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Introduction: PAH is characterized by pulmonary vascular remodeling and right ventricular dysfunction. Sotatercept acts as a reverse remodeling agent proposed to rebalance anti- and pro-proliferative signaling based on pre-clinical models of PAH. Clinical efficacy and safety of sotatercept are being studied in the Phase 2 PULSAR and SPECTRA studies. Sotatercept will be further investigated in a Phase 3 clinical program comprised of 4 studies to establish efficacy, safety, and its potential value on top of background therapy across the spectrum of PAH. Methods: Sotatercept will be administered at a starting dose of 0.3 mg/kg, with a target dose of 0.7 mg/kg, subcutaneously every 21 days. All participants will be on background PAH therapy. The efficacy/safety of sotatercept in patients with WHO FC II/III will be assessed in STELLAR (NCT04576988), a double-blind, placebo-controlled, randomized study. The primary endpoint is change in 6MWD from baseline to week 24. A secondary endpoint is multicomponent improvement (MCI), defined as meeting all the following at week 24 vs baseline: ≥30m increase in 6MWD, decrease in NT-proBNP ≥30% or maintenance/achievement of Results: HYPERION, ZENITH and SOTERIA are active, and STELLAR is recruiting, with a target enrollment of 284 participants. Conclusion: The robust Phase 3 clinical program has the potential to further characterize the efficacy and safety of sotatercept across a broad spectrum of patients with PAH and provide a novel treatment option.

Introduction: PAH is characterized by a loss of pulmonary vascular complexity. In this study, total, arterial, and venous vasculatures of patients with PAH and with ePAH were analyzed using fractal analysis and compared against controls Methods: Data from 1514 consecutive right heart catheterizations from 4/27/2011 to 10/2/2018 representing subjects referred to our dyspnea center were searched for availability of imaging. 388 CT angiography (CTA) scans were identified (used given retrospective availability of thin slice reconstructions). Three initial cohorts (no overlap) were identified from individuals in this set. Control patients had normal resting and exercise hemodynamics and no history of cardiopulmonary disease. The second group met the current definition of PAH (resting mean pulmonary arterial pressure >20mmHg, pulmonary vascular resistance >3 Wood Units, pulmonary capillary wedge pressure Results: Venous fractal dimensions of controls (2.10±0.07) were higher than those of PAH (2.03±0.08; p=3e-6) and of ePAH (2.04±0.13; p=0.008). Total fractal dimension also yielded higher values for controls (2.30±0.05) compared against PAH (2.28±0.07; p=0.009) and ePAH (2.26±0.10; p=0.04). No significant differences were found between arterial fractal dimensions of controls (2.17±0.04) against those of PAH (2.16±0.07; p=0.15) and of ePAH (2.15±0.10; p=0.14). Conclusions: Fractal dimension allows for non-invasive characterization of pulmonary vascular complexity. Using this method, patients with PAH or ePAH were found to have lower total and venous vascular complexities than controls without PAH or ePAH.

Introduction: Increased vascular tortuosity has been proposed as a marker of pulmonary arterial hypertension (PAH). In this analysis, we compared arterial and venous vascular tortuosity between controls and subjects with resting PAH. Furthermore, we examined if abnormalities could be detected in exercise PAH (EPAH), thought to be an early form of PAH. Methods: From an institutional registry, 388 patients with both right heart catheterization and computed tomography angiography (CTA) data were selected. Within this cohort, three distinct groups were identified: 1) controls, who had no cardiopulmonary disease and normal resting and exercise hemodynamics; 2) EPAH, with normal resting hemodynamics but age-adjusted pre-capillary pulmonary hypertension on exertion, and 3) PAH, defined as resting mPAP >20mmHg, pulmonary vascular resistance >3 Wood Units, and pulmonary capillary wedge pressure 10% was defined as the number of arterial segments with tortuosity >10% divided by the same venous measure. Analysis was performed with Wilcoxon rank sum tests in R 3.5. Results: There were 99 patients in the final cohort, including 47 (47.4%) with PAH, 12 (12.1%) with EPAH, and 40 (40.4%) without disease. Compared to controls, median arterial tortuosity was increased in PAH (3.3 ± 0.1% vs. 3.4 ± 0.1%, p=0.0009; Figure 1) but not in EPAH (3.3 ± 0.1%, p=0.82). Median venous tortuosity did not differ between groups. AV>10% was increased in EPAH (vs. controls, 1.86 ± 0.38 vs. 1.56 ± 0.44, p=0.03) and resting PAH (2.0 ± 1.2 p=2e-6). Conclusions: Increased arterial tortuosity on CTA is a biomarker of resting PAH. When corrected for venous tortuosity, arterial tortuosity also appears to be abnormal in EPAH. Figure 1 . Arterial vessels in PAH, EPAH, and control subjects. Red segments have tortuosity > 10%.

