Artery Catheter Research Articles

Deletion of Irisin Mitigates HDAC4 Inhibitor-Elicited Protective Effect in Hemorrhage

Introduction: Histone deacetylate inhibition contributes critically to modulating insulin resistance and cardiovascular function. It remains unknown whether inhibition of specific HDAC isoform 4 could improve cardiac function and attenuates inflammatory response and whether HDAC4 inhibition-induced protection is related to irisin. The objective of this study is to investigate whether HDAC4 inhibition induced protective effect against hemorrhage-induced detrimental effects would be diminished by deletion of irisin. Method: Irisin knockout (irisin−/−) mice was generated by using the CRISPR/Cas-9 genome-editing system. Hemorrhage was induced in mice by achieving a mean arterial blood pressure of 35-45 mmHg for one hour, followed by two hours of resuscitation. Experimental groups were divided as followings: I) Wild type (WT)+Hemorrhage (control) (N=7): WT mice were subjected to hemorrhage for 60 minutes followed by resuscitation; II) NVS-HD-1+Hemorrhage (n=7): The same as the group I except that NVS-HD1, a selective HDAC inhibitor (3mg/kg) was infused during resuscitation; III) Irisin −/− +Hemorrhage (n=6): Irisin −/− mice underwent hemorrhage and resuscitation; IV) NVS-HD-1 + Irisin−/−+Hemorrhage (n=6): The same as the groups III except that NVS-HD-1 was given to Irisin −/− during resuscitation. Myocardial function and hemodynamics were assessed using echocardiography and femoral artery catheterization, respectively. Cytokine releases from serum were measured using Enzyme-linked immunosorbent assay (ELISA). Histological assessment was performed to determine tissue damage in both myocardium and skeletal muscles. TUNEL was carried out to assess apoptotic signal in tissues. Results: As compared to control group, HDAC4 inhibitor significantly improved the cardiac function and recovery of hemodynamics, which was associated with the decreased release of IL6 and TNF-α in hemorrhage. The infiltration of inflammatory cells and TUNEL positive apoptosis in muscles were mitigated by inhibition of HDAC4. However, HDAC4 inhibitor-induced myocardial protection and suppression of inflammation against hemorrhage was lost by genetic deletion of irisin. Conclusion: Selective inhibition of HDAC4 produced protective effects with an improvement in myocardial function and attenuation of inflammation against hemorrhage, which is dependent on irisin. The work is supported by the National Institute of General Medical Sciences (R01GM 141339), United States; the National Heart, Lung, and Blood Institute Grants (R01 HL089405), United States. This is the full abstract presented at the American Physiology Summit 2024 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.

Pulsatile Perfusion Therapy at 0.1 Hz Improves Survival Following Severe Hemorrhage in Rats

Oscillations in arterial pressure and blood flow at 0.1 Hz are associated with protection of tissue oxygenation during conditions of reduced tissue perfusion. Pulsatile Perfusion Therapy (PPT) is a method we have developed to induce these oscillations, and has been associated with increased tolerance to simulated hemorrhage via lower body negative pressure in humans. However, it is unknown how effective this therapy would be in an actual hemorrhage model. The aim for this study was to test the effcacy of PPT in a rat model of severe hemorrhage. We hypothesized that PPT at 0.1 Hz would protect arterial pressure and cerebral blood flow following severe hemorrhage in rats, subsequently improving survival. Eleven adult Sprague-Dawley rats (six female, five male) were anesthetized via isoflurane, then underwent bilateral carotid artery catheterization for assessment of arterial pressure and carotid artery blood flow, while heart rate was assessed via lead II ECG. Following a 15-min baseline period, all animals were hemorrhaged to 50% of their estimated blood volume over 30-min. Rats were then randomly assigned to the PPT group (3 female, 3 male) or the control group (CON; 3 female, 2 male). PPT was administered via inflatable cuffs attached to both hind limbs, oscillating between 0 mmHg and 250 mmHg every 5-s (10-s cycles or 0.1 Hz) for 30-min immediately following hemorrhage. For the CON group, the leg cuffs were also attached but were not inflated for this 30-min period. All animals were then monitored for an additional 150-min recovery period post-hemorrhage, or until death — defined as the absence of ventricular function on the ECG. Survival time and peak mean arterial pressure (MAP), carotid blood flow, and heart rate were assessed to determine the effectiveness of PPT in protecting hemodynamic responses following hemorrhage. PPT increased survival time ( P = 0.02), with 3 of 6 (50%) rats in the PPT group and 0 of 5 (0%) rats in the CON group surviving the entire 180-min recovery period following hemorrhage. During recovery, PPT protected MAP (PPT: −46.5 ± 12.9% vs. CON: −72.6 ± 19.5% from baseline; P = 0.07) and carotid blood flow (PPT: −61.5 ± 17.7% vs. CON: −83.7 ± 6.7% from baseline; P = 0.04), but did not affect heart rate (PPT: 0.11 ± 6.58% vs. CON: −18.70 ± 29.34% from baseline, P = 0.20), although responses were highly variable between subjects. PPT protected arterial pressure and carotid blood flow in rats following severe hemorrhage, subsequently improving survival. These data add further evidence for the use of 0.1 Hz hemodynamic oscillations as a therapeutic intervention for the treatment of hemorrhage. Physiology and Anatomy Department Seed Grant. This is the full abstract presented at the American Physiology Summit 2024 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.

