GPCRs and fibroblast heterogeneity in fibroblast-associated diseases.

G protein-coupled receptors (GPCRs) are the largest and most diverse class of signaling receptors. GPCRs regulate many functions in the human body and have earned the title of "most targeted receptors". About one-third of the commercially available drugs for various diseases target the GPCRs. Fibroblasts lay the architectural skeleton of the body, and play a key role in supporting the growth, maintenance, and repair of almost all tissues by responding to the cellular cues via diverse and intricate GPCR signaling pathways. This review discusses the dynamic architecture of the GPCRs and their intertwined signaling in pathological conditions such as idiopathic pulmonary fibrosis, cardiac fibrosis, pancreatic fibrosis, hepatic fibrosis, and cancer as opposed to the GPCR signaling of fibroblasts in physiological conditions. Understanding the dynamics of GPCR signaling in fibroblasts with disease progression can help in the recognition of the complex interplay of different GPCR subtypes in fibroblast-mediated diseases. This review highlights the importance of designing and adaptation of next-generation strategies such as GPCR-omics, focused target identification, polypharmacology, and effective personalized medicine approaches to achieve better therapeutic outcomes for fibrosis and fibrosis associated malignancies.

Prevalence, associated risk factors, and respiratory event distribution of obstructive sleep apnea in children with Down syndrome.

PURPOSE: Children with Down Syndrome (DS) have a high prevalence of obstructive sleep apnea (OSA). We aimed to assess OSA prevalence in a single center cohort of children with DS, identify associated risk factors of obstructive respiratory events, and examine the influence of different sleep stages and body positions on respiratory events distribution. METHODS: Single center retrospective study that included children with DS who underwent overnight polysomnogram (PSG). OSA severity was categorized by obstructive apnea-hypopnea index (OAHI) as mild (1.5-4.9 events/h), moderate (5-9.9 events/h), and severe (≥ 10 events/h). A logistic regression analysis was used to examine the association between OSA-related risk factors in normal and abnormal OAHI category and in REM and Non-REM predominant AHI groups. RESULTS: PSG data were available for 192 children with a median age of 5 years (IQR 7). OSA prevalence was 82.3% (27.1% mild, 19.8% moderate, and 35.4% severe). A logistic regression model identified BMI and being an African American as significant predictors for OAHI severity. In children with OSA, the median OAHI was 7.6 and obstructive respiratory events were more common in REM sleep and in the supine position. The median REM OAHI was 20 events/h (IQR: 24.4), whereas the median Non-REM OAHI was 5.2 events/h (IQR: 12.6 p < 0.0001). Similarly, supine OAHI was 11.6 (IQR: 19.3) and off supine OAHI was 6.6 (IQR: 11.6, p = 0.0004). Age was a significant predictor (p = 0.012) for Non-REM predominant OSA which was present in 15.2% of children with OSA. CONCLUSION: Children with DS have a high prevalence of OSA. Higher BMI and being an African American were significant associated risk factors for higher OAHI. Obstructive respiratory events in children with DS occur predominantly in REM sleep and in the supine position. Non-REM predominant distribution of respiratory events was noted in older children with DS.

Adenotonsillectomy outcomes in children with down syndrome and obstructive sleep apnea: a single center study.

PURPOSE: This study aimed to evaluate polysomnographic (PSG) outcomes of tonsillectomy and adenoidectomy (T&A) in children with Down Syndrome (DS) and OSA, and the difference in PSG outcomes of T&A between children with DS and age- and gender-matched normally developing (non-DS) children. METHODS: This was a single center retrospective study that included children with DS and OSA who underwent T&A and had pre-operative and post-operative PSG. The baseline and the differences of pre- and post-operative PSG variables were compared with those of an age- and gender-matched group of non-DS children. RESULTS: Forty-eight children with DS were included in the study; the median age was 5 years (IQR 5.5), 58% were males, and the median BMI was 18.2 (IQR 3.3). There was statistically significant improvement noted between pre-operative and post-operative OAHI 17.9 ± 26.7 vs. 9.1 ± 13.6 (p = 0.022) and non-REM AHI 13.9 ± 19.7 vs. 6.9 ± 14.2 (p = 0.027). However, there were no significant changes in sleep architecture, oxygen desaturation nadir, or CO2 levels. 54.2% of the DS children continued to have moderate to severe OSA after T&A. Univariate logistic regression showed that for every 1% increase in oxygen desaturation nadir, the odds of having residual moderate or severe OSA decreased by 28% (p = 0.002) compared to the cured and mild OSA groups. There was no significant pre- and post-operative differences in PSG variables noted in 16 children with DS compared to age- and gender-matched non-DS children. CONCLUSION: Despite the overall significant reduction of OAHI in children with DS and OSA who underwent T&A, there was a residual moderate to severe OSA in about half of the included children. Oxygen desaturation nadir was a predicting factor for persistent moderate to severe OSA. There were no significant pre- and post-operative PSG differences in between DS children compared to non-DS children.

