Citations

With rising healthcare costs and the rapid increase in remote physiologic monitoring and care delivery, there is increasing need for economical, accurate and non-invasive continuous measures of blood analytes. Based on radio-frequency identification (RFID), we have developed a novel electromagnetic platform technology (the Bio-RFID platform) to non-invasively penetrate inanimate surfaces, capture data from individual radio frequencies, and convert those data into physiologically meaningful information and insights. Here we describe ground-breaking proof-of-principle studies using Bio-RFID to accurately measure various concentrations of analytes in deionized water. The in vitro Bio-RFID platform consists of an acrylic cuvette in the shape of a 4 inch x 4 inch x 8 inch rectangular prism mounted on the Bio-RFID sensor. This apparatus is in turn mounted on a balance that allows the determination of the mass of the analyte being scanned to within 0.1g. The hardware scans through several thousand radio frequencies and sends the data to proprietary software running on a laptop computer. The software displays a spectral scan known as the Bio-RFID signature of the analyte and computes a similarity metric to compare different signatures.We tested the hypothesis that the Bio-RFID platform is able to precisely and non-invasively measure and identify a variety of analytes in vitro. For this assessment, varying solutions of 1) water in isopropyl alcohol; 2) salt in water; and 3) commercial bleach in water were tested, using a randomized double-blind trial design, as proxies for biochemical solutions in general. The Bio-RFID technology was able to detect concentrations of 2000 parts per million (ppm), with evidence suggesting the ability to detect considerably smaller concentration differences. The novel application of a Bio-RFID electromagnetic platform technology accurately detects, measures, and quantifies specific molecules in liquid. While these findings have in vitro commercial applications, these proof-of-principle studies provide strong support for the application of Bio-RFID technology for non-invasive bio-monitoring of physiologically and medically relevant analytes, such as alcohol and glucose, in the human body. These studies were funded by a grant from Know Labs to Mayo Clinic. PB and JHA are employed by Know Labs. VKS and Mayo Clinic acknowledge a financial interest in Know Labs. 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.

Introduction: Dent Disease type 1 (DD1) results from X-linked, mutations in CLC-5 (2Cl-/H+ exchanger) and results in progressive renal failure by 20-40. DD1 is characterized by kidney Ca2+ mishandling, and subsequent hypercalcuria, calcium oxalate (CaOx) kidney stones, and kidney calcification as well as proteinuria. We identified Drosophila Clc-c as the CLC-5 homolog with conserved amino acids at DD1 mutation sites. We hypothesize that Clc-c shares functional similarities in Cl- transport, Ca2+ homeostasis and protein processing. Methods and Results: By voltage clamping Xenopus oocytes expressing Clc‑c and CLC-5, we find that both are electrogenic and have the same outward-rectifying current in Cl- solutions. Cl- transport (current at +80mV) was lowered by acidity (2.37±0.55 μA, pH 6.0, P=0.06), but not by alkaline solution (4.45±0.96 μA, pH 8.5, P= 0.7) when compared to the standard solution of pH 7.5 (4.97±1.12 μA). Similarly, Cl- transport was lowered by homologous DD1 mutations S393L (0.67±0.098 μA, P<0.0001), R494W (2.9±0.46 μA, P =0.006), and Q777x (1.13±0.28 μA, P =0.0001) vs. WT (7.4±1.2 μA) as observed previously for CLC-5 DD1 mutations: S244L, R345W, and Q629x (Tang et al, Physiol Rep 4[8], 2016). To determine cell membrane and possible intracellular localization of DD1 mutations, HA-tagged Clcc and mutations (identical placement as in CLC-5-HA, Tang 2016) were made. Likewise, transgenic Drosophila expressing Clc-c-GFP were made to localize Clc-c in cell and intracellular membranes of renal tubules (Malpighian tubules, MT) in vivo (Judd-Mole, U Monash, Dissertation, 2016). RNAi MT knockdowns of Clc-c (Clc-c-KD) were made and resulted in 50% decrease in Clc-c mRNA expression. CaOx crystals in anterior MT (7 days after eclosure) were present in all Clc-c-KD and were more abundant (15±4 crystals/fly) than w1118 controls (5±2 crystals/fly, P= 0.02). MT secretions showed that Clc-c KD flies contained higher [Ca2+] while all other cations (Na+, NH4+, K+, Mg2+), and volume were the same as w1118 . Similarly, urinary protein concentration (4-6 pooled flies per n) appears elevated in DD1 flies (1.41 ± 0.14 mg/mL, n=3) vs w1118 (1.16 ± 0.08 mg/mL, n=5). Conclusion: Drosophila Clc-c has similarities to human CLC-5 including impaired function of voltage-gated Cl- transport, homologous DD1 mutations, increased CaOx crystal formation, and elevated urinary [Ca2+] and protein. Our results indicate that the Drosophila Clc-c avatar may help to provide more direct insights to the cellular and organismal pathophysiology for future investigations of Cl- transport, Ca2+ homeostasis and urinary protein loss in DD1. F32 DK128987, T32 DK007013 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.

