Therapeutic Potential of Treprostinil Inhalation Powder for Patients with Pulmonary Arterial Hypertension: Evidence to Date.

Pulmonary arterial hypertension (PAH) is a complex and incurable disease for which pulmonary vasodilators remain the core therapy. Of the three primary pathways that vasodilators target, the prostacyclin pathway was the earliest to be used and currently has the largest number of modalities for drug delivery. Inhaled treprostinil has been introduced as a treatment option in PAH and, more recently, pulmonary hypertension (PH) due to interstitial lung disease (PH-ILD), and the earlier nebulized form has been joined by a dry powder form allowing for more convenient use. In this review, we discuss inhaled treprostinil, focusing on the dry powder inhalation (DPI) formulation, and explore its dosing, applications, and evidence to support patient tolerance and acceptance. Recent trials underpinning the evidence for use of inhaled treprostinil and the most recent developments concerning the drug are discussed. Finally, the review looks briefly into premarket formulations of inhaled treprostinil and relevant early studies suggesting efficacy in PAH treatment.

Diagnosis and management of chronic thromboembolic pulmonary hypertension (CTEPH) in sickle cell disease: A review.

Pulmonary hypertension in sickle cell disease (SCD) is a complex phenomenon resulting from multiple overlapping etiologies, including pulmonary vasoconstriction in the setting of chronic hemolytic anemia, diastolic dysfunction, and chronic thromboembolic disease. The presence of pulmonary hypertension of any cause in SCD confers a significant increase in mortality risk. Evidence to guide the management of patients with sickle cell disease and chronic thromboembolic pulmonary hypertension (CTEPH) is scant and largely the realm of case reports and small case series. Centered on a discussion of a complex young patient with hemoglobin hemoglobin SC who ultimately underwent treatment with pulmonary thromboendarterectomy, we review the available literature to guide management and discuss and overview of treatment of CTEPH in SCD, considering the unique considerations and challenges facing patients suffering from this multisystem disease.

ß-Blocker Use and Clinical Outcomes in Patients With COPD Following Acute Myocardial Infarction.

Importance: While ß-blockers are associated with decreased mortality in cardiovascular disease (CVD), exacerbation-prone patients with chronic obstructive pulmonary disease (COPD) who received metoprolol in the Beta-Blockers for the Prevention of Acute Exacerbations of Chronic Obstructive Pulmonary Disease (BLOCK-COPD) trial experienced increased risk of exacerbations requiring hospitalization. However, the study excluded individuals with established indications for the drug, raising questions about the overall risk and benefit in patients with COPD following acute myocardial infarction (AMI). Objective: To investigate whether ß-blocker prescription at hospital discharge is associated with increased risk of mortality or adverse cardiopulmonary outcomes in patients with COPD and AMI. Design, Setting, and Participants: This prospective, longitudinal cohort study with 6 months of follow-up enrolled patients aged 35 years or older with COPD who underwent cardiac catheterization for AMI at 18 BLOCK-COPD network hospitals in the US from June 2020 through May 2022. Exposure: Prescription for any ß-blocker at hospital discharge. Main Outcomes and Measures: The primary outcome was time to the composite outcome of death or all-cause hospitalization or revascularization. Secondary outcomes included death, hospitalization, or revascularization for CVD events, death or hospitalization for COPD or respiratory events, and treatment for COPD exacerbations. Results: Among 3531 patients who underwent cardiac catheterization for AMI, prevalence of COPD was 17.1% (95% CI, 15.8%-18.4%). Of 579 total patients with COPD and AMI, 502 (86.7%) were prescribed a ß-blocker at discharge. Among the 562 patients with COPD included in the final analysis, median age was 70.0 years (range, 38.0-94.0 years) and 329 (58.5%) were male; 553 of the 579 patients (95.5%) had follow-up information. Among those discharged with ß-blockers, there was no increased risk of the primary end point of all-cause mortality, revascularization, or hospitalization (hazard ratio [HR], 1.01; 95% CI, 0.66-1.54; P = .96) or of cardiovascular events (HR, 1.11; 95% CI, 0.65-1.92; P = .69), COPD-related or respiratory events (HR, 0.75; 95% CI, 0.34-1.66; P = .48), or treatment for COPD exacerbations (rate ratio, 1.01; 95% CI, 0.53-1.91; P = .98). Conclusions and Relevance: In this cohort study, ß-blocker prescription at hospital discharge was not associated with increased risk of adverse outcomes in patients with COPD and AMI. These findings support use of ß-blockers in patients with COPD and recent AMI.

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.

Phenotypes of Bronchopulmonary Dysplasia in Adults.

Bronchopulmonary dysplasia (BPD), first described by Northway in 1967, is a process of neonatal lung injury that is most strongly associated with prematurity. The "old" form of the disease associated with the oxidative damage and volutrauma from perinatal mechanical ventilation has been increasingly supplanted by a "new" form resulting from interrupted growth of the lung at earlier stages of fetal development. Given the significant improvement in the survival of children with BPD since the 1980s, many more of these patients are living into adulthood and are being seen in adult pulmonary practices. In this review, we present three brief vignettes of patients from our practice to introduce three of the major patterns of disease seen in adult survivors of BPD, namely, asthma-like disease, obstructive lung disease, and pulmonary hypertension. Additional factors shown to affect the lives of adult BPD survivors are also discussed. Finally, we discuss insights into the process of transitioning these complex patients from pediatric to adult pulmonary practices. As survivors of BPD enter adulthood and continue to require specialty pulmonary care, awareness of the disease's varied manifestations and responses to treatment will become increasingly important.

