Retained Metabolic Flexibility of the Failing Human Heart.

BACKGROUND: The failing heart is traditionally described as metabolically inflexible and oxygen starved, causing energetic deficit and contractile dysfunction. Current metabolic modulator therapies aim to increase glucose oxidation to increase oxygen efficiency of adenosine triphosphate production, with mixed results. METHODS: To investigate metabolic flexibility and oxygen delivery in the failing heart, 20 patients with nonischemic heart failure with reduced ejection fraction (left ventricular ejection fraction 34.9±9.1) underwent separate infusions of insulin+glucose infusion (I+G) or Intralipid infusion. We used cardiovascular magnetic resonance to assess cardiac function and measured energetics using phosphorus-31 magnetic resonance spectroscopy. To investigate the effects of these infusions on cardiac substrate use, function, and myocardial oxygen uptake (MVo2), invasive arteriovenous sampling and pressure-volume loops were performed (n=9). RESULTS: At rest, we found that the heart had considerable metabolic flexibility. During I+G, cardiac glucose uptake and oxidation were predominant (70±14% total energy substrate for adenosine triphosphate production versus 17±16% for Intralipid; P=0.002); however, no change in cardiac function was seen relative to basal conditions. In contrast, during Intralipid infusion, cardiac long-chain fatty acid (LCFA) delivery, uptake, LCFA acylcarnitine production, and fatty acid oxidation were all increased (LCFA 73±17% of total substrate versus 19±26% total during I+G; P=0.009). Myocardial energetics were better with Intralipid compared with I+G (phosphocreatine/adenosine triphosphate 1.86±0.25 versus 2.01±0.33; P=0.02), and systolic and diastolic function were improved (LVEF 34.9±9.1 baseline, 33.7±8.2 I+G, 39.9±9.3 Intralipid; P<0.001). During increased cardiac workload, LCFA uptake and oxidation were again increased during both infusions. There was no evidence of systolic dysfunction or lactate efflux at 65% maximal heart rate, suggesting that a metabolic switch to fat did not cause clinically meaningful ischemic metabolism. CONCLUSIONS: Our findings show that even in nonischemic heart failure with reduced ejection fraction with severely impaired systolic function, significant cardiac metabolic flexibility is retained, including the ability to alter substrate use to match both arterial supply and changes in workload. Increasing LCFA uptake and oxidation is associated with improved myocardial energetics and contractility. Together, these findings challenge aspects of the rationale underlying existing metabolic therapies for heart failure and suggest that strategies promoting fatty acid oxidation may form the basis for future therapies.

Assessment of Cardiac Energy Metabolism, Function, and Physiology in Patients With Heart Failure Taking Empagliflozin: The Randomized, Controlled EMPA-VISION Trial.

BACKGROUND: Sodium-glucose co-transporter 2 inhibitors (SGLT2i) have emerged as a paramount treatment for patients with heart failure (HF), irrespective of underlying reduced or preserved ejection fraction. However, a definite cardiac mechanism of action remains elusive. Derangements in myocardial energy metabolism are detectable in all HF phenotypes, and it was proposed that SGLT2i may improve energy production. The authors aimed to investigate whether treatment with empagliflozin leads to changes in myocardial energetics, serum metabolomics, and cardiorespiratory fitness. METHODS: EMPA-VISION (Assessment of Cardiac Energy Metabolism, Function and Physiology in Patients With Heart Failure Taking Empagliflozin) is a prospective, randomized, double-blind, placebo-controlled, mechanistic trial that enrolled 72 symptomatic patients with chronic HF with reduced ejection fraction (HFrEF; n=36; left ventricular ejection fraction ≤40%; New York Heart Association class ≥II; NT-proBNP [N-terminal pro-B-type natriuretic peptide] ≥125 pg/mL) and HF with preserved ejection fraction (HFpEF; n=36; left ventricular ejection fraction ≥50%; New York Heart Association class ≥II; NT-proBNP ≥125 pg/mL). Patients were stratified into respective cohorts (HFrEF versus HFpEF) and randomly assigned to empagliflozin (10 mg; n=35: 17 HFrEF and 18 HFpEF) or placebo (n=37: 19 HFrEF and 18 HFpEF) once daily for 12 weeks. The primary end point was a change in the cardiac phosphocreatine:ATP ratio (PCr/ATP) from baseline to week 12, determined by phosphorus magnetic resonance spectroscopy at rest and during peak dobutamine stress (65% of age-maximum heart rate). Mass spectrometry on a targeted set of 19 metabolites was performed at baseline and after treatment. Other exploratory end points were investigated. RESULTS: Empagliflozin treatment did not change cardiac energetics (ie, PCr/ATP) at rest in HFrEF (adjusted mean treatment difference [empagliflozin - placebo], -0.25 [95% CI, -0.58 to 0.09]; P=0.14) or HFpEF (adjusted mean treatment difference, -0.16 [95% CI, -0.60 to 0.29]; P=0.47]. Likewise, there were no changes in PCr/ATP during dobutamine stress in HFrEF (adjusted mean treatment difference, -0.13 [95% CI, -0.35 to 0.09]; P=0.23) or HFpEF (adjusted mean treatment difference, -0.22 [95% CI, -0.66 to 0.23]; P=0.32). No changes in serum metabolomics or levels of circulating ketone bodies were observed. CONCLUSIONS: In patients with either HFrEF or HFpEF, treatment with 10 mg of empagliflozin once daily for 12 weeks did not improve cardiac energetics or change circulating serum metabolites associated with energy metabolism when compared with placebo. Based on our results, it is unlikely that enhancing cardiac energy metabolism mediates the beneficial effects of SGLT2i in HF. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT03332212.

