Ascending thoracic aortic aneurysm formation differs fundamentally between patients with bicuspid (BAV) and tricuspid (TAV) aortic valve phenotypes, yet current clinical management largely relies on shared diameter thresholds, although clinical and scientific data fail to correlate with diameter and risk of rupture. Over the past two decades, histological, biochemical and biomechanical studies have revealed unique differences between dilated tissue properties from patients with BAV- and TAV-associated idiopathic degenerative ascending aortic aneurysms even at similar aortic diameters. This review focuses on histological, biochemical and biomechanical differences between BAV and TAV aortopathy with a focus on ageing. Idiopathic degenerative TAV aortopathy is characterised by medial degeneration with elastic lamellar fragmentation and loss, smooth muscle cell depletion, medial fibrosis, mucoid extracellular matrix accumulation and inflammatory features. These degenerative changes correlate with ageing and, in region-specific mechanical testing, with reduced delamination resistance and age-dependent biomechanical weakening. In contrast, BAV aortopathy frequently demonstrates relative preservation of medial architecture despite similar dilatation, alongside altered collagen maturation, and distinct osteogenic/microcalcification signatures. Lifespan analyses indicate that TAV follows a maturation-stabilisation-degeneration trajectory, whereas BAV exhibits aberrant vascular maturation without a true stabilisation phase. Importantly, aortic diameter correlates poorly with histological severity or biomechanical vulnerability, particularly in BAV. Collectively, these data support the concept that ascending thoracic aortic aneurysms in BAV and idiopathic degenerative TAV patients represent biologically divergent aortopathies requiring phenotype-informed risk stratification beyond diameter alone.

Skeletal muscle microtissues are valuable in vitro models for studying the stimuli regulating muscle protein synthesis (MPS), the key determinant of changes in muscle mass. Differentiated between opposing posts, microtissues contain aligned, contractile myotubes, providing a controlled system for investigating the responses of skeletal muscle to nutrient and contractile stimulation. However, microtissue MPS responses to these stimuli remain under-characterized. Stable isotope-labelled amino acid tracers deliver sarcoplasmic and myofibrillar fractional synthetic rates (FSR) for MPS in human studies but have not been implemented in engineered skeletal muscle. We close these gaps by characterizing amino acid (AA), ketone and contraction-induced MPS in 3D microtissues and 2D myotubes (without contraction) derived from the same primary myoblast line, using stable isotope tracers and puromycin incorporation. Following 4 h of AA withdrawal microtubes and myotubes underwent 2 h of acute AA and/or ketone treatment (±contraction in microtissues). In microtissues, sarcoplasmic FSR increased significantly during amino acid re-addition (P < 0.0001), whereas myofibrillar FSR displayed a main effect of condition (P = 0.0018), with an overall lesser magnitude of change compared to the sarcoplasmic fraction. However, both fractions were unresponsive to ketone stimulation, and the selected contraction regime (when combined with ketones and/or AA; all P ≥ 0.985). 2D myotubes showed significant increases in sarcoplasmic and myofibrillar FSR in response to amino acid treatment (both P ≤ 0.0003). Notably, microtissues demonstrated a more stable myofibrillar protein fraction, with a sarcoplasmic-to-myofibrillar FSR ratio of ∼2:1 which closely resembled that of native human muscle. The puromycin-based approach only detected subtle differences in 2D myotubes (main effect P = 0.031) with AA provision being greater than ketones (P = 0.0196) with no other post hoc differences (all P ≥ 0.221). Puromycin failed to detect MPS responses to any stimulus in microtissues (all P ≥ 0.834), highlighting the greater sensitivity of tracer-based measurements, particularly where longer time scales are needed to capture an effect. These findings support the use of engineered muscle and isotope-derived measurements of MPS in future studies of stimuli regulating skeletal muscle mass.

