Joyner, Michael J.

BACKGROUND: Pharmacological treatments for fibrocalcific aortic valve stenosis (FCAVS) have been elusive for >50 years. Here, we tested the hypothesis that reactivation of oxidized sGC (soluble guanylate cyclase), the primary receptor for nitric oxide, with ataciguat is a safe and efficacious strategy to slow progression of FCAVS. METHODS: We used quantitative real-time reverse transcription polymerase chain reaction, Western blotting, and immunohistochemistry to characterize sGC signaling and the biological effects of ataciguat on signaling cascades related to nitric oxide, calcification, and fibrosis in excised human aortic valve tissue, aortic valve interstitial cells, and mouse aortic valves. We then conducted randomized, placebo-controlled phase I (14-day safety/tolerance) and phase II (6-month efficacy) trials in patients with moderate aortic valve stenosis. RESULTS: In excised human tissue, we found robust losses in sGC signaling despite upregulation of sGC subunits. In vitro, ataciguat increased sGC signaling and reduced BMP2 (bone morphogenetic protein 2) signaling in aortic valve interstitial cells. In mice with established FCAVS, treatment with ataciguat attenuated BMP signaling and slowed progression of valve calcification and dysfunction. In a phase I, randomized, placebo-controlled trial, treatment with ataciguat for 2 weeks was safe and well tolerated in patients with moderate FCAVS ( https://www.clinicaltrials.gov ; Unique identifier: NCT02049203). In a separate phase II, randomized, placebo-controlled trial, treatment with ataciguat for 6 months slowed the progression of aortic valve calcification and tended to slow the progression of valvular and ventricular dysfunction in patients with moderate FCAVS ( https://www.clinicaltrials.gov ; Unique identifier: NCT02481258). CONCLUSIONS: Collectively, this study highlights the therapeutic potential of the targeted restoration of the diseased/inactive form of sGC for treatment of FCAVS. REGISTRATION: URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02049203. URL: https://www.clinicaltrials.gov ; Unique identifier: NCT02481258.

AbstractIn 1991, I published a physiological model of marathon running performance. My model predicted that it might be possible for a human to run the marathon in less than 2 hours. In this article, I review the genesis of my thinking at that time, share my perspective about what has changed over the last 30 plus years, and speculate about what the future might hold.

ABSTRACTThis essay summarizes and integrates my experiences and observations—starting in the middle 1970s—as an athlete, scientist interested in human performance, biomedical researcher, and “expert,” who sometimes advises athletes, coaches, and sports policy‐makers. In this context, my focus has been primarily on endurance sports and five concepts underpin what I have learned over the last 50 years. (1) The “competitive significance principle” whereby athletes, coaches, and policy‐makers are frequently interested in performance improvements of 1% or less. This is especially true at the elite level. (2) Science frequently explains what coaches and athletes have already discovered in the field. (3) Many science‐based performance improvements have reduced the energy cost of moving a given speed. (4) Varied and eclectic training programs have been used by elite athletes with similar performance outcomes. (5) A few things that are actionable matter. Coaches, athletes, and administrators should focus their efforts on what is actionable.

Sex differences in sports performances continue to attract considerable scientific and public attention, driven in part by high profile cases of: 1) biological male (XY) athletes who seek to compete in the female category after gender transition, and 2) XY athletes with medical syndromes collectively known as disorders or differences of sex development (DSDs). In this perspective, we highlight scientific evidence that informs eligibility criteria and applicable regulations for sex categories in sports. There are profound sex differences in human performance in athletic events determined by strength, speed, power, endurance, and body size such that males outperform females. These sex differences in athletic performance exist before puberty and increase dramatically as puberty progresses. The profound sex differences in sports performance are primarily attributable to the direct and indirect effects of sex-steroid hormones and provide a compelling framework to consider for policy decisions to safeguard fairness and inclusion in sports.

