Cardiac Energetics in Patients With Aortic Stenosis and Preserved Versus Reduced Ejection Fraction.

BACKGROUND: Why some but not all patients with severe aortic stenosis (SevAS) develop otherwise unexplained reduced systolic function is unclear. We investigate the hypothesis that reduced creatine kinase (CK) capacity and flux is associated with this transition. METHODS: We recruited 102 participants to 5 groups: moderate aortic stenosis (ModAS) (n=13), SevAS, left ventricular (LV) ejection fraction ≥55% (SevAS-preserved ejection fraction, n=37), SevAS, LV ejection fraction 0.99). Accompanying the fall in CK flux, total CK and citrate synthase activities and the absolute activities of mitochondrial-type CK and CK-MM isoforms were also lower (P<0.02, all analyses). Median mitochondria-sarcomere diffusion distances correlated well with CK total activity (r=0.86, P=0.003). CONCLUSIONS: Total CK capacity is reduced in SevAS, with median values lowest in those with systolic failure, consistent with reduced energy supply reserve. Despite this, in vivo magnetic resonance spectroscopy measures of resting CK flux suggest that ATP delivery is reduced earlier, at the moderate AS stage, where LV function remains preserved. These findings show that significant energetic impairment is already established in moderate AS and suggest that a fall in CK flux is not by itself a necessary cause of transition to systolic failure. However, because ATP demands increase with AS severity, this could increase susceptibility to systolic failure. As such, targeting CK capacity and flux may be a therapeutic strategy to prevent and treat systolic failure in AS.This study was principally funded by a British Heart Foundation Clinical Training Research Fellowship FS/15/80/31803 (to Dr Peterzan) with support from a British Heart Foundation Program Grant (RG/18/12/34040). Drs Neubauer and Rider acknowledge support from British Heart Foundation Center of Research Excellence. Dr Neubauer acknowledges support from the National Institute of Health Research Oxford Biomedical Research Center. Dr Rodgers receives funding from the Wellcome Trust and the Royal Society (grant no. 098436/Z/12/B) and supported by the National Institute of Health Research Cambridge Biomedical Research Center. Dr Rider is funded by the British Heart Foundation FS/16/70/32157. Dr Miller was supported by a Novo Nordisk Postdoctoral Fellowship run in conjunction with the University of Oxford. The Biotechnology and Biological Sciences Research Council provided Advanced Life Sciences Research Technology Initiative 13 funding for serial block-face scanning electron microscopy through grant BB/C014122/1 (to Prof Chris Hawes, Oxford Brookes University)

Compartment-based reconstruction of 3D acquisition-weighted 31 P cardiac magnetic resonance spectroscopic imaging at 7 T: A reproducibility study.

Funder: Lincoln College, University of Oxford; Id: http://dx.doi.org/10.13039/100010371Funder: National Institute for Health Research; Id: http://dx.doi.org/10.13039/501100000272Funder: Somerville College, University of Oxford; Id: http://dx.doi.org/10.13039/100010358Funder: St. Hugh's College, University of Oxford; Id: http://dx.doi.org/10.13039/100010363Funder: Wadham College, University of OxfordFunder: NIHR Oxford Biomedical Research Centre; Id: http://dx.doi.org/10.13039/501100013373Funder: Novo Nordisk; Id: http://dx.doi.org/10.13039/501100004191Even at 7 T, cardiac 31 P magnetic resonance spectroscopic imaging (MRSI) is fundamentally limited by low signal-to-noise ratio (SNR), leading to long scan times and poor temporal and spatial resolutions. Compartment-based reconstruction algorithms such as magnetic resonance spectroscopy with linear algebraic modeling (SLAM) and spectral localization by imaging (SLIM) may improve SNR or reduce scan time without changes to acquisition. Here, we compare the repeatability and SNR performance of these compartment-based methods, applied to three different acquisition schemes at 7 T. Twelve healthy volunteers were scanned twice. Each scan session consisted of a 6.5-min 3D acquisition-weighted (AW) cardiac 31 P phase encode-based MRSI acquisition and two 6.5-min truncated k-space acquisitions with increased averaging (4 × 4 × 4 central k-space phase encodes and fractional SLAM [fSLAM] optimized k-space phase encodes). Spectra were reconstructed using (i) AW Fourier reconstruction; (ii) AW SLAM; (iii) AW SLIM; (iv) 4 × 4 × 4 SLAM; (v) 4 × 4 × 4 SLIM; and (vi) fSLAM acquisition-reconstruction combinations. The phosphocreatine-to-adenosine triphosphate (PCr/ATP) ratio, the PCr SNR, and spatial response functions were computed, in addition to coefficients of reproducibility and variability. Using the compartment-based reconstruction algorithms with the AW 31 P acquisition resulted in a significant increase in SNR compared with previously published Fourier-based MRSI reconstruction methods while maintaining the measured PCr/ATP ratio and improving interscan reproducibility. The alternative acquisition strategies with truncated k-space performed no better than the common AW approach. Compartment-based spectroscopy approaches provide an attractive reconstruction method for cardiac 31 P spectroscopy at 7 T, improving reproducibility and SNR without the need for a dedicated k-space sampling strategy.This work was supported by the Engineering and Physical Sciences Research Council (EPSRC) and Medical Research Council (MRC) (EP/L016052/1). All authors acknowledge the support of the British Heart Foundation (BHF) (FS/19/18/34252), the Oxford BHF Centre for Research Excellence (RE/13/1/30181) and the UK National Institute for Health Research (NIHR). JYCL acknowledges funding from the NIHR Oxford Biomedical Research Centre and support from the Fulford Junior Research Fellowship at Somerville College. JJM acknowledges support from a Novo Nordisk Postdoctoral Fellowship scheme run in conjunction with the University of Oxford, and also by St Hugh’s and Wadham college and a Starter Grant from the Novo Foundation, (NNF21OC0068683). PAB was supported by a Newton Abraham Visiting Professorship from Lincoln College. LV and CTR are supported by Sir Henry Dale Fellowships from the Wellcome Trust and the Royal Society [Grant numbers 221805/Z/20/Z (LV) and 098436/Z/12/B (CTR)]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. LV acknowledges the Slovak Grant Agencies VEGA (2/0004/23) and APVV (19-0032). CTR acknowledges the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the DHSC

