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

Funder: Gates Cambridge Trust; Id: http://dx.doi.org/10.13039/501100005370Funder: British Heart Foundation Intermediate FellowshipCardiac proton spectroscopy (1H‐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

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

Funder: Gates Cambridge Trust; Id: http://dx.doi.org/10.13039/501100005370Funder: British Heart Foundation Intermediate FellowshipCardiac proton spectroscopy (1H‐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

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)

Localized rest and stress human cardiac creatine kinase reaction kinetics at 3 T.

Changes in the kinetics of the creatine kinase (CK) shuttle are sensitive markers of cardiac energetics but are typically measured at rest and in the prone position. This study aims to measure CK kinetics during pharmacological stress at 3 T, with measurement in the supine position. A shorter "stressed saturation transfer" (StreST) extension to the triple repetition time saturation transfer (TRiST) method is proposed. We assess scanning in a supine position and validate the MR measurement against biopsy assay of CK activity. We report normal ranges of stress CK forward rate (kfCK ) for healthy volunteers and obese patients. TRiST measures kfCK in 40 min at 3 T. StreST extends the previously developed TRiST to also make a further kfCK measurement during <20 min of dobutamine stress. We test our TRiST implementation in skeletal muscle and myocardium in both prone and supine positions. We evaluate StreST in the myocardium of six healthy volunteers and 34 obese subjects. We validated MR-measured kfCK against biopsy assays of CK activity. TRiST kfCK values matched literature values in skeletal muscle (kfCK  = 0.25 ± 0.03 s-1 vs 0.27 ± 0.03 s-1 ) and myocardium when measured in the prone position (0.32 ± 0.15 s-1 ), but a significant difference was found for TRiST kfCK measured supine (0.24 ± 0.12 s-1 ). This difference was because of different respiratory- and cardiac-motion-induced B0 changes in the two positions. Using supine TRiST, cardiac kfCK values for normal-weight subjects were 0.15 ± 0.09 s-1 at rest and 0.17 ± 0.15 s-1 during stress. For obese subjects, kfCK was 0.16 ± 0.07 s-1 at rest and 0.17 ± 0.10 s-1 during stress. Rest myocardial kfCK and CK activity from LV biopsies of the same subjects correlated (R = 0.43, p = 0.03). We present an independent implementation of TRiST on the Siemens platform using a commercially available coil. Our extended StreST protocol enables cardiac kfCK to be measured during dobutamine-induced stress in the supine position.Funded by: a Sir Henry Dale Fellowship from the Wellcome Trust and the Royal Society [098436/Z/12/B] to CTR, the BHF Centre of Research Excellence (OJR), a BHF clinical research training fellowship [FS/15/80/31803] to MAP, a BHF fellowship [FS/14/54/30946] to JJR, an NIHR OBRC fellowship to BR, a BHF programme grant [RG/13/8/30266] to CAL and SN, and a DPhil studentship from the Medical Research Council to WTC. We acknowledge support from the Oxford NIHR Biomedical Research Centre

