Unambiguous detection of cardiac Pi using long TM 31P STEAM

Synopsis Inorganic Phosphate is a resonance that holds important information on the metabolic state of tissues. From its resonance frequency, intracellular pH can be derived. The ratio of P to PCr or ATP are also important markers. Unlike in other tissues, myocardial P is frequently hidden underneath blood DPG signals. Using STEAM's T delay to be one cardiac cycle, blood-pool originating signals are gone and the Pi resonance is clearly visible. In 3 subjects, P signal was detected and quantified. The signal was around 4.89±0.02ppm, corresponding to a pH of 7.08±0.02. This is a breakthrough for the investigation of cardiac metabolism.This work was supported by the Austrian Science Fund (FWF) project J 4043 as well as by the Sir Henry Dale Fellowship from the Wellcome Trust and the Royal Society (098436/Z/12/Z)

Reproducibility of cardiac 31P MRS at 7 T

Synopsis Cardiac PCr/ATP ratios measured by P MRS change in cardiovascular disease giving them value as a biomarker. We scanned 13 healthy volunteers at 7T, assessing their PCr/ATP with 6 ½ min P CSI scans. These data have better reproducibility than a 30min 3T protocol previously published by our centre. Repeated PCr/ATP measurements from subjects in this study were not significantly (P=0.83) different. Measurements were significantly different (P<0.001) from DCM patient data acquired in a previous 7T study using the same coil and pulse sequence. This data will allow us to plan future 7T P-MRS clinical studies.Funded by a Sir Henry Dale Fellowship from the Wellcome Trust and the Royal Society (Grant No. 098436/Z/12/Z). JE receives a DPhil (PhD) studentship from the Medical Research Council (UK)

The effects of iodinated CT contrast agent on phosphorus MRS

Synopsis Contrast-enhanced CT examination can influence H-MRI measurements performed within 24h after the CT scan, due to a reduction in water T and T caused by the iodinated contrast agents used in CT. We have investigated whether contrast from a previous CT examination would also influence metabolic measurements made using P-MRS, by measuring the T of H and P signals in human blood. We find that iodinated CT contrast agent has no effect on phosphorus T s. Therefore, P-MRS examinations will not be influenced by prior CT (unlike H-MRI scans).We acknowledge financial support from the British Heart Foundation (FS/10/002/28078; FS/14/17/30634; RG/11/9/28921), a Sir Henry Dale Fellowship from the Wellcome Trust and the Royal Society (098436/Z/12/Z), a Novo Nordisk Foundation Postdoctoral Research Fellowship and from the Slovak Grant Agencies VEGA (2/0001/17) and APVV (15-0029)

Dilated Cardiomyopathy: Phosphorus 31 MR Spectroscopy at 7 T

Purpose To test whether the increased signal-to-noise ratio of phosphorus 31 (31P) magnetic resonance (MR) spectroscopy at 7 T improves precision in cardiac metabolite quantification in patients with dilated cardiomyopathy (DCM) compared with that at 3 T. Materials and Methods Ethical approval was obtained, and participants provided written informe consent. In a prospective study, 31P MR spectroscopy was performed at 3 T and 7 T in 25 patients with DCM. Ten healthy matched control subjects underwent 31P MR spectroscopy at 7 T. Paired Student t tests were performed to compare results between the 3-T and 7-T studies. Results The phosphocreatine (PCr) signal-to-noise ratio increased 2.5 times at 7 T compared with that at 3 T. The PCr to adenosine triphosphate (ATP) concentration ratio (PCr/ATP) was similar at both field strengths (mean ± standard deviation, 1.48 ± 0.44 at 3 T vs 1.54 ± 0.39 at 7 T, P = .49), as expected. The Cramér-Rao lower bounds in PCr concentration (a measure of uncertainty in the measured ratio) were 45% lower at 7 T than at 3 T, reflecting the higher quality of 7-T 31P spectra. Patients with dilated cardioyopathy had a significantly lower PCr/ATP than did healthy control subjects at 7 T (1.54 ± 0.39 vs 1.95 ± 0.25, P = .005), which is consistent with previous findings. Conclusion 7-T cardiac 31P MR spectroscopy is feasible in patients with DCM and gives higher signal-to-noise ratios and more precise quantification of the PCr/ATP than that at 3 T. PCr/ATP was significantly lower in patients with DCM than in control subjects at 7 T, which is consistent with previous findings at lower field strengths