Association Between Type 2 Diabetes and Changes in Myocardial Structure, Contractile Function, Energetics, and Blood Flow Before and After Aortic Valve Replacement in Patients With Severe Aortic Stenosis.

BACKGROUND: Type 2 diabetes (T2D) is associated with an increased risk of left ventricular dysfunction after aortic valve replacement (AVR) in patients with severe aortic stenosis (AS). Persistent impairments in myocardial energetics and myocardial blood flow (MBF) may underpin this observation. Using phosphorus magnetic resonance spectroscopy and cardiovascular magnetic resonance, this study tested the hypothesis that patients with severe AS and T2D (AS-T2D) would have impaired myocardial energetics as reflected by the phosphocreatine to ATP ratio (PCr/ATP) and vasodilator stress MBF compared with patients with AS without T2D (AS-noT2D), and that these differences would persist after AVR. METHODS: Ninety-five patients with severe AS without coronary artery disease awaiting AVR (30 AS-T2D and 65 AS-noT2D) were recruited (mean, 71 years of age [95% CI, 69, 73]; 34 [37%] women). Thirty demographically matched healthy volunteers (HVs) and 30 patients with T2D without AS (T2D controls) were controls. One month before and 6 months after AVR, cardiac PCr/ATP, adenosine stress MBF, global longitudinal strain, NT-proBNP (N-terminal pro-B-type natriuretic peptide), and 6-minute walk distance were assessed in patients with AS. T2D controls underwent identical assessments at baseline and 6-month follow-up. HVs were assessed once and did not undergo 6-minute walk testing. RESULTS: Compared with HVs, patients with AS (AS-T2D and AS-noT2D combined) showed impairment in PCr/ATP (mean [95% CI]; HVs, 2.15 [1.89, 2.34]; AS, 1.66 [1.56, 1.75]; P<0.0001) and vasodilator stress MBF (HVs, 2.11 mL min g [1.89, 2.34]; AS, 1.54 mL min g [1.41, 1.66]; P<0.0001) before AVR. Before AVR, within the AS group, patients with AS-T2D had worse PCr/ATP (AS-noT2D, 1.74 [1.62, 1.86]; AS-T2D, 1.44 [1.32, 1.56]; P=0.002) and vasodilator stress MBF (AS-noT2D, 1.67 mL min g [1.5, 1.84]; AS-T2D, 1.25 mL min g [1.22, 1.38]; P=0.001) compared with patients with AS-noT2D. Before AVR, patients with AS-T2D also had worse PCr/ATP (AS-T2D, 1.44 [1.30, 1.60]; T2D controls, 1.66 [1.56, 1.75]; P=0.04) and vasodilator stress MBF (AS-T2D, 1.25 mL min g [1.10, 1.41]; T2D controls, 1.54 mL min g [1.41, 1.66]; P=0.001) compared with T2D controls at baseline. After AVR, PCr/ATP normalized in patients with AS-noT2D, whereas patients with AS-T2D showed no improvements (AS-noT2D, 2.11 [1.79, 2.43]; AS-T2D, 1.30 [1.07, 1.53]; P=0.0006). Vasodilator stress MBF improved in both AS groups after AVR, but this remained lower in patients with AS-T2D (AS-noT2D, 1.80 mL min g [1.59, 2.0]; AS-T2D, 1.48 mL min g [1.29, 1.66]; P=0.03). There were no longer differences in PCr/ATP (AS-T2D, 1.44 [1.30, 1.60]; T2D controls, 1.51 [1.34, 1.53]; P=0.12) or vasodilator stress MBF (AS-T2D, 1.48 mL min g [1.29, 1.66]; T2D controls, 1.60 mL min g [1.34, 1.86]; P=0.82) between patients with AS-T2D after AVR and T2D controls at follow-up. Whereas global longitudinal strain, 6-minute walk distance, and NT-proBNP all improved after AVR in patients with AS-noT2D, no improvement in these assessments was observed in patients with AS-T2D. CONCLUSIONS: Among patients with severe AS, those with T2D demonstrate persistent abnormalities in myocardial PCr/ATP, vasodilator stress MBF, and cardiac contractile function after AVR; AVR effectively normalizes myocardial PCr/ATP, vasodilator stress MBF, and cardiac contractile function in patients without T2D.