Polysomnographic outcomes of revision adenoidectomy in children with obstructive sleep apnea and recurrent/residual adenoidal hypertrophy.

INTRODUCTION: Recurrent/residual adenoidal hypertrophy after adenotonsillectomy in children can result in obstructive sleep apnea (OSA). We aimed to assess the polysomnographic (PSG) outcomes of revision adenoidectomy in children with recurrent/residual adenoidal hypertrophy and OSA. METHODS: This was a single-center retrospective study that included children with sleep studies that confirmed OSA and known history of adenotonsillectomy who were diagnosed with adenoidal hypertrophy and subsequently underwent revision adenoidectomy. Pre- and postoperative PSG variables of revision adenoidectomy were included in the analysis. RESULTS: A total of 20 children were included in the study. The cohort included 13 males and 7 females with a mean age of 7.8 years (± 3.6 years). The mean BMI z score was 1.96 [1.31, 2.43]. The median duration from adenotonsillectomy performance was 2.3 years [1.4, 4.0]. Overall, revision adenoidectomy resulted in significant improvements in multiple respiratory parameters, including AHI 6.6 [1.4, 13. 7] vs 14.8 [7.4, 20.7], p = 0.02; oxygen desaturations nadir 88.0 [84.0, 93.0] vs 80.0 [72.2, 88.9], p = 0.01; supine AHI 8.6 [1.5, 14.3] vs 17.6 [8.3, 30.2], p = 0.02; and arousal index 12.2 [9.6, 15.7] vs 18.9 [13.4, 24.9], p = 0.04. CONCLUSIONS: Children with recurrent/residual adenoidal hypertrophy after adenotonsillectomy who undergo revision adenoidectomy experience improvements in respiratory event, gas exchange, and arousal index.

Overview of the cardiovascular effects of environmental metals: New preclinical and clinical insights.

Environmental causes of cardiovascular diseases (CVDs) are global health issues. In particular, an association between metal exposure and CVDs has become evident but causal evidence still lacks. Therefore, this symposium at the Society of Toxicology 2022 annual meeting addressed epidemiological, clinical, pre-clinical animal model-derived and mechanism-based evidence by five presentations: 1) An epidemiologic study on potential CVD risks of individuals exposed occupationally and environmentally to heavy metals; 2) Both presentations of the second and third were clinical studies focusing on the potential link between heavy metals and pulmonary arterial hypertension (PAH), by presenting altered blood metal concentrations of both non-essential and essential metals in the patients with PAH and potential therapeutic approaches; 3) Arsenic-induced atherosclerosis via inflammatory cells in mouse model; 4) Pathogenic effects on the heart by adult chronic exposure to very low-dose cadmium via epigenetic mechanisms and whole life exposure to low dose cadmium via exacerbating high-fat-diet-lipotoxicity. This symposium has brought epidemiologists, therapeutic industry, physicians, and translational scientists together to discuss the health risks of occupational and environmental exposure to heavy metals through direct cardiotoxicity and indirect disruption of homeostatic mechanisms regulating essential metals, as well as lipid levels. The data summarized by the presenters infers a potential causal link between multiple metals and CVDs and defines differences and commonalities. Therefore, summary of these presentations may accelerate the development of efficient preventive and therapeutic strategies by facilitating collaborations among multidisciplinary investigators.

Enteral nutrition better than proton pump inhibitors?

