Identification and Characterization of GAL-021 as a Novel Breathing Control Modulator.

BACKGROUND: The authors describe the preclinical pharmacological properties of GAL-021, a novel peripheral chemoreceptor modulator. METHODS: The ventilatory effects of GAL-021 were characterized using tracheal pneumotachometry (n = 4 to 6), plethysmography (n = 5 to 6), arterial blood gas analyses (n = 6 to 11), and nasal capnography (n = 3 to 4) in naive animals and those subjected to morphine-induced respiratory depression. Morphine analgesia in rats was evaluated by tail-flick test (n = 6). Carotid body involvement in GAL-021 ventilatory effects was assessed by comparing responses in intact and carotid sinus nerve-transected rats. Hemodynamic effects of GAL-021 were evaluated in urethane-anesthetized rats (n = 7). The pharmacological profile of GAL-021 in vitro was investigated using radioligand binding, enzyme inhibition, and cellular electrophysiology assays. RESULTS: GAL-021 given intravenously stimulated ventilation and/or attenuated opiate-induced respiratory depression in rats, mice, and nonhuman primates, without decreasing morphine analgesia in rats. GAL-021 did not alter mean arterial pressure but produced a modest increase in heart rate. Ventilatory stimulation in rats was attenuated by carotid sinus nerve transection. GAL-021 inhibited KCa1.1 in GH3 cells, and the evoked ventilatory stimulation was attenuated in Slo1 mice lacking the pore-forming α-subunit of the KCa1.1 channel. CONCLUSIONS: GAL-021 behaved as a breathing control modulator in rodents and nonhuman primates and diminished opioid-induced respiratory depression without compromising opioid analgesia. It acted predominantly at the carotid body, in part by inhibiting KCa1.1 channels. Its preclinical profile qualified the compound to enter clinical trials to assess effects on breathing control disorders such as drug (opioid)-induced respiratory depression and sleep apnea.

Optimizing Patient Selection for Physiological Pacing in Bradyarrhythmia: Factors Associated With High Ventricular Pacing Burden.

Background: Right ventricular (RV) pacing is established as the most common ventricular pacing (VP) strategy for patients with symptomatic bradyarrhythmia. Some patients with high VP burden suffer deterioration of left ventricular (LV) function, termed pacing-induced cardiomyopathy (PICM). Patients who pace > 20% of the time from the RV apex are at increased risk of PICM, but independent predictors of increased RV pacing burden have not been elucidated in those who have a permanent pacemaker (PPM) inserted for bradyarrhythmia. Methods: We aimed to identify factors that are associated with increased VP burden > 20%, hence determining those at risk for resultant PICM. In this retrospective cohort study, we identified the most recent 300 consecutive cardiac implantable electronic device (CIED) implants in our center and collected past medical history, electrocardiogram (ECG), echo, medication and pacemaker check data. Results: A total of 236 individuals met inclusion criteria. Of the patients, 35% had RV pacing burden < 20%, while 65% had VP burden ≥ 20%; 96.2% of patients with complete heart block (CHB) paced > 20% (P = 0.002). Utilization of DDD or VVI (75.2% and 89.2% of patients, respectively) without mode switch algorithms was associated with VP > 20% (P < 0.001). Male or previous coronary artery bypass grafting (CABG) patients also statistically paced > 20%. Other factors trending towards significance included prolonged PR interval, atrial fibrillation or more advanced age. Conclusion: High-grade atrioventricular (AV) block was associated with an RV pacing burden > 20% over 3 years but this was not consistent in patients with only transient episodes of high-grade AV block. We found a significant association between high VP% and male sex, previous CABG and the absence of mode switching algorithms.

Comparing Left Atrial Low Voltage Areas in Sinus Rhythm and Atrial Fibrillation Using Novel Automated Voltage Analysis: A Pilot Study.