Accelerated 3D multi-channel B 1 + mapping at 7 T for the brain and heart.

PURPOSE: To acquire accurate volumetric multi-channel B 1 + $$ {\mathrm{B}}_1^{+} $$ maps in under 14 s whole-brain or 23 heartbeats whole-heart for parallel transmit (pTx) applications at 7 T. THEORY AND METHODS: We evaluate the combination of three recently proposed techniques. The acquisition of multi-channel transmit array B 1 + $$ {\mathrm{B}}_1^{+} $$ maps is accelerated using transmit low rank (TxLR) with absolute B 1 + $$ {\mathrm{B}}_1^{+} $$ mapping (Sandwich) acquired in a B 1 + $$ {\mathrm{B}}_1^{+} $$ time-interleaved acquisition of modes (B1TIAMO) fashion. Simulations using synthetic body images derived from Sim4Life were used to test the achievable acceleration for small scan matrices of 24 × 24. Next, we evaluated the method by retrospectively undersampling a fully sampled B 1 + $$ {\mathrm{B}}_1^{+} $$ library of nine subjects in the brain. Finally, Cartesian undersampled phantom and in vivo images were acquired in both the brain of three subjects (8Tx/32 receive [Rx]) and the heart of another three subjects (8Tx/8Rx) at 7 T. RESULTS: Simulation and in vivo results show that volumetric multi-channel B 1 + $$ {\mathrm{B}}_1^{+} $$ maps can be acquired using acceleration factors of 4 in the body, reducing the acquisition time to within 23 heartbeats, which was previously not possible. In silico heart simulations demonstrated a RMS error to the fully sampled native resolution ground truth of 4.2° when combined in first-order circularly polarized mode (mean flip angle 66°) at an acceleration factor of 4. The 14 s 3D B 1 + $$ {\mathrm{B}}_1^{+} $$ maps acquired in the brain have a RMS error of 1.9° to the fully sampled (mean flip angle 86°). CONCLUSION: The proposed method is demonstrated as a fast pTx calibration technique in the brain and a promising method for pTx calibration in the body.

Rapid 3D absolute B1 + mapping using a sandwiched train presaturated TurboFLASH sequence at 7 T for the brain and heart.

PURPOSE: To shorten the acquisition time of magnetization-prepared absolute transmit field (B1 + ) mapping known as presaturation TurboFLASH, or satTFL, to enable single breath-hold whole-heart 3D B1 + mapping. METHODS: SatTFL is modified to remove the delay between the reference and prepared images (typically 5 T1 ), with matching transmit configurations for excitation and preparation RF pulses. The new method, called Sandwich, is evaluated as a 3D sequence, measuring whole-brain and gated whole-heart B1 + maps in a single breath-hold. We evaluate the sensitivity to B1 + and T1 using numerical Bloch, extended phase graph, and Monte Carlo simulations. Phantom and in vivo images were acquired in both the brain and heart using an 8-channel transmit 7 Tesla MRI system to support the simulations. A segmented satTFL with a short readout train was used as a reference. RESULTS: The method significantly reduces acquisition times of 3D measurements from 360 s to 20 s, in the brain, while simultaneously reducing bias in the measured B1 + due to T1 and magnetization history. The mean coefficient of variation was reduced by 81% for T1 s of 0.5-3 s compared to conventional satTFL. In vivo, the reproducibility coefficient for flip angles in the range 0-130° was 4.5° for satTFL and 4.7° for our scheme, significantly smaller than for a short TR satTFL sequence, which was 12°. The 3D sequence measured B1 + maps of the whole thorax in 26 heartbeats. CONCLUSION: Our adaptations enable faster B1 + mapping, with minimal T1 sensitivity and lower sensitivity to magnetization history, enabling single breath-hold whole-heart absolute B1 + mapping.

