phosphocreatine and Heart-Failure

Impaired cardiac energy metabolism has been proposed as a mechanism common to different heart failure aetiologies. The energy-depletion hypothesis was pursued by several researchers, and is still a topic of considerable interest. Unlike most organs, in the heart, the creatine kinase system represents a major component of the metabolic machinery, as it functions as an energy shuttle between mitochondria and cytosol. In heart failure, the decrease in creatine level anticipates the reduction in adenosine triphosphate, and the degree of myocardial phosphocreatine/adenosine triphosphate ratio reduction correlates with disease severity, contractile dysfunction, and myocardial structural remodelling. However, it remains to be elucidated whether an impairment of phosphocreatine buffer activity contributes to the pathophysiology of heart failure and whether correcting this energy deficit might prove beneficial. The effects of creatine deficiency and the potential utility of creatine supplementation have been investigated in experimental and clinical models, showing controversial findings. The goal of this article is to provide a comprehensive overview on the role of creatine in cardiac energy metabolism, the assessment and clinical value of creatine deficiency in heart failure, and the possible options for the specific metabolic therapy.

Topics: Adenosine Triphosphate; Creatine; Energy Metabolism; Heart Failure; Humans; Mitochondria, Heart; Myocardium; Phosphocreatine

Adenosintriphosphate is basic unit of cellular energetics, although during situations of high energy demand, cell had developed metabolic inert molecules - phosphagens - including phosphocreatine. Nowadays there are not so many recent publications describing positive effect of phosphocreatine supplementation., its potential benefit in supplementation is mainly in cardiology - acute myocardial infarction, acute or chronic heart failure. Another field of medicine with potential use of phosphocreatine is nephrology - in dialysis patients, or in psotemnopausal women in prevention of osteoporosis. In following article, we present review of studies describing positive effect of using phosphocreatine in specific group of patients in internal medicine. Key words: ATP - ischemia - phosphagens - phosphocreatine.

Topics: Adenosine Triphosphate; Energy Metabolism; Female; Heart Failure; Humans; Internal Medicine; Myocardium; Phosphocreatine

Alterations in myocardial energy metabolism have been implicated in the pathophysiology of cardiac diseases such as heart failure and diabetic cardiomyopathy.

Topics: Adenosine Triphosphate; Animals; Biomarkers; Creatine Kinase; Diabetic Cardiomyopathies; Energy Metabolism; Heart Failure; Humans; Magnetic Resonance Spectroscopy; Myocardial Ischemia; Myocardium; Phosphocreatine; Phosphorus Isotopes

Anthracyclines are frequently used chemotherapeutic agents for childhood cancer that can cause cardiotoxicity during and after treatment. Although several medical interventions in adults with symptomatic or asymptomatic cardiac dysfunction due to other causes are beneficial, it is not known if the same treatments are effective for childhood cancer patients and survivors with anthracycline-induced cardiotoxicity. This review is an update of a previously published Cochrane review.. To compare the effect of medical interventions on anthracycline-induced cardiotoxicity in childhood cancer patients or survivors with the effect of placebo, other medical interventions, or no treatment.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (the Cochrane Library, 2015, Issue 8), MEDLINE/PubMed (1949 to September 2015), and EMBASE/Ovid (1980 to September 2015) for potentially relevant articles. In addition, we searched reference lists of relevant articles, conference proceedings of the International Society for Paediatric Oncology (SIOP), the American Society of Clinical Oncology (ASCO), the American Society of Hematology (ASH), the International Conference on Long-Term Complications of Treatment of Children & Adolescents for Cancer, and the European Symposium on Late Complications from Childhood Cancer (from 2005 to 2015), and ongoing trial databases (the ISRCTN Register, the National Institutes of Health (NIH) Register, and the trials register of the World Health Organization (WHO); all searched in September 2015).. Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing the effectiveness of medical interventions to treat anthracycline-induced cardiotoxicity with either placebo, other medical interventions, or no treatment.. Two review authors independently performed the study selection. One review author performed the data extraction and 'Risk of bias' assessments, which another review author checked. We performed analyses according to the guidelines in the Cochrane Handbook for Systematic Reviews of Interventions.. In the original version of the review we identified two RCTs; in this update we identified no additional studies. One trial (135 participants) compared enalapril with placebo in childhood cancer survivors with asymptomatic anthracycline-induced cardiac dysfunction. The other trial (68 participants) compared a two-week treatment of phosphocreatine with a control treatment (vitamin C, adenosine triphosphate, vitamin E, oral coenzyme Q10) in leukaemia patients with anthracycline-induced cardiotoxicity. Both studies had methodological limitations.The RCT on enalapril showed no statistically significant differences in overall survival, mortality due to heart failure, development of clinical heart failure, and quality of life between treatment and control groups. A post-hoc analysis showed a decrease (that is improvement) in one measure of cardiac function (left ventricular end-systolic wall stress (LVESWS): -8.62% change) compared with placebo (+1.66% change) in the first year of treatment (P = 0.036), but not afterwards. Participants treated with enalapril had a higher risk of dizziness or hypotension (risk ratio 7.17, 95% confidence interval 1.71 to 30.17) and fatigue (Fisher's exact test, P = 0.013).The RCT on phosphocreatine found no differences in overall survival, mortality due to heart failure, echocardiographic cardiac function, and adverse events between treatment and control groups.. Only one trial evaluated the effect of enalapril in childhood cancer survivors with asymptomatic cardiac dysfunction. Although there is some evidence that enalapril temporarily improves one parameter of cardiac function (LVESWS), it is unclear whether it improves clinical outcomes. Enalapril was associated with a higher risk of dizziness or hypotension and fatigue. Clinicians should weigh the possible benefits with the known side effects of enalapril in childhood cancer survivors with asymptomatic anthracycline-induced cardiotoxicity.Only one trial evaluated the effect of phosphocreatine in childhood cancer patients with anthracycline-induced cardiotoxicity. Limited data with a high risk of bias showed no significant difference between phosphocreatine and control treatments on echocardiographic function and clinical outcomes.We did not identify any RCTs or CCTs studying other medical interventions for symptomatic or asymptomatic cardiotoxicity in childhood cancer patients or survivors.High-quality studies should be performed.

Topics: Adult; Adult Survivors of Child Adverse Events; Angiotensin-Converting Enzyme Inhibitors; Anthracyclines; Antibiotics, Antineoplastic; Cardiotonic Agents; Child; Enalapril; Heart Failure; Humans; Neoplasms; Phosphocreatine; Randomized Controlled Trials as Topic

Magnetic resonance spectroscopy (MRS) is an established technique for the non-invasive assessment of myocardial metabolism. MRS is ideal for the evaluation of heart failure, as it allows quantification of the primary energy source for all myocardial cellular functions (ATP), the energy reserve phosphocreatine (PCr), and the creatine kinase reaction, which maintains cellular energy equilibrium. PCr forms the primary ATP buffer in the cell via the creatine kinase (CK) reaction and is involved in transporting the chemical energy from the ATP-producing mitochondria to the ATP-consuming contractile proteins. Using 31phosphorus (31P) MRS, a low cardiac PCr/ATP has consistently been found in patients with heart failure, supporting the hypothesis that the failing heart is energy starved. The use of 1H MRS has allowed the detection of total creatine, which when combined with 31P MRS, provides an in depth examination of the creatine kinase reaction. MRS signals from 31P, 1H, 23Na and 13C, including novel hyperpolarization techniques, have provided considerable insight into the understanding of energy metabolism in the healthy and diseased heart.

Topics: Creatine Kinase; Energy Metabolism; Heart Failure; Humans; Magnetic Resonance Spectroscopy; Myocardium; Phosphocreatine; Phosphorus Isotopes; Protons; Rubidium Radioisotopes; Sodium Isotopes

Anthracyclines are frequently used chemotherapeutic agents for childhood cancer that can cause cardiotoxicity during and after treatment. Although several medical interventions in adults with symptomatic or asymptomatic cardiac dysfunction due to other causes are beneficial, it is not known if the same treatments are effective for childhood cancer patients and survivors with anthracycline-induced cardiotoxicity.. To compare the effect of medical interventions on anthracycline-induced cardiotoxicity in childhood cancer patients or survivors with the effect of placebo, other medical interventions or no treatment.. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) (The Cochrane Library, 2011, issue 1), MEDLINE/PubMed (1949 to May 2011) and EMBASE/Ovid (1980 to May 2011) for potentially relevant articles. We additionally searched reference lists of relevant articles, conference proceedings and ongoing trial databases.. Randomised controlled trials (RCTs) or controlled clinical trials (CCTs) comparing the effectiveness of medical interventions to treat anthracycline-induced cardiotoxicity with either placebo, other medical interventions or no treatment.. Two review authors independently performed the study selection. One review author performed the data extraction and 'Risk of bias' assessments which were checked by another review author.. We identified two RCTs. One trial (135 patients) compared enalapril with placebo in childhood cancer survivors with asymptomatic anthracycline induced cardiac dysfunction. The other trial (68 patients) compared a two-week treatment of phosphocreatine with a control treatment (vitamin C, ATP, vitamin E, oral coenzyme Q10) in leukaemia patients with anthracycline-induced cardiotoxicity. Both studies had methodological limitations.The RCT on enalapril showed no (statistically) significant differences in overall survival, mortality due to heart failure, development of clinical heart failure and quality of life between treatment and control group. A post-hoc analysis showed a decrease (i.e. improvement) in one measure of cardiac function (left ventricular end systolic wall stress (LVESWS): -8.62% change) compared with placebo (+1.66% change) in the first year of treatment (P = 0.036), but not afterwards. Patients treated with enalapril had a higher risk of dizziness or hypotension (RR 7.17, 95% CI 1.71 to 30.17) and fatigue (Fisher's exact test, P = 0.013).The RCT on phosphocreatine found no differences in overall survival, mortality due to heart failure, echocardiographic cardiac function and adverse events between treatment and control group.. For the effect of enalapril in childhood cancer survivors with asymptomatic cardiac dysfunction, only one RCT is available. Although there is some evidence that enalapril temporarily improves one parameter of cardiac function (LVESWS), it is unclear whether it improves clinical outcomes. Enalapril was associated with a higher risk of dizziness or hypotension and fatigue. Clinicians should weigh the possible benefits with the known side-effects of enalapril in childhood cancer survivors with asymptomatic anthracycline-induced cardiotoxicity.For the effect of phosphocreatine in childhood cancer patients with anthracycline-induced cardiotoxicity, only one RCT is available. Limited data with a high risk of bias showed no significant difference between phosphocreatine and control treatment on echocardiographic function and clinical outcomes.We did not identify any RCTs or CCTs studying other medical interventions for symptomatic or asymptomatic cardiotoxicity in childhood cancer patients or survivors.High-quality studies should be performed.

Topics: Adult; Anthracyclines; Antibiotics, Antineoplastic; Child; Enalapril; Heart Failure; Humans; Phosphocreatine; Randomized Controlled Trials as Topic; Survivors

The creatine kinase system, the central regulatory system of cellular energy metabolism, provides ATP in situ at ATP-ases involved in ion transport and muscle contraction. Furthermore, the enzyme system provides relative protection from tissue ischaemia and acidosis. The system could therefore be a target for pharmacologic intervention.. To systematically evaluate evidence regarding the effectiveness of interventions directly targeting the creatine kinase system as compared to placebo control in adult patients with essential hypertension or cardiovascular disease.. Electronic databases searched: Medline (1950 - Feb 2011), Embase (up to Feb 2011), the Cochrane Controlled Trials Register (issue 3, Aug 2009), Latin-American/Caribbean databank Lilacs; references from textbooks and reviews; contact with experts and pharmaceutical companies; and searching the Internet. There was no language restriction.. Randomized controlled trials comparing creatine, creatine phosphate, or cyclocreatine (any route, dose or duration of treatment) with placebo; in adult patients with essential hypertension, heart failure, or myocardial infarction. We did not include papers on the short-term use of creatine during cardiac surgery.. The outcomes assessed were death, total myocardial infarction (fatal or non-fatal), hospitalizations for congestive heart failure, change in ejection fraction, and changes in diastolic and systolic blood pressure in mm Hg or as percent change.. Full reports or abstracts from 1164 papers were reviewed, yielding 11 trials considering treatment with creatine or creatine analogues in 1474 patients with heart failure, ischemic heart disease or myocardial infarction. No trial in patients with hypertension was identified. Eleven trials (1474 patients, 35 years or older) comparing add-on therapy of the creatine-based drug on standard treatment to placebo control in patients with heart failure (6 trials in 1226 / 1474 patients ), or acute myocardial infarction (4 trials in 220 / 1474 patients) or 1 in ischemic heart disease (28 / 1474 patients) were identified. The drugs used were either creatine, creatine phosphate (orally, intravenously, or intramuscular) or phosphocreatinine. In the trials considering heart failure all three different compounds were studied; creatine orally (Gordon 1995, Kuethe 2006), creatine phosphate via intravenous infusion (Ferraro 1996, Grazioli 1992), and phosphocreatinine orally (Carmenini 1994, Maggi 1990). In contrast, the acute myocardial infarction trials studied intravenous creatine phosphate only. In the ischemic heart disease trial (Pedone 1984) creatine phosphate was given twice daily through an intramuscular injection to outpatients and through an intravenous infusion to inpatients. The duration of the study intervention was shorter for the acute patients, from a two hour intravenous infusion of creatine phosphate in acute myocardial infarction (Ruda 1988, Samarenko 1987), to six months in patients with heart failure on oral phosphocreatinine therapy (Carmenini 1994). In the acute myocardial infarction patients the follow-up period varied from the acute treatment period (Ruda 1988) to 28 days after start of the symptoms (Samarenko 1987) or end of the hospitalization period (Zochowski 1994). In the other trials there was no follow-up after discontinuation of treatment, except for Gordon 1995 which followed the patients until four days after stopping the intervention.Only two out of four trials in patients with acute myocardial infarction reported mortality outcomes, with no significant effect of creatine or creatine analogues (RR 0.73, CI: 0.22 - 2.45). In addition, there was no significance on the progression of myocardial infarction or improvement on ejection fraction. The main effect of the interventions seems to be on improvement of dysrhythmia.. This review found inconclusive evidence to decide on the use of creatine analogues in clinical practice. In particular, it is not clear whether there is an effect on mortality, progression of myocardial infarction and ejection fraction, while there is some evidence that dysrhythmia and dyspnoea might improve. However, it is not clear which analogue, dose, route of administration, and duration of therapy is most effective. Moreover, given the small sample size of the discussed trials and the heterogeneity of the population included in these reports, larger clinical studies are needed to confirm these observations.

Topics: Cardiovascular Diseases; Creatine; Creatine Kinase; Heart Failure; Humans; Hypertension; Molecular Targeted Therapy; Myocardial Infarction; Myocardial Ischemia; Phosphocreatine

The ubiquitin proteasome system plays a role in regulating protein activity and is integral to the turnover of damaged and worn proteins. In this review, we discuss the recently described relationship between the ubiquitin proteasome system and the cardiac creatine kinase/phosphocreatine shuttle, an essential component of adenosine triphosphate generation and energy shuttling within the heart. The ubiquitin ligase muscle ring finger-1 (MuRF1) binds creatine kinase, leading to its ubiquitination and possible degradation. Muscle ring finger-1 may also be integral in the regulation of creatine kinase activity in vivo. Because there is a close relationship between the cardiac creatine kinase/phosphocreatine shuttle activity and heart failure, these findings suggest that MuRF1's role in protein quality control of creatine kinase may be vital to the regulation and maintenance of cardiac energetics to protect against heart failure.

Topics: Animals; Creatine Kinase, MB Form; Energy Metabolism; Heart Failure; Humans; Muscle Proteins; Myocardium; Phosphocreatine; Proteasome Endopeptidase Complex; Protein Processing, Post-Translational; Tripartite Motif Proteins; Ubiquitin-Protein Ligases; Ubiquitination

Myocytes of the failing heart undergo impressive metabolic remodelling. The time line for changes in the pathways for ATP synthesis in compensated hypertrophy is: flux through the creatine kinase (CK) reaction falls as both creatine concentration ([Cr]) and CK activity fall; increases in [ADP] and [AMP] lead to increases in glucose uptake and utilization; fatty acid oxidation either remains the same or decreases. In uncompensated hypertrophy and in other forms of heart failure, CK flux and fatty acid oxidation are both lower; any increases in glucose uptake and utilization are not sufficient to compensate for overall decreases in the capacity for ATP supply and [ATP] falls. Metabolic remodelling is under transcriptional and post-transcriptional control. The lower metabolic reserve of the failing heart contributes to impaired contractile reserve.

Topics: Adenosine Triphosphate; Adenylate Kinase; Animals; Cardiomyopathy, Hypertrophic, Familial; Creatine Kinase; Energy Metabolism; Glycolysis; Heart Failure; Humans; Mitochondria, Heart; Myocardial Contraction; Myocardium; Phenotype; Phosphocreatine; Protein Processing, Post-Translational; Time Factors; Transcription, Genetic; Ventricular Remodeling

Magnetic resonance spectroscopy (MRS) has been used for several decades to examine the biochemistry of the myocardium in a non destructive manner. (31)P MRS, in particular, has been used to study heart failure. (31)P MRS allows for the detection of adenosine triphosphate (ATP), the primary energy source for all energy consuming processes in cardiomyocytes, and phosphocreatine (PCr). Via the creatine kinase (CK) reaction PCr forms the primary ATP buffer in the cell and is involved in transporting the chemical energy from the ATP-producing mitochondria to the ATP-consuming contractile proteins. MRS examination of the failing heart has revealed that PCr, and to a lesser extent, ATP is reduced. These findings have led to the concept that the heart is energy starved. The additional application of (1)H MRS has allowed for the detection of total creatine, allowing for in depth examination of the creatine kinase system. Using saturation transfer techniques it is also possible to measure flux through the CK reaction in the intact heart, and the application of this technique has proven that in the failing human heart this flux is reduced. In recent years the study of transgenic animal models by MRS has led to further insights into the role of energy metabolism in heart failure.

Topics: Adenosine Triphosphate; Animals; Creatine Kinase; Heart Failure; Humans; Myocardium; Myocytes, Cardiac; Nuclear Magnetic Resonance, Biomolecular; Phosphocreatine

Magnetic resonance spectroscopy (MRS) allows for the non-invasive detection of a wide variety of metabolites in the heart. To study the metabolic changes that occur in heart failure, (31)P- and (1)H-MRS have been applied in both patients and experimental animal studies. (31)P-MRS allows for the detection of phosphocreatine (PCr), ATP, inorganic phosphate (Pi) and intracellular pH, while (1)H-MRS allows for the detection of total creatine. All these compounds are involved in the regulation of the available energy from ATP hydrolysis via the creatine kinase (CK) reaction. Using cardiac MRS, it has been found that the PCr/CK system is impaired in the failing heart. In both, patients and experimental models, PCr levels as well as total creatine levels are reduced, and in severe heart failure ATP is also reduced. PCr/ATP ratios correlate with the clinical severity of heart failure and, importantly, are a prognostic indicator of mortality in patients. In addition, the chemical flux through the CK reaction, measured with (31)P saturation transfer MRS, is reduced more than the steady-state levels of high-energy phosphates in failing myocardium in both experimental models and in patients. Experimental studies suggest that these changes can result in increased free ADP levels when the failing heart is stressed. Increased free ADP levels, in turn, result in a reduction in the available free energy of ATP hydrolysis, which may directly contribute to contractile dysfunction. Data from transgenic mouse models also suggest that an intact creatine/CK system is critical for situations of cardiac stress.

Topics: Adenosine Triphosphate; Animals; Biomarkers; Creatine Kinase; Heart Failure; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Mice; Mice, Transgenic; Phosphates; Phosphocreatine

Physicians' use of micronutrients to improve symptoms or outcomes in chronic illness has until recently been guided by limited data on the actions of individual agents in vitro or in animal studies. However several recently published clinical trials have provided information about which groups of patients are likely to benefit from which combination of micronutrients. Patients with chronic cardiac failure (CCF), particularly elderly individuals, have several reasons to be deficient in micronutrients including reduced intake, impaired gastrointestinal absorption and increased losses on the background of increased utilisation due for example to increased oxidative stress. Studies of nutritional supplementation in CCF patients have usually concentrated on specific agents. However given that many micronutrients have synergistic influences upon metabolic processes this strategy might merely lead to a shifting of a limiting step. Rather, a strategy of increasing the availability of multiple agents at once might be more logical. The aim of this article is to briefly review the experimental rationale for each of the micronutrients of potential benefit in chronic heart failure and examine the current clinical trial evidence supporting their use.

Topics: Animals; Antioxidants; Ascorbic Acid; Calcium; Carnitine; Copper; Dietary Supplements; Heart Failure; Humans; Magnesium; Magnesium Deficiency; Micronutrients; Niacin; Oxidative Stress; Phosphocreatine; Ubiquinone; Vitamin B Complex; Vitamin B Deficiency; Vitamin E; Zinc

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.

Topics: Adenosine Triphosphate; Adenylate Kinase; Animals; Cardiomyopathy, Hypertrophic, Familial; Creatine Kinase; Diastole; Energy Metabolism; Forecasting; Heart Failure; Humans; Hypertrophy, Left Ventricular; Isoenzymes; Mice; Mitochondria, Heart; Myocardial Ischemia; Phosphocreatine; Stress, Physiological

Magnetic resonance spectroscopy (MRS) can noninvasively provide a window into the metabolic status of the heart. This technique has shown abnormalities in the phosphocreatine-to-adenosine triphosphate ratio in patients with severe cardiomyopathies, either dilated or hypertrophic. Data indicate that abnormal metabolic parameters can risk stratify patients with dilated cardiomyopathy and provide independent prognostic information. Finally, the use of MRS in patients after cardiac transplantation is being explored. The information from cardiac MRS will likely provide the investigator and clinician with unique data and assist in the diagnosis and management of patients with various forms of heart disease.

