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Rationale: Oral treprostinil slows disease progression and improves exercise capacity in pulmonary arterial hypertension; however, titration can be prolonged. Published data suggests prostacyclin-naïve patients achieve total daily oral treprostinil doses of about 6 mg by Week 16, while those on prior parenteral treprostinil reach higher doses at the same timepoint., Objectives: EXPEDITE (NCT03497689), a single-arm, multicenter study, assessed the efficacy of rapid parenteral treprostinil induction to quickly reach higher doses of oral treprostinil for the treatment of pulmonary arterial hypertension., Methods: Parenteral treprostinil was titrated for 2-8 weeks, followed by cross-titration of oral treprostinil. The primary endpoint was percentage of patients reaching ≥12 mg daily of oral treprostinil at Week 16. Secondary endpoints included clinical changes from baseline to Week 16., Results: Twenty-nine prostacyclin-naïve patients were included in efficacy analyses. At Week 16, the mean daily oral treprostinil dose was 16.4 mg; 79% of patients met the primary endpoint. From baseline to Week 16, median REVEAL Lite 2 score improved (decreased) from 6 to 3.5 (p = 0.0006). Statistically significant improvements were also seen in World Health Organization Functional Class, N-terminal-pro brain natriuretic peptide levels, 6-minute walk distance, right atrial area, Borg Dyspnea Score, and emPHasis-10 score. Favorable trends were seen in risk stratification, echocardiography parameters, disease symptoms, and treatment satisfaction., Conclusion: Short-course parenteral treprostinil induction resulted in oral treprostinil doses over twice those reported in de novo initiations and may be a useful approach to quickly achieve the therapeutic benefits of oral treprostinil., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CEM – United Therapeutics Corporation (research, consulting, speakers bureau, advisory board), Janssen (research, speakers bureau, advisory board), Insmed (research), Bayer (advisory board, steering committee); VF – United Therapeutics Corporation (research), Merck (research), Acceleron (research), Johnson & Johnson (research), Respira (research), Aerovate (research), Cereno (research), Abbott (research); JSS – United Therapeutics Corporation (research, speakers bureau), Bayer (research, speakers bureau); VB – United Therapeutics Corporation (consulting); JK – United Therapeutics Corporation (research, consulting, speakers bureau, advisory board), Janssen (research, consulting, speakers bureau, advisory board), Acceleron (research), Gossamer (research), Bayer (consulting, speakers bureau, advisory board); RZ – United Therapeutics Corporation (consulting), Bayer (consulting), Janssen (consulting), Johnson & Johnson (consulting); LMG – United Therapeutics Corporation (research, consulting, advisory board), Janssen (research, consulting), Gossamer bio (research, consulting), Merch (research, consulting), Bayer (research, consulting); JH – Acceleron (research), CardiolRx (research), Aaadi Bioscience (research), Astra Zeneca (spouse); JME – United Therapeutics Corporation (research, consulting), Janssen (research), Liquidia (research, consulting), Phase Bio (research), Gossamer Bio (research, consulting), Bayer (research, consulting), Acceleron (research), Altavant (research, consulting), Aerovate (research consulting), Tenax (research), Pharmosa (research), Merck (consulting); AR – United Therapeutics Corporation (consulting), Bayer (consulting), Actelion (consulting); DC, ES, SS, CMT, MB – United Therapeutics Corporation (employee); RJO – United Therapeutics Corporation (research, consulting), Janssen (research, consulting), Merck (research, consulting), Gossamer Bio (research), Insmed (research)., (Copyright © 2023 The Author(s). Published by Elsevier Ltd.. All rights reserved.)

