Cardiac Metabolic Imaging Research Articles

Considerations for hyperpolarized 13 C MR at reduced field: Comparing 1.5T versus 3T.

In contrast to conventional MR, signal-to-noise ratio (SNR) is not linearly dependent on field strength in hyperpolarized MR, as polarization is generated outside the MR system. Moreover, field inhomogeneity-induced artifacts and other practical limitations associated with field strengths 3T are alleviated at lower fields. The potential of hyperpolarized C spectroscopy and imaging at 1.5T versus 3T is demonstrated in silico, in vitro, and in vivo for applications on clinical MR systems. Theoretical noise and SNR behavior at different field strengths are investigated based on simulations. A thorough field comparison between 1.5T and 3T is performed using thermal and hyperpolarized C spectroscopy and imaging. Cardiac in vivo data is obtained in pigs using hyperpolarized [1- C]pyruvate spectroscopy and imaging at 1.5T and 3T. Based on theoretical considerations and simulations, the SNR of hyperpolarized MR at identical acquisition bandwidths is independent of the field strength for typical coil setups, while adaptively changing the acquisition bandwidth proportional to the static magnetic field allows for net SNR gains of up to 40% at 1.5T compared to 3T. In vitro C data verified these considerations with less than 7% deviation. In vivo feasibility of hyperpolarized [1- C]pyruvate dynamic metabolic spectroscopy and imaging at 1.5T is demonstrated in the pig heart with comparable SNR between 1.5T and 3T while B artifacts are noticeably reduced at 1.5T. Hyperpolarized C MR at lower field strengths is favorable in terms of SNR and off-resonance effects, which makes 1.5T a promising alternative to 3T, especially for clinical cardiac metabolic imaging.

Assessment of Cardiac Sarcoidosis: FDG PET and BMIPP SPECT.

Cardiac sarcoidosis (CS) is an inflammatory disease of unknown etiology that can lead to life-threatening arrhythmias, heart failure, and death. Advanced cardiac imaging modalities have improved the clinician's ability to detect this disease. The purpose of this review is to discuss the recent evidence of cardiac metabolic imaging as assessed by [18F]FDG PET and [123I]BMIPP SPECT in the evaluation of CS patients. [18F]FDG PET is the gold standard to identify myocardial inflammation. [123I]BMIPP SPECT can uncover early myocardial damage as well as advanced stages of CS when fibrosis prevails. In presence of inflammation, myocardial [18F]FDG uptake is increased, but in contrast, BMIPP myocardial uptake is reduced or even suppressed. Thus, a complementary role of cardiac metabolic imaging by [18F]FDG PET and BMIPP SPECT has been proposed to detect the whole spectrum of CS. [18F]FDG PET is considered an important tool to improve the diagnosis and optimize the management of CS. The role of [123I]BMIPP SPECT in diagnosing CS is still under investigation. Further studies are needed to evaluate the clinical utility of combined cardiac metabolic imaging in the diagnosis, prognosis, and for selecting treatments in CS patients.

Magnetic resonance imaging of cardiac metabolism in heart failure: how far have we come?

As one of the highest energy consumer organs in the body, the heart requires tremendous amount of adenosine triphosphate (ATP) to maintain its continuous mechanical work. Fatty acids, glucose, and ketone bodies are the primary fuel source of the heart to generate ATP with perturbations in ATP generation possibly leading to contractile dysfunction. Cardiac metabolic imaging with magnetic resonance imaging (MRI) plays a crucial role in understanding the dynamic metabolic changes occurring in the failing heart, where the cardiac metabolism is deranged. Also, targeting and quantifying metabolic changes in vivo noninvasively is a promising approach to facilitate diagnosis, determine prognosis, and evaluate therapeutic response. Here, we summarize novel MRI techniques used for detailed investigation of cardiac metabolism in heart failure including magnetic resonance spectroscopy (MRS), hyperpolarized MRS, and chemical exchange saturation transfer based on evidence from preclinical and clinical studies and to discuss the potential clinical application in heart failure.

