Abstract
Background
Recurrent Clostridioides difficile infection (rCDI) is associated with loss of microbial diversity and microbe-derived secondary bile acids, which inhibit C. difficile germination ...and growth. SER-109, an investigational microbiome drug of donor-derived, purified spores, reduced recurrence in a dose-ranging, phase (P) 1 study in subjects with multiple rCDIs.
Methods
In a P2 double-blind trial, subjects with clinical resolution on standard-of-care antibiotics were stratified by age (< or ≥65 years) and randomized 2:1 to single-dose SER-109 or placebo. Subjects were diagnosed at study entry by PCR or toxin testing. Safety, C. difficile–positive diarrhea through week 8, SER-109 engraftment, and bile acid changes were assessed.
Results
89 subjects enrolled (67% female; 80.9% diagnosed by PCR). rCDI rates were lower in the SER-109 arm than placebo (44.1% vs 53.3%) but did not meet statistical significance. In a preplanned analysis, rates were reduced among subjects ≥65 years (45.2% vs 80%, respectively; RR, 1.77; 95% CI, 1.11–2.81), while the <65 group showed no benefit. Early engraftment of SER-109 was associated with nonrecurrence (P < .05) and increased secondary bile acid concentrations (P < .0001). Whole-metagenomic sequencing from this study and the P1 study revealed previously unappreciated dose-dependent engraftment kinetics and confirmed an association between early engraftment and nonrecurrence. Engraftment kinetics suggest that P2 dosing was suboptimal. Adverse events were generally mild to moderate in severity.
Conclusions
Early SER-109 engraftment was associated with reduced CDI recurrence and favorable safety was observed. A higher dose of SER-109 and requirements for toxin testing were implemented in the current P3 trial.
Clinical Trials Registration
NCT02437487, https://clinicaltrials.gov/ct2/show/NCT02437487?term=SER-109&draw= 2&rank=4.
In a phase 2 trial, SER-109, an investigational microbiome drug, did not reduce rates of recurrent CDI, despite a previously successful open-label study. Key contributing factors, which led to a redesign of the currently enrolling phase 3 trial, are highlighted.
Emerging evidence indicates gut microbes and their products could activate the autonomic nervous system (ANS), which plays important roles in the initiation and maintenance of atrial fibrillation ...(AF). Trimethylamine N-oxide (TMAO), a metabolite derived from gut microbes, is associated with cardiovascular diseases. The present study aimed to investigate the role of TMAO in the progression of AF.
In part 1: TMAO or saline was locally injected into 4 major atrial ganglionated plexi (GP) to clarify its effect on cardiac ANS and AF inducibility in normal canines. In part 2: TMAO or saline was injected into 4 major atrial GP to test its effect on AF progression in a rapid atrial pacing (RAP)-induced AF model.
In part 1: Local injection of TMAO significantly increased anterior right GP (ARGP) function and neural activity, shortened ERP values. In part 2, compared with the control group, 6-hour RAP significantly shortened the ERP, widened the ∑WOV, enhanced the ARGP function and neural activity, increased the NGF and c-fos expression, and up-regulated the inflammatory cytokines. TMAO aggravated all of these changes by activating the proinflammatory p65 NF-κB signaling pathway.
TMAO could increase the instability of atrial electrophysiology in normal canines and aggravate the acute electrical remodeling in a RAP-induced AF model by exacerbating autonomic remodeling. The increased inflammatory cytokines in the GP due to the activation of p65 NF-κB signaling may contribute to these effects.
•Trimethylamine N-oxide (TMAO) facilitate the progression of atrial fibrillation (AF).•The mechanism relies on the activation of cardiac autonomic nervous system (CANS).•Gut microbes may participate in the progression of AF via regulating CANS by TMAO.
