Miller, Alex J.

Abstract On average, females have smaller airways than males. The largest discrepancy in airway size occurs during puberty, when endogenous sex hormone concentrations diverge between males and females. Transgender individuals often use gender‐affirming hormone therapy (GAHT) to align physical characteristics with gender identity. It is unknown whether GAHT influences airway size (luminal area and length). We evaluated the large conducting airways before starting GAHT and while undergoing years of GAHT. This retrospective within‐subject study included 12 adult transgender individuals who underwent CT scanning before starting GAHT and again after ≥1 year of GAHT. For each transgender individual, we identified two matched cisgender controls (one male and one female) who also underwent two CT scans over a comparable time interval for longitudinal comparison. We used a three‐dimensional reconstruction of CT imaging to measure luminal areas. Within‐subject changes in airway size between scans were assessed using Student's paired t ‐tests in transgender individuals undergoing feminizing hormone therapy. Variance between scans was assessed using Levene's test. Pre‐scans occurred an average of 2.0 ± 3.1 years before beginning GAHT. Transgender persons were on GAHT for an average of 3.3 ± 1.7 years (range, 1.0 – 6.7 years) at their second scan. We found no significant differences in airway luminal cross‐sectional areas for transgender persons on feminizing hormone therapy. The variance in airway size change between scans was not statistically different between transgender individuals and control subjects. Our findings suggest that the size of large conducting airways might remain unchanged after a period (>1 year) on GAHT.

Background: Spontaneous coronary artery dissection (SCAD) is a common type of myocardial infarction in females under the age of 50 years, caused by sudden separation between the coronary arterial wall layers and/or hematoma. The SCAD patient population is mostly females (~80%) with few or no traditional cardiovascular disease risk factors (e.g., obesity, hypertension). Common triggers for SCAD include sympathoexcitatory stimuli, such as intense physical and emotional stress. This implicates the sympathetic nervous system in the pathophysiology of SCAD. Thus, we aimed to investigate sympathetic nervous system responses to mental stress in patients with a history of SCAD. We hypothesized that females with a history of SCAD exhibit a greater increase in muscle sympathetic nerve activity (MSNA) with acute exposure to mental stress compared to healthy females. Methods: Seven females with a history of SCAD (age: 48±9 yrs, BMI: 29±6 kg/m 2 ) and seven age- and BMI-matched healthy female controls (CON, age: 49±9 yrs, BMI: 26±6 kg/m 2 ) participated in the study (both p>0.05). MSNA was measured via peroneal microneurography during a 2-minute rest, a 5-minute Stroop Color Word Test aimed at inducing mental stress, and a 2-minute recovery. Heart rate (HR, 3-lead electrocardiography) and BP (finger photoplethysmography) were continuously recorded during each stage. Data are presented as an absolute change from rest (Δmean±SD). Two-way independent t-tests were used for statistical analyses. Results: Resting mean blood pressure (MBP, SCAD: 96±14 vs CON: 89±7 mmHg, p=0.27), heart rate (HR, SCAD: 56±11vs CON: 65±16 bpm, p=0.25), MSNA burst frequency (SCAD: 22±9 vs CON: 18±7 bursts/minute, p=0.40) and total MSNA (SCAD: 1135±471 vs CON: 951±245 au/min, p=0.41) were not different between the groups. During the Stroop Color Word Test, average changes in MBP (SCAD: Δ10±9 vs CON: Δ8±5 mmHg, p=0.67) and HR (SCAD: Δ11±7 vs CON: Δ14±5 bpm, p=0.35) were not different between the groups. Similarly, average changes in MBP (SCAD: Δ3±4 vs CON: Δ-2±5 mmHg, p=0.13) and HR (SCAD: Δ3±4 vs CON: Δ3±2 bpm, p=0.62) were not different during the recovery. Changes in MSNA burst frequency with the Stroop Color Word Test (SCAD: Δ1±7 vs CON: Δ6±7 bursts/minute, p=0.22) and recovery (SCAD: Δ0±5 vs CON: Δ4±4 bursts/minute, p=0.13) were not different between the groups. Total MSNA changes were also not different during the Stroop Color Word Test (SCAD: Δ267±335 vs CON: Δ606±432 au/min, p=0.15) and recovery (SCAD: Δ68±666 vs CON: Δ217±217 au/min, p=0.61) between the two groups. Conclusion: These preliminary data suggest that contrary to our hypothesis, sympathetic nervous system responses to acute mental stress exposure are not different between females with a history of SCAD and healthy females. Further investigation is needed to understand MSNA association with chronic stress exposure in females with a history of SCAD. Funding: NIH K23 HL155506 This abstract was presented at the American Physiology Summit 2026 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