Topics: Adenosine Triphosphate; Animals; Cardiomyopathy, Dilated; Cardiomyopathy, Hypertrophic; Heart Failure; Heart Transplantation; Humans; Magnetic Resonance Spectroscopy; Muscle, Skeletal; Phosphocreatine; Phosphorus Isotopes; Predictive Value of Tests; Risk Assessment

This article takes three different approaches to the question of whether the failing heart is in an energy-starved state. A brief historical overview introduces the issue and points out problems in both models and methods. Second, current information regarding the energetic state of the failing heart is examined. Finally, the mechanistic and therapeutic implications of a defect in energy production are described.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Coronary Circulation; Energy Metabolism; Heart Failure; Humans; Mitochondria, Heart; Myocardium; Phosphocreatine

Our understanding of the pathogenesis and therapy of heart failure has evolved through three paradigms. Organ physiology, the first paradigm, focused therapy of heart failure on salt and water retention and vasoconstriction, which represent major circulatory responses to, cardiac pumping. The second paradigm of cell biochemistry led to the development of powerful inotropic agents designed to increase myocardial contractility. The third paradigm, gene expression (molecular biology), describes regulatory mechanisms that are both primitive and complex; in the setting of heart failure, this paradigm focuses on the roles of altered myocardial cell growth and composition in explaining the accelerated deterioration of the hypertrophied, failing heart. This review focuses on one aspect of the second paradigm: factors that contribute to a state of energy-starvation and the resulting functional consequences in the failing heart.

Topics: Adenosine Triphosphate; Energy Metabolism; Heart Failure; Humans; Ion Pumps; Myocardial Contraction; Myocardium; Phosphocreatine

Topics: Blood Circulation; Cardiac Volume; Cardiomegaly; Cyclic AMP; Electric Countershock; Glycolysis; Heart; Heart Failure; Heart Transplantation; Heart, Artificial; Humans; Kidney; Myocardial Contraction; Myocardium; Oxidative Phosphorylation; Pacemaker, Artificial; Phosphocreatine; Protein Biosynthesis; Sympathetic Nervous System; Transplantation, Homologous

Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Animals; Calcium; Cardiomegaly; Coronary Disease; Digitalis Glycosides; Heart Failure; Hemodynamics; Humans; Myocardium; Myosins; Necrosis; Norepinephrine; Oxygen Consumption; Phosphocreatine; Propranolol

Topics: Animals; Cardiomyopathies; Cell Nucleus; Cricetinae; Cytoplasm; DNA; Dogs; Golgi Apparatus; Heart Failure; Humans; Hypertrophy; Hypoxia; Microscopy, Electron; Mitochondria, Muscle; Myocardium; Phosphocreatine; Protein Biosynthesis; Rabbits; Rats; RNA; Sarcolemma

Topics: Adenosine Triphosphate; Angina Pectoris; Animals; Aortic Valve Insufficiency; Cricetinae; Dilatation; Dogs; Endoplasmic Reticulum; Golgi Apparatus; Heart Failure; Humans; Hypoxia; Lactates; Microscopy, Electron; Mitochondria, Muscle; Myocardium; Myofibrils; Necrosis; Oxygen Consumption; Papillary Muscles; Phosphates; Phosphocreatine; Polyribosomes; Rabbits; Rats

Topics: Adenosine Triphosphate; Basal Metabolism; Heart Failure; Humans; Kinetics; Mitochondria, Muscle; Muscle Contraction; Myocardium; Myofibrils; Oxygen Consumption; Phosphocreatine

Topics: Adenosine Triphosphate; Amino Acids; Calcium; Cardiomegaly; Endoplasmic Reticulum; Heart Failure; Humans; Mitochondria; Muscle Contraction; Myocardium; Oxygen Consumption; Phosphocreatine; Protein Biosynthesis; Stress, Physiological; Synaptic Transmission

Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Animals; Biomechanical Phenomena; Calcium; Cardiomegaly; Catecholamines; Cats; Chemoreceptor Cells; Dogs; Guinea Pigs; Heart Failure; Heart Ventricles; Humans; Mitochondria, Muscle; Mixed Function Oxygenases; Muscle Contraction; Muscle Proteins; Norepinephrine; Oxidative Phosphorylation; Phosphocreatine; Sympathetic Nervous System; Tyrosine

Impaired myocardial energy homeostasis plays an import role in the pathophysiology of heart failure with preserved ejection fraction (HFpEF). Left ventricular relaxation has a high energy demand, and left ventricular diastolic dysfunction has been related to impaired energy homeostasis. This study investigated whether trimetazidine, a fatty acid oxidation inhibitor, could improve myocardial energy homeostasis and consequently improve exercise haemodynamics in patients with HFpEF.. Trimetazidine did not improve myocardial energy homeostasis and did not improve exercise haemodynamics in patients with HFpEF.

Topics: Adenosine Triphosphate; Aged; Cross-Over Studies; Female; Heart Failure; Humans; Male; Phosphocreatine; Stroke Volume; Trimetazidine

Heart failure is a major cause of morbidity and mortality in society. Current medical therapy centres on neurohormonal modulation with angiotensin converting enzyme inhibitors and β-blockers. There is growing evidence for the use of metabolic manipulating agents as adjunctive therapy in patients with heart failure. We aim to determine the effect of perhexiline on cardiac energetics and alterations in substrate utilisation in patients with non-ischaemic dilated cardiomyopathy.. A multi-centre, prospective, randomised double-blind, placebo-controlled trial of 50 subjects with non-ischaemic dilated cardiomyopathy recruited from University Hospital Birmingham NHS Foundation Trust and Cardiff and Vale NHS Trust. Baseline investigations include magnetic resonance spectroscopy to assess cardiac energetic status, echocardiography to assess left ventricular function and assessment of symptomatic status. Subjects are then randomised to receive 200 mg perhexiline maleate or placebo daily for 4 weeks with serum drug level monitoring. All baseline investigations will be repeated at the end of the treatment period. A subgroup of patients will undergo invasive investigations with right and left heart catheterisation to calculate respiratory quotient, and mechanical efficiency. The primary endpoint is an improvement in the phosphocreatine to adenosine triphosphate ratio at 4 weeks. Secondary end points are: i) respiratory quotient; ii) mechanical efficiency; iii) change in left ventricular (LV) function.. ClinicalTrials.gov: NCT00841139 ISRCTN: ISRCTN72887836.

Topics: Adenosine Triphosphate; Cardiac Catheterization; Cardiomyopathy, Dilated; Cardiovascular Agents; Double-Blind Method; Drug Monitoring; Echocardiography, Doppler; Energy Metabolism; Heart Failure; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Myocardium; Perhexiline; Phosphocreatine; Placebo Effect; Prospective Studies; Recovery of Function; Research Design; Stroke Volume; Time Factors; Treatment Outcome; United Kingdom; Ventricular Function, Left

To investigate the therapeutic effects of phosphocreatine in elderly patients with chronic congestive heart failure (CHF) and its effects on plasma brain natriuretic peptide (BNP).. Forty elderly patients with chronic CHF were randomly divided into two groups to receive basic treatment (control group) and additional phosphocreatine treatment (treatment group) with a treatment course of 8 weeks. The patients were evaluated for improvement in New York Heart Association (NYHA) functional class, symptoms, left ventricular end-diastolic diameter (LVEDD), left ventricular end-systolic diameter (LVESD), and left ventricular ejection fraction (LVEF) and the levels of BNP before and after treatment.. After 8 weeks of treatment, the overall efficacy rate was significantly higher in treatment group than in the control group, and LVESD, LVEDD, LVEF and BNP level of the treatment group were significantly lowered in comparison with those of the control group (P<0.05).. Phosphocreatine in addition to the basic treatment can reduce the BNP level and improve the cardiac systolic and diastolic function in elderly patients with chronic CHF.

Topics: Aged; Aged, 80 and over; Cardiotonic Agents; Female; Heart Failure; Humans; Male; Natriuretic Peptide, Brain; Phosphocreatine; Ventricular Dysfunction, Left

Chronic heart failure (CHF) is associated with abnormalities of skeletal muscle metabolism. This may be due to impaired oxygen delivery as a result of endothelial dysfunction.. We postulated that ascorbic acid would improve oxygen delivery to exercising muscle and improve skeletal muscle metabolism.. We studied skeletal muscle metabolism using (31)P magnetic resonance spectroscopy in 39 CHF patients. Endothelial function was assessed by changes in pulse wave velocity. Subjects were randomised to receive 4 g ascorbic acid daily for 4 weeks in a placebo-controlled double-blind study.. Ascorbic acid significantly increased phosphocreatine utilization during exercise. In addition, glycolytic ATP synthesis increased in the ascorbic acid group (change in rate of ATP synthesis at 1 min -0.21+/-0.76 with placebo, 2.06+/-0.60 following ascorbic acid; p<0.05). Phosphocreatine and ADP recovery after exercise were not changed. The fall in pulse wave velocity during reactive hyperaemia was increased by ascorbic acid from -6.3+/-2.6% to -12.1+/-2.0% (p<0.05).. These findings suggest that ascorbic acid increased both phosphocreatine utilization and glycolytic ATP synthesis during exercise in patients with CHF implying worsened skeletal muscle metabolism despite improvements in endothelial function.

Topics: Adenosine Triphosphate; Aged; Ascorbic Acid; Chronic Disease; Double-Blind Method; Endothelium, Vascular; Female; Heart Failure; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscle, Skeletal; Phosphocreatine; United Kingdom

The addition of trimetazidine to standard treatment has been shown to improve left ventricular (LV) function in patients with heart failure. The aim of this study is to non-invasively assess, by means of in vivo 31P-magnetic resonance spectroscopy (31P-MRS), the effects of trimetazidine on LV cardiac phosphocreatine and adenosine triphosphate (PCr/ATP) ratio in patients with heart failure.. Twelve heart failure patients were randomized in a double-blind, cross-over study to placebo or trimetazidine (20 mg t.i.d.) for two periods of 90 days. At the end of each period, all patients underwent exercise testing, 2D echocardiography, and MRS. New York Heart Association (NYHA) class, ejection fraction (EF), maximal rate-pressure product, and metabolic equivalent system (METS) were evaluated. Relative concentrations of PCr and ATP were determined by cardiac 31P-MRS. On trimetazidine, NYHA class decreased from 3.04+/-0.26 to 2.45+/-0.52 (P = 0.005), whereas EF (34+/-10 vs. 39+/-10%, P = 0.03) and METS (from 7.44+/-1.84 to 8.78+/-2.72, P = 0.03) increased. The mean cardiac PCr/ATP ratio was 1.35+/-0.33 with placebo, but was increased by 33% to 1.80+/-0.50 (P = 0.03) with trimetazidine.. Trimetazidine improves functional class and LV function in patients with heart failure. These effects are associated to the observed trimetazidine-induced increase in the PCr/ATP ratio, indicating preservation of the myocardial high-energy phosphate levels.

Topics: Adenosine Triphosphate; Aged; Cross-Over Studies; Double-Blind Method; Echocardiography; Female; Heart Failure; Hemodynamics; Humans; Magnetic Resonance Angiography; Male; Phosphocreatine; Prospective Studies; Trimetazidine; Vasodilator Agents; Ventricular Dysfunction, Left

The aim of the present study was to investigate the possibility of phosphorus magnetic resonance spectroscopy (MR spectroscopy) in the diagnosis of metabolic lesions of skeletal musculature in patients with intermittent claudication syndrome, chronic cardiac failure, and varicose diseases of the lower limbs. Studies included 50 males: 20 patients with intermittent claudication, 10 patients with chronic cardiac failure, and 10 patients with varicose veins. The control group consisted of 10 healthy volunteers. The following measures were determined: the phosphocreatinine index, the intracellular pH in the gastrocnemius muscle, and the half-recovery time for the phosphocreatinine index. The phosphocreatinine index and the pH at rest did not differ between study groups. Isotonic exercise produced no change in the phosphocreatinine index in the control group; patients with intermittent claudication showed a 26.1% decrease, patients with chronic cardiac failure showed an 8% decrease, and patients with varicose veins showed a 25.6% decrease. The only group showing a significant decrease in pH during exercise was the group of patients with intermittent claudication. This group also showed an inverse correlation between the pressure index and the extent of the decrease in the phosphocreatinine index. Thus, MR spectroscopy provides a non-invasive diagnostic method for lesions of energy metabolism in skeletal musculature in patients with deranged peripheral hemodynamics.

Topics: Adult; Aged; Arteriosclerosis Obliterans; Biomarkers; Energy Metabolism; Heart Failure; Humans; Intermittent Claudication; Leg; Magnetic Resonance Imaging; Male; Middle Aged; Muscle, Skeletal; Phosphocreatine; Phosphorus; Reference Values; Varicose Veins

To investigate whether localised skeletal muscle training, which does not have a great influence on the heart, improves abnormalities of calf muscle metabolism in patients with chronic heart failure.. Seven cardiac patients in New York Heart Association class II and III undertook a random order crossover trial. Training consisted of unilateral calf plantar flexion exercise. Before and after training, the patients' metabolic responses were examined during the calf exercise test with phosphorus-31 nuclear magnetic resonance spectroscopy (31P-MRS) and calf blood flow with plethysmography. The new Borg scale was employed as a subjective fatigue scale.. In a constant load exercise test (70% of maximum load achieved during the incremental exercise), standardised phosphocreatine and intracellular pH decreased less after training (p < 0.05, repeated measures analysis of variance). The new Borg scale improved significantly after training (p < 0.05). Blood flow did not change significantly in either test.. In patients with chronic heart failure, localised calf skeletal muscle training improved oxidative capacity without changes in calf blood flow. This training also improved the subjective fatigue scale. This training method may therefore alleviate leg fatigue experienced in daily activities.

Topics: Aged; Analysis of Variance; Cross-Over Studies; Exercise Therapy; Female; Heart Failure; Humans; Leg; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscle, Skeletal; Phosphocreatine; Plethysmography; Regional Blood Flow

Echocardiography and integral body rheography were made in 174 patients with macrofocal myocardial infarction (MI) to study hemodynamics at six stages of hospital rehabilitation (MI day 1-28). 97 patients received neoton (4 different scheme) in the acute period of MI. Neoton administration was found to prevent progressive left ventricular dilation and emergence of cardiac insufficiency in subacute period of MI, to reduce the risk of cardiac aneurism, recurrence and postinfarction angina. The response to neoton rises with an increase of its dose on the first day of the disease and lessening of the time span from first symptoms of MI and first neoton injection. An optimal scheme of neoton use is proposed.

Topics: Adult; Aged; Cardiotonic Agents; Echocardiography; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Phosphocreatine; Plethysmography, Impedance; Treatment Outcome

The use of metabolic drugs effective in addition to conventional therapy represents a significant challenge in patients with left ventricular dysfunction.. The aim of this double-blind, placebo-controlled study was to investigate the hemodynamic effects of acute intravenous (i.v.) administration of creatine phosphate (CP) and of short-term treatment in patients with congestive heart failure (CHF) from ischemic heart disease (IHD) or dilated cardiomyopathy in addition to conventional therapy.. We compared the hemodynamic effects of exogenous creatine phosphate (CP) and placebo in a double-blind, crossover design study in 13 hospitalized patients (12 men, 1 woman, mean age 52 +/- 8 years) with CHF. All patients were in New York Heart Association (NYHA) class II-III and received conventional pharmacologic therapy for CHF; this was not changed during the study period. The study design consisted of two treatment periods (CP or placebo and placebo or CP, respectively) of 4 days each, separated by a 2-day washout interval. The intravenous infusion consisted of 6 g CP or placebo (acute treatment) or 6 g CP or placebo daily for 4 days (short-term treatment) diluted in 50 ml of NaCl 0.9%; infusion duration was about 10 min. Mono-bidimensional echocardiographic examination (Hewlett Packard Sonos 1000, with a 2.5 MHz transducer) was performed at baseline, after acute infusion, and 12 h after the end of short-term treatment. Data were analyzed by ANOVA and Student's t-test for paired data; the results obtained after acute and short-term therapy were compared with the baseline values.. After placebo therapy, no significant change was observed. The results after treatment with CP showed a significant reduction of end-systolic diameter [baseline: 4.5 +/- 0.6; acute: 4.2 +/- 0.5, (p < 0.001); short-term 4.3 +/- 0.6 cm, (p < 0.05)] and systemic vascular resistance (baseline: 1064.9 +/- 483.7; acute: 947.5 +/- 390.2 (p < 0.05); short-term: 950.7 +/- 394.3 dyne-s-cm-5 (p < 0.05); moreover, a significant increase of percent ejection fraction [baseline: 48 +/- 12%; acute 53 +/- 12% (p < 0.01); short-term 52 +/- 11% (p < 0.01)], and of percent fractional shortening [baseline: 25 +/- 7; acute 28 +/- 8 (p < 0.05); short-term 28 +/- 7% (p < 0.05)] was observed.. CP was shown to improve cardiac function, even in the presence of a conventional CHF pharmacologic therapy.

Topics: Cross-Over Studies; Double-Blind Method; Echocardiography; Female; Heart; Heart Failure; Hemodynamics; Humans; Male; Phosphocreatine

Using nuclear magnetic resonance (NMR), we have examined the relationship of high-energy phosphate metabolism and perfusion in human soleus and gastrocnemius muscles. With 31P-NMR spectroscopy, we monitored phosphocreatine (PCr) decay and recovery in eight normal volunteers and four heart failure patients performing ischemic plantar flexion. By using echo-planar imaging, perfusion was independently measured by a local [inversion-recovery (T1-flow)] and a regional technique (NMR-plethysmography). After correction for its pH dependence, PCr recovery time constant is 27.5 +/- 8.0 s in normal volunteers, with mean flow 118 +/- 75 (soleus and gastrocnemius T1-flow) and 30.2 +/- 9.7 ml.100 ml-1.min-1 (NMR-plethysmography-flow). We demonstrate a positive correlation between PCr time constant and local perfusion given by y = 50 - 0.15x (r2 = 0.68, P = 0.01) for the 8 normal subjects, and y = 64 - 0.24x (r2 = 0.83, P = 0.0001) for the 12 subjects recruited in the study. Regional perfusion techniques also show a significant but weaker correlation. Using this totally noninvasive method, we conclude that aerobic ATP resynthesis is related to the magnitude of perfusion, i.e., O2 availability, and demonstrate that magnetic resonance imaging and magnetic resonance spectroscopy together can accurately assess muscle functional status.

Topics: Adult; Exercise; Heart Failure; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Muscle, Skeletal; Oxidation-Reduction; Phosphocreatine; Plethysmography; Regional Blood Flow; Supine Position

Cardiac creatine levels are depressed in chronic heart failure. Oral supplementation of creatine to healthy volunteers has been shown to increase physical performance.. To evaluate the effects of creatine supplementation on ejection fraction, symptom-limited physical endurance and skeletal muscle strength in patients with chronic heart failure.. With a double-blind, placebo-controlled design 17 patients (age 43-70 years, ejection fraction < 40) were supplemented with creatine 20 g daily for 10 days. Before and on the last day of supplementation ejection fraction was determined by radionuclide angiography as was symptom-limited 1-legged knee extensor and 2-legged exercise performance on the cycle ergometer. Muscle strength as unilateral concentric knee extensor performance (peak torque, Nm at 180 degrees/s) was also evaluated. Skeletal muscle biopsies were taken for the determination of energy-rich phosphagens.. Ejection fraction at rest and at work did not change. Performance before creatine supplementation did not differ between placebo and creatine groups. While no change was seen in the placebo group compared to baseline, creatine supplementation increased skeletal muscle total creatine and creatine phosphate by 17 +/- 4% (P < 0.05) and 12 +/- 4% (P < 0.05), respectively. Increments were seen only in patients with < 140 mmol total creatine/kg d.w. (P < 0.05). One-legged performance (21%, P < 0.05), 2-legged performance (10%, P < 0.05), and peak torque, Nm (5%, P < 0.05) increased. Both peak torque and 1-legged performance increased linearly with increased skeletal muscle phosphocreatine (P < 0.05). The increments in 1-legged, 2-legged and peak torque were significant compared to the placebo group, (P < 0.05).. One week of creatine supplementation to patients with chronic heart failure did not increase ejection fraction but increased skeletal muscle energy-rich phosphagens and performance as regards both strength and endurance. This new therapeutic approach merits further attention.

