Role of S100ß in Patients with Unstable Angina Pectoris: Insights from Quantitative Flow Ratio.

BACKGROUND AND OBJECTIVE: Disturbed autonomic nervous system (ANS) may promote inflammatory, immune, and oxidative stress responses, which may increase the risk of acute coronary events. S100ß has been proposed as a biomarker of neuronal injury that would provide an insightful understanding of the crosstalk between the ANS, immune-inflammatory cells, and plaques that drive atherosclerosis. This study investigates the correlation between S100ß, and functional coronary stenosis as determined by quantitative flow ratio (QFR). METHODS: Patients with unstable angina pectoris (UAP) scheduled for coronary angiography and QFR were retrospectively enrolled. Serum S100ß levels were determined by enzyme-linked immunosorbent assay. The Gensini score was used to estimate the extent of atherosclerotic lesions and the cumulative sum of three-vessel QFR (3V-QFR) was calculated to estimate the total atherosclerotic burden. RESULTS: Two hundred thirty-three patients were included in this study. Receiver operator characteristic (ROC) curve indicated that S100ß>33.28 pg/mL predicted functional ischemia in patients with UAP. Multivariate logistic analyses showed that a higher level of S100ß was independently correlated with a functional ischemia-driven target vessel (QFR ≤0.8). This was also closely correlated with the severity of coronary lesions, as measured by the Gensini score (OR = 5.058, 95% CI: 2.912-8.793, p <0.001). According to 3V-QFR, S100ß is inversely associated with total atherosclerosis burden (B = -0.002, p <0.001). CONCLUSIONS: S100ß was elevated in the functional ischemia stages of UAP. It was independently associated with coronary lesion severity as assessed by Gensini score and total atherosclerosis burden as estimated by 3V-QFR in patients with UAP.

Ultrasound-mediated piezoelectric nanoparticle modulation of intrinsic cardiac autonomic nervous system for rate control in atrial fibrillation.

Rate control is a cornerstone of atrial fibrillation treatment. Barium titanate nanoparticles (BTNPs) are piezoelectric nanomaterials that can generate local electromagnetic fields under ultrasound activation, stimulating nearby neuronal tissue. This study aimed to modulate the inferior right ganglionated plexus (IRGP) of the heart and reduce the ventricular rate during rapid atrial pacing (RAP)-induced atrial fibrillation using ultrasound-mediated BTNPs. Adult male beagles were randomly divided into a phosphate-buffered saline (PBS) group (n = 6) and a BTNP group (n = 6). PBS or nanoparticles were injected into the IRGP of both groups before RAP. The biological safety of the material was evaluated according to electrophysiology recordings, thermal effects and level of inflammation. Compared to the PBS group, the BaTiO3 piezoelectric nanoparticle group had reduced ventricular rates in the sinus rhythm and atrial fibrillation models after stimulating the IRGP by applying ultrasound. In addition, transient stimulation by BTNPs did not lead to sustained neuronal excitation in the IRGP. The activation of the BTNPs did not induce inflammation or thermal damage effects in the IRGP. Ultrasound-mediated BTNP neuromodulation can significantly reduce the ventricular rate by stimulating the IRGP. Thus, ultrasound-mediated BTNP neuromodulation is a potential therapy for atrial fibrillation rate control.

Subthreshold splenic nerve stimulation prevents myocardial Ischemia-Reperfusion injury via neuroimmunomodulation of proinflammatory factor levels.

OBJECTIVES: Clinical outcomes following myocardial ischemia-reperfusion (I/R) injury are strongly related to the intensity and duration of inflammation. The splenic nerve (SpN) is indispensable for the anti-inflammatory reflex. This study aimed to investigate whether splenic nerve stimulation (SpNS) plays a cardioprotective role in myocardial I/R injury and the potential underlying mechanism. METHODS: Sprague-Dawley rats were randomly divided into four groups: sham group, I/R group, SpNS group, and I/R plus SpNS group. The highest SpNS intensity that did not influence heart rate was identified, and SpNS at this intensity was used as the subthreshold stimulus. Continuous subthreshold SpNS was applied for 1 h before ligation of the left coronary artery for 45 min. After 72 h of reperfusion, samples were collected for analysis. RESULTS: SpN activity and splenic concentrations of cholinergic anti-inflammatory pathway (CAP)-related neurotransmitters were significantly increased by SpNS. The infarct size, oxidative stress, sympathetic tone, and the levels of proinflammatory cytokines, including TNF-α, IL-1ß, and IL-6, were significantly reduced in rats subjected to subthreshold SpNS after myocardial I/R injury compared with those subjected to I/R injury alone. CONCLUSIONS: Subthreshold SpNS ameliorates myocardial damage, the inflammatory response, and cardiac remodelling induced by myocardial I/R injury via neuroimmunomodulation of proinflammatory factor levels. SpNS is a potential therapeutic strategy for the treatment of myocardial I/R injury.