Erratum to: Dual-phase imaging of cardiac metabolism using hyperpolarized pyruvate (Magn Reson Med. 2022;87:302-311.).

Erratum to: Dual-phase imaging of cardiac metabolism using hyperpolarized pyruvate (Magn Reson Med. 2022;87:302-311.).

A near-infrared fluorescent long-chain fatty acid toward optical imaging of cardiac metabolism in living mice.

Non-invasive fatty acid (FA) metabolic imaging is crucial for the evaluation of cardiac function in the heart. Currently, single-photon emission computed tomography (SPECT) and positron emission tomography (PET) are widely employed for cardiac metabolic imaging both in pre-clinical and clinical studies. Although SPECT and PET enable highly sensitive cardiac metabolic imaging, there are several disadvantages such as the high cost of instruments and radioactive tracer synthesis. In contrast, near-infrared (NIR) optical imaging using fluorescent FAs provides a simple and useful platform for in vivo imaging of cardiac metabolism. In this work, we synthesized a NIR fluorescence labelled long-chain fatty acid (LCFA) for real-time imaging of cardiac metabolism in vivo. A NIR fluorescence labelled LCFA was designed as an analogue of β-methyl [123I] iodophenyl-pentanedecanoic acid (123I-BMIPP), which is widely used for the diagnosis of heart diseases in clinical practice. As a NIR fluorescent label, we used an Alexa 680 fluorophore that emits over 700 nm. By conjugation of Alexa 680 to Amino-BMPP (15-(4-(3-aminopropyl)phenyl)-3-methylpentadecanoic acid), we prepared a NIR fluorescent BMIPP analogue, Alexa680-BMPP. NIR fluorescence imaging showed that Alexa680-BMPP is taken up by the mouse heart tissue after intravenous injection, showing that Alexa680-BMPP can act as a fluorescent LCFA analogue. Among Alexa680 conjugated FA analogues including short and middle chain NIR fluorescent FAs, Alexa680-BMPP was most efficiently taken up by heart tissues. For fasted and fed mice, the difference in the degree of the uptake of Alexa680-BMPP in their heart tissues was clearly observed by in vivo and ex vivo NIR fluorescence imaging. Herein, we present the synthesis of a NIR fluorescent LCFA, Alexa680-BMPP, and its capability for real-time optical imaging of cardiac metabolism in living mice.

Dual-phase imaging of cardiac metabolism using hyperpolarized pyruvate.

Previous cardiac imaging studies using hyperpolarized (HP) [1-13 C]pyruvate were acquired at end-diastole (ED). Little is known about the interaction between cardiac cycle and metabolite content in the myocardium. In this study, we compared images of HP pyruvate and products at end-systole (ES) and ED. A dual-phase 13 C MRI sequence was implemented to acquire two sequential HP images within a single cardiac cycle at ES and ED during successive R-R intervals in an interleaved manner. Each healthy volunteer (N = 3) received two injections of HP [1-13 C]pyruvate for the dual-phase imaging on the short-axis and the vertical long-axis planes. Spatial distribution of HP 13 C metabolites at each cardiac phase was correlated to multiphase 1 H MRI to confirm the mechanical changes. Ratios of myocardial HP metabolites were compared between ES and ED. Segmental analysis was performed on the midcavity short-axis plane. In addition to mechanical changes, metabolic profiles of the heart detected by HP [1-13 C]pyruvate differed between ES and ED. The myocardial signal of [13 C]bicarbonate relative to [1-13 C]lactate was significantly smaller at ED than the ratio at ES (p < .05), particularly in mid-anterior and mid-inferoseptal segments. The distinct metabolic profiles in the myocardium likely reflect the technical aspects of the imaging approach such as the coronary flow in addition to the cyclical changes in metabolism. The study demonstrates that metabolic profiles of the heart, measured by HP [1-13 C]pyruvate, are affected by the cardiac cycle in which that the data are acquired.

Cardiac metabolic imaging using hyperpolarized [1-13 C]lactate as a substrate.