Introduction: Vitamin D is an essential micronutrient for infant calcium metabolism and bone development. Concentrations of vitamin D in breastmilk are low, despite higher anti-rachitic activity and correlations between infant and maternal serum 25-hydroxyvitamin D (25D) (Taylor, et al., 2008; Oberhelman, et al., 2013). The sulfate-conjugated form of 25D is present in blood at concentrations approximately 40% of unmodified 25D. We hypothesized that sulfate conjugates, vitamin D3-sulfate (VitD-S) and 25-hydroxyvitamin D3-sulfate (25D-S), are present in milk and increase during supplementation. The objectives are (1) developing an LC-MS/MS assay to quantify VitD-S and 25D-S in milk, and (2) determine if these vitamin D sulfates increase with daily vitamin D supplementation. Methods: An LC-MS/MS method was developed to measure VitD-S and 25D-S in milk and in serum. Standards (Toronto Chemicals, Toronto, ON, CA) and internal standard (Glycomyr, Ames, IA) were used to optimize methods. Briefly, Milk (500 uL) and serum (250 uL) were extracted with methanol (MeOH) and resuspended in 150 uL 70% MeOH. Analytes were separated by C18 column with 70% to 100% MeOH with ammonium acetate (NH4OAc) organic phase gradient followed by MS/MS with optimized mass transitions and ESI in negative mode on SCIEX API 5000. An ongoing study is under way for breastmilk and serum collections from healthy lactating women consuming <600 IU vitamin D3/day at enrollment (day 1) and after 28 days of oral 5000 IU vitamin D3/day (day 28). This study was approved by the Mayo Clinic Institutional Review Board. Results: Preliminary analyses have been completed for 3 study participants. Serum 25D status had a trending increase from 30±2 ng/mL 25D on day 1 to 40±2 ng/mL 25D on day 28 ( P=0.1, paired t-test). Limit of detection [signal to noise (s/n) >3] for sulfates were 0.5 ng/mL 25D-S (s/n=7.3) and 0.25 ng/mL VitD-S (s/n=6.2). Upon enrollment, breastmilk sulfates were 3.25±0.12 ng/mL VitD-S (s/n=83.7±20.6) and 0.18±0.02 ng/mL 25D-S (s/n=13.6±3.3), and serum sulfates were 7.5±0.8 ng/mL VitD-S (s/n=39.4±22.5) and 53.2±10.4 ng/mL 25D-S (s/n=22.5±7.2). No statistical differences were observed between day 1 and day 28 in milk or serum sulfates for the 3 participants. However, VitD-S concentrations demonstrated a significant negative correlation between serum and milk ( r=0.87, P=0.03), and serum 25D-S was 21.3 ng/mL greater than unmodified serum 25D ( P=0.009, n=6). This study is ongoing, and data presented will include a greater number of study participants. Conclusions: We have developed an LC-MS/MS assay to measure VitD-S and 25D-S and found that VitD-S and 25D-S are present in freshly expressed breastmilk and in serum from women consuming <600 IU vitamin D3/day. F32 DK128987 & The Mayo Clinic Parker D. Sanders & Isabella G. Sanders Endowed Professorship. 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.

