Essential hypertension remains a major global health problem with poorly defined mechanisms. Increased vascular sympathetic activity and sleep-disordered breathing are common features in hypertensive patients and adult spontaneously hypertensive rats (SHRs), an experimental model of essential hypertension. We hypothesized that SHRs exhibit inherent respiratory dysfunctions during postnatal development, leading to irregular breathing and hypoxaemia that contribute to later sympathetic hyperactivity. We assessed pulmonary ventilation, oxygen consumption, systemic and tissue oxygen levels and cardiovascular parameters in male and female normotensive (Wistar-Kyoto and Sprague-Dawley, NT) rats and SHRs from birth to adulthood. Newborn SHRs (0-2 days old) exhibited hypoventilation, fluctuating respiratory frequency and increased episodes of apnoea and breath-hold, resulting in hypoxaemia and reduced brain oxygen levels in comparison to NT pups. These irregularities and hypoxaemia persisted until postnatal day 12. During hypoxic challenges, SHR pups from 0 to 12 days of life displayed an impaired ventilatory response, contrasting with the developmental increase in hypoxic ventilatory response seen in NT animals. In adult animals, the higher mean arterial pressure levels in SHRs were correlated with postnatal hypoventilation, suggesting a developmental link between postnatal respiratory dysfunction and hypertension. Chronic exposure to hyperoxia (50% O2) during the first 2 weeks of life attenuated respiratory irregularities in neonatal SHRs and reduced sympathetic vasoconstrictor tone in adult SHRs. Our results show that SHRs show early-life respiratory deficits that lead to breathing irregularities and hypoxaemia during postnatal development, which might contribute to the development of sympathetic hyperactivity in essential hypertension. KEY POINTS: Arterial hypertension is a common cardiovascular disease globally; however, its underlying mechanisms are still not fully understood. In spontaneously hypertensive rats (SHRs), a widely used experimental model of arterial hypertension, we identified inherent respiratory dysfunctions that cause breathing irregularities during the postnatal period. Neonatal SHR pups exhibit hypoventilation, fluctuating respiratory frequency and increased episodes of apnoea and breath-hold, leading to hypoxaemia and reduced oxygen levels in the brain. Exposure to high oxygen levels during postnatal life attenuates the respiratory irregularities in neonatal SHRs and reduces sympathetic vasoconstrictor tone in adult SHRs. Our study shows that early-life respiratory irregularities and hypoxaemia are present in SHRs from birth and might contribute to the development of sympathetic hyperactivity in arterial hypertension.

Long dismissed as a passive marker of ventilatory failure, elevated carbon dioxide (PaCO2 > 45 mmHg) is now recognized as a potent signaling molecule that orchestrates complex cellular responses. This review synthesizes recent advances revealing how hypercapnia modulates fundamental processes, immune regulation, tissue repair, and metabolism, through direct molecular mechanisms. We detail how CO2 triggers noncanonical NF-κB signaling, alters Wnt ligand secretion to impair alveolar regeneration, and exacerbates TLR4-primed NLRP3 inflammasome activation; this pro-inflammatory effect is most prominent in specific cell types like microglia and under conditions of sustained high CO2 levels. Furthermore, hypercapnia drives profound metabolic reprogramming and induces lasting epigenetic changes, such as TET1-downregulation-mediated CDH1 hypermethylation, which reinforces immunosuppression in chronic lung disease. Critically, we evaluate emerging tools like CarboSen probes that enable more precise separation of CO2-specific effects from associated acidosis in buffered experimental systems. Therapeutically, these insights argue for precision strategies: macrophage-specific Akt1 inhibition to restore antiviral immunity, localized Wnt agonists to promote repair, or targeting the leptin/STAT3/SOCS3 axis to improve ventilatory drive. However, translation requires navigating significant species differences and unresolved questions regarding epigenetic reversibility. By framing hypercapnia not as a uniform stressor but as a complex modulator whose effects are dictated by concentration, duration, and the specific tissue type involved, this review charts a course toward targeting CO2-driven signaling for therapeutic benefit in conditions ranging from ARDS and COPD to obesity hypoventilation syndrome.