Hyperpolarized (HP) [1-13 C]lactate is an attractive alternative to [1-13 C]pyruvate as a substrate to investigate cardiac metabolism in vivo: it can be administered safely at a higher dose and can be polarized to a degree similar to pyruvate via dynamic nuclear polarization. While 13 C cardiac experiments using HP lactate have been performed in small animal models, they have not been demonstrated in large animal models or humans. Utilizing the same hardware and data acquisition methods as the first human HP 13 C cardiac study, 13 C metabolic images were acquired following injections of HP [1-13 C]lactate in porcine hearts. Data were also acquired using HP [1-13 C]pyruvate for comparison. The 13 C bicarbonate signal was localized to the myocardium and had a similar appearance with both substrates for all animals. No 13 C pyruvate signal was detected in the experiments following injection of HP 13 C lactate. The signal-to-noise ratio (SNR) of injected lactate was 88 ± 4% of the SNR of injected pyruvate, and the SNR of bicarbonate in the experiments using lactate as the substrate was 52 ± 19% of the SNR in the experiments using pyruvate as the substrate. The lower SNR was likely due to the shorter T1 of [1-13 C]lactate as compared with [1-13 C]pyruvate and the additional enzyme-catalyzed metabolic conversion step before the 13 C nuclei from [1-13 C]lactate were detected as 13 C bicarbonate. While challenges remain, the potential of HP lactate as a substrate for clinical metabolic imaging of human heart has been demonstrated.

Synthesis and evaluation of 68Ga labeled palmitic acid for cardiac metabolic imaging

This work evaluates the potential of a 68Ga labeled long chain 16C fatty acid for cardiac metabolic imaging. For radiolabeling with 68Ga, hexadecanedioic acid was coupled with the chelator p-NH2-Bn-NOTA. Under the optimized conditions, NOTA-hexadecanoic acid could be radiolabeled with 68Ga in ≥95% yields. In biodistribution studies carried out in Swiss mice, 68Ga-NOTA-hexadecanoic acid showed low myocardial uptake at 2 min p.i. (3.7 ± 1.3%ID/g). While 68Ga-NOTA-hexadecanoic acid cleared rapidly from non-target organs such as blood, lungs, intestine and kidney, wash out from liver was slow. Radio-HPLC analyses of myocardial extracts of rats injected with 68Ga-NOTA-hexadecanoic acid confirmed its metabolic transformation in the myocardium.

Using a whole-body 31P birdcage transmit coil and 16-element receive array for human cardiac metabolic imaging at 7T.

PurposeCardiac phosphorus magnetic resonance spectroscopy (31P-MRS) provides unique insight into the mechanisms of heart failure. Yet, clinical applications have been hindered by the restricted sensitivity of the surface radiofrequency-coils normally used. These permit the analysis of spectra only from the interventricular septum, or large volumes of myocardium, which may not be meaningful in focal disease. Löring et al. recently presented a prototype whole-body (52 cm diameter) transmit/receive birdcage coil for 31P at 7T. We now present a new, easily-removable, whole-body 31P transmit radiofrequency-coil built into a patient-bed extension combined with a 16-element receive array for cardiac 31P-MRS.Materials and methodsA fully-removable (55 cm diameter) birdcage transmit coil was combined with a 16-element receive array on a Magnetom 7T scanner (Siemens, Germany). Electro-magnetic field simulations and phantom tests of the setup were performed. In vivo maps of B1+, metabolite signals, and saturation-band efficiency were acquired across the torsos of eight volunteers.ResultsThe combined (volume-transmit, local receive array) setup increased signal-to-noise ratio 2.6-fold 10 cm below the array (depth of the interventricular septum) compared to using the birdcage coil in transceiver mode. The simulated coefficient of variation for B1+ of the whole-body coil across the heart was 46.7% (surface coil 129.0%); and the in vivo measured value was 38.4%. Metabolite images of 2,3-diphosphoglycerate clearly resolved the ventricular blood pools, and muscle tissue was visible in phosphocreatine (PCr) maps. Amplitude-modulated saturation bands achieved 71±4% suppression of phosphocreatine PCr in chest-wall muscles. Subjects reported they were comfortable.ConclusionThis easy-to-assemble, volume-transmit, local receive array coil combination significantly improves the homogeneity and field-of-view for metabolic imaging of the human heart at 7T.

