The low acute effectiveness of a high-power short duration radiofrequency current application technique in pulmonary vein isolation for atrial fibrillation.

BACKGROUND: Application of high power radiofrequency (RF) energy for a short duration (HPSD) to isolate pulmonary vein (PV) is an emerging technique. But power and duration settings are very different across different centers. Moreover, despite encouraging preclinical and clinical data, studies measuring acute effectiveness of various HPSD settings are limited. METHODS: Twenty-five consecutive patients with symptomatic atrial fibrillation (AF) were treated with pulmonary vein isolation (PVI) using HPSD. PVI was performed with a contact force catheter (Thermocool SF Smart-Touch) and Carto 3 System. The following parameters were used: energy output 50 W, target temperature 43°C, irrigation 15 mL/min, targeted contact force of > 10 g. RF energy was applied for 6-10 s. Required minimal interlesion distance was 4 mm. Twenty minutes after each successful PVI adenosine provocation test (APT) was performed by administrating 18 mg adenosine to unmask dormant PV conduction. RESULTS: All PVs (100 PVs) were successfully isolated. RF lesions needed per patient were 131 ± 41, the average duration for each RF application was 8.1 ± 1.7 s. Procedure time was 138 ± 21 min and average of total RF energy duration was 16.3 ± 5.2 min and average amount of RF energy was 48209 ± 12808 W. APT application time after PVI was 31.1 ± 8.3 min for the left sided PVs and 22.2 ± 4.6 min (p = 0.005) for the right sided PVs. APT was transiently positive in 18 PVs (18%) in 8 (32%) patients. CONCLUSIONS: Pulmonary vein isolation with high power for 6-10 s is feasible and shortens the procedure and ablation duration. However, acute effectiveness of the HPSD seems to be lower than expected. Further studies combining other ablation parameters are needed to improve this promising technique.

N-acety-b-D-glucosaminidase: A potential biomarker for early detection of acute kidney injury in acute chest pain.

AIM: Acute kidney injury (AKI) is often underdiagnosed due to several limitations of the renal marker creatinine. Tubular urinary biomarkers may substantially contribute to diagnose AKI early. For early detection of AKI, we evaluated for the first time N-acetyl-ß-d-glucosaminidase (NAG), Kidney-injury-molecule-1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) in acute chest pain. METHODS: We included 402 chest pain patients aged 18 to 95 years seen in the emergency department. From 311 subjects, blood and urine samples were collected. RESULTS: Thirty-three patients developed an AKI and showed a significant increase in all three tubular markers compared to patients without AKI (each P < .001). According to receiver operating characteristic (ROC) analysis, combining NAG and creatinine showed a significantly increased area under the curve (AUC) compared to creatinine alone (AUC: 0.75 vs 0.87; P < .001). KIM-1, NGAL and cystatin C showed no significant differences in AUC compared to creatinine. In 120 individuals with blood and urine sampling before contrast media exposure, ROC analysis showed a significantly improved diagnostic performance for the combination of both (AUC: 0.83 vs creatinine AUC: 0.66; P = .004). AKI occurrence showed no dependency from CM volume. NAG presented as an independent AKI predictor beside creatinine, age, the diagnosis of myocardial infarction and mean arterial pressure. Regarding the prognostic value for renal replacement therapy, the combination of NAG and creatinine showed a significantly lager AUC than creatinine (AUC: 0.95 vs AUC: 0.85; P < .001). CONCLUSION: NAG presented as a promising marker of impending AKI and the necessity of renal replacement therapy.

Defective cell death signalling along the Bcl-2 regulated apoptosis pathway compromises Treg cell development and limits their functionality in mice.

The Bcl-2 regulated apoptosis pathway is critical for the elimination of autoreactive lymphocytes, thereby precluding autoimmunity. T cells escaping this process can be kept in check by regulatory T (Treg) cells expressing the transcription and lineage commitment factor Foxp3. Despite the well-established role of Bcl-2 family proteins in shaping the immune system and their frequent deregulation in autoimmune pathologies, it is poorly understood how these proteins affect Treg cell development and function. Here we compared the relative expression of a panel of 40 apoptosis-associated genes in Treg vs. conventional CD4(+) T cells. Physiological significance of key-changes was validated using gene-modified mice lacking or overexpressing pro- or anti-apoptotic Bcl-2 family members. We define a key role for the Bim/Bcl-2 axis in Treg cell development, homeostasis and function but exclude a role for apoptosis induction in responder T cells as relevant suppression mechanism. Notably, only lack of the pro-apoptotic BH3-only protein Bim or Bcl-2 overexpression led to accumulation of Treg cells while loss of pro-apoptotic Bad, Bmf, Puma or Noxa had no effect. Remarkably, apoptosis resistant Treg cells showed reduced suppressive capacity in a model of T cell-driven colitis, posing a caveat for the use of such long-lived cells in possible therapeutic settings.

Shaping the T-cell repertoire: a matter of life and death.

Thymocyte selection aims to shape a T-cell repertoire that, on the one hand, is able to recognize and respond to foreign peptides and, on the other hand, tolerizes the presence of self-peptides in the periphery. Deletion of T cells or their precursors that fail to fulfill these criteria is mainly mediated by the Bcl-2-regulated apoptosis pathway. Absence of T-cell receptor (TCR)-mediated signals or hyperactivation of the TCR by high-affinity self-peptide-major histocompatibility complexes can both trigger apoptotic cell death in developing thymocytes. Notably, TCR-signaling strength also defines survival and outgrowth of the fittest antigen-specific T-cell clones in the periphery. TCR threshold activity leading to such drastically opposing signaling outcomes (life or death) is modulated in part by cytokines and other factors, such as glucocorticoids, that fine-tune the Bcl-2 rheostat, thereby impacting on cell survival. This review aims to highlight the role of Bcl-2-regulated cell death for clonal T-cell selection.