Autoregulatory Function Research Articles

Copper sensing transcription factor ArsR2 regulates VjbR to sustain virulence in Brucella abortus

ABSTRACT Brucellosis, caused by the intracellular pathogen Brucella, is a major zoonotic infection that promotes reproductive disease in domestic animals and chronic debilitating conditions in humans. The ArsR family of transcriptional regulators plays key roles in diverse cellular processes, including metal ion homeostasis, responding to adverse conditions, and virulence. However, little is known about the function of ArsR family members in Brucella. Here, we identified ArsR2 as a nonclassical member of the family that lacks autoregulatory function, but which nevertheless plays a vital role in maintaining copper homeostasis in B. abortus. ArsR2 is a global regulator of 241 genes, including those involved in the VirB type IV secretion system (T4SS). Significantly, ArsR2 regulates T4SS production in B. abortus by targeting VjbR which encodes a LuxR-type family transcriptional regulator. Moreover, copper modulates transcriptional activity of ArsR2, but not of VjbR. Furthermore, deletion of arsR2 attenuated virulence in a mouse model. Collectively, these findings enhance understanding of the mechanism by which ArsR proteins regulate virulence gene expression in pathogenic Brucella species.

An autoregulatory poison exon in Smndc1 is conserved across kingdoms and influences organism growth.

Many of the most highly conserved elements in the human genome are "poison exons," alternatively spliced exons that contain premature termination codons and permit post-transcriptional regulation of mRNA abundance through induction of nonsense-mediated mRNA decay (NMD). Poison exons are widely assumed to be highly conserved due to their presumed importance for organismal fitness, but this functional importance has never been tested in the context of a whole organism. Here, we report that a poison exon in Smndc1 is conserved across mammals and plants and plays a molecular autoregulatory function in both kingdoms. We generated mouse and A. thaliana models lacking this poison exon to find its loss leads to deregulation of SMNDC1 protein levels, pervasive alterations in mRNA processing, and organismal size restriction. Together, these models demonstrate the importance of poison exons for both molecular and organismal phenotypes that likely explain their extraordinary conservation.

Optimal cerebral perfusion pressure in aneurysmal subarachnoid hemorrhage and its relation to perfusion deficits on CT-perfusion.

Preservation of optimal cerebral perfusion is a crucial part of the acute management after aneurysmal subarachnoid hemorrhage (aSAH). A few studies indicated possible benefits of maintaining a cerebral perfusion pressure (CPP) near the calculated optimal CPP (CPPopt), representing an individually optimal condition at which cerebral autoregulation functions at its best. This retrospective observational monocenter study was conducted to investigate, whether "suboptimal" perfusion with actual CPP deviating from CPPopt correlates with perfusion deficits detected by CT-perfusion (CTP). A consecutive cohort of aSAH-patients was reviewed and patients with available parameters for CPPopt-calculation, who simultaneously received CTP, were analyzed. By plotting the pressure reactivity index (PRx) versus CPP, CPP correlating the lowest PRx value was identified as CPPopt. Perfusion deficits on CTP were documented. In 86 out of 324 patients, the inclusion criteria were met. Perfusion deficits were detected in 47% (40/86) of patients. In 43% of patients, CPP was lower than CPPopt, which correlated with detected perfusion deficits (r = 0.23, p = 0.03). Perfusion deficits were found in 62% of patients with CPP<CPPopt compared to 34% in patients without deviation or CPP>CPPopt (OR 3, p = 0.01). These findings support the hypothesis, that a deviation of CPP from CPPopt is an indicator of suboptimal cerebral perfusion.

Resting-state MRI reveals spontaneous physiological fluctuations in the kidney and tracks diabetic nephropathy in rats.