Molecular Imaging of Cardiac Metabolism, Innervation, and Conduction

Cardiac diseases have complex molecular origins. However, current clinical diagnostic tools are often inadequate to uncover specific molecular components of cardiac pathologies. Thus, we are still lacking a detailed understanding of disease progression, and both patient diagnosis and treatment are often inaccurate. Molecular imaging could play a leading role in translating basic research to both preclinical and clinical cardiac research, ultimately improving our understanding and management of human disease. In this review, we highlight the diversity of current molecular imaging tools that have been used in clinical research or have reached the stage of clinical translation. Facilitated by the steadily increasing infrastructure of clinical positron emission tomography and positron emission tomography-magnetic resonance imaging cameras and advancing gating analysis, these tools allow the implementation of clinical cardiac molecular imaging trials to deepen our knowledge of human disease and improve patient care.

Cardiac metabolic imaging: current imaging modalities and future perspectives.

In this review, current imaging techniques and their future perspectives in the field of cardiac metabolic imaging in humans are discussed. This includes a range of noninvasive imaging techniques, allowing a detailed investigation of cardiac metabolism in health and disease. The main imaging modalities discussed are magnetic resonance spectroscopy techniques for determination of metabolite content (triglycerides, glucose, ATP, phosphocreatine, and so on), MRI for myocardial perfusion, and single-photon emission computed tomography and positron emission tomography for quantitation of perfusion and substrate uptake.

68Ga labeled fatty acids for cardiac metabolic imaging: Influence of different bifunctional chelators

Development of 68Ga labeled fatty acids is of immense interest due to the availability of 68Ga through a generator and its superiority over SPECT based tracers in carrying out dynamic imaging on a PET scanner. Our present work explores the influence of different chelators on the cardiac uptake and pharmacokinetics of the 68Ga-labeled fatty acids. Two new 68Ga labeled fatty acids were synthesized by conjugation of 11-aminoundecanoic acid with the bifunctional chelators (BFCs) viz. p-SCN-Bn-DTPA (S-2-(4-isothiocyanatobenzyl)-diethylenetriaminepentaacetic acid) and p-SCN-Bn-NODAGA (S-2-(4-isothiocyanatobenzyl)-1,4,7-triazacyclononane-1-glutaric acid-4,7-acetic acid) and their comparison was carried out with the previously reported 68Ga–NOTA–undecanoic acid. Both the conjugates were radiolabeled with 68Ga in high yields and purities (>95%). Their formation was established by preparation and characterization of their inactive analogs with natGa at macroscopic levels. Biodistribution studies of the complexes in Swiss mice showed lower initial myocardial uptake for 68Ga–NODAGA–undecanoic acid (3.8±0.6%ID/g) and 68Ga–DTPA–undecanoic acid (1.3±0.5%ID/g) complexes in comparison to previously reported 68Ga–NOTA–undecanoic acid complex (7.4±2.8%ID/g) at 2min p.i. However, significant retention of the tracer in the myocardium was observed in the case of 68Ga–NODAGA–undecanoic complex, which led to improved heart/non-target ratios of the complex over time in comparison to the other 68Ga complexes. Similarly, the DTPA complex exhibited increased washout from the liver in comparison to other 68Ga derivatives. The β oxidation mechanism in myocytes was investigated by isolating the myocardial extract post intravenous injection of the respective 68Ga complexes and analyzing them by radio-HPLC, which showed metabolic transformation of the parent fatty acid complex peak in all the three complexes. This study has provided an insight into the design characteristics of 68Ga labeled fatty acids to achieve the desired myocardial imaging characteristics.

