[Therapeutic education for cardiac failure patients: the I-care programme]. / Education thérapeutique des patients insuffisants cardiaques: le programme I-care.

Therapeutic education is becoming increasingly important in the management of chronic diseases including cardiac failure. The I-CARE programme consists of an evaluation of the role of therapeutic education in France, creating standardised tools and setting up training sessions for therapeutic education in the context of cardiac failure. Approximately two thirds of the French centres contacted perform therapeutic education with their available means. The lack of personnel, space, and training tools represent obstacles to the development of therapeutic education. The tools developed in the programme fall into 5 areas: diagnosis education, understanding the illness, diet, physical activity/daily life, and treatment. Training sessions were organised for the teams, consisting of at least one cardiologist and nurse. The I-CARE programme should allow the expansion of therapeutic education for cardiac failure and improve the multidisciplinary management of this disease which increasingly affects often elderly subjects.

Kinetics of PCr to ATP and beta-ATP to beta-ADP phosphoryl conversion are modified in working rat skeletal muscle after training.

Kinetics of phosphoryl transfers from PCr to gamma-ATP and from beta-ATP to beta-ADP were measured by magnetization transfer in an in vivo 31P NMR experiment in working rat skeletal hind leg muscles. Two groups were examined. One group was submitted to a 6-week training program of treadmill running. The other group was composed of sedentary animals. Metabolic oxidative capacity and mechanical performance were improved greatly by training as shown previously. Phosphoryl transfer of PCr-->gamma-ATP or beta-ATP-->beta-ADP total fluxes were identical in resting trained and untrained muscles. Under stimulation, the flux of creatine kinase transfer was significantly inhibited by 23% compared with resting level in untrained muscles; by contrast, it was not inhibited and maintained at the high resting level in trained muscles. Thus physiological changes probably linked to a decrease of the production of anions, which could inhibit creatine kinase, were able to maintain creatine kinase flux. The flux of beta-ATP to beta-ADP transfer were enhanced largely in working muscles from 1.4+/-0.8 and 2+/-0.8 at rest to 4+/-1.6 and 6.6+/-2.7 mM s(-1) for untrained and trained muscles respectively; the effect was more pronounced in trained than in untrained muscles. These results showed an acceleration of phosphoryl turnover in working muscles after training, which could contribute to improve oxidative and mechanical performances. Such kinetic measurements of phosphoryl conversion may provide information on ATP turnover in pathophysiologic situations where ADP accumulates because of impaired ATP synthesis (mitochondrial myopathies, lower perfusion level).

Kinetics of ATP to ADP beta-phosphoryl conversion in contracting skeletal muscle by in vivo 31P NMR magnetization transfer.

The rate constant of the beta-adenosine triphosphate to beta-adenosine diphosphate conversion was measured using 31P nuclear magnetic resonance magnetization transfer in resting and contracting in vivo rat skeletal muscle. Theoretically, the rate constant should be the sum of the rate constants of the reactions catalyzing ATP-ADP exchange. In resting muscle, the conversion rate constant was 0.4 s-1 and beta-ATP intrinsic T1 was 1.7 s. The velocity of conversion was 3.8 mM s-1. During stimulation, phosphocreatine fell to 36% and ATP to 82% of initial values. The rate constant and velocity of beta-phosphoryl conversion increased to 0.8 s-1 and 6.3 mM s-1, respectively, but did not reach expected levels, i.e. the product of the ATP concentration with the sum of pseudo first-rate constants of the individual reactions. These conversion velocities should be higher than reverse creatine kinase velocities, previously measured to be 10 mM s-1 in resting muscle and 7.5 mM s-1 in contacting muscle and confirmed in this work. The discrepancy between expected and observed data could be due either to compartmentation of part of the beta-ATP in pools exchanging slowly with the bulk of cellular ATP, or to ADP binding to macromolecules thus preventing full ADP saturation during magnetization transfer.

Phosphocreatine synthesis by isolated rat skeletal muscle mitochondria is not dependent upon external ADP: a 31P NMR study.