The kidneys maintain fluid-electrolyte balance and excrete waste in the presence of constant fluctuations in plasma volume and systemic blood pressure. The kidneys perform these functions to control capillary perfusion and glomerular filtration by modulating the mechanisms of autoregulation. An effect of these modulations are spontaneous, natural fluctuations in glomerular perfusion. Numerous other mechanisms can lead to fluctuations in perfusion and flow. The ability to monitor these spontaneous physiological fluctuations in vivo could facilitate the early detection of kidney disease. The goal of this work was to investigate the use of resting-state magnetic resonance imaging (rsMRI) to detect spontaneous physiological fluctuations in the kidney. We performed rsMRI of rat kidneys in vivo over 10 min, applying motion correction to resolve time series in each voxel. We observed spatially variable, spontaneous fluctuations in rsMRI signal between 0 and 0.3 Hz, in frequency bands associated with autoregulatory mechanisms. We further applied rsMRI to investigate changes in these fluctuations in a rat model of diabetic nephropathy. Spectral analysis was performed on time series of rsMRI signals in the kidney cortex and medulla. The power from spectra in specific frequency bands from the cortex correlated with severity of glomerular pathology caused by diabetic nephropathy. Finally, we investigated the feasibility of using rsMRI of the human kidney in two participants, observing the presence of similar, spatially variable fluctuations. This approach may enable a range of preclinical and clinical investigations of kidney function and facilitate the development of new therapies to improve outcomes in patients with kidney disease.NEW & NOTEWORTHY This work demonstrates the development and use of resting-state MRI to detect low-frequency, spontaneous physiological fluctuations in the kidney consistent with previously observed fluctuations in perfusion and potentially due to autoregulatory function. These fluctuations are detectable in rat and human kidneys, and the power of these fluctuations is affected by diabetic nephropathy in rats.

Abstract WP152: Association Between Cerebrospinal Fluid Interleukin-6 Levels and Cerebral Autoregulation After Aneurysmal Subarachnoid Hemorrhage

Introduction: Elevated levels of Interleukin-6 (IL-6) levels in cerebrospinal fluid (CSF) have been correlated with delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH). However, the role of neuroinflammation in SAH pathophysiology remains incompletely understood. In a pig stroke model, IL-6 antagonist prevented hypotension-induced pial artery impairment, suggesting a role in post-stroke vascular derangement. This research assesses serial CSF IL-6 levels' relationship with cerebral autoregulation in aSAH patients. Methods: We prospectively enrolled aSAH patients at Yale-New Haven Hospital. Autoregulatory function was measured by interrogating changes in near-infrared spectroscopy-derived tissue oxygenation response to changes in mean arterial pressure (MAP). The resulting autoregulatory index was used to trend the MAP range at which autoregulation was most preserved. Percent time that MAP exceeded the upper limit of autoregulation or decreased below the lower limit of autoregulation was calculated for each patient. IL-6 levels were assessed through serial CSF samples and correlated with hemodynamic parameters. Results: We calculated limits of autoregulation for twenty-two patients (mean age 60 ± 9 years, mean Hunt Hess score 3.4 ± 1.2, mean modified Fisher score 3.7 ± 0.58, average monitoring time 10.1 ± 7.3 hours). Optimal MAP and limits were calculated an average of 74% ± 20% of monitoring time. Our study provides preliminary support for a potential association between IL-6 levels and percent time that MAP was within limits of autoregulation (b = -0.31, p=0.009, Fig. 1A). Additionally, there was a significant correlation between IL-6 levels and the extent to which MAP deviated from computed optimal MAP (r= 0.636, p=0.009, Fig. 1B). Conclusions: IL-6 may contribute to impaired autoregulation post aSAH. Further studies are needed to validate findings and refine MAP management for improved outcomes in aSAH patients.

Abstract 51: Impact of Cerebral Autoregulation on the Relationship Between Blood Pressure Variability and Functional Outcome Following Endovascular Thrombectomy

Background: Both increased blood pressure (BP) variability and impaired autoregulation have been linked to worse outcome after endovascular thrombectomy (EVT). This study examined the combined effect of these variables on the risk of poor outcome in patients with large-vessel occlusion (LVO) stroke. Methods: Autoregulation was continuously measured for up to 24 hours after EVT and quantified as a moving correlation coefficient between arterial BP and the near-infrared spectroscopy-derived cerebral oxygen saturation. Systolic BP variability was assessed using the standard deviation of the mean. Values were averaged for the entire recording period and dichotomized at the lowest tertile for both variables. Functional outcome was assessed using the modified Rankin scale (mRS) at 90 days and dichotomized into good (mRS 0-2) and poor outcome (mRS 3-6). Results: We included 195 patients (mean age 70 + 16, 45% female, mean NIHSS 14, mean monitoring time 15 + 7 hours). After adjusting for age, NIHSS, ASPECTS, and TICI score, patients with low BP variability and intact autoregulation were significantly more likely to achieve a good outcome than those with high BP variability and impaired autoregulation (OR 3.7, 95% CI 1.2-12.1, p=0.028, Figure 1A). We found an interaction between BP variability and autoregulation (p=0.067). Patients with high BP variability showed a gradual decrease in the probability of a good outcome with worsening autoregulation. However, for patients with low BPV, autoregulation had minimal impact. (Figure 1B). No significant correlation was seen between autoregulatory function and BP variability (r=0.07, p=0.33). Conclusions: For LVO stroke patients with high BP variability after EVT, worse 90-day functional outcome may be exacerbated by impaired autoregulation. These results suggest that autoregulatory status should be considered in the management of BP after EVT to identify high-risk patients and develop individualized treatment strategies.