Purpose: Oral treprostinil and selexipag are drugs targeting the prostacyclin pathway and are approved for treatment of pulmonary arterial hypertension (PAH). In the setting of unsatisfactory clinical response or tolerability issues while on selexipag, there is little data on clinical benefit, safety, or strategies on transitioning to oral treprostinil. Using prospective data from the ADAPT registry, we aimed to evaluate clinical outcomes, safety, and transition strategies in ten patients with PAH transitioning from selexipag to oral treprostinil., Methods: ADAPT was a prospective, real-world, multicenter, United States-based registry of patients with PAH newly started on oral treprostinil, with a cohort of patients (n = 10) transitioning from selexipag to oral treprostinil. PAH variables of interest were collected from standard-of-care clinic visits. Clinical improvement was defined by modified REPLACE criterion, and risk was assessed by REVEAL Lite 2 from baseline to last follow-up. Real world transition strategies were recorded. Healthcare utilization or worsening PAH was evaluated within 30 days of transitions., Results: Seven patients transitioned due to worsening PAH or lack of efficacy on selexipag, and three patients transitioned due to tolerability issues. Based on the modified REPLACE criterion, five patients demonstrated clinical improvement after transition from selexipag to oral treprostinil. Using REVEAL Lite 2 to assess risk, three patients improved and five patients maintained risk category from baseline to last follow-up. All transitions occurred in an outpatient setting either as abrupt stop/start or cross-titration, without parenteral treprostinil bridging., Conclusion: Transition from selexipag to oral treprostinil was safe, performed without parenteral prostacyclin bridging, and resulted in clinical and categorical risk improvements in some patients., Competing Interests: Declaration of competing interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: Authors received no specific funding for this work. D. Lachant has received payments for speaking and consulting on behalf of United Therapeutics and has received funds to support research. R. Minkin has no relevant disclosures. J. Swisher has received payments for speaking on behalf of United Therapeutics and Janssen/Johnson and Johnson. M. Mogri has no relevant disclosures. R. Zolty has received payments for consulting on behalf of United Therapeutics, Bayer, and Janssen/Johnson and Johnson. S. Hwang, S. Seaman, and M. Broderick are paid employees of United Therapeutics. S. Sahay has received payments for speaking (promotional/non-promotional), consulting, and research from United Therapeutics, Liquidia Technologies, Gossamer Bio, Bayer, GlaxoSmithKline, and Janssen/Johnson and Johnson., (Copyright © 2023 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Introduction: Distal pulmonary arterial remodeling and elevated pulmonary vascular resistance are characteristic of pulmonary arterial hypertension (PAH). Current approved vasodilator-specific PAH therapy that includes phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators, endothelin receptor antagonists, and prostanoids has demonstrated dramatic enhancement in functional capacity, quality of life, and invasive hemodynamics. However, none of these treatments are curative, underscoring the need to identify new pathophysiologic signaling pathways., Areas Covered: The author provides a comprehensive review on current knowledge and recent development in the understanding of PAH. Furthermore, the author discusses PAH potential genetic causes as well as novel molecular signaling pathways. This article also reviews the currently approved PAH specific therapy based on pivotal clinical trials and ongoing clinical trials using novel compounds that specifically target PAH pathogenesis., Expert Opinion: The discovery of novel signaling pathways - growth factors, tyrosine kinases, BMPs, estrogen, and serotonin - involved in the PAH pathobiology will lead within the next 5 years to the approval of new therapeutic agents targeting these different pathways. If proven beneficial, these new agents may reverse or at least prevent the progression of this devastating and lethal disease.

Introduction : Pulmonary hypertension (PH) secondary to left-sided heart disease (Group 2 PH) is a frequent complication of heart failure (HF) and is a heterogeneous phenotypic disorder that worsens exercise capacity, increases risk for hospitalization and survival independent of left ventricular ejection fraction (LVEF) or stage of HF. Areas covered : In this review, an update of the current knowledge and some potential challenges about the pathophysiology and treatments of group 2 PH in patients with HF of either preserved or reduced ejection fraction are provided. Also, this review discusses the epidemiology and provides hints for the optimal evaluation and diagnosis of these patients to prevent misclassification of their pulmonary hypertension. Expert opinion : There are many of areas lacking knowledge and understanding in the field of pulmonary hypertension associated to left heart disease (PH-LHD) that should be addressed in the future. Further research should be performed, in terms of pathobiology, and understanding the predisposition (genetic susceptibility and contributing factors) of the different phenotypes of this disorder. More clinical trials targeting new therapeutic options and specific PH therapies are warranted to help this increasing important patient group as the current guidelines recommend to only treat the underlying left-sided heart disease.

