The creatine content of the myocardium of normal and abnormal human hearts

Cowan, Donald W.

doi:10.1016/s0002-8703(34)90224-6

Cited by 25 publications

(7 citation statements)

References 10 publications

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“…Still, metabolic dysfunction appears to be general feature of the failing heart, regardless of etiology: concentrations of ATP, its hydrolysis products ADP and Pi, and the related metabolite creatine phosphate (CrP) are altered in the diseased and failing heart compared to normal. 6 , 11 , 12 , 16 , 17 , 24 , 48 Our analysis predicts a roughly 2-fold increase in Pi/ATP ratio in the disease model compared to control, consistent with recent in vivo measurement in hypertrophic cardiomyopathy patients compared to healthy controls. 49 Thus, regardless of the complexity and variability in the clinical presentation of heart failure, the animal model employed here captures the two common features of energetic dysfunction in failing hearts, reduced adenine nucleotides and increased [Pi], that we predict to be the direct metabolic drivers of mechanical dysfunction in heart failure.…”

Section: Discussionsupporting

confidence: 88%

“…While associations between myocardial energy metabolite concentrations and the disease state have been appreciated for some time, 9 , 24 , 25 mechanistic connections between metabolic and mechanical pump function have not been firmly established. 26–28 If indeed impaired cardiac pumping in heart failure is in part a consequence of metabolic derangement, then understanding the underlying mechanisms will be crucial for understanding the natural history of the disease and for developing new therapies.…”

Section: Introductionmentioning

confidence: 99%

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Impaired Myocardial Energetics Causes Mechanical Dysfunction in Decompensated Failing Hearts

et al. 2020

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Cardiac mechanical function is supported by ATP hydrolysis, which provides the chemical free energy to drive the molecular processes underlying cardiac pumping. Physiological rates of myocardial ATP consumption require the heart to resynthesize its entire ATP pool several times per minute. In the failing heart, cardiomyocyte metabolic dysfunction leads to a reduction in the capacity for ATP synthesis and associated free energy to drive cellular processes. Yet it remains unclear if and how metabolic/energetic dysfunction that occurs during heart failure affects mechanical function of the heart. We hypothesize that changes in phosphate metabolite concentrations (ATP, ADP, inorganic phosphate) that are associated with decompensation and failure have direct roles in impeding contractile function of the myocardium in heart failure, contributing to the whole-body phenotype. To test this hypothesis, a transverse aortic constriction (TAC) rat model of pressure overload, hypertrophy, and decompensation was used to assess relationships between metrics of whole-organ pump function and myocardial energetic state. A multi-scale computational model of cardiac mechano-energetic coupling was used to identify and quantify the contribution of metabolic dysfunction to observed mechanical dysfunction. Results show an overall reduction in capacity for oxidative ATP synthesis fueled by either fatty acid or carbohydrate substrates as well as a reduction in total levels of adenine nucleotides and creatine in myocardium from TAC animals compared to sham-operated controls. Changes in phosphate metabolite levels in the TAC rats are correlated with impaired mechanical function, consistent with the overall hypothesis. Furthermore, computational analysis of myocardial metabolism and contractile dynamics predicts that increased levels of inorganic phosphate in TAC compared to control animals kinetically impair the myosin ATPase crossbridge cycle in decompensated hypertrophy/heart failure.

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Section: Discussionsupporting

confidence: 88%

Section: Introductionmentioning

confidence: 99%

Impaired Myocardial Energetics Causes Mechanical Dysfunction in Decompensated Failing Hearts

et al. 2020

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“…Indeed, a rise in P i has been reported for patients with hypertensive heart disease after pharmacologically induced stress (Lamb et al, 1999 ). Moreover, the HCM models predicted that myocardial creatine depletion (Cowan, 1934 ; Herrmann and Decherd, 1939 ) progressively aggravates the loss of cytosolic P i concentration homeostasis. Combined, our simulations support the quantitative hypothesis of cytosolic P i interference with myocardial mechanical function as proposed by Tewari et al ( 2016a ), which may explain progressive heart failure in human HCM.…”