ATP delivery rates in myocardial hypertrophy

This thesis aims to better understand the metabolic dimension of cardiac adaptation to increased work by studying the creatine kinase (CK) system in participants with pathological hypertrophy secondary to severe aortic stenosis with preserved ejection fraction (SevAS-pEF) or secondary to severe primary mitral regurgitation (MR), participants with hearts adapted to exercise training, and participants with no hypertrophy (NH). It also aims to understand why some hearts transition to failure in the presence of pressure overload, by studying a group with severe aortic stenosis with reduced ejection fraction (SevAS-rEF). Broadly speaking there are two pathways for ATP delivery from sites of production in mitochrondria to sites of use at the myofibrils: facilitated diffusion by the CK system and simple diffusion. This thesis aims to investigate both. Closely related to this, CK also has roles in the temporal buffering of adenine nucleotides and the control of respiratory flux over varying work rates, so more broadly represents a kind of metabolic reserve. CK activity can be assessed on freeze-and-extract biochemical assay. Using 31phosphorus-magnetic resonance spectroscopy (MRS) saturation transfer to estimate the CK rate constant (kf) is the first step toward estimates of in vivo flux. Over 60 intra-operative left ventricular (LV) biopsies in participants with pre-operative 31P-MRS are collected to validate the novel TRiST sequence against biochemically-assessed maximum CK rate. Ch. 3 describes non-invasive and invasive predictors of CK total activity and derives a three-variable linear regression model in 37 triplicate datasets to predict CK total activity from total creatine, kf and LV end-systolic volume index. Ch. 4 studies invasive and non-invasive measures of the CK system in participants with sevAS-pEF, sevAS-rEF, and NH. The chapter argues for the assessment of metabolic reserve as a way of identifying – and explaining – the recently described subset of patients whose ventricles deteriorate sooner in the face of pressure overload. A stepwise fall in median CK total activity is found when arranging groups in order of increasing LV mass index. Non-invasive measures are also assessed in participants with moderate AS, healthy volunteers, and sevAS-pEF participants late post-operatively. The CK system is then studied in participants with severe primary MR and preserved systolic function pre- and post-operatively (Ch. 5), and in participants with physiological hypertrophy or normal, non-trained, hearts at rest and during dobutamine stress (Ch. 6). Ch. 7 relates CK activity with ATP diffusion distance using 3D models built from tomographic stacks of electron microscopy images in a subset of LV biopsies.</p

Response by Peterzan et al to Letter Regarding Article, "Cardiac Energetics in Patients With Aortic Stenosis and Preserved Versus Reduced Ejection Fraction".

We appreciate the interest and comments by Mahmood in regards to our recent article (1). In this study we have shown not only that cardiac energetics are impaired early in the aortic stenosis (AS) disease process, being present in a group of patients with moderate aortic stenosis, but also that transition to systolic failure in severe AS is not dependent on further energetic decline. Whilst Mahmood points out correctly that energetic impairment was not a “necessary correlate of systolic failure as assessed by LV ejection fraction (LVEF)” this does not imply that it is unrelated. We would like to clarify that as ATP demands increase with AS severity, a reduction in the capacity to deliver ATP to the myocardium, as established early in the process of AS, could increase susceptibility to systolic failure when the increasing ATP demand exceeds supply.Wellcome Trust Sir Henry Dale Fellowship to CTR [098436/Z/12/B]

Obesity modifies the energetic phenotype in dilated cardiomyopathy

Aims: We sought to determine if myocardial energetics could distinguish obesity cardiomyopathy as a distinct entity from dilated cardiomyopathy. Methods and Results: 16 normal weight participants with dilated cardiomyopathy (DCMNW), and 27 with DCM and obesity (DCMOB), were compared to 26 normal weight controls (CTLNW). All underwent cardiac magnetic resonance imaging and 31 P spectroscopy to assess function and energetics. 19 DCMOB underwent repeat assessment after a dietary weight loss intervention. ATP delivery through creatine kinase (CK flux) was 55% lower in DCMNW than in CTLNW (p=0.004), correlating with left ventricular ejection fraction (LVEF, r=0.4, p=0.015). In contrast, despite similar LVEF (DCMOB 41±7%,DCMNW 38±6%, p=0.14), CK flux was two-fold higher in DCMOB (p50%, p<0.001). Intentional weight loss was associated with positive left ventricular remodelling, with reduced left ventricular end-diastolic volume (by 8%, p<0.001) and a change in LVEF (40±9% vs 45±10%, p=0.002). This occurred alongside a fall in ATP delivery rate with weight loss (by 7%, p=0.049). Conclusions: In normal weight, DCM is associated with reduced resting ATP delivery. In obese DCM, ATP demand through CK is greater, suggesting reduced efficiency of energy utilisation. Dietary weight loss is associated with significant improvement in myocardial contractility, and a fall in ATP delivery, suggesting improved metabolic efficiency. This highlights distinct energetic pathways in obesity cardiomyopathy which are both different from dilated cardiomyopathy, and may be reversible with weight loss