PURPOSE OF REVIEW: Stress ulcer prophylaxis in critically-ill patients has been a subject of extensive research, with multiple clinical trials attempting to study the best method of stress ulcer prophylaxis with the least adverse effects. Until recently, pharmacologic prophylaxis has prevailed as the primary choice for the prevention of stress ulcers but recent clinical studies have attempted to evaluate the role of enteral nutrition in stress ulcer prophylaxis. RECENT FINDINGS: The incidence of stress ulcers that result in clinically important gastrointestinal bleeding (CIGIB) has drastically decreased over the last two decades. Furthermore, in the current era CIGB in the ICU does not seem to be associated with an increased mortality. Multiple recent clinical studies aimed to evaluate the role of proton pump inhibitors (PPIs) in patients who tolerate enteral nutrition in the ICU. SUMMARY: The results of multiple recent clinical studies call for re-evaluation of the routine use of PPIs in critically ill patients who tolerates enteral nutrition in the ICU. Despite the promising preliminary results, definitive recommendations need larger clinical trials that are powered to evaluate any added benefits of using PPI in critically ill patients who tolerate enteral nutrition given the low incidence of CIGB in the current era.

Rapid Inpatient Titration of Intravenous Treprostinil for Pulmonary Arterial Hypertension: Safe and Tolerable.

There is no standard protocol for intravenous treprostinil dose escalation. In most cases, slow up-titration is performed in the outpatient setting. However, rapid up-titration in an inpatient setting is an alternative that provides opportunity for aggressive treatment of common side effects experienced during dose escalation. In this study, we describe our experience with inpatient rapid up-titration of intravenous treprostinil. This was a single-center, retrospective study in which we reviewed the data of subjects with pulmonary arterial hypertension treated at our center who underwent inpatient rapid up-titration of intravenous treprostinil. Our treprostinil dose escalation protocol included initiation at 2 ng·kg·min with subsequent up-titration by 1 ng·kg·min every 6 to 8 hours as tolerated by side effects. A total of 16 subjects were identified. Thirteen subjects were treprostinil naive (naive group), and 3 subjects were receiving subcutaneous treprostinil but were hospitalized for further intravenous up-titration of treprostinil dose (nonnaive group). In the naive group, the median maximum dose achieved was 20 ng·kg·min with an interquartile range (IQR) of 20-23 ng·kg·min. The median up-titration interval was 6 days (IQR: 4-9). In the nonnaive group, the median maximum dose achieved was 20 ng·kg·min (range: 17-30). The median up-titration interval was 8.5 days (range: 1.5-11). Overall, the median maximum dose achieved was 20 ng·kg·min (IQR: 20-23.5), and the median up-titration interval was 6 days (IQR: 4.6-9.25), with no reported significant adverse hemodynamic events. In patients with pulmonary arterial hypertension, rapid inpatient titration of intravenous treprostinil is safe and tolerable.

Pulmonary Hypertension and Atrial Septal Defect: Management Dilemma.

The decision making in patients with an atrial septal defect (ASD) in setting of pulmonary hypertension is complex. In the era of pulmonary arterial vasodilator therapy, every patient should undergo evaluation by pulmonary hypertension experts especially if defect closure is being considered. Defect closure in the inappropriate group can lead to poor outcomes.

Predictive Role of Admission Lactate Level in Critically Ill Patients with Acute Upper Gastrointestinal Bleeding.

BACKGROUND: The predictive role of lactate in critically ill patients with acute upper gastrointestinal bleeding (UGIB) remains to be elucidated. OBJECTIVE: The primary objective of this study was to assess the value of lactate level on admission to predict in-hospital death in patients with UGIB admitted to the intensive care unit (ICU). The secondary objective was to assess whether lactate level adds predictive value to the clinical Rockall score in these patients. METHODS: This was a retrospective cohort study that included 133 patients with acute UGIB admitted to the ICU. Inclusion criteria were age > 18 years and presence of UGIB on admission to the ICU. RESULTS: Mean age was 55.4 years old and 64.7% were male. The most common cause of gastrointestinal bleeding was peptic ulcer disease, followed by erosive esophagitis/gastritis. The in-hospital mortality was 22.6%. Median lactate level in survivors and nonsurvivors was 2.0 (interquartile range [IQR] 1.2-4.2 mmol/L) and 8.8 (IQR 3.4-13.3 mmol/L; p < 0.01), respectively. The receiver operating characteristic (ROC) area to predict in-hospital death for clinical Rockall score and lactate level (0.82) was significantly higher than the ROC area for the clinical Rockall score alone (0.69) (p < 0.01). CONCLUSIONS: In patients admitted to the ICU with acute UGIB, lactate level on admission has a high sensitivity but low specificity for predicting in-hospital death. Lactate level adds to the predictive value of the clinical Rockall score. Given its high sensitivity, lactate level can be used in addition to other prediction tools to predict outcomes in patients with UGIB.