Compartment-based Reconstruction of 3D Acquisition-Weighted 31 P Cardiac MRSI at 7T - a Reproducibility Study.

PURPOSE: Even at 7T, cardiac 31 P MRSI is fundamentally limited by low SNR, leading to long scan times and poor temporal and spatial resolutions. Compartment-based reconstruction algorithms such as magnetic resonance spectroscopy with linear algebraic modelling (SLAM) and spectral localization by imaging (SLIM) may improve SNR or reduce scan time without changes to acquisition. Here we compare the repeatability and SNR performance of these compartment-based methods, applied to three different acquisition schemes at 7T. METHODS: 12 healthy volunteers were scanned twice. Each scan session consisted of a 6.5 minute 3D acquisition-weighted (AW) cardiac 31 P phase-encode based MRSI acquisition and two 6.5 minute truncated k-space acquisitions with increased averaging (4 × 4 × 4 central k-space phase encodes and fSLAM optimized k-space phase encodes). Spectra were reconstructed using: (i) AW Fourier-reconstruction; (ii) AW SLAM; (iii) AW SLIM; (iv) 4 × 4 × 4 SLAM; (v) 4 × 4 × 4 SLIM; and (vi) fSLAM optimized SLAM (fSLAM) acquisition-reconstruction combinations. The PCr/ATP ratio, the PCr SNR, and spatial response functions were computed, in addition to coefficients of reproducibility and variability. RESULTS: Using the compartment-based reconstruction algorithms with the AW 31 P acquisition resulted in a significant increase in SNR compared to previously published Fourier-based MRSI reconstruction methods, while maintaining the measured phosphocreatine-to-adenosine triphosphate ratio and improving inter-scan reproducibility. The alternative acquisition strategies with truncated k-space performed no better than the common AW approach. CONCLUSION: Compartment-based spectroscopy approaches provide an attractive reconstruction method for cardiac 31 P spectroscopy at 7T, improving reproducibility and SNR without the need for a dedicated k-space sampling strategy.This work was supported by the Engineering and Physical Sciences Research Council (EPSRC) and Medical Research Council (MRC) (EP/L016052/1). All authors acknowledge the support of the British Heart Foundation (BHF) (FS/19/18/34252), the Oxford BHF Centre for Research Excellence (RE/13/1/30181) and the UK National Institute for Health Research (NIHR). JYCL acknowledges funding from the NIHR Oxford Biomedical Research Centre and support from the Fulford Junior Research Fellowship at Somerville College. JJM acknowledges support from a Novo Nordisk Postdoctoral Fellowship scheme run in conjunction with the University of Oxford, and also by St Hugh’s and Wadham college and a Starter Grant from the Novo Foundation, (NNF21OC0068683). PAB was supported by a Newton Abraham Visiting Professorship from Lincoln College. LV and CTR are supported by Sir Henry Dale Fellowships from the Wellcome Trust and the Royal Society [Grant numbers 221805/Z/20/Z (LV) and 098436/Z/12/B (CTR)]. For the purpose of open access, the author has applied a CC BY public copyright licence to any Author Accepted Manuscript version arising from this submission. LV acknowledges the Slovak Grant Agencies VEGA (2/0004/23) and APVV (19-0032). CTR acknowledges the NIHR Cambridge Biomedical Research Centre (BRC-1215-20014). The views expressed are those of the authors and not necessarily those of the NIHR or the DHSC

