Detection of low phosphocreatine to ATP ratio in failing hypertrophied human myocardium by 31P magnetic resonance spectroscopy

Conway, Michael; Allis, Jonathan L.; Ouwerkerk, Ronald; Niioka, Takeharu; Rajagopalan, B.; Radda, George K.

doi:10.1016/0140-6736(91)91838-l

Cited by 296 publications

(150 citation statements)

References 9 publications

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“…Interestingly, a reduced ATP level has already been positively associated with the severity of human heart failure [42] and a decreased ATP pool was also observed in heart tissue obtained from patients with a dilated and restricted cardiomyopathy [43]. A reduced single mitochondrion ATP flux may limit sarcomere contraction, leading to a compensatory proliferation of the cardiac mitochondria, while the myocardium may continue to contract inefficiently and dyssynchronously due to its adaptation, as previously anticipated [5,44].…”

Section: Discussionmentioning

confidence: 71%

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

Toczek

Zielonka

Zukowska

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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Huntington's disease (HD) is mainly thought of as a neurological disease, but multiple epidemiological studies have demonstrated a number of cardiovascular events leading to heart failure in HD patients. Our recent studies showed an increased risk of heart contractile dysfunction and dilated cardiomyopathy in HD pre-clinical models. This could potentially involve metabolic remodeling, that is a typical feature of the failing heart, with reduced activities of high energy phosphate generating pathways. In this study, we sought to identify metabolic abnormalities leading to HD-related cardiomyopathy in pre-clinical and clinical settings. We found that HD mouse models developed a profound deterioration in cardiac energy equilibrium, despite AMP-activated protein kinase hyperphosphorylation. This was accompanied by a reduced glucose usage and a significant deregulation of genes involved in de novo purine biosynthesis, in conversion of adenine nucleotides, and in adenosine metabolism. Consequently, we observed increased levels of nucleotide catabolites such as inosine, hypoxanthine, xanthine and uric acid, in murine and human HD serum. These effects may be caused locally by mutant HTT, via gain or loss of function effects, or distally by a lack of trophic signals from central nerve stimulation. Either may lead to energy equilibrium imbalances in cardiac cells, with activation of nucleotide catabolism plus an inhibition of resynthesis. Our study suggests that future therapies should target cardiac mitochondrial dysfunction to ameliorate energetic dysfunction. Importantly, we describe the first set of biomarkers related to heart and skeletal muscle dysfunction in both pre-clinical and clinical HD settings.Keywords: Huntington's disease, cardiomyopathy, arrhythmia, energy imbalance, catabolism of nucleotides, heart failure 3 SUMMARY Huntington's disease (HD) is a fatal neurodegenerative disorder caused by a polyglutamine expansion in the huntingtin protein. HD-related cardiomyopathy has been widely described in different mouse models, however there is little known about the source of the pathological remodelling in HD hearts. We found that contractile dysfunction in HD settings might be caused by components of cellular energy imbalance, changes in catabolism of adenine nucleotides, steady-state internal redox derangements and an activation of AMPK, leading to a shift in the cardiac substrate preference. These changes were accompanied by increased concentrations of adenine nucleotide catabolites (inosine, hypoxanthine, xanthine and uric acid) and uridine in both HD mouse models and HD patients' plasma. These metabolites represent the first identified biomarkers related to striated muscle dysfunction in HD. Our study explores a mechanism that might lead to HD-related cardiomyopathy and opens new avenues for therapeutic treatments in HD. HIGHLIGHTS• Heart dysfunction in HD is caused by the altered metabolism of nucleotides in vivo • Altered energy imbalances may lead to heart malfunction in HD in vivo• Increased lev...

