitative evaluation of the lactate signal loss and its spatial dependence in press localized (1)H NMR spectroscopy.

Localized (1)H NMR spectroscopy using the 90 degrees -t(1)-180 degrees -t(1)+t(2)-180 degrees -t(2)-Acq. PRESS sequence can lead to a signal loss for the lactate doublet compared with signals from uncoupled nuclei which is dependent on the choice of t(1) and t(2). The most striking signal loss of up to 78% of the total signal occurs with the symmetrical PRESS sequence (t(1)=t(2)) at an echo time of 2/J (approximately 290 ms). Calculations have shown that this signal loss is related to the pulse angle distributions produced by the two refocusing pulses which leads to the creation of single quantum polarization transfer (PT) as well as to not directly observable states (NDOS) of the lactate AX(3) spin system: zero- and multiple-quantum coherences, and longitudinal spin orders. In addition, the chemical shift dependent voxel displacement (VOD) leads to further signal loss. By calculating the density operator for various of the echo times TE=n/J, n=1, 2, 3,..., we calculated quantitatively the contributions of these effects to the signal loss as well as their spatial distribution. A maximum signal loss of 75% can be expected from theory for the symmetrical PRESS sequence and TE=2/J for Hamming filtered sinc pulses, whereby 47% are due to the creation of NDOS and up to 28% arise from PT. Taking also the VOD effect into account (2 mT/m slice selection gradients, 20-mm slices) leads to 54% signal loss from NDOS and up to 24% from PT, leading to a maximum signal loss of 78%. Using RE-BURP pulses with their more rectangular pulse angle distributions reduces the maximum signal loss to 44%. Experiments at 1.5 T using a lactate solution demonstrated a maximum lactate signal loss for sinc pulses of 82% (52% NDOS, 30% PT) at TE=290 ms using the symmetrical PRESS sequence. The great signal loss and its spatial distribution is of importance for investigations using a symmetrical PRESS sequence at TE=2/J.

Unveiling extracellular inorganic phosphate signals from blood in human cardiac 31P NMR spectra.

31P NMR spectra of the human heart are usually contaminated by signals that originate from blood. The main blood signals are 2,3-diphosphoglycerate (2,3-DPG), which overlap and sometimes obscure the signal of myocardial inorganic phosphate used to calculate intracellular pH and to monitor metabolic changes in the heart. In this work we demonstrate, first, that even without proton decoupling the resolution of such spectra can be high enough to evaluate intracellular inorganic phosphate of myocardium in about 70% of the spectra and, second, that extracellular inorganic phosphate from blood contributes a signal in the chemical shift region of the 2-phosphate signal of 2,3-DPG.

An interleaved sampling strategy for MR spectroscopy in vivo: applications on human calf musculature.

Assessment of relaxation times, magnetization transfer rates, or apparent diffusion coefficients by volume selective (1)H MR spectroscopy requires data from several single spectra with variable sequence parameters. Unintentional movements during the examination lead to inaccuracies, especially if the spatial distribution of concentrations is inhomogeneous. Improved comparability of the single spectra in a series recorded in vivo were obtained using a modified spectroscopic technique with INTerleaved ACquisiTion of multiple SPECtra (INTACTSPEC). INTACTSPEC series of spectra from the tibialis anterior muscle (m. tib. ant.), soleus muscle (m. soleus), and tibial bone marrow of 20 healthy volunteers were analyzed. Transverse relaxation times T(2) of methylene signals in muscular lipid stores ranged from 77 ms (intramyocellular methylene component in m. tib. ant.) to 88 ms (intramyocellular methylene component in m. soleus) and were similar to those from yellow tibial bone marrow (T(2) = 84 ms). Echo time-dependent signal intensities of choline and creatine deviated markedly from a monoexponential behavior in m. tib. ant., but were nearly exponential in m. soleus. Results from water diffusion measurements parallel and perpendicular to the axis of the lower leg showed significant differences between m. tib. ant. and m. soleus, probably due to the spatial orientation of the muscle fibers. Apparent diffusion coefficients along the leg axis were found to be higher in m. tib. ant. (2.10 +/- 0.08 x 10(-3) mm(2)/s) compared to m. soleus (1.78 +/- 0.11 x 10(-3) mm(2)/s), but m. soleus showed less restricted diffusion in perpendicular orientation (1.59 +/- 0.19 x 10(-3) mm(2)/s versus 1.20 +/- 0.08 x 10(-3) mm(2)/s in m. tib. ant.). Magnetization transfer experiments with various RF preparation pulse amplitudes led to very similar results for m. tib. ant. and m. soleus.