Dysautonomia and activity in the early stroke recovery period.

Maintaining cerebral perfusion in the early stages of recovery after stroke is paramount. Autoregulatory function may be impaired during this period leaving cerebral perfusion directly reliant on intravascular volume and blood pressure (BP) with increased risk for expanding cerebral infarction during periods of low BP and hemorrhagic transformation during BP elevations. We suspected that dysautonomia is common during the acute period related to both pre-existing vascular risk factors and potentially independent of such conditions. Thus, we sought to understand the state of the science specific to dysautonomia and acute stroke. The scoping review search included multiple databases and key terms related to acute stroke and dysautonomia. The team employed a rigorous review process to identify, evaluate, and summarize relevant literature. We additionally summarized common clinical approaches used to detect dysautonomia at the bedside. The purpose of this scoping review is to understand the state of the science for the identification, treatment, and impact of dysautonomia on acute stroke patient outcomes. There is a high prevalence of dysautonomia among persons with stroke, though there is significant variability in the type of measures and definitions used to diagnose dysautonomia. While dysautonomia appears to be associated with poor functional outcome and post-stroke complications, there is a paucity of high-quality evidence, and generalizability is limited by heterogenous approaches to these studies. There is a need to establish common definitions, standard measurement tools, and a roadmap for incorporating these measures into clinical practice so that larger studies can be conducted.

Switchable tetraplex elements in the heterogeneous nuclear ribonucleoprotein K promoter: micro-environment dictated structural transitions of G/C rich elements

We have elucidated the hnRNP K promoter as a hotspot for tetraplex-based molecular switches receptive to micro-environmental stimuli. We have characterised the structural features of four tetraplex-forming loci and identified them as binding sites of transcription factors. These segments form either G-quadruplex or i-motif structures, the structural dynamicity of which has been studied in depth via several biophysical techniques. The tetraplexes display high dynamicity and are influenced by both pH and KCl concentrations in vitro. The loci complementary to these sequences form additional non-canonical secondary structures. In the cellular context, the most eminent observation of this study is the binding of hnRNP K to the i-motif forming sequences in its own promoter. We are the first to report a probable transcriptional autoregulatory function of hnRNP K in coordination with higher-order DNA structures. Herein, we also report the positive interaction of the endogenous tetraplexes with Sp1, a well-known transcriptional regulator. Treatment with tetraplex-specific small molecule ligands further uncovered G-quadruplexes’ functioning as repressors and i-motifs as activators in this context. Together, our findings strongly indicate the critical regulatory role of the identified tetraplex elements in the hnRNP K promoter. Communicated by Ramaswamy H. Sarma

Modeling the interaction between tubuloglomerular feedback and myogenic mechanisms in the control of glomerular mechanics.

