Rationale Despite clear guideline recommendations, few patients with pulmonary hypertension (PH) are referred to expert care, including high-risk patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). Characterizing population-level care networks for patients with PH may inform understanding of referral patterns and help improve PH care quality.Objectives We leveraged social network analysis to characterize existing provider networks for patients with PH and to identify provider-level factors associated with connections to PH experts.Methods We linked patient-level data from the Massachusetts All-Payer Claims Database with provider-level data to identify all adults diagnosed with PH in 2014-2018 and all relevant providers who saw those patients for PH. We constructed provider networks among all patients with PH ("All-PH network") and subsets of patients with risk factors for PAH or CTEPH ("PAH network" and "CTEPH network," respectively). Our provider-level outcome was connection to PH experts, defined as sharing at least 1 patient with an expert. Within each network, we conducted multivariable regression models to determine the association between provider-level variables (specialty, practice location, PH panel volume) and our outcome.Results We identified 4766 providers and 8970 patients with PH, of whom 1768 (19.7%) had PAH risk factors and 2164 (24.1%) had CTEPH risk factors. Few providers shared patients with PH experts (31% All-PH network, 35% PAH network, 19% CTEPH network). Within the All-PH network, primary care providers had 59% decreased odds of PH expert connection compared to nonexpert pulmonologists (adjusted odds ratio, 0.41 [95% confidence interval, 0.32-0.51]). Providers practicing outside the greater Boston area and those with smaller PH panel volumes were also less likely to be connected to a PH expert. Findings were similar among the PAH and CTEPH networks.Conclusions We found significant gaps in connections to expert care, even among providers caring for patients at risk for PAH or CTEPH, which may be driven in part by limited provider experience, geographic barriers, and disconnected providers and care networks. Multifaceted strategies may be needed to improve referral rates for patients with PH.

OBJECTIVES:The objective of the study was to explore left atrial (LA) strain, a quantitative index of left ventricular (LV) diastolic function, in risk stratifying patients with SSc-related pulmonary hypertension (SSc-PH). METHODS:This was an exploratory, retrospective single-centre study of 124 patients with SSc-PH confirmed on right heart catheterization. We quantified and clustered the three components of LA global longitudinal strain (GLS): (i) reservoir (systole); (ii) conduit (early diastole); and (iii) contractile (late diastole), using echocardiograms closest to timing of right heart catheterization. We applied both the Kaplan-Meier method and a Cox proportional hazards model to determine associations with our primary outcome of all-cause mortality. RESULTS:Using k-means clustering, we divided our cohort into three clusters: Cluster 1 (N = 40), Cluster 2 (N = 34) and Cluster 3 (N = 50). Compared with Cluster 1, Cluster 2 had the lowest median LA conduit strain, and Cluster 3 exhibited the lowest median LA contractile strain. There was a statistically significant difference in survival between clusters (log-rank P = 0.005). Median survival was 122.4 months, 67.9 months and 48.4 months for Cluster 1, Cluster 2 and Cluster 3, respectively. Compared with those in Cluster 1, patients in Cluster 2 and Cluster 3 had adjusted hazard ratios of 1.46 (95% CI: 0.71, 2.97) and 2.57 (95% CI: 1.32, 5.02) for all-cause mortality, respectively. CONCLUSION:Of the three LA GLS clusters, Cluster 3 had the shortest median survival. LA GLS may provide further risk stratification of patients with SSc-PH.

OBJECTIVE:The study objective was to use multiplex immunoassays to create a cytokine profile specific for systemic sclerosis-related pulmonary hypertension (SSc-PH) by assessing circulating plasma of patients with SSc. METHODS:This was an observational single-center study using plasma samples collected from 106 patients with SSc (24 with SSc-PH by right heart catheterization) in which we measured 48 circulating cytokines using multiplex immunoassays. We applied a random forest approach to create a full 48-cytokine model and a subsequent collapsed model based on variable importance by the mean decrease in the Gini index. The model was internally validated using a train-test split of the data from which we generated receiver operating characteristic curves and calculated sensitivity, specificity, and accuracy. RESULTS:The 48-cytokine model achieved an area under the curve of 0.82 (95% confidence interval [CI] 0.62-1.00). Monokine induced by gamma interferon was the most important cytokine associated with SSc-PH by Gini index. Using the elbow method, a collapsed model was achieved using six cytokines (monokine induced by gamma interferon, interleukin-8, macrophage inflammatory protein-1β, interleukin-15, interleukin-7, and macrophage-derived chemokine) that yielded an area under the curve of 0.83 (95% CI 0.72-1.00) with a sensitivity, specificity, and accuracy of 0.14 (95% CI 0.00-0.58), 0.96 (95% CI 0.80-1.00), and 0.78 (95% CI 0.60-0.91), respectively. CONCLUSION:Using a single-center SSc cohort that reflects real-world heterogeneity, we generated a highly specific cytokine profile for SSc-PH through a random forest approach. Future work will need to externally validate the cytokine profile through prospective cohorts.