Epicardial adipose tissue (EAT) remodelling is closely related to the pathogenesis of atrial fibrillation (AF). We investigated whether metformin (MET) prevents AF‐dependent EAT remodelling and AF ...vulnerability in dogs. A canine AF model was developed by 6‐week rapid atrial pacing (RAP), and electrophysiological parameters were measured. Effective refractory periods (ERP) were decreased in the left and right atrial appendages as well as in the left atrium (LA) and right atrium (RA). MET attenuated the RAP‐induced increase in ERP dispersion, cumulative window of vulnerability, AF inducibility and AF duration. RAP increased reactive oxygen species (ROS) production and nuclear factor kappa‐B (NF‐κB) phosphorylation; up‐regulated interleukin‐6 (IL‐6), tumour necrosis factor‐α (TNF‐α) and transforming growth factor‐β1 (TGF‐β1) levels in LA and EAT; decreased peroxisome proliferator‐activated receptor gamma (PPARγ) and adiponectin (APN) expression in EAT and was accompanied by atrial fibrosis and adipose infiltration. MET reversed these alterations. In vitro, lipopolysaccharide (LPS) exposure increased IL‐6, TNF‐α and TGF‐β1 expression and decreased PPARγ/APN expression in 3T3‐L1 adipocytes, which were all reversed after MET administration. Indirect coculture of HL‐1 cells with LPS‐stimulated 3T3‐L1 conditioned medium (CM) significantly increased IL‐6, TNF‐α and TGF‐β1 expression and decreased SERCA2a and p‐PLN expression, while LPS + MET CM and APN treatment alleviated the inflammatory response and sarcoplasmic reticulum Ca2+ handling dysfunction. MET attenuated the RAP‐induced increase in AF vulnerability, remodelling of atria and EAT adipokines production profiles. APN may play a key role in the prevention of AF‐dependent EAT remodelling and AF vulnerability by MET.
Objectives We hypothesized that autonomic atrial remodeling can be reversed by low-level (LL) vagosympathetic nerve stimulation (VNS). Background Previously, we showed that VNS can be ...antiarrhythmogenic. Methods Thirty-three dogs were subjected to electrical stimulation (20 Hz) applied to both vagosympathetic trunks at voltages 10% to 50% below the threshold that slowed sinus rate or AV conduction. Group 1 (n = 7): Programmed stimulation (PS) was performed at baseline and during 6-h rapid atrial pacing (RAP). PS allowed determination of effective refractory period (ERP) and AF inducibility measured by window of vulnerability (WOV). LL-VNS was continuously applied from the 4th to 6th hours. Group 2 (n = 4): After baseline ERP and WOV determinations, 6-h concomitant RAP+LL-VNS was applied. Sustained AF was induced by injecting acetylcholine (ACh) 10 mM into the anterior right ganglionated plexus (Group 3, n = 10) or applying ACh 10 mM to right atrial appendage (Group 4, n = 9). Results Group 1: The ERP progressively shortened and the ΣWOV (sum of WOV from all tested sites) progressively increased (p < 0.05) during 3-h RAP then returned toward baseline during 3-h RAP+LL-VNS (p < 0.05). Group 2: 6-h concomitant RAP+LL-VNS did not induce any significant change in ERP and ΣWOV. Group 3 and Group 4: AF duration (AF-D) and cycle length (AF-CL) were markedly altered by 3-h LL-VNS (Group 3: baseline: AF-D = 389 ± 90 s, AF-CL = 45.1 ± 7.8 ms; LL-VNS: AF-D = 50 ± 15 s, AF-CL = 82.0 ± 13.7 ms both p < 0.001; Group 4: baseline: AF-D = 505 ± 162 s, AF-CL = 48.8 ± 6.6 ms; LL-VNS: AF-D = 71 ± 21 s, AF-CL = 101.3 ± 20.9 ms both p < 0.001). Conclusions LL-VNS can prevent and reverse atrial remodeling induced by RAP as well as suppress AF induced by strong cholinergic stimulation. Inhibition of the intrinsic cardiac autonomic nervous system by LL-VNS may be responsible for these salutary results.
The aim of this study was to investigate whether low-level tragus stimulation (LL-TS) treatment could reduce myocardial ischemia-reperfusion injury in patients with ST-segment elevation myocardial ...infarction (STEMI).
The authors' previous studies suggested that LL-TS could reduce the size of myocardial injury induced by ischemia.
Patients who presented with STEMI within 12 h of symptom onset, treated with primary percutaneous coronary intervention, were randomized to the LL-TS group (n = 47) or the control group (with sham stimulation n = 48). LL-TS, 50% lower than the electric current that slowed the sinus rate, was delivered to the right tragus once the patients arrived in the catheterization room and lasted for 2 h after balloon dilatation (reperfusion). All patients were followed for 7 days. The occurrence of reperfusion-related arrhythmia, blood levels of creatine kinase-MB, myoglobin, N-terminal pro-B-type natriuretic peptide and inflammatory markers, and echocardiographic characteristics were evaluated.