Potential pitfall in the determination of free [Mg2+] by 31P NMR when using the beta/alpha-ATP peak height ratio method.

Recently, Clarke et al. (Clarke K, Kashiwaya Y, King MT, Gates D, Keon CA, Cross HR, Radda GK, Veech RL. The beta/alpha peak height ratio of ATP. A measure of free [Mg2+(free)] using 31P NMR, J. Biol. Chem. 1996;271:21142 21150.) reported a new method to noninvasively determine the concentration of intracellular free magnesium ([Mg2+(free)]) based on the measurement of the peak height ratio h(beta/alpha) of the beta- and alpha-ATP signals in 31P NMR spectra. h(beta/alpha) varies with [Mg2+(free)], however, the study presented here shows that h(beta/alpha) also strongly depends on the homogeneity of the static magnetic field. For this reason, we performed at a magnetic field strength of 1.5 T 31P NMR measurements of solutions that mimic intracellular medium. The magnetic field homogeneity was varied by changing the currents in the shim coils, and the effect on hbeta/alpha is demonstrated with and without proton decoupling. In both cases, h(beta/alpha) strongly depends on the magnetic field homogeneity and can therefore lead to a pitfall in the determination of [Mg2+(free)].

Elimination of residual lipid contamination in single volume proton MR spectra of human brain.

Short echo time 1H NMR spectra of the human brain reveal signals from various metabolites. In addition, resonances from macromolecules are present that may provide further useful information in several brain diseases. The detection of all these signals is possible if excellent volume selection is obtained; even small lipid contamination from surrounding fat tissue leads to strong spectral contamination. It affects the macromolecule resonances in the 0.5 to 2.0 ppm region and some adjacent metabolite signals and jeopardizes their quantitative analysis. This paper demonstrates how spatial contamination from insufficiently dephased signals can be recognized, analysed, and removed in localized STEAM spectroscopy of the brain.

31P/1H WALTZ-4 broadband decoupling at 1.5 T: different versions of the composite pulse and consequences when using a surface coil.

Two derivatives of the wideband alternating-phase low-power technique for zero-residual splitting (WALTZ)-4 decoupling sequence for broadband decoupling named WALTZ-4a and WALTZ-4b were compared for their proton decoupling performance in 31P nuclear magnetic resonance (NMR) spectroscopy using a Siemens Magnetom SP 1.5 T whole-body imager. Version WALTZ-4a originally implemented by the manufacturer doubles and triples the transmitter amplitude of the 90 degrees pulse to achieve the 180 degrees and 270 degrees flip angle required for one composite pulse R in the WALTZ sequence. WALTZ-4b follows the sequence reported from Shaka et al. and leaves the transmitter amplitude constant but increases the durations of the 180 degrees and 270 degrees pulses. The decoupling performance of WALTZ-4b is superior because it requires less transmitter power and, therefore, it is advantageous in all in vivo studies where a low specific absorption rate is desired. When WALTZ-4 is used in combination with a surface coil for transmission the theoretically required flip angles cannot be achieved in the entire sensitive volume of the coil. The decoupling performance was therefore investigated at lower and higher flip angles. Again, WALTZ-4b is advantageous and provides, in certain ranges that are off-resonant from the decoupling frequency, a good decoupling quality even for flip angles that are only 60% of the theoretically required.