Topics: Administration, Oral; Adult; Aged; Cardiac Output; Chronic Disease; Creatine; Double-Blind Method; Heart Failure; Humans; Male; Middle Aged; Muscle, Skeletal; Phosphocreatine; Physical Endurance; Radionuclide Angiography

This study investigated the effects of physical training on skeletal muscle metabolism in patients with chronic heart failure.. Skeletal muscle metabolic abnormalities in patients with chronic heart failure have been associated with exercise intolerance. Muscle deconditioning is a possible mechanism for the intrinsic skeletal muscle metabolic changes seen in chronic heart failure.. We used phosphorus-31 nuclear magnetic resonance spectroscopy to study muscle metabolism during exercise in 12 patients with stable ischemic chronic heart failure undergoing 8 weeks of home-based bicycle exercise training in a randomized crossover controlled trial. Changes in muscle pH and concentrations of phosphocreatine and adenosine diphosphate (ADP) were measured in phosphorus-31 spectra of calf muscle obtained at rest, throughout incremental work load plantar flexion until exhaustion and during recovery from exercise. Results were compared with those in 15 age-matched control subjects who performed a single study only.. Before training, phosphocreatine depletion, muscle acidification and the increase in ADP during the 1st 4 min of plantar flexion exercise were all increased (p < 0.04) compared with values in control subjects. Training produced an increase (p < 0.002) in incremental plantar flexion exercise tolerance. After training, phosphocreatine depletion and the increase in ADP during exercise were reduced significantly (p < 0.003) at all matched submaximal work loads and at peak exercise, although there was no significant change in the response of muscle pH to exercise. After training, changes in ADP were not significantly different from those in control subjects, although phosphocreatine depletion was still greater (p < 0.05) in trained patients than in control subjects. The phosphocreatine recovery half-time was significantly (p < 0.05) shorter after training, although there was no significant change in the half-time of adenosine diphosphate recovery. In untrained subjects, the initial rate of phosphocreatine resynthesis after exercise (a measure of the rate of oxidative adenosine triphosphate [ATP] synthesis) and the inferred maximal rate of mitochondrial ATP synthesis were reduced compared with rates in control subjects (p < 0.003) and both were significantly increased (p < 0.05) by training, so that they were not significantly different from values in control subjects.. The reduction in phosphocreatine depletion and in the increase in ADP during exercise, and the enhanced rate of phosphocreatine resynthesis in recovery (which is independent of muscle mass) indicate that a substantial correction of the impaired oxidative capacity of skeletal muscle in chronic heart failure can be achieved by exercise training.

Topics: Adenosine Diphosphate; Adult; Aged; Cardiac Output; Chronic Disease; Exercise Therapy; Exercise Tolerance; Heart Failure; Humans; Male; Middle Aged; Muscles; Oxygen Consumption; Phosphocreatine

By using biopsies, skeletal muscle metabolism was investigated in 22 patients with severe chronic heart failure. All the patients were in New York Heart Association functional class IV and constituted a subgroup of the previously published CONSENSUS trial. After this initial investigation of muscle metabolism in patients with chronic heart failure, the influence of the angiotensin converting enzyme inhibitor, enalapril, on skeletal muscle metabolism was studied by randomizing the patients in a double-blind manner to receive either placebo (n = 11) or enalapril (n = 11) in addition to conventional treatment. At the time of inclusion, the muscle content of energy-rich compounds, i.e. glycogen and the high energy phosphates, adenosine triphosphate (ATP) and phosphocreatine, was reduced as compared with healthy subjects and muscle lactate content tended to be higher than normal. Following study treatment, no significant changes occurred, neither within nor between the two subgroups. Thus, patients with severe chronic congestive heart failure display metabolic derangement in muscle, which, in this study, was not corrected by treatment with enalapril.

Topics: Adenosine Triphosphate; Aged; Aged, 80 and over; Biopsy; Double-Blind Method; Drug Therapy, Combination; Enalapril; Energy Metabolism; Exercise Test; Female; Furosemide; Glycogen; Heart Failure; Hemodynamics; Humans; Lactates; Lactic Acid; Male; Middle Aged; Muscles; Phosphocreatine; Survival Rate

Topics: Adolescent; Adult; Clinical Trials as Topic; Digitalis Glycosides; Diuretics; Heart; Heart Failure; Humans; Middle Aged; Phosphocreatine; Potassium

Topics: Angina Pectoris; Arrhythmias, Cardiac; Arteriosclerosis; Clinical Trials as Topic; Coronary Disease; Heart Failure; Humans; Injections, Intravenous; Myocardial Infarction; Phosphocreatine

To study the efficacy and safety of exogenous phosphocreatine (EF) in patients with chronic heart failure (CHF).. The all-Russian prospective observational study BYHEART included 842 patients who were treated with EF. Before and after the course of EF therapy, the following studies were conducted: a questionnaire on the Minnesota Living with Heart Failure Questionnaire (MLHFQ) and a clinical condition assessment scale (SHOCK), transthoracic echocardiography with an assessment of the left ventricular ejection fraction, a 6-minute walk test, determination of the level of pro-natriuretic N-terminal peptide (NT-proBNP), glomerular filtration rate. All patients before the course of EF received long-term optimal drug therapy of CHF.. Statistical analysis was carried out in the general group of patients (n=842), as well as in groups of patients A (n=418, the course of treatment of EF is less than 20 g /course) and group B (n=424, the course of treatment of EF is greater than or equal to 20 g/course). The results obtained demonstrate a positive effect of the use of the course of therapy of EF in patients with CHF on the quality of life (QOL), reverse left ventricular remodeling, functional class of CHF, as well as the concentration of NT-pro-BNP, especially in the group of patients who received more than 20 grams of the medication.. The use of EF is a promising pharmacological method of treatment in addition to optimal drug therapy in patients with CHF.. Цель. Изучить эффективность и безопасность экзогенного фосфокреатина (ЭФ) у пациентов с хронической сердечной недостаточностью (ХСН). Материалы и методы. В общероссийское проспективное наблюдательное исследование BYHEART включены 842 пациента, которым проведен курс лечения ЭФ. До курса терапии ЭФ и после проводились следующие исследования: анкетирование по Миннесотскому опроснику качества жизни больных с ХСН (MHFLQ) и шкале оценки клинического состояния, трансторакальная эхокардиография с оценкой фракции выброса левого желудочка, тест 6-минутной ходьбы, определение уровня пронатрийуретического N-концевого пептида (NT-proBNP), скорости клубочковой фильтрации. Все пациенты до курса ЭФ получали длительную оптимальную медикаментозную терапию ХСН. Результаты. Статистический анализ проводился в общей группе пациентов (n=842), а также в группах пациентов А (n=418, ЭФ20 г на курс) и Б (n=424, ЭФ20 г на курс). Полученные результаты демонстрируют положительное влияние курса терапии ЭФ у пациентов с ХСН на качество жизни, обратное ремоделирование левого желудочка, функциональный класс ХСН, а также концентрацию NT-proBNP, особенно в группе больных, получивших 20 г или более препарата. Заключение. Применение ЭФ является перспективным фармакологическом методом лечения в дополнение к оптимальной медикаментозной терапии у пациентов с ХСН.

Topics: Chronic Disease; Heart Failure; Humans; Natriuretic Peptide, Brain; Peptide Fragments; Phosphocreatine; Quality of Life; Stroke Volume; Ventricular Function, Left

Aim      Improvement of quality of life is one of the most important goals for the treatment of patients with chronic heart failure (CHF). This study searched for ways to increase the efficiency of CHF treatment based on parameters of quality of life in CHF patients during and after the treatment with exogenous phosphocreatine (EP).Material and methods  The effect of a single course of EP treatment on quality of life of patients with functional class (FC) II-IV CHF with reduced or mid-range left ventricular ejection fraction was studied as a part of the all-Russia prospective observational study BYHEART. The presence of FC II-IV CHF and a left ventricular ejection fraction <50 % were confirmed by results of 6-min walk test (6MWT) and findings of echocardiography after stabilization of the background therapy.Results An interim data analysis showed that the course of EP treatment was associated with a significant improvement of quality-of-life indexes as determined by the Minnesota Living with Heart Failure Questionnaire (LHFQ) total score. These indexes significantly increased and remained at a satisfactory level for 6 mos. following completion of the treatment course. Also, the treatment significantly beneficially influenced the clinical condition of patients (heart failure severity scale), results of 6MWT, and the increase in left ventricular ejection fraction.Conclusion      The conclusions based on results of the interim analysis should be confirmed by results of the completed study. Complete results are planned to be published in 2022.

Topics: Chronic Disease; Heart Failure; Humans; Phosphocreatine; Quality of Life; Stroke Volume; Ventricular Function, Left

Diminished cardiac high-energy phosphate metabolism (phosphocreatine-to-ATP (PCr:ATP) ratio) and cardiac power with age may play an important roles in development of cardiac dysfunction and heart failure. The study defines the impact of age on PCr:ATP ratio and cardiac power and their relationship.. Thirty-five healthy women (young≤50 years, n=20; and old≥60 years, n=15) underwent cardiac MRI with. PCr:ATP ratio was significantly lower in old compared with young age group (1.92±0.48 vs 2.29±0.55, p=0.03), as were peak cardiac power output (3.35±0.73 vs 4.14±0.81W, p=0.01), diastolic function (ie, early-to-late diastolic filling ratio, 1.33±0.54 vs 3.07±1.84, p<0.01) and peak exercise oxygen consumption (1382.9±255.0 vs 1940.3±434.4 mL/min, p<0.01). Further analysis revealed that PCr:ATP ratio shows a significant positive relationship with early-to-late diastolic filling ratio (r=0.46, p=0.02), peak cardiac power output (r=0.44, p=0.02) and peak oxygen consumption (r=0.51, p=0.01).. High-energy phosphate metabolism and peak power of the heart decline with age. Significant positive relationship between PCr:ATP ratio, early-to-late diastolic filling ratio and peak cardiac power output suggests that cardiac high-energy phosphate metabolism may be an important determinant of cardiac function and performance.

Topics: Aged; Aging; Creatine Kinase; Disease Progression; Exercise Test; Female; Heart; Heart Failure; Hemodynamic Monitoring; Humans; Middle Aged; Myocardial Contraction; Myocardium; Oxygen Consumption; Phosphocreatine; Pulmonary Gas Exchange; Statistics as Topic; Stroke Volume

Phosphorus saturation transfer (ST) magnetic resonance spectroscopy can measure the rate of ATP generated from phosphocreatine (PCr) via creatine kinase (CK) in the human heart. Recently, the triple-repetition time ST (TRiST) method was introduced to measure the CK pseudo-first-order rate constant kf in three acquisitions. In TRiST, the longitudinal relaxation time of PCr while γ-ATP is saturated, T1`, is measured for each subject, but suffers from low SNR because the PCr signal is reduced due to exchange with saturated γ-ATP, and the short repetition time of one of the acquisitions. Here, a two-repetition time ST (TwiST) method is presented. In TwiST, the acquisition with γ-ATP saturation and short repetition time is dropped. Instead of measuring T1`, an intrinsic relaxation time T1 for PCr, T1 (intrinsic), is assumed. The objective was to validate TwiST measurements of CK kinetics in healthy subjects and patients with heart failure (HF).. Bloch equation simulations that included the effect of spillover irradiation on PCr were used to derive formulae for T1 (intrinsic) and kf measured by both TRiST and TwiST methods. Spillover was quantified from an unsaturated PCr measurement used in the current protocol for determining PCr and ATP concentrations. Cardiac TRiST and TwiST data were acquired at 3 T from 12 healthy and 17 HF patients.. Simulations showed that both kf measured by TwiST and T1 (intrinsic) require spill-over corrections. In human heart at 3 T, the spill-over corrected T1 (intrinsic) = 8.4 ± 1.4 s (mean ± SD) independent of study group. TwiST and TRiST kf measurements were the same, but TwiST was 9 min faster. Spill-over corrected TwiST kf was 0.33 ± 0.08 s(-1) vs. 0.20 ± 0.06 s(-1) in healthy vs HF hearts, respectively (p < 0.0001).. TwiST was validated against TRiST in the human heart at 3 T, generating the same results 9 min faster. TwiST detected significant reductions in CK kf in HF compared to healthy subjects, consistent with prior 1.5 T studies using different methodology.

Topics: Adenosine Triphosphate; Adult; Case-Control Studies; Computer Simulation; Creatine Kinase; Female; Fourier Analysis; Heart Failure; Humans; Kinetics; Linear Models; Magnetic Resonance Imaging, Cine; Magnetic Resonance Spectroscopy; Male; Middle Aged; Models, Biological; Monte Carlo Method; Myocardium; Phosphocreatine; Predictive Value of Tests; Reproducibility of Results; Young Adult

Impaired energy metabolism has been implicated in the pathogenesis of heart failure. Hyperpolarized (13)C magnetic resonance (MR), in which (13)C-labelled metabolites are followed using MR imaging (MRI) or spectroscopy (MRS), has enabled non-invasive assessment of pyruvate metabolism. We investigated the hypothesis that if we serially examined a model of heart failure using non-invasive hyperpolarized [(13)C]pyruvate with MR, the profile of in vivo pyruvate oxidation would change throughout the course of the disease.. Dilated cardiomyopathy (DCM) was induced in pigs (n = 5) by rapid pacing. Pigs were examined using MR at weekly time points: cine-MRI assessed cardiac structure and function; hyperpolarized [2-(13)C]pyruvate was administered intravenously, and (13)C MRS monitored [(13)C]glutamate production; (31)P MRS assessed cardiac energetics [phosphocreatine (PCr)/ATP]; and hyperpolarized [1-(13)C]pyruvate was administered for MRI of pyruvate dehydrogenase complex (PDC)-mediated pyruvate oxidation via [(13)C]bicarbonate production. Early in pacing, the cardiac index decreased by 25%, PCr/ATP decreased by 26%, and [(13)C]glutamate production decreased by 51%. After clinical features of DCM appeared, end-diastolic volume increased by 40% and [(13)C]bicarbonate production decreased by 67%. Pyruvate dehydrogenase kinase 4 protein increased by two-fold, and phosphorylated Akt decreased by half. Peroxisome proliferator-activated receptor-α and carnitine palmitoyltransferase-1 gene expression decreased by a half and a third, respectively.. Despite early changes associated with cardiac energetics and (13)C incorporation into the Krebs cycle, pyruvate oxidation was maintained until DCM developed, when the heart's capacity to oxidize both pyruvate and fats was reduced. Hyperpolarized (13)C MR may be important to characterize metabolic changes that occur during heart failure progression.

Topics: Adenosine Triphosphate; Animals; Bicarbonates; Carbon Isotopes; Cardiac Pacing, Artificial; Cardiac Volume; Cardiomyopathy, Dilated; Carnitine O-Palmitoyltransferase; Citric Acid Cycle; Disease Models, Animal; Energy Metabolism; Gene Expression; Glutamic Acid; Glycolysis; Heart Failure; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Membrane Transport Proteins; Phosphocreatine; PPAR alpha; Protein Kinases; Pyruvate Dehydrogenase Complex; Pyruvic Acid; Swine; Ventricular Dysfunction, Left

Increasing energy storage capacity by elevating creatine and phosphocreatine (PCr) levels to increase ATP availability is an attractive concept for protecting against ischaemia and heart failure. However, testing this hypothesis has not been possible since oral creatine supplementation is ineffectual at elevating myocardial creatine levels. We therefore used mice overexpressing creatine transporter in the heart (CrT-OE) to test for the first time whether elevated creatine is beneficial in clinically relevant disease models of heart failure and ischaemia/reperfusion (I/R) injury.. CrT-OE mice were selected for left ventricular (LV) creatine 20-100% above wild-type values and subjected to acute and chronic coronary artery ligation. Increasing myocardial creatine up to 100% was not detrimental even in ageing CrT-OE. In chronic heart failure, creatine elevation was neither beneficial nor detrimental, with no effect on survival, LV remodelling or dysfunction. However, CrT-OE hearts were protected against I/R injury in vivo in a dose-dependent manner (average 27% less myocardial necrosis) and exhibited greatly improved functional recovery following ex vivo I/R (59% of baseline vs. 29%). Mechanisms contributing to ischaemic protection in CrT-OE hearts include elevated PCr and glycogen levels and improved energy reserve. Furthermore, creatine loading in HL-1 cells did not alter antioxidant defences, but delayed mitochondrial permeability transition pore opening in response to oxidative stress, suggesting an additional mechanism to prevent reperfusion injury.. Elevation of myocardial creatine by 20-100% reduced myocardial stunning and I/R injury via pleiotropic mechanisms, suggesting CrT activation as a novel, potentially translatable target for cardiac protection from ischaemia.

Topics: Animals; Cell Line; Creatine; Disease Models, Animal; Energy Metabolism; Glycogen; Heart Failure; Magnetic Resonance Imaging, Cine; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Mice, Transgenic; Mitochondria, Heart; Mitochondrial Membrane Transport Proteins; Mitochondrial Permeability Transition Pore; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardial Stunning; Myocardium; Necrosis; Oxidative Stress; Phosphocreatine; Time Factors; Up-Regulation; Ventricular Function, Left; Ventricular Remodeling

The ratio of myocardial phosphocreatine (PCr)/ATP reflects the balance of energy consumption and energy supply in the heart. It is reduced in a range of important physiological conditions including during and after acute hypoxia, after a prolonged visit to high-altitude, and in those suffering from both type 2 diabetes mellitus and various forms of heart failure. Yet despite its significance, the factors underlying the reduced PCr/ATP ratio seen in heart failure remain poorly understood. Given that oxidative phosphorylation is the only viable steady-state provider of ATP in the heart, the argument has been put forward that the observed reduction in myocardial PCr/ATP in all these conditions can be accounted for by some form of mitochondrial insufficiency. Thus we used a computer model of oxidative phosphorylation, coupled with creatine kinase, to study the effects of hypoxia and mitochondrial dysfunction on myocardial PCr/ATP. In physiological normoxia, all oxidative phosphorylation complexes, NADH supply and proton leak exerted comparable (of the same order of magnitude) control over PCr/ATP, as defined within Metabolic Control Analysis (MCA). Under hypoxia, the control increased considerably for all components of the system, especially for cytochrome oxidase and mitochondrial proton leak. Hypoxia alone, without any changes in other factors, exerted a pronounced effect on PCr/ATP. Our simulations support three important ideas: First, that mitochondrial abnormalities can contribute considerably to a blunted PCr/ATP; second, that hypoxia and mitochondrial dysfunction can interact in important ways to determine the energy status of the failing heart; and third, that hypoxia alone can account for significant decreases in cardiac PCr/ATP.

Topics: Adenosine Triphosphate; Cell Hypoxia; Computer Simulation; Creatine Kinase; Energy Metabolism; Heart; Heart Failure; Hypoxia; Mitochondria, Heart; Models, Cardiovascular; Myocardium; Oxidative Phosphorylation; Oxygen; Oxygen Consumption; Phosphocreatine

The metabolic phenotype of the failing heart includes a decrease in phosphocreatine and total creatine concentration [Cr], potentially contributing to contractile dysfunction. Surprisingly, in 32- week-old mice over-expressing the myocardial creatine transporter (CrT-OE), we previously demonstrated that elevated [Cr] correlates with left ventricular (LV) hypertrophy and failure. The aim of this study was to determine the temporal relationship between elevated [Cr] and the onset of cardiac dysfunction and to screen for potential molecular mechanisms. CrT-OE mice were compared with wild-type (WT) littermate controls longitudinally using cine-MRI to measure cardiac function and single-voxel (1)H-MRS to measure [Cr] in vivo at 6, 16, 32, and 52 weeks of age. CrT-OE mice had elevated [Cr] at 6 weeks (mean 1.9-fold), which remained constant throughout life. Despite this increased [Cr], LV dysfunction was not apparent until 16 weeks and became more pronounced with age. Additionally, LV tissue from 12 to 14 week old CrT-OE mice was compared to WT using 2D difference in-gel electrophoresis (DIGE). These analyses detected a majority of the heart's metabolic enzymes and identified seven proteins that were differentially expressed between groups. The most pronounced protein changes were related to energy metabolism: alpha- and beta-enolase were selectively decreased (p<0.05), while the remaining enzymes of glycolysis were unchanged. Consistent with a decrease in enolase content, its activity was significantly lower in CrT-OE hearts (in WT, 0.59+/-0.02 micromol ATP produced/microg protein/min; CrT-OE, 0.31+/-0.06; p<0.01). Additionally, anaerobic lactate production was decreased in CrT-OE mice (in WT, 102+/-3 micromol/g wet myocardium; CrT-OE, 78+/-13; p=0.02), consistent with decreased glycolytic capacity. Finally, we found that enolase may be regulated by increased expression of the beta-enolase repressor transcription factor, which was significantly increased in CrT-OE hearts. This study demonstrates that chronically increased myocardial [Cr] in the CrT-OE model leads to the development of progressive hypertrophy and heart failure, which may be mediated by a compromise in glycolytic capacity at the level of enolase.

Topics: Animals; Aorta; Cardiomegaly; Creatine; Electrophoresis, Gel, Two-Dimensional; Female; Glycolysis; Heart Failure; Heart Ventricles; Magnetic Resonance Imaging; Membrane Transport Proteins; Mice; Mice, Inbred C57BL; Myocardium; Phosphocreatine; Phosphopyruvate Hydratase

A course of adenocine (cardiotonic drug with a pronounced cardioprotective effect) for severe experimental heart failure caused by toxic allergic myocarditis (for 10 days) more effectively restored the systolic and diastolic function of the heart and arrested systemic inflammatory response syndrome than traditional therapy with angiotensin-converting enzyme inhibitors, beta-adrenoblockers, or diuretics in combination with neoton. Adenocine is characterized by a synergistic effect, and none of its ingredients alone (nicotinamide adenine dinucleotide, inosine, beta-acetyldigoxin, oxyfedrine) exhibits similar effect.

Topics: Adrenergic beta-Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiotonic Agents; Disease Models, Animal; Diuretics; Endotoxemia; Heart Failure; Myocarditis; Phosphocreatine; Rabbits; Systemic Inflammatory Response Syndrome; Treatment Outcome

The present study was undertaken to explore the possible involvement of alterations in the mitochondrial energy-producing ability in the development of the right ventricular failure in monocrotaline-administered rats. The rats at the 6th week after subcutaneous injection of 60 mg/kg monocrotaline revealed marked myocardial hypertrophy and fibrosis, that is, severe cardiac remodeling. The time-course study on the cardiac hemodynamics of the monocrotaline-administered rat by the cannula and echocardiographic methods showed a reduction in cardiac double product, a decrease in cardiac output index, and an increase in the right ventricular Tei index, suggesting that the right ventricular failure was induced at the 6th week after monocrotaline administration in rats. The mitochondrial oxygen consumption rate of the right ventricular muscle isolated from the monocrotaline-administered animal was decreased, which was associated with a reduction in myocardial high-energy phosphates. Furthermore, the decrease in mitochondrial oxygen consumption rate was inversely related to the increase in the right ventricular Tei index of the monocrotaline-administered rats. These results suggest that impairment of the mitochondrial energy-producing ability is involved in the development of the right ventricular failure in monocrotaline-induced pulmonary hypertensive rats.