Background: Pulmonary hypertension secondary to left heart disease (WHO Group 2) is a known risk factor in patients with heart failure. The favourable effect of left ventricular assist devices (LVAD) on pulmonary hypertension has been demonstrated before, although this effect has not been well-studied in advanced pulmonary arterial bed disease with a significant elevation in pulmonary vascular resistance., Methods: We reviewed the records of 258 LVAD patients in our institution. Patients with elevated mean pulmonary artery pressure (mPAP>25mmHg) and elevated pulmonary vascular resistance (PVR ≥3 Wood units) were included in the study. Patients were divided into two groups based on their baseline PVR (PVR=3-5 Wood units (WU) vs. PVR>5WU). The groups were studied for the changes in their pulmonary haemodynamics after the placement of LVAD., Results: Fifty-one (51) patients were included in the study. All patients showed a significant improvement in their pulmonary haemodynamic parameters post LVAD placement. In the group with the higher PVR, mPAP dropped from a baseline of 43±7mmHg to 22±6mmHg post LVAD placement (p<0.001), while PVR dropped from 6.3±1.2 Wood units to 2.2±1.1 Wood units (p<0.001). In a subgroup of patients who underwent cardiac transplantation post LVAD (n=14), all patients maintained a normalised PVR (<3WU) one year post cardiac transplantation., Conclusions: Left ventricular assist devices can reverse pulmonary hypertension WHO Group 2 with significantly elevated PVR; this effect is not dependent on the baseline PVR, and is maintained up to one year post cardiac transplantation., (Copyright © 2018 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Background: Galectin-3, a novel binding-lectin involved in inflammation and fibrosis, is elevated in heart failure and is independently predictive of mortality in this condition. We sought to evaluate galectin-3 levels and its prognostic value in patients with pulmonary hypertension (PH), a known inflammatory state, in the setting of pulmonary arterial hypertension (PAH) and in heart failure with preserved ejection fraction-associated PH (HFpEF-PH)., Methods: We measured galectin-3 levels in 76 patients with PH; 37 patients with PAH and 39 patients with HFpEF-PH. Baseline characteristics, and N-terminal prohormone of brain natriuretic peptide (NT-proBNP) levels were assessed. Univariate and multivariate analyses were used to assess the prognostic value of galectin-3., Results: Median (IQR) galectin-3 (ng/mL) for the entire cohort was 24.65 (IQR=10.39, 32.90); 22.33 (IQR=18.94, 27.30) and 28.94 (IQR=21.67, 39.85) in the PAH and HFpEF-PH, respectively (p=0.07). After evaluation of the galectin-3 levels by tertile, mortality rates were 16% (4/25), 34.6% (9/26), and 48% (12/25) in tertiles 1-3, respectively, and Kaplan-Meier analysis revealed a significant increase in mortality across increasing galectin-3 tertiles (log-rank p=0.014). On Cox regression analysis, galectin-3 was a strong predictor of mortality on both univariate HR=2.09 per tertile (95% CI=1.21, 3.62 per tertile; p-trend=0.008) and multivariate analysis HR=2.19 per tertile (95% CI=1.06, 4.54; p-trend=0.035) after adjusting for age, sex, race, glomerular filtration rate (eGFR), NT-proBNP, medications, and aetiology of PH (PAH vs. HFpEF-PH)., Conclusion: Galectin-3 is a strong, independent prognostic marker in PH, regardless of aetiology. Larger studies should further evaluate the role of galectin-3 as a prognostic biomarker and possible therapeutic target in PH., (Copyright © 2017 Australian and New Zealand Society of Cardiac and Thoracic Surgeons (ANZSCTS) and the Cardiac Society of Australia and New Zealand (CSANZ). Published by Elsevier B.V. All rights reserved.)

