Reduced myocardial creatine kinase flux in human myocardial infarction: an in vivo phosphorus magnetic resonance spectroscopy study

Abstract

Background: Energy metabolism is essential for myocellular viability. The high-energy phosphates adenosine triphosphate (ATP) and phosphocreatine (PCr) are reduced in human myocardial infarction (MI), reflecting myocyte loss and/or decreased intracellular ATP generation by creatine kinase (CK), the prime energy reserve of the heart. The pseudo-first-order CK rate constant, k, measures intracellular CK reaction kinetics and is independent of myocyte number within sampled tissue. CK flux is defined as the product of [PCr] and k. CK flux and k have never been measured in human MI.

Methods and results: Myocardial CK metabolite concentrations, k, and CK flux were measured noninvasively in 15 patients 7 weeks to 16 years after anterior MI using phosphorus magnetic resonance spectroscopy. In patients, mean myocardial [ATP] and [PCr] were 39% to 44% lower than in 15 control subjects (PCr=5.4+/-1.2 versus 9.6+/-1.1 micromol/g wet weight in MI versus control subjects, respectively, P<0.001; ATP=3.4+/-1.1 versus 5.5+/-1.3 micromol/g wet weight, P<0.001). The myocardial CK rate constant, k, was normal in MI subjects (0.31+/-0.08 s(-1)) compared with control subjects (0.33+/-0.07 s(-1)), as was PCr/ATP (1.74+/-0.27 in MI versus 1.87+/-0.45). However, CK flux was halved in MI [to 1.7+/-0.5 versus 3.3+/-0.8 micromol(g . s)(-1); P<0.001].

Conclusions: These first observations of CK kinetics in prior human MI demonstrate that CK ATP supply is significantly reduced as a result of substrate depletion, likely attributable to myocyte loss. That k and PCr/ATP are unchanged in MI is consistent with the preservation of intracellular CK metabolism in surviving myocytes. Importantly, the results support therapies that primarily ameliorate the effects of tissue and substrate loss after MI and those that reduce energy demand rather than those that increase energy transfer or workload in surviving tissue.

Conflict of interest statement

Conflict of Interest Disclosures: Other than salary support from the above grants, the authors have no relevant financial conflicts of interest.

Figures

Figure 1

Typical MRI and localized 31P saturation transfer MRS results from a healthy control subject (M, 37 yrs; a, b), and a patient (M, 31 yrs) with a 12-year old anterior-apical MI of mass 38g, representing 31% of the LV (c-e). (a) Scout axial 1H MRI used for positioning MRS detector, annotated with the location of the section from which spectra are acquired in (b). (b) 31P spectra from FAST data sets each acquired in 6.4 min with 60° pulses and control irradiation (left), and with γ-phosphate of ATP saturated (right). Block arrows denote the irradiation frequency. The complete MRS experiment yielded k =0.38 s-1, [PCr] =10.4 μmol/g wet wt, and 3.9 μmol(g.s)-1 for the forward CK flux. (c) These patient spectra are from 2 adjacent 1 cm slices, indicated in the scout images (d). The reduction in PCr height with γ-ATP saturated is comparable to the control, also yielding k =0.38 s-1, but a reduced [PCr] (6.9 μmol/g) and CK flux (2.6 μmol(g.s)-1). (e) Four short-axis, 8-mm thick LGE images from mid-LV (left) moving down to the apex (right) at 1.6 cm intervals. Images are oriented anterior down, with the infarct showing bright (white arrows).

Figure 2

The average myocardial PCr/ATP ratio, [PCr], k, and CK flux (left to right) measured by 31P MRS in the anterior myocardium of MI patients (filled triangles) and controls (open circles). Crosses denote mean values with error bars (±1 SD; *P <0.001 and P <0.001 for [PCr] and CK flux, respectively, in MI vs controls).

Figure 3

The mean fraction of hyper-enhancing tissue or infarct transmurality, as % of antero-septal LV wall (black bar, left axis) in the apical antero-septal region sampled by 31P MRS, and the antero-septal LV [PCr] and [ATP] reductions, as % of mean values in healthy subjects (right axis; lines designate one SD). The reduction in cardiac high-energy phosphates does not exceed the estimate of infarct content in the antero-septal region, suggesting that the metabolite loss is primarily due to tissue loss and infarction (*P =0.04 for [PCr] and P =0.06 for [ATP] vs. infarct transmurality).

Figure 4

The correlation between LV EF and anterior myocardial [PCr] (r =0.57, P =0.03). The line-of-best-fit to the data is computed using the method-of-least-squares.

Figure 5

(a) Comparison of FAST CK reaction rates, k, and (b) forward CK flux measured by FAST 31P MRS from current (hatched bars), and prior studies of normal subjects during a 200% dobutamine-induced increase in cardiac work load (“stress”), LVH without and with CHF, and patients with nonischemic DCM and CHF. Statistical comparisons are as published (*P <0.001 vs k =0.32 ±0.07 s-1 and CK flux =3.2±0.8 μmol(g.s)-1, in 16 normal controls at rest; †P <0.001 and #P=0.01 in 14 resting controls with k =0.32 ±0.06 s-1 and CK flux =3.1 ±0.9 μmol(g.s)-1), and from the current study (§P <0.001, Table 1).