Topics: Adenosine Triphosphate; Animals; Cardiomyopathy, Dilated; Heart; Heart Failure; Hemodynamics; Hypertension, Pulmonary; Male; Mitochondria, Heart; Monocrotaline; Myocardium; Organ Size; Oxygen Consumption; Phosphocreatine; Random Allocation; Rats; Rats, Wistar; Ultrasonography

CHF (chronic heart failure) is associated with a prolonged recovery of skeletal muscle energy stores following submaximal exercise, limiting the ability to perform repetitive daily activities.However, the pathophysiological background of this impairment is not well established. The aim of the present study was to investigate whether muscle metabolic recovery following submaximal exercise in patients with CHF is limited by O2 delivery or O2 utilization. A total of 13 stable CHF patients (New York Heart Association classes II-III) and eight healthy subjects, matched for age and BMI (body mass index), were included. All subjects performed repetitive submaximal dynamic single leg extensions in the supine position. Post-exercise PCr (phosphocreatine) resynthesis was assessed by 31P-MRS (magnetic resonance spectroscopy). NIRS (near-IR spectroscopy) was applied simultaneously, using the rate of decrease in HHb (deoxygenated haemoglobin) as an index of post-exercise muscle re-oxygenation. As expected, PCr recovery was slower in CHF patients than in control subjects (time constant, 47+/-10 compared with 35+/-12 s respectively; P=0.04). HHb recovery kinetics were also prolonged in CHF patients (mean response time, 74+/-41 compared with 44+/-17 s respectively; P=0.04). In the patient group, HHb recovery kinetics were slower than PCr recovery kinetics (P=0.02), whereas no difference existed in the control group(P=0.32). In conclusion, prolonged metabolic recovery in CHF patients is associated with an even slower muscle tissue re-oxygenation, indicating a lower O(2) delivery relative to metabolic demands. Therefore we postulate that the impaired ability to perform repetitive daily activities in these patients depends more on a reduced muscle blood flow than on limitations in O(2) utilization.

Topics: Adult; Case-Control Studies; Chronic Disease; Exercise; Female; Heart Failure; Hemoglobins; Humans; Kinetics; Male; Middle Aged; Muscle, Skeletal; Oxygen; Oxygen Consumption; Phosphocreatine

Overexpression of calcineurin (CLN) in the mouse heart induces severe hypertrophy that progresses to heart failure, providing an opportunity to define the relationship between energetics and contractile performance in the severely failing mouse heart. Contractile performance was studied in isolated hearts at different pacing frequencies and during dobutamine challenge. Energetics were assessed by 31P-NMR spectroscopy as ATP and phosphocreatine concentrations ([ATP] and [PCr]) and free energy of ATP hydrolysis (|Delta G( approximately ATP)|). Mitochondrial and glycolytic enzyme activities, myocardial O2 consumption, and myocyte ultrastructure were determined. In transgenic (TG) hearts at all levels of work, indexes of systolic performance were reduced and [ATP] and capacity for ATP synthesis were lower than in non-TG hearts. This is the first report showing that myocardial [ATP] is lower in a TG mouse model of heart failure. [PCr] was also lower, despite an unexpected increase in the total creatine pool. Because Pi concentration remained low, despite lower [ATP] and [PCr], |Delta G( approximately ATP)| was normal; however, chemical energy did not translate to systolic performance. This was most apparent with beta-adrenergic stimulation of TG hearts, during which, for similar changes in |Delta G( approximately ATP)|, systolic pressure decreased, rather than increased. Structural abnormalities observed for sarcomeres and mitochondria likely contribute to decreased contractile performance. On the basis of the increases in enzyme activities of proteins important for ATP supply observed after treatment with the CLN inhibitor cyclosporin A, we also conclude that CLN directed inhibition of ATP-producing pathways in non-TG and TG hearts.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Calcineurin; Creatine; Energy Metabolism; Heart Failure; In Vitro Techniques; Magnetic Resonance Spectroscopy; Mice; Mice, Transgenic; Microscopy, Electron; Myocytes, Cardiac; Oxygen Consumption; Phosphocreatine

Abnormalities in the excitation-contraction coupling of slow-twitch muscle seem to explain the slowing and increased fatigue observed in congestive heart failure (CHF). However, it is not known which elements of the excitation-contraction coupling might be affected. We hypothesize that the temperature sensitivity of contractile properties of the soleus muscle might be altered in CHF possibly because of alterations of the temperature sensitivity of intracellular Ca(2+) handling. We electrically stimulated the in situ soleus muscle of anesthetised rats that had 6-wk postinfarction CHF using 1 and 50 Hz and using a fatigue protocol (5-Hz stimulation for 30 min) at 35, 37, and 40 degrees C. Ca(2+) uptake and release were measured in sarcoplasmic reticulum vesicles at various temperatures. Contraction and relaxation rates of the soleus muscle were slower in CHF than in sham at 35 degrees C, but the difference was almost absent at 40 degrees C. The fatigue protocol revealed that force development was more temperature sensitive in CHF, whereas contraction and relaxation rates were less temperature sensitive in CHF than in sham. The Ca(2+) uptake and release rates did not correlate to the difference between CHF and sham regarding contractile properties or temperature sensitivity. In conclusion, the discrepant results regarding altered temperature sensitivity of contraction and relaxation rates in the soleus muscle of CHF rats compared with Ca(2+) release and uptake rates in vesicles indicate that the molecular cause of slow-twitch muscle dysfunction in CHF is not linked to the intracellular Ca(2+) cycling.

Topics: Adenosine Triphosphate; Animals; Calcium; Calcium-Transporting ATPases; Electric Stimulation; Heart Failure; Lactic Acid; Male; Muscle Contraction; Muscle, Skeletal; Phosphocreatine; Rats; Rats, Wistar; Sarcoplasmic Reticulum; Temperature

Chronic heart failure (CHF) impairs muscle O2 delivery (QO2) and, at a given O2 uptake (VO2), lowers microvascular O2 pressures (PmvO2: determined by the QO2-to-VO2 ratio), which may impair recovery of high-energy phosphates following exercise. Because CHF preferentially decreases QO2 to slow-twitch muscles, we hypothesized that recovery PmvO2 kinetics would be slowed to a greater extent in soleus (SOL: approximately 84% type I fibres) than in peroneal (PER: approximately 14% type I) muscles of CHF rats. PmvO2 dynamics were determined in SOL and PER muscles of control (CON: n= 6; left ventricular end-diastolic pressure, LVEDP: approximately 3 mmHg), moderate CHF (MOD: n= 7; LVEDP: approximately 11 mmHg) and severe CHF (SEV: n= 4; LVEDP: approximately 25 mmHg) following cessation of electrical stimulation (180 s; 1 Hz). In PER, neither the recovery PmvO2 values nor the mean response time (MRT; a weighted average of the time to 63% of the overall response) were altered by CHF (CON: 66.8 +/- 8.0, MOD: 72.4 +/- 11.8, SEV: 69.1 +/- 9.5 s). In marked contrast, SOL PmvO2, at recovery onset, was reduced significantly in the SEV group ( approximately 6 Torr) and PmvO2 MRT was slowed with increased severity of CHF (CON: 45.1 +/- 5.3, MOD: 63.2 +/- 9.4, SEV: 82.6 +/- 12.3 s; P < 0.05 CON vs. MOD and SEV). These data indicate that CHF slows PmvO2 recovery following contractions and lowers capillary O2 driving pressure in slow-twitch SOL, but not in fast-twitch PER muscle. These results may explain, in part, the slowed recovery kinetics (phosphocreatine and VO2) and pronounced fatigue following muscular work in CHF patients.

Topics: Animals; Chronic Disease; Female; Heart Failure; Microcirculation; Muscle Contraction; Muscle Fibers, Slow-Twitch; Muscle, Skeletal; Oxygen; Oxygen Consumption; Partial Pressure; Peroneal Nerve; Phosphocreatine; Rats; Rats, Sprague-Dawley

It has been suspected for some time that patients with chronic heart failure (CHF) have abnormal muscle metabolism, so in the present study the muscle metabolism of the arm and leg were compared by (31)P magnetic resonance spectroscopy ((31)P-MRS) to examine the relationship to exercise tolerance.. The study group comprised 13 patients and 11 normal controls. Calf-plantar and forearm-wrist flexion were performed to evaluate the metabolic capacity assessed as the phosphocreatine breakdown rate (PCr-slope) and muscle pH at a submaximal (70% peak) work rate (submax-pH). Exercise of both the arm and leg resulted in an earlier decrease in PCr and muscle pH in patients with CHF compared with controls. There were significant correlations between peak oxygen uptake (peak V(O2)) and the PCr-slope in both limbs in patients with CHF (forearm: r=0.63, p<0.05; calf: r=0.60, p<0.05), but no correlations in normal controls. There was a close correlation between the ventilatory anaerobic threshold (AT) and the PCr-slope in the calf (r=0.85, p<0.01), but not in the forearm in patients with CHF. Submax-pH in both upper and lower limbs was not significantly correlated to peak V(O2) or AT in either patients with CHF or controls.. Although metabolic abnormalities during exercise are seen in both arms and legs, leg muscle abnormalities, in particular, are closely related to systemic exercise intolerance in patients with CHF.

Topics: Arm; Case-Control Studies; Chronic Disease; Energy Metabolism; Exercise Test; Heart Failure; Humans; Hydrogen-Ion Concentration; Leg; Magnetic Resonance Imaging; Muscle, Skeletal; Oxygen Consumption; Phosphocreatine; Phosphorus Isotopes

We previously reported that 20% of women with chest pain but without obstructive coronary artery disease (CAD) had stress-induced reduction in myocardial phosphocreatine-adenosine triphosphate ratio by phosphorus-31 nuclear magnetic resonance spectroscopy (abnormal MRS), consistent with myocardial ischemia. The prognostic implications of these findings are unknown.. Women referred for coronary angiography for suspected myocardial ischemia underwent MRS handgrip stress testing and follow-up evaluation. These included (1) n=60 with no CAD/normal MRS, (2) n=14 with no CAD/abnormal MRS, and (3) n=352 a reference group with CAD. Cardiovascular events were death, myocardial infarction, heart failure, stroke, other vascular events, and hospitalization for unstable angina. Cumulative freedom from events at 3 years was 87%, 57%, and 52% for women with no CAD/normal MRS, no CAD/abnormal MRS, and CAD, respectively (P<0.01). After adjusting for CAD and cardiac risk factors, a phosphocreatine-adenosine triphosphate ratio decrease of 1% increased the risk of a cardiovascular event by 4% (P=0.02). The higher event rate in women with no CAD/abnormal MRS was primarily due to hospitalization for unstable angina, which is associated with repeat catheterization and higher healthcare costs.. Among women without CAD, abnormal MRS consistent with myocardial ischemia predicted cardiovascular outcome, notably higher rates of anginal hospitalization, repeat catheterization, and greater treatment costs. Further evaluation into the underlying pathophysiology and possible treatment options for women with evidence of myocardial ischemia but without CAD is indicated.

Topics: Adenosine Triphosphate; Aged; Angina, Unstable; Cardiac Catheterization; Cohort Studies; Coronary Angiography; Coronary Stenosis; Cost-Benefit Analysis; Disease-Free Survival; Female; Follow-Up Studies; Hand Strength; Health Care Costs; Heart Failure; Hospitalization; Humans; Life Tables; Magnetic Resonance Spectroscopy; Middle Aged; Myocardial Infarction; Myocardial Ischemia; Myocardium; Outcome Assessment, Health Care; Phosphocreatine; Prognosis; Risk Factors; Stroke; United States

The failing ventricular myocardium is characterized by reduction of high-energy phosphates and reduced activity of the phosphotransfer enzymes creatine kinase (CK) and adenylate kinase (AK), which are responsible for transfer of high-energy phosphoryls from sites of production to sites of utilization, thereby compromising excitation-contraction coupling. In humans with chronic atrial fibrillation (AF) unassociated with congestive heart failure (CHF), impairment of atrial myofibrillar energetics linked to oxidative modification of myofibrillar CK has been observed. However, the bioenergetic status of the failing atrial myocardium and its potential contribution to atrial electrical instability in CHF have not been determined. Dogs with (n = 6) and without (n = 6) rapid pacing-induced CHF underwent echocardiography (conscious) and electrophysiological (under anesthesia) studies. CHF dogs had more pronounced mitral regurgitation, higher atrial pressure, larger atrial area, and increased atrial fibrosis. An enhanced propensity to sustain AF was observed in CHF, despite significant increases in atrial effective refractory period and wavelength. Profound deficits in atrial bioenergetics were present with reduced activities of the phosphotransfer enzymes CK and AK, depletion of high-energy phosphates (ATP and creatine phosphate), and reduction of cellular energetic potential (ATP-to-ADP and creatine phosphate-to-Cr ratios). AF duration correlated with left atrial area (r = 0.73, P = 0.01) and inversely with atrial ATP concentration (r = -0.75, P = 0.005), CK activity (r = -0.57, P = 0.054), and AK activity (r = -0.64, P = 0.02). Atrial levels of malondialdehyde, a marker of oxidative stress, were significantly increased in CHF. Myocardial bioenergetic deficits are a conserved feature of dysfunctional atrial and ventricular myocardium in CHF and may constitute a component of the substrate for AF in CHF.

Topics: Adenosine Triphosphate; Adenylate Kinase; Animals; Atrial Fibrillation; Cardiac Pacing, Artificial; Creatine Kinase; Dogs; Echocardiography; Electrophysiology; Energy Metabolism; Fibrosis; Heart Atria; Heart Failure; Male; Malondialdehyde; Myocardium; Oxidative Stress; Phosphocreatine

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 31P 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 microg. kg-1. min-1 iv) caused an approximate doubling of myocardial oxygen consumption (MVO2) 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 MVO2 in normal and LVH hearts with no change in PCr/ATP. In contrast, DNP caused no increase in MVO2 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.

Topics: Adenosine Triphosphate; Animals; Coronary Circulation; Disease Models, Animal; Heart Failure; Hypertrophy, Left Ventricular; Magnetic Resonance Spectroscopy; Mitochondria; Myocardium; Oxygen Consumption; Phosphocreatine; Protons; Sus scrofa

Uncoupling proteins, inner mitochondrial membrane proton transporters, are important for regulating myocardial energy efficiency. We investigated the effects of the ACE inhibitor perindopril on cardiac performance, myocardial energy efficiency, and uncoupling protein expression in an aortic regurgitation rat model. Twenty male Sprague-Dawley rats, in which aortic regurgitation was produced, were divided into untreated and perindopril-treated (5 mg x kg(-1) x d(-1)) rats. The treatments were initiated 3 days after operation. Ten control rats were sham-operated. Measurements of blood pressure and echocardiography were repeated before and 100 days after operation (endpoint). Left ventricular uncoupling protein-2 expression, creatine phosphate, and adenosine triphosphate were measured at endpoint. In perindopril-treated rats, systolic and diastolic blood pressure decreased after treatment (92+/-4/65+/-2 mm Hg). At endpoint, left ventricular end-diastolic dimension in untreated (10.7+/-0.2 mm) and treated rats (9.2+/-0.2 mm) was increased, and fractional shortening was reduced in untreated rats (28+/-1%) but did not change in treated rats (36+/-2%). Uncoupling protein-2 mRNA expression increased in untreated rats (3.7-fold) and was suppressed by perindopril (1.5-fold). The creatine phosphate was reduced in untreated rats (10.6+/-0.7 micro mol/g) but not in treated rats (15.9+/-2.0 micro mol/g). In the chronic stage of aortic regurgitation, perindopril improved cardiac performance and myocardial energy efficiency, in which the suppression of uncoupling protein-2 may play an important role.

Topics: Adenosine Triphosphate; Angiotensin-Converting Enzyme Inhibitors; Animals; Aortic Valve Insufficiency; Atrial Natriuretic Factor; Blood Pressure; Echocardiography, Doppler; Energy Metabolism; Heart; Heart Failure; Heart Rate; Ion Channels; Male; Membrane Transport Proteins; Mitochondrial Proteins; Myocardium; Organ Size; Perindopril; Phosphocreatine; Protein Biosynthesis; Proteins; Rats; Rats, Sprague-Dawley; RNA, Messenger; Uncoupling Protein 2

Whereas the number of patients with reduced left ventricular function after myocardial infarction who need revascularization is increasing, the operative outcome is still inadequate. Consequently, drugs that increase myocardial perfusion and decrease oxygen consumption of the remodeled myocardium are of particular interest to cardiac surgeons. Angiotensin-converting enzyme inhibitors (ACE-I) provide this pharmacologic profile. This study tests the hypothesis whether acute ACE inhibition during cardioplegic arrest improves outcome in failing rat hearts.. Male Wistar rats (260+/-15 g) underwent coronary ligation. Ten weeks later the rats had developed heart failure (HF). Hearts were harvested and studied on a red cell-perfused working heart: 60 minutes of ischemia, protected by cold blood cardioplegia (CP) every 20 minutes, and 45 minutes of reperfusion. Rats were randomly assigned to 2 groups, 1 group receiving the ACE-I quinaprilat with CP (QuinaMI, n=11), and 1 group receiving CP only (MI, n=8). Hemodynamic recovery, high-energy phosphates (HEP), and morphometry were analyzed. Groups showed similar degrees of myocardial infarction (44+/-5 versus 39+/-4% of LVmass), LVEDP (5.0+/-1 versus 4+/-1 mm Hg) and no differences in baseline values such as external heart work (EHW) and coronary flow (CF). At the end of reperfusion, EHW and CF were significantly higher in QuinaMI than MI (P<0.05 and 0.01), LVEDP had returned to baseline in QuinaMI (P<0.01). HEP were significantly higher preserved in QuinaMI than MI (P<0.05).. Acute ACE inhibition during CP improves postischemic systolic and diastolic function, coronary perfusion as well as HEP-levels in a rat model of HF. These results may have clinical impact on patients with HF undergoing cardiac surgery.

Topics: Adenine Nucleotides; Angiotensin-Converting Enzyme Inhibitors; Animals; Cardiotonic Agents; Heart; Heart Arrest, Induced; Heart Failure; Hemodynamics; Isoquinolines; Male; Myocardial Infarction; Myocardial Reperfusion Injury; Myocardium; Organ Culture Techniques; Phosphocreatine; Rats; Rats, Wistar; Tetrahydroisoquinolines

Increased rates of glucose uptake and glycolysis have been repeatedly observed in cardiac hypertrophy and failure. Although these changes have been considered part of the fetal gene reactivation program, the functional significance of increased glucose utilization in hypertrophied and failing myocardium is poorly understood.. We generated transgenic (TG) mice with cardiac-specific overexpression of insulin-independent glucose transporter GLUT1 to recapitulate the increases in basal glucose uptake rate observed in hypertrophied hearts. Isolated perfused TG hearts showed a greater rate of basal glucose uptake and glycolysis than hearts isolated from wild-type littermates, which persisted after pressure overload by ascending aortic constriction (AAC). The in vivo cardiac function in TG mice, assessed by echocardiography, was unaltered. When subjected to AAC, wild-type mice exhibited a progressive decline in left ventricular (LV) fractional shortening accompanied by ventricular dilation and decreased phosphocreatine to ATP ratio and reached a mortality rate of 40% at 8 weeks. In contrast, TG-AAC mice maintained LV function and phosphocreatine to ATP ratio and had <10% mortality.. We found that increasing insulin-independent glucose uptake and glycolysis in adult hearts does not compromise cardiac function. Furthermore, we demonstrate that increasing glucose utilization in hypertrophied hearts protects against contractile dysfunction and LV dilation after chronic pressure overload.

Topics: Adenosine Triphosphate; Animals; Aorta; Biological Transport; Constriction; Echocardiography; Glucose; Glucose Transporter Type 1; Heart Failure; Humans; Hypertrophy, Left Ventricular; Mice; Mice, Transgenic; Monosaccharide Transport Proteins; Myocardial Contraction; Myocardium; Organ Culture Techniques; Phosphocreatine; Pressure; Survival Analysis; Ventricular Remodeling

The present study objective involved evaluation of possibilities of magnetic resonance spectroscopy with phosphorus (31P-MRS) in diagnosis of metabolic disorders of skeletal muscles in patients with intermittent claudication, chronic heart failure and varicose disease of the lower extremities. In 20 patients with intermittent claudication, 10 patients with chronic heart failure, 10 patients with varicose disease and 10 volunteers, 31P-MRS was performed with 1.5 T MR system (Magnetom SP 63, Siemens). The following parameters were computed: phosphorus-creatinine index, intracellular pH in calf muscle, and time of half-recovery of the phosphorus-creatinine index. At rest, the phosphorus-creatinine indexes were similar in all groups; pH values at rest did not vary either. During isotonic exercise the phosphorus-creatinine index in the control group remained uncharged. In patients with intermittent claudication, the phosphorus-creatinine index at peak of exercise was decreased by 26.1% (p < 0.001), in patients with varicose disease--by 25.6% (p < 0.001), in patients with chronic heart failure by 8% (p < 0.001). PCr recovery half-time was increased in all patients. The patient group with intermittent claudication showed a reverse correlation between the pressure index and the degree of phosphorus-creatinine index decrease.. 31P-MRS makes it possible to carry out non-invasive diagnosis of energy metabolic disorders of skeletal muscles in patients with impaired peripheral hemodynamics.

