Callosal Influence on Visual Receptive Fields Has an Ocular, an Orientation-and Direction Bias

One leading hypothesis on the nature of visual callosal connections (CC) is that they replicate features of intrahemispheric lateral connections. However, CC act also in the central part of the binocular visual field. In agreement, early experiments in cats indicated that they provide the ipsilateral eye part of binocular receptive fields (RFs) at the vertical midline (Berlucchi and Rizzolatti, 1968), and play a key role in stereoscopic function. But until today callosal inputs to receptive fields activated by one or both eyes were never compared simultaneously, because callosal function has been often studied by cutting or lesioning either corpus callosum or optic chiasm not allowing such a comparison. To investigate the functional contribution of CC in the intact cat visual system we recorded both monocular and binocular neuronal spiking responses and receptive fields in the 17/18 transition zone during reversible deactivation of the contralateral hemisphere. Unexpectedly from many of the previous reports, we observe no change in ocular dominance during CC deactivation. Throughout the transition zone, a majority of RFs shrink, but several also increase in size. RFs are significantly more affected for ipsi- as opposed to contralateral stimulation, but changes are also observed with binocular stimulation. Noteworthy, RF shrinkages are tiny and not correlated to the profound decreases of monocular and binocular firing rates. They depend more on orientation and direction preference than on eccentricity or ocular dominance of the receiving neuron's RF. Our findings confirm that in binocularly viewing mammals, binocular RFs near the midline are constructed via the direct geniculo-cortical pathway. They also support the idea that input from the two eyes complement each other through CC: Rather than linking parts of RFs separated by the vertical meridian, CC convey a modulatory influence, reflecting the feature selectivity of lateral circuits, with a strong cardinal bias

Outcomes in patients with dual antegrade conduction in the atrioventricular node: insights from a multicentre observational study

Background Supraventricular tachycardias induced by dual antegrade conduction via the atrioventricular (AV) node are rare but often misdiagnosed with severe consequences for the affected patients. As long-term follow-up in these patients was not available so far, this study investigates outcomes in patients with dual antegrade conduction in the AV node. Methods and results In this multicentre observational study, patients from six European centres were studied. Catheter ablation was performed in 17 patients (52 +/- 16 years) with dual antegrade conduction via both AV nodal pathways between 2012 and 2018. Patients with the final diagnosis of a manifest dual AV nodal non-re-entrant tachycardia had a mean delay of the correct diagnosis of over 1 year (range 2-31 months). Two patients received prescription of non-indicated oral anticoagulation, two further patients suffered from inappropriate shocks of an implantable cardioverter defibrillator. In 12 patients, a co-existence of dual antegrade and re-entry conduction in the AV node was present. Mean fast pathway conduction time was 138 +/- 61 ms and mean slow pathway conduction time was 593 +/- 134 ms. Successful radiofrequency catheter ablation was performed in all patients. Post-procedurally oral anticoagulation was discontinued, without detection of cerebrovascular events or atrial fibrillation during a long-term follow-up of median 17 months (range 6-72 months). Conclusion This first multicentre study investigating patients with supraventricular tachycardia and dual antegrade conduction in the AV node demonstrates that catheter ablation is safe and effective while long-term patient outcome is good. Autonomic tone dependent changes in ante- vs. retrograde conduction via slow and/or fast pathway can challenge the diagnosis and therapy in some patients. [GRAPHICS]

A novel algorithm for 3-D visualization of electrogram duration for substrate-mapping in patients with ischemic heart disease and ventricular tachycardia

