Chronic Phosphocreatine Depletion by the Creatine Analogue β-Guanidinopropionate Is Associated With Increased Mortality and Loss of ATP in Rats After Myocardial Infarction

Horn, Michael; Remkes, Helga; Strömer, Hinrik; Dienesch, Charlotte; Neubauer, Stefan

doi:10.1161/hc3901.095933

Cited by 48 publications

(43 citation statements)

References 40 publications

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“…In the present study, the contractile benefits of CK-M overexpression were observed only in failing heartsboth acutely in response to adrenergic stimulation ( Figure 7 and Supplemental Figure 4) and chronically in terms of functional ( Figure 5C and Figure 6B) and survival improvements ( Figure 5E). Such observations are consistent with prior studies in which longerterm CK inhibition (>40 minutes) impaired in vivo function in normal porcine hearts (42) or resulted in 100% mortality following myocardial infarction in rats (43). Thus, the role of CK is magnified over time and in the failing heart.…”

Section: Figuresupporting

confidence: 91%

Creatine kinase–mediated improvement of function in failing mouse hearts provides causal evidence the failing heart is energy starved

Gupta¹,

Akki²,

Wang³

et al. 2012

J. Clin. Invest.

126

115

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ATP is required for normal cardiac contractile function, and it has long been hypothesized that reduced energy delivery contributes to the contractile dysfunction of heart failure (HF). Despite experimental and clinical HF data showing reduced metabolism through cardiac creatine kinase (CK), the major myocardial energy reserve and temporal ATP buffer, a causal relationship between reduced ATP-CK metabolism and contractile dysfunction in HF has never been demonstrated. Here, we generated mice conditionally overexpressing the myofibrillar isoform of CK (CK-M) to test the hypothesis that augmenting impaired CK-related energy metabolism improves contractile function in HF. CK-M overexpression significantly increased ATP flux through CK ex vivo and in vivo but did not alter contractile function in normal mice. It also led to significantly increased contractile function at baseline and during adrenergic stimulation and increased survival after thoracic aortic constriction (TAC) surgery-induced HF. Withdrawal of CK-M overexpression after TAC resulted in a significant decline in contractile function as compared with animals in which CK-M overexpression was maintained. These observations provide direct evidence that the failing heart is "energy starved" as it relates to CK. In addition, these data identify CK as a promising therapeutic target for preventing and treating HF and possibly diseases involving energy-dependent dysfunction in other organs with temporally varying energy demands.

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Section: Figuresupporting

confidence: 91%

Creatine kinase–mediated improvement of function in failing mouse hearts provides causal evidence the failing heart is energy starved

Gupta¹,

Akki²,

Wang³

et al. 2012

J. Clin. Invest.

126

115

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“…Inhibitors of CK significantly increase mortality after experimental infarction (16). The reduction in cardiac PCr-to-ATP ratio (PCr/ATP) in experimental postinfarction remodeling is similar to that observed in human heart failure, which, in turn, correlates with clinical severity and predicts overall and cardiovascular mortality (4,10,15,31,34,49).…”

mentioning

confidence: 64%

“…Infarcted, nonviable myocardium lacks PCr and ATP (45,48). In prior 31 P MRS studies (16,18,19,32,33,37) of infarcted rodent hearts, the detected PCr and ATP signals were attributed to the surviving viable regions, even when the entire infarcted region was contained within the region studied by MRS. Based on this accepted practice and our efforts through animal positioning and slice selection to minimize infarcted tissue within the volume of interest, the cardiac PCr/ATP values reported here derive almost entirely from surviving, viable myocardium. Data were compared by ANOVA with STATISTICA software (StatSoft, Tulsa, OK).…”

Section: In Micementioning

confidence: 95%

“…Animal models of heart failure and patients with heart failure typically exhibit abnormalities in the CK reactants with modest reductions in [ATP], larger reductions in [PCr] and total creatine, and significant reductions in the cardiac PCr/ATP (4,10,15,16,29,34). Abnormalities, such as a reduced PCr/ATP, correlate with the severity of the heart failure, improve with clinical recovery, and are stronger predictors of mortality than usual clinical indexes of LV EF and the New York Heart Association class (31).…”

Section: Fig 1 Typical Transverse Short-axis 1 H Magnetic Resonancementioning

confidence: 99%

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Xanthine oxidase inhibitors improve energetics and function after infarction in failing mouse hearts