Topics: Adult; Aged; Arteriosclerosis Obliterans; Biomarkers; Energy Metabolism; Heart Failure; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscle, Skeletal; Phosphocreatine; Phosphorus; Varicose Veins

OKITA, K., K. YONEZAWA, H. NISHIJIMA, A. HANADA, T. NAGAI, T. MURAKAMI, and A. KITABATAKE. Muscle high-energy metabolites and metabolic capacity in patients with heart failure. Med Sci. Sports. Exerc., Vol. 33, No. 3, 2001, pp. 442-448.. Various abnormalities in skeletal muscle have been demonstrated by biopsy in patients with chronic heart failure (CHF). In mammalian muscles, high-energy metabolite composition at rest (HEMC) provides data on important metabolic characteristics; however, the significance of HEMC has not been clarified in patients with CHF. Therefore, we investigated HEMC in normal subjects and patients with CHF and examined its relation to muscle metabolic capacity and exercise tolerance.. High-energy metabolites (phosphocreatine (PCr), inorganic phosphate (Pi), and ATP) in resting calf muscle were measured by 31P-magnetic resonance spectroscopy (31P-MRS), and ratios of Pi to PCr, Pi to ATP, and PCr to ATP were calculated in 34 patients with CHF and 13 age- and size-matched normal subjects. Muscle metabolism was evaluated during local exercise of unilateral plantar flexion by 31P-MRS. Metabolic capacity was estimated by the rate of PCr breakdown in relation to the workload. Systemic exercise capacity was evaluated by a bicycle ergometer.. The ratio of PCr to ATP was significantly increased in patients with CHF compared with controls (3.06 +/- 0.43 vs 2.72 +/- 0.36, P < 0.05) and was significantly correlated with metabolic capacity (r = -0.37, P < 0.01) and with peak oxygen uptake (r = -0.45, P < 0.01). There was a significant correlation between metabolic capacity and peak oxygen uptake (r = 0.53, P < 0.001).. HEMC was altered in patients with CHF, and this change was related to metabolic capacity and exercise capacity. These findings provide new insight into the mechanism of impaired muscle metabolism in CHF.

Topics: Adenosine Triphosphate; Aged; Exercise; Female; Heart Failure; Humans; Male; Middle Aged; Muscle, Skeletal; Oxygen Consumption; Phosphates; Phosphocreatine; Physical Fitness

This study examined high-energy phosphates (HEP) and mitochondrial ATPase protein expression in hearts in which myocardial infarction resulted in either compensated left ventricular remodeling (LVR) or congestive heart failure (CHF). The response of HEP (measured via (31)P magnetic resonance spectroscopy) to a modest increase in the cardiac work state produced by dobutamine-dopamine infusion and pacing (if needed) was examined in 17 pigs after left circumflex coronary artery ligation (9 with LVR and 8 with CHF) and compared with 7 normal pigs. In hearts with LVR, the baseline phosphocreatine (PCr)-to-ATP ratio decreased, and calculated ADP increased; these changes were most severe in hearts with CHF. HEP levels did not change in normal or LVR hearts during dobutamine-dopamine infusion. However, in hearts with CHF, the PCr-to-ATP ratio decreased further, and free ADP increased. The mitochondrial protein levels of the F(0)F(1)-ATPase subunits were normal in hearts with compensated LVR. However, in failing hearts, the alpha-subunit decreased by 36%, the beta-subunit decreased by 16%, the oligomycin sensitivity-conferring protein subunit decreased by 40%, and the initiation factor 1 subunit decreased by 41%. Thus in failing hearts, reductions in mitochondrial F(0)F(1)-ATPase protein expression are associated with increased myocardial free ADP.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Animals; Body Weight; Cardiac Pacing, Artificial; Coronary Circulation; Disease Models, Animal; Dobutamine; Dopamine; Heart Failure; Hemodynamics; Infusions, Intravenous; Magnetic Resonance Spectroscopy; Mitochondria, Heart; Myocardial Infarction; Organ Size; Phosphocreatine; Protein Subunits; Proton-Translocating ATPases; Swine; Ventricular Remodeling

To estimate muscle metabolism and oxygen delivery to skeletal muscle in patients with chronic heart failure.. 13 patients with chronic heart failure and 15 controls performed calf plantar flexion for six minutes at a constant workload of 50% of one repetition maximum. During recovery from exercise, skeletal muscle content of oxygenated haemoglobin (oxy-Hb) and the level of phosphocreatine (PCr) were measured by near-infrared spectroscopy and (31)P-magnetic resonance spectroscopy, respectively.. The mean (SD) time constants of PCr and oxy-Hb during recovery from exercise were significantly greater in patients with chronic heart failure than in normal subjects (tau PCr: 76.3 (30.2) s v 36.5 (5.8) s; tau oxy-Hb: 48.3 (7.3) s v 30.1 (7.7) s; p < 0.01). Both time constants were similar in normal subjects, while the tau PCr was significantly greater than the tau oxy-Hb in patients with chronic heart failure.. The slower recovery of PCr compared with oxy-Hb in patients with chronic heart failure indicates that haemoglobin resaturation is not a major rate limiting factor of PCr resynthesis. It is suggested that muscle metabolic recovery may depend more on oxygen utilisation than on haemoglobin resaturation or oxygen delivery in patients with chronic heart failure.

Topics: Case-Control Studies; Cell Respiration; Exercise Tolerance; Heart Failure; Humans; Magnetic Resonance Spectroscopy; Middle Aged; Muscle, Skeletal; Oxyhemoglobins; Phosphocreatine; Spectroscopy, Near-Infrared

Impaired energy metabolism in the failing human heart could be an important mechanism of functional deterioration. The purpose of this study was to assess the changes of myocardial energy metabolism in the human heart at end-stage heart failure.. The left ventricular myocardium of patients undergoing heart transplantation due to dilated (DCM, n = 14) or hypertrophic cardiomyopathy (HCM, n = 5) and non-diseased donor heart samples (n = 4) were analysed for citrate synthase (CS), enzymes of the glycolytic pathway as well as concentrations of phosphocreatine (PCr), creatine (Cr), adenine and guanine nucleotides.. Total creatine levels (phosphocreatine + creatine) were significantly decreased (P < 0.05) in both groups of diseased hearts (3.87 +/- 0.57 in DCM, 5.09 +/- 1.23 in HCM compared with control 10. 7 +/- 3.5 micromol g-1 wet weight). There was a trend for higher guanine nucleotide content in failing hearts, but no significant differences were observed in total adenine nucleotides and total NAD content. CS was markedly reduced (P < 0.05) in both groups of diseased hearts: in the DCM to 13.8 +/- 1.3 micromol min-1 g-1 wet weight, and in HCM to 11.9 +/- 2.4 compared with the control 29.2 +/- 2.2. Glycolytic enzymes were decreased compared with the control, and this decrease was greater in DCM than in HCM. Echocardiographic indices of contractility were considerably better in hypertrophic cardiomyopathy.. Despite the different mechanisms of cardiac failure and the differences in contractility of the heart we have observed, metabolic changes are very similar in hypertrophic and dilated cardiomyopathy. Depletion of the creatine pool suggests an alteration in the intracellular energy reserves and transfer, whereas the decrease in citrate synthase activity suggests reduced oxidative capacity in both dilated and hypertrophic cardiomyopathy.

Topics: Adenine Nucleotides; Adult; Cardiomyopathy, Dilated; Cardiomyopathy, Hypertrophic; Citrate (si)-Synthase; Creatine; Echocardiography; Energy Metabolism; Female; Glycolysis; Guanine Nucleotides; Heart; Heart Failure; Heart Transplantation; Hemodynamics; Humans; Male; Myocardium; Phosphocreatine

In heart failure, cardiac energy metabolism is compromised. The failing myocardium is characterized by reduced contents of both phosphorylated (phosphocreatine) and non-phosphorylated (free) creatine content as well as decreased energy reserve via creatine kinase (creatine kinase reaction velocity). These changes may contribute to cardiac dysfunction. The purpose of the present study was to determine whether chronic feeding with high-dose dietary creatine prevents the derangement of energy metabolism and the development of left ventricular remodeling in a rat model of heart failure, i.e. post-myocardial infarction (MI).. Rats were subjected to sham operation or left coronary artery ligation. Surviving rats were fed with 0% (untreated) or 3% creatine (related to weight of diet) for 8 weeks. Creatine feeding increased serum creatine levels significantly approximately 2-fold. Thereafter, hearts were isolated, perfused and left ventricular pressure-volume curves obtained. Steady state and dynamic (CK reaction velocity) high-energy phosphate metabolism was determined with 31P NMR spectroscopy. In both MI groups (treated n = 8, untreated n = 7), pressure-volume curves were shifted right- and downward compared to both sham groups (treated n = 5, untreated n = 7), i.e. creatine had no effect on left ventricular remodeling. Likewise, similar reductions of phosphocreatine, free creatine and creatine kinase reaction velocity (untreated sham 12.0 +/- 0.7 mmol/lxs; untreated MI 7.8 +/- 0.7*; treated sham 13.6 +/- 1.0; treated MI 7.2 +/- 1.1*; *p < 0.025 sham vs. MI) were found in both MI groups.. Chronic creatine feeding of post-MI rats is ineffective in preventing the functional and energetic derangements occurring post-MI. Inspite of increased serum creatine levels, neither the normal nor the failing heart accumulates additional creatine.

Topics: Adenosine Triphosphate; Administration, Oral; Animals; Creatine; Heart Failure; Magnetic Resonance Spectroscopy; Myocardial Infarction; Myocardium; Perfusion; Phosphocreatine; Rats; Rats, Wistar; Ventricular Remodeling

Cardiac beta(2)-adrenergic receptor (beta(2)AR) overexpression is a potential contractile therapy for heart failure. Cardiac contractility was elevated in mice overexpressing beta(2)ARs (TG4s) with no adverse effects under normal conditions. To assess the consequences of beta(2)AR overexpression during ischemia, perfused hearts from TG4 and wild-type mice were subjected to 20-minute ischemia and 40-minute reperfusion. During ischemia, ATP and pH fell lower in TG4 hearts than wild type. Ischemic injury was greater in TG4 hearts, as indicated by lower postischemic recoveries of contractile function, ATP, and phosphocreatine. Because beta(2)ARs, unlike beta(1)ARs, couple to G(i) as well as G(s), we pretreated mice with the G(i) inhibitor pertussis toxin (PTX). PTX treatment increased basal contractility in TG4 hearts and abolished the contractile resistance to isoproterenol. During ischemia, ATP fell lower in TG4+PTX than in TG4 hearts. Recoveries of contractile function and ATP were lower in TG4+PTX than in TG4 hearts. We also studied mice that overexpressed either betaARK1 (TGbetaARK1) or a betaARK1 inhibitor (TGbetaARKct). Recoveries of function, ATP, and phosphocreatine were higher in TGbetaARK1 hearts than in wild-type hearts. Despite basal contractility being elevated in TGbetaARKct hearts to the same level as that of TG4s, ischemic injury was not increased. In summary, beta(2)AR overexpression increased ischemic injury, whereas betaARK1 overexpression was protective. Ischemic injury in the beta(2)AR overexpressors was exacerbated by PTX treatment, implying that it was G(s) not G(i) activity that enhanced injury. Unlike beta(2)AR overexpression, basal contractility was increased by betaARK1 inhibitor expression without increasing ischemic injury, thus implicating a safer potential therapy for heart failure.

Topics: Adenosine Triphosphate; Animals; beta-Adrenergic Receptor Kinases; Cyclic AMP-Dependent Protein Kinases; Enzyme Inhibitors; G-Protein-Coupled Receptor Kinase 2; Genetic Predisposition to Disease; Genetic Therapy; Genotype; GTP-Binding Protein alpha Subunits, Gi-Go; Heart Failure; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Male; Mice; Muscle Proteins; Myocardial Contraction; Myocardial Ischemia; Myocardium; Pertussis Toxin; Phosphocreatine; Receptors, Adrenergic, beta-2; Signal Transduction; Virulence Factors, Bordetella

Skeletal muscle abnormalities contribute considerably to the clinical expression of heart failure. Deconditioning, underperfusion and an increased number of type IIb glycolytical fibres lead to early lactate production and muscle fatigue at low exercise levels. Aerobic muscle metabolism may also be impaired, as suggested by biopsy studies. Thus far, no data are available from non-invasive studies to indicate the extent of aerobic muscle dysfunction during low-grade exercise which does not induce acidosis.. Mitochondrial function of skeletal muscle during fibre type I activation was studied in 22 patients with chronic heart failure [NYHA class III, left ventricular ejection fraction 28 +/- 2%, (patients)] on ACE inhibitors, diuretics and digoxin, and in 20 normal subjects, using 31P NMR spectroscopy of a single right forearm flexor muscle during three mild intermittent exercise levels (0-40% of maximum voluntary contraction) and recovery time. At rest, the inorganic phosphate/phosphocreatine ratio was different [0.13 +/- 0.005 (patients) vs 0.09 +/- 0.002 (normal subjects), P = 0.0001]. However, intracellular pH was comparable. Local acidosis (tissue pH < 6.9) was avoided to prevent fibre type IIb activation. Calculated resting phosphate potential levels were comparable, but the slope and intercept of the linear relationship of phosphate potential and workload were significantly lower in patients than in normal subjects (11.7 +/- 0.7 vs 15.8 +/- 0.6 and 139 +/- 7 vs 196 +/- 7, patients vs normal subjects, indicating early exhaustion of intracellular energy at lower exercise levels. Also, maximum calculated workload at which tissue ADP stabilized was lower in patients than in normal subjects (88 +/- 7% vs 120 +/- 4% of maximum voluntary workload, patients vs normal subjects, P < 0.05). Time to recovery to pre-test phosphocreatine levels was prolonged by 46% in patients compared to normal subjects (P < 0.05).. In heart failure, oxidative fibre mitochondrial function in skeletal muscle is impaired, as reflected by the reduced phosphate potential and oxidative phosphorylation rate, early exhaustion and slowed recovery of intracellular energy reserve at workloads, which do not affect intracellular pH.

Topics: Adenosine Triphosphate; Adult; Aged; Analysis of Variance; Case-Control Studies; Exercise Tolerance; Female; Forearm; Heart Failure; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Male; Middle Aged; Mitochondria, Muscle; Muscle Fibers, Slow-Twitch; Muscle, Skeletal; Phosphates; Phosphocreatine; Phosphorylation

31P-NMR was used to monitor myocardial bioenergetics in compensated and failing SHHF/MCC-fa(cp) (SHF) rat hearts. The SHHF/Mcc-fa(cp) (spontaneous hypertension and heart failure) rat is a relatively new genetic model in which all individuals spontaneously develop congestive heart failure, most during the second year of life. Failing SHF rat hearts displayed a pronounced decrease in resting PCr:ATP ratios (P<0.001), which was explained by a significant (P<0. 0001) drop in total creatine (47.2+/-3.1 nmol/mg protein) v age matched controls (106+/-3 nmol/mg protein). In end stage failure, NMR determined PCr was 2.9+/-0.1 micro mol/g wet weight under basal conditions. In contrast, 6- and 20-month-old controls and compensated SHFs had PCr values of 5.3+/-0.1, and 5.1+/-0.5 and 5. 1+/-0.2 micro mol/g wet weight. Both compensated and failing SHF hearts were metabolically compromised when the rate pressure product (RPP) was increased, as evidenced by an increase in Pi and a drop in PCr. Compensated SHF hearts, however, were able to increase rate pressure products (RRP, mmHg X beats/min) from 44.5+/-1.4 to 66.6+/-3. 4 K with dobutamine infusion, whereas hearts in end-stage failure were able to increase their RPP from baseline values of 27+/-4 K to only 37+/-7 K. The data indicate that a pronounced decline in PCr and total creatine signals the transition from compensatory hypertrophy to decompensation and failure in the SHF rat model of hypertensive cardiomyopathy.

Topics: Adenine Nucleotides; Adenosine Triphosphate; Animals; Creatine; Disease Models, Animal; Energy Metabolism; Heart Failure; In Vitro Techniques; Magnetic Resonance Spectroscopy; Male; Myocardium; Perfusion; Phosphocreatine; Phosphorus Isotopes; Rats; Rats, Inbred F344; Rats, Mutant Strains; Rats, Sprague-Dawley; Ventricular Dysfunction, Left

Assessment of left ventricular metabolism and function is important in patients on maintenance dialysis because congestive heart failure occurs quite frequently and has a poor prognosis. The purpose of this study was to evaluate the changes of myocardial high energy metabolism in dialysis patients by using phosphorus-31 (31P) magnetic resonance (MR) spectroscopy.. Phosphorus-31 spectra were obtained from anteroseptal wall of the heart in six normal subjects (mean age, 24 +/- 1 years) and 14 dialysis patients (mean age, 52 +/- 11 years), using a 1.5-tesla clinical MR system. Four patients had previous history of heart failure. Echocardiography was performed in all patients to evaluate left ventricular (LV) hypertrophy and LV function.. The averaged ratio of phosphocreatine (PCr)/beta-adenosine triphosphate (beta-ATP) in dialysis patients (1.15 +/- 0.25 mean +/- standard deviation), was significantly lower than that in healthy subjects (1.63 +/- 0.21; P < 0.01). There was no significant difference in PCr/beta-ATP ratios between the non-LV hypertrophy group (1.21 +/- 0.24; n = 7) and the LV hypertrophy group (1.09 +/- 0.24; n = 7). The averaged PCr/beta-ATP ratio in four patients with history of heart failure (0.96 +/- 0.18) was significantly lower than that of the 10 patients without history of heart failure (1.22 +/- 0.23; P < 0.05).. These results indicate that patients on maintenance dialysis have decreased PCr/beta-ATP ratio and 31P MR spectroscopy can provide noninvasive assessment of altered high energy phosphate metabolism.

Topics: Adenosine Triphosphate; Adult; Aged; Female; Heart Failure; Heart Ventricles; Humans; Kidney Failure, Chronic; Magnetic Resonance Spectroscopy; Male; Middle Aged; Myocardium; Phosphocreatine; Phosphorus; Phosphorus Radioisotopes; Renal Dialysis

We studied the local relation of muscle perfusion and metabolism in patients with severe chronic heart failure. Alterations of skeletal muscle blood flow and oxidative capacity contribute to exercise intolerance in these patients. The interdependence of both parameters has often been questioned.. With the use of nuclear magnetic resonance, we quantified leg and muscle perfusion during reactive hyperemia in 7 patients with heart failure (New York Heart Association class III and IV) and 7 age-matched control subjects from the difference in longitudinal relaxation rate (1/T1). By using 31P nuclear magnetic resonance spectroscopy, we assessed oxidative metabolism from the creatine rephosphorylation time constant after a short ischemic exercise. Phosphocreatine recovery is slowed (74.6 +/- 11.3 vs 49.9 +/- 13.9 seconds, p = .002) and reactive hyperemic flow is reduced (48.5 +/- 24.9 vs 113 +/- 30.4 mL/100 mL per minute, p = .0005).. By using a totally noninvasive protocol, we demonstrated that reactive hyperemic flow correlates with oxidative capacity in calf muscles from patients with heart failure, showing that exercise performance and local circulatory dysfunction are decreased in parallel in severe heart failure.

Topics: Aged; Chronic Disease; Exercise Tolerance; Heart Failure; Humans; Leg; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Middle Aged; Muscle, Skeletal; Oxidative Phosphorylation; Phosphocreatine; Regional Blood Flow

The hypothesis was tested that infusion of a solution containing creatine phosphate (CP) into rats with acutely failing hearts would enhance recovery of cardiac function. The acutely failing heart was produced by constricting the ascending aorta. This overload produced failure in approximately 25 min. At the point of failure the constriction was removed and solutions containing sterile physiological saline (PSS), PSS and CP, PSS and creatine, or PSS and creatine plus phosphate were infused. Cardiac function was assessed from systolic and diastolic blood pressure, +/- dp/dt, heart rate, and cardiac work. Ca2+ uptake by isolated sarcoplasmic reticulum and the concentrations of selected blood and tissue metabolites were measured. Normal cardiac function was restored in the PSS-CP infused rats whereas all other treatments did not restore cardiac function. Adenosine triphosphate and CP had declined in the myocardium of the failing hearts while lactate was elevated. The concentrations of these metabolites were normal in the PSS-CP infused animals. The glycogen concentration in the myocardium was reduced following the constriction. Ca2+ uptake by isolated sarcoplasmic reticulum was depressed in the failed hearts but normal in the hearts of CP-infused animals. These results demonstrate that the infusion of CP into animals with failing hearts can be effective in restoring cardiac function.

Topics: Animals; Cardiotonic Agents; Evaluation Studies as Topic; Heart Failure; Male; Myocardial Contraction; Myocardial Ischemia; Phosphocreatine; Rats; Rats, Sprague-Dawley

To study the mechanisms of limited exercise capacity and skeletal muscle energy production in male patients with congestive heart failure.. Muscle biopsy study.. Skeletal muscle metabolic response to maximal bicycle exercise was studied in 10 patients with chronic congestive heart failure (ejection fraction 0.22 +/- 0.05; peak oxygen consumption, VO2 15.1 +/- 4.9 ml.min-1.kg-1) and in nine healthy subjects (peak VO2 33.5 +/- 6.7 ml.min-1.kg-1). Activities of skeletal muscle enzymes were measured from the vastus lateralis muscle of 48 patients (ejection fraction 0.24 +/- 0.06, peak VO2 17.4 +/- 5.4 ml.min-1.kg-1) and 36 healthy subjects (peak VO2 38.3 +/- 8.4 ml.min-1.kg-1).. Although blood lactate levels were lower in patients than in healthy subjects (2.2 +/- 0.3 vs 5.2 +/- 0.6 mmol.l-1; P < 0.001) at peak exercise (96 +/- 11 W for patients and 273 +/- 14 W for controls), skeletal muscle lactate was similarly elevated (25.6 +/- 3.2 vs 22.7 +/- 2.7 mmol.kg-1) and creatine phosphate was equally depressed (P < 0.02) to low levels (7.0 +/- 1.9 vs 6.7 +/- 0.9 mmol.kg-1). The muscle ATP decreased by 21% (P < 0.05) and 8% (P < 0.01) in the patients and controls, respectively. Activities of rate limiting enzymes of the citric acid cycle (alpha-ketoglutarate dehydrogenase) and oxidation of free fatty acids (carnitine palmitoyltransferase II) were 48% and 21% lower than in controls, but the mean phosphofructokinase activity was unchanged in congestive heart failure.. It seems that the main limiting factor of exercise performance during heavy exercise is the same in congestive heart failure and healthy subjects, a high rate of skeletal muscle lactate accumulation and high-energy phosphate depletion. In congestive heart failure, the low activity of aerobic enzymes is likely to impair energy production and lead to lactate acidosis at low workloads.

