Myocardial creatine kinase exchange rates and <sup>31</sup>P NMR relaxation rates in intact pigs

Martin, Joel F; Guth, Brian D.; Griffey, Richard H.; Hoekenga, David E.

doi:10.1002/mrm.1910110106

Cited by 34 publications

(17 citation statements)

References 19 publications

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“…Whereas mean myocardial CK flux is slightly higher at 3.3 Ϯ 1.2 vs. 2.8 Ϯ 0.7 mol͞g per sec (P ϭ 0.22), this increase is not statistically significant and is not proportionate to the doubled rate-pressure product. The finding that CK flux does not significantly increase with cardiac workload over a physiologic range in humans is different from that seen in isolated rat hearts (25) but similar to prior studies performed in vivo in sheep, pigs, and dogs (18,19,26,27).…”

Section: Resultssupporting

confidence: 65%

ATP flux through creatine kinase in the normal, stressed, and failing human heart

Weiss

Gerstenblith

Bottomley

2005

Proc. Natl. Acad. Sci. U.S.A.

300

348

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The heart consumes more energy per gram than any other organ, and the creatine kinase (CK) reaction serves as its prime energy reserve. Because chemical energy is required to fuel systolic and diastolic function, the question of whether the failing heart is ''energy starved'' has been debated for decades. Despite the central role of the CK reaction in cardiac energy metabolism, direct measures of CK flux in the beating human heart were not previously possible. Using an image-guided molecular assessment of endogenous ATP turnover, we directly measured ATP flux through CK in normal, stressed, and failing human hearts. We show that cardiac CK flux in healthy humans is faster than that estimated through oxidative phosphorylation and that CK flux does not increase during a doubling of the heart rate-blood pressure product by dobutamine. Furthermore, cardiac ATP flux through CK is reduced by 50% in mild-to-moderate human heart failure (1.6 ؎ 0.6 vs. 3.2 ؎ 0.9 mol͞g of wet weight per sec, P < 0.0005). We conclude that magnetic resonance strategies can now directly assess human myocardial CK energy flux. The deficit in ATP supplied by CK in the failing heart is cardiac-specific and potentially of sufficient magnitude, even in the absence of a significant reduction in ATP stores, to contribute to the pathophysiology of human heart failure. These findings support the pursuit of new therapies that reduce energy demand and͞or augment energy transfer in heart failure and indicate that cardiac magnetic resonance can be used to assess their effectiveness.heart failure ͉ magnetic resonance spectroscopy ͉ metabolism A TP provides the chemical energy that fuels myocardial contractile function. Relatively large rates of ATP synthesis are required to sustain normal systolic and diastolic function. The ''energy starvation'' hypothesis of heart failure suggests that inadequate ATP supply underlies the contractile dysfunction present in heart failure (1, 2). Large-scale clinical trials demonstrating that pharmacologic agents such as beta-blockers and angiotensin-converting enzyme inhibitors that reduce metabolic demand improve outcomes in heart failure, whereas those such as positive inotropic agents that increase energetic demand worsen outcomes (3) are consistent with the energy-starvation hypothesis. However, the ability to test the energy-starvation hypothesis has been limited, in part, by an inability to directly measure ATP synthesis in the human heart.Creatine kinase (CK) is central to mammalian energy metabolism and serves as the prime energy reserve of the heart. CK reversibly converts ADP and creatine phosphate (PCr) to ATP and creatine (Cr). This reaction allows tight control of ADP and ATP concentrations in cardiac and skeletal muscle as well as in brain, providing a rapid source of ATP during ischemia and burst activity in skeletal muscle (4-6). It is also hypothesized that the CK reaction serves as an intracellular spatial energy shuttle, facilitating the transfer of high-energy phosphates from the mitochondria (where AT...

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Section: Resultssupporting

confidence: 65%

ATP flux through creatine kinase in the normal, stressed, and failing human heart

Weiss

Gerstenblith

Bottomley

2005

Proc. Natl. Acad. Sci. U.S.A.

300

348

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“…The effect o f N E , presented in this report, is a decrease in PCr, which is in contrast to earlier work [30,31], Some o f the earlier data which was done on pigs can be consid ered to be preliminary in that the number of experiments and the physiological controls were not optimal [30], The work o f Katz et al [31] is on dogs and is carefully done. However, the protocols are somewhat differ ent.…”

Section: Discussioncontrasting

confidence: 53%

“…K f and flux varied with work load [28], In other studies o f the perfused rat heart [29], the flux through the C K reaction was found to be proportional to M V CK In the intact pig. on the other hand [30], an essentially con stant K f was found for the C K reaction un der a wide (2.5-fold change) variation of H R X SBP induced with N E. Furthermore, since no change in the levels o f PCr was found, the flux o f PCr A T P was constant as well. This result was confirmed using ca nine hearts in vivo [31].…”

Section: Discussionmentioning

confidence: 71%

In vivo Mechanisms of Myocardial Functional Stability during Physiological Interventions