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a genetic arrhythmic syndrome caused by mutations in the sarcoplasmic reticulum (SR) calcium (Ca[2+]) release channel RyR2 or its accessory proteins, including calsequestrin-2 (CASQ2). RyR2 dysfunction or leak is the hallmark feature of CPVT and directly triggers arrhythmias. Despite this electrical instability, CPVT hearts are typically anatomically normal and lack pathological remodelling. Therefore, we hypothesized that introducing additional stressors, such as metabolic stress, would worsen cardiac arrhythmias and potentially trigger pathological remodelling. To test this hypothesis, metabolic stress was introduced by crossbreeding a CPVT model of CASQ2[-/-] mice with the Akita mouse, a genetic model of diabetes that also lacks cardiac remodelling. We found that dysregulation of myocyte Ca[2+] handling was exacerbated in Akita-CASQ2[-/-] cells, which exhibited slower Ca[2+] transient decay kinetics and increased arrhythmogenic Ca[2+] waves. Akita-CASQ2[-/-] mice also displayed more severe arrhythmias, diastolic dysfunction, and cardiac hypertrophy, but without evidence of fibrosis, cell death, or worsened metabolic dysfunction. Finally, mitochondrial reactive oxygen species production was increased in Akita-CASQ2[-/-] cardiomyocytes, which may contribute to the more severe pathological phenotype. Overall, our results suggest that metabolic stress can aggravate dysregulated myocyte Ca[2+] handling and promote cardiac dysfunction in CPVT hearts.

Accumulation of ∼200 h of hypoxia exposure (pre-acclimatization) has been suggested to prevent the development of acute mountain sickness when a person is subsequently exposed to high altitude. These pre-exposures are typically undertaken intermittently at or near the place of residence, primarily during sleep in hypoxic tents, and are likely to induce effective ventilatory acclimatization. However, the physiological consequences of different modes of intermittent hypoxia (IH) exposure on ventilatory acclimatization remain largely obscure and are the subject of much controversy. The aim of this review is therefore to summarize and discuss the findings of relevant studies and draw on our long-term practical experience to address the effects of IH exposure on ventilatory acclimatization and to provide suggestions for effective pre-acclimatization. We provide a balanced overview of studies investigating the effects of different types of altitude/hypoxia exposure on the hypoxic ventilatory response and renal compensation to hyperventilation-induced respiratory alkalosis. Although it has been demonstrated convincingly that the hypoxic ventilatory response can increase by 50%-100% with only a few short IH sessions (1 h per day for 7 days), the available data on the effects of IH on renal compensation do not permit definitive conclusions to be drawn. Long-term exposure to IH over several weeks appears to induce renal compensation effectively, allowing for a full ventilatory response and favourable oxygenation at high altitude. To clarify definitively which strategies are most suitable, long-term systematic investigations of various IH strategies are urgently needed.

Heart transplant recipients exhibit reduced exercise tolerance and persistently diminished aerobic capacity despite exercise training. Exercise tolerance depends on integrated oxygen transport and utilization, which are impaired in heart transplant recipients. We synthesize evidence supporting that the combined effects of impaired pulmonary gas exchange, reduced haemoglobin concentration, heart denervation, chronic calcineurin inhibition, decreased muscle capillary density, and detraining from limited physical activity contribute to: (1) reduced pulmonary diffusion and alveolar ventilation-perfusion mismatch that contribute to hypoxemia and increased ventilatory demand; (2) impaired convective oxygen delivery due to anaemia and to heart denervation that limits cardiac output; (3) deficits in endothelial function and reduced muscle capillarization that contribute to diminished convective and diffusive oxygen transport within skeletal muscle. Using Wagner's model, which describes oxygen transport from the atmosphere to muscle mitochondrion, we develop the hypothesis that the persistent reduction in aerobic capacity in heart transplant recipients reflects the combined and interactive effects of impaired convective oxygen transport and reduced muscle oxygen diffusive capacity, rather than a single dominant limitation. This basis generates testable physiological targets for interventions aimed at improving functional capacity after transplantation.