Topics: Adenosine Triphosphate; Adult; Chronic Disease; Epinephrine; Exercise; Exercise Test; Exercise Tolerance; Heart Failure; Humans; Lactates; Male; Middle Aged; Muscle, Skeletal; Norepinephrine; Phosphocreatine

To investigate the metabolic response of skeletal muscle to exercise in patients with chronic heart failure and determine its relation to central haemodynamic variables.. University hospital in Sweden.. 16 patients in New York Heart Association class II-III and 10 healthy controls.. Skeletal muscle biopsies were obtained from the quadriceps muscle at rest and at submaximal and maximal exercise. Right sided heart catheterisation was performed in eight patients.. The patients had lower maximal oxygen consumption than the control group (13.2 (2.9) v 26.8 (4.4) ml/kg/min, P < 0.001). They had reduced activities of citrate synthetase (P < 0.05) and 3-hydroxyacyl-CoA dehydrogenase (P < 0.05) compared with the controls. At maximal exercise adenosine triphosphate (P < 0.05), creatine phosphate (P < 0.01), and glycogen (P < 0.01) were higher whereas glucose (P < 0.001) and lactate (P < 0.06) were lower in the patients than in the controls. Citrate synthetase correlated inversely with skeletal muscle lactate at submaximal exercise (r = -0.90, P < 0.003). No correlations between haemodynamic variables and skeletal muscle glycogen, glycolytic intermediates, and adenosine nucleotides during exercise were found.. Neither skeletal muscle energy compounds nor lactate accumulation were limiting factors for exercise capacity in patients with chronic heart failure. The decreased activity of oxidative enzymes may have contributed to the earlier onset of anaerobic metabolism, but haemodynamic variables seemed to be of lesser importance for skeletal muscle metabolism during exercise.

Topics: Adenosine Triphosphate; Aged; Cardiac Catheterization; Exercise; Exercise Test; Female; Glucose; Glucose-6-Phosphate; Glucosephosphates; Glycogen; Heart Failure; Humans; Lactates; Lactic Acid; Male; Middle Aged; Muscle, Skeletal; Oxygen Consumption; Phosphocreatine

We studied peripheral skeletal muscle metabolism in monocrotaline-treated rats. Two distinct groups emerged: a percentage of the animals developed ventricular hypertrophy, with no signs of heart failure (compensated group), whilst others, besides ventricular hypertrophy, developed the syndrome of congestive heart failure (CFH group). Oxidative metabolism and redox cellular state were expressed in terms of creatine phosphate, purine (ATP, ADP and AMP) and pyridine (NAD and NADH) nucleotides tissue content. Skeletal muscles with different metabolism were studied: (a) Soleus (oxidative), (b) extensor digitorium longus (glycolytic) and tibialis anterior (oxidative and glycolytic). The results showed that in CFH animals a decreased high-energy phosphates content occurs in the soleus and extensor digitorum longus, but not in the tibialis anterior. In the soleus. ATP declined from 20.31 +/- 2.5 of control group to 9.55 +/- 0.61 mumol/g dry wt. while in the extensor digitorum longus ATP declined from 30.92 +/- 2.68 to 22.7 +/- 1.54 mumol/g dry wt. In both these muscles, a shift of NAD/NADH couple towards oxidation was also observed (from 26.58 +/- 3.34 to 6.95 +/- 0.97 and from 18.88 +/- 3.43 to 10.57 +/- 1.61, respectively). These alterations were more evident in the aerobic soleus muscle. On the contrary, no major changes occurred in skeletal muscle metabolism of compensated animals. The results show that: (1) a decrease in muscle high-energy phosphates occurs in CFH; (2) this is accompanied by a decrease of NAD/NADH couple suggesting an impairment in oxygen utilization or availability.

Topics: Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Cardiomegaly; Disease Models, Animal; Female; Heart Failure; Monocrotaline; Muscle, Skeletal; NAD; Organ Size; Oxidation-Reduction; Phosphocreatine; Rats; Rats, Sprague-Dawley

The most serious consequence of heart failure is the shortened life expectancy, which may be associated with myocardial energy starvation.. Eight-week-old male Sprague-Dawley rats received 6 intraperitoneal injections of adriamycin (group A: total dose; 15 mg/kg body weight) or vehicle (group C) over 2 weeks. Rats then received either 272 mg/kg daily of oral 1-carnitine (A-LC and C-LC groups) or saline (A-S and C-S groups) for 6 weeks. The cumulative mortality rate in the A-LC group was significantly lower than in the A-S group (13 vs 42%, P = .028). Myocardial levels of high-energy phosphate compounds (ATP and creatine phosphate) and fatty acid metabolites (free carnitine, short-chain and long-chain acylcarnitine, and long-chain acyl CoA) in the left ventricle were measured the day after the last dose of drug or vehicle was administered. ATP was decreased by 73%, creatine phosphate by 61%, free carnitine by 52%, short-chain acylcarnitine by 48%, and long-chain acylcarnitine by 56% in the A-S group compared to the C-S group. Long-chain CoA was increased by 168% in the A-S group. Levels of myocardial high-energy phosphate compounds and fatty acid metabolites were near normal in adriamycin- and 1-carnitine-treated rats.. Preservation of the myocardial level of carnitine by 1-carnitine treatment prolonged survival of rats with adriamycin-induced failure by improving the myocardial metabolism of fatty acids.

Topics: Acyl Coenzyme A; Adenosine Triphosphate; Administration, Oral; Analysis of Variance; Animals; Carnitine; Culture Techniques; Disease Models, Animal; Doxorubicin; Drug Administration Schedule; Heart Failure; Male; Myocardium; Phosphocreatine; Rats; Rats, Sprague-Dawley; Survival Rate

To evaluate clinicohemodynamic effect of neoton (exogenic phosphocreatine) given in an intravenous course, the drug was added to standard scheme in 53 patients with chronic cardiac failure (6.0 g/day i.v. drip for 5 days or 3.0 g/day for 10 days). 20 control patients received standard therapy alone. A course neoton produced an increase in the ejection fraction, a reduction in end-diastolic and end-systolic left ventricular volumes. It is recommended to include neoton in the scheme of chronic cardiac failure treatment in the dose 3.0 g/day for 10 days.

Topics: Cardiotonic Agents; Chronic Disease; Diuretics; Drug Administration Schedule; Drug Therapy, Combination; Heart Failure; Hemodynamics; Humans; Infusions, Intravenous; Male; Middle Aged; Phosphocreatine; Treatment Outcome

Although pharmacological therapy with angiotensin converting enzyme (ACE) inhibitors has proved to be effective in patients with heart failure (HF), the experimental basis of this effect has not yet been addressed. In the present study, animals with HF were treated with an oral administration of 10 mg/kg/day captopril, 10 mg/kg/day enalapril and 3 mg/kg/day trandolapril from the 2nd to 12th week after the operation. HF was induced by permanent occlusion of the left coronary artery of the rat at 2 mm from its origin. Treatment of the HF rats with the ACE inhibitors enhanced the decrease in mean arterial blood pressure, attenuated the rise in left ventricular end-diastolic pressure, an indirect marker of preload, and diminished the reduction in cardiac output and stroke volume indices of the HF animal. Treatment also reversed the reduction in ATP, creatine phosphate, creatine and the mitochondrial oxygen consumption rate of the viable left and right ventricles of the HF animal. The improvement of the cardiac output index and high-energy phosphate levels of the HF rat by the ACE inhibitors was associated with the recovery of the mitochondrial oxygen consumption rate. In sham-operated animals, treatment with the ACE inhibitors reduced mean arterial pressure and left ventricular systolic pressure, but not metabolic variables concerning myocardial energy metabolism. The present results provide evidence that ACE inhibitor therapy improves cardiac function and myocardial energy metabolism of experimental animals with chronic heart failure. The mechanism underlying the benefit of long-term treatment with ACE inhibitors is probably attributable to recovery or preservation of the mitochondrial function and reduction in preload.

Topics: Adenine Nucleotides; Angiotensin-Converting Enzyme Inhibitors; Animals; Captopril; Enalapril; Energy Metabolism; Heart Failure; Hemodynamics; Indoles; Lactates; Male; Mitochondria, Heart; Myocardial Infarction; Myocardium; Organ Size; Oxygen Consumption; Phosphocreatine; Rats; Rats, Wistar

In the present work, we studied clinical and haemodynamic correlates of impaired cardiac high-energy phosphate metabolism in patients with heart failure due to dilated cardiomyopathy (DCM). Myocardial 31P-magnetic resonance (MR) spectra were obtained at 1.5 T in 14 volunteers and 23 patients with DCM (mean ejection fraction 34%) in order to quantify the creatine phosphate (CP)/ATP ratio. In addition, patients underwent cardiac catheterization and echocardiography. Compared to volunteers (2.02 +/- 0.11), CP/ATP ratios were significantly reduced in DCM patients (1.54 +/- 0.10; P < 0.05), indicating impaired high-energy phosphate metabolism. CP/ATP ratios correlated with the clinical severity of heart failure estimated from the NYHA class (r = 0.47, P < 0.01); also, CP/ATP correlated with left ventricular ejection fraction (r = 0.54, P < 0.01) and left ventricular end-diastolic wall thickness (r = 0.51, P < 0.01). Thus, 31P-MR spectroscopy can detect abnormal cardiac high-energy phosphate metabolism in patients with heart failure due to DCM. These abnormalities correlate with clinical and haemodynamic parameters. Future studies will have to determine whether 31P-MR spectroscopy can contribute to the routine clinical evaluation of patients with heart failure.

Topics: Adenosine Triphosphate; Adult; Cardiomyopathy, Dilated; Energy Metabolism; Female; Heart Failure; Hemodynamics; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Myocardium; Phosphocreatine; Reference Values; Ventricular Function, Left

We studied skeletal muscle phosphate metabolism abnormalities to examine their contribution at an early stage of congestive heart failure (CHF) in rats with aortocaval fistula (ACF) 4 wk after the procedure. In a group of 26 rats (13 with ACF and 13 sham operated), we assessed the degree of CHF. The ACF produced a significant rise in heart weight and plasma atrial natriuretic peptide. In a second group of 26 rats (13 ACF and 13 sham operated), we performed 31P-magnetic resonance spectroscopy in the gastrocnemius muscle during motor activity produced by electrical stimulation. The rate of phosphocreatine depletion, expressed by its initial slope, was higher in the ACF rats compared with controls (0.078 +/- 0.01 vs. 0.041 +/- 0.007; P < 0.03). pH and ATP decreased and phosphodiesters increased in all rats during electrical stimulation, with no difference between ACF rats and controls. The kinetics of phosphocreatine recovery were not different between ACF rats and controls. Together with previous studies, our present results suggest that muscle metabolism abnormalities in CHF may vary according to the experimental model and may be observed early in the course of the disease.

Topics: Adenosine Triphosphate; Animals; Aorta, Abdominal; Arteriovenous Shunt, Surgical; Blood Volume; Electric Stimulation; Heart Failure; Hemodynamics; Hydrogen-Ion Concentration; Kinetics; Magnetic Resonance Spectroscopy; Male; Motor Activity; Muscle, Skeletal; Phosphates; Phosphocreatine; Rats; Rats, Wistar; Vena Cava, Inferior

Several studies of phosphorus 31 (31P) magnetic resonance spectroscopy (MRS) have demonstrated the presence of skeletal muscle metabolic abnormalities during exercise in patients with chronic heart failure (CHF). We studied the contribution of these abnormalities to the limitation of exercise capacity in CHF. In 25 patients (age 57 +/- 2 years, left ventricular ejection fraction [LVEF] 28% +/- 1.6%, peak oxygen consumption (VO2) 16 +/- 1.2 ml/kg/mm) (mean +/- SEM), we studied the calf muscle at rest and during plantar flexion with 31P MRS. The phosphocreatine (PCr) depletion rate was significantly negatively correlated to peak VO2 (r = -0.62, p = 0.001) but not to LVEF. Muscle pH was correlated with the inorganic phosphorus (Pi)/PCr ratio (r = -0.69, p = 0.0001) and with the PCr/adenosine triphosphate beta (ATP beta) ratio (which negatively relates to adenosine diphosphate [ADP] concentration) (r = 0.65, p = 0.00001). Although muscle ATP (ATP/sum of phosphorus [sigma P] remained stable, in 8 patients ATP/sigma P decreased significantly (-15% +/- 4%, p = 0.0002). In this ATP-depleted group, peak VO2 was significantly lower than that of the nondepleted group and PCr depletion more rapid, whereas LVEF did not differ. Skeletal muscle metabolic abnormalities in CHF contribute markedly to the alteration of exercise capacity. Rapid PCr depletion and muscle acidosis are the most relevant abnormalities. ATP depletion and excessive increase in ADP during exercise may contribute further to exercise limitation specifically in patients with more marked CHF.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Adult; Aged; Analysis of Variance; Female; Heart Failure; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscle, Skeletal; Oxygen Consumption; Phosphocreatine; Physical Exertion; Stroke Volume

Using 31P-magnetic resonance spectroscopy during and after exercise, we studied whether forearm metabolic responses to exercise were improved by 1 mo of training in 10 males with heart failure. In the control (untrained) arm, there were no changes in any of the measured variables. In the trained arm, maximal voluntary contraction increased 6% (P = 0.05). During incremental exercise, duration increased 19% (P < 0.05) and submaximal responses improved for pH (6.78 +/- 0.13 pretraining vs. 6.85 +/- 0.17 posttraining; P < 0.01) and PCr/(PCr+Pi) (where PCr is phosphocreatine; 0.48 +/- 0.09 pretraining vs. 0.52 +/- 0.07 posttraining; P < 0.01). The PCr resynthesis rate increased by 48% (P < 0.01), and estimated effective maximal rate of mitochondrial ATP synthesis increased by 37% (P < 0.05). Endurance exercise duration increased by 67% (P < 0.01), and submaximal levels of PCr/(PCr+Pi) (P < 0.05) and pH (P = 0.07) improved. The PCr resynthesis rate (P < 0.01) and the effective maximal rate of mitochondrial ATP synthesis (P < 0.05) also improved. These findings document that impaired oxidative capacity of skeletal muscle can be improved by local muscle training in heart failure, which is compatible with the hypothesis that a part of the abnormality present in heart failure may be due to inactivity.

Topics: Adenosine Triphosphate; Adult; Aged; Forearm; Heart Failure; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Imaging; Male; Middle Aged; Muscle Contraction; Muscles; Phosphocreatine; Physical Education and Training; Physical Endurance

The purpose of this study was to assess high energy phosphate compound metabolism in remodeled left ventricular myocardium.. The development of heart failure several years after myocardial infarction is often unexplained. Certain abnormalities of remodeled myocardium suggest that structural changes occurring in viable myocardium after discrete myocardial damage may contribute to the later appearance of heart failure. Whether these abnormalities alter metabolism in the surviving muscle and thereby possibly contribute to ventricular dysfunction is unknown.. High energy phosphate compound metabolism was assessed using spatially localized phosphorus-31 nuclear magnetic resonance spectroscopy. Eleven dogs with documented left ventricular dysfunction, resulting from infarction produced by transmyocardial direct current shock, were compared with eight normal dogs. Analyses were performed at baseline and during coronary hyperperfusion induced by intravenous adenosine. Myocardial blood flow was measured with radioactive microspheres.. The creatine phosphate/adenosine triphosphate (CP/ATP) ratio was significantly reduced in the left ventricular dysfunction group in both the subepicardium ([mean +/- SE] 1.94 +/- 0.08 vs. 2.32 +/- 0.13, p = 0.019) and the subendocardium (1.71 +/- 0.07 vs. 2.05 +/- 0.07, p = 0.004). Intravenous adenosine produced significant coronary hyperemia in both groups but was less marked in dogs with left ventricular dysfunction. The improvement in myocardial perfusion was accompanied by a significant increase in the subendocardial CP/ATP ratio (from 1.71 +/- 0.07 to 1.92 +/- 0.08, p = 0.01) in dogs with left ventricular dysfunction.. An abnormal transmural distribution of high energy phosphate compounds is evident in remodeled myocardium. This abnormality may be related in part to mismatch of oxygen delivery and demand.

Topics: Adenosine; Adenosine Triphosphate; Animals; Coronary Circulation; Dogs; Heart Failure; Hypertrophy, Left Ventricular; Magnetic Resonance Spectroscopy; Myocardial Infarction; Myocardium; Phosphocreatine; Time Factors; Ventricular Function, Left

Patients with advanced heart failure have bioenergetic abnormalities of skeletal muscle metabolism during exercise. Using 31P magnetic resonance spectroscopy, we sought to determine whether skeletal metabolic responses to exercise are normalized by orthotopic cardiac transplantation.. Four groups were studied: healthy normal volunteers (n = 9), subjects awaiting heart transplantation (n = 10), subjects < 6 months (mean, 4 months) after transplant (n = 9), and subjects > 6 months (mean, 15 months) after transplant (n = 8). None of the posttransplant patients had biopsy evidence of rejection at the time of study. There were no significant differences in age, preoperative functional class, or symptom duration among the three patient groups. Metabolic responses were monitored in the dominant arm during incremental weight pull exercise and 10 minutes of recovery by 31P magnetic resonance spectroscopy, with measurement of pH and the phosphocreatine (PCr)/(PCr + inorganic phosphate [Pi]) ratio, an index of PCr concentration. In addition, based on recovery data, the rate of PCr resynthesis was calculated as a measure of oxidative metabolism that is independent of work level, recruitment, or muscle mass, and the effective maximal rate of mitochondrial ATP synthesis (Vmax) was determined. Analysis was by ANOVA. There were no differences between groups in pH or PCr/(PCr + Pi) at rest. Compared with the normal control group, the pretransplant group had a decreased exercise duration (11.3 +/- 2.5 versus 15.0 +/- 1.3 minutes, P = .02), a lower submaximal exercise PCr/(PCr + Pi) ratio (0.58 +/- 0.11 versus 0.76 +/- 0.08, P < .05), a reduced PCr resynthesis rate (13 +/- 6 versus 22 +/- 9 mmol/L per minute, P < .05), and a lower calculated Vmax (26 +/- 14 versus 53 +/- 26 mmol/L per minute, P < .05). In the group studied early after transplantation, all the changes noted in the pretransplant group persisted and were if anything somewhat worse. In the group studied late after transplantation, there was a significant improvement in the PCr resynthesis rate compared with the early-posttransplant group (27 +/- 6 late versus 15 +/- 6 mmol/L per minute early, P < .05) and statistically nonsignificant trends toward improvements in submaximal exercise pH (6.86 +/- 0.24 late versus 6.72 +/- 0.24 early) and submaximal PCr/(PCr + Pi) ratio (0.56 +/- 0.14 late versus 0.44 +/- 0.15 early) and Vmax (45 +/- 21 late versus 33 +/- 15 mmol/L per minute early). However, compared with normal subjects, exercise duration and submaximal PCr/(PCr + Pi) were still reduced in the late-posttransplant group.. Despite successful heart transplantation, skeletal muscle abnormalities of advanced heart failure persist for indefinite periods, although partial improvement occurred at late times. The persistent abnormalities may contribute to the reduced exercise capacity that is present in most patients after transplantation.

Topics: Energy Metabolism; Exercise; Exercise Tolerance; Female; Follow-Up Studies; Heart Failure; Heart Transplantation; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscles; Phosphates; Phosphocreatine; Time Factors

The hemodynamic effects of acute and long-term administration of creatine phosphate were studied in 23 patients with heart failure (NYHA classes II and III) under stabilized treatment. Acute creatine phosphate (5 g i.v.) induced a significant increase of the ejection fraction (FE) and of other parameters of cardiac contractility. Once these improvements of cardiac contractility were obtained by acute treatment, further significant increases in cardiac function were observed if treatment was continued for six days, i.e. telesystolic diameter and volume, as well as parietal stress were significantly reduced, and ejection fraction and shortening fraction were significantly increased. Creatine phosphate treatment has a favourable influence on the hemodynamics of patients with an obvious contractility deficit and chronic ischemia of the myocardium.