The ability to sense and regulate breathing in response to changes in carbon dioxide (CO2) levels is vital for maintaining respiratory and systemic homeostasis. Impaired CO2 chemosensitivity is a common feature of several debilitating conditions, including chronic obstructive pulmonary disease (COPD), central hypoventilation syndromes, and cervical spinal cord injury (cSCI) and contributes to significant respiratory complications such as reduced ventilatory drive, poor gas exchange, and diminished adaptability to metabolic demands. Chronic cSCI disrupts descending respiratory pathways, leading to impaired ventilatory function and, consequently disrupted CO2 regulation leading to reliance on mechanical ventilation. Currently there are few effective treatments for spinal cord injury induced respiratory dysfunction, particularly in the chronic phase of injury where additional recovery is difficult to elicit. In this study, we investigated whether stimulation of excitatory spinal interneurons (eINs) could enhance respiratory responses to hypercapnia in health and during chronic cSCI. Mid-cervical eINs located in the intermediate lamina were chemogenetically activated via Designer Receptors Exclusively Activated by Designer Drugs (DREADDs), and breathing was assessed during CO2 challenges in awake, unrestrained animals using whole-body plethysmography. Acute stimulation of cervical eINs increased breathing in response to acute respiratory challenges in animals at 8-and 12-weeks post-traumatic cSCI and in uninjured animals. Importantly, this respiratory enhancement occurred without observable affects in non-respiratory motor functions, such as forelimb grip strength, suggesting that the effects of eIN activation were specific to respiratory circuits. Together these findings identify cervical eINs as a promising neuromodulatory target and a promising therapeutic avenue for improving ventilatory function in chronic SCI. More broadly, this approach may offer therapeutic potential for other respiratory conditions characterized by diminished chemosensitivity and ventilatory control, providing a foundation for future translational strategies in respiratory neurorehabilitation.

Obstructive sleep apnea (OSA) is a highly prevalent sleep-related breathing disorder with a considerable healthcare burden. Previously, the 2011 guideline for adult obstructive sleep apnea was largely formulated on the basis of expert opinion and consensus, which played an important role in guiding clinical practice. With the growing body of evidence from high-quality clinical studies, however, guideline development models that rely primarily on expert consensus are no longer adequate to support contemporary clinical decision-making. To further standardize the screening, diagnosis, treatment, and long-term management of OSA in adults, the Sleep Disordered Breathing Assembly of the Chinese Thoracic Society has developed evidence-based clinical practice guidelines. The recommendations were formulated according to the best currently available evidence, following the Appraisal of Guidelines for Research and Evaluation Ⅱ (AGREE Ⅱ) framework and the Reporting Items for Practice Guidelines in Healthcare (RIGHT) statement. Based on an extensive preliminary investigation, the guideline addresses 18 key clinical questions and provides detailed, evidence-based recommendations, aiming to support clinical decision-making and to promote standardized diagnosis, treatment, and management of adults with OSA in China.The clinical questions and recommendations are listed below.Question 1: Which populations should be screened for OSA?Recommendation 1: Routine screening for OSA is not recommended in the general population without high-risk features (1, A). Screening is recommended for individuals at high risk for OSA who exhibit typical symptoms or physical signs, or who have relevant comorbidities. Screening is also recommended for perioperative patients (e.g., candidates for bariatric surgery or other high-risk procedures) (1, A). Screening may be considered for high-risk individuals without typical symptoms (2, B). Screening is also recommended for individuals whose OSA may increase the risk of driving or occupational accidents (1, A).High-risk