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

Abstract

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...

Excitation-contraction coupling and mitochondrial energetics

“…Besides defects in EC coupling, the failing heart is energy-starved [99,187,211]. The total cellular levels of PCr, but also NAD and adenine nucleotides, are reduced in patients with heart failure [11,99,188].…”

“…In patients with heart failure, the decreased ratio of PCr/ATP predicts an adverse outcome [143]. As a more dynamic parameter of energy turnover, in vivo ATP flux through creatine kinase was reduced by 50% in patients with mild-to-moderate heart failure [211].…”

“…Decreased SR Ca 2+ -ATPase activity is partly compensated by increased expression and activity of the NCX [16,65,93,146,178,190] The underlying mechanisms for elevated [Na + ] i are incompletely understood, but may involve a decrease in Na + /K + -ATPase activity [58,156,169,172,175,206], enhanced Na + /H + -exchanger (NHE) activity [2,6,40,142], or an increase in a tetrodotoxin-sensitive persistent (late) I Na [58,121,[203][204][205]. During the AP, increased [Na + ] i facilitates repolarization and pronounced cytosolic Ca 2+ -influx via reverse-mode I NCX , which partly compensates the impaired SR Ca 2+ -release and contractility in failing myocytes [3,58,153,210,212] Are defects in EC coupling linked to energy starvation in heart failure?Besides defects in EC coupling, the failing heart is energy-starved [99,187,211]. The total cellular levels of PCr, but also NAD and adenine nucleotides, are reduced in patients with heart failure [11,99,188].…”

Correcting reaction rates measured by saturation-transfer magnetic resonance spectroscopy

“…In the failing heart, for example, abnormalities in CK flux in cardiomyopathies suggest an underlying energy supply defect [2][3][4]. Saturation-transfer MRS is an established method for measuring the CK reaction rate and flux in vivo, by selectively saturating one of the exchanging moieties, γ-ATP, and measuring the response in the reactant moiety, PCr.…”

Skeletal muscle ATP kinetics are impaired in frail mice

“…As evident from the spectra, the peak height for PCr was lower while that for P i higher in IL10 Figure 2a and b show the representative skeletal muscle MT spectra from control and IL10 tm/tm mice respectively at rest. The reduction in PCr signal intensity with γ-ATP saturated (left vs. right spectrum in each panel) is directly proportional to the rate of ATP synthesis through CK (Weiss et al 2005 (Fig. 3).…”