AbstractInterstitial lung disease (ILD) encompasses pulmonary disorders characterized by chronic inflammation and fibrosis that disrupt pulmonary gas exchange. While ILD‐related changes in the lung parenchyma are well‐documented, less is known about how ILD affects luminal area within the large conducting airways. This retrospective, case–control study tested the hypothesis that patients with ILD would have greater large conducting airway luminal areas than healthy matched controls. Three‐dimensional reconstructions of computed tomography images were used to quantify airway luminal areas in patients with ILD (n = 82; 54% female) and healthy controls matched for age, sex, and height. Patients with ILD had 16%–22% greater airway luminal areas across all seven measured large conducting airways compared to controls (all p < 0.001). Among patients with ILD, males had 17%–34% greater height‐normalized airway luminal areas than females (all p < 0.05). These data provide evidence that ILD is associated with greater large conducting airway luminal area, even when matched for key demographic factors. Consistent with observations in health, males with ILD exhibited greater height‐normalized airway size than females. These findings offer new insight into airway remodeling in ILD and highlight potential sex differences in airway luminal area.

Background: Spontaneous coronary artery dissection (SCAD) is an acute separation of coronary artery wall layers that blocks blood flow to the heart and leads to acute coronary syndrome. Patients with SCAD are relatively young females (~40-50 years) who have few cardiovascular risk factors. Sympathoexcitatory stress often precedes SCAD events (i.e. intense physical and/or emotional stress), suggesting that patients with SCAD may have augmented hemodynamic responses to sympathoexcitatory stressors. As such, we aimed to evaluate hemodynamic responses to cold stress in females with a history of SCAD and females without a history of SCAD. We hypothesized that females with a history of SCAD would have augmented hemodynamic responses to cold stress relative to females without a history of SCAD. Methods: Females with a history of SCAD were matched to females without a history of SCAD for age and body mass index. Heart rate (electrocardiogram) and beat-to-beat blood pressure (finger photoplethysmography) were recorded and averaged during two minutes of resting baseline and the minute during the cold pressor test that produced the peak hemodynamic response. Delta (Δ) values of the hemodynamic parameters were calculated. Data are reported as mean ± SD. Unpaired t-tests were used to analyze demographics, anthropometrics, resting hemodynamics, and hemodynamic responses between females with a history of SCAD and females without a history of SCAD. Results: Age (50±9 vs 56±8 years) and body mass index (27±6 vs 24±3 kg/m 2 ) did not differ between females with a history of SCAD (n=20) and females without a history of SCAD (n=12, both p>0.05), respectively. Resting heart rate ([HR], 57±10 vs 59±11 bpm), systolic blood pressure ([SBP], 112±14 vs 110±13 mmHg), diastolic blood pressure ([DBP], 72±10 vs 72±9 mmHg), and mean arterial pressure ([MAP], 86±11 vs 85±9 mmHg) were not different between females with a history of SCAD and females without a history of SCAD, respectively (all p>0.05). Hemodynamic responses to cold stress (ΔHR, 6±5 vs 7±5 bpm; ΔSBP, 20±16 vs 18±7 mmHg; ΔDBP, 7±11 vs 11±6 mmHg; ΔMAP, 10±14 vs 13±5 mmHg; all p>0.05) were not different between females with a history of SCAD and females without a history of SCAD, respectively. Conclusion: Hemodynamic responses to cold stress were not different between females with a history of SCAD and females without a history of SCAD, indicating that an augmented pressor response to this stress is likely not a primary predisposing factor to a SCAD. However, it remains important to assess other forms of stress to inform future care and counseling of patients with history of SCAD. Funding: K23HL155506 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Introduction: Spontaneous coronary artery dissection (SCAD) is one of the most common causes of myocardial infarction in females under the age of 50 and peripartum females. Furthermore, approximately 10% of patients with a