Introduction: Mechanical stresses and strains exerted on the glomerular cells have emerged as potentially influential factors in the progression of glomerular disease. Renal autoregulation, the feedback process by which the afferent arteriole changes in diameter in response to changes in blood pressure, is assumed to control glomerular mechanical stresses exerted on the glomerular capillaries. However, it is unclear how the two major mechanisms of renal autoregulation, the afferent arteriole myogenic mechanism and tubuloglomerular feedback (TGF), each contribute to the maintenance of glomerular mechanical homeostasis. Methods: In this study, we made a mathematical model of renal autoregulation and combined this model with an anatomically accurate model of glomerular blood flow and filtration, developed previously by us. We parameterized the renal autoregulation model based on data from previous literature, and we found evidence for an increased myogenic mechanism sensitivity when TGF is operant, as has been reported previously. We examined the mechanical effects of each autoregulatory mechanism (the myogenic, TGF and modified myogenic) by simulating blood flow through the glomerular capillary network with and without each mechanism operant. Results: Our model results indicate that the myogenic mechanism plays a central role in maintaining glomerular mechanical homeostasis, by providing the most protection to the glomerular capillaries. However, at higher perfusion pressures, the modulation of the myogenic mechanism sensitivity by TGF is crucial for the maintenance of glomerular mechanical homeostasis. Overall, a loss of renal autoregulation increases mechanical strain by up to twofold in the capillaries branching off the afferent arteriole. This further corroborates our previous simulation studies, that have identified glomerular capillaries nearest to the afferent arteriole as the most prone to mechanical injury in cases of disturbed glomerular hemodynamics. Discussion: Renal autoregulation is a complex process by which multiple feedback mechanisms interact to control blood flow and filtration in the glomerulus. Importantly, our study indicates that another function of renal autoregulation is control of the mechanical stresses on the glomerular cells, which indicates that loss or inhibition of renal autoregulation may have a mechanical effect that may contribute to glomerular injury in diseases such as hypertension or diabetes. This study highlights the utility of mathematical models in integrating data from previous experimental studies, estimating variables that are difficult to measure experimentally (i.e. mechanical stresses in microvascular networks) and testing hypotheses that are historically difficult or impossible to measure.

Impact of Therapeutic Interventions on Cerebral Autoregulatory Function Following Severe Traumatic Brain Injury: A Secondary Analysis of the BOOST-II Study.

The Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase II randomized controlled trial used a tier-based management protocol based on brain tissue oxygen (PbtO2) and intracranial pressure (ICP) monitoring to reduce brain tissue hypoxia after severe traumatic brain injury. We performed a secondary analysis to explore the relationship between brain tissue hypoxia, blood pressure (BP), and interventions to improve cerebral perfusion pressure (CPP). We hypothesized that BP management below the lower limit of autoregulation would lead to cerebral hypoperfusion and brain tissue hypoxia that could be improved with hemodynamic augmentation. Of the 119 patients enrolled in the Brain Oxygen Optimization in Severe Traumatic Brain Injury Phase II trial, 55 patients had simultaneous recordings of arterial BP, ICP, and PbtO2. Autoregulatory function was measured by interrogating changes in ICP and PbtO2 in response to fluctuations in CPP using time-correlation analysis. The resulting autoregulatory indices (pressure reactivity index and oxygen reactivity index) were used to identify the "optimal" CPP and limits of autoregulation for each patient. Autoregulatory function and percent time with CPP outside personalized limits of autoregulation were calculated before, during, and after all interventions directed to optimize CPP. Individualized limits of autoregulation were computed in 55 patients (mean age 38years, mean monitoring time 92h). We identified 35 episodes of brain tissue hypoxia (PbtO2 < 20mm Hg) treated with CPP augmentation. Following each intervention, mean CPP increased from 73 ± 14mm Hg to 79 ± 17mm Hg (p = 0.15), and mean PbtO2 improved from 18.4 ± 5.6mm Hg to 21.9 ± 5.6mm Hg (p = 0.01), whereas autoregulatory function trended toward improvement (oxygen reactivity index 0.42 vs. 0.37, p = 0.14; pressure reactivity index 0.25 vs. 0.21, p = 0.2). Although optimal CPP and limits remained relatively unchanged, there was a significant decrease in the percent time with CPP below the lower limit of autoregulation in the 60min after compared with before an intervention (11% vs. 23%, p = 0.05). Our analysis suggests that brain tissue hypoxia is associated with cerebral hypoperfusion characterized by increased time with CPP below the lower limit of autoregulation. Interventions to increase CPP appear to improve autoregulation. Further studies are needed to validate the importance of autoregulation as a modifiable variable with the potential to improve outcomes.

Blood pressure-cerebral oxygen coupling model: A new approach for stroke risk prediction.

Stroke is a major cause of death and disability worldwide, but predicting its risk remains challenging. This study aimed to evaluate the cerebral blood flow autoregulation function of subjects with different stroke risk levels and predict their stroke risk. The coupling strength between cerebral oxygen and blood pressure signals was calculated by wavelet analysis and dynamic Bayesian inference and used as a quantitative index of cerebral blood flow autoregulation. A stroke prediction model based on the extreme random tree was constructed using the coupling strength and other data as input features. The results showed that the coupling strength was significantly higher in the high-risk group than the other groups. Moreover, the prediction model achieved an average accuracy of 0.80 across the three groups. The coupling strength of cerebral oxygen and blood pressure can be used as an objective index to predict stroke risk, which has implications for stroke prevention and intervention.