Effects of contrast agents on relaxation properties of 31P metabolites.

PURPOSE: Phosphorous MR spectroscopy (31P-MRS) forms a powerful, non-invasive research tool to quantify the energetics of the heart in diverse patient populations. 31P-MRS is frequently applied alongside other radiological examinations, many of which use various contrast agents that shorten relaxation times of water in conventional proton MR, for a better characterisation of cardiac function, or following prior computed tomography (CT). It is, however, unknown whether these agents confound 31P-MRS signals, for example, 2,3-diphosphoglycerate (2,3-DPG). METHODS: In this work, we quantitatively assess the impact of non-ionic, low osmolar iodinated CT contrast agent (iopamidol/Niopam), gadolinium chelates (linear gadopentetic acid dimeglumine/Magnevist and macrocyclic gadoterate meglumine/Dotarem) and superparamagnetic iron oxide nanoparticles (ferumoxytol/Feraheme) on the nuclear T1 and T2 of 31P metabolites (ie, 2,3-DPG), and 1H in water in live human blood and saline phantoms at 11.7 T. RESULTS: Addition of all contrast agents led to significant shortening of all relaxation times in both 1H and 31P saline phantoms. On the contrary, the T1 relaxation time of 2,3-DPG in blood was significantly shortened only by Magnevist (P = .03). Similarly, the only contrast agent that influenced the T2 relaxation times of 2,3-DPG in blood samples was ferumoxytol (P = .02). CONCLUSION: Our results show that, unlike conventional proton MR, phosphorus MRS is unconfounded in patients who have had prior CT with contrast, not all gadolinium-based contrast agents influence 31P-MRS data in vivo, and that ferumoxytol is a promising contrast agent for the reduction in 31P-MRS blood-pool signal.CTR and LV thank the funding of a Sir Henry Dale Fellowship from the Wellcome Trust and the Royal Society (098436/Z/12/B). JJM would like to acknowledge the support of a Novo Nordisk Postdoctoral Fellowship and a Junior Research Fellowship at Wadham College Oxford. Authors also acknowledge the support of the British Heart Foundation (refs. FS/14/17/30634 and FS/16/7/31843). The support of the Slovak Grant Agency VEGA (grant #2/0003/20) and APVV (grant #19-0032) is acknowledged by LV and IF

Rapid and B1-insensitive absolute quantification of the CK Flux reaction with dual-band quasi-adiabatic saturation transfer with Optimal Control

Purpose: Phosphorus saturation-transfer experiments can quantify metabolic fluxes non-invasively. Typically, the forward flux through the creatine-kinase reaction is investigated by observing the decrease in phosphocreatine (PCr) after saturation of γ-ATP. The quantification of total ATP utilisation is currently under-explored, as it requires simultaneous saturation of inorganic phosphate (Pi) and PCr. This is challenging, as currently available saturation pulses reduce the already-low γ-ATP signal present. Methods: Using a hybrid optimal-control and Shinnar-Le-Roux method, a quasi-adiabatic RF pulse was designed for the dual-saturation of PCr and Pi to enable determination of total ATP utilisation. The pulses were evaluated in Bloch equation simulations, compared with a conventional hard-cosine DANTE saturation sequence, before application to perfused rat hearts at 11.7 Tesla. Results: The quasi-adiabatic pulse was insensitive to a > 2.5-fold variation in B1, producing equivalent saturation with a 53% reduction in delivered pulse power and a 33-fold reduction in spillover at the minimum effective B1. This enabled the complete quantification of the synthesis and degradation fluxes for ATP in 30-45 minutes in the perfused rat heart. While the net synthesis flux (4.24 0.8 mM/s, SEM) was not significantly different from degradation flux (6.88 2 mM/s) and both measures are consistent with prior work, nonlinear error analysis highlights uncertainties in the Pi-to-ATP measurement that may explain the possible imbalance. Conclusion: This work demonstrates a novel quasi-adiabatic dual-saturation RF pulse with significantly improved performance that can be used to measure ATP turnover in the heart in vivo.All authors would like to thank the British Heart Foundation for their generous support (refs RG/11/9/28921, FS/14/17/30634, FS/17/58/33072 and FS/15/68/32042), the University of Oxford British Heart Foundation Centre for Research Excellence (RE/13/1/30181) and the NHS National Institute for Health Research Oxford Biomedical Research Centre programme. The views expressed are those of the authors and not necessarily those of the NIHR or the Department of Health and Social Care. JJM would like to acknowledge a Postdoctoral Fellowship run in collaboration with Novo Nordisk and the University of Oxford, and thank financial support provided by St Hugh’s College and Wadham College in the University of Oxford. LV and CTR are funded by a Sir Henry Dale Fellowship from the Royal Society and the Wellcome Trust (098436/Z/12/B). AT would like to acknowledge funding from the Engineering and Physical Sciences Research Council (EPSRC) and Medical Research Council (MRC) [grant number EP/L016052/1]. LV also acknowledges the support of Slovak grant agencies VEGA (2/0003/20) and APVV (15‐0029). PAB was supported by a Newton Abraham Visiting professorship at Oxford