Deletion of irisin exacerbate cardiac dysfunction and increase inflammatory response in hemorrhage

Introduction: Irisin plays an important role in regulating tissue stress, cardiac function, and inflammation. The objective of this study is to investigate whether deletion of irisin would exacerbate hemorrhage induced cardiac depression and inflammatory response. Method: Irisin knockout mice was generated by using the CRISPR/Cas-9 genome-editing system. Hemorrhage was induced in mice by achieving a mean arterial blood pressure of 35-45 mmHg for one hour, followed by two hours of resuscitation. Experimental groups were divided as followings: I) WT+Hemorrhage (control, n=6): WT mice were subjected to hemorrhage for 60 minutes followed by resuscitation; II) Irisin −/− +Hemorrhage (n=6): Irisin −/− mice underwent hemorrhage and resuscitation; III) WT +Hemorrhage+Irisin (n=8): The same as the group I except that irisin (50ng/kg) was infused during resuscitation; IV) Irisin −/− +Hemorrhage+ Irisin (n=7): The same as the groups III except that Irisin −/− was used. Cardiac function and hemodynamics were measured using echocardiography and femoral artery catheterization. Systemic cytokine releases were measured using Enzyme-linked immunosorbent assay (ELISA). Histological analyses were used to determine tissue damage in myocardium and skeletal muscles. TUNEL was carried out to assess apoptosis in tissues. Results: As compared to wild type mice, irisin knockout mice attenuated the cardiac function and recovery of hemodynamics, which was associated with the increased release of IL6 and TNF-α in hemorrhage. The infiltration of inflammatory cells and TUNEL positive apoptosis in muscles were increased by deletion of irisin. Irisin treatment demonstrated the profound protection against hemorrhage-induced detrimental effect as compared to control. Furthermore, re-infusion of irisin into irisin-knockout mice rescued mitigated the detrimental effect in hemorrhage by deletion of irisin. Conclusion. Deletion of irisin exacerbate hemorrhage induced cardiac depression and inflammatory response, suggesting critical protection of irisin in modulating hemorrhage. National Institute of General MedicalSciences (R01GM 141339); National Heart, Lung, andBlood Institute Grants (R01 HL089405). This is the full abstract presented at the American Physiology Summit 2024 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.

Unraveling a Novel Mechanism of Altered Glomerular Hemodynamics in Pre-diabetic Obesity

Background: In pre-diabetic obesity, disrupted glomerular autoregulation leads to increased glomerular capillary pressure and renal blood flow, causing potential barotrauma-induced glomerular damage. A decrease in Afferent arteriole ( Af-Art) resistance causes higher glomerular capillary pressure but the underlying mechanism behind this, specifically in pre-diabetic obesity, remains unclear. Hyperinsulinemia is common in pre-diabetic obesity, but its role in reducing Af-Art resistance in the kidneys is unknown. Kidney blood flow is auto-regulated by vasoconstriction via tubuloglomerular feedback (TGF) and vasodilation through the Distal convoluted tubule-2/connecting tubule (DCT-2/CNT) mechanism. Our earlier studies indicate increased Af-Art dilation in pre-diabetic obese rats through the DCT-2/CNT mechanism without affecting TGF. This DCT-2/CNT induced Af-Art dilation requires initiation from epithelial sodium channels (ENaC) present at this tubular segment and interestingly insulin is a known ENaC activator. Hypothesis: We hypothesize that in the context of pre-diabetic obesity, hyperinsulinemia contributes to an increase in renal cortical blood flow (CBF) by increasing DCT-2/CNT-induced Af-Art dilation, subsequently leading to glomerular injury. Methods: We assessed the effects of insulin on Af-Art dilation by perfusing juxtaposed DCT-2/CNT segments with insulin in normal rabbits. Contribution of DCT-2/CNT induced Af-Art dilation was measured by co-administration of the ENaC blocker benzamil. To study hyperinsulinemia's role in an in-vivo setting without altering blood glucose levels, we used a hyperinsulinemic-euglycemic (HI-EUG) clamp in obese rats with intravenous (IV) glucose and insulin infusions. Renal CBF and blood pressure were monitored using a laser Doppler probe and femoral artery catheter, respectively, both with and without benzamil administration (400 μg/kg, IV). To evaluate insulin's potential role in causation of renal damage, we infused insulin directly into one kidney of lean rats for 6 weeks via a renal sub-capsular catheter, with the contralateral kidney serving as control. Glomerular basement membrane (GBM) thickness, a marker of renal damage, was measured via electron microscopy. Untargeted lipidomic analysis of the renal cortex was performed to identify potential renal damage pathways in insulin infused kidneys. Results: Insulin perfusion in rabbits' DCT-2/CNT potentiated the dilation of adherent Af-Art compared to control infusions with artificial tubular fluid. ENaC inhibition reversed the insulin-induced Af-Art dilation, confirming that insulin increases Af-Art dilation through the ENaC-initiated DCT-2/CNT mechanism. In obese rats, insulin delivery using a HI-EUG clamp resulted in a significant 20.8±4.9% increase in CBF, which was negated by the administration of the ENaC blocker benzamil, indicating the potential involvement of DCT-2/CNT-mediated vasodilation. Neither the HI-EUG clamp nor benzamil infusion affected blood pressure. Additionally, continuous direct insulin infusion into the kidneys of lean rats led to an increase in glomerular basement membrane (GBM) thickness and ceramide accumulation in the renal cortex, both indicative of renal damage. Conclusion: Our study demonstrates that insulin directly augments DCT-2/CNT-mediated Af-Art dilation and increases renal cortical blood flow in obese rats. Chronic renal insulin infusion led to structural changes and damage markers in the kidney, independent of blood glucose and blood pressure levels. Henry Ford Health System Internal Funding. Pilot and Feasibility grant from southeast center for integrated metabolomics. This is the full abstract presented at the American Physiology Summit 2024 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.

