Justin Y.C. Lau

Hyperpolarized 13C Metabolic MRI of the Human HeartNovelty and Significance

Rationale: Altered cardiac energetics is known to play an important role in the progression toward heart failure. A noninvasive method for imaging metabolic markers that could be used in longitudinal studies would be useful for understanding therapeutic approaches that target metabolism. Objective: To demonstrate the first hyperpolarized 13C metabolic magnetic resonance imaging of the human heart. Methods and Results: Four healthy subjects underwent conventional proton cardiac magnetic resonance imaging followed by 13C imaging and spectroscopic acquisition immediately after intravenous administration of a 0.1 mmol/kg dose of hyperpolarized [1-13C]pyruvate. All subjects tolerated the procedure well with no adverse effects reported ≤1 month post procedure. The [1-13C]pyruvate signal appeared within the chambers but not within the muscle. Imaging of the downstream metabolites showed 13C-bicarbonate signal mainly confined to the left ventricular myocardium, whereas the [1-13C]lactate signal appeared both within the chambers and in the myocardium. The mean 13C image signal:noise ratio was 115 for [1-13C]pyruvate, 56 for 13C-bicarbonate, and 53 for [1-13C]lactate. Conclusions: These results represent the first 13C images of the human heart. The appearance of 13C-bicarbonate signal after administration of hyperpolarized [1-13C]pyruvate was readily detected in this healthy cohort (n=4). This shows that assessment of pyruvate metabolism in vivo in humans is feasible using current technology. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02648009.Rationale: Altered cardiac energetics is known to play an important role in the progression toward heart failure. A noninvasive method for imaging metabolic markers that could be used in longitudinal studies would be useful for understanding therapeutic approaches that target metabolism. Objective: To demonstrate the first hyperpolarized 13 C metabolic magnetic resonance imaging of the human heart. Methods and Results: Four healthy subjects underwent conventional proton cardiac magnetic resonance imaging followed by 13 C imaging and spectroscopic acquisition immediately after intravenous administration of a 0.1 mmol/kg dose of hyperpolarized [1- 13 C]pyruvate. All subjects tolerated the procedure well with no adverse effects reported ≤1 month post procedure. The [1- 13 C]pyruvate signal appeared within the chambers but not within the muscle. Imaging of the downstream metabolites showed 13 C-bicarbonate signal mainly confined to the left ventricular myocardium, whereas the [1- 13 C]lactate signal appeared both within the chambers and in the myocardium. The mean 13 C image signal:noise ratio was 115 for [1- 13 C]pyruvate, 56 for 13 C-bicarbonate, and 53 for [1- 13 C]lactate. Conclusions: These results represent the first 13 C images of the human heart. The appearance of 13 C-bicarbonate signal after administration of hyperpolarized [1- 13 C]pyruvate was readily detected in this healthy cohort (n=4). This shows that assessment of pyruvate metabolism in vivo in humans is feasible using current technology. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02648009.

Hyperpolarized 13C Metabolic MRI of the Human Heart: Initial Experience.

Rationale: Altered cardiac energetics is known to play an important role in the progression toward heart failure. A noninvasive method for imaging metabolic markers that could be used in longitudinal studies would be useful for understanding therapeutic approaches that target metabolism. Objective: To demonstrate the first hyperpolarized 13C metabolic magnetic resonance imaging of the human heart. Methods and Results: Four healthy subjects underwent conventional proton cardiac magnetic resonance imaging followed by 13C imaging and spectroscopic acquisition immediately after intravenous administration of a 0.1 mmol/kg dose of hyperpolarized [1-13C]pyruvate. All subjects tolerated the procedure well with no adverse effects reported ≤1 month post procedure. The [1-13C]pyruvate signal appeared within the chambers but not within the muscle. Imaging of the downstream metabolites showed 13C-bicarbonate signal mainly confined to the left ventricular myocardium, whereas the [1-13C]lactate signal appeared both within the chambers and in the myocardium. The mean 13C image signal:noise ratio was 115 for [1-13C]pyruvate, 56 for 13C-bicarbonate, and 53 for [1-13C]lactate. Conclusions: These results represent the first 13C images of the human heart. The appearance of 13C-bicarbonate signal after administration of hyperpolarized [1-13C]pyruvate was readily detected in this healthy cohort (n=4). This shows that assessment of pyruvate metabolism in vivo in humans is feasible using current technology. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02648009.Rationale: Altered cardiac energetics is known to play an important role in the progression toward heart failure. A noninvasive method for imaging metabolic markers that could be used in longitudinal studies would be useful for understanding therapeutic approaches that target metabolism. Objective: To demonstrate the first hyperpolarized 13 C metabolic magnetic resonance imaging of the human heart. Methods and Results: Four healthy subjects underwent conventional proton cardiac magnetic resonance imaging followed by 13 C imaging and spectroscopic acquisition immediately after intravenous administration of a 0.1 mmol/kg dose of hyperpolarized [1- 13 C]pyruvate. All subjects tolerated the procedure well with no adverse effects reported ≤1 month post procedure. The [1- 13 C]pyruvate signal appeared within the chambers but not within the muscle. Imaging of the downstream metabolites showed 13 C-bicarbonate signal mainly confined to the left ventricular myocardium, whereas the [1- 13 C]lactate signal appeared both within the chambers and in the myocardium. The mean 13 C image signal:noise ratio was 115 for [1- 13 C]pyruvate, 56 for 13 C-bicarbonate, and 53 for [1- 13 C]lactate. Conclusions: These results represent the first 13 C images of the human heart. The appearance of 13 C-bicarbonate signal after administration of hyperpolarized [1- 13 C]pyruvate was readily detected in this healthy cohort (n=4). This shows that assessment of pyruvate metabolism in vivo in humans is feasible using current technology. Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT02648009.

