Background Low-voltage areas (LVAs) in the atria of patients with atrial fibrillation are considered local fibrosis. We hypothesized that voltage reduction in the atria is a diffuse process associated with fibrosis and that the presence of LVAs reflects a global voltage reduction. Methods and Results We examined 140 patients with atrial fibrillation and 13 patients with a left accessory pathway (controls). High-density bipolar voltage mapping was performed using a grid-mapping catheter during high right atrial pacing. Global left atrial (LA) voltage (VGLA) in the whole LA and regional LA voltage (VRLA) in 6 anatomic regions were evaluated with the mean of the highest voltage at a sampling density of 1 cm2. Patients with atrial fibrillation were categorized into quartiles by VGLA. LVAs were evaluated at voltage cutoffs of 0.1, 0.5, 1.0, and 1.5 mV. Twenty-eight patients with atrial fibrillation also underwent right atrial septum biopsy, and the fibrosis extent was quantified. Voltage at the biopsy site (Vbiopsy) was recorded. VGLA results by category were Q1 (<4.2 mV), Q2 (4.2-5.6 mV), Q3 (5.7-7.0 mV), and Q4 (≥7.1 mV). VRLA at any region was reduced as VGLA decreased. VGLA and VRLA did not differ between Q4 and controls. The presence of LVAs increased as VGLA decreased at any voltage cutoff. Biopsies revealed 11±6% fibrosis, which was inversely correlated with both Vbiopsy and VGLA (r=-0.71 and -0.72, respectively). Vbiopsy was correlated with VGLA (r=0.82). Conclusions Voltage reduction in the LA is a diffuse process associated with fibrosis. Presence of LVAs reflects diffuse voltage reduction of the LA.

Given our recent evidence for the role of high mobility group box 1 (HMGB1) in chemotherapy-induced peripheral neuropathy (CIPN) in rats, we examined the origin of HMGB1 and the upstream and downstream mechanisms of HMGB1 release involved in paclitaxel-induced neuropathy in mice. Paclitaxel treatment developed mechanical allodynia in mice, as assessed by von Frey test, which was prevented by an anti-HMGB1-neutralizing antibody or thrombomodulin alfa capable of inactivating HMGB1. RAGE or CXCR4 antagonists, ethyl pyruvate or minocycline, known to inhibit HMGB1 release from macrophages, and liposomal clodronate, a macrophage depletor, prevented the paclitaxel-induced allodynia. Paclitaxel caused upregulation of RAGE and CXCR4 in the dorsal root ganglia and macrophage accumulation in the sciatic nerve. In macrophage-like RAW264.7 cells, paclitaxel evoked cytoplasmic translocation of nuclear HMGB1 followed by its extracellular release, and overexpression of CBP and PCAF, histone acetyltransferases (HATs), known to cause acetylation and cytoplasmic translocation of HMGB1, which were suppressed by ethyl pyruvate, N-acetyl-l-cysteine, an anti-oxidant, and SB203580 and PDTC, inhibitors of p38 MAP kinase (p38MAPK) and NF-κB, respectively. Paclitaxel increased accumulation of reactive oxygen species (ROS) and phosphorylation of p38MAPK, NF-κB p65 and I-κB in RAW264.7 cells. In mice, N-acetyl-l-cysteine or PDTC prevented the paclitaxel-induced allodynia. Co-culture of neuron-like NG108-15 cells or stimulation with their conditioned medium promoted paclitaxel-induced HMGB1 release from RAW264.7 cells. Our data indicate that HMGB1 released from macrophages through the ROS/p38MAPK/NF-κB/HAT pathway participates in the paclitaxel-induced peripheral neuropathy in mice, and unveils an emerging therapeutic avenue targeting a neuroimmune crosstalk in CIPN.

This study aimed to histologically validate atrial structural remodelling associated with atrial fibrillation.