Healthcare delivery is increasingly divided into subspecialty domains that are often organ specific. This works well for some organ-centric disease states and provides a comfort level for specialists as far as diagnostic approach and therapeutic decision making. However, this may not work well for complaints such as dyspnea. Dyspnea is a common, nonspecific symptom that presents to primary care provider (PCP) and subspecialty offices. Many patients require a thorough diagnostic evaluation to establish the underlying cause, which can remain elusive after a determined evaluation. The patient often falls into the chasm between subspecialists telling the patient it is not their lungs so back to the cardiologist, or it is not their heart and back to the pulmonologist; patients can bounce between specialists for upward of 2 years.1 The time and cost for the evaluation of dyspnea can be significant and frustrating for both clinician and patient.2 It is for these reasons that there is increasing interest in establishing dyspnea clinics (DCs), which are centered on symptoms, rather than on organ systems. When a patient is referred to a DC, he or she often has had an evaluation initiated by a PCP (Figure). Typically, the PCP (or subspecialist) makes the referral, although self-referrals also occur. DC staff develop a …

Background— Pulmonary hypertension (PH) is driven by diverse pathogenic etiologies. Owing to their pleiotropic actions, microRNA molecules are potential candidates for coordinated regulation of these disease stimuli. Methods and Results— Using a network biology approach, we identify microRNA associated with multiple pathogenic pathways central to PH. Specifically, microRNA-21 (miR-21) is predicted as a PH-modifying microRNA, regulating targets integral to bone morphogenetic protein (BMP) and Rho/Rho-kinase signaling as well as functional pathways associated with hypoxia, inflammation, and genetic haploinsufficiency of BMP receptor type 2. To validate these predictions, we have found that hypoxia and BMP receptor type 2 signaling independently upregulate miR-21 in cultured pulmonary arterial endothelial cells. In a reciprocal feedback loop, miR-21 downregulates BMP receptor type 2 expression. Furthermore, miR-21 directly represses RhoB expression and Rho-kinase activity, inducing molecular changes consistent with decreased angiogenesis and vasodilation. In vivo, miR-21 is upregulated in pulmonary tissue from several rodent models of PH and in humans with PH. On induction of disease in miR-21 –null mice, RhoB expression and Rho-kinase activity are increased, accompanied by exaggerated manifestations of PH. Conclusions— A network-based bioinformatic approach coupled with confirmatory in vivo data delineates a central regulatory role for miR-21 in PH. Furthermore, this study highlights the unique utility of network biology for identifying disease-modifying microRNA in PH.