populations for OSA include: (1) Individuals with typical OSA symptoms, such as habitual snoring, excessive daytime sleepiness, witnessed apneas, nocturnal gasping or choking, morning headaches, morning dry mouth, non-restorative sleep, nocturia, impaired attention, memory decline, and reduced sexual function; (2) Individuals with typical physical signs of OSA, including obesity, increased neck circumference, retrognathia or micrognathia, macroglossia, enlarged uvula and soft palate, and tonsillar hypertrophy; (3) Individuals with OSA-related complications or comorbidities, such as obesity, hypertension, type 2 diabetes mellitus, cardiovascular disease, metabolic syndrome, hypothyroidism, polycystic ovary syndrome, acromegaly, neuromuscular diseases, depression, and anxiety; (4) Specific populations, including middle-aged and older men, pregnant women, and postmenopausal women; (5) Individuals with a family history of OSA, particularly those with first-degree relatives affected by OSA (1, A).Question 2: What is the role of questionnaires, craniofacial assessment, and other predictive tools in screening and evaluating individuals at high risk for OSA?Recommendation 2: The STOP-Bang questionnaire is recommended for OSA screening (1, A). The Berlin questionnaire and STOP questionnaire may also be considered (1, B). The Epworth Sleepiness Scale (ESS) is recommended to assess daytime sleepiness severity but should not be used to diagnose OSA (1, A). Subjective questionnaires alone, without objective sleep monitoring, are not recommended for OSA diagnosis (1, A).A structured physical examination of the upper airway and craniofacial features is recommended, including the modified Mallampati score and Friedman tongue position classification. Further evaluation (e.g., cephalometric radiography, CT or MRI of the upper airway) may be performed when indicated (1, A).Clinically validated consumer-grade sleep monitors and wearable AI devices may be considered to assist self-screening in high-risk individuals and encourage timely medical consultation. However, these are non-medical screening tools and should not replace medical-grade sleep monitoring for diagnosis (1, A).Question 3: How should polysomnography (PSG) and home sleep apnea testing (HSAT) be used in the diagnosis of OSA in adults?Recommendation 3: PSG is the gold standard for diagnosing OSA in adults (1, A). It is recommended as the first choice for complex cases (especially those with comorbid sleep disorders) and individuals in high-risk occupations (1, A). PSG is also preferred for precise assessment of treatment efficacy and follow-up (1, A).HSAT is recommended for diagnosing clinically suspected moderate-to-severe uncomplicated OSA, but should not be used to rule out OSA (1, A). It may also be used for hospitalized patients with limited mobility or critical illness requiring prompt intervention (1, A). HSAT can serve as an adjunct tool for treatment response assessment and follow-up (1, A). It is not recommended for general screening of asymptomatic individuals or for diagnosing mild OSA (1, A).Question 4: What are the diagnostic criteria and severity classification for OSA in adults?Recommendation 4: The ICSD-3-TR diagnostic criteria are recommended for diagnosing OSA in adults (1, A). In resource-limited primary care settings, simplified criteria incorporating history, physical examination, and pulse oximetry may be used (1, A).OSA severity should be classified primarily based on the apnea-hypopnea index (AHI), with nocturnal minimum pulse oxygen saturation as a supplementary measure of hypoxemia burden (1, A). Emerging indices such as HB and SBII may be considered when assessing cardiovascular and comorbidity risks (2, B).Question 5: How should OSA phenotypes and endotypes be assessed?Recommendation 5: There is no universally accepted phenotyping standard. In clinical practice, symptom-based categories are commonly used: excessive daytime sleepiness predominant, sleep disturbance/fragmentation predominant, and asymptomatic/minimally symptomatic phenotypes (1, B). Phenotype assessment should integrate demographics, symptoms, history, PSG data, and validated questionnaires (1, B).Endotyping may be considered using four