Prediction of major adverse cardiovascular events in patients with acute coronary syndrome: Development and validation of a non-invasive nomogram model based on autonomic nervous system assessment.

Background: Disruption of the autonomic nervous system (ANS) can lead to acute coronary syndrome (ACS). We developed a nomogram model using heart rate variability (HRV) and other data to predict major adverse cardiovascular events (MACEs) following emergency coronary angiography in patients with ACS. Methods: ACS patients admitted from January 2018 to June 2020 were examined. Holter monitors were used to collect HRV data for 24 h. Coronary angiograms, clinical data, and MACEs were recorded. A nomogram was developed using the results of Cox regression analysis. Results: There were 439 patients in a development cohort and 241 in a validation cohort, and the mean follow-up time was 22.80 months. The nomogram considered low-frequency/high-frequency ratio, age, diabetes, previous myocardial infarction, and current smoking. The area-under-the-curve (AUC) values for 1-year MACE-free survival were 0.790 (95% CI: 0.702-0.877) in the development cohort and 0.894 (95% CI: 0.820-0.967) in the external validation cohort. The AUCs for 2-year MACE-free survival were 0.802 (95% CI: 0.739-0.866) in the development cohort and 0.798 (95% CI: 0.693-0.902) in the external validation cohort. Development and validation were adequately calibrated and their predictions correlated with the observed outcome. Decision curve analysis (DCA) showed the model had good discriminative ability in predicting MACEs. Conclusion: Our validated nomogram was based on non-invasive ANS assessment and traditional risk factors, and indicated reliable prediction of MACEs in patients with ACS. This approach has potential for use as a method for non-invasive monitoring of health that enables provision of individualized treatment strategies.

Oral Supplementation With Butyrate Improves Myocardial Ischemia/Reperfusion Injury via a Gut-Brain Neural Circuit.

Objective: Butyrate, a short-chain fatty acid (SCFA) produced by the intestinal microbiota, plays a protective role in cardiovascular diseases (CVDs), but the mechanisms involved in this process remain unelucidated. We aimed to explore the effect of butyrate on myocardial ischemia/reperfusion (I/R) injury through the gut-brain neural circuit. Methods: Rats were randomly divided into four groups: sham group (sham), I/R group (I/R), I/R+ butyrate group (butyrate), and I/R+ butyrate+ vagotomy group (vagotomy). The rats were treated with sodium butyrate for 4 weeks, and the gut-brain neural circuit was investigated by subdiaphragmatic vagotomy. Results: Butyrate treatment significantly reduced the infarct size and decreased the expression of creatine kinase (CK), creatine kinase myocardial isoenzyme (CK-MB), and lactate dehydrogenase (LDH) compared with the values found for the I/R group. In addition, the I/R-induced increases in inflammation, oxidative stress, and apoptosis were attenuated by butyrate. However, the above-mentioned protective effects were diminished by subdiaphragmatic vagotomy. The RNA sequencing results also revealed that the butyrate-induced protective changes at the cardiac transcription level were reversed by vagotomy. An analysis of the heart rate variability (HRV) and the detection of norepinephrine (NE) showed that butyrate significantly inhibited the I/R-induced autonomic imbalance, but this inhibition was not observed in the vagotomy group. Butyrate treatment also suppressed the neural activity of the paraventricular nucleus (PVN) and superior cervical ganglion (SCG), and both of these effects were lost after vagotomy. Conclusions: Butyrate treatment significantly improves myocardial I/R injury via a gut-brain neural circuit, and this cardioprotective effect is likely mediated by suppression of the sympathetic nervous system.

The role of iron and myelin in orientation dependent R2* of white matter.

