Pyruvate is included in the energy production of the heart muscle and is metabolized into lactate, alanine, and CO 2 in equilibrium with HCO 3 ؊ . The aim of this study was to evaluate the feasibility of using 13 C hyperpolarization enhanced MRI to monitor pyruvate metabolism in the heart during an ischemic episode. The left circumflex artery of pigs (4 months, male, 29 -34 kg) was occluded for 15 or 45 min followed by 2 hr of reperfusion. Pigs were examined by 13 C chemical shift imaging following intravenous injection of 1-13 C pyruvate. 13 C chemical shift MR imaging was used in order to visualize the local concentrations of the metabolites. After a 15-min occlusion (no infarct) the bicarbonate signal level in the affected area was reduced (25-44%) compared with the normal myocardium. Alanine signal level was normal. After a 45-min occlusion (infarction) the bicarbonate signal was almost absent (0.2-11%) and the alanine signal was reduced (27-51%). Due to image-folding artifacts the data obtained for lactate were inconclusive. These studies demonstrate that cardiac metabolic imaging with hyperpolarized 1-13 C-pyruvate is feasible. The changes in concentrations of the metabolites within a minute after injection can be detected and metabolic maps constructed. Magn Reson Med 59:1005-1013, 2008.

The evolution of magnetic resonance imaging (MRI) has been astounding since the early 1980s, and a broad range of applications has emerged. To date, clinical imaging of nuclei other than protons has been precluded for reasons of sensitivity. However, with the recent development of hyperpolarization techniques, the signal from a given number of nuclei can be increased as much as 100 000 times, sufficient to enable imaging of non-proton nuclei.Technically, imaging of hyperpolarized nuclei offers several unique properties, such as complete lack of background signal and possibility for local and permanent destruction of the signal by means of radio frequency (RF) pulses. These properties allow for improved as well as new techniques within several application areas. Diagnostically, the injected compounds can visualize information about flow, perfusion, excretory function, and metabolic status. In this review article, we explain the concept of hyperpolarization and the techniques to hyperpolarize 13 C. An overview of results obtained within angiography, perfusion, and catheter tracking is given, together with a discussion of the particular advantages and limitations. Finally, possible future directions of hyperpolarized 13 C MRI are pointed out.

A13 C-enriched water-soluble compound (bis-1,1-(hydroxymethyl)-1-13 C-cyclopropane-D 8 ), with a 13 C-concentration of approximately 200 mM, was hyperpolarized to ϳ15% using dynamic nuclear polarization, and then used as a contrast medium (CM) for contrast-enhanced magnetic resonance angiography (CE-MRA). The long relaxation times (in vitro: T 1 Ϸ 82 s, T 2 Ϸ 18 s; in vivo: T 1 Ϸ 38 s, T 2 Ϸ 1.3 s) are ideal for steady-state free precession (SSFP) imaging with a true fast imaging and steady precession (trueFISP) pulse sequence. It was shown both theoretically and experimentally that the optimal flip angle was 180°. CE-MRA was performed in four anesthetized live rats after intravenous injection of 3 ml CM. The angiograms covered the thoracic/abdominal region in two of the animals, and the head-neck region in the other two. Fifteen consecutive images were acquired in each experiment, with a flip-back pulse at the end of each image acquisition. In the angiograms, the vena cava (SNR Ϸ 240), aorta, renal arteries, carotid arteries (SNR Ϸ 75), jugular veins, and several other vessels were visible. The SNR in the cardiac region was 500. Magnetization was preserved from one image acquisition to the next using the flipback technique (SNR cardiac The most widespread technique for MR angiography (MRA) today utilizes an intravenous injection of a T 1 -shortening contrast medium (CM) in combination with T 1 -weighted pulse sequences (1,2). This contrast-enhanced (CE) MRA technique has substantially shorter imaging times than time-of-flight and phase-contrast methods, and is relatively insensitive to variations in blood flow velocity. Consequently, CE-MRA has increased the clinical impact of MRA. An interesting possibility for further elevation of the signal-to-noise ratio (SNR) and contrast-to-noise ratio (CNR) in CE-MRA would be to use a hyperpolarized (HP) CM.It has been demonstrated that certain noble gases ( 3 He and 129 Xe) can be hyperpolarized to a much higher level (Ͼ10%) than that of thermal polarization of 1 H at clinical magnetic fields (ϳ0.0005%). This high degree of polarization compensates for the low spin density of the gases in vivo, and they (mostly 3 He) have been used to image airways and lungs (3-5). HP 3 He and 129 Xe have also been proposed for use in vascular imaging. Helium has low solubility in blood, but it can be delivered to the vascular system using encapsulation techniques (6 -9). Xenon, on the other hand, is directly soluble in blood, and inhalation of the gas is one way to administer HP xenon to the human vascular system (10 -12). Xenon can also be dissolved in a biocompatible carrier (13-16), to be delivered through intravenous injection. However, even if the hyperpolarized gases could be efficiently administered to the blood, the inherently low concentration of a gas makes 3 He and 129 Xe unsuitable as a CM for CE-MRA.A high vascular concentration of a hyperpolarized CM can be obtained if 13 C, as part of a water-soluble molecule, is polarized instead of 129 Xe and 3 He. We have previously...

