Tissue-nonspecific alkaline phosphatase is an anti-inflammatory nucleotidase.

Tissue-nonspecific alkaline phosphatase (TNAP) is necessary for skeletal mineralization by its ability to hydrolyze the mineralization inhibitor inorganic pyrophosphate (PPi), which is mainly generated from extracellular ATP by ectonucleotide pyrophosphatase phosphodiesterase 1 (NPP1). Since children with TNAP deficiency develop bone metaphyseal auto-inflammations in addition to rickets, we hypothesized that TNAP also exerts anti-inflammatory effects relying on the hydrolysis of pro-inflammatory adenosine nucleotides into the anti-inflammatory adenosine. We explored this hypothesis in bone metaphyses of 7-day-old Alpl+/- mice (encoding TNAP), in mineralizing hypertrophic chondrocytes and osteoblasts, and non-mineralizing mesenchymal stem cells (MSCs) and neutrophils, which express TNAP and are present, or can be recruited in the metaphysis. Bone metaphyses of 7-day-old Alpl+/- mice had significantly increased levels of Il-1ß and Il-6 and decreased levels of the anti-inflammatory Il-10 cytokine as compared with Alpl+/+ mice. In bone metaphyses, murine hypertrophic chondrocytes and osteoblasts, Alpl mRNA levels were much higher than those of the adenosine nucleotidases Npp1, Cd39 and Cd73. In hypertrophic chondrocytes, inhibition of TNAP with 25 µM of MLS-0038949 decreased the hydrolysis of AMP and ATP. However, TNAP inhibition did not significantly modulate ATP- and adenosine-associated effects in these cells. We observed that part of TNAP proteins in hypertrophic chondrocytes was sent from the cell membrane to matrix vesicles, which may explain why TNAP participated in the hydrolysis of ATP but did not significantly modulate its autocrine pro-inflammatory effects. In MSCs, TNAP did not participate in ATP hydrolysis nor in secretion of inflammatory mediators. In contrast, in neutrophils, TNAP inhibition with MLS-0038949 significantly exacerbated ATP-associated activation and secretion of IL-1ß, and extended cell survival. Collectively, these results demonstrate that TNAP is a nucleotidase in both hypertrophic chondrocytes and neutrophils, and that this nucleotidase function is associated with autocrine effects on inflammation only in neutrophils.

Low-energy cardioversion of spontaneous atrial fibrillation. Immediate and long-term results.

BACKGROUND: Recent studies have suggested that induced atrial fibrillation (AF) could be successfully terminated by using a two-catheter electrode system and low energy (< 400 V). This study evaluated the efficacy and safety of low-energy cardioversion in spontaneous chronic and paroxysmal AF. METHODS AND RESULTS: Forty-two consecutive patients with spontaneous AF underwent low-energy electrical cardioversion. AF was chronic (> or = 1 month) with a mean duration of 9 +/- 19 months in 28 patients (group I) or paroxysmal with a history of recurrent attacks and a mean duration of the present episode of 7 +/- 16 days in 14 patients (group II). An underlying heart disease was present in 28 patients. A 3/3-ms biphasic shock was delivered between catheters positioned in the right atrium and the coronary sinus in 32 patients. In 10 patients, the left pulmonary artery branch was used. The catheters were connected to a custom external defibrillator. The shocks were synchronized to the R wave. Following a test shock of 60 V, the energy was increased in 40-V steps until a maximum of 400 V or restoration of sinus rhythm. Sinus rhythm was restored in 22 of the 28 patients (78%) of group I by using a mean leading-edge voltage of 297 +/- 57 V (mean energy 3.3 +/- 1.3 J) and in 11 of 14 patients (78%) of group II by using a mean leading-edge voltage of 223 +/- 41 V (mean energy, 1.8 +/- 0.7 J). The energy required for terminating chronic AF was significantly (P < .001) higher than that required for terminating paroxysmal AF. Among the other variables studied, the duration of AF significantly affected the successful voltage. Ventricular proarrhythmia occurred in 1 patient with atrial flutter due to an unsynchronized shock. Of the 22 patients of group I in whom sinus rhythm was restored, 14 (63%) remained in sinus rhythm with a mean follow-up of 9 +/- 3 months. Pain level showed a good correlation with increasing voltage. However, a marked inter-individual variation was noted. CONCLUSIONS: Atrial defibrillation using low energy between two intracardiac catheters with an electrical field between the right and left atria and the protocol used is feasible in patients with persistent spontaneous AF. The technique is safe provided synchronization to the R wave is achieved. A low recurrence rate of AF was seen in patients in whom sinus rhythm was restored.

[Radiofrequency ablation of resistant atrial flutter: a new anatomical approach]. / Ablation par courant de radiofréquence du flutter auriculaire rebelle. Une approche anatomique nouvelle.

Several reports have suggested that radiofrequency ablation could prevent atrial flutter resistant to antiarrhythmic therapy. The usual recommendation is to apply the radiofrequency current in a zone situated between the tricuspid valve and orifice of inferior vena cava. The aim of this study was to assess the efficacy of another site of ablation of flutter extending from the tricuspid valve to the orifice of the coronary sinus, either alone or associated with a site between the coronary sinus and the lateral wall of the right atrium. Twenty patients aged 42 to 78 years (mean : 6 +/- 11 years) were included. Atrial flutter was paroxysmal in 15 patients and chronic in 5 patients. Each patients had documented failure of 1 to 5 antiarrhythmic agents (average 3.1 +/- 1.6). The site of ablation was localised by anatomical criteria alone. During follow-up of 7 +/- 5 months (range 1 to 18 months), 13 patients had no recurrence of atrial flutter after ablation, 5 patients had recurrence and 2 patients had paroxysmal atrial fibrillation alone: the success rate was 15/20 (75%). This study suggests that the zone between the tricuspid valve and coronary sinus may be a site for radiofrequency ablation of atrial flutter. It is valuable alternative to the usually recommended technique.

[Antiarrhythmic drugs in paroxysmal atrial fibrillation. When and how?]. / Les médicaments antiarythmiques dans la fibrillation auriculaire paroxystique. Quand et comment?

Atrial fibrillation (AF), carries a serious risk of systemic embolic complications, especially cerebral. Antiarrhythmic therapy is the most used method for restoring or maintaining sinus rhythm, and for preventing recurrences or of controlling the ventricular response. A clinical classification was recently suggested to define when to use antiarrhythmic drugs. In a first episode of symptomatic AF (Class I), it is not possible to assess the chances of recurrence and preventive antiarrhythmic therapy would not seem justified. In recurrent paroxysmal AF, the arrhythmias may be asymptomatic (Class IIa) and antiarrhythmic therapy may be questionned. When the attacks are infrequent (< 1 every 3 months, Class IIb), episodic pharmacological intervention to restore sinus rhythm or to slow the ventricular rate may be valuable, but the efficacy and safety of such treatment should be assessed. In Class IIc, appropriate antiarrhythmic treatment to prevent recurrence is often indicated. Atrial fibrillation resistant to one or more antiarrhythmic drugs (Class III) may also be subdivised into three subgroups as for Class II. In addition to the use of alternating of antiarrhythmic drugs not previously used, it is justifiable to consider investigations to determine the mechanism of resistant AF use only drugs of the which slow the ventricular rate. The choice of antiarrhythmic drug may be guided by the concepts of the Silician Gambit, taking into consideration the mechanism of AF and the therapeutic objective. In AF, the mechanism is reentry, the vulnerable parameter the atrial refractory period. To increase the refractory period, the target should be the sodium or potassium currents. The status of left ventricular function is an important parameter in the choice of an antiarrhythmic agent.