Cerebrovascular Dysfunction in Atrial Fibrillation

© Copyright © 2020 Junejo, Lip and Fisher. It is now well established that besides being the most common sustained arrhythmia, atrial fibrillation (AF) is a major healthcare burden. Risk of debilitating stroke is increased in AF patients, but even in the absence of stroke, this population is at heightened risk of cognitive decline, depression, and dementia. The reasons for this are complex, multifactorial, and incompletely understood. One potential contributing mechanism is cerebrovascular dysfunction. Cerebral blood flow is regulated by chemical, metabolic, autoregulatory, neurogenic, and systemic factors. The dysfunction in one or more of these mechanisms may contribute to the elevated risk of cognitive decline and cerebrovascular events in AF. This short review presents the evidence for diminished cerebral blood flow, cerebrovascular carbon dioxide reactivity (i.e., cerebrovascular vasodilatory reserve), cerebral autoregulation, and neurovascular coupling in AF patients when compared to control participants in sinus rhythm. Further work is needed to understand the physiological mechanisms underpinning these observations and their clinical significance in atrial fibrillation patients

Exploring the active site of the Streptococcus pneumoniae topoisomerase IV-DNA cleavage complex with novel 7,8-bridged fluoroquinolones.

As part of a programme of synthesizing and investigating the biological properties of new fluoroquinolone antibacterials and their targeting of topoisomerase IV from Streptococcus pneumoniae, we have solved the X-ray structure of the complexes of two new 7,8-bridged fluoroquinolones (with restricted C7 group rotation favouring tight binding) in complex with the topoisomerase IV from S. pneumoniae and an 18-base-pair DNA binding site-the E-site-found by our DNA mapping studies to bind drug strongly in the presence of topoisomerase IV (Leo et al. 2005 J. Biol. Chem. 280, 14 252-14 263, doi:10.1074/jbc.M500156200). Although the degree of antibiotic resistance towards fluoroquinolones is much lower than that of β-lactams and a range of ribosome-bound antibiotics, there is a pressing need to increase the diversity of members of this successful clinically used class of drugs. The quinolone moiety of the new 7,8-bridged agents ACHN-245 and ACHN-454 binds similarly to that of clinafloxocin, levofloxacin, moxifloxacin and trovofloxacin but the cyclic scaffold offers the possibility of chemical modification to produce interactions with other topoisomerase residues at the active site

Light curves and spectra from a thermonuclear explosion of a white dwarf merger

This is the final version of the article. Available from the publisher via the DOI in this record.Double-degenerate (DD) mergers of carbon-oxygen white dwarfs have recently emerged as a leading candidate for normal Type Ia supernovae (SNe Ia). However, many outstanding questions surround DD mergers, including the characteristics of their light curves and spectra. We have recently identified a spiral instability in the post-merger phase of DD mergers and demonstrated that this instability self-consistently leads to detonation in some cases. We call this the spiral merger SN Ia model. Here, we utilize the SuperNu radiative transfer software to calculate three-dimensional synthetic light curves and spectra of the spiral merger simulation with a system mass of 2.1 from Kashyap et al. Because of their large system masses, both violent and spiral merger light curves are slowly declining. The spiral merger resembles very slowly declining SNe Ia, including SN 2001ay, and provides a more natural explanation for its observed properties than other SN Ia explosion models. Previous synthetic light curves and spectra of violent DD mergers demonstrate a strong dependence on viewing angle, which is in conflict with observations. Here, we demonstrate that the light curves and spectra of the spiral merger are less sensitive to the viewing angle than violent mergers, in closer agreement with observation. We find that the spatial distribution of 56Ni and IMEs follows a characteristic hourglass shape. We discuss the implications of the asymmetric distribution of 56Ni for the early-time gamma-ray observations of 56Ni from SN 2014J. We suggest that DD mergers that agree with the light curves and spectra of normal SNe Ia will likely require a lower system mass.This work is supported in part at the University of Chicago by the National Science Foundation under grants AST-0909132, PHY-0822648 (JINA, Joint Institute for Nuclear Astrophysics), and PHY–1430152 (JINA-CEE, Joint Institute for Nuclear Astrophysics). This work used the Extreme Science and Engineering Discovery Environment (XSEDE), which is supported by National Science Foundation grant number ACI-1053575. Simulations at UMass Dartmouth were performed on a computer cluster supported by NSF grant CNS-0959382 and AFOSR DURIP grant FA9550-10-1-0354. The work of E.G.-B., G.A.-S., and P. L.-A. was partially funded by the MINECO AYA2014-59084- P grant and by the AGAUR. This research has made use of NASA’s Astrophysics Data System and the yt astrophysics analysis software suit

