High-Energy Phosphate Metabolism and Creatine Kinase in Failing Hearts

Ye, Yun; Gong, Guangrong; Ochiai, Koichi; Liu, Jingbo; Zhang, Jianyi J

doi:10.1161/01.cir.103.11.1570

Cited by 111 publications

(146 citation statements)

References 35 publications

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“…As shown by our lab17, 23 and others,30, 31, 32 aortic‐banded swine develop significant LV hypertrophy. Regarding our hypothesis, changes in cGMP levels and PDE5 activity following treatment with tadalafil or saxagliptin, respectively, did not limit LV hypertrophic remodeling in response to chronic pressure overload from a gross morphological perspective.…”

Section: Discussionsupporting

confidence: 60%

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

Hiemstra

Lee

Chakir

et al. 2016

JAHA

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BackgroundCyclic guanosine monophosphate‐protein kinase G‐phosphodiesterase 5 signaling may be disturbed in heart failure (HF) with preserved ejection fraction, contributing to cardiac remodeling and dysfunction. The purpose of this study was to manipulate cyclic guanosine monophosphate signaling using the dipeptidyl‐peptidase 4 inhibitor saxagliptin and phosphodiesterase 5 inhibitor tadalafil. We hypothesized that preservation of cyclic guanosine monophosphate cGMP signaling would attenuate pathological cardiac remodeling and improve left ventricular (LV) function.Methods and ResultsWe assessed LV hypertrophy and function at the organ and cellular level in aortic‐banded pigs. Concentric hypertrophy was equal in all groups, but LV collagen deposition was increased in only HF animals. Prevention of fibrotic remodeling by saxagliptin and tadalafil was correlated with neuropeptide Y plasma levels. Saxagliptin better preserved integrated LV systolic and diastolic function by maintaining normal LV chamber volumes and contractility (end‐systolic pressure‐volume relationship, preload recruitable SW) while preventing changes to early/late diastolic longitudinal strain rate. Function was similar to the HF group in tadalafil‐treated animals including increased LV contractility, reduced chamber volume, and decreased longitudinal, circumferential, and radial mechanics. Saxagliptin and tadalafil prevented a negative cardiomyocyte shortening‐frequency relationship observed in HF animals. Saxagliptin increased phosphodiesterase 5 activity while tadalafil increased cyclic guanosine monophosphate levels; however, neither drug increased downstream PKG activity. Early mitochondrial dysfunction, evident as decreased calcium‐retention capacity and Complex II‐dependent respiratory control, was present in both HF and tadalafil‐treated animals.ConclusionsBoth saxagliptin and tadalafil prevented increased LV collagen deposition in a manner related to the attenuation of increased plasma neuropeptide Y levels. Saxagliptin appears superior for treating heart failure with preserved ejection fraction, considering its comprehensive effects on integrated LV systolic and diastolic function.

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Section: Discussionsupporting

confidence: 60%

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

Hiemstra

Lee

Chakir

et al. 2016

JAHA

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“…Thus, lower ADP concentration is sufficient to account for most of the 50% reduction in CK f lux in human heart failure. Others have noted a loss of CK activity in failing animal hearts (39) as well as in patients with end-stage heart failure (36). Because a combination of reduced CK V max (36), and altered ADP concentration and other metabolite pool sizes observed here would result in a 64% reduction in predicted CK f lux, it is likely that lower V max also contributes to lower CK f lux in patients with mild-to-moderate heart failure.…”

Section: Fig 2 the Forward Cardiac Ck Flux Is Reduced In Chronic Hementioning

confidence: 53%

“…Because the release of ADP is a rate-limiting step for the actomyosin-ATPase reaction, an increase in concentration of free ADP could reduce the rate of cross-bridge cycling, impair diastolic function, and lower the free energy of ATP hydrolysis (⌬G ϳATP ) (2). Prior studies of heart failure in animal models have not clearly answered this question, with reports showing that ADP concentration is increased (35), unchanged (37)(38)(39)(40) (44), and intracellular pH as 7.05. When our 31 P MRS data (Table 1) are combined with recent 1 H MRS measures showing reduced total Cr in comparable patients with heart failure (16.1 mol͞g of wet weight in CHF vs. 27.6 mol͞g of wet weight in healthy subjects) (13), myocardial free-ADP concentration calculated from the CK equilibrium reaction is 50% lower in failing hearts (Ϸ45 mol͞ liter) than in normal hearts (Ϸ92 mol͞liter, see Appendix).…”

Section: Fig 2 the Forward Cardiac Ck Flux Is Reduced In Chronic Hementioning

confidence: 99%

ATP flux through creatine kinase in the normal, stressed, and failing human heart

Weiss

Gerstenblith

Bottomley

2005

Proc. Natl. Acad. Sci. U.S.A.