Section: Discussionmentioning

confidence: 99%

“…Alternatively, for HCM mito the mitochondrial capacity to synthesize ATP was reduced by 50% compared to healthy myocardium (Brown et al, 2016 ). For both models, we also explored the effect of reduced myocardial creatine content that has been documented in human HCM (Cowan, 1934 ; Herrmann and Decherd, 1939 ; Nakae et al, 2003 ). Hereto, additional simulations were run with reductions of the myocardial creatine pool size to 75% and to 50% of the normal value (i.e., 25% and 50% depletion, respectively).…”

Section: Methodsmentioning

confidence: 99%

“…However, this assumption is valid, if and only if, the myocardial creatine content is either known or can be assumed to be unchanged compared with healthy hearts (Wu et al, 2009 ). It has long been known that the myocardial creatine content can be reduced in the diseased heart (Cowan, 1934 ; Herrmann and Decherd, 1939 ), thus complicating a straightforward interpretation of measured PCr/ATP ratios in patients. Furthermore, the measured myocardial PCr/ATP ratio only reports on the balance between ATP turnover rate and ATP synthesis at a specific steady-state.…”

Section: Introductionmentioning

confidence: 99%

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Human Cardiac 31P-MR Spectroscopy at 3 Tesla Cannot Detect Failing Myocardial Energy Homeostasis during Exercise

et al. 2017

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Phosphorus-31 magnetic resonance spectroscopy (31P-MRS) is a unique non-invasive imaging modality for probing in vivo high-energy phosphate metabolism in the human heart. We investigated whether current 31P-MRS methodology would allow for clinical applications to detect exercise-induced changes in (patho-)physiological myocardial energy metabolism. Hereto, measurement variability and repeatability of three commonly used localized 31P-MRS methods [3D image-selected in vivo spectroscopy (ISIS) and 1D ISIS with 1D chemical shift imaging (CSI) oriented either perpendicular or parallel to the surface coil] to quantify the myocardial phosphocreatine (PCr) to adenosine triphosphate (ATP) ratio in healthy humans (n = 8) at rest were determined on a clinical 3 Tesla MR system. Numerical simulations of myocardial energy homeostasis in response to increased cardiac work rates were performed using a biophysical model of myocardial oxidative metabolism. Hypertrophic cardiomyopathy was modeled by either inefficient sarcomere ATP utilization or decreased mitochondrial ATP synthesis. The effect of creatine depletion on myocardial energy homeostasis was explored for both conditions. The mean in vivo myocardial PCr/ATP ratio measured with 3D ISIS was 1.57 ± 0.17 with a large repeatability coefficient of 40.4%. For 1D CSI in a 1D ISIS-selected slice perpendicular to the surface coil, the PCr/ATP ratio was 2.78 ± 0.50 (repeatability 42.5%). With 1D CSI in a 1D ISIS-selected slice parallel to the surface coil, the PCr/ATP ratio was 1.70 ± 0.56 (repeatability 43.7%). The model predicted a PCr/ATP ratio reduction of only 10% at the maximal cardiac work rate in normal myocardium. Hypertrophic cardiomyopathy led to lower PCr/ATP ratios for high cardiac work rates, which was exacerbated by creatine depletion. Simulations illustrated that when conducting cardiac 31P-MRS exercise stress testing with large measurement error margins, results obtained under pathophysiologic conditions may still lie well within the 95% confidence interval of normal myocardial PCr/ATP dynamics. Current measurement precision of localized 31P-MRS for quantification of the myocardial PCr/ATP ratio precludes the detection of the changes predicted by computational modeling. This hampers clinical employment of 31P-MRS for diagnostic testing and risk stratification, and warrants developments in cardiac 31P-MRS exercise stress testing methodology.

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Progress in Internal Medicine

Graybiel¹

1935

Arch Intern Med (Chic)

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The creatine content of the myocardium of normal and abnormal human hearts

Cited by 25 publications

References 10 publications

Impaired Myocardial Energetics Causes Mechanical Dysfunction in Decompensated Failing Hearts

Impaired Myocardial Energetics Causes Mechanical Dysfunction in Decompensated Failing Hearts

Human Cardiac 31P-MR Spectroscopy at 3 Tesla Cannot Detect Failing Myocardial Energy Homeostasis during Exercise

Progress in Internal Medicine

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