Detection and alterations of acetylcarnitine (AC) in human liver by 1 H MRS at 3T after supplementation with l-carnitine.

PURPOSE: Acetylcarnitine can be assessed in vivo using proton MRS (1 H-MRS) with long TEs and this has been previously applied successfully in muscle. The aim of this study was to evaluate a 1 H-MRS technique for liver acetylcarnitine quantification in healthy humans before and after l-carnitine supplementation. METHOD: Baseline acetylcarnitine levels were quantified using a STEAM sequence with prolonged TE in 15 healthy adults. Using STEAM with four different TEs was evaluated in phantoms. To assess reproducibility of the measurements, five of the participants had repeated 1 H-MRS without receiving l-carnitine supplementation. To determine if liver acetylcarnitine could be changed after l-carnitine supplementation, acetylcarnitine was quantified 2 h after intravenous l-carnitine supplementation (50 mg/kg body weight) in the other 10 participants. Hepatic lipids were also quantified from the 1 H-MRS spectra. RESULTS: There was good separation between the acetylcarnitine and fat in the phantoms using TE = 100 ms. Hepatic acetylcarnitine levels were reproducible (coefficient of reproducibility = 0.049%) and there was a significant (p < 0.001) increase in the relative abundance after a single supplementation of l-carnitine. Hepatic allylic, methyl, and methylene peaks were not altered by l-carnitine supplementation in healthy volunteers. CONCLUSION: Our results demonstrate that our 1 H-MRS technique could be used to measure acetylcarnitine in the liver and detect changes following intravenous supplementation in healthy adults despite the presence of lipids. Our techniques should be explored further in the study of fatty liver disease, where acetylcarnitine is suggested to be altered due to hepatic inflexibilities.

Three-dimensional, 2.5-minute, 7T phosphorus magnetic resonance spectroscopic imaging of the human heart using concentric rings.

A three-dimensional (3D), density-weighted, concentric rings trajectory (CRT) magnetic resonance spectroscopic imaging (MRSI) sequence is implemented for cardiac phosphorus (31 P)-MRS at 7 T. The point-by-point k-space sampling of traditional phase-encoded chemical shift imaging (CSI) sequences severely restricts the minimum scan time at higher spatial resolutions. Our proposed CRT sequence implements a stack of concentric rings, with a variable number of rings and planes spaced to optimise the density of k-space weighting. This creates flexibility in acquisition time, allowing acquisitions substantially faster than traditional phase-encoded CSI sequences, while retaining high signal-to-noise ratio (SNR). We first characterise the SNR and point-spread function of the CRT sequence in phantoms. We then evaluate it at five different acquisition times and spatial resolutions in the hearts of five healthy participants at 7 T. These different sequence durations are compared with existing published 3D acquisition-weighted CSI sequences with matched acquisition times and spatial resolutions. To minimise the effect of noise on the short acquisitions, low-rank denoising of the spatiotemporal data was also performed after acquisition. The proposed sequence measures 3D localised phosphocreatine to adenosine triphosphate (PCr/ATP) ratios of the human myocardium in 2.5 min, 2.6 times faster than the minimum scan time for acquisition-weighted phase-encoded CSI. Alternatively, in the same scan time, a 1.7-times smaller nominal voxel volume can be achieved. Low-rank denoising reduced the variance of measured PCr/ATP ratios by 11% across all protocols. The faster acquisitions permitted by 7-T CRT 31 P-MRSI could make cardiac stress protocols or creatine kinase rate measurements (which involve repeated scans) more tolerable for patients without sacrificing spatial resolution.

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

Even 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.

Energetic Basis for Exercise-Induced Pulmonary Congestion in Heart Failure With Preserved Ejection Fraction.

