phosphocreatine and Heart-Diseases

Creatine phosphate (CrP) plays a fundamental physiological role by providing chemical energy for cell viability and activity, especially in muscle tissue. Numerous pathological conditions, caused by acute or chronic ischaemic situations, are related to its deficiency. For these reasons, it has been used as a cardioprotective agent in heart surgery and medical cardiology for many years.. This article gives a brief overview of the main characteristics of exogenous CrP.. Previous review articles on CrP were screened for relevant information and references. Results from selected studies were reviewed and classified according to the topics in this review article and provided further interesting information on the pharmacological role of this molecule.. Besides CrP's well known cell energy and function restoring properties, new evidence is emerging regarding its antioxidant and anti-apoptotic properties. Use of CrP is well established clinically as an intraoperative and perioperative adjuvant in heart operations (valve replacement, coronary artery bypass grafting, congenital heart defect repair), and as an additional agent in medical cardiology therapy for acute myocardial infarction and acute and chronic heart failure. In particular, there are promising potential new CrP uses in neurology, such as in cerebral ischaemia and hypoxic ischaemic encephalopathy.. This review article describes the role of CrP treatment in cardiological indications, such as cardioprotection in cardioplegia and in myocardiopathies of various etiopathogenesis, as well as in other clinical indications such as skeletal muscle rehabilitation and neurological conditions.

Topics: Biomedical Research; Cardiology; Cardiotonic Agents; Energy Metabolism; Heart Diseases; Humans; Myocardium; Phosphocreatine

Magnetic Resonant spectroscopy (MRS) in the nuclei of phosphorus is the only noninvasive method of studying the state of myocardial energy metabolism does not require the introduction of radiopharmaceuticals. This method uses the signals from the nuclei of 31P contained in such mattered phosphates like phosphocreatine and adenosine triphosphate. MRS can provide an answer to a variety of theoretical and clinical issues in the study of various cardiac diseases. The first is ischemic heart disease, as well as heart failure, hypertrophy of various origins, etc. In addition, the method can be used to control the various treatments, including therapeutic, interventional or surgical. Combined with magnetic resonance imaging of the heart gives information on the anatomy, size, function, perfusion defects, structural changes of the myocardium, as well as about the state of energy metabolism of myocardium.

Topics: Adenosine Triphosphate; Biomedical Enhancement; Energy Metabolism; Heart Diseases; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Myocardium; Phosphocreatine; Phosphorus

There is convincing evidence that alterations in myocardial substrate use play an important role in the normal and diseased heart. In this review, insights gained by using quantitative molecular imaging by positron emission tomography and magnetic resonance spectroscopy in the study of human myocardial metabolism will be discussed, and attention will be paid to the effects of nutrition, gender, aging, obesity, diabetes, cardiac hypertrophy, ischemia, and heart failure. The heart is an omnivore organ, relying on metabolic flexibility, which is compromised by the occurrence of defects in coronary flow reserve, insulin-mediated glucose disposal, and metabolic-mechanical coupling. Obesity, diabetes, and ischemic cardiomyopathy appear as states of high uptake and oxidation of fatty acids, that compromise the ability to utilize glucose under stimulated conditions, and lead to misuse of energy and oxygen, disturbing mechanical efficiency. Idiopathic heart failure is a complex disease frequently coexisting with diabetes, insulin resistance and hypertension, in which the end stage of metabolic toxicity manifests as severe mitochondrial disturbance, inability to utilize fatty acids, and ATP depletion. The current literature provides evidence that the primary events in the metabolic cascade outlined may originate in extra-cardiac organs, since fatty acid, glucose levels, and insulin action are mostly controlled by adipose tissue, skeletal muscle and liver, and that a broader vision of organ cross-talk may further our understanding of the primary and the adaptive events involved in metabolic heart toxicity.

Topics: Adenosine Triphosphate; Aging; Diabetes Mellitus; Energy Metabolism; Fatty Acids; Female; Glucose; Heart Diseases; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Myocardial Ischemia; Myocardium; Obesity; Oxygen Consumption; Phosphocreatine; Positron-Emission Tomography; Sex Factors

The present review outlines the clinical potential of magnetic resonance (MR) spectroscopy of the heart. The main acquisition and postprocessing techniques of myocardial phosphorous (31P) and proton (1H) MR spectroscopy are illustrated, along with the possibilities these techniques offer for assessing the myocardial metabolism of phosphates and the presence of lipids. Particular attention is paid to the significance of the main peaks of the myocardial spectrum of 31P: phosphomonoesters (PME), inorganic phosphate (Pi), phosphodiesters (PDE), phosphocreatine (PCr), and gamma-, alpha- and beta-adenosine triphosphate (ATP). The main findings of clinical research are presented with regard to myocardial hypertrophy and hypertrophic and dilated cardiomyopathy, ischaemic cardiomyopathy and myocardial involvement in multisystem disease such as muscular dystrophy and diabetes mellitus. Lastly, the recent prospects offered by technological innovations that increase the signal-to-noise ratio and reduce acquisition times are assessed with reference to the radiologist dedicated to cardiac imaging.

