Measurements of hepatic iron concentration (HIC) are important predictors of transfusional iron burden and long-term outcome in patients with transfusiondependent anemias. The goal of this work was to develop a readily available, noninvasive method for clinical HIC measurement. The relaxation rates R2 (1/ T2) and R2* (1/ T2*) measured by magnetic resonance imaging (MRI) have different advantages for HIC estimation. This article compares noninvasive iron estimates using both optimized R2 and R2* methods in 102 patients with iron overload and 13 controls. In the iron-overloaded group, 22 patients had concurrent liver biopsy. R2 and R2* correlated closely with HIC (r 2 > .95) for HICs between 1.33 and 32.9 mg/g, but R2 had a curvilinear relationship to HIC. Of importance, the R2 calibration curve was similar to the curve generated by other researchers, despite significant differences in technique and instrumentation. Combined R2 and R2* measurements did not yield more accurate results than either alone. Both R2 and R2* can accurately measure hepatic iron concentration throughout the clinically relevant range of HIC with appropriate MRI acquisition techniques. (Blood.

Summary Human embryonic stem cell-derived cardiomyocytes (hESC-CMs) show considerable promise for regenerating injured hearts, and we therefore tested their capacity to stably engraft in a translationally relevant preclinical model, the infarcted pig heart. Transplantation of immature hESC-CMs resulted in substantial myocardial implants within the infarct scar that matured over time, formed vascular networks with the host, and evoked minimal cellular rejection. While arrhythmias were rare in infarcted pigs receiving vehicle alone, hESC-CM recipients experienced frequent monomorphic ventricular tachycardia before reverting back to normal sinus rhythm by 4 weeks post transplantation. Electroanatomical mapping and pacing studies implicated focal mechanisms, rather than macro-reentry, for these graft-related tachyarrhythmias as evidenced by an abnormal centrifugal pattern with earliest electrical activation in histologically confirmed graft tissue. These findings demonstrate the suitability of the pig model for the preclinical development of a hESC-based cardiac therapy and provide new insights into the mechanistic basis of electrical instability following hESC-CM transplantation.

Hyperpolarization of spins via dynamic nuclear polarization (DNP) has been explored as a method to non-invasively study real-time metabolic rocesses occurring in vivo using 13 C-labeled substrates. Recently, hyperpolarized 13 C pyruvate has been used to characterize in vivo cardiac metabolism in the rat and pig. Conventional 3D spectroscopic imaging methods require in excess of 100 excitations, making it challenging to acquire a full cardiac-gated, breath-held, whole-heart volume. In this article, the development of a rapid multislice cardiac-gated spiral 13 C imaging pulse sequence consisting of a large flip-angle spectral-spatial excitation RF pulse combined with a singleshot spiral k-space trajectory for rapid imaging of cardiac metabolism is described. This sequence permits whole-heart coverage (6 slices, 8.

Purpose: To optimize R2*(1/T2*) measurements for cardiac iron detection in sickle cell and thalassemia patients. Materials and Methods:We studied 31 patients with transfusion-dependent sickle cell disease and 48 patients with thalassemia major; myocardial R2* was assessed in a single midpapillary slice using a gated gradient-echo pulse sequence. Pixel-wise maps were coregistered among the patients to determine systematic spatial fluctuations in R2*. The contributions of minimum TE, echo spacing, signal-decay model, and region-of-interest (ROI) choice were compared in synthetic and acquired images.Results: Cardiac relaxivity demonstrated characteristic circumferential variations regardless of the degree of iron overload. Within the interventricular septum, a gradient in R2* from right to left ventricle was noted at high values. Pixel-wise and ROI techniques yielded nearly identical values. Signal decay was exponential but a constant offset or second exponential term was necessary to avoid underestimation at high iron concentration. Systematic underestimation of R2* was observed for higher minimum TE, limiting the range of iron concentrations that can be profiled. Fat-water oscillations, although detectable, represented only 1% of the total signal. Conclusion:Clinical cardiac R2* measurements should be restricted to the interventricular septum and should have a minimum TE Յ 2 msec. ROI analysis techniques are accurate; however, offset-correction is essential.

