Myocardial ATP hydrolysis rates in vivo: a porcine model of pressure overload-induced hypertrophy

Abstract

Myocardial ATP hydrolysis rates in vivo: a porcine model of pressure overload-induced hypertrophy. Am J Physiol Heart Circ Physiol 309: H450 -H458, 2015. First published May 29, 2015 doi:10.1152/ajpheart.00072.2015 hypertrophy (LVH) and congestive heart failure are accompanied by changes in myocardial ATP metabolism. However, the rate of ATP hydrolysis cannot be measured in the in vivo heart with the conventional techniques. Here, we used a double-saturation phosphorous-31 magnetic resonance spectroscopy-magnetization saturation transfer protocol to monitor ATP hydrolysis rate in swine hearts as the hearts became hypertrophic in response to aortic banding (AOB). Animals that underwent AOB (n ϭ 22) were compared with animals that underwent sham surgery (n ϭ 8). AOB induced severe LVH (cardiac MRI). LV function (ejection fraction and systolic thickening fraction) declined significantly, accompanied by deferent levels of pericardial effusion, and wall stress increased in aorta banded animals at week 1 after AOB, suggesting acute heart failure, which recovered by week 8 when concentric LVH restored LV wall stresses. Severe LV dysfunction was accompanied by corresponding declines in myocardial bioenergetics (phosphocreatine-to-ATP ratio) and in the rate of ATP production via creatine kinase at week 1. For the first time, the same linear relationships of the rate increase of the constants of the ATP hydrolysis rate (k ATP¡P i ) vs. the LV rate-pressure product increase during catecholamine stimulation were observed in vivo in both normal and LVH hearts. Collectively, these observations demonstrate that the double-saturation, phosphorous-31 magnetic resonance spectroscopy-magnetization saturation transfer protocol can accurately monitor myocardial ATP hydrolysis rate in the hearts of living animals. The severe reduction of LV chamber function during the acute phase of AOB is accompanied by the decrease of myocardial bioenergetic efficiency, which recovers as the compensated LVH restores the LV wall stresses. left ventricle hypertrophy; adenosine triphosphate; heart failure; MR spectroscopy LEFT VENTRICULAR (LV) HYPERTROPHY (LVH) and congestive heart failure are accompanied by myocardial bioenergetic abnormalities, including a decline in the rate of ATP flux through the creatine kinase (CK) system (8,14,17,22,23). The CK system buffers cellular ATP levels by shuttling high-energy phosphate between phosphocreatine (PCr) and ATP (5), and the forward (PCr¡ ATP) rate of CK-mediated ATP flux can be measured via phosphorus-31 magnetic resonance spectroscopy magnetization-saturation transfer ( 31 P-MRS-MST). However, conventional MRS-MST techniques are unable to determine the rate of myocardial ATP hydrolysis in vivo, because the method requires the quantification of myocardial free inorganic phosphate (P i ) levels, which are low, and because the signal for P i magnetization overlaps with the signal for 2,3-diphosphoglycerate (2,3-DPG) from the erythrocytes in the LV cavity blood (4, 6). For the experiments described in this...

Decreased ATP production and myocardial contractile reserve in metabolic heart disease

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“…Although its chemical shifts depend on blood oxygenation, red blood cell 2,3‐DPG has been reported to be 100% visible in vitro by 31 P NMR. Observation of blood 2,3‐DPG 31 P signals have been reported in the PME and P i region (5–7 ppm) in several cardiac 31 P studies in vivo . In some cases, the 2,3‐DPG signals can be resolved into 2 separate peaks .…”

A porcine model of heart failure with preserved ejection fraction: magnetic resonance imaging and metabolic energetics

“…In addition to the progressive LVPO model, and our previously described sheep model of acute aortic constriction, which induced rapid deterioration to HF/death, others have also employed aortic constriction in pigs. Acute onset aortic constriction beyond the carotid bifurcation resulted in rapid induction of LVH with reduced LVEF and acute HF by Day 7 (including death in 4/22 pigs), which then over 7 weeks evolved into a compensated phase of concentric LVH with restored cardiac function . Thus, there is need to induce LVPO in a progressive nature as implemented in this study to induce progressive LVH without systolic dysfunction.…”

“…Acute onset aortic constriction beyond the carotid bifurcation resulted in rapid induction of LVH with reduced LVEF and acute HF by Day 7 (including death in 4/22 pigs), which then over 7 weeks evolved into a compensated phase of concentric LVH with restored cardiac function. 25 Thus, there is need to induce LVPO in a progressive nature as implemented in this study to induce progressive LVH without systolic dysfunction. Other authors banded ascending aorta of minipigs (25-30 kg) but showed no significant LVH or change in left atrial volume or LVEDP over 20 weeks and did not report of plasma BNP.…”