Pulmonary artery vasodilators for treatment of pulmonary hypertension complicating fibrosing mediastinitis.

Fibrosing mediastinitis (FM) is a heterogeneous disease characterized by sclerosing fibrosis of mediastinal structures. Pulmonary hypertension (PH) may complicate the course of the disease and can contribute significantly to the morbidity of FM. Due to the rarity and complexity of the disease, evidence-based guidelines are not currently available, and the optimal treatment approach is unknown. Management approaches should be individualized, and current techniques are often unsatisfactory. Here, we present two cases of PH complicating FM that were managed using pulmonary artery vasodilator therapy with excellent hemodynamic response.

A hypothesis: Potential contributions of metals to the pathogenesis of pulmonary artery hypertension.

Pulmonary artery hypertension (PAH) is characterized by vasoconstriction and vascular remodeling resulting in both increased pulmonary vascular resistance (PVR) and pulmonary artery pressure (PAP). The chronic and high-pressure stress experienced by endothelial cells can give rise to inflammation, oxidative stress, and infiltration by immune cells. However, there is no clearly defined mechanism for PAH and available treatment options only provide limited symptomatic relief. Due to the far-reaching effects of metal exposures, the interaction between metals and the pulmonary vasculature is of particular interest. This review will briefly introduce the pathophysiology of PAH and then focus on the potential roles of metals, including essential and non-essential metals in the pathogenic process in the pulmonary arteries and right heart, which may be linked to PAH. Based on available data from human studies of occupational or environmental metal exposure, including lead, antimony, iron, and copper, the hypothesis of metals contributing to the pathogenesis of PAH is proposed as potential risk factors and underlying mechanisms for PAH. We propose that metals may initiate or exacerbate the pathogenesis of PAH, by providing potential mechanism by which metals interact with hypoxia-inducible factor and tumor suppressor p53 to modulate their downstream cellular proliferation pathways. These need further investigation. Additionally, we present future research directions on roles of metals in PAH.

Accurate Modeling of Ejection Fraction and Stroke Volume With Mobile Phone Auscultation: Prospective Case-Control Study.

BACKGROUND: Heart failure (HF) contributes greatly to morbidity, mortality, and health care costs worldwide. Hospital readmission rates are tracked closely and determine federal reimbursement dollars. No current modality or technology allows for accurate measurement of relevant HF parameters in ambulatory, rural, or underserved settings. This limits the use of telehealth to diagnose or monitor HF in ambulatory patients. OBJECTIVE: This study describes a novel HF diagnostic technology using audio recordings from a standard mobile phone. METHODS: This prospective study of acoustic microphone recordings enrolled convenience samples of patients from 2 different clinical sites in 2 separate areas of the United States. Recordings were obtained at the aortic (second intercostal) site with the patient sitting upright. The team used recordings to create predictive algorithms using physics-based (not neural networks) models. The analysis matched mobile phone acoustic data to ejection fraction (EF) and stroke volume (SV) as evaluated by echocardiograms. Using the physics-based approach to determine features eliminates the need for neural networks and overfitting strategies entirely, potentially offering advantages in data efficiency, model stability, regulatory visibility, and physical insightfulness. RESULTS: Recordings were obtained from 113 participants. No recordings were excluded due to background noise or for any other reason. Participants had diverse racial backgrounds and body surface areas. Reliable echocardiogram data were available for EF from 113 patients and for SV from 65 patients. The mean age of the EF cohort was 66.3 (SD 13.3) years, with female patients comprising 38.3% (43/113) of the group. Using an EF cutoff of ≤40% versus >40%, the model (using 4 features) had an area under the receiver operating curve (AUROC) of 0.955, sensitivity of 0.952, specificity of 0.958, and accuracy of 0.956. The mean age of the SV cohort was 65.5 (SD 12.7) years, with female patients comprising 34% (38/65) of the group. Using a clinically relevant SV cutoff of <50 mL versus >50 mL, the model (using 3 features) had an AUROC of 0.922, sensitivity of 1.000, specificity of 0.844, and accuracy of 0.923. Acoustics frequencies associated with SV were observed to be higher than those associated with EF and, therefore, were less likely to pass through the tissue without distortion. CONCLUSIONS: This work describes the use of mobile phone auscultation recordings obtained with unaltered cellular microphones. The analysis reproduced the estimates of EF and SV with impressive accuracy. This technology will be further developed into a mobile app that could bring screening and monitoring of HF to several clinical settings, such as home or telehealth, rural, remote, and underserved areas across the globe. This would bring high-quality diagnostic methods to patients with HF using equipment they already own and in situations where no other diagnostic and monitoring options exist.

