On the theoretical limits of detecting cyclic changes in cardiac high-energy phosphates and creatine kinase reaction kinetics usingin vivo³¹P MRS

Abstract

Adenosine triphosphate (ATP) is absolutely required to fuel normal cyclic contractions of the heart. The creatine kinase (CK) reaction is a major energy reserve that rapidly converts creatine phosphate (PCr) to ATP during the cardiac cycle and times of stress and ischemia, but is significantly impaired in conditions such as hypertrophy and heart failure. Because the magnitude of possible in vivo cyclic changes in cardiac high-energy phosphates (HEPs) during the cardiac cycle are not well known from prior work, this study uses mathematical modeling to assess whether and to what extent, cyclic variations of HEPs and in the rate of ATP synthesis through CK (CK flux) could exist in the human heart, and whether they could be measured with current in vivo phosphorus magnetic resonance spectroscopy (31P MRS) methods. Multi-site exchange models incorporating enzymatic rate equations were used to study cyclic dynamics of the CK reaction, and Bloch equations were used to simulate 31P MRS saturation transfer measurements of the CK reaction. The simulations show that short-term buffering of ATP by CK requires temporal variations over the cardiac cycle in the CK reaction velocities modeled by enzymatic rate equations. The maximum variation in HEPs in the normal human heart beating at 60min−1 was approximately 0.4mM and proportional to the velocity of ATP hydrolysis. Such HEP variations are at or below the current limits of detection by in vivo 31P MRS methods. Bloch equation simulations show that 31P MRS saturation transfer estimates the time-averaged pseudo-first-order forward rate constant, kf,ap’, of the CK reaction and that periodic short-term fluctuations in kf’ and CK flux are not likely to be detectable in human studies employing current in vivo 31P MRS methods.

Increased Titin Compliance Reduced Length-Dependent Contraction and Slowed Cross-Bridge Kinetics in Skinned Myocardial Strips from Rbm20ΔRRM Mice

“…Relaxing solution: pCa 8.0, 5 EGTA, 5 MgATP, 1 Mg 2+ , 0.3 P i , 20 BES, 35 phosphocreatine, 300 U/mL creatine kinase, 200 ionic strength adjusted with Na methanesulfonate, pH 7.0. Adding 0.3 mM P i matches estimates for cardiac muscle (Wu et al, 2008 ; Weiss et al, 2015 ), though others use higher [Pi] (Wang et al, 2014 ). Activating solution: Same as relaxing with pCa 4.8.…”

Cardiac work is related to creatine kinase energy supply in human heart failure: a cardiovascular magnetic resonance spectroscopy study

“…While CK flux might also vary cyclically, there is no evidence of cyclic PCr changes in the normal heart at rest [ 39 ]. Arguably, physiological changes in k f could not meaningfully register in time-frames much shorter than about 1/ k f ≈ 3 s anyway, and analyses of the temporal dynamics of the CK reaction and the 31 P MRS experiment predict that cyclic variations in k f would be too small to detect over physiological parameter ranges [ 40 ]. Moreover, CK flux does not change in healthy subjects when cardiac work-load is doubled [ 8 ].…”

Understanding the physiology of the ageing individual: computational modelling of changes in metabolism and endurance

“…Cyclic ATP synthesis, O 2 consumption, electron flow, and reduction and oxidation of electron carriers, for instance during cyclic contraction in heart and skeletal muscle might stimulate oxygen radical formation [5]. When activities of the buffering enzyme creatine kinase are lower during heart failure, there is an increased amplitude of oscillation and a lower minimal concentration of ADP during heart muscle contraction [5,91] which may induce higher oxygen radical formation that in turn may cause heart failure. We propose that investigation of oxygen radical formation in mitochondrial systems in vitro in combination with modelling at the molecular level may make it possible to understand the regulation of oxygen radical formation better.…”

“…Exchange of metabolites between blood and tissue can be determined by measuring the concentrations in arterial and venous blood and multiplying their difference with the local blood flow [69]. NMR spectroscopy makes it possible to measure metabolites and metabolic fluxes in tissue non-invasively, although with limited sensitivity [90,91]. Providing the body with nutrients that have been labelled with stable isotopes makes it possible to follow metabolism by taking samples from blood, gut content [88], tissue samples [92][93][94][95] or measuring metabolic fluxes non-invasively by positron emission tomography or NMR spectroscopy [96].…”