phosphocreatine and Atrial-Fibrillation

The β3-adrenoceptor (β3-AR) is implicated in cardiac remodeling. Since metabolic dysfunction due to loss of mitochondria plays an important role in heart diseases, we examined the effects of β3-AR on mitochondrial biogenesis and energy metabolism in atrial fibrillation (AF).. Atrial fibrillation was created by rapid atrial pacing in adult rabbits. Rabbits were randomly divided into 4 groups: control, pacing (P7), β3-AR antagonist (L748337), and β3-AR agonist (BRL37344) groups. Atrial effective refractory period (AERP) and AF induction rate were measured. Atrial concentrations of adenine nucleotides and phosphocreatine were quantified through high-performance liquid chromatography. Mitochondrial DNA content was determined. Real-time polymerase chain reaction and Western blot were used to examine the expression levels of signaling intermediates related to mitochondrial biogenesis.. After pacing for 7 days, β3-AR was significantly upregulated, AERP was reduced, and the AF induction rate was increased. The total adenine nucleotides pool was significantly reduced due to the decrease in adenosine triphosphate (ATP). The P7 group showed decreased activity of F0F1-ATPase. Mitochondrial DNA content was decreased and mitochondrial respiratory chain subunits were downregulated after pacing. Furthermore, expression of transcription factors involved in mitochondrial biogenesis, including peroxisome proliferator-activated receptor γ coactivator 1α (PGC-1α), nuclear respiratory factor 1 (NRF-1), and mitochondrial transcription factor A (Tfam), was lower in the P7 group in response to β3-AR activation. Further stimulation of β3-AR with BRL37344 exacerbated these effects, together with a significant decrease in the levels of phosphocreatine. In contrast, inhibition of β3-AR with L748337 partially restored mitochondrial biogenesis and energy metabolism of atria in the paced rabbits.. The activation of β3-AR contributes to atrial metabolic remodeling via transcriptional downregulation of PGC-1α/NRF-1/Tfam pathway that are involved in mitochondrial biogenesis, which ultimately perturbs mitochondrial function in rapid pacing-induced AF. The β3-AR is therefore a potential novel therapeutic target for the treatment or prevention of AF.

Topics: Adenine Nucleotides; Adrenergic beta-3 Receptor Agonists; Adrenergic beta-3 Receptor Antagonists; Animals; Anti-Arrhythmia Agents; Atrial Fibrillation; Atrial Function, Right; Atrial Remodeling; Cardiac Pacing, Artificial; Disease Models, Animal; DNA, Mitochondrial; Electron Transport Complex IV; Energy Metabolism; Female; Gene Expression Regulation; Heart Rate; Male; Mitochondria, Heart; Mitochondrial Proteins; NF-E2-Related Factor 1; Organelle Biogenesis; Phosphocreatine; Proton-Translocating ATPases; Rabbits; Receptors, Adrenergic, beta-3; Signal Transduction; Time Factors

Perturbations in energetic metabolism and impaired atrial contractility may play an important role in the pathogenesis of atrial fibrillation (AF). Besides, atrial stretch is commonly associated with AF. However, the atrial energetics of stretch-related AF are poorly understood. Here, we measured indicators of energy metabolism during acute stretch-related AF. PCr, adenine nucleotides, and derivatives concentrations as well as the activity of the F(0)F(1)-ATPase and Na,K-ATPase were obtained after 1 h of stretch and/or AF in isolated rabbit hearts and compared to control hearts without stretch and AF.. After 1 h of stretch-related AF, the total adenine nucleotides' pool was significantly lower (42.2 +/- 2.6 vs. 63.7 +/- 8.3 micromol/g protein in control group, P < 0.05) and the PCr/ATP ratio significantly higher (2.3 +/- 0.3 vs. 1.1 +/- 0.1 in control group P < 0.05), because of ATP, ADP, and AMP decrease and PCr increase. The sum of high-energy phosphate compounds did not change. There were no significant differences in F(0)F(1)-ATPase nor Na,K-ATPase activity between the groups.. Results show that in this experimental model, acute stretch-related AF induces specific modifications of atrial myocytes energetics that may play a pivotal role in the perpetuation of the arrhythmia.