Topics: Adenosine Triphosphate; Heart Diseases; Humans; Lipid Metabolism; Magnetic Resonance Spectroscopy; Myocardium; Phosphates; Phosphocreatine; Phosphoric Diester Hydrolases

Topics: Adenosine Triphosphate; Animals; Energy Metabolism; Heart Diseases; Humans; Myocardium; Nuclear Magnetic Resonance, Biomolecular; Phosphocreatine

Topics: Adenosine Triphosphate; Animals; Heart Diseases; Humans; Magnetic Resonance Spectroscopy; Myocardium; Phosphocreatine; Phosphorus Isotopes; Sensitivity and Specificity

Noninvasive measurements of high-energy phosphate metabolism in the anterior myocardium of heart patients are now possible with image-guided, localized nuclear magnetic resonance (MR) spectroscopy. The results, reviewed herein, are largely consistent with those of prior animal studies. Quantification with phosphorus-31 MR yields normal phosphocreatine (PCr) and adenosine triphosphate (ATP) concentrations of about 11 and 6 mumol per gram wet weight, respectively, with a PCr/ATP ratio of around 1.8. Studies of patients with hypertrophic and dilated cardiomyopathy, left ventricular hypertrophy, valve disease, transplanted hearts, myocardial infarction, or reversible ischemia reveal abnormalities in the PCr/ATP ratio and/or the metabolite concentrations. Differences in reported findings for cardiomyopathies might be attributable to statistical sensitivity and the presence of heart failure. The technique might find use in the clinic for identifying failure when other factors complicate diagnosis. The PCr/ATP ratio is often reduced in transplanted hearts but is not a reliable predictor of histologic rejection involving myocyte necrosis. In myocardial infarction, metabolite levels may be reduced while the remaining PCr and ATP signals likely reflect surrounding surviving tissue. Stress-test studies of anterior myocardial ischemia produce transient reductions in the PCr/ATP ratio, which appear to be specific for ischemic disease. This may lead to a new way of assessing ischemia, particularly if the technology can gain access to a larger portion of the heart. Cardiac spectroscopy with nuclei other than P-31 shows promise.

Topics: Adenosine Triphosphate; Heart Diseases; Heart Transplantation; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Myocardium; Phosphocreatine

To determine the clinical feasibility of rapid-sequence phosphorus-31 magnetic resonance spectroscopy (31P-MRS) of the heart with cardiac patients using a 1.5T clinical MR system.. Twenty cardiac patients, i.e. dilated cardiomyopathy (DCM) 13 cases, hypertrophic cardiomyopathy (HCM) 3 cases, hypertensive heart diseases (HHD) 3 cases, and aortic regurgitation (AR) 1 case were examined using rapid cardiac 31P-MRS. Complete three-dimensional localization was performed using a two-dimensional phosphorus chemical-shift imaging sequence in combination with 30-mm axial slice-selective excitation. The rapid-sequence 31P-MRS procedure was phase encoded in arrays of 8 x 8 steps with an average of 4 acquisitions. The total examination time, including proton imaging and shimming, for the rapid cardiac 31P-MRS procedure, ranged from 10 to 15 min, depending on the heart rate. Student's t test was used to compare creatine phosphate (PCr)/adenosine triphosphate (ATP) ratios from the cardiac patients with those of the control subjects (n = 13).. The myocardial PCr/ATP ratio obtained by rapid 31P-MRS was significantly lower (P < 0.001) in DCM patients (1.82 +/- 0.33, mean +/- SD), and in patients with global myocardial dysfunction (combined data for 20 patients: 1.89 +/- 0.32) than in normal volunteers (2.96 +/- 0.59). These results are similar to previous studies.. Rapid-sequence 31P-MRS may be a valid diagnostic tool for patients with cardiac disease.

Topics: Adenosine Triphosphate; Diagnostic Techniques, Cardiovascular; Electrocardiography; Feasibility Studies; Female; Heart Diseases; Humans; Imaging, Three-Dimensional; Magnetic Resonance Spectroscopy; Male; Middle Aged; Myocardium; Phosphocreatine; Phosphorus Isotopes; Reference Values; Sensitivity and Specificity; Time Factors

Cardiac energetic dysfunction has been reported in patients with type 2 diabetes (T2D) and is an independent predictor of mortality. Identification of the mechanisms driving mitochondrial dysfunction, and therapeutic strategies to rescue these modifications, will improve myocardial energetics in T2D. We demonstrate using 31P-magnetic resonance spectroscopy (31P-MRS) that decreased cardiac ATP and phosphocreatine (PCr) concentrations occurred before contractile dysfunction or a reduction in PCr/ATP ratio in T2D. Real-time mitochondrial ATP synthesis rates and state 3 respiration rates were similarly depressed in T2D, implicating dysfunctional mitochondrial energy production. Driving this energetic dysfunction in T2D was an increase in mitochondrial protein acetylation, and increased ex vivo acetylation was shown to proportionally decrease mitochondrial respiration rates. Treating T2D rats in vivo with the mitochondrial deacetylase SIRT3 activator honokiol reversed the hyperacetylation of mitochondrial proteins and restored mitochondrial respiration rates to control levels. Using 13C-hyperpolarized MRS, respiration with different substrates, and enzyme assays, we localized this improvement to increased glutamate dehydrogenase activity. Finally, honokiol treatment increased ATP and PCr concentrations and increased total ATP synthesis flux in the T2D heart. In conclusion, hyperacetylation drives energetic dysfunction in T2D, and reversing acetylation with the SIRT3 activator honokiol rescued myocardial and mitochondrial energetics in T2D.

Topics: Acetylation; Adenosine Triphosphate; Animals; Anti-Arrhythmia Agents; Biphenyl Compounds; Diabetes Mellitus, Experimental; Diabetes Mellitus, Type 2; Diet, High-Fat; Energy Metabolism; Heart Diseases; Lignans; Male; Mitochondria, Heart; Myocardium; Phosphocreatine; Rats; Rats, Wistar

The heart's energy demand per gram of tissue is the body's highest and creatine kinase (CK) metabolism, its primary energy reserve, is compromised in common heart diseases. Here, neural-network analysis is used to test whether noninvasive phosphorus (. The data comprised the extant 178 complete sets of PCr and ATP concentrations, k. The network differentiated healthy, HF and non-HF cardiac disease with an overall accuracy of 84% and AUC > 90% for each category using the four CK metabolic parameters, alone. HF patients with DCM, hypertrophy, and different NYHA severity were differentiated with ~ 80% overall accuracy independent of CMRS methodology.. While sample-size was limited in some sub-classes, a neural network classifier applied to noninvasive cardiac. ClinicalTrials.gov Identifier: NCT00181259.

