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.

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.

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.

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.

Potential Roles of Metals in the Pathogenesis of Pulmonary and Systemic Hypertension.

Pulmonary and systemic hypertension (PH, SH) are characterized by vasoconstriction and vascular remodeling resulting in increased vascular resistance and pulmonary/aortic artery pressures. The chronic stress leads to inflammation, oxidative stress, and infiltration by immune cells. Roles of metals in these diseases, particularly PH are largely unknown. This review first discusses the pathophysiology of PH including vascular oxidative stress, inflammation, and remodeling in PH; mitochondrial dysfunction and metabolic changes in PH; ion channel and its alterations in the pathogenesis of PH as well as PH-associated right ventricular (RV) remodeling and dysfunctions. This review then summarizes metal general features and essentiality for the cardiovascular system and effects of metals on systemic blood pressure. Lastly, this review explores non-essential and essential metals and potential roles of their dyshomeostasis in PH and RV dysfunction. Although it remains early to conclude the role of metals in the pathogenesis of PH, emerging direct and indirect evidence implicates the possible contributions of metal-mediated toxicities in the development of PH. Future research should focus on comprehensive clinical metallomics study in PH patients; mechanistic evaluations to elucidate roles of various metals in PH animal models; and novel therapy clinical trials targeting metals. These important discoveries will significantly advance our understandings of this rare yet fatal disease, PH.

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.

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.

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.

Metallomics in pulmonary arterial hypertension patients.

Pulmonary arterial hypertension (PAH) prevalence is increasing worldwide, and the prognosis is poor with 5-year survival < 50% in high risk patients. The relationship between metal exposure/essential metal dyshomeostasis and PAH/right ventricular dysfunction is less investigated. The aim of this study is to investigate vegetable consumptions and metal levels between PAH patients and controls. This was a prospective, single center pilot study. Questionnaires were completed by all study subjects (20 PAH patients and 10 healthy controls) on smoking, metal exposure risks, metal supplements, and vegetable consumptions. Blood and urine samples were collected to measure 25 metal levels in blood, plasma, and urine using an X Series II quadrupole inductively coupled plasma mass spectrometry. Statistical analysis was conducted using SAS 9.5 and results with p value < 0.05 were considered significant. Vegetables consumptions (broccoli risk ratio [RR] = 0.4, CI = (0.2, 0.9)], cabbage [RR = 0.2, CI = (0.1, 0.8)], and brussel sprouts [RR = 0.2, CI = (0.1, 0.5)]) are associated with less risks of PAH. In the plasma samples, silver (p < 0.001), and copper (p = 0.002) levels were significantly higher in PAH patients. There was significant positive correlation between cardiac output and cardiac index with plasma levels of silver (r = 0.665, p = 0.001 and r = 0.678 p = 0.001), respectively. There was significant correlation between mixed venous saturation, 6-min walk distance, and last BNP with plasma levels of chromium (r = -0.520, p = 0.022; r = -0.55, p = 0.014; r = 0.463, p = 0.039), respectively. In conclusion, there are significant differences between PAH and control groups in terms of vegetable consumptions and metal concentrations. Silver and chromium levels are correlated with clinical indicators of PAH severities.

Role of neck radiography in assessing recurrent/residual adenoid hypertrophy in children with OSA and history of adenotonsillectomy: a sleep physician perspective.