Background: Low voltage areas (LVAs) have been proposed as surrogate markers for left atrial (LA) scar. Correlation between voltages in sinus rhythm (SR) and atrial fibrillation (AF) have previously been measured via point-by-point analysis. We sought to compare LA voltage composition measured in SR to AF, utilizing a high-density automated voltage histogram analysis (VHA) tool in those undergoing pulmonary vein isolation (PVI) for persistent AF (PeAF). Methods: We retrospectively analyzed patients with PeAF undergoing de novo PVI. Maps required ≥ 1,000 voltage points in each rhythm and had a standardized procedure (mapped in AF then remapped in SR post-PVI). We created six anatomical segments (AS) from each map: anterior, posterior, roof, floor, septal and lateral AS. These were analyzed by VHA, categorizing atrial LVAs into 10 voltage aliquots 0 - 0.5 mV. Data were analyzed using SPSS v.26. Results: We acquired 58,342 voltage points (n = 10 patients, mean age: 67 ± 13 years, three females). LVA burdens of ≤ 0.2 mV, designated as "severe LVAs", were comparable between most AS (except on the posterior wall) with good correlation. Mapped voltages between the ranges of 0.21 and 0.5 mV were labeled as "diseased LA tissue", and these were found significantly more in AF than SR. Significant differences were seen on the roof, anterior, posterior, and lateral AS. Conclusions: Diseased LA tissue (0.21 - 0.5 mV) burden is significantly higher in AF than SR, mainly in the anterior, roof, lateral, and posterior wall. LA "severe LVA" (≤ 0.2 mV) burden is comparable in both rhythms, except with respect to the posterior wall. Our findings suggest that mapping rhythm has less effect on the LA with voltages < 0.2 mV than 0.2 - 0.5 mV across all anatomical regions, excluding the posterior wall.

Ablation Index Outcome in Redo Persistent Atrial Fibrillation Ablation: Results of a Short-Term Study.

Background: Ablation index (AI) is a novel catheter-based parameter that has improved the outcome and safety of radiofrequency (RF) ablation of pulmonary vein isolations (PVIs). This index incorporates contact force (CF) (g), time (s), and power (W) parameters. The role of AI in redo ablations for persistent atrial fibrillation (peAF) has not been fully investigated. Hence, the impact of AI on the success of the redo PVI during the short-term follow-up period is the aim of this study. Methods: A retrospective analysis of 39 consecutive patients who underwent redo PVI ablations for peAF was carried out between January 2016 and December 2018. Target values for AI were 500 - 550 for anterior and roof and 400 - 380 for posterior and inferior regions. We compared outcomes between AI-guided and catheter CF ablations (i.e., forced time integral (FTI) of more than 400 g/s) during a follow-up of 24 months. Results: Pulmonary vein reconnections at redo procedure were similar in both groups (P = 0.1). AF free burden period was non-significant (mean 15.53 ± 2.4 months in AI group vs. 15.22 ± 1.9 months in CF group, P = 0.79) at 24 months. The AI group demonstrated greater numbers of patients for whom anti-arrhythmic therapy could be de-escalated over 1 year (n = 11 (65%) in AI vs. n = 6 (27%) in CF, P = 0.02). Fewer patients underwent escalation of their anti-arrhythmic therapy (n = 2 (12%) in AI vs. n = 7 (32%) in CF, P = 0.15). The AI group trended towards a shorter procedure time (111.6 ± 27 min) compared to the CF group (133 ± 40 min) (P = 0.06). Other procedural details were comparable. Conclusion: Redo PVI interventions using AI lead to a significant de-escalation in medication during follow-up. Procedure time and radiation dose using AI tends to be shorter. Both techniques are safe with minimal complications.

Transient bilateral chorea secondary to digoxin toxicity in a female with acute kidney injury: a case report.