Regardless of the study drug being tested, as part of a clinical trial, the subject population commonly includes a range of patients with the targeted disorder. The overriding purpose of a clinical trial is to estimate the average effect of the intervention on the study population. Registration trials require the development of prospective protocols and analysis plans that describe the inclusion and exclusion criteria for patients, the treatment and its delivery, outcome assessment, and the statistical analyses. A key feature is the prospective identification of both primary and secondary outcome measures. Clinicians want to know the likely benefits and risks for an individual patient. However, applying clinical trial outcomes to study population subgroups or individual patients can be challenging. The treatment of patients with pulmonary arterial hypertension (PAH) has changed considerably since the first PAH-specific agent, epoprostenol, was approved in 1995.1,2 Therapeutic options now target 3 pathways that include the prostacyclin pathway, the endothelin pathway, and the nitric oxide pathway,3,4 either as monotherapy or in combination. The World Health Organization (WHO) functional classification is a measure of disease severity based on a patient’s description of their level of function and symptoms of disease in relation to their everyday activity. WHO functional class (FC) is a strong predictor of survival, both before and during treatment,5–7 but surprisingly has little correlation with degree of hemodynamic abnormality.8 In untreated patients with idiopathic PAH or heritable PAH, historical data showed a median survival of 6 months for WHO FC IV, 2.5 years for WHO FC III, and 6 years for WHO FC I and II.9 However, WHO FC is a subjective measure that is also affected by comorbidities such as connective tissue disease, obesity, and age, to name a few. Although lacking on …

Pulmonary arterial hypertension (PAH) is characterized by vascular remodeling and cellular proliferation that leads to narrowing and obstruction of small pulmonary arteries. The arteriopathy is clinically manifest as increased pulmonary vascular resistance and elevation of pulmonary arterial pressures. PAH is considered a progressive vasculopathy that ultimately leads to right heart failure and death. Although there is no cure for PAH, current pharmacological therapies have improved morbidity, and in some cases, mortality. The current 3-year survival for patients with PAH managed with state-of-the-art multiple drug therapy remains troubling at ≈58%.1 This is slightly better than in the 1980s, when there were no approved treatments. Article see p 624 In PAH endothelial dysfunction and platelet activation causes an imbalance of arachidonic acid metabolites with reduced prostacyclin levels and increased thromboxane A2 production. Prostacyclin has both vasodilatory and antiproliferative affects on vascular smooth muscle and inhibits platelet aggregation. Prostacyclin synthase levels are decreased in pulmonary arteries of patients with PAH.2 An imbalance between these two arachidonic acid metabolites favoring thromboxane A2 plays an important role in the pathogenesis of PAH.3 This imbalance is addressed by the exogenous administration of prostanoids as therapy in advanced PAH. Epoprostenol was the first prostacyclin used in the treatment of PAH. Intravenous epoprostenol improves hemodynamics, functional capacity, and survival.4–7 The second-generation prostanoid, Treprostinil, which has a considerably longer half-life (4.5 hours versus 4–6 minutes for epoprostenol),8 can be administered subcutaneously, intravenously, or by inhalation, and also improves pulmonary hemodynamics, symptoms, exercise capacity, and survival in PAH.9–11 Prostacyclin remains a mainstay of PAH therapy and is the only therapy with a proven survival …

Patients with heart failure with preserved ejection fraction (HFpEF) have an increased mortality and morbidity similar to patients with systolic heart failure and reduced ejection fraction.1 The incidence of HFpEF is increasing,2 and roughly 30% to 50% of all patients with heart failure have a normal ejection fraction.3 The underlying pathophysiology is increased left ventricular diastolic stiffness that leads to high filling pressures.4,5 Additionally, left ventricular hypertrophy,6 accumulation of cardiac collagen,7 endothelial dysfunction,8 a shift in titin isoform, and increased passive stiffness of cardiac myocytes9 all contribute to these changes. For reasons that are yet uncertain, a subset of patients with HFpEF will go on to develop pulmonary hypertension (PH). Patients with HFpEF and PH can be subdivided into those with a normal pulmonary vascular resistance (PVR) and those with an increased PVR and pulmonary arterial remodeling. In fact, patients with HFpEF account for a significant percentage of patients with PH and right-sided heart dysfunction.10 Article see p 164 Importantly, both PH and right ventricular dysfunction are associated with decreased survival compared with HFpEF patients without PH.11 Although the underlying pathophysiology is poor left ventricular diastolic compliance, treatment focused on improving stiffness has been lacking, and management of patients with HFpEF has focused on control of factors known to exert effects on left ventricular end-diastolic pressure. The main emphasis has been on aggressive treatment of systemic blood pressure and heart rate, limiting pressure and volume overload of …