PURPOSE: Human cutaneous circulation is used as an in vivo bioassay to examine mechanisms of systemic vascular dysfunction in cohorts of patients with accelerated cardiovascular disease risk. Local drug infusions, including atorvastatin (statin; LOX inhibitor) and systemic interventions to investigate anti-inflammatory mechanisms (e.g., oral salsalate) have been used to elucidate mechanisms underlying microvascular dysfunction. However, in healthy cohorts, high antioxidant load can attenuate total vasodilation and nitric oxide (NO)-dependent vasodilation. Thus, we aimed to examine endothelial function during high antioxidant load from these localized and systemic treatments in healthy control groups. We hypothesized that combined localized and systemic treatments will attenuate endothelial function in healthy women. METHODS: In a randomized placebo control design, oral salsalate (1500mg/twice daily/5 days) was used to assess the impact of systemic inflammation on cutaneous vascular function. Four intradermal microdialysis fibers were placed into the intradermal space of the ventral forearm of six healthy women (32±7 years). Laser-Doppler flowmeter probes, used to measure cutaneous blood flow, were placed in local heating units set to 33°C. Increasing concentrations of acetylcholine (ACh; endothelium-dependent vasodilator) from 10-10 to 10-1 M were co-perfused with one of the following: Lactated Ringer’s (control), 0.02 mM statin, 15 mM NG-nitro-L-arginine methyl ester (L-NAME; nitric oxide synthase inhibitor), and statin + L-NAME (COMBO) sequentially for 5 min each. Following the dose-response protocol, maximal cutaneous vasodilation was induced by increasing local skin temperature to 43°C and perfusing 28 mM sodium nitroprusside. Cutaneous vascular conductance (CVC) was calculated as the quotient of red blood cell flux and mean arterial pressure and normalized as a percentage of the site-specific maximum (%CVCmax). Data at each intervention were compared with control using a two-way (dose x site) analysis of variance. Responses at each dosage were compared using paired t-tests and corrected for multiple comparisons. RESULTS: Following oral salsalate, there was no difference in the %CVCmax response to ACh with local L-NAME (p=0.896) or COMBO interventions (p=0.617) as compared to the placebo. However, following oral salsalate, there was a significant reduction in %CVCmax in the statin treated site at higher ACh concentrations (10-5 M, 10-4 M, 10-3 M; all p<0.01). CONCLUSION: Endothelial function was attenuated when subjects were introduced to a combination of oral salsalate and statin localized treatments. Five-day oral salsalate intake and local statin may result in high antioxidant load in healthy women creating a shift in redox balance, thus leading to impaired endothelial function. Supported by NIH Grant R01 HL161000 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.

