Cardiopulmonary Disorders Research Articles

Evaluation of Biologics ACE2/Ang(1–7) Encapsulated in Plant Cells for FDA Approval: Safety and Toxicology Studies

Background/Objectives: For several decades, protein drugs (biologics) made in cell cultures have been delivered as sterile injections, decreasing their affordability and patient preference. Angiotensin Converting Enzyme 2 (ACE2) gum is the first engineered human blood protein expressed in plant cells approved by the FDA without the need for purification and is a cold-chain and noninvasive drug delivery. This biologic is currently being evaluated in human clinical studies to debulk SARS-CoV-2 in the oral cavity to reduce coronavirus infection/transmission (NCT 0543318). Methods: Chemistry, manufacturing, and control (CMC) studies for the ACE2/Ang(1–7) drug substances (DSs) and ACE2 gum drug product (DP) were conducted following USP guidelines. GLP-compliant toxicology studies were conducted on Sprague Dawley rats (n = 120; 15/sex/group) in four groups—placebo, low (1.6/1.0 mg), medium (3.2/2.0 mg), and high (8.3/5.0 mg) doses IP/kg/day. Oral gavage was performed twice daily for 14 days (the dosing phase) followed by the recovery phase (35 days). Plasma samples (n = 216) were analyzed for the product Ang(1–7) by ELISA. Results: The ACE2 protein was stable in the gum for at least up to 78 weeks. The toxicology study revealed the dose-related drug delivery to the plasma and increases in the AUC (56.6%) and Cmax (52.9%) after 28 high-dose gavages (95% C.I.), although this quantitation excludes exogenously delivered membrane-associated ACE2/Ang(1–7). Vital biomarkers and organs were not adversely affected despite the 10-fold higher absorption in the tissues, demonstrating the safety for the first in-human clinical trials of ACE2/Ang(1–7). The NOAEL observed in the rats was 2.5–7.5-fold higher than that of the anticipated efficacious therapeutic dose in humans for the treatment of cardiopulmonary disorders, and it was 314-fold higher than the NOAEL for topical delivery via chewing gum. Conclusions: This report lays the foundation for the regulatory process approval for noninvasive and affordable human biologic drugs bioencapsulated in plant cells.

Cardiovascular prognostic factors, gamma glutamil transferase levels and other biochemical parameters related to morbidity and mortality in COVID-19

Aims: COVID-19 may exacerbate cardiovascular risk factors and pre-existing cardiovascular disease or lead to the development of new cardiovascular complications. Gama glutamil transferaz (GGT) is an enzyme found in the cell membranes of many tissues, especially the liver, bile duct and kidneys. Recent studies have shown that increased GGT levels are strongly associated with prognosis in cardiopulmonary disorders. Studies to date have reported on the increased predictive value of serum GGT level for cardiovascular disease and have shown marginal improvements in risk estimation. In the light of all this information, in this study, it was aimed to investigate the effect of serum GGT level on the clinical classification of the disease, cardiovascular risk and morbidity and mortality in COVID-19, in addition to known cardiovascular prognostic markers. Methods: The study included 128 patients over the age of 18 who were found to have positive SARS-CoV-2 reverse transcription polymerase chain reaction (RT-PCR) in the nasopharyngeal and oropharyngeal samples taken during their admission to Kahramanmaraş Sütçü İmam University (KSU) Medical Faculty Chest Diseases outpatient clinic and emergency department. According to the most recently published 2019 novel coronavirus pneumonia diagnosis and treatment program (version 7), COVID-19 disease is divided into groups as mild, moderate, severe and critical illness. Demographic data, comorbidities, symptoms and signs, laboratory findings, and chest computed tomography (CT) scans were reviewed. The presence of heart failure, coronary artery disease or arrhythmia in the included patients was defined as cardiovascular disease. Patients were excluded if they were younger than 18 years old, pregnant, had a history of hepatobiliary disorders, alcohol abuse or other acute illnesses, died at the time of admission, had incomplete baseline data, or were transferred to other designated hospitals during hospitalization. Results: Fifty-five (43%) of the participants were female and 73 (57%) were male, with a mean age of 55.6 years. When examined in terms of age, the difference between the groups was statistically significant. The difference between the individuals with and without hypertension and diabetes mellitus was found to be significant in terms of disease severity. When examined in terms of symptoms, 23 (71.9%) of the patients in the mild group were symptomatic, 9 (28.1%) were asymptomatic, and all of the patients in the moderate, severe and critical groups were symptomatic (100%). Cardiovascular biomarkers and GGT values were found to be significantly higher in the severe and critical disease group than in the mild and moderate disease group. However, having cardiovascular disease did not cause a significant difference in GGT levels fo the disease groups. GGT levels were found to be statistically similar in individuals with and without the disease. When blood gas parameters were analyzed in terms of disease severity, oxygen saturation (SpO2) and PO2 were found to be significantly lower in the severe and critical illness group than in the mild and moderate disease group. When the effect of blood parameters on mortality was analyzed by logistic regression analysis, only the effect of PO2 parameter on mortality was found to be statistically significant. In addition, the effects of cardiovascular diseases and age variables on mortality were found to be statistically significant (p=0.031, p=0.007; respectively). The effect of cardiovascular disease on mortality was 4,325 times (ODDS ratio) higher compared to individuals without cardiovascular disease. Conclusion: In this study, we determined two important findings. First, the serum level of GGT was found to be significantly higher in the severe and critical disease group than in the mild and moderate disease group. Second, cardiovascular disease, advanced age, and hypoxemia were associated with mortality from COVID-19 disease. Although GGT provides no increased benefit for predicting cardiovascular disease risk, its potential causal relationship with cardiovascular disease deserves attention.