Background: Pulmonary hypertension (PH) is a deadly vascular disease with enigmatic molecular origins. Facets of PH have been characterized in isolation, but many have yet to be unified by a common upstream regulator. Methods & Results: We constructed a network in silico of 247 genes and 2,274 functional interactions involved in PH. Using this model and advanced network analysis, we predicted the miR-130/301 family to have the most diverse pool of PH-relevant target genes among conserved microRNAs (miRNAs). Guided by these predictions, we found that this family was up-regulated by hypoxia, inflammatory cytokines, and factors genetically linked to PH. MiR-130/301 family members were also up-regulated in remodeled pulmonary vessels in 7 animal models and 3 human subtypes of PH. Via gain- and loss-of-function experiments in vitro , we found that miR-130/301 suppressed a cohort of PPARgamma-related targets to regulate two pro-proliferative pathways (the apelin-miR-424/503-FGF2 axis in PAECs and the STAT3-miR-204-SRC axis in PASMCs); vasomotor tone ( e.g. , endothelin-1 and endothelial nitric oxide synthase); and extracellular matrix remodeling ( e.g. , the collagen crosslinking enzyme LOX). In turn, delivery of miR-130a mimic oligonucleotides in pulmonary vessels of mice altered expression of the predicted cohort of PPARgamma-related factors, leading to increased vascular remodeling (19.62±1.36 percent muscularized arterioles for miR-130a vs. 6.98±0.55 percent for scrambled control, p3 *dyn*s*cm -5 ] for miR-130a vs. 462±25.4 for control, pin vivo via antisense oligonucleotides mitigated these effects. Conclusions: We used network modeling to identify miR-130/301 as a master regulator of PH and a novel potential therapeutic target. These findings provide critical support for the evolving application of network modeling to discover the hidden molecular origins of PH and other human diseases.

We thank Drs Naeije and Melot for their careful review of our article.1 As they note, the intent of our article was to demonstrate that exercise-induced pulmonary arterial hypertension (EIPAH) is a clinically relevant syndrome, an inference drawn largely from our demonstration that EIPAH occupies a physiological domain (including Vo2 max and central hemodynamics) intermediate between normal and established resting pulmonary arterial hypertension. We used accepted tools of human incremental exercise testing, relating cardiopulmonary responses to pulmonary …

Background— The clinical relevance of exercise-induced pulmonary arterial hypertension (PAH) is uncertain, and its existence has never been well studied by direct measurements of central hemodynamics. Using invasive cardiopulmonary exercise testing, we hypothesized that exercise-induced PAH represents a symptomatic stage of PAH, physiologically intermediate between resting pulmonary arterial hypertension and normal. Methods and Results— A total of 406 consecutive clinically indicated cardiopulmonary exercise tests with radial and pulmonary arterial catheters and radionuclide ventriculographic scanning were analyzed. The invasive hemodynamic phenotype of exercise-induced PAH (n=78) was compared with resting PAH (n=15) and normals (n=16). Log-log plots of mean pulmonary artery pressure versus oxygen uptake (V̇ o 2 ) were obtained, and a “join-point” for a least residual sum of squares for 2 straight-line segments (slopes m1, m2) was determined; m2m1=“takeoff” pattern. At maximum exercise, V̇ o 2 (55.8±20.3% versus 66.5±16.3% versus 91.7±13.7% predicted) was lowest in resting PAH, intermediate in exercise-induced PAH, and highest in normals, whereas mean pulmonary artery pressure (48.4±11.1 versus 36.6±5.7 versus 27.4+3.7 mm Hg) and pulmonary vascular resistance (294±158 versus 161±60 versus 62±20 dyne · s · cm −5 , respectively; P o 2 max (60.6±15.1% versus 72.0±16.1% predicted) and maximum cardiac output (78.2±17.1% versus 87.8±18.3% predicted) and a higher resting pulmonary vascular resistance (247±101 versus 199±56 dyne · s · cm −5 ; P Conclusions— Exercise-induced PAH is an early, mild, and clinically relevant phase of the PAH spectrum.