Detection of phosphomonoester signals in proton-decoupled 31P NMR spectra of the myocardium of patients with myocardial hypertrophy.

Proton-decoupled 31P NMR spectroscopy at 1.5 T of the anterior left ventricular myocardium was used to monitor myocardial phosphate metabolism in asymptomatic patients with hypertrophic cardiomyopathy (HCM, n = 14) and aortic stenosis (AS, n = 12). In addition to the well-known phosphorus signals a phosphomonoester (PME) signal was detected at about 6.9 ppm in 7 HCM and 2 AS patients. This signal was not observed in the spectra of normal controls (n = 11). We suggest that in spectra of patients with myocardial hypertrophy the presence of a PME signal reflects alterations in myocardial glucose metabolism.

Influence of pulse angle variations on stimulated echo acquisition mode proton nuclear magnetic resonance spectra of AB spin systems: theory and experiments with citrate.

The influence of pulse angle variations in the localization sequence stimulated echo acquisition mode (STEAM) on the signal of strongly coupled AB spin systems has been examined. Experimental 1H nuclear magnetic resonance (NMR) spectra of citrate were recorded on a 1.5 T whole-body imager. Theoretically calculated spectra were generated, with good correlation to experimental results. The dependence of the signal intensity on sequence timing and pulse angles was calculated analytically. For longer sequence timings, the ratio of the signal intensity from citrate to the signal intensity from uncoupled nuclei depends strongly on the applied flip angles. The shape of spectra also changes with varying flip angles. These effects are clearly less pronounced for STEAM than for point resolved spectroscopy (PRESS). The results have to be considered for quantitative measurements of citrate in spectroscopic investigations as, e.g. of prostate neoplasms.

Proton-decoupled myocardial 31P NMR spectroscopy reveals decreased PCr/Pi in patients with severe hypertrophic cardiomyopathy.

Disturbed myocardial energy metabolism may occur in patients with primary hypertrophic cardiomyopathy (HCM). A noninvasive way to gain insight into cardiac energy metabolism is provided by in vivo 31P nuclear magnetic resonance (NMR) spectroscopy. 31P NMR spectroscopy with proton decoupling was performed in 13 patients aged 13-36 years with HCM on a 1.5 T Magnetom with a double resonant surface coil. A 2D chemical shift imaging (CSI) sequence in combination with slice selective excitation was used to acquire spectra of the anteroseptal region of the left ventricle (volume element: 38 mL). The chemical shifts of the phosphorus metabolites, intracellular pHi, and coupling constants J(alphabeta) and J(gammabeta) were calculated. Peak areas of 2,3-diphosphoglycerate (DPG), Pi, and adenosine triphosphate (ATP) were determined and corrected for blood contamination, saturation, and differences in nuclear Overhauser enhancements (NOE). The maximum thickness of the interventricular septum (IVSmax) was determined from tomographic long-axis images and expressed as number of standard deviations above the mean of the normal population (Z score). The patients were then divided into 2 groups: 6 patients with moderate HCM (HCMm, Z score < or = 5) and 7 patients with severe HCM (HCMs, Z score > 5). No differences between both groups and a control group of healthy volunteers (n = 16) were found with respect to phosphocreatine (PCr)/gamma-ATP ratio, pHi, or the coupling constants. Only the PCr/Pi ratio differed significantly from the control group (HCM(all), alpha < 0.05, HCMs, alpha < 0.02, 2-sided U test). The decrease of the PCr/Pi ratio in patients with HCM is probably caused by ischemically decreased oxygen supply in the severely hypertrophied myocardium.

Phosphorus J-coupling constants of ATP in human brain.