16-Channel Surface Coil for 13C-Hyperpolarized Spectroscopic Imaging of Cardiac Metabolism in Pig Heart

Magnetic resonance spectroscopy (MRS) of hyperpolarized 13C pyruvate and its metabolites in large animal models is a powerful tool for assessing cardiac metabolism in patho-physiological conditions. In 13C studies, a high signal-to-noise ratio (SNR) is crucial to overcome the intrinsic data quality limitation due to the low molar concentration of certain metabolites as well as the low flux of conversion. Since 13C-MRS is essentially a semi-quantitative technique, the SNR of the spectra acquired in different myocardial segments should be homogeneous. MRS coil design plays an important role in achieving both targets. In this study, a 16-channel receive surface coil was designed for 13C hyperpolarized studies of the pig heart with a clinical 3-T scanner. The coil performance was characterized by phantom experiments and compared with that of a birdcage coil used in transmit/receive mode. Segmental signal distribution in the left ventricle (LV) was assessed by experiments on six healthy mini pigs. The proposed coil showed a significant increase in SNR for the LV wall close to the coil surface with respect to that for the birdcage but also significant segmental inhomogeneity. Hence, the use of the 16-channel coil is recommended for studies of septal and anterior LV walls.

Development of 68Ga-labeled fatty acids for their potential use in cardiac metabolic imaging.

While [(11)C]palmitate continues to be a promising tracer for cardiovascular Positron Emission Tomography (PET) imaging, unfavourable logistics due to the short half-life of (11)C (20 min) and cumbersome labeling methodologies are the major impediments that limit its widespread use. In order to circumvent such limitations, an attempt has been made to explore the potential of (68)Ga-labeled fatty acid analogs for metabolic imaging owing to the availability of (68)Ga through a (68)Ge/(68)Ga generator on an on-demand basis. In this study, two fatty acid conjugates were synthesized by conjugation of p-SCN-benzyl NOTA with the ω-amino group of 11-amino undecanoic acid and 12-amino dodecanoic acid, respectively, under alkaline conditions. Both derivatives were radiolabeled in high yields with (68)Ga obtained from an in-house (68)Ge/(68)Ga generator. Biodistribution studies in Swiss mice showed reasonable myocardial uptake at 2 min for both derivatives (7.4 ± 2.8% ID/g for 11-carbon fatty acid-NOTA conjugate and 6.4 ± 2.1% ID/g for 12-carbon fatty acid-NOTA conjugate), which cleared rapidly over 30 min. However, significant activity was found in blood for both tracers, with heart/blood ratios observed to be below 0.5 at all time points, diminishing the potential of the synthesized complexes for cardiac imaging.

Hybrid multiband excitation multiecho acquisition for hyperpolarized (13) C spectroscopic imaging.

Fast dynamic imaging of hyperpolarized (13) C-labeled pyruvate and its downstream metabolites shows great potential for probing metabolic changes in the heart. Sequences that allow for fast encoding of the spectral and spatial information of the myocardial metabolism and optimal signal excitation are usually limited by gradient performance, especially at high magnetic fields. Here we propose a combination of a spectral-spatial multiband excitation and multiecho readout to overcome these limitations. By using a low-bandwidth, two-pulse excitation, a thinner slice compared with conventional spectral-spatial excitation is achieved, while at the same time allowing for low flip angle excitation on pyruvate and high flip angle excitation on bicarbonate and lactate, which optimizes signal-to-noise ratio (SNR) in cardiac metabolic imaging. The implementation was evaluated in 13 healthy female Sprague-Dawley rats at 9.4T. Using a slice thickness of 4 mm, a mean (± standard deviation) peak SNR of 18.3 (±8.4), 15.2 (±6.6), and 8.6 (±2.0) was observed for pyruvate, lactate, and bicarbonate, respectively. This approach provides high SNR in metabolic images while at the same time allowing for a thin slice selection even at high magnetic fields. This is crucial in metabolic imaging in small animal models.

Multi-echo single-shot EPI for hyperpolarized 13C cardiac metabolic imaging of small animals

Background Cardiac metabolic imaging based on hyperpolarized 13C-labeled pyruvate shows great potential for assessing the metabolic changes that the heart undergoes during ischemia [1]. Rodent animal models offer unique opportunities to study ischemic processes, however, methods based on spectral-spatial excitation [2] of the individual metabolites is challenging due to the large minimal slice thickness that can be achieved with available gradient systems. A thick slice introduces both signal dephasing over the slice and errors due to partial volume effects. In this work, we explore multi-echo measurements using single-shot echo-planar imaging (EPI) readouts for thin slice dynamic cardiac metabolic imaging of small animals.