Rapid, B1-insensitive, dual-band quasi-adiabatic saturation transfer with optimal control for complete quantification of myocardial ATP flux

Purpose: Phosphorus saturation-transfer experiments can quantify metabolic fluxes non-invasively. Typically, the forward flux through the creatine-kinase reaction is investigated by observing the decrease in phosphocreatine (PCr) after saturation of γ-ATP. The quantification of total ATP utilisation is currently under-explored, as it requires simultaneous saturation of inorganic phosphate (Pi) and PCr. This is challenging, as currently available saturation pulses reduce the already-low γ-ATP signal present. Methods: Using a hybrid optimal-control and Shinnar-Le-Roux method, a quasi-adiabatic RF pulse was designed for the dual-saturation of PCr and Pi to enable determination of total ATP utilisation. The pulses were evaluated in Bloch equation simulations, compared with a conventional hard-cosine DANTE saturation sequence, before being applied to perfused rat hearts at 11.7 Tesla. Results: The quasi-adiabatic pulse was insensitive to a > 2.5-fold variation in B1, producing equivalent saturation with a 53% reduction in delivered pulse power and a 33-fold reduction in spillover at the minimum effective B1. This enabled the complete quantification of the synthesis and degradation fluxes for ATP in 30-45 minutes in the perfused rat heart. While the net synthesis flux (4.24±0.8 mM/s, SEM) was not significantly different from degradation flux (6.88 ± 2 mM/s, p = 0.06) and both measures are consistent with prior work, nonlinear error analysis highlights uncertainties in the Pi-to-ATP measurement that may explain a trend suggesting a possible imbalance. Conclusion: This work demonstrates a novel quasi-adiabatic dual-saturation RF pulse with significantly improved performance that can be used to measure ATP turnover in the heart in vivo

Non-Invasive In Vivo Assessment of Cardiac Metabolism in the Healthy and Diabetic Human Heart Using Hyperpolarized 13C MRI.