Topics: Animals; Atrial Fibrillation; Energy Metabolism; In Vitro Techniques; Mitochondria; Phosphates; Phosphocreatine; Proton-Translocating ATPases; Rabbits; Refractory Period, Electrophysiological; Sarcolemma; Sodium-Potassium-Exchanging ATPase; Stress, Mechanical

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

Prolonged atrial fibrillation (AF) results in (ultra)structural remodelling of atrial cardiomyocytes resembling alterations seen in ischemia-induced ventricular hibernation. The mechanisms underlying these changes are incompletely understood. In the present study we explored the hypothesis that a profound imbalance in energy status during chronic AF acts as a stimulus for structural remodelling.. The content of high energy-phosphates and related compounds together with a selected number of mitochondrial enzymes, known to be altered under ischemic conditions, were determined in tissue samples taken from atria of goats in sinus rhythm (SR) and after 1, 2, 4, 8 and 16 weeks of AF maintained by burst pacing. Atrial remodelling was quantified by counting the percentage of cells with >10% myolysis. During AF structural remodelling developed progressively, after 8 weeks about 40% of the atrial myocytes were affected. The concentration of adenine nucleotides and their degradation products did not change significantly during AF. Also the activity of mitochondrial cytochrome c oxidase activity was similar during AF and SR. Mitochondrial NADH-oxidase and proton-translocating ATPase activities were not induced by AF. The tissue content of phosphocreatine decreased during the first week by 60%, but completely recovered between 8 and 16 weeks of AF.. The analysis of adenine nucleotides during AF provided no indication for the development of severe atrial ischemia. This notion is supported by enzyme cytochemical findings. However, AF-induced atrial remodelling was associated with a transient lowering of phosphocreatine content, suggesting an increase in energy demand during the early phase of AF. The subsequent recovery of the phosphocreatine pool indicates restoration of the balance between energy demand and supply in chronically fibrillating atria.

Topics: Adenosine Triphosphatases; Animals; Atrial Appendage; Atrial Fibrillation; Cardiac Pacing, Artificial; Chronic Disease; Creatine; Dogs; Female; Goats; Heart Atria; Immunohistochemistry; Microscopy, Electron; Mitochondria, Heart; Multienzyme Complexes; Myocardium; NADH, NADPH Oxidoreductases; Phosphates; Phosphocreatine; Statistics, Nonparametric

Reduced atrial contractility occurs after cessation of atrial fibrillation. Its mechanism is unknown, and no pharmacological treatment exists. It has been hypothesized that this atrial contractile dysfunction results from intracellular calcium overload due to rapid depolarizations during fibrillation. Accordingly, we examined the effects of drugs that reduce or increase transsarcolemmal calcium influx on postfibrillation atrial dysfunction. Furthermore, we examined whether the dysfunction could be attributed to atrial ischemia.. Atrial contractility after atrial fibrillation was examined in open-chest pigs paced with a constant ventricular rate after complete AV block. Atrial contractility was computed as systolic shortening of left atrial diameter divided by atrial preload. Three groups of six pigs each were subjected to two 5-minute periods of atrial fibrillation separated by 1 hour of AV pacing. Verapamil or the calcium channel agonist BAY K8644 was administered intravenously before the second fibrillation period. The degree and duration of postfibrillation atrial contractile dysfunction were reduced with verapamil but increased with BAY K8644. In a control group, parallel changes occurred after the first and second fibrillation periods. Atrial tissue content of creatine phosphate declined slightly during fibrillation, whereas the tissue content of ATP and lactate remained unchanged.. Atrial contractile dysfunction after short-term atrial fibrillation is reduced by the calcium antagonist verapamil, which suggests that transsarcolemmal calcium influx contributed to this dysfunction. The calcium agonist BAY K8644 increased postfibrillation atrial contractile dysfunction. Atrial ischemia was not observed during fibrillation.

Topics: 3-Pyridinecarboxylic acid, 1,4-dihydro-2,6-dimethyl-5-nitro-4-(2-(trifluoromethyl)phenyl)-, Methyl ester; Adenosine Triphosphate; Animals; Atrial Fibrillation; Calcium Channel Agonists; Female; Heart Atria; Lactates; Lactic Acid; Male; Myocardial Contraction; Phosphocreatine; Swine; Verapamil