Impact of redo ablation for atrial fibrillation on patient-reported outcomes and quality of life.

INTRODUCTION: Catheter ablation for atrial fibrillation (AF) is frequently used for the purpose of rhythm control and improved quality of life (QoL). Although success rates are high, a significant proportion of patients require redo ablation. Data are scarce on patient-centered outcomes and QoL in patients undergoing redo AF ablation. We aimed to assess QoL and clinical outcomes using a large prospectively maintained patient-reported outcomes (PRO) registry. METHODS: All patients undergoing redo AF ablation (2013-2016) at our center were enrolled in a prospective registry for outcomes and assessed for QoL using automated PRO surveys (baseline, 3 and 6 months after ablation, every 6 months thereafter). Data were collected over 3 years of follow-up. The atrial fibrillation symptom severity scale (AFSSS) was used as the main measure for QoL. Additional variables included patient-reported improvement, AF burden, and AF-related healthcare utilization including emergency room (ER) visits and hospitalizations. RESULTS: A total of 848 patients were included (28% females, mean age 63.8, 51% persistent AF). By automated PRO, significant improvement in QoL was noted (baseline median AFSSS of 12 [5-18] and ranged between 2 and 4 on subsequent assessments; p < .0001), with ≥70%of patients reported remarkable improvement in their AF-related symptoms. The proportion of patients in AF at the time of baseline survey was 36%, and this decreased to <8% across all time points during follow-up (p < .0001). AF burden was significantly reduced (including frequency and duration of episodes; p < .0001), with an associated decrease in healthcare utilization after 6 months from the time of ablation (including ER visits and hospitalizations; p < .0001). The proportion of patients on anticoagulants or antiarrhythmics decreased on follow-up across all time points (p < .0001 for all variables). CONCLUSION: Most patients derive significant QoL benefit from redo AF ablation; with reduction of both AF burden and healthcare utilization.

Role of sigma-1 receptors in neurodegenerative diseases.

Neurodegenerative diseases with distinct genetic etiologies and pathological phenotypes appear to share common mechanisms of neuronal cellular dysfunction, including excitotoxicity, calcium dysregulation, oxidative damage, ER stress and mitochondrial dysfunction. Glial cells, including microglia and astrocytes, play an increasingly recognized role in both the promotion and prevention of neurodegeneration. Sigma receptors, particularly the sigma-1 receptor subtype, which are expressed in both neurons and glia of multiple regions within the central nervous system, are a unique class of intracellular proteins that can modulate many biological mechanisms associated with neurodegeneration. These receptors therefore represent compelling putative targets for pharmacologically treating neurodegenerative disorders. In this review, we provide an overview of the biological mechanisms frequently associated with neurodegeneration, and discuss how sigma-1 receptors may alter these mechanisms to preserve or restore neuronal function. In addition, we speculate on their therapeutic potential in the treatment of various neurodegenerative disorders.

Lymphopenia in the Adult Population With Fontan Physiology: A Potential New Marker for Disease Assessment.

Background: Patients with complex congenital heart disease and Fontan palliation frequently develop extracardiac disease, including hematologic abnormalities, such as lymphopenia. However, the clinical implications of this finding are poorly understood and are therefore the topic of this investigation. Methods: Patients with Fontan physiology in our centre (1999-2018) were evaluated for the presence and impact of lymphopenia. The cohort was divided into a group with lymphopenia (L) (2 consecutive absolute lymphocyte counts ≤ 1∗103 K/ µL) and a group who had never had lymphopenia (NL). Clinical characteristics and hospital admissions (762 patient-years) were evaluated. Results: In 62 adult patients with Fontan physiology (aged 34 ± 9 years; 32 women [52%]), the patients who developed lymphopenia earliest did so 8 years after Fontan completion, with up to 60% of patients developing lymphopenia by 30 years. Lymphopenia was found to be associated with portal hypertension (varices, ascites, splenomegaly, and thrombocytopenia [VAST] score)-NL: 0 (0-2) vs L: 2 (0-4), P < 0.0001). A total of 76 heart failure and 81 arrhythmia-associated admissions occurred per 1000 patient-years. At 40 years post-Fontan, the probability of a heart failure admission was higher in the L group (L: 51 [86%] vs NL: 8 [14%], P < 0.01). Conclusions: Adult patients with Fontan physiology and lymphopenia demonstrated portal hypertension and lymphatic dysfunction more commonly, perhaps suggesting that this may be a marker of Fontan congestion and early Fontan failure. Further investigation into the relationship between lymphopenia, clinical outcomes, and Fontan function is needed.

