bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ventilatory Variability Is Increased at Rest in Pulmonary Arterial Hypertension
Authors: Plunkett Michael , Sayegh Ana , McWilliams Tanya , Sithamparanathan Sasiharan , F.R Paton Julian , Fisher James 
Published: May 2024

Ventilatory instability is associated with adverse outcomes in left heart failure, with periodic breathing during awake, rest, sleep and exercise (exercise oscillatory ventilation) associated with increased mortality. Increased peripheral and central chemoreflex sensitivities and impairment of cardiac output have been implicated as causative mechanisms of ventilatory instability in heart failure. As these factors are also present in pulmonary arterial hypertension (PAH), we tested the hypothesis that variability of breath-by-breath ventilation at rest would be increased in PAH compared with healthy controls. In fourteen patients with PAH (9 female, age 48.4±12.8 years, mean ± SD) and 14 healthy participants (9 female, age 49.4±14.2 years) breath-by-breath measurement of tidal volume and breathing frequency was undertaken with a pneumotachometer connected via a mouthpiece with nose-clip for 10 minutes while they rested awake and supine. Ventilatory (V̇E) variability was assessed using root mean square of successive differences (RMSSD), standard deviation (SD), average real variability (ARV, i.e., sum of absolute differences in successive observations), coeffcient of variation (CoV), as well as Poincaré analysis and compared between PAH and healthy controls (Student’s t-test). Correlations between measures of ventilatory variability and pulmonary hemodynamic characteristics, exercise capacity and function were assessed with Pearson’s correlation coeffcient. Resting V̇E was higher in PAH compared to healthy controls (14.3±1.1 and 12.1±0.5 L·min−1 respectively; p=0.009). Measures of variability for V̇E were increased in PAH compared to healthy controls. More specifically, RMSSD (3.59±1.36 vs. 2.48±0.87 L·min−1, p=0.017), SD (2.92±1.14 vs. 1.98±0.53 L·min−1, p=0.012), ARV (2.47±0.97 vs. 1.67±0.60 L·min−1, p=0.016), Poincaré SD1 (short-term variability, p=0.020) and SD2 (long-term variability, p=0.028) were increased in PAH compared to healthy controls, respectively. No correlations were found between measures of ventilatory variability and pulmonary hemodynamics (mean pulmonary artery pressure, pulmonary vascular resistance, and cardiac output), six-minute walk distance or WHO functional class. In summary, resting ventilatory variability is increased in PAH and not associated with haemodynamic factors and exercise capacity. Whether such raised ventilatory variability in PAH is related to increased chemoreflex sensitivity requires exploration. This study received funding support from the Greenlane Research and Educational Fund (21/01/4153), Health Research Council of New Zealand (19/687), and the Sidney Taylor Trust. 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.
Sex Differences In The Phenotype Of Sleep-Disordered Breathing In C57BL/6J Mice
Authors: Kim Lenise , Pham Luu , Polotsky Vsevolod 
Published: May 2024

Sex differences in sleep-disordered breathing (SDB) are widely recognized. SDB is more prevalent in men, but women appear to exhibit more symptoms at lower levels of SDB severity, including insomnia symptoms. Mechanisms underlying sex differences in SDB are unknown. In this study, we compared the sleep architecture and breathing patterns during sleep between male and female mice and examined the effects of ovariectomy on SDB. We hypothesized that female and male mice differed in sleep and SDB, which are related to differences in carbon dioxide (CO2) chemosensitivity between sexes. Adult male (n=9) and female (n=10) C57BL/6J mice underwent full-polysomnography inside a whole-body plethysmography chamber. Arousals from sleep and apneas were manually scored. Breathing variability was assessed with Poincaré plots of minute ventilation. Hypercapnic ventilatory response (HCVR) was assessed during wakefulness and NREM sleep by acute administration of 8% CO2. In female mice, we performed bilateral ovariectomy and repeated sleep studies after 14 days. We found that arousal index was 55% increased in females compared to males, but sleep fragmentation was mainly attributed to spontaneous arousals in both groups. Surprisingly, apnea severity was significantly increased in female mice compared to males (32.4±6.7 vs 11.8±4.5, P=0.001). Breathing instability was also increased in females. HCVR was positively correlated with apnea index (r=0.55, P=0.05) and was significantly augmented in females compared to males. Ovariectomy did not affect sleep fragmentation, but attenuated CO2 sensitivity and improved breathing stability during sleep. Our results have suggested different SDB phenotypes between male and female C57BL/6J mice. SDB in female mice is associated with a hyperarousal state and increased HCVR compared to males. An exacerbated CO2 responsiveness related to ovarian hormones in females is an important determinant of differences in SDB severity and respiratory patterns between male and female sex. American Heart Association Postdoctoral Fellowship Award 828142 (to L.J.K.), NHLBI grant 2R01 HL133100-05, NIH R01 HL128970, and R01 HL13892 (to V.Y.P.), 1K23HL155730 and American Academy of Sleep Medicine Foundation 238-BS-20 (to L.V.P.). 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.