Inflammation is an increasingly recognized hallmark of pulmonary hypertension (PH). Statins have been shown to attenuate key pathologic mechanisms via pleiotropic effects in animal models. However, clinical benefit of statins in patients with PH is unknown and their effect on mortality has not been studied. We performed a retrospective analysis of patients between January 2002 to January 2012, with severe PH (pulmonary artery systolic pressure ≥60 mmHg) and preserved left ventricular function (ejection fraction ≥50%), defined by transthoracic echocardiograms. Patients were divided into two groups based on statin therapy for 12 consecutive months after diagnosis of PH. Propensity score matching was performed. Subgroup analysis was done based on COPD status. Study endpoint was 1-year all-cause mortality and hospitalization. 2363 patients (age 71 ± 16; 31% male) were included; 140 (6%) were on statin therapy. Overall 1-year mortality was 34%. Following propensity score matching, 138 patients were included in the statin group and 624 patients in the no-statin group; all-cause mortality was significantly lower in the statin group compared with the no-statin group [15.2 vs. 33.8%, HR 0.42 (95% CI 0.27, 0.66), p < 0.001], but hospitalization was comparable between two groups. After stratifying patients based on COPD status, patients with COPD showed a marginally significant survival benefit from statins [HR 0.53 (95% CI 0.26, 1.10), p = 0.09]; and statins significantly reduced 1-year all-cause mortality in patients without COPD [HR 0.36 (95% CI 0.19, 0.67), p = 0.001]. We found no significant difference in the effect of statins on patients with COPD compared to those without (p = 0.16). Statin therapy is associated with reduced mortality risk in patients with severe PH and preserved left ventricular function. This beneficial effect was not found to be dependent on COPD status. These novel findings should be confirmed in large randomized trials.

Background: Established prognostic factors for pulmonary hypertension (PH) include brain natriuretic peptide, troponins and hemodynamic measures such as central venous pressure and cardiac output. The prognostic role of thrombocytopenia, however, has yet to be determined in patients with PH. The aim of this study was to evaluate effect of thrombocytopenia on mortality in patients with PH., Methods: 521 patients with severe PH, defined by a pulmonary artery systolic pressure >60 mm Hg on transthoracic echocardiography and a platelet count measured within one month after diagnosis were enrolled from three hospitals of Montefiore Medical Center. The cohort was divided into two groups: mild thrombocytopenia to a normal platelet count (platelet count 100,000-450,000 per uL); and moderate to severe thrombocytopenia (platelet count <100,000 per uL). Inpatient and social security death records were used to determine 1-year all-cause mortality., Results: Mean age was 70.3 ± 15.6 with 40% of patients being male. Overall mortality at 1 year was 30.7%, with increased mortality in PH patients with mild thrombocytopenia compared to those with moderate to severe thrombocytopenia (46.5% vs. 27.0%, p < 0.001). In multivariate analysis, moderate to severe thrombocytopenia remained an independent predictor of mortality (HR 1.798, 95% CI 1.240-2.607, p = 0.002)., Conclusions: Moderate to severe thrombocytopenia is an independent predictor of higher mortality in patients with severe PH. These findings may support the use of thrombocytopenia as a useful prognostic indicator in patients with severe PH., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Background: Heart failure with preserved ejection fraction (HFpEF) has been increasingly recognized as a leading cause of pulmonary hypertension (HFpEF-PH). It remains unknown how HFpEF-PH fares in relation to systolic HF (reduced ejection fraction)-induced PH (HFrEF-PH). Therefore, we sought to determine the long-term morbidity and mortality of HFpEF-PH and HFrEF-PH., Methods and Results: We studied all patients over a 6-year period with symptomatic HF and severe PH (PASP ≥65 mm Hg) in The Bronx, New York. We classified patients as having either preserved (≥50%) or reduced (≤35%) left ventricular ejection fraction. Trends in mortality and HF readmission rates were defined in 650 patients (HFrEF-PH: n = 277; HFpEF-PH: n = 373). HFpEF-PH patients were older and more often female and white. HFrEF-PH patients were more often black, had ischemic cardiomyopathy, and were on typical HF drug regimens. Patients with HFpEF-PH had a significantly increased all-cause 5-year mortality (52% vs 42%; P = .024). HFpEF-PH was a significant predictor of mortality (adjusted hazard ratio 1.70; P = .012). Patients with HFrEF-PH had more HF readmissions (≥1) than patients with HFpEF-PH (28.6% vs 15%; P = .003), especially within the 1st year (9.1% vs 1.7%; P = .005)., Conclusions: Patients with HFrEF-PH and HFpEF-PH have a significantly elevated long-term mortality, with HFpEF-PH having a higher 5-year mortality rate. These findings testify to the overall poor prognosis of World Health Organization Group II PH, especially HFpEF-PH., (Copyright © 2014 Elsevier Inc. All rights reserved.)