Contexte: Chez les patients atteints d'une cardiopathie congénitale complexe ayant subi une intervention de Fontan, il est fréquent de voir apparaître des maladies extracardiaques, dont des anomalies hématologiques, comme la lymphopénie. Cependant, les implications cliniques de cette observation sont mal comprises et font donc l'objet de cette étude. Méthodologie: La présence et l'impact d'une lymphopénie ont été évalués chez des patients présentant une physiologie de Fontan dans notre centre (1999-2018). La cohorte a été divisée en un groupe composé de sujets atteints de lymphopénie (L) (2 mesures consécutives du nombre absolu de lymphocytes ≤ 1 x 103 K/µL) et un groupe de sujets n'ayant jamais présenté de lymphopénie (NL). Les caractéristiques initiales et les hospitalisations (762 années-patients) ont été évaluées. Résultats: Chez 62 adultes présentant une physiologie de Fontan (âgés de 34 ± 9 ans; 32 femmes [52 %]), la lymphopénie est apparue au plus tôt 8 ans après l'intervention de Fontan, avant 30 ans chez jusqu'à 60 % des patients. La lymphopénie a été associée à l'hypertension portale (score varices, ascite, splénomégalie et thrombocytopénie [VAST]) ­ NL : 0 (0-2) vs L : 2 (0-4), p < 0,0001. Au total, il y a eu 76 hospitalisations pour insuffisance cardiaque et 81 pour arythmie pour 1000 années-patients. Quarante ans après l'intervention de Fontan, la probabilité d'une hospitalisation pour insuffisance cardiaque était plus élevée dans le groupe L que dans le groupe NL (L : 51 [86 %] vs NL : 8 [14 %], p < 0,01). Conclusions: L'hypertension portale et la dysfonction lymphatique étaient plus fréquentes chez les adultes présentant une physiologie de Fontan et une lymphopénie, ce qui laisse peut-être entendre que ce pourrait être un marqueur d'une congestion et d'une défaillance précoce du système Fontan. D'autres recherches sur le lien entre la lymphopénie, les issues cliniques et la fonction du système Fontan sont nécessaires.

Super and Nonresponders to Catheter Ablation for Atrial Fibrillation: A Quality-of-Life Assessment Using Patient Reported Outcomes.

[Figure: see text].

Assessment of irritability in school-aged children by pediatric, family practice, and psychiatric providers.

BACKGROUND: Irritability, a common behavioral problem for school-aged children, is often first assessed by primary care providers, who manage about a third of mental health conditions in children. Until recent changes in the Diagnostic and Statistical Manual of Mental Disorders (DSM), irritability was often associated with mood disorders, which may have led to increases in bipolar disorder diagnosis and prescription of mood stabilizing medication. OBJECTIVE: Our aim was to explore differences between the approaches psychiatric and primary care providers use to assess irritability. METHODS: A single trained interviewer conducted detailed interviews and collected demographic data from a homogeneous group of physicians that saturated with a sample size of 17 pediatric, family medicine, and psychiatric providers who evaluate and treat school-aged children. Qualitative and quantitative data were collected and analyzed. RESULTS: In general, primary care providers chose to refer children with irritability to mental health specialists when medication management became complex, while the psychiatric providers chose behavior modification and parent education strategies rather than medications. The psychiatric group had a significantly higher caseload mix, prior experience with irritability, and more confidence in their assessment capabilities. There was lack of continuing medical education about irritability in all groups. CONCLUSION: This preliminary study highlights the importance of collaboration between primary care and subspecialties to promote accurate assessment and subsequent treatment of school-aged children with irritability, who can represent a safety concern for self and others. More research is needed to establish an efficient method of assessing and managing irritability in primary care and better utilization of specialists.

A Qualitative Study to Assess How Primary Care Versus Psychiatric Providers Evaluate and Treat Pediatric Patients With Irritability.

OBJECTIVE: To determine how primary care versus specialist practitioners assess and treat school-aged children with irritability. METHODS: Seventeen providers from family medicine, pediatrics, and psychiatry participated in in-depth interviews from June to August 2016 about the process they use to evaluate irritability. Data on demographic traits and measures of confidence were also collected. RESULTS: Primary care (family medicine and pediatrics) participants expressed frustration over the lack of time and specialized knowledge they had to accurately assess children with irritability, even though they were often the first clinician consulted when problems arose. There were clear and sometimes contradictory differences between how practitioners with a general versus specialized practice assessed mental health status in the clinic setting. Input on treatment approaches revealed that medication prescription was more common by primary care participants, and therapy was preferred by the psychiatry participants. CONCLUSIONS: Overall, family medicine and pediatric practitioners were significantly less confident in their ability to evaluate mental health status, while child and adolescent psychiatry participants were supportive of having more initial triage and possible treatment occur at the primary care level, suggesting a need for more training about childhood irritability in the primary care setting.

Deuterated (d6)-dextromethorphan elicits antidepressant-like effects in mice.