Lower Mitochondrial Genome Turnover and Greater Mutation Frequency in Skeletal Muscle of Aged Compared to Adult OKC-HET Rats
Authors: Musci Robert , Fuqua Jordan , Peelor Frederick , Richardson Arlan , Miller Benjamin , Wanagat Jonathan 
Published: May 2024

Mitochondrial genomic integrity, which is supported by processes such as replication, repair, and turnover, is critical in supporting metabolism and organismal health. Accumulation of mitochondrial DNA (mtDNA) mutations contributes to mitochondrial and whole-tissue dysfunction, which lead to chronic diseases including sarcopenia. The underlying mechanisms that promote generation and age-related accumulation of mtDNA mutations are unclear. mtDNA mutants may have a replicative advantage over wild-type mtDNA that propagates the accumulation of mtDNA mutations with age. However, there is limited in vivo data regarding effects of age on mtDNA replication, particularly in skeletal muscle. We hypothesized mtDNA synthesis rates would increase with age as mutation burden increased in skeletal muscle in both male and female rats. Methods: We measured mtDNA synthesis over 14 days using the stable isotope tracer deuterium oxide (D2O) and assessed mtDNA copy number and mutation deletion frequency using digital PCR in quadriceps muscle of 9- and 26 month-old (mo) male and female OKC-HET rats, which have heterogenous mtDNA backgrounds. Results: There were no differences in mtDNA copy number between sexes or ages. However, 26 month-od rats had lower rates of mtDNA synthesis compared to 9 month-old rats (9 mo: 0.509 ± 0.009 %/day, 26 month: 0.371 ± 0.048 %/day; p=0.0024) and greater mtDNA half-lives (9 mo: 132 ± 1.79 days, 216 ± 25.63 days; p=0.0009). Concomitant with lower mtDNA synthesis, 26 month-old rats had greater (p=0.003) mtDNA deletion mutation frequency (2.023e-004 ± 7.18e-005) than 9 month-old rats (9.310e-005 ± 2.404e-005). 26 month-old female rats (1.309e-004 ± 2.386e-005) had a lower (p=0.008) mutation burden than male rats (2.74e-004 ± 4.484e-005). Conclusion: Contrary to our hypothesis, mtDNA synthesis declined with age as mutation burden increased in the quadriceps. Because mtDNA copy number was not different between ages, while synthesis decreased, mtDNA turnover declined with age. Altogether, these results suggest lower mtDNA turnover rates may contribute to age-related mtDNA mutation burden. Future studies should test how modulating mtDNA turnover affects mutation frequency and mitochondrial function. This study was supported by funding from NIH grants R21AG072137 and 5T32AG052363-04. 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 in vivo effects of an ENaC Na+ self inhibition-enhancing mutation
Authors: Nickerson Andrew , Sheng Shaohu , Wang Xueqi , Mutchler Stephanie , Chen Jingxin , Marciszyn Allison , Whelan Sarah 
Published: May 2024

Background: Epithelial Na+ channel (ENaC)-mediated Na+ reabsorption in the distal nephron is a critical regulator of extracellular fluid volume and K+ homeostasis. Physiologic concentrations of extracellular Na+ reduce channel activity (open probability; PO) via an allosteric mechanism termed “Na+ self-inhibition,” which involves Na+ ions binding to specific sites in the channel’s extracellular domains. Recent studies have identified human ENaC mutations that alter the Na+ self-inhibition response when assayed in vitro. Such mutations may confer sensitivity or resistance to salt-induced blood pressure changes. Using CRISPR-Cas9 technology, we generated mice carrying a mutation previously shown to enhance Na+ self-inhibition (αH282R) to assess the effects on ENaC-dependent Na+ transport in vivo. We predicted that ENaC activity would be reduced in these mice, leading to enhanced sensitivity to Na+ deprivation or K+ loading, along with accompanying compensatory changes to overcome the predicted loss of function. Methods: We measured urinary electrolyte handling in wild type (WT) and αH282R mice maintained on normal, low Na+, or high K+ diets using metabolic cages. We assessed ENaC activity ex vivo using patch clamp