Accelerated 3D echo-planar imaging with compressed sensing for time-resolved hyperpolarized (13) C studies.

To enable large field‐of‐view, time‐resolved volumetric coverage in hyperpolarized 13C metabolic imaging by implementing a novel data acquisition and image reconstruction method based on the compressed sensing framework.

Using [1‐13C]lactic acid for hyperpolarized 13C MR cardiac studies

Hyperpolarized [1‐13C]lactate in solution may be a clinically relevant and safe substrate for real time MR investigations of key metabolic pathways. The potential of using hyperpolarized [1‐13C]lactate for magnetic resonance studies of cardiac metabolism in vivo was explored.

A calibration‐based approach to real‐time in vivo monitoring of pyruvate C1 and C2 polarization using the JCC spectral asymmetry

A calibration‐based technique for real‐time measurement of pyruvate polarization by partial integral analysis of the doublet from the neighbouring J‐coupled carbon is presented. In vitro calibration data relating the C2 and C1 asymmetries to the instantaneous C1 and C2 polarizations, respectively, were acquired in blood. The feasibility of using the in vitro calibration data to determine the instantaneous in vivo C1 and C2 polarizations was demonstrated in the analysis of rat kidney and pig heart spectral data. An approach for incorporating this technique into in vivo protocols is proposed. Copyright

Characterization of the ultrashort-TE (UTE) MR collagen signal†

Although current cardiovascular MR (CMR) techniques for the detection of myocardial fibrosis have shown promise, they nevertheless depend on gadolinium‐based contrast agents and are not specific to collagen. In particular, the diagnosis of diffuse myocardial fibrosis, a precursor of heart failure, would benefit from a non‐invasive imaging technique that can detect collagen directly. Such a method could potentially replace the need for endomyocardial biopsy, the gold standard for the diagnosis of the disease. The objective of this study was to measure the MR properties of collagen using ultrashort TE (UTE), a technique that can detect short T2* species. Experiments were performed in collagen solutions. Via a model of bi‐exponential T2* with oscillation, a linear relationship (slope = 0.40 ± 0.01, R2 = 0.99696) was determined between the UTE collagen signal fraction associated with these properties and the measured collagen concentration in solution. The UTE signal of protons in the collagen molecule was characterized as having a mean T2* of 0.75 ± 0.05 ms and a mean chemical shift of −3.56 ± 0.01 ppm relative to water at 7 T. The results indicated that collagen can be detected and quantified using UTE. A knowledge of the collagen signal properties could potentially be beneficial for the endogenous detection of myocardial fibrosis. Copyright

Intensity correction for multichannel hyperpolarized 13C imaging of the heart.

Develop and test an analytic correction method to correct the signal intensity variation caused by the inhomogeneous reception profile of an eight‐channel phased array for hyperpolarized 13C imaging.

Hyperpolarized MRI of Cancer Metabolism

This review will highlight recent advances in hyperpolarized 13C MR spectroscopic imaging, which can be used to noninvasively interrogate tumor metabolism. After providing an overview of MR and hyperpolarization, we will discuss the latest advances in data acquisition techniques. Next, we will shift our focus to hyperpolarized probe design and provide an overview of the latest hyperpolarized 13C MR spectroscopic imaging probes developed in the last several years.

Voxel‐by‐voxel correlations of perfusion, substrate, and metabolite signals in dynamic hyperpolarized 13C imaging

In this study, a mixture of pyruvic acid and the perfusion agent HP001 was co‐polarized for simultaneous assessment of perfusion and metabolism in vivo. The pre‐polarized mixture was administered to rats with subcutaneous MDA‐MB‐231 breast cancer xenografts and imaged using an interleaved sequence with designed spectral–spatial pulses and flyback echo‐planar readouts. Voxel‐by‐voxel signal correlations from 10 animals (15 data sets) were analyzed for tumour, kidney, and muscle regions of interest. The relationship between perfusion and hyperpolarized signal was explored on a voxel‐by‐voxel basis in various metabolically active tissues, including tumour, healthy kidneys, and skeletal muscle. Positive pairwise correlations between lactate, pyruvate, and HP001 observed in all 10 tumours suggested that substrate delivery was the dominant factor limiting the conversion of pyruvate to lactate in the tumour model used in this study. On the other hand, in cases where conversion is the limiting factor, such as in healthy kidneys, both pyruvate and lactate can act as excellent perfusion markers. In intermediate cases between the two limits, such as in skeletal muscle, some perfusion information may be inferred from the (pyruvate + lactate) signal distribution. Co‐administration of pyruvate with a dynamic nuclear polarization (DNP) perfusion agent is an effective approach for distinguishing between slow metabolism and poor perfusion and a practical strategy for lactate signal normalization to account for substrate delivery, especially in cases of rapid pyruvate‐to‐lactate conversion and in poorly perfused regions with inadequate pyruvate signal‐to‐noise ratio for reliable determination of the lactate‐to‐pyruvate ratio. Copyright

Dual-Echo EPI sequence for integrated distortion correction in 3D time-resolved hyperpolarized 13C MRI: Dual-Echo 13C 3D EPI

To provide built‐in off‐resonance correction in time‐resolved, volumetric hyperpolarized 13C metabolic imaging by implementing a novel dual‐echo 3D echo‐planar imaging (EPI) sequence and reconstruction.