BACKGROUND: Transient pulmonary congestion during exercise is emerging as an important determinant of reduced exercise capacity in heart failure with preserved ejection fraction (HFpEF). We sought to determine whether an abnormal cardiac energetic state underpins this process. METHODS: We recruited patients across the spectrum of diastolic dysfunction and HFpEF (controls, n=11; type 2 diabetes, n=9; HFpEF, n=14; and severe diastolic dysfunction attributable to cardiac amyloidosis, n=9). Cardiac energetics were measured using phosphorus spectroscopy to define the myocardial phosphocreatine to ATP ratio. Cardiac function was assessed by cardiovascular magnetic resonance cine imaging and echocardiography and lung water using magnetic resonance proton density mapping. Studies were performed at rest and during submaximal exercise using a magnetic resonance imaging ergometer. RESULTS: Paralleling the stepwise decline in diastolic function across the groups (E/e' ratio; P<0.001) was an increase in NT-proBNP (N-terminal pro-brain natriuretic peptide; P<0.001) and a reduction in phosphocreatine/ATP ratio (control, 2.15 [2.09, 2.29]; type 2 diabetes, 1.71 [1.61, 1.91]; HFpEF, 1.66 [1.44, 1.89]; cardiac amyloidosis, 1.30 [1.16, 1.53]; P<0.001). During 20-W exercise, lower left ventricular diastolic filling rates (r=0.58; P<0.001), lower left ventricular diastolic reserve (r=0.55; P<0.001), left atrial dilatation (r=-0.52; P<0.001), lower right ventricular contractile reserve (right ventricular ejection fraction change, r=0.57; P<0.001), and right atrial dilation (r=-0.71; P<0.001) were all linked to lower phosphocreatine/ATP ratio. Along with these changes, pulmonary proton density mapping revealed transient pulmonary congestion in patients with HFpEF (+4.4% [0.5, 6.4]; P=0.002) and cardiac amyloidosis (+6.4% [3.3, 10.0]; P=0.004), which was not seen in healthy controls (-0.1% [-1.9, 2.1]; P=0.89) or type 2 diabetes without HFpEF (+0.8% [-1.7, 1.9]; P=0.82). The development of exercise-induced pulmonary congestion was associated with lower phosphocreatine/ATP ratio (r=-0.43; P=0.004). CONCLUSIONS: A gradient of myocardial energetic deficit exists across the spectrum of HFpEF. Even at low workload, this energetic deficit is related to markedly abnormal exercise responses in all 4 cardiac chambers, which is associated with detectable pulmonary congestion. The findings support an energetic basis for transient pulmonary congestion in HFpEF.

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 noninvasively. 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 utilization is currently underexplored, 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 utilization. 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 T. 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 = .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. CONCLUSIONS: 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.

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.

Noninvasive assessment of steatosis and viability of cold-stored human liver grafts by MRI.

PURPOSE: A shortage of suitable donor livers is driving increased use of higher risk livers for transplantation. However, current biomarkers are not sensitive and specific enough to predict posttransplant liver function. This is limiting the expansion of the donor pool. Therefore, better noninvasive tests are required to determine which livers will function following implantation and hence can be safely transplanted. This study assesses the temperature sensitivity of proton density fat fraction and relaxometry parameters and examines their potential for assessment of liver function ex vivo. METHODS: Six ex vivo human livers were scanned during static cold storage following normothermic machine perfusion. Proton density fat fraction, T1 , T2 , and T2∗ were measured repeatedly during cooling on ice. Temperature corrections were derived from these measurements for the parameters that showed significant variation with temperature. RESULTS: Strong linear temperature sensitivities were observed for proton density fat fraction (R2 = 0.61, P < .001) and T1 (R2 = 0.78, P < .001). Temperature correction according to a linear model reduced the coefficient of repeatability in these measurements by 41% and 36%, respectively. No temperature dependence was observed in T2 or T2∗ measurements. Comparing livers deemed functional and nonfunctional during normothermic machine perfusion by hemodynamic and biochemical criteria, T1 differed significantly: 516 ± 50 ms for functional versus 679 ± 60 ms for nonfunctional, P = .02. CONCLUSION: Temperature correction is essential for robust measurement of proton density fat fraction and T1 in cold-stored human livers. These parameters may provide a noninvasive measure of viability for transplantation.

Water-suppression cycling 3-T cardiac 1 H-MRS detects altered creatine and choline in patients with aortic or mitral stenosis.