Human cerebrovascular responses to diving are not related to facial cooling

© 2020 The Authors. Experimental Physiology © 2020 The Physiological Society New Findings: What is the central question of this study? Does facial cooling-mediated stimulation of cutaneous trigeminal afferents associated with the diving response increase cerebral blood flow or are factors associated with breath-holding (e.g. arterial carbon dioxide accumulation, pressor response) more important in humans? What is the main finding and its importance? Physiological factors associated with breath-holding such as arterial carbon dioxide accumulation and the pressor response, but not facial cooling (trigeminal nerve stimulation), make the predominant contribution to diving response-mediated increases in cerebral blood flow in humans. Abstract: Diving evokes a pattern of physiological responses purported to preserve oxygenated blood delivery to vital organs such as the brain. We sought to uncouple the effects of trigeminal nerve stimulation on cerebral blood flow (CBF) from other modifiers associated with the diving response, such as apnoea and changes in arterial carbon dioxide tension. Thirty-seven young healthy individuals participated in separate trials of facial cooling (FC, 3 min) and cold pressor test (CPT, 3 min) under poikilocapnic (Protocol 1) and isocapnic conditions (Protocol 2), facial cooling while either performing a breath-hold (FC +BH) or breathing spontaneously for a matched duration (FC −BH) (Protocol 3), and BH during facial cooling (BH +FC) or without facial cooling (BH −FC) (Protocol 4). Under poikilocapnic conditions neither facial cooling nor CPT evoked a change in middle cerebral artery blood flow velocity (MCA vmean; transcranial Doppler) (P > 0.05 vs. baseline). Under isocapnic conditions, facial cooling did not change MCA vmean (P > 0.05), whereas CPT increased MCA vmean by 13% (P  0.05). Finally, MCA vmean and ICAQ were similarly increased by BH either with or without facial cooling. These findings suggest that physiological factors associated with BH, and not facial cooling (i.e. trigeminal nerve stimulation) per se, make the predominant contribution to increases in CBF during diving in humans

Association between atrial high rate episode burden and autonomic and vascular function in patients with implanted cardiac device

Abstract Background Patients who experience frequent atrial high rate episodes (AHREs), recorded on implantable cardiac devices, are at an increased risk of stroke and systemic embolism. Increased duration of AHRE is related to higher risk of thromboembolic event. The underlying pathophysiology is unclear; however, autonomic and/or endothelial dysfunction may contribute. Purpose We tested the hypothesis that patients with high AHRE burden have worse autonomic and vascular function compared to patients with low AHRE burden. Design We studied 44 patients split in two groups: high AHRE burden (longest AHRE ≥24 hours; n=22) and low AHRE burden (longest AHRE &amp;lt;24 hours; n=22). Resting time- and frequency-domain measures of HRV were determined to index cardiac autonomic function. High-resolution ultrasound was used to measure brachial artery diameter at rest and during reactive hyperaemia (endothelium-dependent flow mediated dilation (FMD)). Results FMD was higher in the low AHRE burden group compared to high AHRE group (5.5% [95% confidence interval (CI):3.4–7.6] vs 3.1% [95% CI: 1.9–6.2]; p=0.04) (table 1). Mean heart rate (p&amp;lt;0.001) and AHRE burden (p=0.02) were independent predictors of FMD on multivariate analysis. Time-domain, frequency-domain and non-linear indices of HRV were not significantly different between the groups. A slower heart rate (Spearman's rho 0.369; p=0.01) and high AHRE burden (Spearman's rho −0.315; p=0.04) were independently associated with changes seen on FMD following adjustment for multiple variables (p=0.001 and p=0.03 respectively). Conclusion Endothelium-dependent FMD is impaired in patients with high AHRE burden, while HRV derived indices of autonomic function were not affected by AHRE burden. Endothelial dysfunction may play an important role in the adverse outcomes seen in patients who experience frequent AHRE. Funding Acknowledgement Type of funding sources: None. </jats:sec