Cardiovascular health disparities are present in several minority racial and ethnic groups including African Americans, who exhibit an increased risk of hypertension compared to non-Hispanic Whites. Somali Americans, a subgroup of African Americans of East African origins, exhibit high rates of diabetes and obesity, conditions often comorbid with impaired blood pressure (BP) regulation. Importantly, it remains unknown whether the disparate cardiovascular risk profile, namely poor nocturnal BP regulation, manifested in African Americans can be applied to Somali Americans. We therefore examined 24-hour BP patterns in Somali Americans compared to White control participants. We hypothesized that Somali Americans would present with heightened nocturnal BP and heart rate (HR). We utilized ambulatory blood pressure monitoring (ABPM) to quantify 24-hour BP patterns in 25 Somali (10 female, 15 male; age: 34 ± 3 years; BMI: 27 ± 1 kg/m2) and 25 White (13 female, 12 male; age: 38 ± 3 years; BMI: 27 ± 1 kg/m2) individuals. Each ABPM recorded a BP reading every 20 minutes throughout the 24-hour period. Subjects were instructed to abstain from caffeine, alcohol, and vigorous exercise during the recording period. From the 24-hour recording, an ambulatory arterial stiffness index (AASI) was calculated as 1 minus the regression slope of systolic (SAP) and diastolic (DAP) arterial pressure. SAP, DAP, and HR obtained between 12:00am and 6:00am were averaged to compute nocturnal means. BP and HR dipping was determined as the percent change between daytime and nocturnal BP and HR. Statistical analysis included independent samples t-tests to determine differences in BP and HR between racial groups (i.e., Somali vs. White). Nocturnal SAP (105 ± 2 vs. 106 ± 3 mmHg, p = 0.364) and DAP (60 ± 1 vs. 58 ± 2 mmHg, p = 0.093) were not different between Somali and White participants. In contrast, nocturnal HR was significantly higher in Somalis compared to Whites (72 ± 2 vs. 64 ± 2 beats/minute, p = 0.009). Similarly, SAP (12 ± 2% vs. 12 ± 1%, p = 0.437) and DAP (18 ± 2% vs. 21 ± 2%, p = 0.127) dipping were comparable between groups, while Somali individuals exhibited blunted HR dipping (11 ± 2% vs. 19 ± 2%, p = 0.008) compared to Whites. AASI (0.32 ± 0.03 vs. 0.24 ± 0.03 a.u., p = 0.031) was higher in Somali compared to White individuals. These findings suggest Somali Americans present with impaired nocturnal cardiovascular regulation and increased arterial stiffness, which may place this racial minority at increased cardiovascular risk. Future work to investigate the mechanistic relationships of cardiovascular dysfunction in Somali Americans is warranted. Research grant from Sleep Number to Mayo Clinic for studies of sleep and cardiovascular risk in Somali Americans, and by NIH R01-HL160619, T32-DK007013, T32-HL007111, and T32-HL105355. 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.

Background: Females with uterine fibroids (UF), benign tumors of the myometrium, have a higher risk of hypertension than females without UF. The relationship between UF and hypertension is not fully understood. Case studies have reported hypertension in patients with large UF that compress the ureters, resulting in hydronephrosis. However, this pathophysiology is not present in all females with UF and hypertension. It is unknown if UF volume is correlated with blood pressure in the absence of renal compromise. Therefore, the goal of this study was to determine the potential associations between blood pressure and 1) volume of the largest UF and 2) volume of the uterus (a surrogate for total UF volume) in females with UF. Methods: We utilized the Mayo Clinic Data Explorer to identify patients, who had pelvic ultrasound or magnetic resonance imaging (MRI) studies performed at Mayo Clinic-Rochester in 2021 that reported the presence of UF, and who were ages 18-65 years old. From this system, we collected brachial blood pressure data (systolic, diastolic, and mean), assessed in the outpatient setting within 14 days of imaging. For each patient, dimensions of the largest UF and the uterus were abstracted from radiology reports. The largest UF was assessed, as it reliably had all three dimensions reported. Volume of the uterus was used as a surrogate for total UF volume to consider the possibility of multiple UF that were not detailed in the radiology report. Volumes of the largest UF and uterus were each calculated as for ellipsoid structures, (length✕depth✕width)✕0.523 in cm3. The Pearson correlation coefficient (r) was calculated to assess the linear relationship between blood pressure and largest UF volume, and blood pressure and uterine volume. A p-value <0.05 denoted statistical significance. Results: One hundred thirteen females (48±9 years old) were included in the analysis, 88 with ultrasound and 25 with MRI reports. Average blood pressures were as follows, systolic: 121±16 mmHg (range: 92-185 mmHg), diastolic: 76±9 mmHg (52-101 mmHg), and mean: 91±11 mmHg (67-129 mmHg). Twenty-nine females (25.7%) had a diagnosis of hypertension. Hydronephrosis was not reported in any of the imaging reports. A mean of 2±2 UF were present per uterus (range: 1-15). Average volume of the largest UF was 75.0±115.9 cm3. Largest UF volume was not associated with systolic (r=0.023, p=0.812), diastolic (r=-0.040, p=0.677), or mean (r=-0.014, p=0.881) blood pressures. Average volume of the uterus was 219.6±215.6 cm3. Volume of the uterus was not associated with systolic (r=0.040, p=0.688), diastolic (r=0.102, p=0.305), or mean (r=0.071, p=0.475) blood pressures. Conclusion: In females with UF, blood pressure is not associated with the largest UF or uterine volumes. These data suggest that in the absence of hydronephrosis, the association between UF and blood pressure is not related to UF size. It is unknown if these findings differ based on factors, such as race. AHA 898649, NIH K01 HL1148144 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.