Functional sympatholysis of Neuropeptide Y-mediated vasoconstriction in humans

Metabolic inhibition of sympathetic vasoconstriction (functional sympatholysis) is essential for adequate perfusion of skeletal muscle during exercise. Functional sympatholysis occurs primarily through post-junctional attenuation of norepinephrine and α-adrenergic-mediated vasoconstriction, though other non-adrenergic neurotransmitters are co-released with norepinephrine. Neuropeptide Y (NPY) is a neurotransmitter that elicits robust vasoconstriction and is co-released with norepinephrine during exercise in an intensity dependent manner. Evidence from animal models indicate that NPY is sensitive to metabolic inhibition, however metabolic inhibition of NPY-mediated vasoconstriction has not been tested in humans. We tested the hypothesis that NPY-mediated vasoconstriction would be attenuated during handgrip exercise in humans. In 10 healthy adults (7M:3F, age: 30±7 years, BMI: 24±5) we measured forearm blood flow (Doppler ultrasound), blood pressure (brachial artery catheter), and calculated changes in forearm vascular conductance (FVC) to local intra-arterial infusions of phenylephrine (PE; α1-agonist) or NPY (Y1R-agonist) during 1) intra-arterial infusion of sodium nitroprusside (SNP; nitric oxide donor) to serve as a non-metabolic vasodilatory control or 2) dynamic rhythmic handgrip exercise (EX; 15% maximal voluntary contraction). The vasoconstrictor responses to PE and NPY were quantified as a percent ΔFVC during each condition (SNP vs. EX) and were compared by two-way RM-ANOVA. The magnitude of sympatholysis (ΔFVC during exercise expressed as a percent of control) for PE and NPY was compared by a paired t-test. As expected, the vasoconstrictor response to PE was attenuated during handgrip exercise compared to SNP (ΔFVC: SNP: -50±24 vs. EX: -17±9 %; p=0.002). Similarly, NPY-mediated vasoconstriction was blunted during handgrip exercise compared to SNP (ΔFVC: SNP: -32±22 vs. EX: -11±7 %; p=0.029). There was no difference in the magnitude of sympatholysis between PE and NPY (PE: 68±18, NPY: 52±34 %; p=0.28). These data indicate that NPY-mediated vasoconstriction is sensitive to metabolic inhibition in humans, and the magnitude of sympatholysis is not different from α1-adrenergic vasoconstriction. Funding: NIH R00HL153777. This is the full abstract presented at the American Physiology Summit 2024 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.

Effect of curcumin on inflammatory and oxidative stress markers in Lipopolysaccharide induced animal models of pre-eclampsia

Introduction: A substantial percentage of fetal, maternal, and neonatal morbidity and mortality is traced to Pre-eclampsia, a life threatening disease. Typical symptoms of the disease include de novo hypertension, proteinuria, renal failure, neurological problems, elevated liver enzymes, and uteroplacental dysfunction. It is estimated that almost 8-10% of all pregnancies are affected by preeclampsia in India. Pre-eclampsia incidentally also involves immune system changes on similar lines as a typical pregnancy. Immune cells like CD4+ T-helper 1 (TH1) cells, cytotoxic NK cells, and autoreactive B cells secrete substances that cause an increase in innate immune activation and inflammation in the maternal circulation and uteroplacental unit, instead of immune changes that promote tolerance and inhibit reactivity to the fetus and placenta. Placental and systemic oxidative stress are the key factors in the emergence of preeclampsia. A number of physiological changes, mineral shortages, and increased oxygen use during pregnancy can all be considered potential causes of oxidative stress. There is yet no effective and secure pharmaceutical treatment for preeclampsia. Pregnancy related safety concerns and the complex aetiology are two significant barriers to the development of pre-eclampsia medications. Medicinal plants and derived products have long been recognized as valuable assets in the treatment of a variety of diseases. Curcumin is a naturally occurring substance with significant in vitro therapeutic promise. The objective of this study was to develop LPS (lipopolysaccharide) induced animal model of Pre-eclampsia and to estimate and compare the hemodynamic parameters, inflammatory markers, oxidative stress markers and proteinuria in pregnant control, LPS-induced Pre-eclampsia, and curcumin-treated Pre-eclampsia in experimental rats. Material and methods: Pre-eclampsia was induced by single dose of 0.5μg/kg LPS. Wistar rats were divided into 8 groups of 8 animals. Female wistar rats were placed with male rats overnight and examined the next morning for the presence of sperm in vaginal smears. The day on which sperm was detected was designated as gestational day 0. After confirmation of pregnancy, each rat was weighed and randomized into groups. Pregnant Wistar rats were given 0.5 μg /kg of body weight LPS intraperitoneally on gestational day 5 for developing Pre-eclampsia models. Protein estimation in urine was done after 24 hours. On 19th or 20th gestation day animals were anesthetized and blood pressure was measured through a non-invasive tail-cuff method using the AD instrument and also through invasive method by inserting a arterial catheter in either of the carotid arteries towards the heart. ECG recording was done through surface ECG recording. Blood was collected by cardiac puncture, centrifuged, and stored at -80ºC on 19th or 20th gestation day. Inflammatory markers were estimated through ELISA reader. Oxidative stress markers were estimated. Pregnancy outcome was assessed through placental weight, number of pup’s delivered and pup’s weight. Statistical analysis was done using one way analysis of variance (ANOVA) followed by post hoc Tukey‘s test for intergroup comparisons. Results: In LPS induced model of pre-eclampsia, single-dose treatment with LPS (0.5ug/kg) induced marked pre-eclampsia in rats. Treatment with curcumin significantly decreased the level of proteinuria, hemodynamic parameters, inflammatory markers and oxidative stress markers in pregnant LPS+ curcumin-treated group when compared with the pregnant LPS group. Treatment with curcumin significantly increases pup’s weight and number of pups. Conclusion: On the basis of this experimental study, it is proposed that curcumin appears to be a potential therapeutic agent as measured by effect on hemodynamic changes, proteinuria, inflammatory markers, oxidative stress markers and pregnancy outcomes in LPS-induced pre- eclampsia. This is the full abstract presented at the American Physiology Summit 2024 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.