Cerebrovascular carbon dioxide reactivity and flow-mediated dilation in young healthy South Asian and Caucasian European men

Copyright © 2020 the American Physiological Society South Asians living in the United Kingdom have a 1.5-fold greater risk of ischemic stroke than the general population. Impaired cerebrovascular carbon dioxide (CO2) reactivity is an independent predictor of ischemic stroke and cardiovascular mortality. We sought to test the hypothesis that cerebrovascular CO2 reactivity is reduced in South Asians. Middle cerebral artery blood velocity (MCA Vm) was measured at rest and during stepwise changes in end-tidal partial pressure of CO2 (PETCO2) in South Asian (n = 16) and Caucasian European (n = 18) men who were young (~20 yr), healthy, and living in the United Kingdom. Incremental hypercapnia was delivered via the open-circuit steady-state method, with stages of 4 and 7% CO2 (~21% oxygen, nitrogen balanced). Cerebrovascular CO2 reactivity was calculated as the change in MCA Vm relative to the change in PETCO2. MCA Vm was not different in South Asians [59 (9) cm/s, mean (standard deviation)] and Caucasian Europeans [61 (12) cm/s; P > 0.05]. Similarly, cerebrovascular CO2 reactivity was not different between the groups [South Asian 2.53 (0.76) vs. Caucasian European 2.61 (0.81) cm·s-1·mmHg-1; P > 0.05]. Brachial artery flow-mediated dilation was lower in South Asians [5.48 (2.94)%] compared with Caucasian Europeans [7.41 (2.28)%; P 0.05). Flow-mediated dilation was not correlated with cerebrovascular CO2 reactivity measures. In summary, cerebrovascular CO2 reactivity and flow-mediated dilation corrected for shear rate are preserved in young healthy South Asian men living in the United Kingdom. NEW & NOTEWORTHY Previous reports have identified an increased risk of ischemic stroke and peripheral endothelial dysfunction in South Asians compared with Caucasian Europeans. The main finding of this study is that cerebrovascular carbon dioxide reactivity (an independent predictor of ischemic stroke) is not different in healthy young South Asian and Caucasian European men

A greater burden of atrial fibrillation is associated with worse endothelial dysfunction in hypertension

© 2020, The Author(s), under exclusive licence to Springer Nature Limited. Atrial fibrillation (AF) and hypertension often co-exist and both are associated with endothelial dysfunction. We hypothesised that AF would further worsen endothelium-dependent flow-mediated dilatation (FMD) in hypertension patients compared to those without AF. In a cross-sectional comparison, we measured brachial artery diameter at rest and during reactive hyperaemia following 5 min of arterial occlusion in two patient groups: AF (and hypertension) (n = 61) and hypertension control groups (n = 33). The AF (and hypertension) subgroups: permanent AF (n = 30) and paroxysmal AF (n = 31) were also assessed. The permanent AF patients received heart rate and blood pressure (BP) control optimisation and were then followed up after eight weeks for repeat FMD testing. There was no significant difference in FMD between AF (and hypertension) group and hypertension control group (4.6%, 95% CI [2.6–5.9%] vs 2.6%, 95% CI [1.9–5.3%]; p = 0.25). There was a significant difference in FMD between permanent AF and paroxysmal AF groups (3.1%, 95% CI [2.3–4.8%] vs 5.9%, 95% CI [4.0–8.1%]; p = 0.02). Endothelium-dependent FMD response showed a non-significant improvement trend following eight weeks of heart rate and BP optimisation (3.1%, 95% CI [2.3–4.8%] (baseline) vs 5.2%, 95% CI [3.9–6.5%] (follow up), p = 0.09). Presence of AF generally does not incrementally worsen endothelial dysfunction in hypertension patients, although the duration and frequency of AF (paroxysmal AF to permanent AF) does lead to worsening endothelial function. Eight weeks of BP optimisation did not significantly improve endothelial dysfunction as measured by FMD