Multichannel receiver coils for improved coverage in cardiac metabolic imaging using prepolarized 13 C substrates

MR imaging using hyperpolarized (13)C substrates has become a promising tool to study real-time cardiac-metabolism in vivo. For such fast imaging of nonrecoverable prepolarized magnetization it is important to optimize the RF-coils to obtain the best signal-to-noise ratio possible, given the required coverage. In this work, three different receiver-coil configurations were computed in pig and human models. The sensitivity maps were demonstrated in phantoms and in vivo experiments performed in pigs. Signal-to-noise ratio in the posterior heart was increased up to 80% with the best multichannel coil as expected. These new coil configurations will allow imaging of the different metabolite signals even in the posterior regions of the myocardium, which is not possible with a single-channel surface-coil.

DNP Methods for Cardiac Metabolic Imaging with Hyperpolarized [1-13C]pyruvate Large Dose Injection in Pigs

In this study we set up and optimized a dynamic nuclear polarization (DNP) procedure for the hyperpolarization of a large dose suitable for cardiac metabolic imaging in vivo in swine models. The dose range proposed in this study allowed chemical shift imaging of cardiac metabolism with hyperpolarized [1-13C]pyruvate in pigs. We investigated the typical pattern of distribution of [1-13C]pyruvate and its downstream metabolites: we analysed the variation of the maximum value of the normalized [1-13C]pyruvate signal and the global pyruvate signal in left ventricle (LV). The study reports data obtained with a large dose increase compared to small animal studies: 20 ml of 230 mM [1-13C]pyruvate with 16 ± 3 % polarization (mean ± SD), using a DNP system operating at ~1.4 K with a magnetic field of 3.35 T. A significant correlation between the maximum value of the normalized [1-13C]pyruvate signal and the global pyruvate signal in the LV was found. The characterization of the dynamic range of the signal and the optimization of the standardized dose could be a starting point for designing pathophysiological studies in experimental large animal models. With this approach the hyperpolarization of metabolic substrates could be applied in biomedical magnetic resonance, which could become one of the most promising models for cardiovascular imaging.

Cardiac fatty acid metabolism and ischemic memory imaging with nuclear medicine techniques

There has been a dramatic improvement in the clinical management of myocardial diseases with the advent of cardiac metabolic and molecular imaging. Although both myocardial perfusion and metabolic imaging provide insight of myocardium at risk for infarction or ischemia, it is known that metabolic derangements precede perfusion abnormalities, especially after reperfusion therapy. Deranged myocyte loses its flexibility of choosing the right substrate for energy production and it switches its substrate, especially between fatty acid (FA) and glucose depending on disease condition; for example, predominance of FA metabolism is noted in diabetic heart disease, whereas glucose metabolism is enhanced in pressure overload conditions such as left ventricular hypertrophy. We thus hypothesize that with better technological advancements and different substrates, the metabolic footprint of various heart diseases can be charted out in future to help in the optimization of patient management. This review attempts to discuss the importance of radionuclide-labeled FAs in cardiac metabolic and ischemic memory imaging.

Rapid multislice imaging of hyperpolarized 13C pyruvate and bicarbonate in the heart

Hyperpolarization of spins via dynamic nuclear polarization (DNP) has been explored as a method to non-invasively study real-time metabolic processes 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 single-shot spiral k-space trajectory for rapid imaging of cardiac metabolism is described. This sequence permits whole-heart coverage (6 slices, 8.8-mm in-plane resolution) in any plane, allowing imaging of the metabolites of interest, [1-(13)C] pyruvate, [1-(13)C] lactate, and (13)C bicarbonate, within a single breathhold. Pyruvate and bicarbonate cardiac volumes were acquired, while lactate images were not acquired due to low lactate levels in the animal model studied. The sequence was demonstrated with phantom experiments and in vivo testing in a pig model.