Heparin vs Saline Infusion For Maintaining the Patency of Arterial Catheters in Children

Heparin vs Saline Infusion For Maintaining the Patency of Arterial Catheters in Children

Hemorrhage Magnitude Correlates with Sympathetic Vasomotion in Conscious Rabbits

Each year, over 1.8 million people die from hemorrhagic shock, and the median time from onset to death is only two hours, making early recognition and prompt action the cornerstone of management. The sympathetic nervous system is the most rapid physiological hemodynamic compensatory mechanism, and we have developed a novel measure of sympathetic vascular control called sympathetic vasomotion which could serve as an early marker of hemorrhage. We performed unilateral renal denervation on six rabbits and instrumented these rabbits with bilateral renal flow probes and arterial pressure telemeters to allow for measurement of sympathetic vasomotion. After a two-week recovery period, the rabbits then underwent controlled blood withdrawal via an auricular arterial catheter. The differences in admittance gain and phase shift occurrence between the innervated and denervated kidneys increased significantly before any other hemodynamic changes. Over the first 15 minutes of hemorrhage, the differences in admittance gain and phase shift correlated with hemorrhage magnitude (r = 0.69 and 0.63, respectively), whereas the differences in coherence did not. The sum of the admittance gain and phase shift differences showed a slightly higher correlation with hemorrhage magnitude (r = 0.71). This data suggests that some features of sympathetic vasomotion may be useful as a biomarker for diagnosing early-stage normotensive hemorrhage and assessing treatment response. Further studies are needed to evaluate the utility of sympathetic nervous system monitoring in clinical contexts. Supported by NIH P01 HL62222 and NIH F30 HL118974. This is the full abstract presented at the American Physiology Summit 2024 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.

Testosterone enhances adipose tissue-blood pressure axis in obese mice exposed to early life stress

Previously, we have shown that male and female mice exposed to maternal separation and early weaning (MSEW), a model of early life stress, display exacerbated obesity-induced hypertension in response to chronic high fat diet. However, only male mice showed higher sympathetic tone at baseline, along with increased neuronal activation in PVN and pressor response to the acute stimulation of TRVP1 channels with capsaicin, a mechanism known as adipose afferent reflex (AAR). The aim of this study was to investigate whether obese male MSEW mice show 1) increased intracellular calcium in response to capsaicin in neuronal cultures of dorsal ganglia root (DRG), and 2) a role for sex hormones in AAR reactivity in vivo. Six-months-old control and MSEW fed a high fat diet (HFD, 60% kcal fat) were injected with pAAV-CAG-tdTomato (59462-PHP.S, 1012 viral particles); 8 sites; 4 ul/site; bilateral). After 6 weeks, mice were decapitated and DRGs (L5-T12) were collected and placed in ice-cold HBSS solution, dissociated and mixed with Collagenase P (1 mg/ml in HBSS, 15 min, 37 oC). After 0.25% Trypsin-EDTA incubation, neurons were mechanically dissociated, collected by centrifugation and resuspended in DMEM-10% FBS, plated onto the Matrigel Basement Membrane Matrix covered coverslips and maintained at 37 oC for 15-16 hours. Neuronal cultures were incubated in Ca2+ imaging solution with 2 μM Fura-2 AM, 30 min in dark conditions. After de-estirification, intracellular Ca2+ transients were visualized by exciting Fura-2 at 340 ± 20 nm and 380 ± 20 nm using a high-speed filter changer to obtain a ratiometric value independent of indicator concentration. Emitted light was passed through a dichroic filter (400-nm high pass) and an emitter filter (520 ± 30 nm) and was digitized onto the sensor of an EMCCD camera. Background subtraction and normalization to baseline were used to quantify changes in fluorescence. Despite similar resting uncalibrated ratios of calcium levels between groups (~0.6 ratio units, n=3), sensory neurons from MSEW mice tended to display larger responses to capsaicin (50 uM), showing elevated calcium kinetics vs. controls (0.56±0.09 vs. 0.31±0.12 delta ratio, respectively, p=0.063) as well as longer transients, perhaps indicative of reduced clearance or buffering. A separate set of age-matched mice were gonadectomized. After 4 weeks, anesthetized mice were fitted with carotid artery catheter for direct blood pressure measurement in response to the infusion of perigonadal fat with capsaicin (1.5 pmol/μL during 2 minutes in 4 sites, bilaterally). Capsaicin-induced pressor response was exacerbated in intact MSEW male mice compared to intact controls (9.0±0.2 vs. 1.3±0.2 delta mmHg, respectively, n=6, p<0.05). Orchidectomy attenuated delta blood pressure in MSEW mice to 7.0±0.2 mmHg (p<0.05 vs. intact MSEW), while enhanced delta blood pressure in control mice to 7.5±0.2 mmHg (p<0.05 vs. intact control). MSEW did not influence the pressor response to perigonadal fat stimulation with capsaicin either in intact or ovariectomized obese female mice (n=4-6 per group, p>0.05), suggesting that estradiol may not to play a protective role in obese females AAR reactivity. This data indicates that testosterone could buffer the AAR reactivity of obese control mice, while MSEW exerts an opposite effect. Thus, investigating testosterone signaling on calcium handling mechanisms (i.e., buffers, pumps, ER-mediated calcium release) in sensory neurons innervating visceral fat will provide insights on the sex-specific contribution of afferent sympathoexitatory signals to obesity-hypertension in male MSEW mice. This study was supported by NIH R01 HL135158, and SALT pilot - University of Kentucky to ASL. This is the full abstract presented at the American Physiology Summit 2024 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.