Cardiac proton spectroscopy (1 H-MRS) is widely used to quantify lipids. Other metabolites (e.g. creatine and choline) are clinically relevant but more challenging to quantify because of their low concentrations (approximately 10 mmol/L) and because of cardiac motion. To quantify cardiac creatine and choline, we added water-suppression cycling (WSC) to two single-voxel spectroscopy sequences (STEAM and PRESS). WSC introduces controlled residual water signals that alternate between positive and negative phases from transient to transient, enabling robust phase and frequency correction. Moreover, a particular weighted sum of transients eliminates residual water signals without baseline distortion. We compared WSC and the vendor's standard 'WET' water suppression in phantoms. Next, we tested repeatability in 10 volunteers (seven males, three females; age 29.3 ± 4.0 years; body mass index [BMI] 23.7 ± 4.1 kg/m2 ). Fat fraction, creatine concentration and choline concentration when quantified by STEAM-WET were 0.30% ± 0.11%, 29.6 ± 7.0 µmol/g and 7.9 ± 6.7 µmol/g, respectively; and when quantified by PRESS-WSC they were 0.30% ± 0.15%, 31.5 ± 3.1 µmol/g and 8.3 ± 4.4 µmol/g, respectively. Compared with STEAM-WET, PRESS-WSC gave spectra whose fitting quality expressed by Cramér-Rao lower bounds improved by 26% for creatine and 32% for choline. Repeatability of metabolite concentration measurements improved by 72% for creatine and 40% for choline. We also compared STEAM-WET and PRESS-WSC in 13 patients with severe symptomatic aortic or mitral stenosis indicated for valve replacement surgery (10 males, three females; age 75.9 ± 6.3 years; BMI 27.4 ± 4.3 kg/m2 ). Spectra were of analysable quality in eight patients for STEAM-WET, and in nine for PRESS-WSC. We observed comparable lipid concentrations with those in healthy volunteers, significantly reduced creatine concentrations, and a trend towards decreased choline concentrations. We conclude that PRESS-WSC offers improved performance and reproducibility for the quantification of cardiac lipids, creatine and choline concentrations in healthy volunteers at 3 T. It also offers improved performance compared with STEAM-WET for detecting altered creatine and choline concentrations in patients with valve disease.

Hydration and glycogen affect T1 relaxation times of liver tissue.

T1 mapping is a useful tool for the assessment of patients with nonalcoholic fatty liver disease but still suffers from a large unexplained variance in healthy subjects. This study aims to characterize the potential effects of liver glycogen concentration and body hydration status on liver shortened modified Look-Locker inversion recovery (shMOLLI) T1 measurements. Eleven glycogen phantoms and 12 healthy volunteers (mean age: 31 years, three females) were scanned at 3 T using inversion recovery spin echo, multiple contrast spin echo (in phantoms), shMOLLI T1 mapping, multiple-echo spoiled gradient recalled echo and 13 C spectroscopy (in healthy volunteers). Phantom r1 and r2 relaxivities were determined from measured T1 and T2 values. Participants underwent a series of five metabolic experiments to vary their glycogen concentration and hydration levels: feeding, food fasting, exercising, underhydration, and rehydration. Descriptive statistics were calculated for shMOLLI T1 , inferior vena cava to aorta cross-sectional area ratio (IVC/Ao) as a marker of body hydration status, glycogen concentration, T2 * and proton density fat fraction values. A linear mixed model for shMOLLI R1 was constructed to determine the effects of glycogen concentration and IVC/Ao ratio. The mean shMOLLI T1 after fasting was 737 ± 67 ms. The mean within-subject change was 80 ± 45 ms. The linear mixed model revealed a glycogen r1 relaxivity in volunteers (0.18 M-1 s-1 , p = 0.03) close to that determined in phantoms (0.28 M-1 s-1 ). A unit change in IVC/Ao ratio was associated with a drop of -0.113 s-1 in R1 (p < 0.001). This study demonstrated a dependence of liver shMOLLI T1 values on liver glycogen concentration and overall body hydration status. Interparticipant variation of hydration status should be minimized in future liver MRI studies. Additionally, caution is advised when interpreting liver T1 measurements in participants with excess liver glycogen.

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.