The incidence of reperfusion-related ventricular arrhythmia during the first 24 h was significantly attenuated by LL-TS. In addition, the area under the curve for creatine kinase-MB and myoglobin over 72 h was smaller in the LL-TS group than the control group. Furthermore, blood levels of inflammatory markers were decreased by LL-TS. Cardiac function, as demonstrated by the level of N-terminal pro-B-type natriuretic peptide, the left ventricular ejection fraction, and the wall motion index, was markedly improved by LL-TS.
LL-TS reduces myocardial ischemia-reperfusion injury in patients with STEMI. This proof-of-concept study raises the possibility that this noninvasive strategy may be used to treat patients with STEMI undergoing primary percutaneous coronary intervention.
The mechanism(s) underlying the maintenance of atrial fibrillation (AF) during the first few hours after AF was initiated remains poorly understood.
To investigate the roles of the intrinsic cardiac ...autonomic nervous system in the maintenance of AF at the early stage.
In 10 anesthetized dogs, we attached multielectrode catheters on atria and pulmonary veins. Microelectrodes inserted into the anterior right ganglionated plexi recorded neural activity. At baseline, programmed stimulation determined the effective refractory period (ERP) and window of vulnerability (WOV), a measure of AF inducibility. For the next 6 hours, AF was simulated by rapid atrial pacing (RAP) and the same parameters were measured hourly during sinus rhythm. A circular catheter was positioned in the superior vena cava for high-frequency stimulation (20 Hz) of the adjacent vagal preganglionics. During 4-6 hours of RAP, we delivered low-level vagal stimulation in the superior vena cava (LL-SVCS), 50% below that which induced slowing of the sinus rate.
During the 6-hour RAP, there was a progressive decrease in the ERP and an increase in ERP dispersion, WOV, and neural activity. With LL-SVCS during 4-6-hour RAP, ERP, WOV, and neural activity returned toward baseline levels (all P <.05, compared with the third-hour RAP values).
RAP not only induces atrial electrical remodeling but also promotes autonomic remodeling. These 2 remodeling processes may form a vicious cycle and each may perpetuate the other. These findings may help to explain how AF maintains itself in its very early stage. LL-SVCS both reversed remodeling processes and can potentially break the vicious cycle of "AF begets AF" in the first few hours of AF.
We studied the effects of transcutaneous electrical stimulation at the tragus, the anterior protuberance of the outer ear, for inhibiting atrial fibrillation (AF).
To develop a noninvasive ...transcutaneous approach to deliver low-level vagal nerve stimulation to the tragus in order to treat cardiac arrhythmias such as AF.
In 16 pentobarbital anesthetized dogs, multielectrode catheters were attached to pulmonary veins and atria. Three tungsten-coated microelectrodes were inserted into the anterior right ganglionated plexi to record neural activity. Tragus stimulation (20 Hz) in the right ear was accomplished by attaching 2 alligator clips onto the tragus. The voltage slowing the sinus rate or atrioventricular conduction was used as the threshold for setting the low-level tragus stimulation (LL-TS) at 80% below the threshold. At baseline, programmed stimulation determined the effective refractory period (ERP) and the window of vulnerability (WOV), a measure of AF inducibility. For hours 1-3, rapid atrial pacing (RAP) was applied alone, followed by concomitant RAP+LL-TS for hours 4-6 (N = 6). The same parameters were measured during sinus rhythm when RAP stopped after each hour. In 4 other animals, bivagal transection was performed before LL-TS.
During hours 1-3 of RAP, there was a progressive and significant decrease in ERP, increase in WOV, and increase in neural activity vs baseline (all P < .05). With RAP+LL-TS during hours 4-6, there was a linear return of ERP, WOV, and neural activity toward baseline levels (all P < .05, compared to the third-hour values). In 4 dogs, bivagal transection prevented the reversal of ERP and WOV despite 3 hours of RAP+LL-TS.
LL-TS can reverse RAP-induced atrial remodeling and inhibit AF inducibility, suggesting a potential noninvasive treatment of AF.
Intrinsic Cardiac Ganglia Activity Inhibited by Low‐Level Vagal Stimulation. Introduction: We hypothesized that low‐level vagosympathetic stimulation (LL‐VNS) can suppress atrial fibrillation (AF) by ...inhibiting the activity of the intrinsic cardiac autonomic nervous system (ICANS).