history of SCAD have recurrent SCAD within 5 years. In a subset of patients, SCAD events are preceded by sympathoexcitatory stimuli, such as emotional or physical stress. This implicates the sympathetic nervous system in the pathophysiology of SCAD. Thus, we aimed to investigate this relationship through measuring muscle sympathetic nerve activity (MSNA) and quantifying MSNA transduction into diastolic blood pressure (BP) in females with a history of SCAD compared to healthy female controls. We hypothesized that females with a history of SCAD would have both augmented MSNA and MSNA transduction at rest compared to their healthy counterparts. Methods: Females with a history of SCAD and healthy controls (HC) were recruited for the study. MSNA was continuously recorded using microneurography at the peroneal nerve during 10-minute supine rest. Heart rate (HR, 3-lead electrocardiography) and BP (finger photoplethysmography) were continuously recorded during this period. We plotted binned MSNA burst areas against diastolic BP, using linear regression analysis in MATLAB R2023a to quantify the transduction slope. We compared peak bins of transduction slopes between the two groups. Data are presented as mean±SD. Independent samples t-tests were performed for statistical analyses. Results: Seven females with a history of SCAD (49±11 years; BMI: 28.5±7 kg/m 2 ) and six controls (51±8 years; BMI: 26.2±6.3 kg/m 2 ) participated in the study (both p>0.05). Resting systolic BP (SCAD: 121±8 vs. HC: 122±15 mmHg), diastolic BP (SCAD: 78±9 vs. HC: 75±7 mmHg) and HR (SCAD: 59±13 vs. HC: 67±18 bpm) were not different between groups (all p >0.05). MSNA burst frequency (SCAD: 25±12 vs. HC: 27±7 bursts/minute), burst incidence (SCAD: 42±18 vs. HC: 46±15 bursts/100 heartbeats), and total MSNA (SCAD: 820±286 vs. HC: 1050±119 au/minute) did not differ between groups (all p >0.05). MSNA transduction at rest was not different between females with a history of SCAD and healthy controls (0.02±0.03 vs. 0.05±0.05 mmHg(%·s) -1 , p>0.05). Conclusions: These preliminary data suggest that resting MSNA and transduction do not differ between females with a history of SCAD and healthy controls, contrary to our hypothesis. Further investigation is needed to determine if this observation is preserved with exposure to sympathoexcitatory stimuli. Funding: NIH K23 HL155506, T32 DK07352, K01 HL148144, UL1 TR0022377, and AHA 898649 This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Background: During acute hypoxia, Thehuman brainemploys complex regulatory mechanisms to compensate for high O 2 demand and low O 2 blood saturation. High hemoglobin-oxygen (Hb-O 2 ) affinity improves arterial oxygen saturation (S a O 2 ) in low oxygen environments providing a potential physiologic benefit in humans. However, the impact of high Hb-O 2 affinity on cerebral blood flow (CBF) and cerebral tissue oxygenation (S t O 2 ) has yet to be examined. This work aimed to determine the influence of an acute increase in Hb-O 2 affinity from Etavopivat, a selective red blood cell pyruvate kinase activator, on CBF regulation and S t O 2 during handgrip exercise in normoxia and hypoxia. Methods: 16 healthy adults (31±8 yr, 5 females) completed two visits; before and after Etavopivat (400 mg daily, 7 days) administration,. Each visit included graded handgrip (~3 min stages each) exercise (rest, 10% maximal voluntary contraction (MVC), 20% MVC) while participants inspired normoxic (NORM, 21% O 2 ), moderate (MH, 15% O 2 ), and severe (SH, 10% O 2 ) hypoxic gas mixtures. Hb-O 2 binding affinity (P 50 ), was measured using dual-wavelength spectrophotometry (pH~7.4 and 37ºC). Blood sampling through catheterization of the non-exercising arm measured S a O 2 . CBF was approximated by the peak middle cerebral artery velocity, measured with a 2MHz transcranial doppler ultrasound through the transtemporal window. S t O 2 was measured using frequency-domain near infrared spectroscopy of the frontal cortex. CBF and S t O 2 between visits were compared using separate two-way RM ANOVA models to determine the effects of Etavopivat [before (baseline) or after 7d Etavopivat exposure (post)] and exercise intensity [rest, 10% MVC, 20% MVC] for each inspirate. Results: P 50 was reduced after Etavopivat exposure (Baseline: 28.6±1.6 mmHg, Etavo: 24.8±1.3, P <0.001) without impacting hematocrit ( P =0.97). S a O 2 was higher following Etavopivat exposure during each inspirate ( P <0.001 for each). There was no significant effect of handgrip exercise on CBF or S t O 2 within any