Abstract 4138731: Clonal Hematopoiesis of Indeterminant Potential is Associated with Pulmonary Arterial Hypertension

Background: Pulmonary Arterial Hypertension (PAH) is a fatal cardiopulmonary disorder characterized by adverse vascular remodelling of small pulmonary arteries, which increases resistance and demand on the right ventricle (RV), ultimately leading to RV fibrosis and failure. Emerging evidence suggests that inflammation plays a crucial role in PAH pathogenesis. Here, we study Clonal Hematopoiesis of Indeterminate Potential (CHIP), a disorder characterized by somatic mutations in genes such as DNMT3A and TET2 , that promotes an inflammatory phenotype, in the development of PAH. Methods: We performed deep, targeted panel sequencing on 1659 PAH patients from the PAH Biobank and 3644 controls (3401 Vanderbilt University Biorepository patients and 243 participants recruited by the Queen’s Genomics Centre at Ongwanada). Variants in known CHIP genes expressed at a variant allele frequency (VAF) > 2% were classified as CHIP. Genes with a VAF > 25% and <50% were considered CHIP if located in reported CHIP hotspot regions. The prevalence of CHIP mutations was compared between controls and PAH patients. Logistic regression was used for statistical analysis. Results: We identified 242 CHIP variants in the 1659 PAH patients. DNMT3A was the most mutated gene (116/242 = 48%), followed by TET2 (46/242=19%). After adjusting for age and sex, we identified a significant association between all CHIP variants combined and PAH (OR: 23.35 [7.67, 71.03]; p<0.0001). Further, DNMT3A CHIP (OR: 25.44 [5.37, 120.40]; p<0.0001), non- DNMT3A CHIP (OR: 26.80 [5.56, 129.23]; p<0.0001) and TET2 CHIP (OR: 13.69 [1.29, 145.30]; p=0.03) were all associated with PAH. A higher proportion of PAH patients under the age of 70 were found to have CHIP variants compared to controls and this was significant for individuals between 60-69 years of age (p=0.037). While there was a 3.8:1 female-to-male ratio of PAH patients, there was a 5.8:1 female-to-male preponderance of DNMT3A variants (p=0.039) (4.3:1 for all CHIP; p=ns), suggesting DNMT3A variants are more common in female patients. The presence of CHIP variants had no significant effect on PAH patient 10-year survival. Conclusion: This research reveals a significant association between CHIP variants, specifically in DNMT3A and TET2, and PAH. The prevalence of CHIP is higher in PAH patients aged 40 to 70 compared to controls and is more common in female patients. These findings suggest that CHIP is a significant risk factor for the development of PAH.

Echocaridographic assessment of pulmonary hypertension: improving the probability

Abstract Introduction Pulmonary hypertension (PH) is a cardio-pulmonary disorder characterised by raised pulmonary artery pressure (mPAP >20mmHg) leading to right ventricular failure, and death if left untreated. Transthoracic echocardiography (TTE) assessment of PH uses a probability-based approach, combining peak tricuspid regurgitant velocity with other supporting signs. We evaluated the latest ESC TTE PH guidelines in a real-world UK dataset and identified markers that may improve the sensitivity of the existing algorithm. Method Retrospective analysis of 447 patients referred for initial PH assessment. This was a select population of patients who underwent both TTE and right heart catheter (RHC) (mean time to RHC = 40±30 days). In addition to current TTE PH probability markers we analysed right ventricular free wall strain (RVFWS). Measurements were made by a single operator using Tomtec Arena 2020. Crosstabulation, ROC curve analysis and T-tests were used to compare variables between PH and no PH. Results Mean sample age was 64±15 yrs (61% female). 6.9% (n=4) of the no PH group had pulmonary mid-systolic notching, which may be due to pseudo-notching attributable to incomplete Doppler envelope. Sensitivity and specificity of current ESC TTE probability guidelines were 83%, and 65% respectively (95% C.I.). However, within the low probability group (i.e. those felt to be less likely to have PH) 62% (n=63) had confirmed PH at RHC (mPAP = 28±9). The addition of RVFWS as an additional marker to the existing supporting signs of PH (Table 1) resulted in an improvement of the sensitivity of the algorithm to 92% with a mild reduction in specificity (63%). The number of false negatives were reduced by 51%. Of these, the majority were in the low TTE probability group (n = 32). Conclusions Using current PH TTE probability algorithms classifies a significant proportion of those with PH as having a low TTE PH probability. The addition of RVFWS improves the sensitivity of the existing algorithm to 92% and reduces false negatives by 51%.