Topics: Adenosine Triphosphate; Adult; Aged; Aged, 80 and over; Biomarkers; Creatine Kinase; Energy Metabolism; Female; Heart Diseases; Humans; Kinetics; Machine Learning; Magnetic Resonance Spectroscopy; Male; Middle Aged; Myocardium; Neural Networks, Computer; Phosphocreatine; Phosphorus Isotopes; Predictive Value of Tests; Reproducibility of Results; Severity of Illness Index; Young Adult

The present study was designed to further explore the role and the underlying molecular mechanism of phosphocreatine (PCr) for cardiac fibrosis

Topics: Animals; Apoptosis; Disease Models, Animal; Fibrosis; Gene Expression Regulation; Heart Diseases; Humans; Isoproterenol; JNK Mitogen-Activated Protein Kinases; Matrix Metalloproteinase 9; Myocytes, Cardiac; NF-kappa B; Phosphocreatine; Rats; Signal Transduction; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta1

Age is a known susceptibility factor for the cardiotoxicity of several anticancer drugs, including mitoxantrone (MTX). The impact of anticancer drugs in young patients is underestimated, thus we aimed to evaluate the cardiotoxicity of MTX in juvenile and adult animals. Juvenile (3 week-old) and adult (8-10 week-old) male CD-1 mice were used. Each group was treated with a 9.0mg/kg cumulative dose of MTX or saline; they were maintained in a drug-free period for 3-weeks after the last administration to allow the development of late toxicity (protocol 1), or sacrificed 24h after the last MTX administration to evaluate early cardiotoxicity (protocol 2). In protocol 1, no adult mice survived, while 2 of the juveniles reached the end of the protocol. High plasma aspartate aminotransferase/alanine aminotransferase ratio and a high cardiac reduced/oxidized glutathione ratio were found in the surviving MTX-treated juvenile mice. In protocol 2, a significant decrease in plasma creatine-kinase MB in juveniles was found 24h after the last MTX-administration. Cardiac histology showed that both MTX-treated populations had significant damage, although higher in adults. However, MTX-treated juveniles had a significant increase in fibrotic tissue. The MTX-treated adults had higher values of cardiac GSSG and protein carbonylation, but lower cardiac noradrenaline levels. For the first time, mature adult animals were shown to be more susceptible to MTX as evidenced by several biomarkers, while young animals appear to better adjust to the MTX-induced cardiac injury. Even so, the higher level of fibrotic tissue and the histological damage showed that MTX also causes cardiac damage in the juvenile population.

Topics: Age Factors; Animals; Antineoplastic Agents; Aspartate Aminotransferases; Biomarkers; Body Weight; Cardiotoxicity; Caspase 3; Caspase 8; Caspase 9; Creatine; Creatine Kinase, MB Form; Dose-Response Relationship, Drug; Epinephrine; Fibrosis; Glutathione Disulfide; Heart; Heart Diseases; Kidney; Lipid Peroxidation; Liver; Male; Mice; Mitoxantrone; Myocardium; Norepinephrine; Organ Size; Phosphocreatine; Protein Carbonylation

Sepsis is common in intensive care units (ICU) and is associated with high mortality. Cardiac dysfunction complicating sepsis is one of the most important causes of this mortality. This dysfunction is due to myocardial inflammation and reduced production of energy by the heart. A number of studies have shown that hydrogen-rich saline (HRS) has a beneficial effect on sepsis. Therefore, we tested whether HRS prevents cardiac dysfunction by increasing cardiac energy. Four groups of rats received intraperitoneal injections of one of the following solutions: normal saline (NS), HRS, lipopolysaccharide (LPS), and LPS plus HRS. Cardiac function was measured by echocardiography 8 h after the injections. Gene and protein expression related to fatty acid oxidation (FAO) were measured by quantitative polymerase chain reaction (PCR) and Western blot analysis. The injection of LPS compromised heart function through decreased fractional shortening (FS) and increased left ventricular diameter (LVD). The addition of HRS increased FS, palmitate triphosphate, and the ratio of phosphocreatinine (PCr) to adenosine triphosphate (ATP) as well as decreasing LVD. The LPS challenge reduced the expression of genes related to FAO, including perioxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α), perioxisome proliferator-activated receptor alpha (PPARα), Estrogen-related receptor alpha (ERRα), and their downstream targets, in mRNA and protein level, which were attenuated by HRS. However, HRS had little effect on glucose metabolism. Furthermore, HRS inhibited c-Jun N-terminal kinase (JNK) activation in the rat heart. Inhibition of JNK by HRS showed beneficial effects on LPS-challenged rats, at least in part, by restoring cardiac FAO.

Topics: Adenosine Triphosphate; Animals; Echocardiography; Fatty Acids; Heart; Heart Diseases; Heart Ventricles; Hydrogen; Inflammation; Injections, Intraperitoneal; Intensive Care Units; JNK Mitogen-Activated Protein Kinases; Lipopolysaccharides; Male; Myocardium; Oxygen; Peroxisome Proliferator-Activated Receptor Gamma Coactivator 1-alpha; Phosphocreatine; Polymerase Chain Reaction; PPAR alpha; Rats; Rats, Sprague-Dawley; Sepsis; Sodium Chloride; Transcription Factors