Abstract 020: Undulating Flow Velocities as an Induced Test of Autoregulation After Thrombectomy for Acute Ischemic Stroke

Introduction Loss of autoregulation after endovascular therapy (EVT) for large‐artery acute ischemic stroke (AIS) is well documented. [1] This might result in worse outcomes, despite successful recanalization, from hyper‐ or hypoperfusion with a risk for hemorrhagic conversion or larger stroke volume, respectively. Transcranial doppler (TCD) was previously used to document this phenomenon using spontaneous fluctuations in reactivity. Herein, we present a patient with suspected obstructive sleep apnea (OSA) with undulating flow velocities on TCD, serving as a test for induced vasoreactivity with pre‐ and post‐EVT TCD. Methods A case‐report. Results A middle‐aged patient was admitted with acute left cerebellar stroke (figure 1A). An Embolic etiology was suspected and a 20‐minuteTCD was done for spontaneous emboli detection on bilateral middle cerebral arteries (MCA). The patient fell asleep during the study and it incidentally revealed a bilaterally symmetric undulating velocity, which is a pattern that was previously described with OSA as a result of vasomotor response to multiple apnea and hypopnea episodes occurring in succession (Figure 1D – Pre‐EVT). [2] This pattern indicates intact vasomotor reactivity to fluctuating O2 and CO2 levels during episodes of apnea. Six days later, the patient developed acute right MCA stroke (Figure 1B) and was treated with EVT with successful reperfusion (TICI 2B67) (Figure 1C). TCD was repeated after EVT, and the previously seen undulating pattern was lost with significantly reduced variability on the right MCA compared to the contralateral side (figure 1E – Post‐EVT). This indicates a significant reduction in vasomotor reactivity and autoregulatory capacity of the right MCA. Follow up imaging revealed hemorrhagic conversion in the bed of the stroke with intraparenchymal bleeding (PH1) (Figures 1F‐H). This case is unique since it provides an induced test of autoregulation and compares pre‐ and post‐EVT autoregulatory function. Prior reports did not use any stressors to test for autoregulation. While in this case, apnea served as a natural test for autoregulation allowing for easier detection. This can serve as a future marker that can be easily quantified and might guide post‐EVT care. Using breath holding maneuvers or medication (e.g., Acetazolamide) might be considered in the future to quantify the autoregulatory response. Further studies are required to investigate the utility of induced, instead of spontaneous, autoregulation assessment post‐EVT to guide blood pressure goals and the duration of strict blood pressure control after endovascular intervention. Conclusion Induced tests for autoregulation using TCD might be feasible and should be considered in the future as an easy method for quantifying autoregulation post‐EVT. Further studies are required to clarify the utility of this biomarker in guiding post‐EVT care.

Closely-Spaced Repetitions of CAMTA Trans-Factor Binding Sites in Promoters of Model Plant MEP Pathway Genes

Previous research has demonstrated the presence of two closely spaced repetitions of the rapid stress-responsive cis-active element RSRE (G/A/C)CGCG(C/G/T) in the 5′UTR of S. miltiorrhiza2C-methyl-D-erithrytol 2,4-cyclodiphosphate synthase (MECPS) gene. The product of MECPS activity, represented by 2C-methyl-D-erithrytol 2,4-cyclodiphosphate (MECPD), indicates its retrograde regulatory role and activates CAMTA trans-factors. Since the complete activation of CAMTA trans-factors requires the cooperative interaction of CAMTA3 with CAMTA2 or CAMTA4, the closely spaced RSREs recognized by CAMTA trans-factors could be used to promote CAMTA trans-factor dimerization. The present study aims to evaluate if the occurrence of these two closely spaced RSREs in the 5′UTR is specific to S. miltiorrhiza or could be observed in other MECPS genes. An analysis of nineteen MECPS gene sequences from seven selected model plants indicated the closely spaced repetition of RSREs in the 5′UTR region of two maize (Zea mays) MECPS genes, Zm00001d051458 and Zm00001d017608. This observation suggests the potential autoregulatory function of MECPD in relation to the MECPS transcription rate. Moreover, an analysis of eighty-five promoter regions of other plastidial methyl-D-erythritol phosphate (MEP) pathway genes indicated such closely spaced RSREs in the proximal promoter of Zea mays2-C-methyl-D-erythritol 4-phosphate cytidylyltransferase (CMS) (Zm00001d012197) and Oryza sativa4-hydroxy-3-methylbut-2-enyl diphosphate reductase (HDR) (Os03t0732000-00).