Postthoracotomy Pain: The Unanswered Question Yet – A Clinical and Technical Report

Abstract Thoracotomy which is a major surgical procedure of making an incision through the thoracic wall in order to gain access to the thoracic organs, is a cornerstone of diagnosis and management of numerous cardiopulmonary disorders. Nonetheless, most essential area of patient care, postoperative pain management, presents several obstacles. Published literature shows that about three-quarters of the thoracotomy patients reported immediate pain or discomfort during the early postoperative period, and up to 30%–50% patients might even develop chronic pain that has implications on their health related quality of life. Consequently, the causes of continued pain after thoracotomy are numerous and range from the intricacy of the procedure, patients’ tolerance to pain and diseases among others. Pain control is essential to avoid the risk of the deterioration of lung function, poor patient mobilization, and prolonged hospital stay. It is therefore undoubted that if pain continues for a long period, one may develop chronic pain syndromes that drag down the quality of life even further. In attempts to resolve these problems, different types of analgesic measures have been attempted. Some interventional procedures have been reported recently to be useful: Fascial plane blocks, which interfere with the flow of pain messages. Routes such as thoracic paravertebral block, intercostal nerve block, serratus anterior plane block, pectoral nerve block, and the retrolaminar block give variable levels of anesthesia in the required area. Some newer blocks such as the rhomboid intercostal and serratus sparing (RISS) block seem to provide a wide complete analgesia of the posterior and lateral chest walls. Thus, in an intermediate-term pain management strategy, fascial plane blocks can be used together with medications such as paracetamol and nonsteroidal anti-inflammatory drugs (NSAIDs). It is a kind-of medicine that is frequently used because of its effectiveness accompanied by a tendency to produce minimal side effects and interact well with opioids without posing the risks inherent in the application of NSAIDs. They have significant analgesic and anti-inflammatory properties thus decreasing the dependence on opioids. Their use, therefore, comes with a lot of precautions due, prompt for example per both gastrointestinal bleeding and renal impairment, hence, requires patient spotlight and assessment. Therefore, in enhancing postthoracotomy pain regime, a multimodal approach that includes the use of fascial plane blocks in combination with paracetamol and prudent use of NSAID can improve the recovery process and henceforth the patient’s outcomes without subjecting the patients to adverse effects.

Albumin adjuvant therapy for acute ischemic stroke with large vessel occlusion (AMASS-LVO): rationale, design, and protocol for a phase 1, open-label, clinical trial.

Acute ischemic stroke (AIS) is an acute brain injury caused by sudden occlusion of a blood vessel. Endovascular therapy is the most effective way to restore blood flow. However, despite the restoration of blood flow in some patients, their clinical prognosis often remains unsatisfactory. Albumin has shown neuroprotective effects in animal models of AIS. Therefore, this study aims to evaluate the safety, feasibility, and efficacy of local arterial infusions of 20% human serum albumin solution as an adjuvant therapy after endovascular therapy in patients with AIS. This study is a prospective, therapeutic exploratory, non-randomized, open-label, phase 1 clinical trial testing the use of 20% human serum albumin solution injected via the artery immediately after successful reperfusion in patients with AIS. The study is divided into two stages. In the first stage, a single-dose-finding will explore the maximum safe dose according to the 3 + 3 dose escalation principle;, with the maximum dose being 0.60 g/kg. After recanalizing the occluded blood vessel, human serum albumin solution will be injected into the internal carotid artery region through a guiding catheter for 30 min. The second stage involves an albumin adjuvant therapy cohort (AT) and an endovascular treatment lonely cohort (ET). The AT cohort will encompass at least 15 additional participants to complete safety trials at the maximum safe dose determined in the first stage. The ET cohort will include well-matched patients receiving endovascular therapy alone, derived from a contemporaneous prospective registry, who will be excluded from having cardiopulmonary disorders and from receiving any neuroprotective therapy. The primary outcome of this study will be symptomatic intracranial hemorrhage. Efficacy outcomes will include the proportion of patients with the progression of cerebral infarction volume, a modified Rankin Scale of 0-2 on day 90 after randomization. An exploratory secondary outcome will be the analysis of thromboinflammatory and neuroprotective molecule profiles. This pilot trial aims to explore the safety and efficacy of arterial infusion of an albumin solution after occlusive vessel opening in AIS. The results will provide data parameters for subsequent tests on the arterial infusion of albumin solutions. ClinicalTrials.gov, NCT05953623.