Inhaled treprostinil in patients with pulmonary hypertension associated with interstitial lung disease with less severe haemodynamics: a post hoc analysis of the INCREASE study.

BACKGROUND: Inhaled treprostinil (iTre) is the only treatment approved for pulmonary hypertension due to interstitial lung disease (PH-ILD) to improve exercise capacity. This post hoc analysis evaluated clinical worsening and PH-ILD exacerbations from the 16-week INCREASE study and change in 6-minute walking distance (6MWD) in the INCREASE open-label extension (OLE) in patients with less severe haemodynamics. METHODS: Patients were stratified by baseline pulmonary vascular resistance (PVR) of <4 Wood units (WU) versus ≥4 WU and <5 WU versus ≥5 WU. Exacerbations of underlying lung disease, clinical worsening and change in N-terminal prohormone of brain natriuretic peptide (NT-proBNP) in INCREASE were evaluated. For the OLE, patients previously assigned to placebo were considered to have a 16-week treatment delay. 6MWD and clinical events in the OLE were evaluated by PVR subgroup. RESULTS: Of the 326 patients enrolled in INCREASE, patients with less severe haemodynamics receiving iTre had fewer exacerbations of underlying lung disease and clinical worsening events. This was supported by the Bayesian analysis of the risk of disease progression (HR<1), and significant decreases in NT-proBNP levels. In the OLE, patients without a treatment delay had improved exercise capacity after 1-year compared with those with a 16-week treatment delay (22.1 m vs -10.3 m). Patients with a PVR of ≤5 WU without a treatment delay had a change of 5.5 m compared with -8.2 m for those with a treatment delay. Patients without a treatment delay had a prolonged time to hospitalisation, lung disease exacerbation and death. CONCLUSION: Treatment with iTre led to consistent benefits in clinical outcomes in patients with PH-ILD and less severe haemodynamics. Earlier treatment in less severe PH-ILD may lead to better exercise capacity long-term, however, the subgroup analyses in this post hoc study were underpowered and confirmation of these findings is needed.

Pulmonary hypertension inhaled therapies: An updated review.

Treatments of pulmonary hypertension (PH) continue to evolve with approval of new therapies. The currently FDA approved inhaled PH therapies include inhaled iloprost for group 1 pulmonary arterial hypertension (PAH), inhaled treprostinil solution and treprostinil dry powder inhaler for both group 1 PAH and group 3 PH associated with interstitial lung disease (PH-ILD). Inhaled treprostinil was recently approved for group 3 PH-ILD based on the results of INCREASE trial and the newer formulation of treprostinil dry powder that comes with a new inhaler was recently approved for both group 1 PAH and group 3 PH-ILD based on BREEZE study. The pipeline for inhaled PH therapies includes several promising molecules that can enrich the current PH therapeutic era and mitigate several systemic side effects by directly delivering the drug to the target organ. In this review article we summarize the evidence for the currently approved inhaled PAH/PH therapies, discuss the available inhalation devices, present a roadmap for successful treatment strategy, and present several inhaled PAH/PH therapies in the pipeline.