300

354

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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 mol͞g 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 and͞or augment energy transfer in heart failure and indicate that cardiac magnetic resonance can be used to assess their effectiveness.heart failure ͉ magnetic resonance spectroscopy ͉ metabolism A TP provides the chemical energy that fuels myocardial contractile function. Relatively large rates of ATP synthesis are required to sustain normal systolic and diastolic function. The ''energy starvation'' hypothesis of heart failure suggests that inadequate ATP supply underlies the contractile dysfunction present in heart failure (1, 2). Large-scale clinical trials demonstrating that pharmacologic agents such as beta-blockers and angiotensin-converting enzyme inhibitors that reduce metabolic demand improve outcomes in heart failure, whereas those such as positive inotropic agents that increase energetic demand worsen outcomes (3) are consistent with the energy-starvation hypothesis. However, the ability to test the energy-starvation hypothesis has been limited, in part, by an inability to directly measure ATP synthesis in the human heart.Creatine kinase (CK) is central to mammalian energy metabolism and serves as the prime energy reserve of the heart. CK reversibly converts ADP and creatine phosphate (PCr) to ATP and creatine (Cr). This reaction allows tight control of ADP and ATP concentrations in cardiac and skeletal muscle as well as in brain, providing a rapid source of ATP during ischemia and burst activity in skeletal muscle (4-6). It is also hypothesized that the CK reaction serves as an intracellular spatial energy shuttle, facilitating the transfer of high-energy phosphates from the mitochondria (where AT...

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“…In the present study, a supravalvular aortic stenosis was applied in juvenile swine to produce an initial pressure gradient of ϳ70 mmHg across the constriction (35). The animals subsequently developed myocardial hypertrophy as the degree of aortic narrowing remained fixed in the face of normal body growth.…”

Section: Discussionmentioning

confidence: 97%

Oxidative capacity in failing hearts

Gong

Liu

Liang

et al. 2003

American Journal of Physiology-Heart and Circulatory Physiology

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Although high-energy phosphate metabolism is abnormal in failing hearts [congestive heart failure (CHF)], it is unclear whether oxidative capacity is impaired. This study used the mitochondrial uncoupling agent 2,4-dinitrophenol (DNP) to determine whether reserve oxidative capacity exists during the high workload produced by catecholamine infusion in hypertrophied and failing hearts. Left ventricular hypertrophy (LVH) was produced by ascending aortic banding in 21 swine; 9 animals developed CHF. Basal myocardial phosphocreatine (PCr)/ATP measured with 31 P NMR spectroscopy was decreased in both LVH and CHF hearts (corresponding to an increase in free [ADP]), whereas ATP was decreased in hearts with CHF. Infusion of dobutamine and dopamine (each 20 g ⅐ kg Ϫ1 ⅐ min Ϫ1 iv) caused an approximate doubling of myocardial oxygen consumption (MV O2) in all groups and decreased PCr/ATP in the normal and LVH groups. During continuing catecholamine infusion, DNP (2-8 mg/kg iv) caused further increases of MV O2 in normal and LVH hearts with no change in PCr/ATP. In contrast, DNP caused no increase in MV O2 in the failing hearts; the associated decrease of PCr/ATP suggests that DNP decreased the mitochondrial proton gradient, thereby causing ADP to increase to maintain adequate ATP synthesis. heart failure; left ventricular hypertrophy; mitochondria; high-energy phosphates; nuclear magnetic resonance IN NORMAL MYOCARDIUM, it is unclear whether peak O 2 utilization is ultimately limited by maximal oxidative ATP synthetic capacity or by the maximal capacities of the myosin and other ATPases to utilize ATP. In failing myocardium, abnormalities of excitation-contraction coupling as well as downregulation of ␤-adrenergic receptors and the downstream adenylyl cyclase system (25) make it even more difficult to determine whether ATP synthetic capacity limits contractile performance. Hence, the hypothesis that primary "energy starvation" limits function in heart failure (14) remains to be rigorously tested in vivo despite evidence that left ventricular (LV) hypertrophy (LVH) and congestive heart failure (CHF) are associated with abnormalities of myocardial energy metabolism (2,21,22,38,39).Consequently, the present study was performed to determine whether administration of a classical mitochondrial uncoupling agent [2,4-dinitrophenol (DNP)] could further increase myocardial oxygen consumption (MV O 2 ) in hearts with compensated LVH or overt cardiac failure that were already functioning at a high work state produced by catecholamine stimulation. DNP accelerates intramitochondrial metabolism proximal to ATP synthase by decreasing the proton gradient across the inner mitochondrial membrane (17,30). In response to DNP, MV O 2 increases in concert with intermediary metabolism and electron transport activity to maintain the mitochondrial proton gradient that drives ATP synthesis (15,17,30). Although it is unlikely that DNP can define the maximal oxygen utilization capacity in the intact heart (8), it can be used to determine whether there ...

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High-Energy Phosphate Metabolism and Creatine Kinase in Failing Hearts

Abstract: In this new model of heart failure/hypertrophy, the abnormal myocardial HEP metabolism is related to the decreased CK-Mt protein level, which in turn is related to the severity of the hypertrophy.

Cited by 111 publications

References 35 publications

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

Saxagliptin and Tadalafil Differentially Alter Cyclic Guanosine Monophosphate (cGMP) Signaling and Left Ventricular Function in Aortic‐Banded Mini‐Swine

ATP flux through creatine kinase in the normal, stressed, and failing human heart

Oxidative capacity in failing hearts

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