Human Cardiac 31P-MR Spectroscopy at 3 Tesla Cannot Detect Failing Myocardial Energy Homeostasis during Exercise

Abstract

Phosphorus-31 magnetic resonance spectroscopy (31P-MRS) is a unique non-invasive imaging modality for probing in vivo high-energy phosphate metabolism in the human heart. We investigated whether current 31P-MRS methodology would allow for clinical applications to detect exercise-induced changes in (patho-)physiological myocardial energy metabolism. Hereto, measurement variability and repeatability of three commonly used localized 31P-MRS methods [3D image-selected in vivo spectroscopy (ISIS) and 1D ISIS with 1D chemical shift imaging (CSI) oriented either perpendicular or parallel to the surface coil] to quantify the myocardial phosphocreatine (PCr) to adenosine triphosphate (ATP) ratio in healthy humans (n = 8) at rest were determined on a clinical 3 Tesla MR system. Numerical simulations of myocardial energy homeostasis in response to increased cardiac work rates were performed using a biophysical model of myocardial oxidative metabolism. Hypertrophic cardiomyopathy was modeled by either inefficient sarcomere ATP utilization or decreased mitochondrial ATP synthesis. The effect of creatine depletion on myocardial energy homeostasis was explored for both conditions. The mean in vivo myocardial PCr/ATP ratio measured with 3D ISIS was 1.57 ± 0.17 with a large repeatability coefficient of 40.4%. For 1D CSI in a 1D ISIS-selected slice perpendicular to the surface coil, the PCr/ATP ratio was 2.78 ± 0.50 (repeatability 42.5%). With 1D CSI in a 1D ISIS-selected slice parallel to the surface coil, the PCr/ATP ratio was 1.70 ± 0.56 (repeatability 43.7%). The model predicted a PCr/ATP ratio reduction of only 10% at the maximal cardiac work rate in normal myocardium. Hypertrophic cardiomyopathy led to lower PCr/ATP ratios for high cardiac work rates, which was exacerbated by creatine depletion. Simulations illustrated that when conducting cardiac 31P-MRS exercise stress testing with large measurement error margins, results obtained under pathophysiologic conditions may still lie well within the 95% confidence interval of normal myocardial PCr/ATP dynamics. Current measurement precision of localized 31P-MRS for quantification of the myocardial PCr/ATP ratio precludes the detection of the changes predicted by computational modeling. This hampers clinical employment of 31P-MRS for diagnostic testing and risk stratification, and warrants developments in cardiac 31P-MRS exercise stress testing methodology.

Short echo time relaxation‐enhanced MR spectroscopy reveals broad downfield resonances

“…The spectral quality in iRE‐MRS experiments was comparable to the gold‐standard PRESS experiments within the targeted BWs. Multiplets corresponding to 2 CH 2 , 3 CH 2 , and 4 CH 2 GABA resonances (Figure C) as well as NAA's prominent methyl singlet (Figure D) were well‐reproduced using iRE‐MRS. Phase differences between PRESS and iRE spectra, attributed to the different J‐evolution in each sequence, were noted for these multiplets.…”

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

“…Bakermans et al tested the reproducibility of a 7 min sequence in the human heart at 3 T, performing spatial localization with 3D ISIS or a combination of 1D ISIS and 1D CSI either perpendicular or parallel to the surface coil . 3D ISIS was found to be the most reproducible of these methods, giving a PCr/ATP of 1.57 ± 0.17 (mean ± SD) and a CR of 0.64.…”

“…There is some debate in the literature about the possible magnitude of changes in PCr/ATP. Bakermans et al suggested by simulations that the changes in PCr/ATP in healthy subjects upon exercise are on the order of 10%, which they concluded would be impossible to detect by 31 P‐MRS at 3 T . Exercise‐induced changes in patients with disease are known to be more substantial, perhaps because their hearts have only a limited energetic reserve because of having to compensate for disease at rest.…”

“…Bakermans et al tested the reproducibility of a 7 min sequence in the human heart at 3 T, performing spatial localization with 3D ISIS or a combination of 1D ISIS and 1D CSI either perpendicular or parallel to the surface coil. 24 3D ISIS was found to be the most reproducible of these methods, giving a PCr/ATP of 1.57 ± 0.17 (mean ± SD) and a CR of 0.64. The reproducibility of this 7 min 3 T scan is the same as that achieved in a 6½ min 7 T scan in this work (CR 0.64 at 3 T versus CR 0.67 in this work) but used substantially larger voxel sizes: 3D ISIS voxel size 512 mL.…”

Altered mitochondrial metabolism in the insulin‐resistant heart

“…Cardiac PCr/ATP ratios have also been found to be reduced during catecholamine stress or exercise in people with obesity and insulin resistance, although another study failed to confirm this latter observation . Whether a lower myocardial PCr/ATP ratio in diabetic cardiomyopathy is a cause or effect of the progression to heart failure is currently unknown …”