The over-the-counter antitussive dextromethorphan (DM) may have rapid antidepressant actions based on its overlapping pharmacology with ketamine, which has shown fast antidepressant effects but whose widespread use remains limited by problematic side effects. We have previously shown that DM produces antidepressant-like effects in the forced swim test (FST) and tail suspension test (TST) that are mediated in part through α-amino-3-hydroxy-5-methyl-4-isoxazole propionic (AMPA) and sigma-1 receptors, two protein targets associated with a faster onset of antidepressant efficacy. To utilize DM clinically, however, a major challenge that must be addressed is its rapid first-pass metabolism. Two strategies to inhibit metabolism of DM and maintain stable therapeutic blood levels are 1) chemically modifying DM and 2) adding quinidine, an inhibitor of the primary metabolizer of DM, the cytochrome P450 (CYP) 2D6 enzyme. The purpose of this study was to determine if modified DM (deuterated (d6)-DM) elicits antidepressant-like effects and if AMPA and sigma-1 receptors are involved. Furthermore, d6-DM was tested in conjunction with quinidine to determine if further slowing the metabolism of d6-DM affects its antidepressant-like actions. In the FST and TST, d6-DM produced antidepressant-like effects. Upon further investigation in the FST, the most validated animal model for predicting antidepressant efficacy, d6-DM produced antidepressant-like effects both in the absence and presence of quinidine. However, pretreatment with neither an AMPA receptor antagonist (NBQX) nor sigma-1 receptor antagonists (BD1063, BD1047) significantly attenuated the antidepressant-like effects. The data suggest d6-DM has antidepressant-like effects, though it may be recruiting different molecular targets and/or acting through a different mix or ratio of metabolites from regular DM.

Behavioral and biochemical effects of ketamine and dextromethorphan relative to its antidepressant-like effects in Swiss Webster mice.

Ketamine has been shown to produce rapid and robust antidepressant effects in depressed individuals; however, its abuse potential and adverse psychotomimetic effects limit its widespread use. Dextromethorphan (DM) may serve as a safer alternative on the basis of pharmacodynamic similarities to ketamine. In this proof-of-concept study, behavioral and biochemical analyses were carried out to evaluate the potential involvement of brain-derived neurotrophic factor (BDNF) in the antidepressant-like effects of DM in mice, with comparisons to ketamine and imipramine. Male Swiss, Webster mice were injected with DM, ketamine, or imipramine and their behaviors were evaluated in the forced-swim test and the open-field test. Western blots were used to measure BDNF and its precursor, pro-BDNF, protein expression in the hippocampus and the frontal cortex of these mice. Our results show that both DM and imipramine reduced immobility time in the forced-swim test without affecting locomotor activity, whereas ketamine reduced immobility time and increased locomotor activity. Ketamine also rapidly (within 40 min) increased pro-BDNF expression in an α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor-dependent manner in the hippocampus, whereas DM and imipramine did not alter pro-BDNF or BDNF levels in either the hippocampus or the frontal cortex within this timeframe. These data show that DM shares some features with both ketamine and imipramine. Additional studies examining DM may aid in the development of more rapid, safe, and efficacious antidepressant treatments.

Involvement of sigma-1 receptors in the antidepressant-like effects of dextromethorphan.

Dextromethorphan is an antitussive with a high margin of safety that has been hypothesized to display rapid-acting antidepressant activity based on pharmacodynamic similarities to the N-methyl-D-aspartate (NMDA) receptor antagonist ketamine. In addition to binding to NMDA receptors, dextromethorphan binds to sigma-1 (σ1) receptors, which are believed to be protein targets for a potential new class of antidepressant medications. The purpose of this study was to determine whether dextromethorphan elicits antidepressant-like effects and the involvement of σ1 receptors in mediating its antidepressant-like actions. The antidepressant-like effects of dextromethorphan were assessed in male, Swiss Webster mice using the forced swim test. Next, σ1 receptor antagonists (BD1063 and BD1047) were evaluated in conjunction with dextromethorphan to determine the involvement of σ receptors in its antidepressant-like effects. Quinidine, a cytochrome P450 (CYP) 2D6 inhibitor, was also evaluated in conjunction with dextromethorphan to increase the bioavailability of dextromethorphan and reduce exposure to additional metabolites. Finally, saturation binding assays were performed to assess the manner in which dextromethorphan interacts at the σ1 receptor. Our results revealed dextromethorphan displays antidepressant-like effects in the forced swim test that can be attenuated by pretreatment with σ1 receptor antagonists, with BD1063 causing a shift to the right in the dextromethorphan dose response curve. Concomitant administration of quinidine potentiated the antidepressant-like effects of dextromethorphan. Saturation binding assays revealed that a Ki concentration of dextromethorphan reduces both the Kd and the Bmax of [(3)H](+)-pentazocine binding to σ1 receptors. Taken together, these data suggest that dextromethorphan exerts some of its antidepressant actions through σ1 receptors.