ABSTRACT:Sickle cell disease (SCD), caused by a point mutation in the β-globin gene (HBB), results in the production of sickle hemoglobin (HbS). Deoxy-HbS polymerizes, deforming red blood cells (RBCs) and leading to a cascade of clinical complications, including vaso-occlusion, hemolysis, inflammation, and progressive organ damage. An effective strategy to mitigate disease severity is the reactivation of fetal hemoglobin (HbF), which interferes with HbS polymerization. We explored the therapeutic potential of ZLN005, a small-molecule activator of the transcriptional coactivator PGC-1α (peroxisome proliferator-activated receptor gamma coactivator 1-α), by evaluating its impact on HbF induction in CD34+ hematopoietic progenitor cells derived from patients with SCD, in β-YAC transgenic mice carrying a normal human HBB cluster, and in SCD mice. ZLN005 increased γ-globin expression and HbF+ cells without impairing erythroid differentiation of CD34+ cells. Oral administration of ZLN005 to SCD mice increased HbF+ cells, reduced sickled RBCs, increased hemoglobin levels, lowered reticulocyte counts, and decreased spleen and liver pathology related to SCD. ZLN005 or related compounds could represent a promising new class of orally available HbF-inducing therapeutics.

The optimal use of vasoactive medications in patients with pulmonary arterial hypertension with shock remains unknown. Using a national database, we benchmarked initial vasoactive practices. Twenty-five distinct strategies were identified, most commonly norepinephrine, vasopressin, phenylephrine, and milrinone. Marked practice variation underscores clinical equipoise and the need for comparative effectiveness studies.

BACKGROUND:In 2017 Boston Medical Center's (BMC) general pediatric inpatient unit implemented bi-level positive airway pressure (BiPAP) as supportive noninvasive ventilation for acute chest syndrome prevention (SNAP) to prevent adverse respiratory outcomes among medically stable, hospitalized patients with sickle cell disease. Barriers and facilitators to SNAP implementation at BMC differ from those in other settings. OBJECTIVE:To examine contextual determinants of SNAP implementation across different settings. METHODS:We conducted semi-structured interviews with inpatient clinicians at three sites (Site 1: extensive implementation, Site 2: limited implementation, Site 3: not implemented) about factors that would affect SNAP implementation. Interviews and analysis were guided by the Promoting Action on Research Implementation in Health Services (PARiHS) framework. RESULTS:We interviewed 29 healthcare workers (physicians, nurses, physician assistants, child life specialists, respiratory therapists and psychologists). Five major themes emerged: (1) Communication between staff, particularly between the night and day shift, is critical for BiPAP initiation and success. (2) Nurses are key to successful SNAP implementation. (3) SNAP implementation requires multidisciplinary support, including integration of respiratory therapists and child life. (4) Individual unit level size, culture and workflow influence implementation (5) Hospital resources and leadership support are important for SNAP implementation. CONCLUSIONS:Successful SNAP implementation across different contexts will require optimized communication between healthcare team members and the integration of respiratory therapy and child life early in the process of BiPAP initiation. Adapting to the unique features of each institution will be critical.

To study the contribution of QRS prolongation to transplant-free survival, we conducted an observational study of 68 patients with sarcoidosis-related pulmonary hypertension. Every 10-ms increase in QRS interval was associated with an adjusted HR of 1.23 (95% CI: 1.06, 1.44) for the composite outcome of lung transplantation and all-cause mortality.