Physiologic Validation of the Compensatory Reserve Metric Obtained From Pulse Oximetry Waveforms

Background: The compensatory reserve metric (CRM) provides a novel marker of hemodynamic status in prediction of sudden cardiovascular decompensation during central hypovolemia. The CRM has previously been calculated using arterial waveforms obtained from a photoplethysmographic volume-clamp technique. However, the in-field use of pulse oximetry is becoming more prominent in research and medicine. To improve in-field applicability of the CRM, this project aimed to validate pulse-oximetry derived CRM values relative to physiologic data during simulated hemorrhage through application of lower body negative pressure (LBNP). Methods: Forty-nine healthy adults (25 females) underwent a graded LBNP protocol with the following 5-minute stages: -0, -15, -30, -45, -60, -70, -80, -90, and 100 mmHg, or until the onset of pre-syncopal symptoms (tolerance) was reached. Arterial waveforms were sampled using pulse oximetry (Massimo Radical 7). The CRM was calculated using a validated one-dimensional convolutional neural network. A brachial artery catheter was used to measure intraarterial pressure. A 3-lead ECG was used to measure heart rate. SpO2 was measured using pulse oximetry. Cardiac output and stroke volume were estimated using the photoplethysmographic volume-clamp. Data were binned for the last thirty seconds of each completed stage, and at tolerance. Fixed-effect linear mixed models with repeated measures were used to examine the association between CRM values and physiologic variables. A priori significance was set at P<0.05. Results: The median LBNP stage reached was 70 mmHg (Range: 45-100 mmHg). Relative to baseline, at tolerance there was a 50±12% ( P<0.001) mean reduction in stroke volume, 65±27% ( P<0.001) increase in heart rate, 18±8% ( P<0.001) reduction in mean arterial pressure, 21±7% ( P<0.001) systolic blood pressure, 8±9% ( P<0.001) diastolic blood pressure, and 39±12% ( P<0.001) pulse pressure. The CRM obtained using pulse oximetry was significantly associated with a reduction in stroke volume ( P<0.001), increase in heart rate ( P<0.001), and reductions in systolic ( P=0.033), diastolic ( P=0.036), and pulse pressure ( P=0.002). There was no statistically significant association between CRM and cardiac output ( P=0.421), SpO2 ( P=0.408), or mean arterial pressure ( P=0.214). Conclusion: The CRM obtained using pulse oximetry may be a valid, reliable marker of hemodynamic status with promising in-field applications. Future studies warrant investigation of feasibility and applicability within various contexts ranging from the operating room to the battlefield. The presented work was funded in part by the Congressionally Directed Medical Research Program (Award No. DM180240) and Offce of Naval Research (Awards No. N00014-18-D-7001 and N00014-19-C-2017). This is the full abstract presented at the American Physiology Summit 2024 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.

Central α2-adrenergic mechanisms differentially affect baroreflex control of sympathetic and cardiovagal outflow