Right Heart Failure in Pulmonary Hypertension.

Right heart failure is a major cause of morbidity and mortality in pulmonary hypertension. Its pathophysiology is complex and involves both adaptive and maladaptive patterns of right ventricular change. In addition to the gold standard of right heart catheterization, noninvasive imaging such as echocardiography is useful in diagnosis and risk assessment. Management focuses on optimizing preload, reducing afterload, and supporting the function of the right ventricle with vasopressors and inotropes, if necessary. If required, mechanical support is increasingly used to facilitate recovery or as a bridge to transplant.

Pulmonary Hypertension in COPD: A Case Study and Review of the Literature.

Pulmonary hypertension (PH) is a frequently encountered complication of chronic obstructive pulmonary disease (COPD) and is associated with worsened clinical symptoms and prognosis. The prevalence of PH-COPD is not concretely established as classification criteria vary historically, but the presence of severe disease out of proportion to underlying COPD is relatively rare. Right heart catheterization, the gold standard in diagnosis of PH, is infrequently performed in COPD, and the overlap in the clinical symptoms of PH and COPD presents diagnostic challenges. Proven treatments are limited. Trials exploring the use of vasodilator therapy in this patient group generally demonstrate improvements in hemodynamics accompanied by worsening gas exchange without clearly demonstrated improvements in clinically meaningful outcomes. In-depth workup of underlying pulmonary hypertension and use of pulmonary vasodilator medications may be appropriate on an individual basis. We present a case study and a review and discussion of the pertinent literature on this topic.

Integrating multiple aspects of mitochondrial dynamics in neurons: age-related differences and dynamic changes in a chronic rotenone model.

Changes in dynamic properties of mitochondria are increasingly implicated in neurodegenerative diseases, particularly Parkinson's disease (PD). Static changes in mitochondrial morphology, often under acutely toxic conditions, are commonly utilized as indicators of changes in mitochondrial fission and fusion. However, in neurons, mitochondrial fission and fusion occur in a dynamic system of axonal/dendritic transport, biogenesis and degradation, and thus, likely interact and change over time. We sought to explore this using a chronic neuronal model (nonlethal low-concentration rotenone over several weeks), examining distal neurites, which may give insight into the earliest changes occurring in PD. Using this model, in live primary neurons, we directly quantified mitochondrial fission, fusion, and transport over time and integrated multiple aspects of mitochondrial dynamics, including morphology and growth/mitophagy. We found that rates of mitochondrial fission and fusion change as neurons age. In addition, we found that chronic rotenone exposure initially increased the ratio of fusion to fission, but later, this was reversed. Surprisingly, despite changes in rates of fission and fusion, mitochondrial morphology was minimally affected, demonstrating that morphology can be an inaccurate indicator of fission/fusion changes. In addition, we found evidence of subcellular compartmentalization of compensatory changes, as mitochondrial density increased in distal neurites first, which may be important in PD, where pathology may begin distally. We propose that rotenone-induced early changes such as in mitochondrial fusion are compensatory, accompanied later by detrimental fission. As evidence, in a dopaminergic neuronal model, in which chronic rotenone caused loss of neurites before cell death (like PD pathology), inhibiting fission protected against the neurite loss. This suggests that aberrant mitochondrial dynamics may contribute to the earliest neuropathologic mechanisms in PD. These data also emphasize that mitochondrial fission and fusion do not occur in isolation, and highlight the importance of analysis and integration of multiple mitochondrial dynamic functions in neurons.

Bioenergetics of neurons inhibit the translocation response of Parkin following rapid mitochondrial depolarization.

Recent studies delineate a pathway involving familial Parkinson's disease (PD)-related proteins PINK1 and Parkin, in which PINK1-dependent mitochondrial accumulation of Parkin targets depolarized mitochondria towards degradation through mitophagy. The pathway has been primarily characterized in cells less dependent on mitochondria for energy production than neurons. Here we report that in neurons, unlike other cells, mitochondrial depolarization by carbonyl cyanide m-chlorophenyl hydrazone did not induce Parkin translocation to mitochondria or mitophagy. PINK1 overexpression increased basal Parkin accumulation on neuronal mitochondria, but did not sensitize them to depolarization-induced Parkin translocation. Our data suggest that bioenergetic differences between neurons and cultured cell lines contribute to these different responses. In HeLa cells utilizing usual glycolytic metabolism, mitochondrial depolarization robustly triggered Parkin-mitochondrial translocation, but this did not occur in HeLa cells forced into dependence on mitochondrial respiration. Declining ATP levels after mitochondrial depolarization correlated with the absence of induced Parkin-mitochondrial translocation in both HeLa cells and neurons. However, intervention allowing neurons to maintain ATP levels after mitochondrial depolarization only modestly increased Parkin recruitment to mitochondria, without evidence of increased mitophagy. These data suggest that changes in ATP levels are not the sole determinant of the different responses between neurons and other cell types, and imply that additional mechanisms regulate mitophagy in neurons. Since the Parkin-mitophagy pathway is heavily dependent on bioenergetic status, the unique metabolic properties of neurons likely influence the function of this pathway in the pathogenesis of PD.