Speed and signal-to-noise ratio (SNR) are critical for localized magnetic resonance spectroscopy (MRS) of low-concentration metabolites. Matching voxels to anatomical compartments a priori yields better SNR than the spectra created by summing signals from constituent chemical-shift-imaging (CSI) voxels post-acquisition. Here, a new method of localized Spectroscopy using Linear Algebraic Modeling (SLAM) is presented, that can realize this additional SNR gain. Unlike prior methods, SLAM generates spectra from C signal-generating anatomic compartments utilizing a CSI sequence wherein essentially only the C central k-space phase-encoding gradient steps with highest SNR are retained. After MRI-based compartment segmentation, the spectra are reconstructed by solving a sub-set of linear simultaneous equations from the standard CSI algorithm. SLAM is demonstrated with one-dimensional CSI surface coil phosphorus MRS in phantoms, the human leg and the heart on a 3T clinical scanner. Its SNR performance, accuracy, sensitivity to registration errors and inhomogeneity, are evaluated. Compared to one-dimensional CSI, SLAM yielded quantitatively the same results 4-times faster in 24 cardiac patients and healthy subjects. SLAM is further extended with fractional phase-encoding gradients that optimize SNR and/or minimize both inter- and intra-compartmental contamination. In proactive cardiac phosphorus MRS of six healthy subjects, both SLAM and fractional-SLAM (fSLAM) produced results indistinguishable from CSI while preserving SNR gains of 36-45% in the same scan-time. Both SLAM and fSLAM are simple to implement and reduce the minimum scan-time for CSI, which otherwise limits the translation of higher SNR achievable at higher field strengths to faster scanning.

Topics: Adenosine Triphosphate; Algorithms; Computer Simulation; Heart; Heart Diseases; Humans; Image Processing, Computer-Assisted; Leg; Linear Models; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Models, Statistical; Monte Carlo Method; Myocardium; Phantoms, Imaging; Phosphocreatine; Signal-To-Noise Ratio; Thorax

Structural changes in the heart are studied at an experimental widespread purulent peritonitis. It was established that in 6 hours after initiation of peritonitis in a myocardium the severe disorders of blood circulation, interstitial edema, the phenomena of kariopyknosis, development of systemic toxic damages specifying in high speed at this disease were observed. One of the mechanism of their development is a energy deficiency. The proof of this is destructive changes of cardiomyocytes mitochondria. The comparative analysis of use of metabolic preparations "Citoflavin", containing amber acid, and "Neoton", containing phosphocreatine, for the purpose of pharmacological support of cardiac activity at an experimental widespread purulent peritonitis has revealed high efficiency of the preparation "Citoflavin". It caused more intensive decrease of inflammatory changes in a myocardium, preventing of cardiomyocytes necrobiosis, contribution to preservation of normal structure and growth of quantity of mitochondria.

Topics: Animals; Cardiotonic Agents; Disease Models, Animal; Heart Diseases; Mitochondria, Heart; Myocardium; Organs at Risk; Peritonitis; Phosphocreatine; Photomicrography; Rabbits; Severity of Illness Index; Suppuration; Treatment Outcome

The use of cardiac magnetic resonance (CMR) has emerged in the last decades. Technical innovations provide fast and high-quality imaging sequences and CMR is often proposed as a gold-standard for the in vivo evaluation of cardiac function, morphologic details and infarct size. Also the 31-phosphorous magnetic resonance spectroscopy (MRS) is a unique tool to investigate the human myocardial high-energy phosphate (HEP) metabolism in vivo. PCr/b-ATP ratio examined by MRS is mainly used as an index for cardiac energy metabolism. We have described decreased PCr/b-ATP ratios in patients with diabetes mellitus, hypercholesterolemia and hemochromatosis. The use of CMR to study the effects of ischemia time on the evolution of myocardial infarct characteristics after an acute myocardial infarction (AMI) treated with a primary angioplasty (p-PTCA) is a promising new application of this technique. Results of this study will further help to clarify the impact of ischemia time on myocardial regional functional recovery after p-PTCA.

Topics: Adenosine Triphosphate; Angioplasty, Balloon, Coronary; Contrast Media; Energy Metabolism; Heart Diseases; Humans; Magnetic Resonance Imaging; Magnetic Resonance Imaging, Cine; Magnetic Resonance Spectroscopy; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Phosphocreatine; Prognosis; Stents; Ventricular Dysfunction, Left

In the heart, thermal injury activates a group of intracellular cysteine proteases known as caspases, which have been suggested to contribute to myocyte inflammation and dyshomeostasis. In this study, Sprague-Dawley rats were given either a third-degree burn over 40% total body surface area plus conventional fluid resuscitation or sham burn injury. Experimental groups included 1) sham burn given vehicle, 400 microl DMSO; 2) sham burn given Q-VD-OPh (6 mg/kg), a highly specific and stable caspase inhibitor, 24 and 1 h prior to sham burn; 3) burn given vehicle, DMSO as above; 4) burn given Q-VD-OPh (6 mg/kg) 24 and 1 h prior to burn. Twenty-four hours postburn, hearts were harvested and studied with regard to myocardial intracellular sodium concentration, intracellular pH, ATP, and phosphocreatine (23Na/31P nuclear magnetic resonance); myocardial caspase-1, -3,and -8 expression; myocyte Na+ (fluorescent indicator, sodium-binding benzofurzan isophthalate); myocyte secretion of TNF-alpha, IL-1beta, IL-6, and IL-10; and myocardial performance (Langendorff). Burn injury treated with vehicle alone produced increased myocardial expression of caspase-1, -3, and -8, myocyte Na+ loading, cytokine secretion, and myocardial contractile depression; cellular pH, ATP, and phosphocreatine were stable. Q-VD-OPh treatment in burned rats attenuated myocardial caspase expression, prevented burn-related myocardial Na+ loading, attenuated myocyte cytokine responses, and improved myocardial contraction and relaxation. The present data suggest that signaling through myocardial caspases plays a pivotal role in burn-related myocyte sodium dyshomeostasis and myocyte inflammation, perhaps contributing to burn-related contractile dysfunction.