inspirate. Cerebral S t O 2 was higher during each inspirate (all P <0.002)– NORM (Baseline: 65.3±12.3%, Post: 68.8±9.8%), MH (Baseline: 61.0±11.7 %, Post: 66.1±10.5%) and SH (Baseline: 47.7±13.5%, Post: 56.6±11.5%). In addition, CBF was increased during each inspirate (all P <0.001)– NORM (Baseline: 62.2±12.2 cm/s, Post: 69.2±12.5 cm/s), MH (Baseline: 60.8±13.1 cm/s, Post: 67.9±12.3 cm/s) and SH (Baseline: 69.8±16.3 cm/s, Post: 79.2±18.0 cm/s). Conclusion: The acute pharmacological induction of high Hb-O 2 affinity leads to increased CBF and cerebral S t O 2 during acute hypoxic exposure in conditions of mild muscular exertion. Whether the improvement of cerebral S t O 2 is associated increased S a O 2 or CBF (or both) is unclear. These findings are the first to investigate the complex determinants of cerebral S t O 2 as a function of an acute increase in Hb-O 2 affinity. These improvements in S t O 2 during hypoxic exposure may lead to a host of theoretical benefits such as improved hypoxia tolerance, and mitigated decrements in cognitive function during hypoxic exposure. This study was funded by Forma Therapeutics Inc, which was acquired by Novo Nordisk on October 14, 2022, Novo Nordisk A/S. This abstract was presented at the American Physiology Summit 2025 and is only available in HTML format. There is no downloadable file or PDF version. The Physiology editorial board was not involved in the peer review process.

Three-dimensional reconstruction of airways has shown increased luminal area in patients with COVID-19 and post-acute sequelae of COVID-19 when compared with healthy controls. These findings suggest the role of large conducting airways in the pathogenesis of post-acute sequelae of COVID 19.

Background: Cystic fibrosis (CF) is a genetic disorder in which patients have dysfunctional cystic fibrosis transmembrane regulatory (CFTR) proteins in the lungs that disrupt ion regulation resulting in a thick, viscous mucus layer on the airway epithelium. Consequential poor mucociliary clearance leads to repeated infections and chronic inflammation contributing to bronchiectasis which is associated with increased airway luminal area. CFTR modulator therapy can improve and even restore the function and expression of a mutated CFTR gene which has been shown to improve sweat chloride levels and pulmonary symptoms rapidly. However, the effect of CFTR modulator therapy on large conducting airway luminal area is unclear. We compared large conducting airway luminal area in patients with CF before and after initiating CFTR modulator therapy. We hypothesized that airway luminal area would normalize (decrease) after initiating CFTR modulator therapy. Methods: Twenty-three patients with CF (32±15 years, 11 female) with computed tomography (CT) imaging of their lungs before and after initiating CFTR modulator therapy were included in analyses. In each patient we measured seven large conducting airways (trachea, left and right main bronchus, bronchus intermediate, left and right upper lobe, and left lower lobe) before and after CFTR modulator therapy initiation. To control the potential effect of height, airway luminal area (mm2) was divided by patient height (cm). Paired t-tests compared differences between luminal area before after initiating CFTR modulator therapy. Results: Patients were taking CFTR modulator therapy for a median of 1.1 years (range: 22–2111 days) at the time of their CT imaging after initiating CFTR modulator therapy. Large conducting airway luminal area was not different before and after initiating CFTR modulator therapy in all seven airways: trachea (1.50±0.35 vs. 1.56±0.34 mm2/cm, p=0.14), right main bronchus (1.05±0.21 vs. 1.09±0.19 mm2/cm, p=0.11), bronchus intermediate (0.68±0.16 vs. 0.68±0.16 mm2/cm, p=0.54), right upper lobe (0.42±0.10 vs. 0.45±0.09 mm2/cm, p=0.27), left main bronchus (0.81±0.19 vs. 0.83±0.18 mm2/cm, p=0.21), left upper lobe (0.51±0.13 vs. 0.52±0.13 mm2/cm, p=0.45), and left lower lobe (0.44±0.11 vs. 0.46±0.10 mm2/cm, p=0.42). Conclusion: There was no change in large conducting airway luminal area after initiating CFTR modulator therapy suggesting CFTR modulator therapy may not reverse CF-associated airway luminal area changes. However, longitudinal analysis and investigation into the small airways are necessary for a comprehensive understanding of the effect of CFTR modulator therapy on airway luminal area changes. Funding: NIH (HL139854 to MJJ, HL131151 to SEB) and NSERC (PDF-577750-2023 to AHR). 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.