and Ussing chamber methods. We also measured blood chemistry and aldosterone levels in WT and αH282R mice under the dietary conditions described above. Results: When maintained on a normal chow diet (0.3% NaCl), αH2832R mice expressed ENaCs in the distal nephron with reduced PO compared to WT littermates (0.026 vs. 0.067; p<0.01), while ENaC subunit protein expression was unaltered. Amiloride-sensitive short-circuit currents were reduced in the distal colons of αH283R mice versus WT littermates (-12.6 vs. -3.9 μA/cm2; p<0.01). Plasma aldosterone levels were also higher in αH283R versus WT mice on a control diet (610 vs 288 pg/mL; p=0.02), while no other differences in baseline blood chemistry were observed. When challenged with either dietary Na+ restriction (<0.01% NaCl) or K+ loading (10% KCl), WT and αH283R mice responded similarly in terms of body weight maintenance, urinary Na+ and K+ excretion, and systemic electrolyte and metabolic parameters, with the exception of higher aldosterone levels in Na+-restricted αH282R mice compared to WT littermates (2,759 vs. 1271 pg/mL; p<0.01). Conclusions: The αH282R mutation, which enhances Na+ self-inhibition, confers reduced ENaC activity in mice. However, this loss of function may be compensated by ENaC-independent Na+/K+ handling mechanisms and/or increased aldosterone signaling during adaptation to dietary salt stressors. P30DK079307, T32DK061296. 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.
Circulating Fetal Troponin I May Reflect Cardiomyocyte Proliferation
Authors: Jonker Sonnet , Louey Samantha 
Published: May 2024

INTRODUCTION: Circulating biomarkers such as Troponin I (TnI) that are typically indicative of myocardial damage in adults have been reported to be detectable in cord blood of healthy infants delivered both vaginally and by cesarean section prior to labor. We performed serial sampling of healthy fetal sheep from ~20 days before spontaneous birth to 5 days postnatal in order to describe normal developmental values of circulating TnI. METHODS: Seven fetal sheep were surgically instrumented with indwelling catheters advanced into the ascending aorta and the superior vena cava. Following surgical recovery, daily blood samples were taken first thing in the morning into heparin, and the plasma was frozen for later determination of high-sensitivity (hs) TnI levels (BeckmanCoulter UniCel DxI Access IA; log transformed limit of detection =0.30, limit of quantification =0.78, and 99th%ile =1.78). Positive and negative control samples were drawn from an adult ewe during a terminal experimental ligation of the left anterior descending coronary artery and similarly assessed. hs-TnI data were log transformed from ng/L, visually assessed, and outliers removed by the ROUT method. RESULTS: Log(hs-TnI) was 1.47±0.30 at 20 days before birth and declined to 0.88±0.36 in fetuses 12±4 hour before birth (p<0.0001, R2=0.8444). Birth stimulated a delayed, transient peak in hs-TnI (P=0.0058). In the newborn, 43±19 min after birth, levels were 1.39±0.40 (P=0.0650 vs. fetus on day of birth). The day after birth, log(hs-TnI) increased to 2.14±0.63 (P=0.0331 vs. newborn). The second day after birth, levels declined to 1.65±0.48 (P=0.0238 vs. day 1). Adult ewe log(hs-TnI) was below the limit of detection; three hours following coronary artery ligation, levels were 3.21. CONCLUSIONS: This study confirms that hs-TnI levels are moderate to high in healthy sheep fetuses, and reports for the first time that they decline towards term. Why TnI is elevated in the healthy fetus is unknown. If cardiomyocyte TnI is leaked during cytokinesis, the decline towards birth may reflect the diminishing rate of proliferation in this same period. The postnatal hs-TnI peak, above the clinical threshold for evidence of myocardial ischemia in adult humans, may result from hemodynamic, oxidative, or metabolic stresses associated with the establishment of postnatal physiology. This work was funded by an award from the NHLBI (R01HL142483). 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.