Topics: Adenosine Triphosphate; Amino Acid Chloromethyl Ketones; Animals; Burns; Calcium; Caspase 1; Caspase 3; Caspase 8; Caspase Inhibitors; Caspases; Cysteine Proteinase Inhibitors; Disease Models, Animal; Heart Diseases; Homeostasis; Hydrogen-Ion Concentration; Interleukin-10; Interleukin-1beta; Interleukin-6; Magnetic Resonance Spectroscopy; Male; Myocardial Contraction; Myocytes, Cardiac; Phosphocreatine; Quinolines; Rats; Rats, Sprague-Dawley; Severity of Illness Index; Signal Transduction; Sodium; Tumor Necrosis Factor-alpha; Ventricular Pressure

Hemochromatosis is a hereditary iron overload syndrome characterized by increased iron storage, followed by liver cirrhosis and is often associated with restrictive cardiomyopathy. The purpose of this study was to detect alterations of cardiac high-energy phosphate metabolism in patients with hereditary hemochromatosis (HHC) prior to the development of structural heart diseases. Therefore cardiac phosphorus-31 two-dimensional chemical shift imaging ((31)P 2D CSI) was employed. Twenty-four male patients (mean age 47.2 +/- 12 years) homozygous for the C282Y mutation in the hemochromatosis associated HFE gene and twenty-four male healthy volunteers (mean age 47 +/- 11 years) as age-matched controls were included in this study. Using a 1.5-Tesla whole-body magnetic resonance scanner, electrocardiograph-triggered transversal 31P 2D CSI was performed. Left ventricle mean phosphocreatine (PCr) to beta-adenosine triphosphate (beta-ATP) ratios of patients with HHC (1.60 +/- 0.41) were significantly decreased in comparison to healthy volunteers (1.93 +/- 0.36; p = 0.004). Furthermore, we detected moderate, negative correlations between left ventricular PCr to beta-ATP ratios and transferrin saturation, cholesterol, low-density lipoprotein as well as triglyceride. This study shows that 31P 2D CSI permits the detection of alterations of cardiac high-energy phosphate metabolism in patients with HHC, but without any evidence for heart disease. The decreased PCr to beta-ATP ratios in HHC might be caused by mitochondrial impairment due to cardiac iron overload.

Topics: Adenosine Triphosphate; Adult; Biomarkers; Cholesterol, LDL; Echocardiography; Electrocardiography; Ferritins; Genetic Predisposition to Disease; Heart Diseases; Heart Ventricles; Hemochromatosis; Homozygote; Humans; Iron; Magnetic Resonance Imaging; Male; Middle Aged; Mutation; Phosphocreatine; Phosphorus Isotopes; Transferrin; Triglycerides

Cardiovascular abnormalities represent the major cause of death in patients with acromegaly. We evaluated cardiac structure, function, and energy status in adult transgenic mice overexpressing bovine GH (bGH) gene. Female transgenic mice expressing bGH gene (n = 11) 8 months old and aged matched controls (n = 11) were used. They were studied with two-dimensional guided M-mode and Doppler echocardiography. The animals (n = 6) for each group were examined with 31P magnetic resonance spectroscopy to determine the cardiac energy status. Transgenic mice had a significantly higher body weight (BW), 53.2+/-2.4 vs. 34.6+/-3.7 g (P < 0.0001) and hypertrophy of left ventricle (LV) compared with normal controls: LV mass/BW 5.6+/-1.6 vs. 2.7+/-0.2 mg/g, P < 0.01. Several indexes of systolic function were depressed in transgenic animals compared with controls mice such as shortening fraction 25+/-3.0% vs. 39.9+/-3.1%; ejection fraction, 57+/-9 vs. 77+/-5; mean velocity of circumferential shortening, 4.5+/-0.8 vs. 7.0+/-1.1 circ/sec, p < 0.01. Creatine phosphate-to-ATP ratio was significantly lower in bGH overexpressing mice (1.3+/-0.08 vs. 2.1+/-0.23 in controls, P < 0.05). Ultrastructural examination of the hearts from transgenic mice revealed substantial changes of mitochondria. This study provides new insight into possible mechanisms behind the deteriorating effects of long exposure to high level of GH on heart function.

Topics: Acromegaly; Adenosine Triphosphate; Animals; Body Weight; Cattle; Echocardiography; Energy Metabolism; Female; Gene Expression; Growth Hormone; Heart Diseases; Hypertrophy, Left Ventricular; Magnetic Resonance Spectroscopy; Mice; Mice, Transgenic; Myocardium; Organ Size; Phosphocreatine; Systole

Although usually steady-state fluxes and metabolite levels are assessed for the study of metabolic regulation, much can be learned from studying the transient response during quick changes of an input to the system. To this end we study the transient response of O2 consumption in the heart during steps in heart rate. The time course is characterized by the mean response time of O2 consumption which is the first statistical moment of the impulse response function of the system (for mono-exponential responses equal to the time constant). The time course of O2 uptake during quick changes is measured with O2 electrodes in the arterial perfusate and venous effluent of the heart, but the venous signal is delayed with respect to O2 consumption in the mitochondria due to O2 diffusion and vascular transport. We correct for this transport delay by using the mass balance of O2, with all terms (e.g. O2 consumption and vascular O2 transport) taken as function of time. Integration of this mass balance over the duration of the response yields a relation between the mean transit time for O2 and changes in cardiac O2 content. Experimental data on the response times of venous [O2] during step changes in arterial [O2] or in perfusion flow are used to calculate the transport time between mitochondria and the venous O2 electrode. By subtracting the transport time from the response time measured in the venous outflow the mean response time of mitochondrial O2 consumption (tmito) to the step in heart rate is obtained. In isolated rabbit heart we found that tmito to heart rate steps is 4-12 s at 37 degrees C. This means that oxidative phosphorylation responds to changing ATP hydrolysis with some delay, so that the phosphocreatine levels in the heart must be decreased, at least in the early stages after an increase in cardiac ATP hydrolysis. Changes in ADP and inorganic phosphate (Pi) thus play a role in regulating the dynamic adaptation of oxidative phosphorylation, although most steady state NMR measurements in the heart had suggested that ADP and Pi do not change. Indeed, we found with 31P-NMR spectroscopy that phosphocreatine (PCr) and Pi change in the first seconds after a quick change in ATP hydrolysis, but remarkably they do this significantly faster (time constant approximately 2.5 s) than mitochondrial O2 consumption (time constant 12 s). Although it is quite likely that other factors besides ADP and Pi regulate cardiac oxidative phosphorylation, a fascinating alternativ