SOX9 promotes hypoxic pulmonary hypertension through stabilization of DPP4 in pulmonary artery smooth muscle cells

Pulmonary hypertension (PH) is a progressive cardiopulmonary disorder characterized by pulmonary vascular remodeling (PVR), primarily due to the excessive proliferation of pulmonary artery smooth muscle cells (PASMCs). This study aimed to investigate the role and molecular mechanism of SOX9 in hypoxic PH in rats. The findings revealed that SOX9 was upregulated in the pulmonary arteries and PASMCs of hypoxia-exposed rats. SOX9 knockdown inhibited hypoxia-induced proliferation and migration of PASMCs, reduced PVR, and subsequently alleviated hypoxia-induced PH in rats, suggesting that SOX9 plays a critical role in PH. Further investigation demonstrated that SOX9 interacted with DPP4, preventing its ubiquitin degradation in hypoxia-exposed PASMCs. DPP4 knockdown inhibited hypoxia-induced PASMC proliferation and migration, and administration of the DPP4 inhibitor sitagliptin (5 mg/kg) significantly reduced PVR and alleviated hypoxia-induced PH in rats, indicating that SOX9 contributes to PH by stabilizing DPP4. The results also showed that hypoxia induced YAP1 expression and dephosphorylation, leading to YAP1 nuclear localization. YAP1 knockdown promoted the degradation of HIF-1α in hypoxia-exposed PASMCs and inhibited hypoxia-induced proliferation and migration of PASMCs. Additionally, HIF-1α, as a transcription factor, promoted SOX9 expression by binding to the SOX9 promoter in hypoxia-exposed PASMCs. In conclusion, hypoxia promotes the proliferation and migration of PASMCs through the regulation of the YAP1/HIF-1α/SOX9/DPP4 signaling pathway, leading to PH in rats. These findings suggest that SOX9 may serve as a potential prognostic marker and therapeutic target for PH.

The Relevance of the Endothelium in Cardiopulmonary Disorders.

The endothelium is a cell monolayer that lines vessels and separates tissues from blood flow. Endothelial cells (ECs) have a multitude of functions, including regulating blood flow and systemic perfusion through changes in vessel diameter. When an injury occurs, the endothelium is affected by altering its functions and structure, which leads to endothelial dysfunction, a characteristic of many vascular diseases. Understanding the role that the endothelium plays in pulmonary vascular and cardiopulmonary diseases, and exploring new therapeutic strategies is of utmost importance to advance clinically. Currently, there are several treatments able to improve patients' quality of life, however, none are effective nor curative. This review examines the critical role of the endothelium in the pulmonary vasculature, investigating the alterations that occur in ECs and their consequences for blood vessels and potential molecular targets to regulate its alterations. Additionally, we delve into promising non-pharmacological therapeutic strategies, such as exercise and diet. The significance of the endothelium in cardiopulmonary disorders is increasingly being recognized, making ECs a relevant target for novel therapies aimed at preserving their functional and structural integrity.

A Retrospective Study of Sildenafil Administration in 55 Cats with Cardiopulmonary Disease (2009-2021).

Sildenafil is a drug used to successfully manage a variety of cardiopulmonary disorders in people and dogs, but there is limited information on its use in cats. The objective was to review the medical records of cats that received sildenafil as part of their clinical management. Medical records and pharmacy databases were searched for cats that received sildenafil for ≥24 h between 2009 and 2021, and data were collected from medical records. Fifty-five cats received sildenafil for ≥24 h and were included in the study: 43 with primary cardiac disease (acquired, n = 28; congenital, n = 15) and 12 with primary respiratory disease. Side effects possibly attributed to sildenafil were identified in two cats (systemic hypotension, n = 1; polydipsia, n = 1), and sildenafil was discontinued in the cat with hypotension. Sildenafil was discontinued in an additional three cats due to a lack of improvement in clinical signs. No cat was documented to develop worsening pulmonary edema within 72 h of starting sildenafil. Median duration of sildenafil administration was 87 days (range, 2-2362 days). Sildenafil administration in cats appeared to be generally well-tolerated. Studies are needed to determine whether sildenafil administration to cats with cardiopulmonary disease improves the quality of life or survival times.