Topics: Acute Disease; Aged; Cardiomyopathy, Dilated; Chronic Disease; Drug Evaluation; Echocardiography; Female; Heart Failure; Hemodynamics; Humans; Male; Middle Aged; Myocardial Ischemia; Phosphocreatine

Spiraprilat, a new angiotensin-converting enzyme (ACE) inhibitor, was compared with enalaprilat for its ability to improve left ventricular (LV) function and metabolism in anesthetized open-chest dogs with a new model of acute LV failure (ALVF) induced by embolization of the left coronary artery with 50 microns plastic microspheres followed by intravenous (i.v.) infusion of methoxamine. With this procedure, LV end-diastolic pressure (LVEDP) increased from 4.2 +/- 0.7 to 12.8 +/- 1.3 mm Hg and remained at approximately 12 mm Hg throughout the experiment. Cardiac output (CO) decreased from 1.25 +/- 0.12 to 0.79 +/- 0.06 and 0.55 +/- 0.02 L/min at 30 and 90 min after methoxamine infusion, respectively. LVdP/dtmax and dP/dt/P decreased, while total peripheral resistance (TPR) increased. These hemodynamic changes indicated establishment of stable ALVF of a moderate degree. Moreover, decreases in myocardial lactate consumption and contents of creatine phosphate in the myocardium indicated the existence of moderate ischemia. The new ACE inhibitor, spiraprilat, as well as enalaprilat (30 micrograms/kg i.v.) effectively decreased mean aortic pressure (30%), LVEDP (20%), and TPR (30%) and increased stroke volume (SV) CO, and dP/dt/P. Both agents decreased myocardial oxygen consumption (20%) and caused a significant increase in myocardial creatine phosphate contents. These data indicate that the beneficial effects of both inhibitors extended not only to LV function but also to myocardial energy metabolism in ALVF.

Topics: Adenosine Triphosphate; Anesthesia; Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Pressure; Coronary Vessels; Disease Models, Animal; Dogs; Enalapril; Heart Failure; Lactates; Lactic Acid; Methoxamine; Microspheres; Myocardium; Oxygen Consumption; Phosphocreatine; Vascular Resistance; Ventricular Function, Left

The purpose of this study was to investigate the prevalence of skeletal muscle atrophy and its relation to exercise intolerance and abnormal muscle metabolism in patients with heart failure (HF).. Peak VO2, percent ideal body weight (% IBW), 24-hour urine creatinine (Cr), and anthropometrics were measured in 62 ambulatory patients with HF. 31P magnetic resonance spectroscopy (MRS) and imaging (MRI) of the calf were performed in 15 patients with HF and 10 control subjects. Inorganic phosphorus (Pi), phosphocreatine (PCr), and intracellular pH were measured at rest and during exercise. Calf muscle volume was determined from the sum of the integrated area of muscle in 1-cm-thick contiguous axial images from the patella to the calcaneus. A reduced skeletal muscle mass was noted in 68% of patients, as evidenced by a decrease in Cr-to-height ratio of less than 7.4 mg/cm and/or upper arm circumference of less than 5% of normal. Calf muscle volume (MRI) was also reduced in the patients with HF (controls, 675 +/- 84 cm3/m2; HF, 567 +/- 112 cm3/m2; p less than 0.05). Fat stores were largely preserved with triceps skinfold of less than 5% of normal and/or IBW of less than 80% in only 8% of patients. Modest linear correlations were observed between peak VO2 and both calf muscle volume per meter squared (r = 0.48) and midarm muscle area (r = 0.36) (both p less than 0.05). 31P metabolic abnormalities during exercise were observed in the patients with HF, which is consistent with intrinsic oxidative abnormalities. The metabolic changes were weakly correlated with muscle volume (r = -0.42, p less than 0.05).. These findings indicate that patients with chronic HF frequently develop significant skeletal muscle atrophy and metabolic abnormalities. Atrophy contributes modestly to both the reduced exercise capacity and altered muscle metabolism.

Topics: Exercise; Exercise Test; Female; Heart Failure; Humans; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscles; Muscular Atrophy; Phosphocreatine; Phosphorus; Prevalence

To elucidate the mechanism of acute contractile failure induced by adriamycin, the intracellular concentrations of free calcium ([Ca2+]i) and energy-related phosphate compounds were determined in isolated ferret hearts. The time-averaged [Ca2+]i was measured at 10 min resolution using fluorine nuclear magnetic resonance (NMR) spectroscopy and the NMR-sensitive Ca2+ indicator 5F-BAPTA. [Ca2+]i significantly increased from a control of 381 +/- 66 nM (mean +/- SEM, N = 5) to 789 +/- 171 nM during 30 min of perfusion with adriamycin (30 mg/L), and remained elevated for at least 30 min after washout. The isovolumic LV pressure decreased to 80.7 +/- 8.9% of control (N = 12, p less than 0.05) and did not recover after washout. Intramyocardial contents of energy-related phosphates were determined by phosphorus NMR spectroscopy in seven other hearts. No significant change in myocardial energy metabolism was observed during adriamycin exposure and after washout; inorganic phosphate did not increase, and phosphocreatine and ATP did not decrease. These results indicate that Ca overload induced by adriamycin is associated with acute contractile failure. Adriamycin has been reported to inhibit Na-Ca exchange and to affect the gating of Ca2+ release channels in sarcoplasmic reticulum. Whatever the cause of the calcium overload, the fact that dysfunction persists as an aftereffect of adriamycin is consistent with the hypothesis that calcium overload, in the absence of ischemia, can leave behind long-lasting contractile dysfunction.

Topics: Adenosine Triphosphate; Animals; Calcium; Doxorubicin; Egtazic Acid; Energy Metabolism; Ferrets; Heart; Heart Failure; Homeostasis; In Vitro Techniques; Magnetic Resonance Spectroscopy; Male; Myocardium; Phosphates; Phosphocreatine

1. Using 31P nuclear magnetic resonance, it has previously been demonstrated that patients with congestive heart failure exhibit a greater than normal phosphocreatine (PCr) depletion in the working skeletal muscles of the arm. We have studied the importance of the work necessary to reach a similar PCr depletion ([PCr]/([PCr] + [Pi]) = 0.5) in calf muscle. Our results show significantly lower values for patients with congestive heart failure in both aerobic and ischaemic conditions (respectively: 0.009 +/- 0.007 vs 0.026 +/- 0.013 W/kg body weight, P less than 0.01; 0.29 +/- 0.16 vs 0.90 +/- 0.25 J/kg body weight, P less than 0.01). 2. This original model of skeletal muscle exercise facilitates a comparison of PCr recovery rate due to a similarity in the PCr depletion and intracellular pH in the two series at the start of recovery. However, the PCr recovery rate is similar after both normoxic and ischaemic exercise, i.e. respective percentages of PCr increase in the first 25 s recovery spectrum were: (a) aerobic exercise, congestive heart failure 133 +/- 18%, control series 138 +/- 18%; (b) ischaemic exercise, congestive heart failure 114 +/- 13%, control series 118 +/- 12%. The absence of a difference in PCr recovery rate and the greater PCr depletion by ischaemic work in patients with congestive heart failure suggest modifications that cannot be explained by a reduced blood flow to the muscle. 3. When comparing the two series, intracellular pH evolved similarly in normoxia and ischaemia during both work and recovery. Thus, no increase in anaerobic glycolytic activity appears when equivalent PCr depletion has occurred.

Topics: Adult; Aged; Exercise; Heart Failure; Humans; Hydrogen-Ion Concentration; Ischemia; Leg; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscles; Phosphocreatine

To examine the ability of the skeletal muscle of congestive heart failure (CHF) patients to adapt to chronic exercise, five patients performed localized nondominant wrist flexor training for 28 d. Inorganic phosphate (Pi) and phosphocreatine (PCr) were monitored by magnetic resonance spectroscopy in both forearms at rest and during submaximal wrist flexion exercise at 6, 12, 24, and 36 J.min-1 before and after exercise training. Simultaneous measurements of limb blood flow were made by plethysmography at 12, 24, and 36 J.min-1. Forearm muscle mass and endurance were measured by magnetic resonance imaging and wrist flexion exercise before and after training. The Pi/PCr ratio and pH were calculated from the measured Pi and PCr. Exercise cardiac output, heart rate, plasma norepinephrine, and lactate measured during training were not elevated above resting values, confirming that training was localized to the forearm flexor muscles. After training, muscle bioenergetics, as assessed by the slope of the regression line relating Pi/PCr to submaximal workloads, were improved in the trained forearm of each patient, although muscle mass, limb blood flow, and pH were unchanged. Forearm endurance increased by greater than 260% after training. In the dominant untrained forearm, none of the measured indices were affected. We conclude that localized forearm exercise training in CHF patients improves muscle energetics at submaximal workloads in the trained muscle, an effect which is independent of muscle mass, limb blood flow, or a central cardiovascular response during training. These findings indicate that peripheral muscle metabolic and functional abnormalities in CHF can be improved without altering cardiac performance.

Topics: Aged; Arm; Cardiac Output; Energy Metabolism; Exercise; Heart Failure; Heart Rate; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Imaging; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscles; Organ Size; Oxygen Consumption; Phosphocreatine; Regional Blood Flow

Serial changes in left ventricular (LV) size and function during the adaptation to chronic pressure overload and the transition to pump failure were studied in 16 conscious dogs (aortic bands placed at 8 weeks of age). Echocardiographic data at baseline and at 3, 6, 9, and 12 months after banding revealed a progressive increase in LV mass in all dogs. In six dogs with LV pump failure, there was a progressive decline in circumferential fiber shortening (29 +/- 4% at 12 months); this was significantly less than that seen in five littermate controls (38 +/- 3%, p less than 0.05). The average LV to body weight ratio in this group was 9.8 +/- 2.7 g/kg. In 10 dogs without pump failure (compensated LVH group), shortening exceeded that seen in the controls (43 +/- 4%, p less than 0.05); the LV to body weight ratio was 7.7 +/- 1.0 g/kg. At 12 months (cardiac catheterization), the LV end-diastolic pressure was higher in the failure (25 +/- 15 mm Hg) than in the compensated group (8 +/- 5 mm Hg, p less than 0.05); mean systolic stress was also higher in the failure group (313 +/- 67 g/cm2) than in the compensated group (202 +/- 53 g/cm2, p less than 0.05). The transmural distribution of myocardial blood flow was measured (at 12 months) with the radioactive microsphere technique; flow data were then related to an index of demand (a stress-time index). There was preferential blood flow to the subendocardial layers in the control (endo/epi = 1.28) and compensated hearts (endo/epi = 1.10), but in the failure group there was a relative decrease in subendocardial flow (endo/epi = 0.92). However, the absolute values for subendocardial flow in the normal, compensated, and failure groups were 77 +/- 54, 125 +/- 48, and 113 +/- 64 ml/min/100 g; the stress-time indexes in the subendocardial shell were 38 +/- 11, 74 +/- 19, and 93 +/- 34 g sec.10(2)/cm2/min. Despite what appears to be a marginal balance between blood flow and the stress time index in the failure group, the myocardial high energy phosphates were not depleted and the inoptropic state was not depressed. In this model of LV hypertrophy, the observed differences in fiber shortening can be explained on the basis of the inverse afterload-shortening relation; pump failure was due to an inadequate LV hypertrophy with afterload excess.(ABSTRACT TRUNCATED AT 400 WORDS)

Topics: Adenosine Triphosphate; Animals; Cardiac Catheterization; Cardiomegaly; Coronary Circulation; Dogs; Echocardiography; Heart Failure; Myocardial Contraction; Myocardium; Phosphocreatine; Stroke Volume

Dobutamine has been shown to exert disparate clinical effects in patients with cardiomyopathy and heart failure. This study evaluated the effects of dobutamine on hemodynamics and energetics in isolated, perfused myopathic hamster hearts at a moderate and advanced stage of heart failure. Biochemical changes were correlated with left ventricular developed pressure, coronary flow, and myocardial oxygen consumption. During dobutamine treatment left ventricular developed pressure increased in the control and moderate heart failure group 28.0 +/- 1.0% and 114.2 +/- 11.6%, respectively. Myocardial oxygen consumption increased 50.1 +/- 9.1% and 45.5 +/- 16.0%, respectively. There were no significant changes of left ventricular developed pressure and myocardial oxygen consumption in the advanced heart failure group. Inorganic phosphate (Pi) increased in the control group from 6.8 +/- 0.5 to 11.4 +/- 1.2 mmol (p less than 0.005) and in the advanced heart failure group from 10.4 +/- 1.1 to 15.3 +/- 1.2 mmol (p less than 0.01). Phosphocreatine (PCr) and beta-ATP (adenosine triphosphate) decreased in the control group from 12.2 +/- 0.4 to 8.7 +/- 0.7 mmol (p less than 0.001) and 10.4 +/- 0.8 to 7.7 +/- 0.7 mmol (p less than 0.02), respectively. PCr/Pi ratio, reflecting mitochondrial function, fell in the control and advanced heart failure group from 1.84 +/- 0.14 to 0.84 +/- 0.14 (p less than 0.02) and 0.81 +/- 0.16 to 0.37 +/- 0.08 (p less than 0.03), respectively. Thus in cardiomyopathic hamsters dobutamine improved mechanical performance and thermodynamic efficiency in moderate stages of heart failure by improving mitochondrial activity, but did not improve mechanical performance in an advanced stage of heart failure. These experiments provide into the disparate clinical effects of dobutamine at various stages of heart failure.

Topics: Adenosine Triphosphate; Animals; Cricetinae; Dobutamine; Heart; Heart Failure; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Mesocricetus; Myocardium; Oxygen Consumption; Phosphates; Phosphocreatine

Topics: Captopril; Extremities; Heart; Heart Failure; Hemodynamics; Humans; Magnetic Resonance Spectroscopy; Muscles; Oxygen Consumption; Phosphocreatine; Physical Exertion; Regional Blood Flow

Patients with heart failure frequently report leg fatigue during exercise. At present, however, there is no objective method of detecting leg muscle abnormalities in such patients. To determine if phosphorus-31 nuclear magnetic resonance spectroscopy can provide such information, this technique was used to compare calf responses to stair climbing and plantarflexion in 20 patients with heart failure (peak oxygen consumption (VO2) of 13.6 +/- 5 ml/kg/min, ejection fraction 20 +/- 5%) and 9 age-matched normal subjects. Work was quantified by measuring VO2. At rest, both groups exhibited similar inorganic phosphorus to phosphocreatine (Pi/PCr) ratios (patients with heart failure 0.21 +/- 0.07, normal subjects 0.21 +/- 0.06, difference not significant) and pH levels (patients with heart failure 7.06 +/- 0.17, normal subjects 7.05 +/- 0.11, difference not significant). In both normal subjects and patients with heart failure, exercise resulted in a progressive rise in Pi/PCr as VO2 increased. However, examination of the relation of VO2 versus Pi/PCr revealed steeper slopes in patients with heart failure during both stair climbing and plantar-flexion. Neither form of exercise decreased calf pH in normal subjects. In the patients with heart failure, significant decreases in pH were noted during the highest work level of plantarflexion (pH of heart failure patients 6.86 +/- 0.20, pH of normal subjects 7.07 +/- 0.14, p less than 0.01). Metabolic recovery time was also prolonged in the patients with heart failure versus normal subjects (3.3 +/- 0.8 vs 2.1 +/- 0.5 minutes, respectively, p less than 0.002). These findings indicate that phosphorus-31 nuclear magnetic resonance provides objective evidence of leg muscle abnormalities in patients with heart failure.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Blood Pressure; Heart Failure; Heart Rate; Humans; Leg; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscles; Oxygen Consumption; Phosphocreatine; Phosphorus; Physical Exertion

Muscle metabolism of the finger flexor muscle of the dominant arm was examined in patients with congestive heart failure and age-related controls. Phosphocreatine utilization and decrease in pH during exercise was significantly greater in patients than in controls. Recovery rates were slow in some of these patients. Measurements of forearm blood flow at rest or during exercise were not significantly reduced in patients compared with controls. The inorganic phosphate peak was split during exercise in some of the patients, suggesting the presence of more glycolytic fibers in their muscles. These observations suggest that metabolic abnormalities may be present in the skeletal muscles of patients with heart failure that are not due to reduced nutritive blood flow. This may, in part, explain the lack of correlation between measurements of cardiac function and exercise tolerance in these patients.

Topics: Adenosine Triphosphate; Fingers; Forearm; Heart Failure; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscles; Phosphates; Phosphocreatine; Physical Exertion; Regional Blood Flow; Vascular Resistance

A total of 40 patients with complicated myocardial infarction (MI), with life threatening arrhythmias and congestive heart failure. II-IV degree after Walk's classification, with a concomitant pathology were investigated. Phosphocreatine (PC) therapy (i. v. infusions for 3 days at a total dose of 144 g) made a positive effect on a course of disease. A degree of clinical symptoms of heart failure lessened in 26 patients, disturbed cardiac rhythm got stable in 23 patients. A PC positively inotropic effect was observed. The comparison of the results of PC therapy with those of 173 MI patients on routine therapy showed heart contractility preserved at a higher level and the improvement of gas exchange. A conclusion was made of a favorable effect of the drug on a course of complicated MI.

Topics: Adult; Aged; Aged, 80 and over; Arrhythmias, Cardiac; Drug Evaluation; Heart Failure; Humans; Male; Middle Aged; Myocardial Infarction; Phosphocreatine; Risk; Time Factors

In patients with congestive heart failure (CHF), exercise limitation correlates poorly with central hemodynamic abnormalities, suggesting that additional abnormalities in skeletal muscle blood flow or metabolism play an important pathophysiologic role. Therefore, muscle metabolism was examined by 31P nuclear magnetic resonance (NMR) at rest and during repetitive bulb squeeze exercise in 11 patients with New York Heart Association class II to IV CHF and 7 age-matched control subjects. Serial spectra were obtained at rest, at 2 levels of exercise and during recovery. At rest, the only abnormal finding was an elevated inorganic phosphate (Pi) concentration (5.0 +/- 1.5 vs 3.6 +/- 0.4 mM, p less than 0.01). At the lower exercise level, phosphocreatine (PCr) utilization, which was followed as the ratio of [PCr]/[( PCr] + [Pi]), was greater (0.36 +/- 0.16 vs 0.53 +/- 0.10, p less than 0.02), and pH fell more rapidly and to a lower value (6.38 +/- 0.25 vs 6.85 +/- 0.17, p less than 0.001). At the higher level of exercise, the patients could not work effectively and the group differences narrowed. Compared with control subjects, acidification was disproportionately greater in relation to PCr depletion in patients, further suggesting excessive dependence on glycolytic metabolism. The Pi peak was prominently double in 5 patients, indicating presence of a population of muscle fibers undergoing unusually active glycolysis. PCr resynthesis, a reflection of oxidative phosphorylation, was delayed in 4 patients. These findings indicate that in many patients with CHF, exercising muscle has marked metabolic changes consistent with impaired substrate availability and altered biochemistry.

Topics: Adenosine Triphosphate; Heart Failure; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscles; Phosphates; Phosphocreatine; Phosphorus Isotopes; Physical Exertion

We and others have previously demonstrated excessive phosphocreatine (PCr) depletion and acidosis in skeletal muscle during exercise in patients with congestive heart failure (CHF). In the present study, we performed serial measurements of PCr and pH during gradually incremental flexor digitorum superficialis exercise in 22 patients with CHF and 11 age-matched controls to determine: (1) whether abnormalities were present at the same relative workloads (a comparison that would at least partially compensate for differences in muscle mass), (2) the temporable course of the metabolic changes, (3) the relationship of the metabolic findings to clinical variables, and (4) the relationship of the metabolic abnormalities to forearm blood flow. The patients with CHF had significantly lower [PCr] and pH at all submaximal levels of exercise, and these abnormalities were apparent from the onset of low-level exercise. There was considerable heterogeneity among the patients with CHF with respect to the metabolic findings, with 14 of 22 exhibiting either PCr or pH values more than 2 SDs below normal. Patients whose capacity was more limited during the protocol had lower [PCr], and especially pH, at low loads than did other patients with CHF or the control subjects. The more symptomatic patients and those with more limited bicycle exercise tolerance also had lower pH values. In contrast, there were no significant differences in forearm blood flow between the patients and controls and no relationship between forearm blood and either clinical variables or the metabolic findings. These results indicate that skeletal muscle metabolic abnormalities are present in many patients with CHF and that they are not primarily due to either muscle atrophy or impaired blood flow. These changes may explain in part the marked heterogeneity of symptom status and exercise capacity of patients with similar degrees of cardiac dysfunction.

Topics: Blood Flow Velocity; Forearm; Heart Failure; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscles; Phosphocreatine; Physical Exertion; Plethysmography; Regional Blood Flow; Vascular Resistance

Energy metabolism was assessed in dilated (congestive) and hypertrophic myopathic hearts from Syrian hamsters after isolated, working heart perfusion with palmitate and/or glucose as substrates. Hearts with these two types of cardiomyopathy were found to be distinctively different from control hearts, and also different from each other. Both cardiomyopathic groups had developed hypertrophy by 3 months but the dilated hearts had a decreased muscle mass by 6 months. In the hypertrophic hearts coronary flow rates per gram of non-collagen protein and, thus, oxygen delivery were markedly increased. With either substrate the hypertrophic hearts maintained more normal levels of adenosine triphosphate in contrast to the dilated hearts whose levels were approximately 50% lower than controls by 6 months of age despite similar heart rates and left ventricular systolic pressure development in all three groups. Lactate to pyruvate ratios in the diseased hearts were comparable to control values. Total coenzyme A levels were statistically lower in the dilated compared to the control group of hearts. Carnitine and its acyl esters, on the other hand, varied markedly with levels of total carnitine decreasing to 50% of control levels in both cardiomyopathic groups by 6 months. In spite of this, the mass action ratios for the carnitine acyl-CoA transferase enzyme complexes were not markedly altered in the control or myopathic hearts regardless of whether palmitate and/or glucose were the perfusate substrates. These results suggest that the decreased carnitine levels are not of sufficient magnitude at this stage in the disease to cause a decrease in cardiac function secondary to restricted energy production. Total carnitine levels were found to be increased in liver and serum of the cardiomyopathic hamsters but unchanged in skeletal muscle. Thus, the deficiency in myocardial carnitine would appear to be due to a specific myocardial problem and not due to a problem of synthesis or supply.