Iron overload is a serious condition for patients with b-thalassemia, transfusion-dependent sickle cell anemia, and inherited disorders of iron metabolism. MRI is becoming increasingly important in noninvasive quantification of tissue iron, overcoming the drawbacks of traditional techniques (liver biopsy). Effective transverse relaxation rate (1/effective transverse relaxation time) rises linearly with iron while transverse relaxation rate (1/T 2 ) has a curvilinear relationship in human liver. Although recent work has demonstrated clinically valid estimates of human liver iron, the calibration varies with MRI sequence, field strength, iron chelation therapy, and organ imaged, forcing recalibration in patients. To understand and correct these limitations, a thorough understanding of the underlying biophysics is of critical importance. Toward this end, a Monte Carlo-based approach, using human liver as a ''model'' tissue system, was used to determine the contribution of particle size and distribution on MRI signal relaxation. Relaxivities were determined for hepatic iron concentrations ranging from 0.5 to 40 mg iron per gram dry tissue weight. Model predictions captured the linear and curvilinear relationship of effective transverse relaxation rate and transverse relaxation rate with hepatic iron concentrations, respectively, and were within in vivo confidence bounds; contact or chemical exchange mechanisms were not necessary. A validated and optimized model will aid understanding and quantification of iron-mediated relaxivity in tissues where biopsy is not feasible (heart and spleen). Magn Reson Med 65:837-847, 2011. V C 2010 WileyLiss, Inc.Key words: iron overload; liver; Monte Carlo; relaxation; relaxivity Iron overload is a life-threatening condition for patients with b-thalassemia, transfusion-dependent sickle cell anemia, and inherited disorders of iron metabolism (1). Excess iron accumulates in liver, heart, spleen, and endocrine organs, causing oxidative damage. Liver biopsy is the prevailing clinical standard for monitoring total body iron stores; however, it is invasive, painful (2), expensive, and prone to sampling error (3) and provides only indirect information regarding other inaccessible organs. As an alternative, MRI has gained importance in noninvasive quantification of tissue iron, overcoming the drawbacks of traditional techniques. Superparamagnetic substances such as iron oxide particles (ferritin and hemosiderin complexes) produce magnetic field disturbances that increase MRI relaxivities effective transverse relaxation rate (1/effective transverse relaxation time) [R* 2 (1/T* 2 )] and R 2 (1/T 2 ), indirectly reflecting tissue iron loading. Recent studies by St. Pierre et al. (4) In spite of recent success with studies showing good intermachine and interstudy reproducibility for individual pulse sequences (4,6), relaxivity-iron relationships still vary between investigators in complicated ways. Iron calibration appears to vary with acquisition method [single spin echo, multiple spin echo, o...

Iron-induced cardiac dysfunction is a leading cause of death in transfusion-dependent anemia. MRI relaxation rates R 2 (1/T 2 ) and R* 2 (1/T* 2 ) accurately predict liver iron concentration, but their ability to predict cardiac iron has been challenged by some investigators. Studies in animal models support similar R 2 and R* 2 behavior with heart and liver iron, but human studies are lacking. To determine the relationship between MRI relaxivities and cardiac iron, regional variations in R 2 and R* 2 were compared with iron distribution in one freshly deceased, unfixed, iron-loaded heart. R 2 and R* 2 were proportionally related to regional iron concentrations and highly concordant with one another within the interventricular septum. A comparison of postmortem and in vitro measurements supports the notion that cardiac R* 2 should be assessed in the septum rather than the whole heart. These data, along with measurements from controls, provide bounds on MRI-iron calibration curves in human heart and further support the clinical use of cardiac MRI in iron-overload syndromes. Magn Reson Med 56: 681-686, 2006.

MRI is becoming an increasingly important tool to assess iron overload disorders, but the complex nature of proton-iron interactions has troubled noninvasive iron quantification. Intersite and intersequence variability as well as methodological inaccuracies have been limiting factors to its widespread clinical use. It is important to understand the underlying proton relaxation mechanisms within the (human) tissue environment to address these differences. In this respect, NMR relaxometry was performed on 10 fresh human liver biopsy specimens taken from patients with transfusion-dependent anemia. T 1 (1/R 1 ) inversion recovery, T 2 (1/R 2 ) single echo, and multiecho T 2 CPMG measurements were performed on a 60-MHz Bruker Minispectrometer. NMR parameters were compared to quantitative iron levels and tissue histology. Relaxivities R 1 and R 2 both increased linearly with hepatic iron content, with R 2 being more sensitive to iron. CPMG data were well described by a chemical-exchange model and predicted effective iron center dimensions consistent with hemosiderin-filled lysosomes. Nonexponential relaxation was evident at short refocusing intervals with R 2 and amplitude behavior suggestive of magnetic susceptibility-based compartmentalization rather than anatomic subdivisions. NMR relaxometry of human liver biopsy specimens yields unique insights into the mechanisms of tissue-iron relaxivity. Magn Reson Med 54:1185-1193, 2005.

Pathophysiological responses after acute myocardial infarction include edema, hemorrhage, and microvascular obstruction along with cellular damage. The in vivo evolution of these processes simultaneously throughout infarct healing has not been well characterized. The purpose of our study was to quantitatively monitor the time course of these mechanisms by MRI in a porcine model of myocardial infarction. Ten pigs underwent MRI before coronary occlusion with subgroups studied at day 2 and weeks 1, 2, 4, and 6 post-infarction. Tissue characterization was performed using quantitative T2 and T2* maps to identify edema and hemorrhage, respectively. Contrast-enhanced MRI was used for infarct/ microvascular obstruction delineation. Inflammation was reflected by T2 fluctuations, however at day 2, edema and hemorrhage had counter-acting effects on T2. Hemorrhage (all forms) and mineralization (calcium) could be identified by T2* in the presence of edema. Simultaneous resolution of microvascular obstruction and T2* abnormality suggested that the two phenomenon were closely associated during the healing process. Our study demonstrates that quantitative T2 and T2* mapping techniques allow regional, longitudinal, and cross-subject comparisons and give insights into histological and tissue remodeling processes. Such in vivo characterization will be important in grading severity and evaluating treatment strategies for myocardial infarction, potentially improving clinical outcomes. Magn Reson Med 66:1129-1141, 2011. V C 2011 Wiley-Liss, Inc.