STUDY OBJECTIVES: Recurrent/residual adenoid hypertrophy after adenotonsillectomy in children can result in obstructive sleep apnea (OSA). We aimed to assess the role of soft tissue neck X-ray (STN-XR) in evaluating recurrent/residual adenoid tissue hypertrophy. METHODS: This was a single-center retrospective study that included children with sleep study-confirmed OSA and a known history of adenotonsillectomy who underwent STN-XR to evaluate for recurrent/residual adenoid tissue hypertrophy. STN-XR nasopharyngeal obliteration and baseline polysomnographic data were analyzed. Multiple linear regression was used to assess the independent relationship between the results of STN-XR and the total apnea-hypopnea index, while controlling for relevant characteristics. RESULTS: The study included 160 participants with a median age of 10 years (quartile [Q] 1 = 7, Q3 = 12.25). More than half of the children were male (59.4%) and the median body mass index z-score was 2.11 (Q1 = 1.23, Q3 = 2.54). STN-XR was normal in 39.4%, and it showed mild, moderate, and complete nasopharyngeal obliteration in 20.6%, 32.5%, and 7.5% of the participants, respectively. Multiple regression analysis showed that moderate and complete nasopharyngeal obliteration was associated with an increase in the mean total apnea-hypopnea index by 109% (P = .0002) and 185% (P = .001), respectively, when compared with children without nasopharyngeal obliteration. However, mild nasopharyngeal obliteration, body mass index z-score, age, sex, and race were not significantly associated with an increase in the total apnea-hypopnea index. CONCLUSIONS: STN-XR was useful in assessing recurrent/residual adenoid tissue hypertrophy in children with OSA and a history of adenotonsillectomy. Moderate and complete nasopharyngeal obliteration were associated with significantly increased apnea-hypopnea index. Pediatric sleep physicians may consider STN-XR in the evaluation of children with OSA and previous history of adenotonsillectomy. CITATION: Senthilvel E, Nguyen QL, Gunaratnam B, Feygin YB, Palani R, El-Kersh K. Role of neck radiography in assessing recurrent/residual adenoid hypertrophy in children with OSA and history of adenotonsillectomy: a sleep physician perspective. J Clin Sleep Med. 2023;19(6):1027-1033.

Derivation of a Risk Score (REVEAL-ECHO) Based on Echocardiographic Parameters of Patients With Pulmonary Arterial Hypertension.

BACKGROUND: Multiparametric risk assessment tools determine mortality risk in patients with pulmonary arterial hypertension (PAH) by combining invasive and noninvasive variables so management strategies can be tailored to individuals. RESEARCH QUESTION: Can a risk score based on common echocardiographic parameters risk-stratify patients with PAH? STUDY DESIGN AND METHODS: A Registry to Evaluate Early and Long-Term PAH Disease Management (REVEAL) echocardiographic risk score (REVEAL-ECHO) was derived using retrospective echocardiographic data from 2,400 adult patients with PAH enrolled in the REVEAL registry database. A stepwise Cox regression model identified echocardiographic parameters significantly predictive of survival. Values were assigned to each selected parameter based on survival at 12 months' follow-up (Kaplan-Meier estimates). The REVEAL-ECHO risk score was the sum of individual values. Patients were categorized as having low, intermediate, or high risk based on Kaplan-Meier-predicted 12-month survival. RESULTS: The risk score included four echocardiographic parameters-right ventricular (RV) chamber enlargement, reduced RV systolic function, tricuspid regurgitation severity, and pericardial effusion-and accounted for PAH etiology. Higher REVEAL-ECHO risk scores signaled lower probability of 12-month survival. Statistically significant separation of mortality risk was observed among the risk strata: intermediate vs low (hazard ratio [HR], 1.43; 95% CI, 1.17-1.75; P = .0004) and high vs low (HR, 2.60; 95% CI, 2.19-3.10; P < .0001). Augmentation of the REVEAL Lite 2 risk calculator with REVEAL-ECHO risk scores achieved separation of REVEAL Lite 2 into four risk groups and identified a subgroup of patients with a low REVEAL Lite 2 risk score who were at higher risk (intermediate-low risk) and a subgroup of patients with an intermediate REVEAL Lite 2 risk score who also were at higher risk (intermediate-high risk). INTERPRETATION: A REVEAL-ECHO risk score, derived using four echocardiographic parameters, may discriminate risk further when used as an adjunct to current risk assessment scores. Further validation is required.

Cardiovascular Effects of Environmental Metal Antimony: Redox Dyshomeostasis as the Key Pathogenic Driver.