Naumova¹,

Chacko²,

Ouwerkerk³

et al. 2006

American Journal of Physiology-Heart and Circulatory Physiology

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After myocardial infarction, ventricular geometry and function, as well as energy metabolism, change markedly. In nonischemic heart failure, inhibition of xanthine oxidase (XO) improves mechanoenergetic coupling by improving contractile performance relative to a reduced energetic demand. However, the metabolic and contractile effects of XO inhibitors (XOIs) have not been characterized in failing hearts after infarction. After undergoing permanent coronary ligation, mice received a XOI (allopurinol or oxypurinol) or matching placebo in the daily drinking water. Four weeks later, 1 H MRI and 31 P magnetic resonance spectroscopy (MRS) were used to quantify in vivo functional and metabolic changes in postinfarction remodeled mouse myocardium and the effects of XOIs on that process. End-systolic (ESV) and end-diastolic volumes (EDV) were increased by more than sixfold after infarction, left ventricle (LV) mass doubled (P Ͻ 0.005), and the LV ejection fraction (EF) decreased (14 Ϯ 9%) compared with control hearts (59 Ϯ 8%, P Ͻ 0.005) at 1 mo. The myocardial phosphocreatine (PCr)-to-ATP ratio (PCr/ATP) was also significantly decreased in infarct remodeled hearts (1.4 Ϯ 0.6) compared with control animals (2.1 Ϯ 0.5, P Ͻ 0.02), in agreement with prior studies in larger animals. The XOIs allopurinol and oxypurinol did not change LV mass but limited the increase in ESV and EDV of infarct hearts by 50%, increased EF (23 Ϯ 9%, P ϭ 0.01), and normalized cardiac PCr/ATP (2.0 Ϯ 0.5, P Ͻ 0.04). We conclude that XOIs improve ventricular function after infarction and normalize high-energy phosphate ratio in heart failure. Thus XOI therapy offers a new and potentially complementary approach to limit the adverse contractile and metabolic consequences after infarction. postinfarction remodeled myocardium; cardiac metabolism; magnetic resonance spectroscopy; allopurinol VENTRICULAR REMODELING occurs after myocardial infarction (MI) in many species, including humans, and is typically characterized by progressive ventricular dilatation, eccentric hypertrophy, and contractile dysfunction (27,36,38). Patients with post-MI remodeling experience increased rates of heart failure and cardiovascular mortality, whereas interventions that reduce geometric ventricular remodeling improve outcomes (27,40,41,44). In addition to the geometric and contractile abnormalities associated with post-MI remodeling, adverse changes in energy metabolism also occur (15,29,32). Abnormalities in energy metabolism after MI include reductions in ATP, phosphocreatine (PCr), and in the activity of the creatine kinase (CK) reaction, the primary energy reserve reaction of the heart (20, 21, 29, 31). Inhibitors of CK significantly increase mortality after experimental infarction (16). The reduction in cardiac PCr-to-ATP ratio (PCr/ATP) in experimental postinfarction remodeling is similar to that observed in human heart failure, which, in turn, correlates with clinical severity and predicts overall and cardiovascular mortality (4,10,15, 31,34,49). Taken together, the ene...

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“…80 Another is the example shown studying myocardial infarction in the rat. 81 Myocardial [PCr] and CK reaction velocity were decreased by Ϸ90% and [ATP] by 18% (a profile similar to the heart failure phenotype) in rats fed with the creatine analog ␤-guanidinoproprionic acid, a competitive inhibitor of creatine transport and the CK reaction. Unlike control rat hearts that survived acute myocardial infarction, the 24-hour mortality of rats with severely compromised CK-PCr system was 100%.…”

Section: Increased Susceptibility Of the Hypertrophied And Failing Hementioning

confidence: 99%

Is the Failing Heart Energy Starved?

Ingwall

Weiss

2004

Circulation Research

553

281

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Abstract-The requirement of chemical energy in the form of ATP to support systolic and diastolic work of the heart is absolute. Because of its central role in cardiac metabolism and performance, the subject of this review on energetics in the failing heart is ATP. We briefly review the basics of myocardial ATP metabolism and describe how this changes in the failing heart. We present an analysis of what is now known about the causes and consequences of these energetic changes and conclude by commenting on unsolved problems and opportunities for future basic and clinical research. Key Words: adenosine triphosphate Ⅲ phosphocreatine Ⅲ creatine kinase Ⅲ familial hypertrophic cardiomyopathy Ⅲ heart failure T he energy starvation hypothesis suggesting that the failing heart is energy-starved is decades old. 1,2 Because ATP is required for normal systolic and diastolic contractile performance, the idea that the failing heart is unable to meet the hemodynamic requirements of the body because there is not enough chemical energy available is logical. The hypothesis was initially set aside for several reasons. First, it was unclear whether the concentration of ATP ([ATP]) decreased. Second, it was reasoned that even if there were decreases in [ATP] in the failing heart, the remaining ATP should be sufficient to supply the ATP-requiring reactions in the myocyte. Third, our understanding of how ATP synthesis and use are regulated was remarkably incomplete. A good example of our ignorance about cardiac energetics was the use of inotropic agents to increase performance of the failing human heart. While increasing performance, these agents did so at great energetic cost and often resulted in increased, rather than decreased, heart failure mortality.There is now renewed interest in the energy-starvation hypothesis. 3,4 New biophysical tools such as nuclear magnetic resonance (NMR) spectroscopy, positron emission tomography (PET), and transgenesis using the mouse have allowed old questions to be revisited and new ones to be formulated. Combining old and new strategies to address the "energy starvation" hypothesis, we have learned much. We now know when and by how much [ATP] decreases in the hypertrophied and failing heart. We now know that despite increases in some ATP synthesizing pathways such as glycolysis, other pathways such as the creatine kinase (CK)-phosphocreatine (PCr) system decrease. Finally, we now have a better understanding of how the myocyte accomplishes the tasks of maintaining (near) normal ATP supply Original

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Chronic Phosphocreatine Depletion by the Creatine Analogue β-Guanidinopropionate Is Associated With Increased Mortality and Loss of ATP in Rats After Myocardial Infarction

Cited by 48 publications

References 40 publications

Creatine kinase–mediated improvement of function in failing mouse hearts provides causal evidence the failing heart is energy starved

Creatine kinase–mediated improvement of function in failing mouse hearts provides causal evidence the failing heart is energy starved

Xanthine oxidase inhibitors improve energetics and function after infarction in failing mouse hearts

Is the Failing Heart Energy Starved?

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