Although diabetic cardiomyopathy is widely recognized, there are no specific treatments available. Altered myocardial substrate selection has emerged as a candidate mechanism behind the development of cardiac dysfunction in diabetes. As pyruvate dehydrogenase (PDH) activity appears central to the balance of substrate use, we aimed to investigate the relationship between PDH flux and myocardial function in a rodent model of type 2 diabetes and to explore whether or not increasing PDH flux, with dichloroacetate, would restore the balance of substrate use and improve cardiac function. All animals underwent in vivo hyperpolarized [1][2][3][4][5][6][7][8][9][10][11][12][13] C]pyruvate magnetic resonance spectroscopy and echocardiography to assess cardiac PDH flux and function, respectively. Diabetic animals showed significantly higher blood glucose levels (10.8 6 0.7 vs. 8.4 6 0.5 mmol/L), lower PDH flux (0.005 6 0.001 vs. 0.017 6 0.002 s -1 ), and significantly impaired diastolic function (transmitral early diastolic peak velocity/early diastolic myocardial velocity ratio [E/E9] 12.2 6 0.8 vs. 20 6 2), which are in keeping with early diabetic cardiomyopathy. Twenty-eight days of treatment with dichloroacetate restored PDH flux to normal levels (0.018 6 0.002 s -1 ), reversed diastolic dysfunction (E/E9 14 6 1), and normalized blood glucose levels (7.5 6 0.7 mmol/L). The treatment of diabetes with dichloroacetate therefore restored the balance of myocardial substrate selection, reversed diastolic dysfunction, and normalized blood glucose levels. This suggests that PDH modulation could be a novel therapy for the treatment and/or prevention of diabetic cardiomyopathy.It is now firmly established that type 2 diabetes contributes to an increased risk for the development of heart failure (1). Although some of this risk can be attributed to increased coronary artery disease and hypertension, it is becoming clear that patients with type 2 diabetes are also at risk for the development of "diabetic cardiomyopathy" (2-5), which manifests across a spectrum from subclinical left ventricular (LV) diastolic dysfunction (i.e., transmitral early diastolic peak velocity/early diastolic myocardial velocity ratio [E/E9]) to overt systolic failure (6). As the incidence of type 2 diabetes is rapidly increasing, understanding the pathophysiology behind diabetic cardiomyopathy and developing new treatment strategies is of increasing clinical importance.Cardiac metabolism and altered substrate use are now emerging as candidate mechanisms underpinning diabetic cardiomyopathy and, as such, are targets for novel treatments (7,8). The cardiac metabolic changes in type 2 diabetes are linked to an increase in circulating fatty acid levels that results from insulin insensitivity and a failure to suppress adipose tissue hormone-sensitive lipase (9). This increase in fatty acid availability, and consequently increased cardiac usage, is thought to result in a loss of efficiency between substrate use and ATP production in the diabetic heart (10). Chan...

mRNA can direct dose-dependent protein expression in cardiac muscle without genome integration, but to date has not been shown to improve cardiac function in a safe, clinically applicable way. Herein, we report that a purified and optimized mRNA in a biocompatible citrate-saline formulation is tissue specific, long acting, and does not stimulate an immune response. In small- and large-animal, permanent occlusion myocardial infarction models, VEGF-A 165 mRNA improves systolic ventricular function and limits myocardial damage. Following a single administration a week post-infarction in mini pigs, left ventricular ejection fraction, inotropy, and ventricular compliance improved, border zone arteriolar and capillary density increased, and myocardial fibrosis decreased at 2 months post-treatment. Purified VEGF-A mRNA establishes the feasibility of improving cardiac function in the sub-acute therapeutic window and may represent a new class of therapies for ischemic injury.