RATIONALE: Patients admitted to intensive care units (ICU) with pulmonary arterial hypertension (PAH) and acute congestive heart failure (CHF) have complex hemodynamics that may require right heart catheterization (RHC) to guide therapy. However, in the context of unclear effectiveness of RHC among all patients in the ICU, it is unclear if patients with PAH and CHF are also undergoing potentially inappropriately fewer RHC or if RHC use is being replaced by less invasive transthoracic echocardiography (TTE). In this multicenter cohort study, we assessed RHC and TTE practices among patients with PAH and CHF. METHODS: We used the Premier Inc. database, a multicenter enhanced-claims database of ∼25% of United States hospital admissions (2016-2022). We included adults admitted to ICUs with PAH (PAH International Classification of Diseases, Tenth Revision codes and use of ≥1 PAH-specific medication) and CHF. We used charge data to identify the use of RHC and TTE and reported rates of usage overall, by admission year, and by hospital. We used random effect models adjusted for patient- and hospital-level variables to calculate RHC and TTE interclass correlation coefficients (ICC), the percentage of variation in practice attributable to admission hospital. We quantified correlation between adjusted rates of RHC and TTE use at each hospital use using the Spearman coefficient. RESULTS: We identified 2,140 patients (306 hospitals); median age was 61 (IQR 50-69). 706 (33%) patients received a RHC and 1749 (81%) received a TTE. RHC use decreased from 41% in 2016 to 32% in 2022 (relative change -20.3%) whereas TTE use was somewhat stable (82% vs 80%) (relative change -4%). Across hospitals, the overall median use of RHC was 32% (IQR 30%-37%) and TTE was 81% (IQR 80%-83%). The ICCs for RHC and TTE use were 8.8% and 17.0%, respectively. There was no correlation between adjusted hospital rate of RHC use and TTE use (Spearman coefficient -0.024 [95% CI -0.13-0.089]; p=0.68]). DISCUSSION: In a large multicenter study of patients with PAH and acute CHF, use of RHC decreased over time while TTE use stayed constant. Although there was moderate hospital variation in use of RHC and TTE, there was no association between RHC and TTE use. These results suggest that factors other than increased TTE use are driving the reduced RHC use and its unwarranted variation, and this should be the focus of future studies.

Rationale: Guidelines recommend early referral to pulmonary hypertension experts for patients with confirmed or suspected pulmonary arterial hypertension (PAH) or chronic thromboembolic pulmonary hypertension (CTEPH), among others. Yet patients often have advanced disease at the time of referral. The drivers of these referral delays are not well known. Objectives: Building on our prior qualitative findings on barriers to timely pulmonary hypertension care along the care continuum, we sought to identify patient-level factors associated with referral to pulmonary hypertension experts. Methods: We leveraged the Massachusetts All-Payer Claims Database to identify all patients with incident pulmonary hypertension from 2015 to 2017 using a validated algorithm (sensitivity 28%, specificity 100%) and further identified subgroups with risk factors for PAH and CTEPH. Our outcome was the presence or absence of referral to a pulmonary hypertension expert during the study period. On the basis of our prior qualitative work, our three primary exposures were 1) Medicaid enrollment, 2) mental health diagnoses, and 3) distance to the nearest pulmonary hypertension center. We conducted separate multivariable logistic regression models to determine the association between each of our primary exposures and outcome, among our entire cohort and among those with risk factors for PAH and CTEPH. Results: Among our entire cohort (n = 12,505), 704 (5.6%) were seen by pulmonary hypertension experts. Among the subset with risk factors for PAH (n = 2,393) and CTEPH (n = 3,167), 242 (10.1%) and 185 (5.8%) were seen by pulmonary hypertension experts, respectively. Patients less likely to be referred included Medicaid recipients (adjusted odds ratio [aOR], 0.64 [95% confidence interval (CI), 0.53-0.77]), those with mental health diagnoses (aOR, 0.69 [95% CI, 0.58-0.83]), and those living further from a pulmonary hypertension center (aOR, 0.78 [95% CI, 0.74-0.82] for each 10-mile increase in distance to a pulmonary hypertension center). Findings were similar among those with risk factors for PAH and CTEPH. Conclusions: Few patients with pulmonary hypertension are referred to pulmonary hypertension experts, including those with risk factors for PAH and CTEPH. Factors associated with expert referral identified in this study highlight barriers to timely pulmonary hypertension care and offer targeted areas of future study to improve the timeliness of pulmonary hypertension care.