This study aimed to investigate the impact of central α2-adrenergic mechanisms on arterial baroreflex control of sympathetic and cardiovagal outflow in healthy humans. R-R interval (ECG), blood pressure (brachial arterial catheter), and muscle sympathetic nerve activity (MSNA; peroneal microneurography) were measured in eight healthy participants (5 females; 28±7 years). Sympathetic action potentials (AP) were extracted from the filtered MSNA neurogram (continuous wavelet transform) during a 5-minute baseline (BSL) and an intravenous dexmedetomidine infusion consisting of a loading dose (LD; 10 minutes at 0.225 μg/kg/hr) and a maintenance dose (MD; ~0.15 μg/kg/hr). Sympathetic AP baroreflex threshold gain was measured as the slope of the linear relationship between AP discharge probability and diastolic blood pressure. The linear relationship between R-R interval and systolic blood pressure (sequence technique) quantified cardiovagal baroreflex gain. Mixed-effects analyses and post-hoc t-tests were performed. Data are reported as mean ± SD. Dexmedetomidine reset the baroreflex threshold operating points for all sympathetic AP clusters downwards to lower firing probabilities (cluster 4; BSL: 20±6, LD: 13±8, MD: 6±5%, both p<0.01 vs. BSL) and leftwards to lower diastolic pressures (BSL: 72±9, LD: 69±8, MD: 65±10 mmHg, both p<0.01 vs. BSL). Dexmedetomidine reduced baroreflex threshold gain for the subpopulation of medium-sized sympathetic APs (cluster 4; BSL: -6.5±2.0, LD: -2.6±1.6, MD: -2.0±0.7 %/mmHg, both p<0.01 vs. BSL). Dexmedetomidine did not affect baroreflex threshold gain of small (cluster 1; BSL: -1.9±1.1, LD: -1.3±1.6, MD: -1.1±0.8 %/mmHg, both P>0.88 vs. BSL) or large AP clusters (cluster 9; BSL: -0.8±0.4, LD: -0.8±1.0, MD: -0.2±0.7 %/mmHg, both P>0.98 vs. BSL). Dexmedetomidine reset the cardiovagal baroreflex to lower systolic pressures but did not affect R-R interval (BSL: 1035±261, LD: 1025±308, MD: 1005±292ms, Main effect P=0.45) or gain (BSL: 24±11, LD: 30±20, MD: 26±25 ms/mmHg, Main effect P=0.63). These findings suggest that central α2-adrenergic mechanisms differentially affect arterial baroreflex control of sympathetic and cardiovagal outflow in humans by minimally affecting cardiovagal baroreflex gain but strongly affecting the baroreflex gain for the subpopulation of medium-sized sympathetic APs. This work was supported by the Natural Sciences and Engineering Research Council of Canada (NSERC) and the National Institutes of Health (NIH). This is the full abstract presented at the American Physiology Summit 2024 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.

NADPH Oxidase 4 Knockout in Dahl Salt-Sensitive Rats Impacts Kidney O2 Consumption and UCP2 Responses to a High Salt Diet

Rationale: The effects of a high salt (HS) diet upon renal metabolism and O2 utilization have not been extensively studied and there is a significant gap in our understanding of the role of oxidative stress in the effciency of energy production and substrate metabolism. The present study compared the effects of a HS diet (4% NaCl) on changes in O2 consumption and transcriptomic profiles in Dahl salt-sensitive (SS) rats to SS rats with a global knockout of NADPH oxidase 4 (NOX4) gene (SS Nox4−/−). Methods: Male SS (n=9) and SS Nox4−/− (n=10) rats were fed a 0.4% NaCl (LS) diet. At 7-8 weeks of age, the rats were implanted with a renal artery ultrasonic flow probe (Transonic) together with a femoral arterial catheter and a renal venous catheter. Renal blood flow (RBF) and mean arterial pressure (MAP) were measured continuously (24/7) and arterial (A) and renal venous (Vr) blood was sampled intermittently when rats were fed the LS and on days 7, 14, and 21 after switching to the HS diet. A and Vr blood O2 content was immediately measured by radiometer. From separate groups of rats subjected to the same protocol, the renal cortical tissue (Cx) and outer medulla (OM) were removed for mRNAseq analysis (Novogene, Inc). Results: When switching to the HS diet, the average 24-hour MAP of SS rats rose from 122 ± 2 to 140 ± 2 on HS7 to 164 ± 5 mmHg by HS21. In contrast, MAP in SS Nox4−/− rats increased from 121 ± 2 at LS to 132 ± 1 at HS7 to 152 ± 3 mmHg at HS21 (p<0.05, compared to SS). RBF, normalized by changes of kidney weights obtained in another group of SS and SS Nox4−/− rats fed the same HS diet, SS rats exhibited a significant reduction of RBF over the 3 weeks of the HS diet averaging LS 7.2 ± 0.6, HS7 5.1 ± 0.5 and HS21 4.6 ± 0.7 mL/min/g kidney weight (gkw). This reduction of RBF was not observed in SS Nox4−/− rats (LS 6.8 ± 0.8, HS7 6.6 ± 0.6, HS21 6.0 ± 0.6 mL/min/gkw). The kidney O2 extraction ratio at LS tended to be lower in SS Nox4−/− (11.2 ± 1.7%) compared to SS (14.0 ± 1.1%) (p=0.10). When switched to the HS diet, O2 extraction was significantly reduced in the SS Nox4−/− rats reaching 8.3 ± 1.0% at HS21 (p<0.05), while it did not change significantly in SS (12.7 ± 1.4%) at HS21. Notably, as determined by RNAseq analysis, Ucp2 expression in cortical tissue was significantly greater in SS fed HS than in SS Nox4−/−rats at HS21 . A gene enrichment analysis of the mRNAseq cortical tissue data (GSEA-KEGG pathways) focused on metabolic pathways indicated that knockout of Nox4 resulted in reduced expression of linoleic acid, lysine, and histidine metabolism pathways at LS when compared to SS. Those differences were not observed after HS feeding. However, upregulation of oxidative phosphorylation pathway was observed at HS21 in SS Nox4−/− when compared to SS rats. In the OM, a greater expression of genes associated with fatty acid degradation and carbon metabolism was observed in SS Nox4−/− rats when fed LS which was observed also at HS21. Conclusion: The preliminary results of this study suggest that reduced extraction of O2 in the SS Nox4−/− rats compared to SS rats may be partially explained by the differential response of Ucp2 to salt. Further studies are needed to determine whether the effciency of ATP production is enhanced in SS Nox4−/− as consequence of reduction of reactive oxygen species (e.g., H2O2) and the related downstream pathways such as phosphorylation of mTORC1. R01 HL151587, AHA 23POST1008714. This is the full abstract presented at the American Physiology Summit 2024 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.