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Cardiomegaly; Carnitine; Coenzyme A; Coronary Circulation; Cricetinae; Diaphragm; Energy Metabolism; Glucose; Heart Failure; Heart Rate; Kidney; Lactates; Lactic Acid; Liver; Male; Mesocricetus; Palmitic Acid; Palmitic Acids; Phosphocreatine; Pyruvates; Pyruvic Acid

Using phosphorous nuclear magnetic resonance, we have previously demonstrated that patients with heart failure often exhibit abnormal forearm muscle metabolism during forearm exercise. To determine if this altered metabolism is due to reduced muscle flow, we measured forearm blood flow with plethysmography and forearm muscle inorganic phosphate (Pi), phosphocreatine (PCr), and pH with 31P nuclear magnetic resonance spectroscopy at rest and during mild forearm exercise (0.2, 0.4, and 0.6 W) in 21 men with heart failure and in 12 age-matched normal male subjects. The Pi/PCr ratio was correlated with power output and the slope of this relationship was used as an index of forearm metabolism. At rest, both groups had similar Pi/PCr ratios (normal subjects 0.11 +/- 0.05; patients with heart failure 0.11 +/- 0.03; p = NS) and forearm blood flows (normal subjects 2.9 +/- 1.4 ml/min/100 ml; patients with heart failure 2.6 +/- 1.2 ml/min/100 ml; p = NS). In both groups, exercise resulted in a progressive increase in both Pi/PCr and forearm blood flow as power output increased. However, the patients exhibited a steeper slope of the Pi/PCr-to-power output relationship than did the normal subjects (normal subjects 1.4 +/- 0.6 Pi/PCr U/W; patients with heart failure 3.0 +/- 2.4 Pi/PCr U/W; p less than .03). In contrast, forearm blood flow was similar in both groups during exercise (at 0.2 W, 6.3 +/- 3.3 and 6.8 +/- 3.2 ml/min/100 ml in normal subjects and patients with heart failure, respectively; at 0.4 W, 8.7 +/- 6.5 and 8.3 +/- 3.3; at 0.6 W, 12.8 +/- 7.9 and 12.0 +/- 4.6; all p = NS). Nine of the 21 patients with heart failure had slopes of the Pi/PCr-to-power output relationship above the normal range. These nine patients also had forearm blood flows comparable to flows observed in the normal subjects. These data indicate that forearm muscle metabolism during forearm exercise is altered in a subpopulation of patients with heart failure. This metabolic alteration does not appear to be due to decreased muscle blood flow, suggesting that other mechanisms, such as alterations in mitochondrial population or substrate utilization, may be responsible.

Topics: Adult; Aged; Chronic Disease; Energy Metabolism; Exercise Test; Forearm; Heart Failure; Hemodynamics; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscles; Phosphates; Phosphocreatine; Plethysmography; Time Factors

Blood flow to working skeletal muscle is frequently reduced in patients with heart failure or peripheral vascular disease. To determine if phosphorus nuclear magnetic resonance (NMR) can noninvasively detect such muscle underperfusion, gated phosphorus-31 NMR spectroscopy was used to compare muscle inorganic phosphate, phosphocreatine and pH during mild wrist flexion exercise at 0.2, 0.4 and 0.6 W in eight normal men, before and after reduction of forearm blood flow. Forearm flow was reduced by cuff inflation to a pressure determined by Doppler ultrasound to bring flow to 40 to 60% of control. Attention was focused on the inorganic phosphate to phosphocreatine (Pi/PCr) ratio and pH, two variables potentially sensitive to muscle oxygen delivery. At rest with normal flow, Pi/PCr averaged 0.12 +/- 0.03 and pH averaged 7.02 +/- 0.04. Exercise produced a progressive increase in Pi/PCr (0.2 W = 0.43 +/- 0.12; 0.4 W = 0.75 +/- 0.31; 0.6 W = 1.04 +/- 0.47) and a modest decrease in pH (0.2 W = 6.94 +/- 0.04; 0.4 W = 6.86 +/- 0.18; 0.6 W = 6.85 +/- 0.06). Flow reduction had no effect on Pi/PCr or pH at rest. In contrast, flow reduction during exercise was associated with higher Pi/PCr at all three work loads (0.2 W = 0.60 +/- 0.27; 0.4 W = 0.99 +/- 0.50; 0.6 W = 2.00 +/- 1.26 [all p less than 0.05 versus normal flow]) and lower pH (0.2 W = 6.78 +/- 0.12; 0.4 W = 6.69 +/- 0.23; 0.6 W = 6.65 +/- 0.30 [p less than 0.01 versus normal flow at 0.2 and 0.4 W; p = 0.05 at 0.6 W]).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adult; Energy Metabolism; Heart Failure; Humans; Hydrogen-Ion Concentration; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscles; Oxygen; Phosphates; Phosphocreatine; Physical Exertion; Regional Blood Flow; Vascular Diseases

Exertional fatigue is a major limiting symptom in patients with heart failure. To investigate the metabolic basis of this fatigue, we used gated nuclear magnetic resonance spectroscopy to compare inorganic phosphate (Pi), phosphocreatine (PCr) and pH levels, and fatigue (1 to 4+) during mild forearm exercise in eight normal men and nine men with heart failure. Wrist flexion every 5 sec for 7 min was performed at 1, 2, and 3 J (average power output = 0.2, 0.4, and 0.6 W). In both groups linear relationships were noted between power output and Pi/PCr; the slope of this relationship was used to compare PCr depletion patterns. At rest both groups had similar Pi/PCr ratios (normal subjects 0.12 +/- 0.06, those with heart failure 0.15 +/- 0.03) and pH (normal subjects 7.04 +/- 0.13, those with heart failure 7.10 +/- 0.11). In normal subjects exercise resulted in a progressive increase in Pi/PCr (slope = 1.17 +/- 0.20 Pi/PCr units/W), a reduction in pH only at 0.6 W (0.2 W: 7.03 +/- 0.10, 0.4 W: 7.01 +/- 0.10, 0.6 W: 6.88 +/- 16) and moderate fatigue (0.2 W: 0 +/- 0, 0.4 W: 1.3 +/- 0.5, 0.6 W: 1.9 +/- 0.6). In patients with heart failure exercise resulted in significantly greater fatigue at all workloads (0.2 W: 1.0 +/- 0.5, 0.4 W: 1.9 +/- 0.6, 0.6 W: 2.9 +/- 0.5).(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine Triphosphate; Aged; Energy Metabolism; Forearm; Heart Failure; Humans; Magnetic Resonance Spectroscopy; Male; Middle Aged; Muscles; Oxygen Consumption; Phosphates; Phosphocreatine; Phosphorus; Physical Exertion; Radionuclide Imaging

Tissue contents of intermediates of fatty acid metabolism were determined in isolated volume-overloaded rat hearts, 3 months after creation of an aorto-caval fistula. In the absence of any modification of blood carnitine, tissue levels of total carnitine were reduced by 33% in overloaded hearts compared to normal hearts. Total tissue CoA was unchanged. Fifteen minutes of whole-heart ischemia (i.e. a 50% reduction in coronary flow) did not increase levels of long-chain acyl esters of CoA and carnitine of the overloaded myocardium, in the presence of glucose as the only exogenous substrate. This was associated with lower than normal levels of long-chain acyl carnitine under normoxic conditions. The addition of exogenous palmitate (1.5 mM) resulted in an ischemia-induced accumulation of long-chain acyl-CoA and acyl carnitine in the overloaded heart although to a smaller extent than in the normal heart under similar perfusion conditions.

Topics: Acyl Coenzyme A; Adenosine Triphosphate; Animals; Cardiomegaly; Carnitine; Coenzyme A; Coronary Disease; Energy Metabolism; Fatty Acids; Female; Heart Failure; Myocardium; Phosphocreatine; Rats; Rats, Inbred Strains

Three metabolic adaptive or compensatory mechanisms of heart failure were discussed: Adaptation of energy production and of energy availability in the myocardial cell. With increased myocardial oxygen demands this is achieved by a progressive displacement of the mass action ratio of the creatine phosphokinase reaction, so that pronounced changes in the creatine phosphate-ratio, related to myocardial oxygen consumption, are accompanied by only small changes in adenosine-5'-triphosphate adenosine-5'-diphosphate and hence in free energy of the adenine-nucleotide system. Adjustment of the oxygen availability by adaptation of the hemoglobin dissociation curve due to an increase in the erythrocyte content of 2, 3-diphosphoglycerate. This is accompanied by a swelling of erythrocytes as a consequence of an increase in the Gibbs-Donnan potential. In patients with congestive heart failure 2,3-diphosphoglycerate-synthesis is augmented due to respiratory alkalosis and increased concentrations of deoxygenated hemoglobin. Increase in the sympathetic drive of the heart due to increased net discharge of the neurotransmitter caused by reduced neuronal reuptake of norepinephrine. The diminished myocardial norepinephrine content in heart failure is due to the diminished neuronal uptake and to insufficient de novo catecholamine synthesis in the heart. Rather than tyrosine-hydroxylase the transformation of dopamine to norepinephrine seems to be the rate limiting step for catecholamine synthesis in heart failure.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Diphosphoglyceric Acids; Energy Metabolism; Erythrocytes; Heart Failure; Hemoglobins; Humans; Myocardium; Norepinephrine; Oxygen Consumption; Phosphocreatine; Stroke Volume; Sympathetic Nervous System

The following studies were carried out to examine energy metabolites and cardiac performance of the failing heart (hereditary cardiomyopathy) of the Syrian hamster (strain UM-X7.1) perfused either by normal or stress conditions, and to determine whether cyclical changes in energy-related metabolites occurred in the glucose-perfused hearts of both normal and heart failure animals. Hamster hearts from 250-day-old animals with moderate heart failure were removed and perfused either as nonworking hearts (Langendorff method, an afterload pressure of 90 mm Hg and 2.5 mM calcium in the perfusate) or as working hearts with stress conditions [an afterload of 110 mm Hg, high calcium concentrations in the perfusate (3.5 mM), and 10(-8) M isoproterenol]. Mechanical parameters (developed pressure and max dP/dt) and measurements of oxygen consumption indicated that both contractility and oxygen consumption had fallen 50% in myopathic hearts, compared with those of normal hamsters perfused with either of the two conditions. By means of a specially designed stimulator-triggered freeze clamp, hearts were terminated at systole and diastole, and tissue content of ATP, ADP, AMP, adenosine, phosphocreatine, creatine, pyruvate, lactate, and inorganic phosphate were analyzed. A 50% reduction in cardiac performance of the cardiomyopathic hamster hearts was associated with a corresponding reduction in systolic ATP, adenosine, and phosphocreatine values, while inorganic phosphate and lactate increased. With glucose as the sole substrate, the high energy phosphates, ATP and phosphocreatine, reached maximum values during diastole and minimum values during systole.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Adenosine; Adenosine Diphosphate; Adenosine Triphosphate; Animals; Cricetinae; Energy Metabolism; Heart Failure; Lactates; Lactic Acid; Mesocricetus; Myocardial Contraction; Myocardium; Oxygen Consumption; Phosphates; Phosphocreatine; Systole

In order to determine the status of the energy production system of the heart during cardiac failure of sheep with gousiekte, observations were made of the heart tissue levels of adenosine triphosphate (ATP), creatine phosphate (CrP), inorganic phosphate, reduced nicotine adenine dinucleotide (NADH) and lactate. Some measurements on oxidative phosphorylation were also made. A significant decrease in ATP and CrP levels coincided with a simultaneous rise in the ATP:CrP ratio and lactate levels in gousiekte hearts. No significant deviations in inorganic phosphate and NADH levels could be demonstrated. These abnormalities were accompanied by a decreased uptake of oxygen by isolated mitochondria of gousiekte hearts. There was a marked increase in the anaerobic state of the hearts of dying gousiekte sheep, while the values of NADH and the ATP:CrP ratio at a presymptomatic stage indicated a possible early derangement in the energy metabolism of sheep fed the toxic material. No hypertrophy could be detected for the failing ventricles of gousiekte sheep after being corrected for a significant amount of oedema found in the heart tissue of these animals. It was concluded that the depressed ATP and CrP levels in the heart tissue of gousiekte sheep during cardiac failure could at least in part, be attributed to a depressed aerobic energy production. It is not possible, however, to state whether this is a primary or a secondary response due to intoxication and also whether it could be seen as a cause or effect of cardiac failure.

Topics: Adenosine Triphosphate; Animals; Energy Metabolism; Heart Failure; Lactates; Lactic Acid; Male; Mitochondria, Heart; Myocardium; NAD; Oxidative Phosphorylation; Phosphates; Phosphocreatine; Sheep; Sheep Diseases

Skeletal muscle metabolite concentrations were determined in 19 patients in either cardiogenic shock or severe left ventricular failure by obtaining a needle biopsy specimen of lateral thigh muscle. Evidence of anaerobic skeletal muscle metabolism was found in both patient groups with the greatest lactate accumulation and most severe high-energy phosphate depletion present in the patients in cardiogenic shock. The skeletal muscle lactate accumulation was most pronounced in the patients that died. Blood lactate values did not absolutely predict skeletal muscle lactate concentrations in those patients in whom skeletal muscle lactate concentrations were the highest. The patients in cardiogenic shock and severe left ventricular failure who survived demonstrated a reduction in skeletal muscle lactate levels and a restoration of high-energy phosphates over several days which correlated with clinical and hemodynamic improvement.

Topics: Adenosine Triphosphate; Adult; Aged; Biopsy, Needle; Carbon Dioxide; Female; Glucose; Glucosephosphates; Glycogen; Heart Failure; Humans; Hydrogen-Ion Concentration; Lactates; Male; Middle Aged; Muscles; Oxygen; Partial Pressure; Phosphocreatine; Shock, Cardiogenic

Overdoses of several volatile anesthetics (ether, chloroform, ethyl chloride, halothane, methoxyflurane) as well as of various barbiturates lead to severe contractile failure of the heart. In all cases it was found that at the stage of maximal failure the myocardial stores of ATP and phosphocreatine were increased, indicative of reduced high energy phosphate utilization. Barbiturate-induced failure can be fully reversed by the intravenous injection of CaCl2, isoproterenol, or strophanthin. Simultaneously ATP and phosphocreatine concentrations become normal. In contrast, cardiac failure caused by volatile anesthetics proved to be resistant to this therapy. Electron micrographs showed a normal structure of the transverse tubules in the case of barbiturate failure. On the other hand, after the application of volatile anesthetics, a striking dilatation of the transverse tubular system was observed. The irreversibility of this latter type of contractile failure is probably caused by permanent damage of myocardial ultrastructures involved in excitation-contraction coupling.

Topics: Adenosine Diphosphate; Adenosine Triphosphate; Anesthetics; Animals; Calcium; Chloroform; Guinea Pigs; Halothane; Heart; Heart Failure; Isoproterenol; Myocardial Contraction; Myocardium; Pentobarbital; Phosphates; Phosphocreatine; Strophanthins

Topics: Adenine Nucleotides; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphate; Animals; Coronary Circulation; Coronary Disease; Disease Models, Animal; Heart; Heart Failure; Lactates; Male; Myocardium; Oxygen Consumption; Phosphocreatine; Rats; Regional Blood Flow; Time Factors

Topics: Adenine Nucleotides; Animals; Calcium; Dogs; Energy Metabolism; Glucose; Heart Failure; Hypoxia; In Vitro Techniques; Male; Mitochondria, Muscle; Myocardial Contraction; Myocardium; Phosphocreatine; Rats; Sarcoplasmic Reticulum; Starvation

Topics: Adult; Aged; Coronary Disease; Digitalis Glycosides; Female; Heart Failure; Humans; Male; Middle Aged; Phosphocreatine

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

Topics: Adaptation, Physiological; Adenine Nucleotides; Adenosine Diphosphate; Adenosine Monophosphate; Adenosine Triphosphatases; Adenosine Triphosphate; Animals; Aortic Valve Insufficiency; Biopsy; Cardiomegaly; Glycogen; Heart Failure; Heart Ventricles; Lactates; Muscle Proteins; Myocardium; Phosphocreatine; Rabbits

Topics: Adenine Nucleotides; Animals; Asphyxia; Cardiomegaly; Cricetinae; Disease Models, Animal; Energy Metabolism; Heart Failure; Mesocricetus; Phosphocreatine; Rats

Topics: Adenosine Triphosphate; Animals; Blood Pressure; Cardiac Output; Chronic Disease; Creatine; Disease Models, Animal; Dogs; Elasticity; Heart; Heart Failure; Heart Rate; Heart Ventricles; Muscle Contraction; Myocardium; Oxygen Consumption; Pacemaker, Artificial; Phosphocreatine; Statistics as Topic; Tachycardia

Topics: Aged; Bufanolides; Electrocardiography; Heart Failure; Humans; Phosphocreatine; Phytotherapy; Plants, Medicinal; Strophanthins

Topics: Adaptation, Physiological; Altitude; Animals; Aortic Coarctation; Cerebral Cortex; Disease Models, Animal; Glycogen; Heart; Heart Failure; Hypoxia; Methods; Muscle Contraction; Myocardium; Phosphocreatine; Protein Biosynthesis; Rats; RNA

Topics: Adenine Nucleotides; Adenosine Triphosphate; Animals; Cardiomyopathies; Diet; Disease Models, Animal; Heart Failure; Microscopy, Electron; Mitochondria, Muscle; Myocardium; Norepinephrine; Oxygen Consumption; Phosphocreatine; Rabbits; Rats

Topics: Adenosine Triphosphatases; Adenosine Triphosphate; Calcium; Coronary Disease; Heart Failure; Humans; Muscle Contraction; Muscle Proteins; Myocardium; Phosphocreatine; Water-Electrolyte Balance

Topics: Adenosine Triphosphate; Animals; Cats; Heart Failure; Heart Ventricles; Papillary Muscles; Phosphocreatine

Topics: Adenosine Triphosphate; Cardiomegaly; Heart; Heart Failure; Humans; Phosphocreatine

Topics: Adenine Nucleotides; Adenosine Triphosphate; Animals; Glucose; Glycogen; Glycolysis; Heart Failure; Hexosephosphates; Lactates; Myocardium; Nitrobenzenes; Perfusion; Phosphates; Phosphocreatine; Pyruvates; Rabbits

Topics: Arrhythmias, Cardiac; Coronary Disease; Heart Failure; Humans; Phosphocreatine

Topics: Animals; Blood Pressure; Blood Volume; Guinea Pigs; Heart Failure; Myocardium; Phosphocreatine

Topics: Animals; Coronary Disease; Dogs; Heart Failure; Hemodynamics; Phosphocreatine

Topics: Animals; Calcium; Cardiomegaly; Cats; Chromatography, Paper; Guinea Pigs; Heart Failure; Humans; Hypoxia; Myocardium; Phosphates; Phosphocreatine; Rats

Topics: Adenine Nucleotides; Adenosine Triphosphate; Animals; Biochemical Phenomena; Biochemistry; Cardiomegaly; Chromatography; Coenzymes; Creatine; Creatinine; Cytosine Nucleotides; Dogs; Flavin-Adenine Dinucleotide; Guanine Nucleotides; Heart Failure; Metabolism; Myocardium; NAD; Nucleotides; Phosphates; Phosphocreatine; Pulmonary Valve Stenosis; Purines; Pyrimidine Nucleotides; Research; Uracil Nucleotides

Topics: Adenine Nucleotides; Adenosine Triphosphate; Animals; Heart Failure; Myocardium; Phosphocreatine; Phosphorus; Rats

Topics: Adenosine Triphosphate; Animals; Barbiturates; Biological Transport; Cell Membrane Permeability; Chromatography, Paper; Digitalis Glycosides; Dogs; Guinea Pigs; Heart; Heart Failure; Hypoxia; Myocardium; Phenylbutazone; Phosphates; Phosphocreatine; Potassium; Rats; Renal Dialysis; Shock; Sodium; Water-Electrolyte Balance

The results reported in this paper indicate that dinitrophenol acts directly on the isolated heart, increasing its metabolic rate. It also produces heart failure associated with a low phosphocreatine content of the muscle but with no change in adenosine triphosphate, which may or may not be due to a relative hypoxia of the cardiac tissue. Experimental arterial hypoxaemia, if severe, produces a similar picture of heart failure with a decrease in phosphocreatine and no change in adenosine triphosphate. Ligation of the coronary arteries results in disappearance of the major part of the phosphocreatine within a few minutes regardless of whether or not ventricular fibrillation ensues; the adenosine triphosphate remains unchanged.

Topics: Adenosine Triphosphate; Animals; Blood Circulation; Coronary Vessels; Dinitrophenols; Dogs; Heart; Heart Failure; Humans; Hypoxia; Ischemia; Myocardium; Nitrophenols; Phosphocreatine; Phosphorus; Phosphorus Compounds

Hypoxaemia, resulting from increased tissue metabolism, is an important factor in dinitrophenol failure in the conventional heart-lung preparation. Improved oxygenation of the blood by a technique described in this paper prolongs the life of dinitrophenol-treated hearts. Dinitrophenol acts very rapidly; oxygen consumption and coronary flow increase in a few minutes and the increase is proportional to the dose. The increase in oxygen consumption diminishes with time. Dinitrophenol decreases the phosphocreatine content of the heart, even when there is no failure or hypoxia. There is no evidence that dinitrophenol failure can be due to a decrease of phosphocreatine or adenosine triphosphate content of the heart, although this is to be expected in view of the observed "uncoupling" action of dinitrophenol.

Topics: Adenosine Triphosphate; Dinitrophenols; Heart; Heart Arrest; Heart Failure; Humans; Nitrophenols; Oxygen Consumption; Phosphocreatine

Topics: Biochemical Phenomena; Creatine; Heart; Heart Failure; Humans; Myocardium; Phosphocreatine