Impact of Idiopathic Scoliosis on the Cardiopulmonary Capacity of Adolescents.

Chest deformities in children with scoliosis may result in cardiopulmonary disorders, lowering cardiopulmonary capacity levels. However, results regarding the dependence of cardiopulmonary capacity on the severity level of scoliosis remain controversial. We aimed to use dynamic cardiopulmonary exercise testing (CPET) to investigate exercise capacity in reference to spinal deformity in patients with mild or moderate idiopathic scoliosis by means of multivariate analyses. Methods: We included 92 children and adolescents aged 10-17 years with mild and moderate idiopathic scoliosis and 94 healthy peers. The study consisted of three parts: (1) medical record analyses; (2) anthropometric measurements; and (3) CPET. Results: Our results revealed that the mean VO2peak and VO2peak/kg values of the participants with scoliosis were 0.27 L/min and 0.37 mL/min/kg lower than their healthy peers, respectively, regardless of age and gender. Furthermore, the occurrence of scoliosis correlates with a mean decrease in minute ventilation volume by 10.10 L/min, tidal volume by 0.11 L, breathing frequency by 3.78 bpm, and breathing reserve by 14.34%, regardless of the age and gender of the participants. Children and adolescents with mild-to-moderate scoliosis during CPET exhibit a lower ventilation capacity and lower VO2 max than healthy adolescents matched in age but their cardiorespiratory fitness parameters do not depend on the Cobb angle value and the angle rotation of the primary spinal curvature. Conclusions: Physical therapy and activity should be recommended to prevent cardiorespiratory failure in later life in patients with scoliosis. This study may also provide CPET reference values for healthy children and adolescents with scoliosis.

Cardiovascular Sequelae of Bronchopulmonary Dysplasia in Preterm Neonates Born before 32 Weeks of Gestational Age: Impact of Associated Pulmonary and Systemic Hypertension.

Bronchopulmonary dysplasia (BPD) remains the most common respiratory disorder of prematurity for infants born before 32 weeks of gestational age (GA). Early and prolonged exposure to chronic hypoxia and inflammation induces pulmonary hypertension (PH) with the characteristic features of a reduced number and increased muscularisation of the pulmonary arteries resulting in an increase in the pulmonary vascular resistance (PVR) and a fall in their compliance. BPD and BPD-associated pulmonary hypertension (BPD-PH) together with systemic hypertension (sHTN) are chronic cardiopulmonary disorders which result in an increased mortality and long-term problems for these infants. Previous studies have predominantly focused on the pulmonary circulation (right ventricle and its function) and developing management strategies accordingly for BPD-PH. However, recent work has drawn attention to the importance of the left-sided cardiac function and its impact on BPD in a subset of infants arising from a unique pathophysiology termed postcapillary PH. BPD infants may have a mechanistic link arising from chronic inflammation, cytokines, oxidative stress, catecholamines, and renin-angiotensin system activation along with systemic arterial stiffness, all of which contribute to the development of BPD-sHTN. The focus for the treatment of BPD-PH has been improvement of the right heart function through pulmonary vasodilators. BPD-sHTN and a subset of postcapillary PH may benefit from afterload reducing agents such as angiotensin converting enzyme inhibitors. Preterm infants with BPD-PH are at risk of later cardiac and respiratory morbidities as young adults. This paper reviews the current knowledge of the pathophysiology, diagnosis, and treatment of BPD-PH and BPD-sHTN. Current knowledge gaps and emerging new therapies will also be discussed.

Appointment Blitz: Optimizing Patient-Therapist Rehab Scheduling.

Taiwan has a well-structured healthcare insurance system that offers accessible medical resources to the public through nominal health insurance fees. Consequently, individuals in need of care willingly pay nominal charges for medical services, including rehabilitation treatment. This study delves into the rehabilitation department of a medical center in southern Taiwan. Despite offering comprehensive traditional rehabilitation services covering neurological, musculoskeletal, pediatric, cardiopulmonary, communication, and swallow disorders, the demand for appointments significantly surpasses the number of available therapists. Therefore, this paper proposes an efficiently method to optimize patient-therapist appointment. With a Complex Conditional Logic that we have designed in this paper, we aim to simplify the scheduling processing for patient seeking appointment either online or via phone calls. More than 50,000 cases have been treated since the system's launch within a year, facilitates hospital resource allocation and enhancing patient medical experiences.

Exploring the pathogenesis of pulmonary vascular disease.