ObjectiveWe sought to investigate the relationship between serum biomarkers of cardiac dysfunction, longitudinal strain on echocardiography, and all-cause mortality in patients with systemic sclerosis.MethodsThis was an observational study using a biorepository of serum samples of patients with systemic sclerosis who underwent echocardiography. We investigated 3 biomarkers: periostin, galectin-3, and N-terminal prohormone brain natriuretic peptide and applied a K-means clustering resulting in 3 patient clusters. We subsequently measured left ventricular and right ventricular free wall longitudinal strain in each cluster. We then determined the association between each cluster and time to all-cause mortality compared to N-terminal prohormone brain natriuretic peptide, alone.ResultsThe 125 patients with systemic sclerosis included in the study were divided into 3 clusters based on biomarker levels (Cluster 1: N = 75; Cluster 2: N = 39; Cluster 3: N = 11). Compared to Cluster 1, Cluster 2 had only elevated periostin levels whereas Cluster 3 had elevated levels of all 3 serum biomarkers and was characterized by reduced left ventricular and right ventricular free wall longitudinal strain, regionally and globally. When adjusted for age, sex, systemic sclerosis disease duration, and forced vital capacity, patients in Cluster 3 had a HR of 14.42 (95% CI: 4.82, 43.18) for all-cause mortality compared to those in Cluster 1.ConclusionIn conclusion, combining N-terminal prohormone brain natriuretic peptide, periostin, and galectin-3 as serum biomarkers enhances risk stratification and sensitivity in detection of cardiac disease in patients with systemic sclerosis. However, before implementation in routine care, further prospective studies must refine biomarker sensitivity, specificity, and accuracy together with optimizing detection strategies and establishing clinical protocols for integration.

BACKGROUND:Without clear guidelines, contemporary use of reperfusion therapy for intermediate-risk and high-risk pulmonary embolism (PE) may vary widely. We assessed variation and trends in use of reperfusion therapies (systemic thrombolysis, catheter-directed thrombolysis, mechanical thrombectomy) and how practices change when hospitals adopt mechanical thrombectomy. METHODS:Using the national Premier Inc. AI Database (2016-2022), we identified adults with intermediate-risk or high-risk PE. For each reperfusion therapy, our primary outcome was intraclass correlation coefficient (ICC, representing between-hospital variation unexplained by patient/hospital characteristics; a priori, ICC > 15 % deemed "high" variation) and proportion trends over time with hierarchical regression models and assessed trends in use. Among hospitals that adopted mechanical thrombectomy, we conducted interrupted time series analysis to assess changes in use of systemic thrombolysis, catheter-directed thrombolysis, and any reperfusion therapy. RESULTS:We assessed 13,777 patients (11,846 intermediate-risk; 1931 high-risk PE) admitted in the US between 2016 and 2022. High variation was observed in catheter-directed thrombolysis (intermediate-risk: ICC 23.1 %; high-risk: ICC 23.8 %) and thrombectomy use (intermediate-risk: ICC 35.4 %; high-risk: ICC 25.1 %). Mechanical thrombectomy use increased from 0.6 % to 14.3 % between 2016 and 2022 (p < 0.001). Hospital adoption of mechanical thrombectomy was associated with a deceleration in growth of catheter-directed thrombolysis rates. CONCLUSIONS:Among patients with intermediate-risk and high-risk PE in the US, reperfusion therapy use varies widely, and the use of mechanical thrombectomy increased between 2016 and 2022. At hospitals adopting mechanical thrombectomy, thrombectomy supplants catheter-directed thrombolysis without increasing total use of reperfusion therapy. These results raise questions about standardization of care, optimal resource allocation, and impact on patient outcomes.

Inhaled epoprostenol has remained an attractive and viable option for the delivery of prostacyclin to offset abnormalities in ventilation and perfusion mismatch while minimizing the typical adverse effects associated with systemic administration. There is a need to better understand pharmacologic properties of inhaled epoprostenol and its application to diseases affecting the cardiopulmonary system. The goal of this review is to provide an overview of inhaled epoprostenol and outline its use specifically in the medical management of acute hypoxemic respiratory failure and pulmonary vascular disease. Among patients with acute respiratory distress syndrome who ultimately required invasive ventilation, inhaled epoprostenol has not improved ventilator-free days, intensive care unit length of stay, or mortality. However, it may be beneficial in certain select patient populations. In the management of pulmonary hypertension, inhaled epoprostenol has allowed for continued maintenance of chronic pulmonary arterial hypertension-specific therapy and for possibly improving right ventricular function as an attractive option in the critical care management of pulmonary hypertension.