physiological traits: critical closing pressure, arousal threshold, loop gain, and upper airway muscle responsiveness (1, B). Techniques such as CPAP pressure titration and esophageal pressure monitoring may be used to assess OSA endotypes (1, B). Alternatively, OSA endotypes may be estimated through advanced analysis of PSG signals (2, B).Individualized assessment of patients with OSA may also incorporate potentially treatable traits, including daytime functional impairment (e.g., excessive daytime sleepiness), co-existing sleep disorders (e.g., insomnia), specific high-risk factors (e.g., obesity), and underlying pathophysiological mechanisms, such as those described in the PALM framework (2, B).Question 6: Which health complications and safety risks should be prioritized in adults with OSA?Recommendation 6: Adults with OSA should be specifically monitored for cardiovascular disease, cerebrovascular disease, metabolic disorders, cognitive impairment, and traffic-or occupation-related safety risks (1, A). Evaluation for other potential risks, including malignancy, depression, chronic cough, asthma, and chronic obstructive pulmonary disease (COPD), is also recommended (1, B).Question 7: How should comprehensive management of adults with OSA be implemented?Recommendation 7: Comprehensive management of adult OSA should be multidisciplinary, individualized, and long-term, based on disease severity, etiology, lifestyle, and patient preferences (1, A).Lifestyle interventions are recommended for all patients, including dietary control, alcohol avoidance, smoking cessation, cautious use or avoidance of sedative-hypnotic agents and other medications that may induce or exacerbate OSA, sleep hygiene, and regular physical activity (1, A). Positional therapy is recommended for position-dependent OSA (1, A). Active weight management with a body mass index (BMI)-based stepwise strategy is recommended (1, A).Question 8: What are the indications for positive airway pressure (PAP) therapy in adults with OSA?Recommendation 8: PAP therapy is recommended as first-line treatment for adults with moderate-to-severe OSA (AHI≥15 events/h) (1, A). It may also be considered for patients with mild OSA who have cardiovascular or cerebrovascular disease, hypertension, diabetes, COPD, or prominent symptoms such as EDS, cognitive impairment, insomnia, or depression, as well as for perioperative patients (1, B).Question 9: How should PAP modalities be selected for adults with OSA?Recommendation 9: CPAP, APAP and BPAP are comparable in efficacy, safety, and adherence. CPAP is recommended as the default modality due to lower cost (1, A). APAP is recommended for patients intolerant to CPAP, or with positional, sleep-stage dependent, or alcohol-related OSA, or significant weight fluctuations (1, A). For asymptomatic patients, CPAP or APAP is recommended (1, A). BPAP is indicated if obstructive events persist at CPAP pressures≥15 cmH2O (1 cmH2O=0.098 kPa), for intolerance to high CPAP pressures, or for OSA with chronic hypoventilation disorders such as COPD, neuromuscular diseases, or obesity hypoventilation syndrome (1, A).Question 10: What are the principles and procedures for PAP titration?Recommendation 10: PAP pressure titration is recommended before initiating therapy (1, A). In-laboratory, full-night manual titration during PSG is the gold standard (1, A). For moderate-to-severe OSA, split-night in-laboratory titration or home auto-titration are acceptable alternatives (1, A). Manual titration is preferred over auto-titration in patients with congestive heart failure, severe pulmonary disease, neuromuscular disease, prior uvulopalatopharyngoplasty, need for nocturnal oxygen, or expected desaturation from non-OSA causes (e.g., hypoventilation or central sleep apnea syndromes) (1, A).Question 11: How can adherence to PAP therapy be improved?Recommendation 11: A structured, regular follow-up system is recommended, including telemedicine (remote monitoring, phone/video consultations, AI/smartphone apps) and behavioral or psychosocial interventions (e.g., motivational enhancement therapy, motivational interviewing) (1, A).Question 12: What are the indications for oral appliance therapy?Recommendation 12: Oral appliance