Methods for Collecting Milk from Mice

Mouse models offer unique opportunities to study mammary gland biology and lactation. Phenotypes within the mammary glands, especially those caused by genetic modification, often arise during lactation, and their study requires the collection of adequate volumes of milk. We describe two approaches for collecting milk from lactating mice. Both methods are inexpensive, are easy to use in the laboratory or classroom, are non-invasive, and yield adequate volumes of milk for subsequent analyses

Assessing metabolism and function of normothermically perfused ex vivo livers by multinuclear MR imaging and spectroscopy

Synopsis Liver transplantation is the only cure for end-stage liver disease. Unfortunately, 20% of patients die waiting for a donor. New techniques for preserving transplant livers, such as normothermic machine perfusion (NMP), provide an opportunity to utilise ‘marginal’ (currently discarded) donated livers if their viability can be assessed accurately. We present initial results from a CE-marked NMP system that we adapted for use in an MRI scanner. We demonstrate the power of NMP-MRI to assess structure and metabolism in a freshly donated pig liver, dynamically over a 10-hour period. Our protocol includes H imaging, P spectroscopy, and hyperpolarised C spectroscopy.This work was funded by a Sir Henry Dale Fellowship from the Wellcome Trust and the Royal Society (Grant No. 098436/Z/12/Z) and by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre (BRC)

Lone Atrial Fibrillation Is Associated With Impaired Left Ventricular Energetics That Persists Despite Successful Catheter Ablation

Background: Lone atrial fibrillation (AF) may reflect a subclinical cardiomyopathy that persists after sinus rhythm (SR) restoration, providing a substrate for AF recurrence. To test this hypothesis, we investigated the effect of restoring SR by catheter ablation on left ventricular (LV) function and energetics in patients with AF but no significant comorbidities. Methods: Fifty-three patients with symptomatic paroxysmal or persistent AF and without significant valvular disease, uncontrolled hypertension, coronary artery disease, uncontrolled thyroid disease, systemic inflammatory disease, diabetes mellitus, or obstructive sleep apnea (ie, lone AF) undergoing ablation and 25 matched control subjects in SR were investigated. Magnetic resonance imaging quantified LV ejection fraction (LVEF), peak systolic circumferential strain (PSCS), and left atrial volumes and function, whereas phosphorus-31 magnetic resonance spectroscopy evaluated ventricular energetics (ratio of phosphocreatine to ATP). AF burden was determined before and after ablation by 7-day Holter monitoring; intermittent ECG event monitoring was also undertaken after ablation to investigate for asymptomatic AF recurrence. Results: Before ablation, both LV function and energetics were significantly impaired in patients compared with control subjects (LVEF, 61% [interquartile range (IQR), 52%–65%] versus 71% [IQR, 69%–73%], P<0.001; PSCS, –15% [IQR, –11 to –18%] versus −18% [IQR, –17% to –19%], P=0.002; ratio of phosphocreatine to ATP, 1.81±0.35 versus 2.05±0.29, P=0.004). As expected, patients also had dilated and impaired left atria compared with control subjects (all P<0.001). Early after ablation (1–4 days), LVEF and PSCS improved in patients recovering SR from AF (LVEF, 7.0±10%, P=0.005; PSCS, –3.5±4.3%, P=0.001) but were unchanged in those in SR during both assessments (both P=NS). At 6 to 9 months after ablation, AF burden reduced significantly (from 54% [IQR, 1.5%–100%] to 0% [IQR 0%–0.1%]; P<0.001). However, LVEF and PSCS did not improve further (both P=NS) and remained impaired compared with control subjects (P<0.001 and P=0.003, respectively). Similarly, there was no significant improvement in atrial function from before ablation (P=NS), and this remained lower than in control subjects (P<0.001). The ratio of phosphocreatine to ATP was unaffected by heart rhythm during assessment and AF burden before ablation (both P=NS). It was unchanged after ablation (P=0.57), remaining lower than in control subjects regardless of both recovery of SR and freedom from recurrent AF (P=0.006 and P=0.002, respectively). Conclusions: Patients with lone AF have impaired myocardial energetics and subtle LV dysfunction, which do not normalize after ablation. These findings suggest that AF may be the consequence (rather than the cause) of an occult cardiomyopathy, which persists despite a significant reduction in AF burden after ablation