Succinate dehydrogenase (SDH) is a key enzyme in the tricarboxylic acid (TCA) cycle, as well as Complex II of the electron transport chain (ETC). In the SDH reaction, succinate is oxidized to fumarate in the TCA cycle, producing FADH2 contributing to the proton gradient that drives the reduction of ubiquinone to ubiquinol in the ETC. Thus, measurement of the maximum velocity of the SDH reaction (SDHmax) provides insight into both TCA cycle and ETC contributions to the maximum respiratory capacity of mitochondria. The goal of the present study was to use a quantitative histochemical technique, which we previously developed in skeletal muscle fibers, to quantify the SDHmax in permeabilized (45 μg/mL saponin) cardiomyocytes isolated from male Sprague-Dawley rats. In the SDH reaction, the oxidation of succinate (80 mM succinate; determined to be the maximum substrate concentration) to fumarate is coupled to the reduction of nitroblue tetrazolium (NBT; 1.5 mM) to its diformazan (NBTdfz) using 1-methoxyphenazine methosulphate (mPMS; 1 mM) as an exogenous electron carrier and azide (0.75 mM) to inhibit Complex IV. The progressive accumulation of NBTdfz as the reaction proceeds is measured by repeated densitometric (at 570 nm, the peak absorbance wavelength for NBTdfz) measurements. The optical density (OD) measurements are converted to mM fumarate using the Beer-Lambert-Bouger equation based on pathlength for light absorbance and the molar extinction coefficient for NBTdfz. Importantly, the pathlength for light absorbance must be controlled. In cross-sections of skeletal muscle fibers, pathlength was controlled by cryosectioning at 6 μm. In the present study, pathlength was controlled by optical sectioning using a confocal microscope. The isolated cardiomyocytes were imaged in 3D using a Nikon Eclipse A1 laser scanning confocal system with a ×40x/1.3 NA oil-immersion lens with an optical slice set at 0.5 μm. Changes in OD within a series of 10 optical slices were measured every 15 s over a 5 min period and expressed as mM fumarate/min using the Beer-Lambert-Bouger equation. We found that the SDH reaction was linear across 5 min, and that the change in OD was consistent throughout all 10 optical slices within a cardiomyocyte, suggesting that NBTdfz accumulates in the cytoplasm. Our results confirm that this assay of SDHmax is reproducible in cardiomyocytes and offers a single cell alternative to high-resolution respirometry. The ability to measure SDHmax in single cells is in contrast to respirometry, which only measures the average O2 consumption of aggregates of cells (isolated or in tissue). Thus, a direct measurement of SDHmax can provide valuable physiological insight into variation in mitochondrial function across a population of cardiomyocytes, e.g., as might occur with ischemic injury. Supported by the Mayo Clinic 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.