Remodeling of the Human Skeletal Muscle Proteome Found After Long-Term Endurance Training but Not After Strength Training
Authors: Emanuelsson Eric , Arif Muhammad , Reitzner Stefan , Perez Sean , Lindholm Malene , Mardinoglu Adil , Daub Carsten 
Published: May 2024

Regular exercise training has tremendous systemic tissue-specific health benefits, but the molecular adaptations to long-term exercise training are not completely understood. The aim of the current study was to investigate the skeletal muscle proteome of highly endurance-trained, strength-trained and untrained individuals and performed exercise- and sex-specific analyses. As a previous investigation from our lab showed limited baseline differences at the gene expression level between highly strength-trained males and untrained males, we hypothesized that the that long-term resistance training results in baseline differences in protein abundances. Additionally, we hypothesized that endurance-trained individuals would have a greater abundance of mitochondrial proteins compared with the untrained and the strength-trained individuals. Liquid-chromatography followed by mass-spectrometry (LC-MS/MS) was performed on skeletal muscle tissue from all individuals. A total of 6713 proteins were detected, with 4269 proteins being expressed in at least 50% of the samples. Over 650 proteins were differentially expressed in the skeletal muscle of endurance-trained individuals compared with controls. Strikingly, 92% of the shared proteins with higher expression in both the male and female endurance groups were known mitochondrial proteins. In contrast to the findings in endurance trained individuals, minimal differences were found in strength-trained individuals and between females and males. Lastly, to determine the preventive-medicine capabilities of long-term training, a co-expression network and comparative literature analysis revealed key proteins and pathways related to the health benefits of exercise, which were primarily related to differences in mitochondrial protein abundance. This network is available as an interactive database resource ( https://inetmodels.com ) where investigators can correlate clinical data with global gene and protein expression data for hypothesis generation. In conclusion, we suggest that long-term endurance training but not strength training results in a r emodeling of the skeletal muscle proteome in humans. This work was financially supported by grants from the Swedish Research Council (2018-02932), the Swedish Center for Sports Research (2020-D0007, P2022-0082), the National Science Foundation (Award Number: 1951792), the Whitaker International Program and the Karolinska Institute. 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.
Insulin-Mediated Capillary Recruitment Is Absent in the Cutaneous Microvasculature of Women with a History of Gestational Diabetes Mellitus
Authors: Maurer Grace , Hernandez Paola , Schwartz Kelsey , Brustkern Kaila , Jalal Diana , Stanhewicz Anna 
Published: May 2024

Women with a history of gestational diabetes mellitus (GDM) have a significantly greater risk of developing cardiovascular disease and type II diabetes compared to women who had an uncomplicated pregnancy (HC). Although the mechanisms underlying this increased risk are unclear, emerging evidence suggests that microvascular endothelial dysfunction, mediated via reduced nitric oxide (NO)-dependent dilation, persists after pregnancy complicated by GDM. Whether this microvascular dysfunction reduces insulin-mediated responses in these women is unexplored. We hypothesized that insulin-mediated capillary recruitment would be attenuated in women with a history of GDM via NO-dependent mechanisms. 