Advanced Pulmonary Arterial Hypertension Research Articles

BMPR2 Loss Activates AKT by Disrupting DLL4/NOTCH1 and PPARγ Signaling in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disease characterized by pathologic vascular remodeling of small pulmonary arteries. Endothelial dysfunction in advanced PAH is associated with proliferation, apoptosis resistance, and endothelial to mesenchymal transition (EndoMT) due to aberrant signaling. DLL4, a cell membrane associated NOTCH ligand, plays a pivotal role maintaining vascular integrity. Inhibition of DLL4 has been associated with the development of pulmonary hypertension, but the mechanism is incompletely understood. Here we report that BMPR2 silencing in pulmonary artery endothelial cells (PAECs) activated AKT and suppressed the expression of DLL4. Consistent with these in vitro findings, increased AKT activation and reduced DLL4 expression was found in the small pulmonary arteries of patients with PAH. Increased NOTCH1 activation through exogenous DLL4 blocked AKT activation, decreased proliferation and reversed EndoMT. Exogenous and overexpression of DLL4 induced BMPR2 and PPRE promoter activity, and BMPR2 and PPARG mRNA in idiopathic PAH (IPAH) ECs. PPARγ, a nuclear receptor associated with EC homeostasis, suppressed by BMPR2 loss was induced and activated by DLL4/NOTCH1 signaling in both BMPR2-silenced and IPAH ECs, reversing aberrant phenotypic changes, in part through AKT inhibition. Directly blocking AKT or restoring DLL4/NOTCH1/PPARγ signaling may be beneficial in preventing or reversing the pathologic vascular remodeling of PAH.

Disruption of DLL4/NOTCH1 Causes Dysregulated PPARγ/AKT Signaling in Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a progressive cardiopulmonary disease characterized by vascular remodeling of small pulmonary arteries. Endothelial dysfunction in advanced PAH is associated with proliferation, apoptosis resistance, and endothelial to mesenchymal transition (EndoMT) due to aberrant signaling. DLL4, a cell membrane associated NOTCH ligand, activates NOTCH1 signaling and plays a pivotal role maintaining vascular integrity. Inhibition of DLL4 has been associated with the development of pulmonary hypertension, but the mechanism is incompletely understood. Here we report that BMPR2 silencing in PAECs activated AKT and decreased DLL4 expression. DLL4 loss was also seen in lungs of patients with IPAH and HPAH. Over-expression of DLL4 in PAECs induced BMPR2 promoter activity and exogenous DLL4 increased BMPR2 mRNA through NOTCH1 activation. Furthermore, DLL4/NOTCH1 signaling blocked AKT activation, decreased proliferation and reversed EndoMT in BMPR2-silenced PAECs and ECs from IPAH patients. PPARγ, suppressed by BMPR2 loss, was induced and activated by DLL4/NOTCH1 signaling in both BMPR2-silenced and IPAH PAECs, reversing aberrant phenotypic changes, in part through AKT inhibition. Finally, leniolisib, a well-tolerated oral PI3Kδ/AKT inhibitor, decreased cell proliferation, induced apoptosis and reversed markers of EndoMT in BMPR2-silenced PAECs. Restoring DLL4/NOTCH1/PPARγ signaling and/or suppressing AKT activation may be beneficial in preventing or reversing the pathologic vascular remodeling of PAH.

Transseptal Balloon Atrial Septostomy in Patients with Advanced Pulmonary Arterial Hypertension and Systemic Lupus Erythematosus

Transseptal Balloon Atrial Septostomy in Patients with Advanced Pulmonary Arterial Hypertension and Systemic Lupus Erythematosus

AV-101, a novel inhaled dry-powder formulation of imatinib, in healthy adult participants: a phase 1 single and multiple ascending dose study.