Hypertension is commonly observed with obstructive sleep apnea (OSA), partly due to dysregulation of sympathetic activity. As OSA is considered male-dominant, potential sex differences in the sympathetic regulation of BP have yet to be explored. Hemodynamic responses to an orthostatic challenge have implications for cardiovascular risk and are sympathetically-modulated. Therefore, we tested the hypothesis that females with OSA have differential BP and HR responses to orthostasis relative to males with OSA. 160 individuals not taking antihypertensive medications completed an overnight polysomnography to identify OSA (apnea-hypopnea index ≥5 events/hr). Orthostatic responses were quantified as the changes (Δ) in BP and HR (assessed via brachial cuff) from rest (10min supine) to 60sec post-standing. Females with (n=17, 42±14yrs, 30.7±6.0kg/m2) and without (n=43, 39±12yrs, 27.6±5.7kg/m2) OSA were compared to males with (n=60, 45±11yrs, 31.4±3.8kg/m2) and without (n=40, 39±13yrs, 27.4±3.1kg/m2) OSA using a one-way ANOVA. There were no between-group differences in age (p>0.05 for post-hoc comparisons) and BMI was lower in both females, and males, without OSA relative to males with OSA (p<0.05 for both). ΔSBP did not differ between females with (1±8mmHg) and without (2±8mmHg) OSA nor between males with (4±8mmHg) and without OSA (5±12mmHg, ANOVA p=0.37). Females with OSA had a blunted ΔDBP relative to females without OSA (5±7 vs. 10±6mmHg, p<0.05), whereas males with and without OSA demonstrated similar responses (9±8 vs. 10±6mmHg, p=0.95). ΔHR did not differ between females with (8±8beats/min) and without OSA (9±11beats/min) nor between males with (13±10beats/min) and without OSA (12±10beats/min, ANOVA p=0.06). ΔDBP was not associated with the apnea-hypopnea index (Spearman's r=-0.19, p=0.47; Spearman’s r=0.23, p=0.08) nor nadir SpO2 (Spearman's r=0.27, p=0.29; Spearman’s r=0.06, p=0.64) in females or males with OSA. These data suggest that OSA influences the DBP response to orthostasis in females to a greater extent than males. As DBP is associated with sympathetic activation, this finding could indicate greater sympathetic dysregulation in females, relative to males, with OSA. This work was supported by the National Institutes of Health T32-HL007111 (JMB), HL134808 (NC), HL065176 (PS and VKS), and HL134885 (VKS). 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.

The central neural mechanisms affecting sympathetic neuronal discharge strategies supporting homeostatic adjustments in human muscle sympathetic nerve activity (MSNA) remain unclear. This study investigated the hypothesis that central alpha-2 adrenergic mechanisms affect sympathetic action potential (AP) discharge, recruitment, and latency patterns within human MSNA (peroneal nerve microneurography and continuous wavelet transform). An alpha-2 adrenergic agonist (dexmedetomidine) was infused in eight healthy male and female participants (5 females; 28 ± 7years). Data were recorded during a 5-minute resting control condition, a 10-minute intravenous dexmedetomidine loading dose (0.225 μg/kg), and a dexmedetomidine maintenance dose (~0.1 μg/kg/hr). Data are reported as mean (SD) for the 5-minute control condition and 2-minutes of the dexmedetomidine infusion when MSNA bursting activity was demonstrably reduced. Two-tailed paired t-tests were performed. Dexmedetomidine reduced mean pressure (92 ± 7 to 80 ± 8 mmHg; P < 0.01) but did not affect heart rate (61 ± 13 to 60 ± 14 bpm; P = 0.75). Dexmedetomidine reduced integrated MSNA burst frequency (14 ± 6 to 4 ± 3 bursts/min; P < 0.01), sympathetic AP frequency (75 ± 46 to 16 ± 14 AP/min; P < 0.01), APs per burst (5 ± 1 to 4 ± 1 AP/burst; P = 0.01), AP clusters per burst (3.5 ± 0.7 to 3.0 ± 0.7 clusters/burst; P = 0.03), and de-recruited the largest AP clusters (12 ± 3 to 7 ± 2 AP clusters; P < 0.01). Despite de-recruiting large AP clusters with short conduction times, dexmedetomidine elicited shorter sympathetic