Brain myelin and iron content are important parameters in neurodegenerative diseases such as multiple sclerosis (MS). Both myelin and iron content influence the brain's R2* relaxation rate. However, their quantification based on R2* maps requires a realistic tissue model that can be fitted to the measured data. In structures with low myelin content, such as deep gray matter, R2* shows a linear increase with increasing iron content. In white matter, R2* is not only affected by iron and myelin but also by the orientation of the myelinated axons with respect to the external magnetic field. Here, we propose a numerical model which incorporates iron and myelin, as well as fibre orientation, to simulate R2* decay in white matter. Applying our model to fibre orientation-dependent in vivo R2* data, we are able to determine a unique solution of myelin and iron content in global white matter. We determine an averaged myelin volume fraction of 16.02 ± 2.07% in non-lesional white matter of patients with MS, 17.32 ± 2.20% in matched healthy controls, and 18.19 ± 2.98% in healthy siblings of patients with MS. Averaged iron content was 35.6 ± 8.9 mg/kg tissue in patients, 43.1 ± 8.3 mg/kg in controls, and 47.8 ± 8.2 mg/kg in siblings. All differences in iron content between groups were significant, while the difference in myelin content between MS patients and the siblings of MS patients was significant. In conclusion, we demonstrate that a model that combines myelin-induced orientation-dependent and iron-induced orientation-independent components is able to fit in vivo R2* data.

A narrative review of the success of intramuscular gluteal injections and its impact in psychiatry.

There are 12 billion injections given worldwide every year. For many injections, the intramuscular route is favoured over the subcutaneous route due to the increased vascularity of muscle tissue and the corresponding increase in the bioavailability of drugs when administered intramuscularly. This paper is a review of the variables that affect the success of intramuscular injections and the implications that these success rates have in psychiatry and general medicine. Studies have shown that the success rates of intended intramuscular injections vary between 32 and 52%, with the rest potentially resulting in inadvertent subcutaneous drug deposition. These rates are found to be even lower for certain at-risk populations, such as obese patients and those on antipsychotic medications. The variables associated with an increased risk of injection failure include female sex, obesity, site of injection, and subcutaneous fat depth. New guidelines and methods are needed in order to address this challenge and ensure that patients receive optimum care. Looking forward, the best way to improve the delivery of intramuscular injections worldwide is to develop uniform algorithms or innovative medical devices to confirm or guarantee successful delivery at the bedside.

The effect of realistic geometries on the susceptibility-weighted MR signal in white matter.

PURPOSE: To investigate the effect of realistic microstructural geometry on the susceptibility-weighted MR signal in white matter (WM), with application to demyelination. METHODS: Previous work has modeled susceptibility-weighted signals under the assumption that axons are cylindrical. In this study, we explored the implications of this assumption by considering the effect of more realistic geometries. A three-compartment WM model incorporating relevant properties based on the literature was used to predict the MR signal. Myelinated axons were modeled with several cross-sectional geometries of increasing realism: nested circles, warped/elliptical circles, and measured axonal geometries from electron micrographs. Signal simulations from the different microstructural geometries were compared with measured signals from a cuprizone mouse model with varying degrees of demyelination. RESULTS: Simulation results suggest that axonal geometry affects the MR signal. Predictions with realistic models were significantly different compared with circular models under the same microstructural tissue properties, for simulations with and without diffusion. CONCLUSION: The geometry of axons affects the MR signal significantly. Literature estimates of myelin susceptibility, which are based on fitting biophysical models to the MR signal, are likely to be biased by the assumed geometry, as will any derived microstructural properties. Magn Reson Med 79:489-500, 2018. © 2017 International Society for Magnetic Resonance in Medicine.

Domain-domain interactions in filamin A (16-23) impose a hierarchy of unfolding forces.

The quaternary structure of Filamin A (FLNa) 16-23 was recently shown to exhibit multiple domain-domain interactions that lead to a propeller-like construction. Here we present single-molecule force spectroscopy experiments to show a wide variety of mechanical responses of this molecule and compare it with its linear counterpart FLNa 1-8. The compact structure of FLNa 16-23 leads to a broad distribution of rupture forces and end-to-end lengths in the force-extension mode and multiple unraveling timescales in the force-clamp mode. Moreover, a subset of force-extension trajectories reveals a mechanical hierarchy in which the rupture of domain-domain interactions at high forces (>200 pN) liberates the unfolding of individual domains at low forces (∼100 pN). This mechanism may also explain the order-of-magnitude difference in the rates of the biexponential fits to the distribution of unfolding dwell times under force-clamp. Overall, FLNa 16-23 under a force of 100 pN is more compliant than the linear FLNa 1-8. Because a physiological role of FLNa is to crosslink actin filaments, this range of responses allows it to accommodate a broad spectrum of forces exerted by the cell and its environment.