Background : Maintaining oxygen delivery during conditions of hypoxia is important, particularly for patients with hemoglobinopathies.Evidence in comparative physiology indicates that high hemoglobin-oxygen (Hb-O2) affinity serves as a beneficial hematological adaptation to chronic hypoxia exposure. The improved hypoxia tolerance is likely due to an increase in arterial oxygen saturation with high Hb-O2 affinity. However, the relationship between high Hb-O2 affinity and hypoxia tolerance in humans is not well understood. Etavopivat is a potent, selective, once-daily, oral activator of the red blood cell (RBC) pyruvate kinase isozyme (PKR), with a half-life of ~13 hours, under investigation for the treatment of sickle cell disease (SCD) and other hematological conditions. Etavopivat has a multimodal mechanism of action in RBCs by decreasing 2,3-diphosphoglycerate (2,3-DPG) levels to increase Hb-O2 affinity and increasing adenosine triphosphate (ATP) levels to improve RBC health. In Phase 1 trials etavopivat increased Hb-O2 affinity in healthy volunteers (HVs; Forsyth et al. Clin Pharmacol Drug Dev 2022) and patients with SCD (Saraf et al. Blood Adv 2024) in room air. Aim: To investigate arterial oxygenation changes with etavopivat under conditions of moderate and severe hypoxia in HVs. Methods: HVs visited the laboratory for assessments at baseline and following 7 days of etavopivat exposure (400 mg once daily). Participants completed rhythmic handgrip exercises (rest, 10% and 20% maximum voluntary contraction [MVC]) during graded hypoxic exposure, breathing room air (21% O2), moderate hypoxic gas (15% O2), and severe hypoxic gas (10% O2), resulting in acute duration (~12 minutes) of exposure to each level of hypoxia. Hb-O2 affinity was assessed by partial pressure of oxygen at 50% Hb saturation (P50), measured using dual-wavelength spectrophotometry at a standardized pH (~7.4) and temperature (37 ºC). Arterial catheterization was used to collect samples for fractional oxygen saturation (FO2Hb) and Hb and to measure arterial blood pressure. Blood gases were analyzed after 5 minutes of resting exposure to each inspirate, then ~2.5 minutes after commencing each of the 3-minute handgrip exercises (10% followed by 20% MVC). Liquid chromatography-tandem mass spectrometry was used to evaluate 2,3-DPG and ATP levels in whole blood. Data for FO2Hb and heart rate were analyzed using separate repeated measures 2 (treatment) x 3 (intensity) ANOVA for each inspirate and all other hematological data pre vs post etavopivat were analyzed using paired-sample t-tests. Statistical significance was set at P<0.05. Data presented are mean ± standard deviation. Results: Sixteen HVs (five women) aged 32 ±8 years were enrolled. After 7 days of oral once-daily 400 mg etavopivat, P50 decreased from 28.6 ±1.6 at baseline to 24.8 ±1.3 mmHg (P<0.001). Hb concentration remained unchanged from baseline (14.6 ±1.1 g/dL), post etavopivat (14.5 ±1.1 g/dL; P>0.05). FO2Hb at rest decreased from 96.0% ±0.6 under normal oxygen conditions to 74.6% ±6.7 during severe hypoxic exposure; however, this decrease in FO2Hb was mitigated post etavopivat exposure (79.7% ±5.2, P<0.001). A similar mitigation of the FO2Hb decrease was observed during the handgrip exercise (20% MVC, P<0.001). Concentrations of 2,3-DPG decreased and RBC ATP increased following etavopivat exposure during both normoxia and moderate hypoxia (P<0.001). Mean arterial pressure was lower post etavopivat exposure under normoxia, but not during moderate or severe hypoxia. Heart rate showed no change post etavopivat exposure during normoxia and hypoxia (P>0.50). Etavopivat was well tolerated with no unexpected adverse events reported. Conclusions: Etavopivat enhanced FO2Hb during brief hypoxic episodes with an apparent relationship to hypoxia severity for which the greatest improvements were observed at more severe hypoxic exposure. In SCD, high Hb-O2 affinity is beneficial for maintaining Hb ‘R’ state, thereby reducing the risk of polymerization and associated sickling. Increased Hb-O2 affinity, together with maintenance of a high FO2Hb under hypoxic conditions, demonstrates etavopivat's ability to promote oxygen exchange and subsequent delivery. Together with projected improvement of RBC health, also achieved via PKR activation, this indicates a potential clinical benefit with etavopivat for hemoglobinopathies and beyond.

Abstract Females likely experience larger performance benefits from androgenic‐anabolic steroids than males. We set out to determine if there were temporal differences in select athletics (track and field) records between females and males. Exploratory aims included: (1) evaluating the improvements in female and male world records over time, and (2) investigating the influence of doping programs on male and female world records before and after 1990, when sports governing bodies began to implement random out‐of‐competition and systematic in‐competition drug testing. We collected the top 500 performances of all time for both sexes from an online database (worldathletics.org) in four running events (100, 200, 400 and 800 m) and two throwing events (discus throw and shot‐put). Data were stratified into quintiles based on world record ranking (1st to 100th, 101st to 200th, etc.). The temporal distribution of the top 100 female performers was significantly earlier than the top 100 male performers (year: 2000 ± 1 vs. 2005 ± 1, respectively; P < 0.0001). Within the event, the top performances occurred significantly earlier for females in the 800 m (year: 1995 ± 15 vs. 2003 ± 12; P = 0.0007) and shot‐put (year: 1992 ± 14 vs. 2003 ± 17; P = 0.0004). Among females, world records rapidly improved through the 1980s, but following 1990, the world records ceased to improve. Geographically, there was a greater representation of countries with state‐sponsored doping programs, specifically among female performances. We postulate these sex differences in the temporal distribution of top performances are likely associated with enhanced effectiveness of exogenous androgens (steroid doping) among female athletes with lower endogenous androgen hormones compared to males.

The purpose of sympathetic neuronal discharge and the recruitment of neuronal subpopulations for human circulatory homeostasis remains unknown. This study tested the hypothesis that sympathetic neuronal discharge and recruitment patterns regulate neuropeptide Y (NPY) bioavailability. Across baseline and an intravenous dexmedetomidine infusion (α2-adrenergic agonist) sympathetic action potential (AP) frequency and total sympathetic AP clusters were associated with NPY bioavailability. This is the first study to report that sympathetic neuronal discharge and recruitment patterns regulate NPY bioavailability to support circulatory homeostasis in humans.