Immunohistochemical characteristics of local sites that trigger atrial arrhythmias in response to high-frequency stimulation.

AIMS: The response to high frequency stimulation (HFS) is used to locate putative sites of ganglionated plexuses (GPs), which are implicated in triggering atrial fibrillation (AF). To identify topological and immunohistochemical characteristics of presumed GP sites functionally identified by HFS. METHODS AND RESULTS: Sixty-three atrial sites were tested with HFS in four Langendorff-perfused porcine hearts. A 3.5 mm tip quadripolar ablation catheter was used to stimulate and deliver HFS to the left and right atrial epicardium, within the local atrial refractory period. Tissue samples from sites triggering atrial ectopy/AF (ET) sites and non-ET sites were stained with choline acetyltransferase (ChAT) and tyrosine hydroxylase (TH), for quantification of parasympathetic and sympathetic nerves, respectively. The average cross-sectional area (CSA) of nerves was also calculated. Histomorphometry of six ET sites (9.5%) identified by HFS evoking at least a single atrial ectopic was compared with non-ET sites. All ET sites contained ChAT-immunoreactive (ChAT-IR) and/or TH-immunoreactive nerves (TH-IR). Nerve density was greater in ET sites compared to non-ET sites (nerves/cm2: 162.3 ± 110.9 vs. 69.65 ± 72.48; P = 0.047). Overall, TH-IR nerves had a larger CSA than ChAT-IR nerves (µm2: 11 196 ± 35 141 vs. 2070 ± 5841; P < 0.0001), but in ET sites, TH-IR nerves were smaller than in non-ET sites (µm2: 6021 ± 14 586 vs. 25 254 ± 61 499; P < 0.001). CONCLUSIONS: ET sites identified by HFS contained a higher density of smaller nerves than non-ET sites. The majority of these nerves were within the atrial myocardium. This has important clinical implications for devising an effective therapeutic strategy for targeting autonomic triggers of AF.

Development of a pro-arrhythmic ex vivo intact human and porcine model: cardiac electrophysiological changes associated with cellular uncoupling.

We describe a human and large animal Langendorff experimental apparatus for live electrophysiological studies and measure the electrophysiological changes due to gap junction uncoupling in human and porcine hearts. The resultant ex vivo intact human and porcine model can bridge the translational gap between smaller simple laboratory models and clinical research. In particular, electrophysiological models would benefit from the greater myocardial mass of a large heart due to its effects on far-field signal, electrode contact issues and motion artefacts, consequently more closely mimicking the clinical setting. Porcine (n = 9) and human (n = 4) donor hearts were perfused on a custom-designed Langendorff apparatus. Epicardial electrograms were collected at 16 sites across the left atrium and left ventricle. A total of 1 mM of carbenoxolone was administered at 5 ml/min to induce cellular uncoupling, and then recordings were repeated at the same sites. Changes in electrogram characteristics were analysed. We demonstrate the viability of a controlled ex vivo model of intact porcine and human hearts for electrophysiology with pharmacological modulation. Carbenoxolone reduces cellular coupling and changes contact electrogram features. The time from stimulus artefact to (-dV/dt)max increased between baseline and carbenoxolone (47.9 ± 4.1-67.2 ± 2.7 ms) indicating conduction slowing. The features with the largest percentage change between baseline and carbenoxolone were fractionation + 185.3%, endpoint amplitude - 106.9%, S-endpoint gradient + 54.9%, S point - 39.4%, RS ratio + 38.6% and (-dV/dt)max - 20.9%. The physiological relevance of this methodological tool is that it provides a model to further investigate pharmacologically induced pro-arrhythmic substrates.

A Single Injection of Docosahexaenoic Acid Induces a Pro-Resolving Lipid Mediator Profile in the Injured Tissue and a Long-Lasting Reduction in Neurological Deficit after Traumatic Brain Injury in Mice.

Traumatic brain injury (TBI) can lead to life-changing neurological deficits, which reflect the fast-evolving secondary injury post-trauma. There is a need for acute protective interventions, and the aim of this study was to explore in an experimental TBI model the neuroprotective potential of a single bolus of a neuroactive omega-3 fatty acid, docosahexaenoic acid (DHA), administered in a time window feasible for emergency services. Adult mice received a controlled cortical impact injury (CCI) and neurological impairment was assessed with the modified Neurological Severity Score (mNSS) up to 28 days post-injury. DHA (500 nmol/kg) or saline were injected intravenously at 30 min post-injury. The lipid mediator profile was assessed in the injured hemisphere at 3 h post-CCI. After completion of behavioral tests and lesion assessment using magnetic resonance imaging, over 7 days or 28 days post-TBI, the tissue was analyzed by immunohistochemistry. The single DHA bolus significantly reduced the injury-induced neurological deficit and increased pro-resolving mediators in the injured brain. DHA significantly reduced lesion size, the microglia and astrocytic reaction, and oxidation, and decreased the accumulation of beta-amyloid precursor protein (APP), indicating a reduced axonal injury at 7 days post-TBI. DHA reduced the neurofilament light levels in plasma at 28 days. Therefore, an acute single bolus of DHA post-TBI, in a time window relevant for acute emergency intervention, can induce a long-lasting and significant improvement in neurological outcome, and this is accompanied by a marked upregulation of neuroprotective mediators, including the DHA-derived resolvins and protectins.

Grouping puts figure-ground assignment in context by constraining propagation of edge assignment.

Figure-ground organization involves the assignment of edges to a figural shape on one or the other side of each dividing edge. Established visual cues for edge assignment primarily concern relatively local rather than contextual factors. In the present article, we show that an assignment for a locally unbiased edge can be affected by an assignment of a remote contextual edge that has its own locally biased assignment. We find that such propagation of edge assignment from the biased remote context occurs only when the biased and unbiased edges are grouped. This new principle, whereby grouping constrains the propagation of figural edge assignment, emerges from both subjective reports and an objective short-term edge-matching task. It generalizes from moving displays involving grouping by common fate and collinearity, to static displays with grouping by similarity of edge-contrast polarity, or apparent occlusion. Our results identify a new contextual influence on edge assignment. They also identify a new mechanistic relation between grouping and figure-ground processes, whereby grouping between remote elements can constrain the propagation of edge assignment between those elements. Supplemental materials for this article may be downloaded from http://app.psychonomic-journals.org/content/supplemental.