31 P magnetic resonance spectroscopy in skeletal muscle: Experts' consensus recommendations.

Skeletal muscle phosphorus-31 31 P MRS is the oldest MRS methodology to be applied to in vivo metabolic research. The technical requirements of 31 P MRS in skeletal muscle depend on the research question, and to assess those questions requires understanding both the relevant muscle physiology, and how 31 P MRS methods can probe it. Here we consider basic signal-acquisition parameters related to radio frequency excitation, TR, TE, spectral resolution, shim and localisation. We make specific recommendations for studies of resting and exercising muscle, including magnetisation transfer, and for data processing. We summarise the metabolic information that can be quantitatively assessed with 31 P MRS, either measured directly or derived by calculations that depend on particular metabolic models, and we give advice on potential problems of interpretation. We give expected values and tolerable ranges for some measured quantities, and minimum requirements for reporting acquisition parameters and experimental results in publications. Reliable examination depends on a reproducible setup, standardised preconditioning of the subject, and careful control of potential difficulties, and we summarise some important considerations and potential confounders. Our recommendations include the quantification and standardisation of contraction intensity, and how best to account for heterogeneous muscle recruitment. We highlight some pitfalls in the assessment of mitochondrial function by analysis of phosphocreatine (PCr) recovery kinetics. Finally, we outline how complementary techniques (near-infrared spectroscopy, arterial spin labelling, BOLD and various other MRI and 1 H MRS measurements) can help in the physiological/metabolic interpretation of 31 P MRS studies by providing information about blood flow and oxygen delivery/utilisation. Our recommendations will assist in achieving the fullest possible reliable picture of muscle physiology and pathophysiology.

Feasibility of absolute quantification for 31 P MRS at 7 T.

PURPOSE: Phosphorus spectroscopy can differentiate among liver disease stages and types. To quantify absolute concentrations of phosphorus metabolites, sensitivity calibration and transmit field ( B1+ ) correction are required. The trend toward ultrahigh fields (7 T) and the use of multichannel RF coils makes this ever more challenging. We investigated the constraints on reference phantoms, and implemented techniques for the absolute quantification of human liver phosphorus spectra acquired using a 10-cm loop and a 16-channel array at 7 T. METHODS: The effect of phantom conductivity was assessed at 25.8 MHz (1.5 T), 49.9 MHz (3 T), and 120.3 MHz (7 T) by electromagnetic modeling. Radiofrequency field maps ( B1± ) were measured in phosphate phantoms (18 mM and 40 mM) at 7 T. These maps were used to assess the correction of 4 phantom 3D-CSI data sets using 3 techniques: phantom replacement, explicit normalization, and simplified normalization. In vivo liver spectra acquired with a 10-cm loop were corrected with all 3 methods. Simplified normalization was applied to in vivo 16-channel array data sets. RESULTS: Simulations show that quantification errors of less than 3% are achievable using a uniform electrolyte phantom with a conductivity of 0.23-0.86 S.m-1 at 1.5 T, 0.39-0.58 S.m-1 at 3 T, and 0.34-0.42 S.m-1 (16-19 mM KH2 PO4(aq) ) at 7 T. The mean γ-ATP concentration quantified in vivo at 7 T was 1.39 ± 0.30 mmol.L-1 to 1.71 ± 0.35 mmol.L-1 wet tissue for the 10-cm loop and 1.88 ± 0.25 mmol.L-1 wet tissue for the array. CONCLUSION: It is essential to select a calibration phantom with appropriate conductivity for quantitative phosphorus spectroscopy at 7 T. Using an 18-mM phosphate phantom and simplified normalization, human liver phosphate metabolite concentrations were successfully quantified at 7 T.

Reproducibility of human cardiac phosphorus MRS (31 P-MRS) at 7 T.

PURPOSE: We test the reproducibility of human cardiac phosphorus MRS (31 P-MRS) at ultra-high field strength (7 T) for the first time. The primary motivation of this work was to assess the reproducibility of a 'rapid' 6½ min 31 P three-dimensional chemical shift imaging (3D-CSI) sequence, which if sufficiently reproducible would allow the study of stress-response processes. We compare this with an established 28 min protocol, designed to record high-quality spectra in a clinically feasible scan time. Finally, we use this opportunity to compare the effect of per-subject B0 shimming on data quality and reproducibility in the 6½ min protocol. METHODS: 10 healthy subjects were scanned on two occasions: one to test the 28 min 3D-CSI protocol, and one to test the 6½ min protocol. Spectra were fitted using the OXSA MATLAB toolbox. The phosphocreatine to adenosine triphosphate concentration ratio (PCr/ATP) from each scan was analysed for intra- and intersubject variability. The impact of different strategies for voxel selection was assessed. RESULTS: There were no significant differences between repeated measurements in the same subject. For the 28 min protocol, PCr/ATP in the midseptal voxel across all scans was 1.91 ± 0.36 (mean ± intersubject SD). For the 6½ min protocol, PCr/ATP in the midseptal voxel was 1.76 ± 0.40. The coefficients of reproducibility (CRs) were 0.49 (28 min) and 0.67 (6½ min). Per-subject B0 shimming improved the fitted PCr/ATP precision (for 6½ min scans), but had negligible effect on the CR (0.67 versus 0.66). CONCLUSIONS: Both 7 T protocols show improved reproducibility compared with a previous 3 T study by Tyler et al. Our results will enable informed power calculations and protocol selection for future clinical research studies.