Osbakken

Blum²,

Wang³

et al. 1991

Cardiology

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Metabolic regulatory mechanisms are designed to maintain stable myocardial function during extremes in physiological insult; they can now be studied in vivo and may provide insight into mechanisms of altered myocardial functional decompensation during disease processes. To determine mechanisms of myocardial stability during hypoxia and acute pressure loading, creatine kinase (CK) kinetics (forward rate constant, K_f, and flux of phosphocreatine, PCr, to adenosine triphosphate, ATP), and nicotinamide adenine dinucleotide (NADH) redox state were determined with ³¹P nuclear magnetic resonance (NMR) and NADH fluorometry, respectively, and correlated with heart work (heart rate × systolic blood pressure, HR × SBP), cardiac output (CO) and O₂ consumption (MVO₂) in 15 anesthetized open chest dogs. Hypoxia (Pa_o2 of 30-35 mm Hg) was produced in 6 dogs with an inspired O₂/N₂ of 200/3,000. Cardiac loading was produced in 9 dogs by administration of norepinephrine (NE, 1 µg/kg/min). Each dog acted as its own control. Baseline NADH fluorometry, ³¹P-NMR saturation transfer and cardiac function measurements were performed simultaneously in each dog, after which the experimental interventions were made. Similar increases in HR × SBP, CO, and MVO2 which occurred during both interventions were associated with different bioenergetic responses. During NE infusion, the K_f of CK increased from control; during hypoxia, the K_f decreased from control (p < 0.05). Flux of PCr → ATP was significantly lower during hypoxia than during NE infusion (p < 0.05). PCr was decreased significantly during NE infusion (p < 0.05). In addition, NADH redox state increased (from baseline of 100%) during hypoxia (140 ± 10%) and decreased during NE infusion (78 ± 6%). These data indicate that the myocardial response to demand is not universally regulated by adenosine diphosphate (ADP) or redox state. In addition, metabolic regulators can induce changes related to the type of intervention irrespective of similarity of workload.

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“…The surprising finding of similar T 1's for CP and ATP resonances under our experimental conditions cannot be easily explained. It must, however, be mentioned, that none of the previous animal work (3)(4)(5)(6)(7)(8)(9)(10) 2.8, 3.3, and 3.6 s. In contrast, rabbit skeletal muscle examined at 4.7 T showed Tl's for CP and [y-PIATP of 1.9 and 0.7 s, respectively ( 2 4 ) . Thus, although Tl's for both CP and ATP are increased as field strength is decreased, it appears that the field dependence of T 1 ATP is more pronounced than that for T lCp.…”

Section: Discussionmentioning

confidence: 72%

“…Although spin-lattice relaxation times (T 1 's) of phosphorus metabolites visible in 31P-MR spectra are well defined for animal and human skeletal muscle ( 1 , 2), and TI'S for cardiac muscle have been determined in various animal studies (3)(4)(5)(6)(7)(8)(9)(10), T1 values of phosphorus metabolites in human myocardium have not been reported. This may be due to the fact that human 31P-MR spectra necessitate long acquisition times, and measurement of TI'S requires acquisition of a number of consecutive spectra.…”

Section: Introductionmentioning

confidence: 98%

Direct measurement of spin‐lattice relaxation times of Phosphorus Metabolites in Human Myocardium

Neubauer

Krahe

Schindler

et al. 1992

Magnetic Resonance in Med

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T1 values of phosphorus metabolites visible in human cardiac 31P-MR spectra were determined in 12 volunteers at 1.5 T. Consecutive spectra were acquired with varying pulse repetition time (TR) from 1.6 to 24 s; volume selection was achieved with ISIS. T1's of creatine phosphate (CP), [gamma-P], [alpha-P], and [beta-P]ATP, 2-3 diphosphoglycerate, and phosphodiesters were 6.1 +/- 0.5, 5.4 +/- 0.5, 5.5 +/- 0.5, 5.8 +/- 1.0, 7.6 +/- 1.0, and 5.0 +/- 1.0 s, respectively. CP/ATP ratios showed little change with varying TR; linear regression of CP/ATP vs TR was of borderline significance (r = 0.28, P = 0.06). T1's for CP and ATP were also determined in standard solution (20 mM CP, 10 mM ATP) yielding T1CP of 8.7 +/- 0.2 and T1[gamma-P]-ATP of 9.9 +/- 0.7 s. Thus, T1's for CP and ATP were similar at 1.5 T in both human heart and standard solution. In human cardiac 31P-MR spectra, CP/ATP ratios may need little correction for partial saturation.

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Myocardial creatine kinase exchange rates and ³¹P NMR relaxation rates in intact pigs

Cited by 34 publications

References 19 publications

ATP flux through creatine kinase in the normal, stressed, and failing human heart

ATP flux through creatine kinase in the normal, stressed, and failing human heart

In vivo Mechanisms of Myocardial Functional Stability during Physiological Interventions

Direct measurement of spin‐lattice relaxation times of Phosphorus Metabolites in Human Myocardium

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Myocardial creatine kinase exchange rates and 31P NMR relaxation rates in intact pigs

Cited by 34 publications

References 19 publications

ATP flux through creatine kinase in the normal, stressed, and failing human heart

ATP flux through creatine kinase in the normal, stressed, and failing human heart

In vivo Mechanisms of Myocardial Functional Stability during Physiological Interventions

Direct measurement of spin‐lattice relaxation times of Phosphorus Metabolites in Human Myocardium

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Myocardial creatine kinase exchange rates and ³¹P NMR relaxation rates in intact pigs