Adult-onset Still's Disease (AOSD), often though as the adult variant of systemic juvenile idiopathic arthritis (JIA), has an incidence of 1-3 cases per 1 million. Cardinal manifestations include fever, arthritis, skin rash, sore throat, hepatosplenomegaly and lymphadenopathy. Prolongation in diagnosing this disease results from its similarity to infectious, malignant and rheumatic diseases and lack of biomarkers. Pulmonary arterial hypertension (PAH) is a rare pulmonary complication of AOSD, and we are aware of only six cases reported in literature to date. Here we present a patient with AOSD who has developed pulmonary hypertension as a complication. We report a case of AOSD complicated by PAH treated successfully with tocilizumab, a humanized monoclonal antibody to human interleukin (IL)-6 receptor. A Pubmed and Medline search for evidence of pulmonary hypertension in AOSD and use of IL-6 inhibition in management was performed. Data for this study was collected from the patient's chart records. No infectious or neoplastic cause of her disease was identified and after extensive diagnostic workup, the patient was diagnosed with AOSD fulfilling Yamaguchi criteria. After initiation of IL-6 therapy the patient was followed over time to monitor the hemodynamic changes in pulmonary vasculature. Following treatment with Tocilizumab, the patient showed dramatic improvement in her clinical symptoms and remains in remission, through combination of tocilizumab (8 mg/kg), methotrexate and prednisone. Improvement of systemic symptoms, right heart catheterization (RHC) findings and the VECTRA-DA score served as a measure of treatment response. Tocilizumab has been effective in demonstrating marked improvement in both the clinical and laboratory parameters. Tocilizumab is an effective novel treatment for AOSD with PAH. This is the first documented report of successful use of tocilizumab in AOSD patients presenting with PAH. Prospective comparative studies could help validate its efficacy and safety., (© 2014 Asia Pacific League of Associations for Rheumatology and Wiley Publishing Asia Pty Ltd.)

Background: Hyponatremia is known to be an important marker and prognosticator in left-sided heart failure. However, less is known about the significance of hyponatremia in pulmonary hypertension, particularly in the absence of left ventricular dysfunction., Methods and Results: We identified 635 patients with pulmonary hypertension and preserved ejection fraction who were normonatremic (n = 493) or hyponatremic (n = 142). End points were mortality and readmission at 1 year. Overall, 27% of all of the patients died within 1 year. Hyponatremia was significantly associated with an increased rate of 1-year mortality (hazard ratio [HR] 1.82, 95% confidence interval [CI] 1.27-2.61; P = .001) and trended toward an association with the composite of mortality and readmission (HR 1.25, 95% CI 0.97-1.62; P = .08). Additionally, the severity of hyponatremia was directly related to the rate of 1-year mortality (P < .001)., Conclusions: Hyponatremia is an indicator of poor prognosis in patients with echocardiographic evidence of pulmonary hypertension., (Copyright © 2013 Elsevier Inc. All rights reserved.)

Treatment of right ventricular failure (RVF) can be challenging due to the correlation between RVF and worsening renal function with diuretic therapy. Nesiritide has been studied in patients with left ventricular failure but has not been evaluated in isolated RVF. The authors retrospectively analyzed 140 patients admitted with RVF, pulmonary hypertension (PH), and preserved left ventricular systolic function. Seventy patients were treated with nesiritide while the remaining patients received only furosemide (no nesiritide group). Serum creatinine and GFR at baseline, 72 hours, discharge, and 1 month post-treatment, as well as hemodynamic data were compared between the groups. In the nesiritide group, there was a significant decrease in mean GFR (42.77±25.33, P<.001) at day of discharge and 1 month post-nesiritide infusion (41.17±24.94, P<.001) but not in the no nesiritide group. There was a significant difference in >25% decrease in GFR anytime through day 30 (47.14% vs. 25.71%, P=.036) between the two groups. On multivariate analysis, nesiritide remained an important predictor of renal function at discharge and at 1 month (P<.01) as well as a predictor of >25% decrease in GFR anytime through day 30 (P=.007). Thus, nesiritide is associated with worsening kidney function in patients with RVF in the setting of PH., (© 2011 Wiley Periodicals, Inc.)