Background Myocardial slow conduction is a cornerstone of ventricular tachycardia (VT). Prolonged electrogram (EGM) duration is a useful surrogate parameter and manual annotation of EGM characteristics are widely used during catheter-based ablation of the arrhythmogenic substrate. However, this remains time-consuming and prone to inter-operator variability. We aimed to develop an algorithm for 3-D visualization of EGM duration relative to the 17-segment American Heart Association model. Methods To calculate and visualize EGM duration, in sinus rhythm acquired high-density maps of patients with ischemic cardiomyopathy undergoing substrate-based VT ablation using a 64- mini polar basket-catheter with low noise of 0.01 mV were analyzed. Using a custom developed algorithm based on standard deviation and threshold, the relationship between EGM duration, endocardial voltage and ablation areas was studied by creating 17-segment 3-D models and 2-D polar plots. Results 140,508 EGMs from 272 segments (n = 16 patients, 94% male, age: 66±2.4, ejection fraction: 31±2%) were studied and 3-D visualization of EGM duration was performed. Analysis of signal processing parameters revealed that a 40 ms sliding SD-window, 15% SD-threshold and >70 ms EGM duration cutoff was chosen based on diagnostic odds ratio of 12.77 to visualize rapidly prolonged EGM durations. EGMs > 70 ms matched to 99% of areas within dense scar (<0.2 mV), in 95% of zones within scar border zone (0.2-1.0 mV) and detected ablated areas having resulted in non-inducibility at the end of the procedure. Ablation targets were identified with a sensitivity of 65.6% and a specificity of 94.6% avoiding false positive labeling of prolonged EGMs in segments with healthy myocardium. Conclusion The novel algorithm allows rapid visualization of prolonged EGM durations. This may facilitate more objective characterization of arrhythmogenic substrate in patients with ischemic cardiomyopathy.PeerReviewe

A Simplified Approach to Pulmonary Vein Visualization during Cryoballoon Ablation of Atrial Fibrillation

Background and Objectives: Selective pulmonary vein (PV) angiography has been established as the gold standard for PV visualization in cryoballoon (CB)-based pulmonary vein isolation (PVI). We sought to simplify this approach to reduce procedural complexity and radiation exposure. Materials and Methods: Patients with paroxysmal and recently diagnosed persistent AF undergoing CB-based PVI from January 2015 to December 2017 were retrospectively analyzed. Patients underwent either selective PV angiography or conventional left atrial (LA) angiography for PV visualization. Results: A total of 336 patients were analyzed. A total of 87 patients (26%) received PV angiography and 249 (74%) LA angiography. LA angiography required fewer cine-sequences for PV visualization, translating into a significant reduction in procedure duration, fluoroscopy time and dose area product. Additionally, less contrast medium was utilized. PV occlusion by the CB, CB temperature and time to isolation showed no significant differences. The number of CB applications and total application time (LA angiography: 1.4 &plusmn; 0.02 vs. PV Angiography: 1.6 &plusmn; 0.05; p &lt; 0.0001; LA angiography: 297.9 &plusmn; 4.62 vs. PV-Angiography: 348.9 &plusmn; 11.03; p &lt; 0.001, respectively) per vein were slightly but significantly higher in the PV angiography group. We observed no difference in late AF recurrence (24.7% LA angiography vs. 21.3% PV angiography; p = 0.2657). Conclusions: A simplified protocol, using LA angiography for PV visualization, entails a reduction in procedure time and radiation exposure while equally maintaining procedural efficiency and safety in both groups

A modified approach for programmed electrical stimulation in mice: Inducibility of ventricular arrhythmias.

BACKGROUND:Electrophysiological studies in mice, the prevailing model organism in the field of basic cardiovascular research, are impeded by the low yield of programmed electrical stimulation (PES). OBJECTIVE:To investigate a modified approach for ventricular arrhythmia (VA) induction and a novel scoring system in mice. METHOD:A systematic review of literature on current methods for PES in mice searching the PubMed database revealed that VA inducibility was low and ranged widely (4.6 ± 10.7%). Based on this literature review, a modified PES protocol with 3 to 10 extrastimuli was developed and tested in comparison to the conventional PES protocol using up to 3 extrastimuli in anesthetized wildtype mice (C57BL/6J, n = 12). Induced VA, classified according to the Lambeth Convention, were assessed by established arrhythmia scores as well as a novel arrhythmia score based on VA duration. RESULTS:PES with the modified approach raised both the occurrence and the duration of VA compared to conventional PES (0% vs 50%; novel VA score p = 0.0002). Particularly, coupling of >6 extrastimuli raised the induction of VA. Predominantly, premature ventricular complexes (n = 6) and ventricular tachycardia <1s (n = 4) were observed. Repeated PES after adrenergic stimulation using isoprenaline resulted in enhanced induction of ventricular tachycardia <1s in both protocols. CONCLUSION:Our findings suggest that the presented approach of modified PES enables effective induction and quantification of VA in wildtype mice and may well be suited to document and evaluate detailed VA characteristics in mice

Characterization of the HCN Interaction Partner TRIP8b/PEX5R in the Intracardiac Nervous System of TRIP8b-Deficient and Wild-Type Mice