Assessment of cerebral autoregulatory function and inter-hemispheric blood flow in older adults with internal carotid artery stenosis using transcranial Doppler sonography-based measurement of transient hyperemic response after carotid artery compression

Unhealthy vascular aging promotes atherogenesis, which may lead to significant internal carotid artery stenosis (CAS) in 5 to 7.5% of older adults. The pathogenic factors that promote accelerated vascular aging and CAS also affect the downstream portion of the cerebral microcirculation in these patients. Primary treatments of significant CAS are eversion endarterectomy or endarterectomy with patch plasty. Factors that determine adequate hemodynamic compensation and thereby the clinical consequences of CAS as well as medical and surgical complications of carotid reconstruction surgery likely involve the anatomy of the circle of Willis (CoW), the magnitude of compensatory inter-hemispheric blood flow, and the effectiveness of cerebral microcirculatory blood flow autoregulation. This study aimed to test two hypotheses based on this theory. First, we hypothesized that patients with symptomatic and asymptomatic CAS would exhibit differences in autoregulatory function and inter-hemispheric blood flow. Second, we predicted that anatomically compromised CoW would associate with impaired inter-hemispheric blood flow compensation. We enrolled older adults with symptomatic or asymptomatic internal CAS (>70% NASCET criteria; n = 46) and assessed CoW integrity by CT angiography. We evaluated transient hyperemic responses in the middle cerebral arteries (MCA) after common carotid artery compression (CCC; 10 s) by transcranial Doppler sonography (TCD). We compared parameters reflecting autoregulatory function (e.g., transient hyperemic response ratio [THRR], return to baseline time [RTB], changes of vascular resistance) and inter-hemispheric blood flow (residual blood flow velocity). Our findings revealed that CAS was associated with impaired cerebral vascular reactivity. However, we did not observe significant differences in autoregulatory function or inter-hemispheric blood flow between patients with symptomatic and asymptomatic CAS. Moreover, anatomically compromised CoW did not significantly affect these parameters. Notably, we observed an inverse correlation between RTB and THRR, and 49% of CAS patients exhibited a delayed THRR, which associated with decreased inter-hemispheric blood flow. Future studies should investigate how TCD-based evaluation of autoregulatory function and inter-hemispheric blood flow can be used to optimize surgical techniques and patient selection for internal carotid artery revascularization.

Comparison of Near-Infrared Spectroscopy-Based Cerebral Autoregulatory Indices in Extremely Low Birth Weight Infants.

Premature infants are born with immature cerebral autoregulation function and are vulnerable to pressure passive cerebral circulation and subsequent brain injury. Measurements derived from near-infrared spectroscopy (NIRS) have enabled continuous assessment of cerebral vasoreactivity. Although NIRS has enabled a growing field of research, the lack of clear standardization in the field remains problematic. A major limitation of current literature is the absence of a comparative analysis of the different methodologies. To determine the relationship between NIRS-derived continuous indices of cerebral autoregulation in a cohort of extremely low birth weight (ELBW) infants. Premature infants of birth weight 401-1000 g were studied during the first 72 h of life. The cerebral oximetry index (COx), hemoglobin volume index (HVx), and tissue oxygenation heart rate reactivity index (TOHRx) were simultaneously calculated. The relationship between each of the indices was assessed with Pearson correlation. Fifty-eight infants with a median gestational age of 25.8 weeks and a median birth weight of 738 g were included. Intraventricular hemorrhage (IVH) was detected in 33% of individuals. COx and HVx demonstrated the highest degree of correlation, although the relationship was moderate at best (r = 0.543, p < 0.001). No correlation was found either between COx and TOHRx (r = 0.318, p < 0.015) or between HVx and TOHRx (r = 0.287, p < 0.029). No significant differences in these relationships were found with respect to IVH and no IVH in subgroup analysis. COx, HVx, and TOHRx are not numerically equivalent. Caution must be applied when interpreting or comparing results based on different methodologies for measuring cerebral autoregulation. Uniformity regarding data acquisition and analytical methodology are needed to firmly establish a gold standard for neonatal cerebral autoregulation monitoring.

