Box Isolation of Fibrotic Areas (BIFA): A Patient-Tailored Substrate Modification Approach for Ablation of Atrial Fibrillation.

BACKGROUND: Catheter ablation strategies beyond pulmonary vein isolation (PVI) for treatment of atrial fibrillation (AF) are less well defined. Increasing clinical data indicate that atrial fibrosis is a critical common left atrial (LA) substrate in AF patients (pts). OBJECTIVE: We applied a new substrate modification concept according to the individual fibrotic substrate as estimated from electroanatomic voltage mapping (EAVM) in 41 pts undergoing catheter ablation of AF. RESULTS: First, EAVM during sinus rhythm was done in redo cases of 10 pts with paroxysmal AF despite durable PVI. Confluent low-voltage areas (LVA) were found in all pts and were targeted with circumferential isolation, so-called box isolation of fibrotic areas (BIFA). This strategy led to stable sinus rhythm in 9/10 pts and was transferred prospectively to first procedures of 31 pts with nonparoxysmal AF. In 13 pts (42%), no LVA (<0.5 mV) were identified, and only PVI was performed. In 18 pts (58%), additional BIFA strategies were applied (posterior box in 5, anterior box in 7, posterior plus anterior box in 5, no box in 1 due to diffuse fibrosis). Mean follow-up was 12.5 ± 2.4 months. Single-procedure freedom from AF/atrial tachycardia was achieved in 72.2% of pts and in 83.3% of pts with 1.17 procedures/patient. CONCLUSIONS: In approximately 40% of pts with nonparoxysmal AF, no substantial LVA were identified, and PVI alone showed high success rate. In pts with paroxysmal AF despite durable PVI and in approximately 60% of pts with nonparoxysmal AF, individually localized LVA were identified and could be targeted successfully with the BIFA strategy.

Catheter ablation of atrial fibrillation: how to modify the substrate?

A frequent need for re-ablations and limited overall success rates are still major limitations of catheter ablation procedures for the treatment of atrial fibrillation (AF). These limitations include not only the durability of the pulmonary vein isolation (PVI) lines, but also the pathophysiological understanding of the arrhythmia's substrate. Long-term single procedure success rates in non-paroxysmal AF are disappointingly low for current stepwise ablation approaches adding the placement of linear lines and electrogram-based ablation after circumferential PVI isolation. In the future, substrate modification in AF ablation should move toward individualized patient-tailored ablation procedures. Magnetic resonance imaging could play a major role for noninvasively describing the localization and extent of fibrotic areas. Specific new strategies that could be used include precise localization and ablation of rotors that maintain the arrhythmia using multielectrode mapping during AF and box isolation of fibrotic areas guided by electroanatomic voltage mapping during sinus rhythm.

Histone deacetylase inhibition improves differentiation of dendritic cells from leukemic blasts of patients with TEL/AML1-positive acute lymphoblastic leukemia.

Histone deacetylase inhibitors (HdI) could potentially improve the differentiation of leukemic dendritic cells (DC). Therefore, bone marrow samples from 100 children with acute lymphoblastic leukemia (ALL) were cultured in the cytokines TNF-alpha, GM-CSF, c-kit ligand, and fetal liver tyrosine kinase 3 ligand, with or without IL-3 and -4 and after administration of HdI valproic acid (VAL), suberoylanilide hydroxamic acid (SAHA), isobutyramid, or trichostatin A. Among the tested samples, 25 were positive for the chromosomal translocation t(12;21), encoding the fusion gene translocation ETS-like leukemia/acute myeloid leukemia 1 (TEL/AML1). SAHA increased CD83 expression of TEL/AML1-positive blasts in conditions without ILs, and SAHA and VAL increased the number of CD86(+)80(-) cells in the presence of ILs. VAL and isobutyramid supported the allostimulatory capacities of TEL/AML1-positive, leukemic DC; VAL and SAHA reduced those of TEL/AML1-negative DC. Cytotoxic T cells sensitized with leukemic DC produced more IFN-gamma and TNF-alpha upon presentation of the TEL/AML1 peptide. They also induced the cytotoxic lysis of nondifferentiated blasts, which was enhanced when TEL/AML1-positive DC had developed after addition of VAL or SAHA. Therefore, the use of HdI in the differentiation of leukemic DC from patients with TEL/AML1-positive ALL is recommended.