The tetratricopeptide repeat-containing Rab8b-interacting protein (TRIP8b/PEX5R) is an interaction partner and auxiliary subunit of hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which are key for rhythm generation in the brain and in the heart. Since TRIP8b is expressed in central neurons but not in cardiomyocytes, the TRIP8b-HCN interaction has been studied intensely in the brain, but is deemed irrelevant in the cardiac conduction system. Still, to date, TRIP8b has not been studied in the intrinsic cardiac nervous system (ICNS), a neuronal network located within epicardial fat pads. In vitro electrophysiological studies revealed that TRIP8b-deficient mouse hearts exhibit increased atrial refractory and atrioventricular nodal refractory periods, compared to hearts of wild-type littermates. Meanwhile, heart rate, sino-nodal recovery time, and ventricular refractory period did not differ between genotypes. Trip8b mRNA was detected in the ICNS by quantitative polymerase chain reaction. RNAscope in situ hybridization confirmed Trip8b localization in neuronal somata and nerve fibers. Additionally, we found a very low amount of mRNAs in the sinus node and atrioventricular node, most likely attributable to the delicate fibers innervating the conduction system. In contrast, TRIP8b protein was not detectable. Our data suggest that TRIP8b in the ICNS may play a role in the modulation of atrial electrophysiology beyond HCN-mediated sino-nodal control of the heart

Disease-associated HCN4 V759I variant is not sufficient to impair cardiac pacemaking

The hyperpolarization-activated cation current

Disruption of cardiac cholinergic neurons enhances susceptibility to ventricular arrhythmias

The parasympathetic nervous system plays an important role in the pathophysiology of atrial fibrillation. Catheter ablation, a minimally invasive procedure deactivating abnormal firing cardiac tissue, is increasingly becoming the therapy of choice for atrial fibrillation. This is inevitably associated with the obliteration of cardiac cholinergic neurons. However, the impact on ventricular electrophysiology is unclear. Here we show that cardiac cholinergic neurons modulate ventricular electrophysiology. Mechanical disruption or pharmacological blockade of parasympathetic innervation shortens ventricular refractory periods, increases the incidence of ventricular arrhythmia and decreases ventricular cAMP levels in murine hearts. Immunohistochemistry confirmed ventricular cholinergic innervation, revealing parasympathetic fibres running from the atria to the ventricles parallel to sympathetic fibres. In humans, catheter ablation of atrial fibrillation, which is accompanied by accidental parasympathetic and concomitant sympathetic denervation, raises the burden of premature ventricular complexes. In summary, our results demonstrate an influence of cardiac cholinergic neurons on the regulation of ventricular function and arrhythmogenesi

Reduced heart rate response after premature ventricular contraction depending on severity of atrial fibrillation symptoms – Analysis on heart rate turbulence in atrial fibrillation patients

Background: The severity of symptoms during atrial fibrillation (AF) may be influenced by heart rate and blood pressure variation, due to irregular beats and the related adaptations in baroreflex sensitivity. This study investigated whether heart rate turbulence (HRT) as a reflection of baroreflex sensitivity is related to symptom severity during AF. Method: Ninety-seven patients (pts) who underwent electrophysiological study were enrolled. Consecutive 56 pts had paroxysmal AF (21 with milder symptoms [EHRA I or II; Group-M], 35 with severe symptoms [EHRA III or IV; Group-S]), and 41 age-matched controls without AF were included. After delivering a single ventricular extrastimulus during sinus rhythm and repeating the process 10 times, the quantification of HRT was performed by measuring turbulence onset (TO: heart rate acceleration) and turbulence slope (TS: rate of heart rate deceleration). Results: Group-M pts showed significantly diminished TO as compared to controls and Group-S pts (P = 0.012). There was no significant difference of the TS between the 3 groups. Given that a TO ≥ 0% or TS ≤ 2.5 ms/RR was considered abnormal, Group-M pts showed significantly higher incidences of abnormal HRT as compared to controls and Group-S pts (71% vs 40% vs 21%, respectively, P = 0.0012). Regression analysis demonstrated an independent and significant association between a diminished TO and milder AF symptoms (P < 0.05). Conclusions: The usual heart rate acceleration after premature ventricular contraction is significantly diminished in pts with milder AF symptoms as compared to pts with severe AF symptoms. The mechanism of association between this diminished response and symptoms should be further investigated. Keywords: Heart rate turbulence, Turbulence onset, Baroreflex sensitivity, Atrial fibrillatio