Phosphocreatine synthesis by mitochondria isolated from rat skeletal muscle was determined in presence of inorganic phosphate, creatine, and either ATP or ADP, using 31P NMR spectroscopy in a new protocol maintaining mitochondria for several hours in a well-coupled state. Maximal velocity of phosphocreatine synthesis was identical with 0.4 mM of ADP or 0.5 mM ATP at a rate of 0.063 mM/min. External ATP and ADP were always present in the spectra, demonstrating that in skeletal muscle cells as in heart muscle cells, mitochondrial creatine kinase coupled to translocase has a very strong amplifying effect on oxidative phosphorylation and converts external inorganic phosphate and creatine into phosphocreatine without net adenine nucleotide consumption. Therefore, adenine nucleotides can be considered as cofactors rather than regulators of mitochondria metabolism. This is in agreement with the "phosphocreatine-circuit" theory.

Effects of dimethylformamide on in vivo fatigue and metabolism in rat skeletal muscle measured by 31P-NMR.

Dimethylformamide (DMF) is widely used as an industrial solvent in spite of well-established hepatotoxicity and adverse effects on in vitro muscle contractility. The doses used in the studies describing these effects were higher than the doses required to solubilize drugs to be injected at very low levels and the potential effects of DMF at very low levels has not yet been explored. The goal of this work was to study the effects of an acute, low dose of DMF (3 mu/100 g body weight, administered i.p.) on mechanical parameters and energy metabolism of contracting rat skeletal muscle. Metabolic changes were followed by 31P nuclear magnetic resonance spectroscopy. Tension was significantly lower during the fatigue test in DMF-treated rats than in controls. Phosphomonoesters and inorganic phosphorus level were lower, and intracellular pH was higher in DMF-treated rats than in controls, showing that energy metabolism was activated to a lesser degree, in relation with the lower mechanical performance, after DMF. Skeletal muscle is a target organ for dimethylformamide which has a major effect on muscle contractility by decreasing the tension developed. The effects of DMF suggest that it is unsuitable for use as a drug vehicle for in vivo injections, even at a very low nonhepatotoxic doses.

Improvement of muscular oxidative capacity by training is associated with slight acidosis and ATP depletion in exercising muscles.

Metabolic and mechanical properties of female rat skeletal muscles, submitted to endurance training on a treadmill, were studied by a 60-min in vivo multistep fatigue test. 31P-NMR was used to follow energy metabolism and pH. Mechanical performance was greatly improved in trained muscles. The oxidative capacity of the skeletal muscles was evaluated from the relationship between ADP calculated from the creatine kinase equilibrium and work and from the measure of the rate of phosphocreatine (PCr) resynthesis following exercise. In trained muscles, ADP production was lower per unit of mechanical performance, showing an improvement of oxidative metabolism. However, the PCr resynthesis rate was not modified. Slight acidosis and ATP depletion were observed from the beginning of the fatigue test. These modifications suggest changes of the creatine kinase equilibrium favoring mitochondrial ATP production. Our results indicate that muscle status improvement could be accompanied by ATP depletion and minimal acidosis during contraction; this would be of particular importance for objective evaluation of muscle regeneration processes and of gene therapy in muscle diseases.

In vivo evidence of abnormal mechanical and oxidative functions in the exercised muscle of dystrophic hamsters by 31P-NMR.

Mechanical properties and metabolic adaptation to exercise in skeletal muscle of dystrophic hamsters were studied with an in vivo 31P-NMR multistep fatigue test. Three successive 20-min steps with increasing rhythms of tetanic stimulation were followed by a 20-min recovery period. Fatigue in dystrophic hamsters (DH) developed more rapidly and was greater than in normal hamsters (NH); total mechanical performance per min increased step by step in NH while it decreased in DH, showing a progressive mechanical impairment of the dystrophic muscles. ADP and PCr recovery rates were significantly reduced in DH muscles. Acidosis appeared in both DH and NH and persisted in DH throughout the test, suggesting reduced mitochondrial oxidative capacity of the dystrophic muscle. The pH recovery rate was reduced in DH muscles suggesting a reduction in export protons capacity. These results provide evidence of impaired mitochondrial function and intracellular ionic regulation in the dystrophic muscle, associated with the lack of dystrophin and dystrophin-associated glycoproteins in the DH.