Significance: Cardiovascular diseases (CVDs) are the leading cause of death worldwide, which may be due to sedentary lifestyles with less physical activity and over nutrition as well as an increase in the aging population; however, the contribution of pollutants, environmental chemicals, and nonessential metals to the increased and persistent CVDs needs more attention and investigation. Among environmental contaminant nonessential metals, antimony has been less addressed. Recent Advances: Among environmental contaminant nonessential metals, several metals such as lead, arsenic, and cadmium have been associated with the increased risk of CVDs. Antimony has been less addressed, but its potential link to CVDs is being gradually recognized. Critical Issues: Several epidemiological studies have revealed the significant deleterious effects of antimony on the cardiovascular system in the absence or presence of other nonessential metals. There has been less focus on whether antimony alone can contribute to the pathogenesis of CVDs and the proposed mechanisms of such possible effects. This review addresses this gap in knowledge by presenting the current available evidence that highlights the potential role of antimony in the pathogenesis of CVDs, most likely via antimony-mediated redox dyshomeostasis. Future Directions: More direct evidence from preclinical and mechanistic studies is urgently needed to evaluate the possible roles of antimony in mitochondrial dysfunction and epigenetic regulation in CVDs. Antioxid. Redox Signal. 38, 803-823.

Upper gastrointestinal blood cast due to massive oropharyngeal bleeding.

We present a case of a patient with recurrent squamous cell cancer of the base of the tongue and right tonsil who developed severe haematemesis. An elongated blood cast of the upper gastrointestinal tract was noted in the emesis. The patient required emergent intubation and blood transfusions. A CT scan with contrast revealed the presence of a pseudoaneurysm of the right lingual artery. Successful control of bleeding was achieved with coil embolisation of the pseudoaneurysm and its feeding artery. This case highlights that oropharyngeal bleeding can mimic gastrointestinal bleeding.

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.

Acute Eosinophilic Pneumonia Associated With COVID-19 Infection.

The knowledge about COVID-19 infection and sequelae is evolving. Acute eosinophilic pneumonia (AEP) is not a well-recognized complication of COVID-19 infection, with few cases reported in the literature. We report a case of a 60-year-old male with a history of an orthotopic heart transplant on chronic immunosuppression who had AEP three weeks after a COVID-19 infection. He presented with diarrhea and acute kidney injury without respiratory symptoms. After discharge, the patient experienced progressive fevers, dyspnea, and cough resulting in a second admission to the hospital with acute hypoxic respiratory failure requiring supplemental oxygen. Imaging demonstrated ground-glass opacities with areas of consolidation and bronchoalveolar lavage fluid demonstrated AEP. The patient was treated with steroids resulting in the resolution of his symptoms and radiographic findings. This case highlights the potential for AEP to complicate COVID-19 infections.

Social determinants of health in pulmonary arterial hypertension patients in the United States: Clinician perspective and health policy implications.

Social determinants of health (SDoH) can impact the vulnerable pulmonary arterial hypertension (PAH) population, especially during the COVID-19 pandemic. Providers' understanding of SDoH at the point of care and their impact is unknown. We conducted semi-structured virtual interviews with US clinicians at 17 pulmonary hypertension (PH) centers and one patient advocate from the Pulmonary Hypertension Association. We sought participants' perspective on SDoH in PAH and their impact. Transcripts were developed and analyzed for key themes to assess potential policy implications. Participants served a large PAH population and demonstrated high awareness of SDoH and its impact on treatment and outcomes. They reported that patients' SDoH, including socioeconomic status, health insurance, access to health care, education levels, health literacy, employment status, and insecurities associated with housing, food, transportation, and family support, impacted health and well-being. COVID-19-related social isolation, mental health, and substance abuse contributed to significant inequities in care provision and outcomes. While telemedicine helped clinicians manage patients remotely during the pandemic, there was a concern for patients with limited access to this medium. Participants reported no formal screening for SDoH at the point of care. With the recognition and the desire to act upon health inequities associated with SDoH, participants felt that it was vital for their centers to have a dedicated PH social worker and support staff to optimize care and outcomes. An approach that integrates SDoH in PAH care management, streamlined through institutional policy, could address health disparities leading to improved healthcare access, outcomes, and quality of care.