Methods and Results:
Wire electrodes inserted into both vagosympathetic trunks allowed LL‐VNS at 10% or 50% below the voltage required to slow the sinus rate or atrioventricular conduction. Multielectrode catheters were attached to atria, atrial appendages and all pulmonary veins. Electrical stimulation at the anterior right and superior left ganglionated plexi (ARGP, SLGP) was used to simulate a hyperactive state of the ICANS. Effective refractory period (ERP) and window of vulnerability (WOV) for AF were determined at baseline and during ARGP+SLGP stimulation in the presence or absence of LL‐VNS. Neural activity was recorded from the ARGP or SLGP. ARGP+SLGP stimulation induced shortening of ERP, increase of ERP dispersion and increase of AF inducibility (WOV), all of which were suppressed by LL‐VNS (10% or 50% below threshold) at all tested sites. Sham LL‐VNS failed to induce these changes. The effects of LL‐VNS were mediated by inhibition of the ICANS, as evidenced by (1) LL‐VNS suppression of the ability of the ARGP stimulation to slow the sinus rate, (2) the frequency and amplitude of the neural activity recorded from the ARGP or SLGP was markedly suppressed by LL‐VNS, and (3) the spatial gradient of the ERP and WOV from the PV‐atrial junction toward the atrial appendage was eliminated by LL‐VNS.
Conclusions:
LL‐VNS suppressed AF inducibility by inhibiting the neural activity of major GP within the ICANS. (J Cardiovasc Electrophysiol, Vol. 22, pp. 455‐463)
Importance
Intraocular pressure (IOP) is often reduced following cataract surgery. Postoperative changes in corneal stiffness are likely to be at least partly responsible for any reduction in IOP ...measured with applanation tonometry.
Background
To determine the effect of cataract surgery and corneal incision size on corneal biomechanics.
Design
Prospective randomized trial.
Participants
One hundred prospectively enrolled patients qualifying for cataract surgery.
Methods
Participants were randomized to clear corneal incisions with a 2.20 or 2.85 mm keratome. Corneal Visualisation Scheimpflug Technology (Corvis‐ST) tonometry and dynamic corneal response measurements were obtained preoperatively, and 3 mo postoperatively. Multiple regression analysis was completed using R software.
Main Outcome Measures
Corvis‐ST biomechanical parameters.
Results
Ninety‐three eyes of 93 patients were included in the final analysis. Mean Corvis‐ST biomechanically corrected IOP decreased by 3.63 mmHg postoperatively (95% confidence interval = 2.97‐4.35, P ≤ 0.01), and central pachymetry increased by 6.96 μm (4.33‐9.59, P ≤ 0.01). Independent of IOP and pachymetry changes, mean (±SE) corneal first applanation stiffness parameter reduced by 9.761 ± 3.729 (P = 0.01) postoperatively. First applanation velocity increased by 0.007 ± 0.002 ms, second applanation velocity increased by 0.012 ± 0.004 ms (P ≤ 0.01), the first applanation deformation amplitude increased by 0.008 ± 0.002 mm (P ≤ 0.01) and the deflection amplitude at highest concavity increased by 0.030 ± 0.069 (P ≤ 0.01). There were no significant differences between different incision size groups.
Conclusions and Relevance
Corneal stiffness is reduced 3 mo following cataract surgery and is associated with falsely low IOP measurements. This finding may be important for glaucoma patients and in particular when assessing the effectivity of minimally invasive glaucoma surgery devices.
Many developmental signaling pathways have been implicated in lineage-specific differentiation; however, mechanisms that explicitly control differentiation timing remain poorly defined in mammals. We ...report that murine Hedgehog signaling is a heterochronic pathway that determines the timing of progenitor differentiation. Hedgehog activity was necessary to prevent premature differentiation of second heart field (SHF) cardiac progenitors in mouse embryos, and the Hedgehog transcription factor GLI1 was sufficient to delay differentiation of cardiac progenitors in vitro. GLI1 directly activated a de novo progenitor-specific network in vitro, akin to that of SHF progenitors in vivo, which prevented the onset of the cardiac differentiation program. A Hedgehog signaling-dependent active-to-repressive GLI transition functioned as a differentiation timer, restricting the progenitor network to the SHF. GLI1 expression was associated with progenitor status across germ layers, and it delayed the differentiation of neural progenitors in vitro, suggesting a broad role for Hedgehog signaling as a heterochronic pathway.
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