Proton decoupled 31P NMR spectroscopy of the occipital brain of healthy volunteers was performed with a 1.5 T whole-body imager. By use of two-dimensional chemical-shift imaging in combination with slice-selective excitation well resolved localized spectra (38 ml) were obtained within 34 min from which the homonuclear 31P-31P J-coupling constants of ATP could be determined: J(gammabeta) = 16.1 Hz +/- 0.2 Hz and J(alphabeta) = 16.3 Hz +/- 0.1 Hz (mean +/- SEM, n = 14). Both, the J-coupling constants and the chemical-shift difference between alpha- and beta-ATP (delta(alphabeta) = 8.61 ppm +/- 0.01 ppm) were used to calculate the concentration of intracellular free magnesium. The concentrations are 0.39 mM +/- 0.09 mM by using the average of both coupling constants of each spectrum, which is in fair agreement with 0.32 mM +/- 0.01 mM obtained from the chemical shift of alpha and beta phosphate resonances, which is the more accurate result.

Magnetization transfer contrast of hepatic lesions in breath-hold gradient-echo images of different T1 weighting.

Seventeen patients with hepatic lesions [six metastases from colon, breast, and gallbladder carcinoma; one gallbladder carcinoma; five hepatocellular carcinoma; three focal nodular hyperplasia (FNH); one adenoma; and one cyst] were examined by MR breath-hold two-dimensional gradient-echo imaging to assess the potential of magnetization transfer contrast (MTC) for improved conspicuity and classification. Imaging sequences were applied with and without irradiation of off-resonant radiofrequency (RF) prepulses, but other parameters were unchanged. Therefore, quantitative assessment of MTC could be performed. In contrast to former examinations of other researchers, no significant difference of MTC was found between malignant liver lesions and benign lesions as FNH or adenoma. MTC might provide differentiation between hemangioma and cysts versus solid tumors, but MTC is not capable of distinguishing benign and malignant types of solid liver tumors. Effects of unchanged MTC prepulses on signal intensity of normal liver tissue and most lesions were more pronounced for nearly proton density-weighted fast low-angle shot (FLASH) images than for T1-weighted FLASH images, obtained by using higher excitation flip angles. Liver-to-lesion contrast could not be improved clearly by MTC prepulses. The contrast between liver and lesions in the gradient-echo breath-hold images was compared with standard T1- and T2-weighted spin-echo images. Liver-to-lesion contrast in the breath-hold images was found to be inferior to T2-weighted spin-echo images in 14 of 17 cases. Lesion conspicuity in regions near the diaphragm was better in breath-hold images, because problems with marked breathing motion (as in standard imaging) could be avoided.

Assessment of the composition of bone marrow prior to and following autologous BMT and PBSCT by magnetic resonance.

Lumbar bone marrow was assessed by means of magnetic resonance (MR) in 23 examinations of eight patients who underwent autologous bone marrow transplantation (ABMT) or peripheral blood stem cell transplantation (PBSCT). Various imaging and spectroscopic techniques were applied for measurements carried out prior to conditioning for ABMT/PBSCT and in the course of reconstitution and correlated with clinical and blood chemistry data in these patients. The signal intensity from lumbar bone marrow was determined in T1-weighted and water- and fat-selective MR images. The distribution of the magnetic field was demonstrated by a field-mapping method. Localized proton spectroscopy was performed from volume elements of 2 ml located in the central region of vertebral bodies in order to evaluate the fraction of the water signals, the transverse relaxation times T2 of the signals from water and lipids, and the line widths of the spectral signals. Regions of bone marrow after inflammatory conditions or intensive irradiation are shown to be not involved in marrow reconstitution. Additional information about marrow composition was obtained by the magnetic field mapping and by the line widths in the spectra. Considerable alterations of the amount of paramagnetic hemosiderin were revealed following transplantation. Patients with low water signal and strong local inhomogeneities of the magnetic field in the marrow prior to transplantation had a delayed hematopoietic reconstitution compared with the patients lacking these MR features.

Lipid selective MR imaging and localized 1H spectroscopy of bone marrow during therapy of leukemia.