Background: Spontaneous coronary artery dissection (SCAD) causes acute coronary syndrome or sudden cardiac death due to a separation of arterial wall layers. The majority of patients with SCAD are females (>80%) with few to no traditional cardiovascular risk factors. Though the physiological mechanisms that predispose to SCAD are unknown, common triggers for SCAD events include sympathoexcitatory stimuli, such as mental and emotional stress. Additionally, studies report high prevalence of depression and anxiety among patients with SCAD. Our study aimed to investigate cardiovascular responses to mental stress in patients with SCAD. We hypothesized that patients with SCAD would have exaggerated cardiovascular responses to mental stress compared to healthy controls. Methods: Four female patients with SCAD were age-, and BMI-matched with 4 healthy females. Participants underwent 2 minutes of baseline quiet rest, a 5-minute Stroop Color Word Test to induce mental stress, followed by 2 minutes of recovery. Continuous beat-to-beat blood pressure (BP, finger photoplethysmography) and heart rate (HR, 3-lead ECG) were recorded. Venous occlusion plethysmography was used to measure forearm blood flow (FBF). Forearm vascular conductance (FVC) was calculated as FBF/mean BP×100. Data are presented as change from baseline (Δmean±SD). Group data were compared using independent samples t-tests. Results: Resting hemodynamic parameters (Systolic [SBP], Diastolic [DBP], and Mean BP [MBP], Pulse pressure [PP], and HR) and FVC were similar between groups. Patients with SCAD had greater increases in DBP (Δ12±5 vs. Δ1±5 mmHg, p=0.02) and PP (Δ5±3 vs. Δ-7±8 mmHg, p=0.04) during the last minute of mental stress test compared to controls. Although, there were no differences in the changes of SBP (Δ17±7 vs. Δ-1±13 mmHg, p=0.05), MBP (Δ13±6 vs. Δ3±8 mmHg, p=0.08), HR (Δ8±0 vs. Δ10±2 bpm, p=0.12), or FVC (Δ1.5±1.2 vs. Δ1.8±1.3 ml/min/100 mmHg, p=0.80) between groups. During the last minute of recovery, there were no differences in hemodynamic parameters (SBP: Δ6±9 vs. Δ-4±10 mmHg, p=0.23; DBP: Δ2±7 vs. Δ-3±2 mmHg, p=0.22; MBP: Δ3±7 vs. Δ-3±5 mmHg, p=0.22; PP: Δ4±5 vs. Δ-1±8 mmHg, p= 0.35; HR: Δ-1±3 vs. Δ0±3 bpm, p=0.64), or FVC (Δ1.3±1.7 vs. Δ0.5±0.3 ml/min/100 mmHg, p= 0.35) between groups. Conclusion: These preliminary data suggest that patients with SCAD have greater increases in DBP and PP in response to mental stress compared to healthy controls. These exaggerated pressor responses might have implications for the pathophysiology of SCAD. NIH K23 HL155506, T32 DK07352, K01 HL148144, UL1 TR0022377, and AHA 898649. 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.