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Energy Metabolism; Heart; Heart Diseases; Heart Rate; Magnetic Resonance Spectroscopy; Mitochondria; Myofibrils; Oxidative Phosphorylation; Oxygen Consumption; Phosphocreatine; Rabbits; Temperature

MR spectroscopy opens a window to the non-invasive evaluation of various aspects of cardiac metabolism. Experimentally, the method has extensively been used since 1970's. 31P-MR allows the registration of cardiac high-energy phosphate metabolism to non-invasively estimate the energetic state of the heart: ATP, phosphocreatine, inorganic phosphate, monophosphate esters and intracellular pH can all be quantitated. In conjunction with extracellular shift reagents such as [DyTTHA]3- or [TmDOTP]5-, 23Na- and 39K-MR allow the measurement of intra- and extra-cellular cation pools. 1H-MR spectroscopy allows the detection of a large number of metabolites such as, e.g. creatine, lactate, or carnitine. Human cardiac spectrocsopy has so far been confined to the 31P nucleus. Localization techniques (DRESS, ISIS, 3D-CSI etc.) are required to confine the acquired signal to the heart region. Relative quantification is straightforward (phosphocreatine/ATP ratio), absolute quantification (mM) is under development. Cardiac 31P-MR spectroscopy has research application in at least three clinical areas: (1) Coronary artery disease: A biochemical stress test for non-invasive ischemia detection (decrease of phosphocreatine with exercise) and viability assessment via quantification of ATP may become feasible. (2) Heart failure: The phosphocreatine/ATP ratio may provide an independent index for grading of heart failure, allow to monitor the longterm effects of different forms of drug therapy on cardiac energy metabolism in heart failure, and may also hold prognostic information on survival. (3) Valve disease: It is possible that the decrease of phosphocreatine/ATP can be used to guide the timing for the valve replacement. At the present time, no routine clinical applications can be defined for the use of human cardiac spectroscopy in patients with cardiac disease. However, the technique holds great potential for the future as a non-invasive approach to cardiac metabolism, and in coming years routine applications may become reality.

Topics: Adenosine Triphosphate; Animals; Energy Metabolism; Heart Diseases; Heart Ventricles; Humans; Magnetic Resonance Spectroscopy; Myocardium; Phosphocreatine; Phosphorus Isotopes; Rats

We investigated whether a brief ischaemic episode (ischaemic pretreatment) preconditioning might attenuate the acute cardiotoxicity of the anthracycline, epirubicin. Isolated rat hearts perfused at a constant flow rate of 10 ml/min, were preconditioned with 5 min. of global ischaemia and 10 min. of reperfusion (preconditioned hearts), or were perfused for 15 min. (control hearts). The hearts were then subjected to 20 min. of infusion with epirubicin (2 mg/ml) or vehicle by a side arm of the perfusion system at a rate of 0.1 ml/min. (0.2 mg epirubicin/min.). Attenuation of cardiotoxicity of a total dose of 4 mg of epirubicin was assessed by functional and metabolic parameters during infusion and during the following 30 min. recovery period. Cardiotoxic effects were reduced in preconditioned hearts compared to control hearts. Thus left ventricular developed pressure and heart rate product after 20 min. of epirubicin infusion was depressed to 27 +/- 7% (mean +/- S.D.) and 40 +/- 4% (mean +/- S.D.) of baseline values in the control group and the preconditioned group, respectively (P < 0.05). Furthermore, we observed less contracture during epirubicin infusion and more effective reversal of contracture during the recovery period in the preconditioned hearts. Improvement in cardiac function was associated with a significantly lower (P < 0.05) myocardial content of epirubicin in the preconditioned group at the end of the infusion period. We conclude that ischaemic preconditioning attenuates the acute cardiotoxicity of epirubicin, probably by reducing the myocardial accumulation of the anthracycline.

Topics: Adenosine Triphosphate; Animals; Antibiotics, Antineoplastic; Blood Pressure; Epirubicin; Heart Diseases; Heart Rate; In Vitro Techniques; Ischemic Preconditioning; L-Lactate Dehydrogenase; Male; Myocardium; Phosphocreatine; Rats; Rats, Wistar; Ventricular Function, Left

The working rat heart model was used for 31P nuclear magnetic resonance (NMR) studies during normoxia, hypoxia and reoxygenation. Aortic flows of about 35 ml/min could be achieved which equals 65% of the values obtained outside the NMR magnet. Addition of dihydrolipoic acid (DHL) at a concentration of 0.3 mumol/l during hypoxia accelerated the recovery of aortic flow and stabilized it during reoxygenation. During hypoxia, inorganic phosphate contents (Pi) were significantly higher in controls. The phosphate shift indicated a pH decrease in control to 6.98, in DHL treated hearts the calculated pH was 7.15. During both hypoxia and reoxygenation, the phosphocreatinine (PCr) contents were higher in the DHL treated hearts than in controls. In the controls, saturation transfer measurements revealed a decrease of the flux PCr-->ATP during initial reoxygenation, whereas after addition of 0.3 mumol/l of DHL during hypoxia creatine kinase flux remained constant or increased. In isolated rat heart mitochondria, creatine kinase activities were measured under saturating and non-saturating concentrations of PCr. An increase in activity was observed under low PCr (non-saturating) conditions in the presence of 0.7 nmol DHL per mg of protein. At higher concentrations of DHL, creatine kinase activity was increased under all conditions. An increase in ATP synthesis in the working rat heart under influence of DHL is corroborated by NMR spectroscopy.