Cryptochrome 1 in Retinal Cone Photoreceptors Suggests a Novel Functional Role in Mammals

Cryptochromes are a ubiquitous group of blue-light absorbing flavoproteins that in the mammalian retina have an important role in the circadian clock. In birds, cryptochrome 1a (Cry1a), localized in the UV/violet-sensitive S1 cone photoreceptors, is proposed to be the retinal receptor molecule of the light-dependent magnetic compass. The retinal localization of mammalian Cry1, homologue to avian Cry1a, is unknown, and it is open whether mammalian Cry1 is also involved in magnetic field sensing. To constrain the possible role of retinal Cry1, we immunohistochemically analysed 90 mammalian species across 48 families in 16 orders, using an antiserum against the Cry1 C-terminus that in birds labels only the photo-activated conformation. In the Carnivora families Canidae, Mustelidae and Ursidae, and in some Primates, Cry1 was consistently labeled in the outer segment of the shortwave-sensitive S1 cones. This finding would be compatible with a magnetoreceptive function of Cry1 in these taxa. In all other taxa, Cry1 was not detected by the antiserum that likely also in mammals labels the photo-activated conformation, although Western blots showed Cry1 in mouse retinal cell nuclei. We speculate that in the mouse and the other negative-tested mammals Cry1 is involved in circadian functions as a non-light-responsive protein

The interplay between metabolic alterations, diastolic strain rate and exercise capacity in mild heart failure with preserved ejection fraction

Background: Heart failure (HF) is characterized by altered myocardial substrate metabolism which can lead to myocardial triglyceride accumulation (steatosis) and lipotoxicity. However its role in mild HF with preserved ejection fraction (HFpEF) is uncertain. We measured myocardial triglyceride content (MTG) in HFpEF and assessed its relationships with diastolic function and exercise capacity. Methods: 27 HFpEF (clinical features of HF, left ventricular EF >50%, evidence of mild diastolic dysfunction and evidence of exercise limitation as assessed by cardiopulmonary exercise test) and 14 controls underwent 1H-magnetic resonance spectroscopy (1H-MRS) to measure MTG (lipid/water, %), 31P-MRS to measure myocardial energetics (phosphocreatine-to-adenosine triphosphate - PCr/ATP) and feature-tracking magnetic resonance imaging for diastolic strain rate. Results: When compared to controls, HFpEF had 2.3 fold higher in MTG (1.45±0.25% vs. 0.64±0.16%, p=0.009) and reduced PCr/ATP (1.60±0.09 vs. 2.00±0.10, p=0.005). HFpEF had significantly reduced diastolic strain rate and maximal oxygen consumption (VO2 max), which both correlated significantly with elevated MTG and reduced PCr/ATP. On multivariate analyses, MTG was independently associated with diastolic strain rate while diastolic strain rate was independently associated with VO2 max. Conclusions: Myocardial steatosis is pronounced in mild HFpEF, and is independently associated with impaired diastolic strain rate which is itself related to exercise capacity. Steatosis may adversely affect exercise capacity by indirect effect occurring via impairment in diastolic function. As such, myocardial triglyceride may become a potential therapeutic target to treat the increasing number of patients with HFpEF.This work was supported by Chest Heart and Stroke Association, Scotland. MM acknowledges support from the National University of Malaysia and Ministry of Higher Education Malaysia. SN and OR acknowledge support from the Oxford NIHR Biomedical Research Centre and the Oxford British Heart Foundation Centre of Research Excellence. JES is a Senior BHF Basic Science Research Fellow (FS/11/50/29038). CTR is funded by a Sir Henry Dale Fellowship from the Wellcome Trust and the Royal Society [098436/Z/12/Z/B]. OR is a BHF Clinical Intermediate Research Fellow FS/16/70/32157