Femoral arterial cannulation for surgical repair of stanford type A aortic dissection.

The benefits and harms associated with femoral artery cannulation over other sites of arterial cannulation for surgical repair of acute Stanford type A aortic dissection (TAAD) are not conclusively established. We evaluated the outcomes after surgery for TAAD using femoral artery cannulation, supra-aortic arterial cannulation (i.e., innominate/subclavian/axillary artery cannulation), and direct aortic cannulation. 3751 (96.1%) patients were eligible for this analysis. In-hospital mortality using supra-aortic arterial cannulation was comparable to femoral artery cannulation (17.8% vs. 18.4%; adjusted OR 0.846, 95% CI 0.799-1.202). This finding was confirmed in 1028 propensity score-matched pairs of patients with supra-aortic arterial cannulation or femoral artery cannulation (17.5% vs. 17.0%, p=0.770). In-hospital mortality after direct aortic cannulation was lower compared to femoral artery cannulation (14.0% vs. 18.4%, adjusted OR 0.703, 95% CI 0.529-0.934). Among 583 propensity score-matched pairs of patients, direct aortic cannulation was associated with lower rates of in-hospital mortality (13.4% vs. 19.6%, p=0.004) compared to femoral artery cannulation. Switching of the primary site of arterial cannulation was associated with increased rate of in-hospital mortality (36.5% vs. 17.0%; adjusted OR 2.730, 95% CI 1.564-4.765). Ten-year mortality was similar in the study cohorts. In this study, the outcomes of surgery for TAAD using femoral arterial cannulation were comparable to those using supra-aortic arterial cannulation. However, femoral arterial cannulation was associated with higher in-hospital mortality than direct aortic cannulation. ClinicalTrials.gov registration code: NCT04831073.

The stochastic characteristics of wideband-wavelength track irregularity on Chinese HSRs and its application to dynamic wheel–rail interaction

Track irregularities are the major excitations which lead to unfavourable wheel–rail dynamic interaction. In this work, the stochastic characteristics of longitudinal level irregularity on Chinese ballastless high-speed railway (HSR) are analysed based on a series of large-scale measurement campaigns on various arterial lines in Chinese HSR network. The power spectrum density (PSD) of longitudinal level irregularities of various track types is obtained, covering short and middle-to-long wavelength range, as well as the periodical irregularities caused by characteristic lengths of track components. An irregularity spectrum is proposed to represent the stochastic characteristics of the longitudinal level irregularities. Unlike existing irregularity spectra which represent the short and middle-to-long wavelength irregularities separately, the proposed spectrum covers a wide range of wavelength from 0.002 m to 100 m. A vehicle–track model which couples flexible wheelsets and the ballastless track is employed to demonstrate the suitability of the spectrum. It is shown that the proposed spectrum is more suitable than the latter to represent Vehicle–Track Interaction (VTI) on Chinese HSRs. The fitted short-wave spectrum and the proposed wideband wavelength spectrum therefore provide more appropriate representatives of track irregularities for accurate modelling of VTI on Chinese HSRs and railway lines which adopt similar technologies.

Case Report: Percutaneous intercostal artery catheterization to treat a difficult-to-access spinal dural arteriovenous fistula

Spinal dural arteriovenous fistulas (SDAVF) are a subtype of spinal arteriovenous malformation (AVM). Although rare, SDAVF are the most common spinal vascular malformations and have potential devastating neurologic consequences, sometimes irreversible. Originally, they were treated with surgery alone, however endovascular treatment of SDAVF has evolved recently with good results and the understanding of the anatomy plays a key role. The feeder vessel of the AV shunt is supplied by the radiculomedullary or radiculopial artery, the shunt is usually located within the root sleeve of the dura and the SDAVF is drained by the medullary vein via retrograde flow. Generally the endovascular approach uses the catheterization of the segmental arteries; however, aortic thoracolumbar aneurysms can render endovascular access difficult and risky. We present a case where an SDAVF in woman with aneurysmal dilation of the descending aorta and a mural thrombus was successfully treated through percutaneous catheterization of intercostal artery.

Ultrasound-guided In-plane vs Out-of-plane Approach for Radial Arterial Cannulation after Transradial Cardiac Catheterization: A Randomized Prospective Study

Ultrasound-guided In-plane vs Out-of-plane Approach for Radial Arterial Cannulation after Transradial Cardiac Catheterization: A Randomized Prospective Study

Novel Blood Pressure-Lowering Effect of Spathulenol in Rats

In recent years, natural compounds from plant sources are sought after as alternative anti-hypertensive treatments. Spathulenol (Spa), a terpenoid plant metabolite obtained mainly from the Origanum species has shown anecdotal evidence of blood pressure (BP)-lowering properties probably through the effects on vasoreactivity. This study aimed to investigate the BP-lowering activities of Spa in vivo as well as to ascertain the mechanisms of action in vitro. Male Sprague-Dawley (SD) rats (n=16) and spontaneously hypertensive rats (SHR) (n=16) with their normotensive Wistar-Kyoto (WKY) rats (n=16) as controls were subjected to anaesthesia and administered intravenous boluses of Spa at 0.0, 0.045, 0.90, 0.18, 0.36, and 0.7 mg/kg or positive control losartan at 0.0, 0.6, 1.2, 1.8, 2.4 and 3.0 mg/kg. The BP and heart rate (HR) of the rats were recorded by a computerised physiographical system (Power Lab) through carotid arterial cannulation that was connected to a pressure transducer. The data were analysed by using the Lab Chart 6 software. Spathulenol was also tested for angiotensin-converting enzyme (ACE) inhibitory activity by using the ACE1 inhibitor screening kit (PromoKine). Spathulenol was able to decrease the BP of rats in a dose-dependent manner with the BP-lowering effect being significantly (p < 0.05) higher in the SHRs than in the WKY controls. Furthermore, Spa was able to inhibit the ACE activity suggesting the possibility that this could be one of the mechanisms underlying the observed BP-lowering effect.

