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Impaired ATP kinetics in failing in vivo mouse heart
Ashish Gupta1, Vadappuram P Chacko, Michael Schär
1Department of Medicine, Division of Cardiology, The Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Insights
Heart failure (HF) may stem from energy starvation. New magnetic resonance spectroscopy in mice shows reduced ATP synthesis rates in HF, similar to human patients, offering a powerful research tool.
Area of Science:
- Cardiovascular Physiology
- Biophysics
- Medical Imaging
Background:
- Heart failure (HF) is linked to reduced ATP synthesis via the creatine kinase (CK) reaction, the heart's main energy reserve.
- Previous studies in HF models lacked noninvasive methods to measure in vivo ATP synthesis rates in mouse hearts.
Purpose of the Study:
- To utilize noninvasive magnetic resonance spectroscopy to measure ATP flux through CK in live mouse hearts.
- To quantify reductions in ATP synthesis in a murine model of HF.
Main Methods:
- Validated the Triple Repetition Time Saturation Transfer (TRiST) magnetic resonance spectroscopy technique in skeletal muscle.
- Measured in vivo CK pseudo-first-order-rate constant (k(F)) and ATP synthesis rates in normal and thoracic aortic constriction (TAC) mouse hearts.
Main Results:
- TRiST yielded results comparable to conventional saturation transfer methods.
- Normal mouse hearts showed an ATP synthesis rate of 3.16±0.47 micromol/g/s.
- TAC reduced k(F) by 31% and ATP synthesis by 51%, mirroring human HF findings.
Conclusions:
- In vivo ATP synthesis rates through CK are similar in mouse and human hearts and are comparably reduced in HF.
- The murine TAC model and TRiST offer a potent noninvasive approach to study altered energetics in HF.
Background:
The hypothesis that the failing heart may be energy-starved is supported in part by observations of reduced rates of adenosine 5'-triphosphate (ATP) synthesis through the creatine kinase (CK) reaction, the primary myocardial energy reservoir, in patients with heart failure (HF). Although murine models have been used to probe HF pathophysiology, it has not been possible to noninvasively measure the rate of ATP synthesis through CK in the in vivo mouse heart. The purpose of this work was to exploit noninvasive spatially localized magnetic resonance spectroscopy techniques to measure ATP flux through CK in in vivo mouse hearts and determine the extent of any reductions in murine HF.
Methods And Results:
The Triple Repetition Time Saturation Transfer (TRiST) magnetic resonance spectroscopy method of measuring ATP kinetics was first validated in skeletal muscle, rendering similar results to conventional saturation transfer magnetic resonance spectroscopy. In normal mouse hearts, the in vivo CK pseudo-first-order-rate constant, k(F), was 0.32±0.03 s(-1) (mean±SD) and the rate of ATP synthesis through CK was 3.16±0.47 micromol/g/s. Thoracic aortic constriction reduced k(F) by 31% (0.23±0.03 s(-1), P<0.0001) and ATP synthesis through CK by 51% (1.54±0.25 micromol/g/s, P<0.0001), values analogous to those in failing human hearts.
Conclusions:
Despite the small size and high murine heart rate, the ATP synthesis rate through CK is similar in vivo in murine and human hearts and comparably reduced in HF. Because murine thoracic aortic constriction shares fundamental energetic similarities with human HF, this model and new magnetic resonance spectroscopy approach promise a powerful means to noninvasively probe altered energetics in HF.