Pulmonary hypertension (PH) is a complex cardiopulmonary disorder impacting the lung vasculature, resulting in increased pulmonary vascular resistance that leads to right ventricular dysfunction. Pulmonary hypertension comprises of 5 groups (PH group 1 to 5) where group 1 pulmonary arterial hypertension (PAH), results from alterations that directly affect the pulmonary arteries. Although PAH has a complex pathophysiology that is not completely understood, it is known to be a multifactorial disease that results from a combination of genetic, epigenetic and environmental factors, leading to a varied range of symptoms in PAH patients. PAH does not have a cure, its incidence and prevalence continue to increase every year, resulting in higher morbidity and mortality rates. In this review, we discuss the different pathologic mechanisms with a focus on epigenetic modifications and their roles in the development and progression of PAH. These modifications include DNA methylation, histone modifications, and microRNA dysregulation. Understanding these epigenetic modifications will improve our understanding of PAH and unveil novel therapeutic targets, thus steering research toward innovative treatment strategies.

СИСТЕМНАЯ ФОРМА ЮВЕНИЛЬНОГО АРТРИТА, СИНДРОМ МАКРОФАГАЛЬНОЙ АКТИВАЦИИ И КАРДИОПУЛЬМОНАРНЫЕ НАРУШЕНИЯ – ЧТО НУЖНО ЗНАТЬ РЕВМАТОЛОГУ?

Systemic juvenile idiopathic arthritis (sJIA) is the most severe variant of JIA that can be characterized by a life-threatening course. sJIA manifests with fever, arthralgia/arthritis, hepatosplenomegaly, leukocytosis and systemic inflammation markers. Macrophage activation syndrome (MAS) is the most severe complication of this disease. This Article represents up-to-date information on pathogeneses of sJIA and MAS, describes approaches to diagnosis, treatment of both uncomplicated and complicated forms of sJIA and refractory variants of the MAS course. Current data regarding the monitoring of sJIA therapy effectiveness and safety is presented as well. Predictors for the most recently discovered, i.e. relatively new “target organs” in patients with sJIA and cardiopulmonary disorders in particular are given.

Modern engineering solutions for an original domestic nitric oxide generator (“Tianox”)

Nitric oxide (NO) is a biologically active molecule approved for the treatment of persistent pulmonary hypertension in newborns in the USA, Japan, and most European countries in 1999 – 2008. Inhaled NO is currently used to treat a spectrum of cardiopulmonary disorders, including pulmonary hypertension in children and adults. A commercially available NO delivery system uses pressurized cylinders as a source of NO. Current cylinder-based delivery systems are widely used around the world, but they are bulky, expensive and dependent on a reliable supply chain. The aim of the work was to present an original domestic generator for NO inhalation therapy. Over the past few years, to overcome the limitations of the balloon technology, specialists from the Federal State Unitary Enterprise “Russian Federal Nuclear Center – All-Russian Research Institute of Experimental Physics” have developed a plasma-chemical NO generator that produces NO from ambient air using a nonequilibrium spark discharge plasma. In this case, a diffuse discharge mode is implemented, which ensures the most efficient synthesis of NO with the participation of excited nitrogen molecules (N2+) according to a chain mechanism similar to the Zeldovich – Semenov chain reaction. The result is a high-quality NO-containing gas mixture that does not contain toxic by-products (electrode material, ozone, etc.) usually formed in the known systems of this type. Conclusion. Based on the developed generator, the Federal State Unitary Enterprise “Russian Federal Nuclear Center – All-Russian Research Institute of Experimental Physics” designed and created the world’s first commercially available device for inhalation therapy, “Tianox”. The device was approved for circulation on the territory of the Russian Federation by order of the Federal Service for Surveillance in Healthcare (2020) based on the results of technical and clinical tests. Serial production of “Tianox” meets the requirements of ISO 13485-2016 and GOST ISO 13485-2017.

Effect of Circulating Extracellular Vesicles from Adults with Spinal Cord Injury on Pulmonary Artery Endothelial Cell Function

