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 micromol/g 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 and/or augment energy transfer in heart failure and indicate that cardiac magnetic resonance can be used to assess their effectiveness.

Fig. 1.

MRI/MRS detection of CK energy flux in the human heart. Shown are cardiac MRI and ³¹P spectra from FAST studies of a normal subject acquired at rest (a and b) and during dobutamine stress (c), and of a 37-year-old patient with NYHA class III heart failure at rest (d and e). Horizontal white lines in images denote the source of the spectra in the anterior myocardium. The white box shows the detector coil location. Arrows on the spectra identify the frequency of the saturating irradiation tuned to the γ-ATP resonance (spectra on right) and in a symmetric control location, relative to PCr (spectra on left). With γ-ATP saturated, the PCr resonance decreases (oblique lines) in direct proportion to the forward CK flux because the saturated γ-ATP signal is unable to contribute to the PCr signal by the reverse reaction: the greater the flux the greater the decrease. Dobutamine stress had a dramatic 2-fold effect on cardiac workload (rate-pressure product), but did not dramatically alter CK flux in the heart (b and c). At rest, the flux in the patient is lower (e). In each study, four such ³¹P data sets are acquired with saturation and two different flip angles (20); then a ³¹P and a ¹H data set are acquired without saturation to measure concentrations (10, 11, 22). The spectral scale is chemical shift in ppm.

Fig. 2.

The forward cardiac CK flux is reduced in chronic heart failure (CHF). Forward myocardial CK flux is measured in normal subjects at rest (at left), during dobutamine stress (in the center, filled symbols), and in patients with NYHA class I-IV CHF (at right). Square symbols with vertical error bars denote means ± SD. ^*, P < 0.0005 vs. normal subjects at rest.

Fig. 3.

Cardiac CK flux is significantly decreased in human CHF. (a) Myocardial PCr/ATP. (b) PCr concentration ([PCr]) (μmol/g of wet weight). (c) ATP concentration ([ATP]) (μmol/g of wet weight). (d) CK forward rate constant, k_for (sec^-1). (e) ATP synthesis through CK (μmol/g of wet weight per sec), for normal subjects (gray bars) and patients with heart failure (black bars). Note that the reduction in CK flux with heart failure is disproportionate to the reduction in metabolite levels. ^*, P = 0.03; †, P < 0.0005; §, P < 0.0005.