Topics: Adenosine Triphosphate; Animals; Creatine Kinase; Heart; Heart Diseases; Hypoxia; In Vitro Techniques; Indicators and Reagents; Magnetic Resonance Spectroscopy; Male; Mitochondria, Heart; Oxygen; Perfusion; Phosphates; Phosphocreatine; Rats; Rats, Wistar; Thioctic Acid

Phosphorus nuclear magnetic resonance spectroscopy has been proposed as a method of studying the metabolism of the myocardium in patients. Little is known about 31P nuclear magnetic resonance spectroscopy of diseased human hearts.. Two donor hearts meeting the requirements for heart transplantation and 11 diseased hearts were removed during a transplantation procedure and were studied in a horizontal 2.35 T superconducting magnet. Spectra were obtained at 0 degrees C about 30 minutes after the excision. The areas of the inorganic phosphate peak (Pi) and of the phosphocreatine peak (PCr) were summed and expressed as a ratio with respect to the area of the beta ATP peak.. The ratio (Pi + PCr)/beta ATP was found to be significantly lower in five hearts with a myocardial infarct (0.77 (0.18)) than in hearts with dilated cardiomyopathy (1.25 (0.29)) and in normal hearts (1.69 (0.11)). The area of the phosphodiester peak was expressed as a ratio with respect to the area of the beta ATP peak: no differences were found between the three groups.. These results suggest that the phosphocreatine concentration is lower in ischaemic heart disease than in dilated cardiomyopathy and that the phosphodiester peak is probably not useful in distinguishing between these two types of heart disease.

Topics: Adenosine Triphosphate; Cardiomyopathy, Dilated; Heart Diseases; Humans; Magnetic Resonance Spectroscopy; Myocardial Infarction; Myocardium; Phosphates; Phosphocreatine

The goals of this study were to determine whether abnormalities in phosphorus metabolism could be noninvasively detected using phosphorus-31 nuclear magnetic resonance spectroscopy in patients with dilated cardiomyopathy and left ventricular hypertrophy, and whether these patient groups could be distinguished from each other based on parameters obtained using this technique. Seventeen patients and 14 control subjects were studied using nuclear magnetic resonance spectroscopy. Spectra were obtained from the human heart at rest using 3-dimensional spectroscopic imaging as a localization technique. Data were acquired over an average volume of 48 cc in 26.3 minutes using a 2 tesla imaging and spectroscopy unit. The ratio of phosphocreatine to adenosine triphosphate was 0.89 +/- 0.88 (mean +/- standard error) in normal subjects and did not differ significantly in patients with dilated cardiomyopathy or left ventricular hypertrophy. A prominent peak in the phosphodiester region was seen much more frequently in patients with dilated cardiomyopathy, resulting in significantly higher ratios of phosphodiester to phosphocreatine (1.28 +/- 0.35) and phosphodiester to adenosine triphosphate (0.79 +/- 0.18) in this group compared to normal subjects (0.33 +/- 0.08 and 0.29 +/- 0.08, respectively). However, the various patient groups could not be reliably distinguished from each other based on spectral patterns. These studies demonstrate the feasibility of performing phosphorus-31 nuclear magnetic resonance spectroscopic imaging in patients with myocardial disease. The initial results indicate that, under resting conditions, the ratio of phosphocreatine to adenosine triphosphate is not consistently altered in patients with severe global cardiomyopathies or hypertrophy. Phosphodiesters are elevated in some patients with dilated cardiomyopathy, a finding that may signify abnormal phospholipid metabolism in this condition.

Topics: Adenosine Triphosphate; Adolescent; Adult; Cardiomegaly; Cardiomyopathy, Dilated; Echocardiography; Heart Diseases; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Middle Aged; Myocardium; Phosphocreatine; Phosphorus

The cardioprotective effects of nifedipine, verapamil, diltiazem, bepridil, CERM 11956, lidoflazine, mioflazine and the coronary vasodilator dipyridamole were evaluated in the guinea-pig working heart with respect to cardiac function and high energy phosphate content after 45 min of global ischaemia and 25 min of reperfusion. All drugs, with the exception of dipyridamole, induced a negative inotropic effect, which resulted in a decrease of the aortic pressure (AoP), of its first derivative dAoP/dt and the cardiac output. To compare the anti-ischaemic effect of the calcium antagonists, concentrations were selected that reduced the dAoP/dt by 10% (EC10) and 30% (EC30), respectively. With the exception of nifedipine at the EC10 and bepridil and CERM 11956 at the EC30, perfusion with the calcium antagonists and dipyridamole (3 mumol/l) improved the recovery of contractile function after global ischaemia and reperfusion to a value between 60 and 80% of the controls in normoxic hearts. Pretreatment with nifedipine, verapamil, diltiazem, lidoflazine and mioflazine, but not with bepridil, CERM 11956 and dipyridamole led to slightly increased ATP levels in ischaemic hearts as compared to the control value in ischaemic hearts. After subsequent reperfusion for 25 min, for all drugs, ATP levels were further enhanced to 50% of the level in normoxic hearts; phosphocreatine levels reached normoxic values. In particular at the EC30, the effects of calcium antagonists on cardiac function varied in accordance with their known pharmacological and physiological profile. However, there appeared to exist no direct relationship between their beneficial effects on contractile activity and those on the levels of high energy phosphates after ischaemia and reperfusion.

Topics: Adenine Nucleotides; Animals; Blood Pressure; Calcium Channel Blockers; Cardiac Output; Coronary Circulation; Coronary Disease; Dipyridamole; Guinea Pigs; Heart; Heart Diseases; In Vitro Techniques; Male; Myocardial Contraction; Myocardial Reperfusion Injury; Myocardium; Phosphocreatine

Eight beagles receiving heterotopic (cervical) cardiac allografts from outbred donors were evaluated by serial 31P NMR, septal endocardial biopsy, and left ventricular pressure measurements for signs of rejection. Early postoperative myocardial energy levels, as assessed by ratios of phosphocreatine to inorganic phosphate (PCr/Pi) and phosphocreatine to beta-ATP (PCr/B-ATP), were acceptable in all recipients. In these nonimmunosuppressed animals, the mean ratios of PCr/Pi and PCr/B-ATP progressively decreased, with a greater than 25% reduction noted by postoperative day two and greater than 50% reduction by day three. In sharp contrast, left ventricular end-diastolic pressures remained stable and at baseline levels for the first three postoperative days, and only then markedly increased. Likewise, histologic evidence of rejection did not become prominent until postoperative day four. These results suggest that metabolic abnormalities significantly precede either functional or histologic changes in rejecting allografts. The early detection of these metabolic changes by 31P NMR appears to have important potential for the noninvasive diagnosis of cardiac allograft rejection.

