Altered creatine kinase adenosine triphosphate kinetics in failing hypertrophied human myocardium

Abstract

Background: The progression of pressure-overload left ventricular hypertrophy (LVH) to chronic heart failure (CHF) may involve a relative deficit in energy supply and/or delivery.

Methods and results: We measured myocardial creatine kinase (CK) metabolite concentrations and adenosine triphosphate (ATP) synthesis through CK, the primary energy reserve of the heart, to test the hypothesis that ATP flux through CK is impaired in patients with LVH and CHF. Myocardial ATP levels were normal, but creatine phosphate levels were 35% lower in LVH patients (n = 10) than in normal subjects (n = 14, P < 0.006). Left ventricular mass and CK metabolite levels in LVH were not different from those in patients with LVH and heart failure (LVH+CHF, n = 10); however, the myocardial CK pseudo first-order rate constant was normal in LVH (0.36 +/- 0.04 s(-1) in LVH versus 0.32 +/- 0.06 s(-1) in normal subjects) but halved in LVH+CHF (0.17 +/- 0.06 s(-1), P < 0.001). The net ATP flux through CK was significantly reduced by 30% in LVH (2.2 +/- 0.7 micromol x g(-1) x s(-1), P = 0.011) and by a dramatic 65% in LVH+CHF (1.1 +/- 0.4 micromol x g(-1) x s(-1), P < 0.001) compared with normal subjects (3.1 +/- 0.8 micromol x g(-1) x s(-1)).

Conclusions: These first observations in human LVH demonstrate that it is not the relative or absolute CK metabolite pool sizes but rather the kinetics of ATP turnover through CK that distinguish failing from nonfailing hypertrophic hearts. Moreover, the deficit in ATP kinetics is similar in systolic and nonsystolic heart failure and is not related to the severity of hypertrophy but to the presence of CHF. Because CK temporally buffers ATP, these observations support the hypothesis that a deficit in myofibrillar energy delivery contributes to CHF pathophysiology in human LVH.

Figure 1

Axial spin-echo MR image (A) of a patient with LVH+CHF lying prone over a ³¹P surface coil (white box) and the corresponding localized ³¹P MR spectra from the chest (lower 2 spectra) and left ventricle (upper 2 spectra). The resonances derive from PCr and the γ-, α-, and β -phosphate resonances of ATP. The spectra were acquired with a 60° flip angle in the presence of chemically selective saturating irradiation (arrows) either in the control (B) or γ-ATP position (C). The decrease in the height of the PCr peak between control and γ-ATP saturation (dotted lines) is directly related to the rate of ATP synthesis through the CK reaction.

Figure 2

A, CK myocardial pseudo first-order rate constant (K_for) for healthy subjects (Normal), patients with LVH, and others with LVH with CHF (LVH+CHF). Note that K_for is not reduced by LVH but only in LVH+CHF. B, Net ATP flux through the CK reaction (CK flux) in healthy subjects (Normal), patients with LVH, and others with LVH with CHF (LVH+CHF).

Figure 3

LVH severity, as indexed by left ventricular mass index (LVMI; A and B) and left ventricular ejection fraction (EF; C and D) versus ATP kinetics, as indexed by K_for (above) and CK flux (below) for LVH (▲) and LVH+CHF (○). Neither K_for nor CK flux correlated with the severity of LVH (r² < 0.03 for both in all 20 patients) or with ejection fraction. It is the presence of CHF, not the severity of LVH, that is associated with reduced ATP synthesis through CK. Reduced CK flux occurs in failing hearts with impaired and preserved ejection fractions.