RATIONALE: Treatment for hospitalized patients with pulmonary embolism has evolved rapidly over the past decade, particularly with the introduction of new devices and therapeutic strategies. We assessed changes in trends in utilization of advanced treatments (systemic thrombolysis, catheter-directed thrombolysis, and large-bore embolectomy) and hospital practices following the adoption of large-bore embolectomy for patients with intermediate- and high-risk pulmonary embolism. METHODS: Using the PINC AI Healthcare Database (approximately 25% of U.S. hospitalizations) we identified adult patients (age ≥ 18 years) admitted to an intensive care (ICU) or intermediate care unit between January 2016 and September 2022. We included patients with intermediate-risk (International Classification of Diseases [ICD-10] diagnosis code I26.x and an elevated troponin level) and high-risk pulmonary embolism (met definition for intermediate-risk and required vasopressors on day one). Patients with diagnoses of ST-elevation myocardial infarction, peripheral arterial disease, or acute ischemic stroke were excluded due to possibility of receiving catheter-directed thrombolysis or embolectomy for these indications. We assessed annual proportions of patients receiving advanced treatments. Cochran-Armitage tests were performed to evaluate significant trends. To quantify hospital-level adoption of large-bore embolectomy and its association with changes in treatment rates, we conducted interrupted time series analysis with segmented regression for both intermediate-risk and high-risk cohorts. We defined “hospital adopters” of large-bore embolectomy as those with at least one large-bore embolectomy following at least four consecutive quarters without any large-bore embolectomies performed. RESULTS: Among patients with intermediate-risk pulmonary embolism, systemic thrombolysis use decreased from 3.9% in 2016 to 3.2% by 2022 (p < 0.001). Large-bore embolectomy increased significantly from 0.8% to 13.8% (p < 0.001) while catheter-directed thrombolysis decreased from 9.4% to 4.6% (p < 0.001). For patients with high-risk pulmonary embolism, large-bore embolectomy usage increased from 0% to 12.7% (p < 0.001). After hospitals adopted large-bore embolectomy, there was no significant change in systemic thrombolysis rates for either cohort. However, there were statistically significant decreases in catheter-directed thrombolysis use following adoption for both intermediate-risk and high-risk cohorts (p=0.045 and p=0.004 respectively) (Figure 1). CONCLUSIONS: Between 2016 and 2022, treatment strategies for pulmonary embolism shifted toward large-bore embolectomy. The adoption of this technique was associated with decreased catheter-directed thrombolysis rates, suggesting a shift in treatment preference rather than an overall increase in advanced interventions. This shift in practice has been in the absence of specific evidence-based guidelines and further research is needed to determine patient-centered outcome differences from this change.

Ralinepag is a potent, titratable, orally administered prostacyclin (IP) receptor agonist to treat pulmonary arterial hypertension. A phase II randomized, double-blind, parallel-group, placebo-controlled, 22-week study of immediate-release (IR) ralinepag safety and efficacy met its primary endpoint, significantly reducing pulmonary vascular resistance (PVR) compared with placebo. This phase II open-label extension (OLE) study assessed long-term safety and tolerability of ralinepag. Participants were eligible for the OLE if they completed the parent study or experienced a clinical worsening event while receiving placebo. Those previously receiving IR ralinepag remained on their current dose, and participants formerly administered placebo were titrated to the highest tolerated dose. Participants were transitioned to an extended-release ralinepag formulation toward the end of the OLE. The primary objective evaluated long-term safety and tolerability; secondary endpoints included changes in 6-min walk distance (6MWD), World Health Organization/New York Heart Association functional class, clinical worsening, and hemodynamic measures. In total, 45/61 participants enrolled in the OLE study, 30 from the IR ralinepag group and 15 from the placebo group. The most common adverse events (AEs) were known prostacyclin-related effects (e.g., headache, 64.4

The right heart catheterization (RHC) remains an important diagnostic tool for a spectrum of cardiovascular disease processes including pulmonary hypertension (PH), shock, valvular heart disease, and unexplained dyspnea. While it gained widespread utilization after its introduction, the role of the RHC has evolved to provide valuable information for the management of advanced therapies in heart failure (HF) and cardiogenic shock (CS) to name a few. In this review, we provide a comprehensive overview on the indications, utilization, complications, interpretation, and calculations associated with RHC.