24 women (n=12/group; HC: 35±1 years, 24±4 months post-partum; GDM: 33±1 years, 21±3 months postpartum) underwent intradermal microdialysis, which involved the placement of 2 fibers in the ventral forearm for the local delivery of 10−4M insulin alone or 10−4M insulin+15mM NG-nitro-L-arginine methyl ester (L-NAME, NO-synthase inhibitor). The cutaneous blood flow response to post-occlusive reactive hyperemia (PORH; 5 minutes) was assessed before and during insulin perfusion. Red blood cell flux was measured continuously over each microdialysis site by laser-Doppler flowmetry. Cutaneous vascular conductance was calculated (CVC=flux/mean arterial pressure), normalized to maximum (%CVCmax), and presented as PORH area under the curve (AUC, %CVCmax• sec−1). Microvascular capillary recruitment was assessed as ΔAUC (pre-insulin AUC - insulin AUC). Insulin perfusion increased PORH in HC (pre-insulin: 4066±490 vs. insulin: 7848±978 AUC; p=0.03) but had no effect in GDM (pre-insulin: 3765±293 vs. insulin: 6196±779 AUC; p=0.26). Insulin perfusion did not increase PORH at the L-NAME site in either group (p>0.05). Within groups, L-NAME perfusion reduced insulin-mediated capillary recruitment in HC (control: 3781±1109 vs. L-NAME: 470±945 ΔAUC; p=0.04) but not GDM (control: 2431±796 vs. L-NAME: -41±1014 ΔAUC, p=0.11). These data suggest that insulin-mediated capillary recruitment assessed by PORH in the cutaneous circulation is mediated by NO-dependent mechanisms in healthy women with a history of uncomplicated pregnancy and attenuated in healthy women with a history of GDM. This reduction in insulin-mediated microvascular responses may contribute to the increased risk of cardiovascular disease and type II diabetes in these women. UI Fraternal Order of Eagles Diabetes Research Center Catalyst Grant; NIH HL169201. 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.
Mindfulness-Based Stress Reduction and Autonomic Modulation in Chronic Kidney Disease
Authors: Jeong Jinhee , Zanuzzi Matias , DaCosta Dana , Li Sabrina , Park Jeanie 
Published: May 2024

Intro: Chronic kidney disease (CKD) is characterized by chronic overactivation of the sympathetic nervous system (SNS) that leads to increased blood pressure and cardiovascular disease risk. Mindfulness-Based Stress Reduction (MBSR) is an 8-week mindfulness meditation training program that has previously been shown to reduce blood pressure and improve autonomic balance in healthy and some clinical populations; however, MBSR has never previously been tested in CKD and the long-term effects of mindfulness mediation on SNS activity are unknown. Thus, we tested the hypothesis that 8 weeks of MBSR reduces SNS activity and reactivity in CKD patients. Method: In a randomized controlled trial, participants with CKD stages III-IV were randomized to 8 weeks of MBSR (n=17, 64±8 yr, 88% males) or a health education program (HEP, n=12, 63±10 yr, 83% males) that served as the active control intervention. MBSR was comprised of eight 2.5-hour group meetings and a retreat session focused on mindfulness training. HEP was administered in a similar structure and focused on health education. Direct intraneural measures of SNS activity directed to muscle (MSNA) was recorded via microneurography with concomitant beat-to-beat blood pressure and EKG monitoring at rest and during mental stress before and after the 8-week intervention. MSNA reactivity during mental arithmetic-induced stress (3 minutes) was compared between baseline and end of study (EOS) in the MBSR and HEP groups. Results. Baseline characteristics, kidney function, and comorbidities were comparable between groups. There was a significant Group (MBSR vs. HEP) by Time (baseline vs. EOS) interaction in the change in MSNA reactivity to mental stress. The MBSR group had a significant reduction in MSNA reactivity during the 1st, 2nd and 3rd minute of mental arithmetic at EOS (p<0.05 for all), while no change was observed within the HEP group. Resting MSNA and reactivity in blood pressure and heart rate during mental arithmetic remained unchanged in both groups from baseline to EOS. Conclusion. Patients with CKD had an amelioration of sympathetic reactivity during mental stress following 8-weeks of MBSR but not after HEP (control intervention). Our findings demonstrate that mindfulness training is feasible and may have potential beneficial effects on autonomic function in CKD. NIH R01HL135183; NIH R61AT10457; NIH KL2TR002381; VA Merit I01CX001065. 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.