BACKGROUND: Chorea secondary to digoxin toxicity is rare, with only three published cases describing the phenomenon. We report the case of a 78-year-old female presenting with intermittent vomiting and diarrhoea for 4 weeks. She had a history of chronic kidney disease and digoxin use for atrial fibrillation. CASE SUMMARY: A 78-year-old lady presented to the emergency department with a 4-week history of intermittent vomiting and diarrhoea. These symptoms commenced after a course of antibiotics prescribed by her general practitioner for a urinary tract infection. Her admission electrocardiogram demonstrated atrial fibrillation at a rate of 32, with evidence of digitalis toxicity. Her creatinine was 396 µmol/L (44-80 µmol/L) with digoxin level 8.1 nmol/L (0.77-1.5 nmol/L). Initially, treatment was with digoxin-specific antibody (FAB) and fluid resuscitation. Within 24 h, she developed transient head, neck, and bilateral upper limb chorea. Review of medications revealed no other likely causative agent. Neuroimaging showed no new ischaemia, but stable established bilateral infarcts of the basal ganglia. Haloperidol 0.5 mg twice daily was commenced. Three days later as digoxin levels normalized, the chorea resolved entirely without recurrence. DISCUSSION: We have identified three reported cases of digoxin-induced chorea. Our case resembles two of the published cases where a transient bilateral chorea, associated with digitalis toxicity and resolving within a few days of normalization of digoxin levels was demonstrated. There were no other focal neurological signs or symptoms. It has been postulated that an alteration to dopaminergic neuronal activity is a potential mechanism, as digoxin also demonstrates neuropsychiatric side effects such as psychosis and depression.

Left atrial scar identification and quantification in sinus rhythm and atrial fibrillation.

Identification and quantification of low voltage areas (LVA) in atrial fibrillation (AF), identified by their bipolar voltages (BiV) via electro-anatomical voltage mapping is an area of interest to prognosis of AF free burden. LVAs have been linked to diseased left atrial (LA) tissue which results in pro-fibrillatory potentials. These LVAs are dominantly found within the pulmonary veins, however, as the disease progresses other areas of the LA show low voltage. The scar burden of the LA is linked to recurrence of the arrhythmia and can be a target of further modification. This burden is classically assessed once sinus rhythm (SR) is attained, but this is susceptible to operator variability with overestimated dense LA scar (<0.2 mV) and underestimated diseased LA tissue (<0.5 mV). The novel automated voltage histogram analysis (VHA) tool may increase accuracy, however, is yet to be fully validated. A recent study indicates that LVAs can be assessed just as reliably in AF as SR, but BiV is lower with linear correlation to SR values (0.24-0.5 mV respectively). In this paper, we review current data as well as review current methods of identifying, quantifying, and grading LA scar. We also compared AF vs SR voltages of a patient undergoing catheter ablation in our site using our VHA tool to compare the results. In keeping with the cited papers, we found lower voltages in our patient measured in AF. This area warrants further study to assess correlation in more patients, with view to developing prognostic and therapeutic grading systems.

Dynamic Local Activation Time Mapping in Heavily Scarred Left Atrium and Persistent Atrial Fibrillation: A proof of concept case report.

We report the case of a 68-year-old male, presenting with persistent atrial fibrillation (Pe AF) refractory to anti arrhythmic medications and cardioversion, on a background history of ischaemic heart disease. Pre and post standard pulmonary vein isolation (PVI), left atrial (LA) voltageanalyses wereperformed, followed by dynamic local activation time (DLAT) mapping in addition to focal activity identification.Thisdemonstrated a heavily scarred LA, and a number ofareas of focal activity. The patient remained in atrial fibrillation (AF) post rotor (focal activity) targeting,howevernotable changes in AF cycle length (CL)werenotedandslowed by an average of 25.3 milliseconds. Comparison between DLAT mappingpre and post PVI were anatomically similar but not identical. The anatomical distribution of heavy scar areas in the LA did not correspond to the DLAT areas of interest. The patient subsequentlyremained in normal sinus rhythm (SR) for 6 monthson a low dose Beta blockade in a short follow up period. DLAT mapping and its characteristics in heavily scarred LA are reported in this case.

Indications of Cardiac Resynchronization in Non-Left Bundle Branch Block: Clinical Review of Available Evidence.

Cardiac resynchronization therapy (CRT) benefits have been firmly established in patients with heart failure and reduced left ventricular ejection fraction (HFrEF), who remain in New York Heart Association (NYHA) functional classes II and III, despite optimal medical therapy, and have a wide QRS complex. An important and consistent finding in published systematic reviews and in subgroup analyses is that the benefits of CRT are maximum for patients with a broader QRS durations, typically described as QRS duration > 150 ms, and for patients with a typical left bundle branch block (LBBB) QRS morphology. It remains uncertain whether patients with non-LBBB QRS complex morphology clearly benefit from CRT or only modestly respond.