Rationale: The recent development of hyperpolarized 13C Magnetic Resonance Spectroscopy (MRS) has made it possible to measure cellular metabolism in vivo, in real time. Objective: By comparing participants with and without type 2 diabetes (T2DM), we report the first case-control study to use this technique to record changes in cardiac metabolism in the healthy and diseased human heart. Methods and Results: Thirteen people with type 2 diabetes (HbA1c 6.9{plus minus}1.0%) and 12 age-matched healthy controls underwent assessment of cardiac systolic and diastolic function, myocardial energetics (31P-MRS) and lipid content (1H-MRS) in the fasted state. In a subset (5 T2DM, 5 control), hyperpolarized [1-13C]pyruvate MR spectra were also acquired and in five of these participants (3 T2DM, 2 controls), this was successfully repeated 45 minutes after a 75g oral glucose challenge. Downstream metabolism of [1-13C]pyruvate via pyruvate dehydrogenase (PDH, [13C]bicarbonate), lactate dehydrogenase ([1-13C]lactate) and alanine transaminase ([1-13C]alanine) was assessed. Metabolic flux through cardiac PDH was significantly reduced in the people with type 2 diabetes (Fasted:0.0084{plus minus}0.0067[Control] vs. 0.0016{plus minus}0.0014[T2DM], Fed:0.0184{plus minus}0.0109 vs. 0.0053{plus minus}0.0041, p=.013). In addition, a significant increase in metabolic flux through PDH was observed after the oral glucose challenge (p<.001). As is characteristic of diabetes, impaired myocardial energetics, myocardial lipid content and diastolic function were also demonstrated in the wider study cohort. Conclusions: This work represents the first demonstration of the ability of hyperpolarized 13C MRS to non-invasively assess physiological and pathological changes in cardiac metabolism in the human heart. In doing so, we highlight the potential of the technique to detect and quantify metabolic alterations in the setting of cardiovascular disease.This study was funded by a programme grant from the British Heart Foundation (RG/11/9/28921). The authors would also like to acknowledge financial support provided by the British Heart Foundation (BHF) in the form of Clinical Research Training Fellowships, a BHF Intermediate Clinical Research Fellowship and a BHF Senior Research Fellowship respectively (OR: FS/14/54/30946, AA: FS/17/18/32449, AL: RE/08/004/23915, MP: FS/15/80/31803, DJT: FS/14/17/30634). JJM and MSD would like to acknowledge the financial support provided by Novo Nordisk Postdoctoral Fellowships. JJM would also like to acknowledge financial support from EPSRC. FAG would like to acknowledge Cancer Research UK (CRUK), the CRUK Cambridge Centre, the Wellcome Trust and the Cambridge Biomedical Research Centre. All authors would also like to acknowledge the support provided by the OXFORD-BHF Centre for Research Excellence (grant RE/13/1/30181) and the National Institute for Health Research Oxford Biomedical Research Centre programme

Quantifying the effect of dobutamine stress on myocardial Pi and pH in healthy volunteers: A 31 P MRS study at 7T.

PURPOSE: Phosphorus spectroscopy (31 P-MRS) is a proven method to probe cardiac energetics. Studies typically report the phosphocreatine (PCr) to adenosine triphosphate (ATP) ratio. We focus on another 31 P signal: inorganic phosphate (Pi), whose chemical shift allows computation of myocardial pH, with Pi/PCr providing additional insight into cardiac energetics. Pi is often obscured by signals from blood 2,3-diphosphoglycerate (2,3-DPG). We introduce a method to quantify Pi in 14 min without hindrance from 2,3-DPG. METHODS: Using a 31 P stimulated echo acquisition mode (STEAM) sequence at 7 Tesla that inherently suppresses signal from 2,3-DPG, the Pi peak was cleanly resolved. Resting state UTE-chemical shift imaging (PCr/ATP) and STEAM 31 P-MRS (Pi/PCr, pH) were undertaken in 23 healthy controls; pH and Pi/PCr were subsequently recorded during dobutamine infusion. RESULTS: We achieved a clean Pi signal both at rest and stress with good 2,3-DPG suppression. Repeatability coefficient (8 subjects) for Pi/PCr was 0.036 and 0.12 for pH. We report myocardial Pi/PCr and pH at rest and during catecholamine stress in healthy controls. Pi/PCr was maintained during stress (0.098 ± 0.031 [rest] vs. 0.098 ± 0.031 [stress] P = .95); similarly, pH did not change (7.09 ± 0.07 [rest] vs. 7.08 ± 0.11 [stress] P = .81). Feasibility for patient studies was subsequently successfully demonstrated in a patient with cardiomyopathy. CONCLUSION: We introduced a method that can resolve Pi using 7 Tesla STEAM 31 P-MRS. We demonstrate the stability of Pi/PCr and myocardial pH in volunteers at rest and during catecholamine stress. This protocol is feasible in patients and potentially of use for studying pathological myocardial energetics.AA [FS/17/18/32449] and MP [FS/15/80/31803] are supported by British Heart Foundation Clinical Research Training Fellowships. OJR is supported by a British Heart Foundation Intermediate Fellowship. DT is supported by a British Heart Foundation Senor Fellowship [FS/14/17/30634]. DT, JL and EMT are supported by the National Institute for Health Research (NIHR) Oxford Biomedical Research Centre. SN acknowledges the support of the Oxford BHF Centre of Research Excellence. CTR and LV are funded by the Wellcome Trust and the Royal Society [098436/Z/12/B]. AIS was supported through the Austrian Science Fund’s (FWF) Schrödinger fellowship (J 4043). LV also acknowledges support of the Slovak Grant Agencies VEGA [2/0003/20] and APVV [#19–0032]. This research was also supported by the NIHR Cambridge Biomedical Research Centre. The views expressed are those of the author(s) and not necessarily those of the NHS, the NIHR or the Department of Health and Social Care