Exogenous ketosis induced by ketone ester (KE) ingestion has attracted growing interest as a potential strategy to enhance physiological tolerance to reduced O2 availability. Reported benefits arise largely from KE-induced hyperventilation, which can improve systemic and tissue oxygenation during altitude exposure and hypoxic exercise, potentially complemented by favourable effects on cellular bioenergetics. Whether these responses translate to breath-hold diving, however, remains unknown. Breath-hold performance is constrained by the integrated effects of progressive hypoxaemia, CO2 accumulation, acid-base disturbance, altered cerebrovascular regulation and chemoreflex-mediated respiratory drive. Because ventilation ceases during apnoea, interventions that alter pre-apnoeic acid-base status or CO2 signalling might modify the chemical, neural and perceptual stimuli underlying the urge to breathe without slowing O2 depletion. Safety therefore depends not only on preserving cerebral O2 delivery, but also on maintaining the chemoreflex and perceptual warning signals that ordinarily precede hypoxic loss of consciousness. This review evaluates whether the established physiological effects of KE are mechanistically compatible with the unique demands of apnoea, focusing on acid-base regulation, CO2-dependent cerebrovascular control, autonomic integration and training-related adaptations in elite freedivers, including reduced chemoreflex sensitivity and enhanced cortical control of respiratory drive. We propose that benefits observed during maintained ventilation might not translate to breath-hold diving and could create a mechanistic mismatch with uncertain consequences for performance and safety. Direct apnoea-specific studies are required to determine whether KE supplementation is beneficial, neutral or harmful.

Abortion aetiology is critically linked to increased myometrial contractions and maternal psychological stress. Given the limited efficacy of current therapies such as progesterone, investigating novel therapeutic interventions is essential. Melatonin exerts reproductive benefits. Agomelatine stands out as an agent that exerts antidepressant effects through serotonin receptor (5-HT2C) antagonism in addition to its potent melatonergic activity. Furthermore, agomelatine inhibits myometrial contractions. In this context, this study investigates agomelatine's therapeutic potential in an abortion model across behavioural, biochemical and histological parameters. Eighty female Sprague-Dawley rats were randomized into eight groups: control, sham, abortion, melatonin (M), agomelatine (A), progesterone (P) and combinations (MP, AP). Following pregnancy (Day 0), oral treatments were administered daily for 14 days. Abortion was induced via mifepristone on Day 11. Depressive-like behaviours were assessed using a forced swimming test on Day 13. The next day, rats were sacrificed for serum hormone analysis and uterine histological evaluation. The forced swimming test showed shorter immobility time in the AP group compared to the abortion group. An enzyme-linked immunosorbent Assay revealed lower serum prostaglandin F2α level in the AP group and lower serum oxytocin levels in the M, A, MP and AP groups versus the abortion group. Histologically, M, A, P, MP and AP groups exhibited higher scores for complete fetus, decidual congestion, decidual inflammation and cytotrophoblast-syncytiotrophoblast cells compared to the abortion group. Additionally, the abortion group showed higher decidual necrosis than controls. In conclusion, agomelatine-containing protocols demonstrated restorative effects in abortion across behavioural, biochemical and histological parameters. These effects of agomelatine provide a new perspective on the currently limited options for treatment of abortion.

Sedentary behaviour is increasingly recognized as a risk factor for systemic disorders; however, its effects on male reproductive health and penile tissue integrity remain insufficiently understood. Furthermore, the therapeutic role of whole-body vibration (WBV) has not been investigated. This study evaluated the effects of sedentary behaviour on testicular and penile tissues and examined whether WBV could attenuate these alterations. We hypothesized that sedentary behaviour would impair spermatogenesis and penile tissue integrity, whereas WBV would attenuate these effects. Thirty-two male Wistar rats were randomized into four groups (n = 8/group): Control, Sedentary, Sedentary+WBV and WBV. Sedentary conditions were induced for 28 days via a reduced-cage model, with daily WBV application (45 Hz, 3 mm). Serum testosterone, sperm parameters, testicular histology and penile smooth muscle-to-collagen ratio were assessed. Sedentary behaviour impaired spermatogenesis, with lower Johnsen scores (P = 0.008), reduced sperm concentration (P = 0.006) and motility (P < 0.001), and increased morphological abnormalities (P < 0.001). It also reduced the penile smooth muscle-to-collagen ratio (P < 0.001), indicating adverse structural remodelling in erectile tissue. In sedentary animals, WBV attenuated several alterations, preserving sperm quality and cavernosal smooth muscle content. However, WBV alone impaired spermatogenesis and increased sperm morphological abnormalities in non-sedentary animals. Serum testosterone levels did not differ significantly. In conclusion, prolonged sedentary behaviour impaired male reproductive indices and induced adverse structural remodelling of penile tissue in male rats. WBV showed context-dependent effects, attenuating alterations under sedentary conditions while showing adverse associations in non-sedentary animals. These findings warrant further translational investigation into the context-dependent effects of WBV on male reproductive and penile tissues.