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Section: Discussionmentioning

confidence: 71%

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

Toczek

Zielonka

Zukowska

et al. 2016

Biochimica et Biophysica Acta (BBA) - Molecular Basis of Diseas

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“…Myocardial energy deficits precede the development of heart failure Although studies providing evidence of energy deficit in heart failure abound, 23,[46][47][48][49] whether alterations in substrate metabolism and energy deficit are a cause or consequence of heart failure has not been clearly delineated. In a model of aortic arch constriction, Doenst et al 60 investigated cardiac function and fatty acid and glucose metabolism during the development of hypertrophy and heart failure.…”

Section: Cardiac Metabolism In Left Heart Failurementioning

confidence: 99%

“…46 A number of studies have shown decreased phosphocreatine and ATP levels in failing myocardium of both animals and humans. 23,[47][48][49] Myocardial ATP content can decrease by 30%-40% in the failing heart relative to the normal heart. It has been proposed that the failing heart switches from primarily using fatty acids as energy substrates to primarily using glucose for energy production.…”

Section: Cardiac Metabolism In Left Heart Failurementioning

confidence: 99%

Cardiac Energy Metabolic Alterations in Pressure Overload–Induced Left and Right Heart Failure (2013 Grover Conference Series)

Sankaralingam

Lopaschuk

2015

Pulm. circ.

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Pressure overload of the heart, such as seen with pulmonary hypertension and/or systemic hypertension, can result in cardiac hypertrophy and the eventual development of heart failure. The development of hypertrophy and heart failure is accompanied by numerous molecular changes in the heart, including alterations in cardiac energy metabolism. Under normal conditions, the high energy (adenosine triphosphate [ATP]) demands of the heart are primarily provided by the mitochondrial oxidation of fatty acids, carbohydrates (glucose and lactate), and ketones. In contrast, the hypertrophied failing heart is energy deficient because of its inability to produce adequate amounts of ATP. This can be attributed to a reduction in mitochondrial oxidative metabolism, with the heart becoming more reliant on glycolysis as a source of ATP production. If glycolysis is uncoupled from glucose oxidation, a decrease in cardiac efficiency can occur, which can contribute to the severity of heart failure due to pressure-overload hypertrophy. These metabolic changes are accompanied by alterations in the enzymes that are involved in the regulation of fatty acid and carbohydrate metabolism. It is now becoming clear that optimizing both energy production and the source of energy production are potential targets for pharmacological intervention aimed at improving cardiac function in the hypertrophied failing heart. In this review, we will focus on what alterations in energy metabolism occur in pressure overload induced left and right heart failure. We will also discuss potential targets and pharmacological approaches that can be used to treat heart failure occurring secondary to pulmonary hypertension and/or systemic hypertension.

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“…This technique facilitates in vivo exploration of intracellular metabolism. A low phosphocreatine-to-ATP ratio (PCr/ ATP), indicating a cardiac energy deficit, has been shown in the failing human heart (Beer et al 2002;Conway et al 1991;Hardy et al 1991;Neubauer et al 1997;Neubauer et al 1992). This ratio is correlated with clinical symptoms (Conway et al 1998) and predicts mortality better than the left ventricular ejection fraction (Neubauer et al 1997).…”

Section: Introductionmentioning

confidence: 99%

Mitochondria in the human heart

Lemieux

Hoppel

2009

J Bioenerg Biomembr

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The heart relies mainly on mitochondrial metabolism to provide the energy needed for pumping blood to oxygenate the organs of the body. The study of mitochondrial function in the human heart faces many obstacles and elucidation of the role of mitochondria in cardiac diseases has relied mainly on studies with animal models. Cardiac diseases are the leading cause of mortality worldwide. With the emergence of new therapies to treat and prevent heart disease, some aiming at metabolic modulation, a need for acquiring a better understanding of mitochondrial function in the human heart becomes apparent. Our review is aimed at specific evaluation of the human heart in terms of (1) methods to understand mitochondrial function, with particular emphasis on integrated function, (2) data on the role of mitochondrial dysfunction in cardiovascular disease, and (3) possible applications of this knowledge in the treatment of patients with cardiac disease.

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Detection of low phosphocreatine to ATP ratio in failing hypertrophied human myocardium by 31P magnetic resonance spectroscopy

Cited by 296 publications

References 9 publications

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

An impaired metabolism of nucleotides underpins a novel mechanism of cardiac remodeling leading to Huntington's disease related cardiomyopathy

Cardiac Energy Metabolic Alterations in Pressure Overload–Induced Left and Right Heart Failure (2013 Grover Conference Series)

Mitochondria in the human heart

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