Coronary microvascular dysfunction in heart failure patients.

Coronary microcirculation has multiple layers of autoregulatory function to maintain resting flow and augment hyperemic flow in response to myocardial demands. Functional or structural alterations in the coronary microvascular function are frequently observed in patients with heart failure with preserved or reduced ejection fraction, which may lead to myocardial ischemic injury and resultant worsening of clinical outcomes. In this review, we describe our current understanding of coronary microvascular dysfunction in the pathogenesis of heart failure with preserved and reduced ejection fraction.

Aortic stiffness and impairments in cerebrovascular function in cancer survivorship

An established consequence of anti-cancer treatment is increased aortic stiffness, which impairs the aortic damping of cardiac-generated pulsatile pressure and blood flow. These increased pulsations may result in vascular injury in the microcirculation of target end organs like the brain. The aim of the present study was to determine the ramifications of elevated aortic stiffness on cerebral macro- and microvascular pulsatility and autoregulatory function in cancer survivors. We hypothesized that cerebrovascular pulsatility would be enhanced, and cerebrovascular reactivity (CVR) to elevations in arterial CO 2 would be impaired, both in the large and small cerebral vessels in patients with a history of cancer and anti-cancer treatment versus healthy age- and sex-matched non-cancer controls. Aortic arch pulse wave velocity (aaPWV), a regional measure of stiffness in the proximal aorta, was calculated from echocardiographic views of the aortic valve and the descending aortic arch. Subjects then breathed room air for 60s followed by ~2 minutes of rebreathing with simultaneous collection of end-tidal pressure of CO 2 (P ET CO 2 ). Middle cerebral artery blood flow velocity (MCAv) was assessed using transcranial doppler. Oxygenated (oxy-[Hb]) and deoxygenated (deoxy-[Hb]) cerebral microvascular hemoglobin concentrations were monitored using two near-infrared spectroscopy probes placed over the prefrontal cortices. Pulsatility was assessed at baseline using Gosling’s Pulsatility Index (PI) for both the microvasculature and MCA. To account for changes in perfusion pressure, MAP was collected via finger plethysmography and cerebrovascular conductance indices were calculated for both oxy-[Hb] (CVCi oxy ) and MCAv (CVCi MCA ). CVR was calculated as the slope of CVCi oxy and CVCi MCA over P ET CO 2 during rebreathing. Six women were recruited (n = 3/group). Age was similar between the healthy non-cancer controls (HC) and patients with a history of cancer and anti-cancer treatment (CS) (31.0 ± 7 vs. 32.7 ± 13 years). Baseline ventilatory (P ET CO 2 ), central and cerebral hemodynamics were also similar (all p &gt; 0.05). aaPWV was significantly elevated in CS compared to HC (5.3 ± 0.6 vs. 3.1 ± 1.1 m/s, p = 0.04). Cerebral microcirculation PI in CS was significantly elevated (0.04 ± 0.01 vs. 0.02 ± 0.01, p = 0.02), but MCA PI was not different (p &gt; 0.05). CVR-CVCi oxy was impaired in CS (-3.6 ± 2.8 vs. 1.5 ± 0.5 nM·mmHg -1 /mmHg, p = 0.03), and CVR-CVCi MCA was similarly reduced (-0.05 ± 0.06 vs. 0.15 ± 0.01 mm/sec·mmHg -1 /mmHg, p &lt; 0.01). The increase in MAP during hypercapnia was similar between groups. Consistent with our hypothesis, both CVR-CVCi oxy and CVR-CVCi MCA were attenuated in patients with a history of anti-cancer treatment. Additionally, the microvascular pulsatility was greater in CS. This suggests an impaired cerebrovascular function, possibly related to increased transmission of pulsatility into the brain, in the years following cancer diagnoses and treatment. This is the full abstract presented at the American Physiology Summit 2023 meeting and is only available in HTML format. There are no additional versions or additional content available for this abstract. Physiology was not involved in the peer review process.