AP conduction times (1.18 ± 0.12 to 1.14 ± 0.13 s; P = 0.03). Six participants performed a Valsalva Maneuver (20 s, 40 mmHg mouth pressure) during the control condition and during the dexmedetomidine maintenance dose. Data are reported as mean (SD) change (Δ) from the 2-minute period preceding the Valsalva Maneuver to the Valsalva Maneuver for each condition. During the control condition, Valsalva Maneuver increased AP frequency (Δ 311 ± 317 AP/min; P = 0.048), recruited larger previously silent AP clusters (Δ 2 ± 1 AP clusters; P < 0.01), and elicited shorter AP conduction times (Δ ‑0.09 ± 0.07 s; P = 0.02). Compared to the control condition, Valsalva Maneuver performed during the dexmedetomidine maintenance dose condition elicited lesser increases in AP frequency (Δ 116 ± 189 AP/min; P vs. control = 0.02) and lesser recruitment of larger previously silent AP clusters (Δ 0 ± 1 AP clusters; P vs. control = 0.02). Dexmedetomidine did not affect the latency reduction elicited by Valsalva Maneuver (Δ ‑0.07 ± 0.14 s; P vs. control = 0.61). These data suggest that human central alpha-2 adrenergic mechanisms affect: i) sympathetic postganglionic neuronal discharge and recruitment patterns, and ii) synaptic delays within the sympathetic neurocircuitry influencing AP latency. 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 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.

Background: Heart failure patients with preserved ejection fraction (HFpEF) exhibit exercise intolerance and exertional dyspnea. The underlying pathophysiology is complex and involves multiple physiological systems. To this point, HFpEF patients exhibit pulmonary abnormalities at rest and during exercise. For example, HFpEF patients have higher work of breathing during exercise due to greater inspiratory and expiratory resistive work of breathing. Importantly, this greater resistive work of breathing is not associated with higher inspiratory and expiratory flow rates suggesting pulmonary resistance is elevated in HFpEF patients. One potential explanation for the increase in resistive work of breathing during exercise in HFpEF patients is smaller luminal area of the airways. Purpose: The purpose of this study was to determine if differences exist in the luminal area of the large conducting airways in HFpEF patients compared to controls. We hypothesized that HFpEF patients will exhibit smaller luminal areas of the large conducting airways compared to controls. Methods: HFpEF patients (n=9; 67±7 yrs; 30±3 kg/m2) and controls (n=8; 62±9 yrs; 24±3 kg/m2) were enrolled. All participants performed pulmonary function testing and a thoracic computerized tomographic (CT) scan (assessed at total lung capacity). The airway luminal area was quantified from three-dimensional reconstructions from the high-resolution CT scans. The luminal areas of the large conducting airways were measured at three discreet points (corresponding to the beginning, middle, and end of the airway), averaged, and indexed to height. Results: The luminal area of the trachea was not different between groups (p=0.95). HFpEF patients had smaller luminal area of the right main bronchus (control: 1.38±0.21 vs. HFpEF: 1.18±0.13 mm2/cm) and left main bronchus (control: 0.98±0.20 vs. HFpEF: 0.79±0.15 mm2/cm) (both, p<0.04) than controls. HFpEF patients also had smaller luminal area of the bronchus intermedius (control: 0.82±0.14 vs. HFpEF: 0.67±0.15 mm2/cm) and left lower lobe bronchus (control: 0.48±0.13 vs. HFpEF: 0.36±0.07 mm2/cm) compared to controls (both, p<0.04). No differences were present between groups in the right and left upper lobe bronchi (both, p>0.40). Conclusion: HFpEF patients have smaller luminal areas of some, but not all large conducting airways compared to controls. These findings provide support for smaller large conducting airways in HFpEF contributing to the pulmonary abnormalities during exercise in these patients. 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.