Epilepsy is characterized by the occurrence of at least two unprovoked seizures occurring more than 24 h apart, reflecting a predisposition to recurrent epileptic events. The role of dietary amino acids (AAs) in epilepsy is not clearly understood. To the best of our knowledge, this study is the first to investigate the link between the odds of developing epilepsy and dietary AA patterns. This cross-sectional study, derived from the Prospective Epidemiologic Research Studies in Iran (PERSIAN) Sabzevar Cohort Study, included 112 individuals diagnosed with prevalent epilepsy and 3951 participants without epilepsy. Dietary intake was estimated using a validated semi-quantitative food frequency questionnaire. Principal component analysis was applied to identify two distinct dietary AA patterns: one predominantly derived from animal sources and the other from plant food sources. Participants with epilepsy were more likely to be male, have lower levels of education, be married, be unemployed and also to exhibit lower intakes of all assessed AAs. In the fully adjusted model, no significant association was observed between the animal AA pattern and the odds of having epilepsy (odds ratio (OR) (Q4 vs. Q1): 0.62, 95% CI: 0.35-1.08, P = 0.094), although the P-value for trend across quartiles was statistically significant (Ptrend = 0.002). By contrast, higher adherence to the plant AA pattern was associated with 63% lower odds of having epilepsy (OR (Q4 vs. Q1): 0.37, 95% CI: 0.20-0.67, P = 0.001). The P-value for trend across quartiles was significant (Ptrend = 0.001). In conclusion, greater adherence to the plant-based AA pattern was associated with lower odds of having epilepsy. These findings may inform dietary strategies, but prospective studies are needed to determine whether these associations reflect a causal relationship.

Acute mountain sickness (AMS) affects many individuals ascending to high altitude annually, carrying potential morbidity and mortality risks (e.g., high-altitude cerebral oedema). The objective of this pilot study was to record overnight pulse oximetry during ascent to 4554 m and determine whether: (1) extracted overnight biomarkers had any relationship to AMS; and (2) AMS at 4554 m could be predicted by oximetry biomarkers using classification models trained/validated on overnight data from lower altitudes. Twenty lowlanders (five females, 36.8 ± 18.5 years old) completed a 4 day ascent to 4554 m, where AMS status was determined by clinical examination. Oximetry was recorded continuously each night, with >40 biomarkers extracted and compared between AMS and non-AMS. Exploratory classification models (5-fold cross-validation) were tested for nightly data with a systematic approach to feature selection. Model performances were evaluated based on predictions of AMS at 4554 m. A significant effect of ascent was observed for many overnight biomarkers; however, no effect of AMS status was evident, nor were any differences observed between AMS and non-AMS for any overnight biomarkers during ascent. AMS at 4554 m was most accurately predicted from overnight recordings collected at 2600 m (accuracy, 100%; true positive rate, 100%) and 3647 m (accuracy, 80%; true positive rate, 90.9%) using k-nearest neighbour and support vector machine classification models. Biomarkers were extracted from overnight oximetry recordings, with limited differences observed between AMS and non-AMS. In conclusion, AMS at 4554 m can be predicted from overnight oximetry using machine learning; however, these preliminary findings need confirmation in a larger cohort, with additional investigation into the most clinically relevant biomarkers.