PCr/ATP Ratios and Mitochondrial Function in The Heart. A Comparative Study in Humans.

Abstract

Objectives The objective of the study was to validate PCr/ATP ratios as an in vivo marker for cardiac mitochondrial function.Background Cardiac energy status, measured as PCr/ATP ratio with 31P-MRS in vivo, was shown to be a prognostic factor in heart failure and is lowered in cardiometabolic disease. As mitochondrial function is also hampered in these diseases and oxidative phosphorylation is the major contributor to ATP synthesis, the PCr/ATP ratio might be a reflection of cardiac mitochondrial function.Methods Thirty-eight patients scheduled for open heart surgery were enrolled in this study. Before surgery, cardiac 31P-MRS was performed. During surgery, tissue specimens from the right atrial appendage were obtained for the ex vivo assessment of mitochondrial function using high-resolution respirometry.Results The patient population included was heterogenous resulting in wide ranges of PCr/ATP ratios and ADP-stimulated respiration rates (PCr/ATP ranging from 0.533 to 1.717; ADP-stimulated respiration rates ranging from 28.5 to 94.6 pmol/mg/s). Correlation analysis however showed no relationship between PCr/ATP and ADP-stimulated respiration rates fueled by various substrates (octanoylcarnitine R2 < 0.005, p = 0.74; pyruvate R2 < 0.025, p = 0.41). Also, no correlations between PCr/ATP and maximally uncoupled respiration were found (octanoylcarnitine R2 = 0.005, p = 0.71; pyruvate R2 = 0.040, p = 0.26).Conclusions Our results do not support the use of cardiac energy status (PCr/ATP) as a surrogate marker of mitochondrial function in the heart. The dissociation of the two parameters in the present study suggests that mitochondrial function is not the only determinant of cardiac energy status.Condensed abstractThis study does not support the use of in vivo cardiac energy status (PCr/ATP ratio) as a surrogate marker of ex vivo mitochondrial function (maximal oxidative respiration). Although both PCr/ATP and mitochondrial function are reduced in cardiovascular disease, the dissociation of the two parameters in the present study shows that PCr/ATP is determined by more factors than only mitochondrial function. Hence, PCr/ATP is not a good marker for mitochondrial function, but it can be a valuable marker for cardiometabolic health in cardiometabolic studies.Trial registration: https://clinicaltrials.gov (NCT03049228).

Perfusion-Independent Tissue Hypoxia in Cardiac Hypertrophy in Mice Measured by64Cu-CTS PET Imaging

“…Although we cannot use our approach to quantify absolute intracellular oxygen concentration, we would argue that this parameter would only be useful if the oxygen thresholds at which critical biochemical processes are compromised in vivo are also known (which is rarely true). Arguably, the most appropriate technique for detecting prognostically useful energetic compromise in ischemic cardiac syndromes would be 31 P NMR spectroscopy(29), but it is not widespread because it is technically challenging and its poor sensitivity results in poor spatial and temporal resolution and long scan times. Our approach of correlating [ 64 Cu]CuCTS uptake with cardiac energetics could provide similarly useful mechanistic information for identification and sub-stratification of disease but without these limitations.…”