Replicate high-density rat genome oligonucleotide microarrays reveal hundreds of regulated genes in the dorsal root ganglion after peripheral nerve injury.

BACKGROUND: Rat oligonucleotide microarrays were used to detect changes in gene expression in the dorsal root ganglion (DRG) 3 days following sciatic nerve transection (axotomy). Two comparisons were made using two sets of triplicate microarrays, naïve versus naïve and naïve versus axotomy. RESULTS: Microarray variability was assessed using the naïve versus naïve comparison. These results support use of a P < 0.05 significance threshold for detecting regulated genes, despite the large number of hypothesis tests required. For the naïve versus axotomy comparison, a 2-fold cut off alone led to an estimated error rate of 16%; combining a >1.5-fold expression change and P < 0.05 significance reduced the estimated error to 5%. The 2-fold cut off identified 178 genes while the combined >1.5-fold and P < 0.05 criteria generated 240 putatively regulated genes, which we have listed. Many of these have not been described as regulated in the DRG by axotomy. Northern blot, quantitative slot blots and in situ hybridization verified the expression of 24 transcripts. These data showed an 83% concordance rate with the arrays; most mismatches represent genes with low expression levels reflecting limits of array sensitivity. A significant correlation was found between actual mRNA differences and relative changes between microarrays (r2 = 0.8567). Temporal patterns of individual genes regulation varied. CONCLUSIONS: We identify parameters for microarray analysis which reduce error while identifying many putatively regulated genes. Functional classification of these genes suggest reorganization of cell structural components, activation of genes expressed by immune and inflammatory cells and down-regulation of genes involved in neurotransmission.

Mechanistic and cytotoxicity studies of group IV ß-diketonate complexes.

Group IV metal complexes have previously shown promise as novel anticancer agents. Here, we discuss the mechanistic and cytotoxic nature of a series of group IV ß-diketonate coordination complexes. Clear evidence that the ligands are exchangeable on the metal centre and that the ß-diketonate ligands can act as potential drug delivery vehicles of the group IV metal ions was obtained. When evaluated for the cytotoxicity against human colon adenocarcinoma (HT-29) and human breast adenocarcinoma (MCF-7) cell lines, a general trend of decreasing potency down the group IV metals was observed. The most promising results obtained were for the hafnium complexes, with the tris diphenyl ß-diketonate hafnium complex exhibiting IC50 values of 4.9 ± 0.9 µM and 3.2 ± 0.3 µM against HT-29 and MCF-7, respectively, which are comparable with the activity of cisplatin against the same cell lines. This tri ß-diketonate hafnium complex is the first to show potent in vitro cytotoxic activity. The results reported show that ligand design has a significant effect on the cytotoxic potential of the complexes, and that these group IV complexes warrant further evaluation as novel metal-containing anticancer agents.

Discovery and development of respirable antisense therapeutics for asthma.

Respirable antisense oligonucleotides (RASONs) represent a novel class of respiratory therapeutic molecules with the potential to specifically address the challenges posed by the successes of the Human Genome Program, namely, the need to rapidly identify the critical pulmonary disease-relevant drugable targets from the vast pool of 30,000-40,000 human genes and to discover and develop drugs that specifically attack these targets. We have shown that EPI-2010, a RASON targeting the adenosine A1 receptor, a G-protein coupled receptor that has been implicated in the regulation of three major determinants of asthma, can be delivered directly to the target disease tissue as an aerosol formulation. In vivo efficacy, absorption, distribution, metabolism, and excretion (ADME), and safety studies of inhaled EPI-2010 employing animal models of human asthma suggest that the RASON approach enables the specific delivery of efficacious, safe, and long-acting doses of phosphorothioate oligonucleotides to the respiratory tract. Moreover, these data indicate that RASONs truly have the potential to address the respiratory drug discovery bottleneck of the postgenomic era, that is, the ability to rapidly validate disease targets and develop pulmonary disease therapeutics for these validated targets.