Topics: Animals; Blood Pressure; Dogs; Energy Metabolism; Graft Rejection; Heart Diseases; Heart Transplantation; Magnetic Resonance Spectroscopy; Phosphates; Phosphocreatine; Time Factors

Topics: Adenosine Triphosphate; Heart; Heart Arrest, Induced; Heart Diseases; Humans; Myocardial Contraction; Myocardium; Phosphocreatine; Random Allocation; Ventricular Fibrillation

Previous studies have suggested that one of the mechanisms of adriamycin (ADR) cardiomyopathy is depletion of high-energy phosphate stores (HEP). To examine this hypothesis, we used 31P nuclear magnetic resonance to assess the adenosine triphosphate-to-phosphocreatine ratio (ATP-to-PCr ratio) in Langendorff-perfused rabbit hearts. Using either an acute (5 days of therapy at 5 mg/kg/day) or chronic model (7 to 10 weeks of therapy at 1.2 or 1.5 mg/kg twice a week), we compared isovolumetric LV systolic pressure, heart rate, ATP-to-PCr ratios, and histologic lesions between the treated and control animals in each model. In the acute model, there was a significant increase in the ATP-to-PCr ratio (P less than 0.02), without significant changes in myocardial function. Despite significant hemodynamic and histologic alterations in the chronic model, compared to controls, we were unable to identify significant differences in ATP-to-PCr ratios. We conclude that there appear to be differences in energy metabolism between the acute cardiotoxicity and the chronic cardiomyopathy of ADR in the rabbit model and the mechanism of the chronic cardiomyopathy from ADR therapy does not appear to be related to progressive impairment of cellular high-energy phosphate metabolism as measured by the ATP-to-PCr ratio.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Cardiomyopathies; Disease Models, Animal; Doxorubicin; Energy Metabolism; Heart Diseases; Heart Rate; Magnetic Resonance Spectroscopy; Male; Phosphates; Phosphocreatine; Rabbits

The effect of ethanol on the myocardial metabolism of experimental animals was studied in acute and in chronic models. Thirty minutes after intraperitoneal injection of ethanol in a dose of 250 mg/100 gm of body weight there was a significant increase of glycolysis and slight decrease of mitochondrial respiration as well as of respiratory control ratio. No changes were observed in the concentration of high energy phosphates in the heart muscle. The metabolic changes in these acute experiments were of a transitory character; they disappeared parallel with the decline of ethanol level in the blood and in the myocardium. The chronic alcoholic model was observed for 10 weeks. Ethanol (250 mg/100 gm) was injected daily. The analyses of the heart muscle were carried out 24 hr after the last injection of ethanol. In this model ethanol also provoked considerable disturbances of metabolic processes in the myocardium: decrease of glycolysis and of glycogen content, decrease of mitochondrial respiration as well as of respiratory control ratio of isolated mitochondria and decrease of adenosine triphosphate and creatine phosphate with simultaneous increase of inorganic phosphate in the myocardium.

Topics: Adenosine Triphosphate; Animals; Ethanol; Glycogen; Glycolysis; Heart; Heart Diseases; Mitochondria, Muscle; Myocardium; Oxygen Consumption; Phosphates; Phosphocreatine; Rats

Topics: Adenosine Triphosphate; Animals; Glucose; Glycogen; Heart; Heart Diseases; Hypoxia; Isoproterenol; Lactates; Male; Myocardium; Necrosis; Perfusion; Phosphocreatine; Rats; Time Factors

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animal Nutritional Physiological Phenomena; Animals; Citric Acid Cycle; Dose-Response Relationship, Drug; Glyoxylates; Heart; Heart Diseases; Lactates; Male; Myocardium; Oxidoreductases; Perfusion; Phosphocreatine; Pyruvates; Rats; Thiamine Deficiency; Tricarboxylic Acids

Topics: Aged; Alcohols; Cardiac Complexes, Premature; Chronic Disease; Coronary Disease; Electrocardiography; Female; Heart Diseases; Humans; Male; Middle Aged; Myocardial Infarction; Phosphocreatine; Tachycardia

Topics: Aged; Cardiac Complexes, Premature; Chronic Disease; Coronary Disease; Electrocardiography; Female; Heart Diseases; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Phosphocreatine; Tachycardia

Topics: Aged; Alcohols; Electrocardiography; Female; Heart Diseases; Humans; Male; Middle Aged; Phosphocreatine; Pulse; Strophanthins

Topics: Animals; Deficiency Diseases; Glucose; Heart Diseases; Phosphocreatine; Rabbits

Topics: Adult; Femoral Artery; Heart Diseases; Hemodynamics; Humans; Hypotension; Phosphocreatine; Pulse; Raynaud Disease

Topics: Animals; Cats; Dogs; Energy Transfer; Guinea Pigs; Heart Diseases; Heart Function Tests; Mice; Myocardium; Phosphocreatine; Rats

Topics: Animals; Heart Diseases; Phosphocreatine; Phosphorus; Rabbits; Tuberculosis

Topics: Animals; Calcinosis; Clinical Enzyme Tests; Creatine Kinase; Cricetinae; Genetics; Heart Diseases; Mesocricetus; Muscular Dystrophies; Necrosis; Pathology; Phosphocreatine; Research