Abstract 9: Autoregulation-based Blood Pressure Targets After Endovascular Thrombectomy

Background: Optimal level blood pressure (BP) targets in acute stroke remain elusive. Tailored hemodynamic management after endovascular thrombectomy (EVT) may reduce the risk of reperfusion injury and promote penumbral recovery. Our study aimed to evaluate the relationship between personalized autoregulation-based BP targets, secondary brain injury, and functional outcomes. Methods: We prospectively enrolled 200 patients with acute ischemic stroke who underwent EVT. Autoregulatory function was continuously measured for &gt;=24 hours using simultaneous recordings of near-infrared spectroscopy and mean arterial pressure (MAP). The resulting autoregulatory index was used to calculate and trend the BP range at which autoregulation was most preserved. Percent time and “dose” that MAP exceeded the upper limit or dropped below the lower limit of autoregulation (ULA, LLA) were calculated for each patient. Hemodynamic parameters were correlated with short-term clinical endpoints (symptomatic ICH), biomarkers of secondary brain injury (net water uptake, hemorrhagic transformation (HT), infarct progression), and 90-day functional outcomes. Results: Personalized BP targets were successfully computed in 195 patients (mean age 70 ± 16, 45% female, mean NIHSS 14, mean monitoring time 31 ± 28 hours). Time above the ULA was associated with worse functional outcomes at 90-days after adjusting for age, sex, NIHSS, ASPECTS and TICI (adjusted OR per 10% increase 1.4, 95% CI 1.1-1.6, P=0.004). The burden of hyperperfusion was significantly greater among patients with HT (median 2.7 vs. 3.2 mmHg*min, p=0.01) and sICH (median 2.8 vs. 4.8 mmHg*min, p=0.05) than in those without it. Furthermore, time spent above the ULA was significantly correlated with net water uptake at 72 hours (r=0.37, p=0.03). Among patients with unsuccessful reperfusion, there was a non-significant correlation between time below the LLA and infarct progression (r=0.35, p=0.064). Conclusions: In the largest study conducted to date, deviations from personalized BP targets were associated with an increased risk of secondary brain injury and worse functional outcomes. Autoregulation-oriented BP management represents a promising strategy for maximizing recovery after ischemic stroke.

Three distinct Atoh1 enhancers cooperate for sound receptor hair cell development

Cochlear hair cells (HCs) in the inner ear are responsible for sound detection. For HC fate specification, the master transcription factor Atoh1 is both necessary and sufficient. Atoh1 expression is dynamic and tightly regulated during development, but the cis-regulatory elements mediating this regulation remain unresolved. Unexpectedly, we found that deleting the only recognized Atoh1 enhancer, defined here as Eh1, failed to impair HC development. By using the assay for transposase-accessible chromatin with high-throughput sequencing (ATAC-seq), we discovered two additional Atoh1 enhancers: Eh2 and Eh3. Notably, Eh2 deletion was sufficient for impairing HC development, and concurrent deletion of Eh1 and Eh2 or all three enhancers resulted in nearly complete absence of HCs. Lastly, we showed that Atoh1 binds to all three enhancers, consistent with its autoregulatory function. Our findings reveal that the cooperative action of three distinct enhancers underpins effective Atoh1 regulation during HC development, indicating potential therapeutic approaches for HC regeneration.

A novel computational model for cerebral blood flow rate control mechanisms to evaluate physiological cases

In this study, a new numerical model simulating interaction among static cerebral autoregulation, cerebrovascular CO2 and O2 reactivities and systemic peripheral resistance regulation was developed and integrated into a cardiovascular system model including heart chambers, systemic and pulmonary circulations, and cerebral circulation with Circle of Willis. Simulations were performed to evaluate cerebral blood flow in a healthy condition, effect of altered static cerebral autoregulation in heart failure, effect of impaired static cerebral autoregulation in malignant hypertension, effects of arterial CO2 and O2 pressures in hypercapnia, hypocapnia and hypoxemia on cerebral blood flow. Also, sensitivity analysis was performed to assess influence of arterial CO2 and O2 pressure, aortic pressure set point in the cerebral flow autoregulatory function, systemic peripheral resistance, left ventricular active and passive properties on the cerebral blood flow rate. There was a high and positive correlation between cerebral blood flow rate and arterial CO2 pressure whereas left ventricular contractility influenced cerebral blood flow rate slightly. Cerebral blood flow rate in the healthy condition, heart failure, malignant hypertension, hypercapnia, hypocapnia and hypoxemia was 721 mL/min, 606 mL/min, 1313 mL/min, 950 mL/min, 504 mL/min and 972 mL/min, respectively. Simulation results and sensitivity analysis showed that the new numerical model can be used to evaluate cerebral blood flow in various physiological cases.