Harnessing extracellular cold-inducible RNA binding protein by PS-OMe miR130: A promising shield against hemorrhage-induced lung injury.

Hemorrhagic shock (HS) poses a life-threatening condition with the lungs being one of the most susceptible organs to its deleterious effects. Extracellular cold-inducible RNA binding protein has emerged as a pivotal mediator of inflammation, and its release has been observed as a case of HS-induced tissue injury. Previous studies unveiled a promising engineered microRNA, designated PS-OMe miR130, which inhibits extracellular cold-inducible RNA binding protein, thereby safeguarding vital organs. In this study, we hypothesized that PS-OMe miR130 serves as a protective shield against HS-induced lung injury by curtailing the overzealous inflammatory immune response. Hemorrhagic shock was induced in male C57BL6 mice by withdrawing blood via a femoral artery cannula to a mean arterial pressure of 30 mm Hg for 90 minutes. The mice were resuscitated with twice the shed blood volume with Ringer's lactate solution. They were then treated intravenously with either phosphate-buffered saline (vehicle) or 62.5 nmol PS-OMe miR130. At 4 hours later, blood and lungs were harvested. Following PS-OMe miR130 treatment in HS mice, a substantial decrease was observed in serum injury markers including aspartate aminotransferase, alanine transaminase, lactate dehydrogenase, and blood urea nitrogen. Serum interleukin (IL)-6 exhibited a similar reduction. In lung tissues, PS-OMe miR130 led to a significant decrease in the messenger RNA expressions of pro-inflammatory cytokines (IL-6, IL-1β, and tumor necrosis factor α), chemokines (keratinocyte-derived chemokine and macrophage inflammatory protein 2), and an endothelial injury marker, E-selectin. PS-OMe miR130 also produced substantial inhibition of lung myeloperoxidase activity and resulted in a marked reduction in lung injury as evidenced by histological evaluation. This was further confirmed by the observation that PS-OMe miR130 significantly reduced the presence of lymphocyte antigen 6 family member G-positive neutrophils and terminal deoxynucleotidyl transferase dUTP nick end labeling-positive apoptotic cells. PS-OMe miR130 emerges as a potent safeguard against HS-induced lung injury by effectively inhibiting pro-inflammation and injuries, offering a promising therapeutic strategy in such critical clinical condition.

Double arterial vs. single axillary cannulation in acute type A aortic dissections: a meta-analysis.

Aim: To evaluate the effects of double (axillary and femoral) vs. single (axillary) cannulation on early outcomes of acute type A aortic dissection (ATAAD). Materials & methods: Meta-analysis using PubMed/MEDLINE, Scopus, and Cochrane databases through August 23, 2023. Focused on operative mortality, postoperative stroke, re-exploration for bleeding, spinal cord injury, and renal replacement therapy. Results: Among 5 propensity score-matched studies with 2127 patients, double cannulation showed comparable mortality and higher rates of postoperative stroke (pooled odds ratio: 1.69, 95% confidence interval: 1.19-2.39) and need for renal replacement therapy (pooled odds ratio: 1.35, 95% confidence interval: 1.13-1.60) compared with single cannulation. Conclusion: Double arterial cannulation in ATAAD surgery is associated with increased postoperative stroke and renal replacement therapy than single cannulation.

Perioperative arterial catheterization: A prospective evaluation of ultrasound, infection, and patient-focused outcomes.

There is little information regarding complications of arterial catheterization in modern clinical care. We aimed to determine the incidence of abnormal duplex vascular ultrasound and catheter related infections following perioperative arterial catheterization. Patients requiring arterial catheterization for elective surgery were included and insertion details collected prospectively. Duplex ultrasound evaluation was performed 24 h after catheter removal. Symptomatic patients were identified by self-reported questionnaire. On Day 7, patients answered questions by telephone, related to the insertion site, pain, and function. Results of catheter tip and blood culture analyses were sought. Univariate associations of patient and surgical characteristics with abnormal ultrasound were assessed with p < 0.05 considered significant. Of 339 catheterizations, 105 (40%) had ultrasound evaluation. Catheters were indwelling for median (IQR, range) duration of 6.0 h (4.4-8.2, 1.8-28) with no catheter-related infections. There were 16 (15.2%, 95% CI 9.0%-23.6%) abnormal results, including 14 radial artery thromboses, one radial artery dissection, and one radial vein thrombosis. Those with abnormal ultrasound results were more likely to have had Arrow catheters inserted (68.8% vs 27%, p = 0.023) and more than one skin puncture (37.5% vs 26.8%, p = 0.031). Two of the 16 (12.5%) patients with abnormal ultrasound results reported new symptoms related to the hand compared with nine of the 88 (10.2%) with normal results (p = 0.1). No patients required urgent referral for management. Thrombosis was the most common abnormality and was usually asymptomatic. There were no infections, few post-operative symptoms, and minimal functional impairment following arterial catheterization.