therapy is recommended for primary snoring and mild-to-moderate OSA (1, A). It is also recommended as an alternative or adjunct for patients with poor PAP tolerance or adherence (1, A). Custom-made oral appliances are preferred over non-custom devices to improve adherence and effectiveness (1, A).Question 13: What are the indications for oropharyngeal myofunctional therapy?Recommendation 13: Oropharyngeal myofunctional therapy is recommended as an adjunct or combined therapy in patients with OSA (1, A).Question 14: What are the indications for upper airway surgery?Recommendation 14: Upper airway surgery may be considered for adults with significant anatomical abnormalities who are intolerant or nonadherent to PAP therapy, after a careful evaluation of the potential benefits and risks (1, A).Question 15: What are the indications for pharmacological therapy?Recommendation 15: Pharmacological therapy is not recommended as routine treatment for all adults with OSA (1, A). It may be considered as adjunctive treatment for specific phenotypes or treatable traits such as EDS, insomnia, or obesity, with appropriate patient selection (1, B).For OSA-related EDS: After careful clinical evaluation, wake-promoting agents may be considered for patients with OSA-related EDS who meet one or more of the following criteria: 1. Residual EDS despite adequate and adherent standard OSA therapy (including CPAP, oral appliance therapy, or surgery), with other causes of EDS excluded; 2. Presence of EDS in patients who refuse, are intolerant of, or are nonadherent to standard OSA therapy; 3. EDS that substantially impairs quality of life, interferes with work or study, or significantly increases the risk of traffic or occupational accidents (e.g., documented accidents or near-miss events)(Expert consensus; no grading). For patients with residual EDS despite adequate and adherent OSA therapy, treatment with solriamfetol or modafinil is recommended to improve daytime sleepiness (1, A). For patients with EDS who refuse or cannot tolerate standard OSA therapy, individualized treatment with solriamfetol is recommended (1, A), while modafinil may be considered (2, B). During pharmacologic treatment, continued counseling and encouragement to initiate or resume standard OSA therapy are recommended.For COMISA: With attention to interindividual variability in treatment response, short-term use of non-benzodiazepine hypnotic agents may be considered to improve insomnia symptoms (1, B). When non-benzodiazepine hypnotics are deemed necessary, they should be used under close monitoring or in combination with CPAP therapy (1, B). Benzodiazepines are not recommended for the treatment of COMISA (1, A).For OSA with obesity: For patients with moderate-to-severe OSA complicated by obesity, who have not achieved adequate control despite structured weight-management interventions (including dietary modifications and exercise), treatment with dual GIP/GLP-1 receptor agonists (e.g., tirzepatide) may be considered as an adjunctive therapy (1, A).Question 16: How can phenotype-and endotype-based evaluation guide individualized treatment?Recommendation 16: An individualized treatment strategy based on OSA phenotypes and endotypes may be considered in adults with OSA (1, B).Question 17: How should long-term follow-up of adults with OSA be planned?Recommendation 17: Follow-up should assess symptoms, sleep-related quality of life, patient-reported sleep quality, treatment adherence, adverse events, and patient/family satisfaction (1, A). Tools may include questionnaires (ESS, PSQI, SF) and objective tests (PSG, HSAT, pulse oximetry, MSLT, MWT) (1, A). Follow-up intervals should be tailored to the treatment; for PAP therapy, visits at 1 week, 1 month, and 3 months are recommended, and then every 6-12 months if stable (1, A).Question 18: What are the major applications of telemedicine in comprehensive OSA management?Recommendation 18: Telemedicine is valuable for remote diagnosis, treatment, and follow-up. It is recommended to improve PAP adherence (1, A). Remote diagnostic pathways combining HSAT with electronic questionnaires may be considered (2, B). Quality control measures should be implemented to ensure safety and effectiveness (1, A).