Spinal cord injury (SCI) is associated with an increased risk and prevalence of cardiopulmonary and cerebrovascular disease-related morbidity and mortality. Despite an improved understanding of the neurological and physical consequences associated with SCI, factors that initiate, promote and accelerate cardiopulmonary disease are poorly understood. It has become apparent that the increased incidence of pulmonary disorders in adults with chronic SCI is not solely due to worsening of traditional risk factors, but also involves ill-defined factors. Several studies have implicated circulating endothelial cell-derived microvesicles (EMVs) in the etiology of cardiopulmonary diseases. We have previously reported that circulating EMVs are elevated in adults with chronic SCI and the expression of their microRNA cargo promotes disease. Reduction in pulmonary nitric oxide (NO) bioavailability and increased endothelin (ET)-1 production underly many cardiopulmonary disorders associated with SCI. The experimental aim of this study was to determine the effect of EMVs isolated from adults with chronic tetraplegic SCI on pulmonary endothelial cell NO and ET-1 production. As part of an ongoing study, circulating EMVs (CD144-PE) were isolated (flow cytometry) from 7 non-injured adults (all male; age: 38±4 yr) and 7 motor complete SCI adults with tetraplegic SCI (male; 44±5 yr). All subjects were free of overt cardiometabolic disease. Human pulmonary artery endothelial cells (HPAECs) were cultured and separately treated with EMVs from each subject for 24 hr. Expression of intracellular NO and ET-1 proteins of interest was determined by capillary electrophoresis immunoassay. Circulating EMV concentrations were significantly higher (~200%) in SCI vs non-injured (154±36 vs 54±7 EMV/μL). Expression of p-eNOS (Ser1177), the primary activation site for eNOS, was ~30% lower (96.0±2.3 vs 140.7±8.9 AU; p<0.01) and p-eNOS (Thr495), primary inhibitory site, ~40% higher (40.7±1.7 vs 28.8±3.1 AU; p<0.01) in cells treated with EMVs from SCI vs non-injured. As a result, NO production was ~20% lower (6.5±0.3 vs 8.3±0.7 μmol/L; P=0.03) in HPAECs treated with EMVs from adults with SCI. SCI-associated EMVs also significantly increased (~70%) the expression of Big ET-1 (60.6±3.6 vs 36.1±2.7 AU) resulting in enhanced endothelial ET-1 production (884.0±22.9 vs 778.7±18.0 pg/mL). In conclusion, EMVs harvested from adults with SCI markedly reduced eNOS activation and NO production and increased ET-1 synthesis and release in pulmonary endothelial cells in vitro. Circulating EMVs represent a potential mechanistic factor underlying pulmonary disorders and increased disease risk with SCI. 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.

Early recognition and treatment of OSA in hospitalized patients and its impact on health care utilization in rural population: a real-world study.

Obstructive sleep apnea (OSA) is a highly prevalent, yet underdiagnosed, condition. Due to its adverse impact on risk for cardiopulmonary disorders, there is interest in proactive screening of OSA in hospitalized patients. We studied the long-term outcome of such screened patients who were initiated on positive airway pressure therapy. Hospitalized patients who screened positive for OSA and were confirmed with postdischarge polysomnography were dichotomized by positive airway pressure therapy adherence and followed for a period of 12 months to evaluate for the composite end point of hospital readmissions and emergency department visits for cardiopulmonary reasons. Cost analysis between the 2 groups was also conducted. A total of 2,042 hospitalized patients were assessed for OSA as part of a hospital sleep medicine program from August 2019-June 2023. Of these, 293 patients were diagnosed with OSA and prescribed positive airway pressure therapy. Of these 293 patients, 108 were adherent to therapy and 185 were nonadherent. The overall characteristics of the groups included a mean (standard deviation) age of 58 years (12.82), mean body mass index (kg/m2) of 39.72 (10.71), 57% male sex, and apnea-hypopnea index of 25.49 (26). Of the patients, 78%, 41%, and 43% had hypertension, congestive heart failure, and diabetes mellitus, respectively. The composite end point of hospital readmissions and emergency department visits for cardiovascular and pulmonary reasons was significantly higher in the nonadherent group than in the adherent group (hazard ratio, 1.24; 95% confidence interval, 1-1.54) (P = .03). The cost of care for both hospital billing as well as professional billing was higher for the nonadherent group ($1,455.60 vs $1,723.50, P = .004 in hospital billing cost and $130.90 vs $144.70, P < .001 in professional billing). Length of stay was higher for nonadherent patients (2.7 ± 5.1 days vs 2.3 ± 5.9 days). Hospitalized patients diagnosed with OSA and adherent to therapy have reduced readmissions and emergency department visits for cardiopulmonary reasons 12 months after discharge. Adherent patients have reduced cost of health care and length of stay during hospitalizations. Sharma S, Stansbury R, Srinivasan P, etal. Early recognition and treatment of OSA in hospitalized patients and its impact on health care utilization in rural population: a real-world study. J Clin Sleep Med. 2024;20(8):1313-1319.