Measuring inorganic phosphate and intracellular pH in the healthy and hypertrophic cardiomyopathy hearts by in vivo 7T 31P-cardiovascular magnetic resonance spectroscopy.

BACKGROUND: Cardiovascular phosphorus MR spectroscopy (31P-CMRS) is a powerful tool for probing energetics in the human heart, through quantification of phosphocreatine (PCr) to adenosine triphosphate (ATP) ratio. In principle, 31P-CMRS can also measure cardiac intracellular pH (pHi) and the free energy of ATP hydrolysis (ΔGATP). However, these require determination of the inorganic phosphate (Pi) signal frequency and amplitude that are currently not robustly accessible because blood signals often obscure the Pi resonance. Typical cardiac 31P-CMRS protocols use low (e.g. 30°) flip-angles and short repetition time (TR) to maximise signal-to-noise ratio (SNR) within hardware limits. Unfortunately, this causes saturation of Pi with negligible saturation of the flowing blood pool. We aimed to show that an adiabatic 90° excitation, long-TR, 7T 31P-CMRS protocol will reverse this balance, allowing robust cardiac pHi measurements in healthy subjects and patients with hypertrophic cardiomyopathy (HCM). METHODS: The cardiac Pi T1 was first measured by the dual TR technique in seven healthy subjects. Next, ten healthy subjects and three HCM patients were scanned with 7T 31P-MRS using long (6 s) TR protocol and adiabatic excitation. Spectra were fitted for cardiac metabolites including Pi. RESULTS: The measured Pi T1 was 5.0 ± 0.3 s in myocardium and 6.4 ± 0.6 s in skeletal muscle. Myocardial pH was 7.12 ± 0.04 and Pi/PCr ratio was 0.11 ± 0.02. The coefficients of repeatability were 0.052 for pH and 0.027 for Pi/PCr quantification. The pH in HCM patients did not differ (p = 0.508) from volunteers. However, Pi/PCr was higher (0.24 ± 0.09 vs. 0.11 ± 0.02; p = 0.001); Pi/ATP was higher (0.44 ± 0.14 vs. 0.24 ± 0.05; p = 0.002); and PCr/ATP was lower (1.78 ± 0.07 vs. 2.10 ± 0.20; p = 0.020), in HCM patients, which is in agreement with previous reports. CONCLUSION: A 7T 31P-CMRS protocol with adiabatic 90° excitation and long (6 s) TR gives sufficient SNR for Pi and low enough blood signal to permit robust quantification of cardiac Pi and hence pHi. Pi was detectable in every subject scanned for this study, both in healthy subjects and HCM patients. Cardiac pHi was unchanged in HCM patients, but both Pi/PCr and Pi/ATP increased that indicate an energetic impairment in HCM. This work provides a robust technique to quantify cardiac Pi and pHi.

MR compatible ergometers for dynamic 31P MRS.

Magnetic Resonance (MR) compatible ergometers are specialized ergometers used inside the MR scanners for the characterization of tissue metabolism changes during physical stress. They are most commonly used for dynamic phosphorous magnetic resonance spectroscopy (31P MRS), but can also be used for lactate production measurements, perfusion studies using arterial spin labelling or muscle oxygenation measurements by blood oxygen dependent contrast sequences. We will primarily discuss the importance of ergometers in the context of dynamic 31P MRS. Dynamic 31P MRS can monitor muscle fatigue and energy reserve during muscle contractions as well as the dynamics of recuperation of skeletal muscle tissue during the following recovery through signal changes of phosphocreatine (PCr), inorganic phosphate and adenosine triphosphate (ATP). Based on the measured data it is possible to calculate intracellular pH, metabolic flux of ATP through creatine-kinase reaction, anaerobic glycolysis and oxidative phosphorylation and other metabolic parameters as mitochondrial capacity. This review primarily focuses on describing various technical designs of MR compatible ergometers for dynamic 31P MRS that must be constructed with respect to the presence of magnetic field. It is also expected that the construction of ergometers will be easy for the handling and well accepted by examined subjects.