Diaphragmatic dysfunction, whether unilateral or bilateral, partial or complete, is often an overlooked cause of dyspnea, sleep disturbances, and, in more advanced stages, chronic alveolar hypoventilation. It may result from injury to the phrenic nerve, the diaphragm muscle itself, or central nervous system pathways. The diagnosis is frequently suspected when an elevated hemidiaphragm is incidentally observed on chest imaging. A comprehensive assessment combining clinical examination, pulmonary function tests, arterial blood gas analysis, and targeted imaging is essential to confirm the dysfunction, identify its underlying cause, evaluate its severity, and guide management. In its advanced form, chronic hypercapnic respiratory failure may occur, often requiring non-invasive ventilation in addition to treatment of the underlying cause. This review outlines a structured and practical approach to the evaluation of diaphragmatic dysfunction, incorporating recent advances and key clinical considerations.

Prior to 2024, pulmonary hypertension (PH) associated with chronic lung diseases (group 3 in the classification of PH) was subclassified according to the type of ventilatory disorder (obstructive, restrictive lung disease or mixed patterns) and not according to the lung disease itself. In 2024, the 7th World Symposium on PH proposed a revised classification, describing associations with specific lung diseases, such as COPD, interstitial lung disease and combined pulmonary fibrosis and emphysema. This update highlights the distinct pathophysiological mechanisms, clinical manifestations, outcomes and management strategies across these subgroups. Of note, a nonparenchymal restrictive lung disease subgroup has been identified, which includes patients with hypoventilation syndromes (due to kyphoscoliosis, diaphragmatic diseases, obesity hypoventilation syndrome, central hypoventilation syndromes, etc.) or pneumonectomy. Paradoxically, despite being one of the earliest forms of PH described, PH associated with nonparenchymal restrictive lung diseases remains among the least studied subtypes. As with all causes of group 3 PH, the primary focus of management is to address the underlying condition whenever possible. There are few data on the efficacy, safety and tolerability of the treatments approved for pulmonary arterial hypertension in this specific population. This review aims to provide updates on this condition and its management, to highlight the mechanisms of PH in each nonparenchymal restrictive lung disease and to study the relevance of the new classification and the necessary avenues of research.

Background: Obesity is associated with a broad range of complications that frequently develop before the onset of type 2 diabetes mellitus (T2DM). Identifying early metabolic markers associated with such complications is essential for improving risk stratification and supporting complication-driven therapeutic strategies. Plasma glucose measured at 1 h during the oral glucose tolerance test (OGTT) has emerged as a sensitive marker of early dysglycemia and adverse cardiometabolic outcomes, but its relationship with established obesity-related complications in individuals without diabetes remains incompletely characterized. We aimed to investigate the association between 1 h post-load plasma glucose levels during OGTT and obesity-related complications in adults living with obesity without T2DM. Methods: This observational cross-sectional study included 47 adults with obesity evaluated during their first visit to obesity clinics. Individuals with T2DM or prior use of anti-obesity pharmacotherapy were excluded. All participants underwent a standard 75-g OGTT with plasma glucose and insulin measurements at fasting, 1 h, and 2 h. Obesity-related complications were recorded retrospectively through structured questionnaires, clinical assessment, and medical record review. Between-group comparisons were performed using non-parametric tests, and repeated OGTT measurements were analyzed using non-parametric longitudinal models. Results: Higher 1 h post-load glucose levels were observed in participants with arterial hypertension (p < 0.001), dyslipidemia (p = 0.020), metabolic dysfunction-associated steatotic liver disease (p = 0.005), impaired glucose tolerance (p = 0.027), obesity hypoventilation syndrome (p = 0.039), urinary incontinence (p = 0.038), and chronic kidney disease (p = 0.048). In most comparisons, 1 h post-load glucose demonstrated stronger discriminatory capacity than fasting or 2 h glucose values. Insulin levels increased markedly after glucose loading in all participants, reflecting generalized insulin resistance, but showed limited ability to discriminate between complication phenotypes. Conclusions: In people living with obesity without T2DM, elevated 1 h post-load plasma glucose during OGTT is consistently associated with multisystem obesity-related complications. These findings support the clinical relevance of 1 h post-load glucose as an integrated marker of early metabolic and systemic burden that may inform complication-driven risk stratification in obesity. Due to the observational study design, causality cannot be inferred.