The appropriate technique for blood pressure measurement in healthy geriatric cats using an automatic oscillometric device

Currently, the popularity of owning cats is increasing, together with improvements in diet, management, and veterinary specialism. The population of older cats has accordingly increased markedly. There are several health problems that accompany aging, such as degenerative diseases and cardiopulmonary disorders. Hypertension is the most common clinical sign that has been found in aging cats. Therefore, early screening for hypertension is necessary to prevent disease progression. However, cats are sensitive and are likely to develop mental stress during the measurement procedure, so an appropriate technique is required. The experiment was performed in 60 healthy elderly cats, whereby each cat was randomly assigned to one of the two trial groups. There were two groups in the experiment: 1) the cuff was placed on the forelimb at all times and the blood pressure was measured at 0, 5, 15, 30, and 60 minutes, and 2) the cuff was placed after waiting to rest at 30 and 60 minutes, followed by blood pressure measurement using the automatic oscillometric device. The results showed that blood pressure measurement at 15 minutes while placing the forelimb cuff at all times provided appropriate clinical reliability. Thus, this procedure could be used for hypertension screening in geriatric cats

Mechanistic Investigation of Calcium Channel Regulation-Associated Genes in Pulmonary Arterial Hypertension and Signatures for Diagnosis.

Pulmonary arterial hypertension (PAH) is a severe cardiopulmonary disorder with complex causes. Calcium channel blockers have long been used in its treatment. Our study aimed to validate experimental results showing increased calcium ion concentration in PAH patients. We investigated the impact of genes related to calcium channel regulation on PAH development and developed an accurate diagnostic model. Clinical trial data from serum of 18 healthy individuals and 18 patients with PAH were retrospectively analyzed. Concentrations of calcium and potassium ions were determined and compared. Datasets were retrieved, selecting genes associated with calcium ion release. R packages processed the datasets, filtering 174 common genes, and conducting Gene Ontology and Kyoto Encyclopedia of Genes and Genomes enrichment analyses. Six hub genes were identified, and nomogram and logistic regression prediction models were constructed. Random forest filtered cross genes, and a diagnostic model was developed and validated using an artificial neural network. The 174 intersection genes related to calcium ions showed significant correlations with biological processes, cellular components, and molecular functions. Six key genes were obtained by constructing a protein-protein interaction network. A diagnostic model with high accuracy (> 90%) and diagnostic capability (AUC = 0.98) was established using a neural network algorithm. This study validated the experimental results, identified key genes associated with calcium ions, and developed a highly accurate diagnostic model using a neural network algorithm. These findings provide insights into the role of calcium release genes in PAH and demonstrate the potential of the diagnostic model for clinical application. However, due to limitations in sample size and a lack of prognosis data, the regulatory mechanisms of calcium ions in PAH patients and their impact on the clinical prognosis of PAH patients still need further exploration in the future.

Salidroside protects pulmonary artery endothelial cells against hypoxia-induced apoptosis via the AhR/NF-κB and Nrf2/HO-1 pathways

BackgroundThe apoptosis of pulmonary artery endothelial cells (PAECs) is an important factor contributing to the development of pulmonary hypertension (PH), a serious cardio-pulmonary vascular disorder. Salidroside (SAL) is a bioactive compound derived from an herb Rhodiola, but the potential protective effects of SAL on PAECs and the underlying mechanisms remain elusive. PurposeThe objective of this study was to determine the role of SAL in the hypoxia-induced apoptosis of PAECs and to dissect the underlying mechanisms. Study designMale Sprague-Dawley (SD) rats were subjected to hypoxia (10% O2) for 4 weeks to establish a model of PH. Rats were intraperitoneally injected daily with SAL (2, 8, and 32 mg/kg/d) or vehicle. To define the molecular mechanisms of SAL in PAECs, an in vitro model of hypoxic cell injury was also generated by exposed PAECs to 1% O2 for 48 h. MethodsVarious techniques including hematoxylin and eosin (HE) staining, immunofluorescence, flow cytometry, CCK-8, Western blot, qPCR, molecular docking, and surface plasmon resonance (SPR) were used to determine the role of SAL in rats and in PAECs in vitro. ResultsHypoxia stimulation increases AhR nuclear translocation and activates the NF-κB signaling pathway, as evidenced by upregulated expression of CYP1A1, CYP1B1, IL-1β, and IL-6, resulting in oxidative stress and inflammatory response and ultimately apoptosis of PAECs. SAL inhibited the activation of AhR and NF-κB, while promoted the nuclear translocation of Nrf2 and increased the expression of its downstream antioxidant proteins HO-1 and NQO1 in PAECs, ameliorating the hypoxia-induced oxidative stress in PAECs. Furthermore, SAL lowered right ventricular systolic pressure, and decreased pulmonary vascular remodeling and right ventricular hypertrophy in hypoxia-exposed rats. ConclusionsSAL may attenuate the apoptosis of PAECs by suppressing NF-κB and activating Nrf2/HO-1 pathways, thereby delaying the progressive pathology of PH.