In most patients with acute leukemia very low or absent lipid signals from central red bone marrow are detected using magnetic resonance (MR) techniques, in contrast to healthy persons with considerable signals from both, water and lipid protons. The proliferation of the malignant leukemic cells causes the displacement of fat cells in the marrow. This disorder is reversible during successful cytotoxic chemotherapy of acute leukemia: Lipid signals from vertebral bodies arise again due to the replacement of hypercellular leukemic marrow by fat. Different approaches for lipid selective MR imaging and spectroscopy are reported and results from typical examples are demonstrated and discussed. The report is based on examinations of 12 patients with leukemia in follow-up studies, 11 patients with other disorders of bone marrow, and 26 healthy volunteers.

Lipids in bone tumors assessed by magnetic resonance: chemical shift imaging and proton spectroscopy in vivo.

The methods of fat and water selective magnetic resonance (MR) imaging and localized 1H MR spectroscopy were evaluated in the course of 37 examinations on 27 primary bone tumors. These methods are capable of demonstrating small amounts of lipids inside the tumors and subtle edema in the adacent bone marrow, in contrast to the usually applied spin-echo and gradient-echo sequences providing signals dependent on the total proton density and on the relaxation times. The tumor masses of the malignant tumors were free of signals in the fat selective images, whereas in three out of six osteochondroma fat signals could be detected. Localized MR spectroscopy was more sensitive even to very low lipid content (lipid portion < 0.5%) in the tumors and revealed signals with J-coupling from seven out of 13 malignant tumors.

31P NMR studies of human soleus and gastrocnemius show differences in the J gamma beta coupling constant of ATP and in intracellular free magnesium.

Localized proton decoupled 31P in vivo NMR spectroscopy of the human calf muscle was performed using a 1.5-T whole-body imager and the slice selective two-dimensional chemical-shift-imaging (2D-CSI) technique. The 31P-31P coupling constants and the chemical shifts of ATP were compared in gastrocnemius and soleus. Significant differences were found in the coupling constant J gamma beta: (18.1 +/- 0.7) Hz versus (17.1 +/- 0.6) Hz (means +/- SD, P < 10-5). Differences were also observed in the chemical shift separation delta alpha beta between the alpha- and beta-ATP signal: (8.498 +/- 0.023) ppm versus (8.522 +/- 0.222) ppm (p < 0.001) in gastrocnemius and soleus, respectively. A higher [MgATP]/[ATPfree] ratio and a significantly higher level of intracellular free magnesium of (0.52 +/- 0.06) mM in gastrocnemius versus (0.46 +/- 0.05) mM in soleus (p < 0.001) can be derived based on delta alpha beta and KDMgATP. Heterogeneity needs to be taken into account in clinical studies on magnesium by NMR methods in calf muscle. The coupling constant J gamma beta provides additional information, possibly on enzymatic processes, and correlates with [Mg2+free]. The detailed analysis of muscles with different fiber type characteristics lends support to the significance of this parameter in evaluating metabolism. The data reported can be used as prior knowledge for fits in which the coupling constants are set to a fixed value.

Change in chemical shift and splitting of 31P gamma-ATP signal in human skeletal muscle during exercise and recovery.

Proton decoupled 31P in vivo NMR spectroscopy of the human finger flexor muscles was performed during exercise and recovery using a 1.5 T whole-body imager. Predominantly the gamma-ATP signal shows a splitting caused by different signal contributions with chemical shifts that vary independently. Studies on the human gastrocnemius and biceps femoris muscle were undertaken to investigate the appearance of the splitting in these muscles as well. In all cases more than one signal contribution was found which might represent the different muscle fibre types and their recruitment pattern following exercise. An analysis of the chemical shifts (delta) of ATP results in changes of up to 0.4 ppm and 0.1 ppm for delta gamma- and delta beta-ATP, respectively. Based solely on the chemical shifts of the ATP 31P signals the tissue pH value following exercise was determined. The result was in good agreement with the value derived from delta Pi.