Oral imatinib has been shown to be effective, but poorly tolerated, in patients with advanced pulmonary arterial hypertension (PAH). To maintain efficacy while improving tolerability, AV-101, a dry powder inhaled formulation of imatinib, was developed to deliver imatinib directly to the lungs. This phase 1, placebo-controlled, randomised single ascending dose (SAD) and multiple ascending dose (MAD) study evaluated the safety/tolerability and pharmacokinetics of AV-101 in healthy adults. The SAD study included five AV-101 cohorts (1 mg, 3 mg, 10 mg, 30 mg, 90 mg) and placebo, and a single-dose oral imatinib 400-mg cohort. The MAD study included three AV-101 cohorts (10 mg, 30 mg, 90 mg) and placebo; dosing occurred twice daily for 7 days. 82 participants (SAD n=48, MAD n=34) were enrolled. For the SAD study, peak plasma concentrations of imatinib occurred within 3 h of dosing with lower systemic exposure compared to oral imatinib (p<0.001). For the MAD study, systemic exposure of imatinib was higher after multiple doses of AV-101 compared to a single dose, but steady-state plasma concentrations were lower for the highest AV-101 cohort (90 mg) compared to simulated steady-state oral imatinib at day 7 (p=0.0002). Across AV-101 MAD dose cohorts, the most common treatment-emergent adverse events were cough (n=7, 27%) and headache (n=4, 15%). AV-101 was well tolerated in healthy adults, and targeted doses of AV-101 significantly reduced the systemic exposure of imatinib compared with oral imatinib. An ongoing phase 2b/phase 3 study (IMPAHCT; clinicaltrials.gov identifier NCT05036135) will evaluate the safety/tolerability and clinical benefit of AV-101 for PAH.

Behavior of right atrial strain in patients with advanced idiopathic pulmonary arterial hypertension after initiation of specific combined therapy

Abstract Background Right atrial (RA) function has emerged as an important determinant of outcome in pulmonary arterial hypertension (PAH). However, studies exploring RA function and assessing its behavior in response to specific PAH combination therapy, independent of RA size in patients with PAH is not adequately investigated. Purpose Assess the behavior of strain based measures of RA in response to combined PAH therapy, independent of RA size in patients with PAH. Methods RA peak longitudinal strain (PLS) and peak active contraction strain (PACS) were retrospectively assessed in 38 patients with advanced idiopathic pulmonary arterial hypertension (IPAH) who were referred to Aswan heart Centre and not receiving proper GDMT; at baseline and during follow-up after initiation of specific PAH combination therapy in the form of either Sildenafil/Bosentan or Sildenafil/Macitentan. Results Most of the patients were females with median (IR) age 34 (27–39) years. All patients presented with dyspnea WHO-FC III. At baseline, all patients were receiving only monotherapy in the form of sildenafil. Median (IR) time to echocardiographic follow-up was 11 (8–18) months. Patients presented with markedly right ventricle (RV) and RA enlargement, depressed RV systolic function, and reduced RA strain parameters compared with values previously reported in healthy controls. Among various baseline associations of the RA PLS, the strongest were with baseline RA area (rho: −0.659; p&amp;lt;0.001) and RVEF by CMR (rho: 0.570; p&amp;lt;0.001). At follow up; RA PLS and PACS significantly increased (16.6 vs 24 and 7.06 vs 11.42, respectively: p&amp;lt;0.001); however, RA area did not show significant decrease. Only RV TDI &amp; FAC showed significant improvement among different RV function parameters measured by echocardiography. During the follow up period, 11 out of 38 patients (28.9%) were hospitalized. RA PLS change was significantly lower in the hospitalized group than the non-hospitalized group (4.40 vs 10.2; p=0.014). RA PLS change was independently associated with hospitalization in the multivariate regression analysis (95% CI: −0.061 to −0.010; p=0.008). Conclusion Initiation of specific PAH combination therapy in undertreated patients with IPAH showed improvement in RA strain parameters despite no change in RA area during follow up. Funding Acknowledgement Type of funding sources: None.

Evolving Concepts in Endothelial Pathobiology of Pulmonary Arterial Hypertension.

Pulmonary arterial hypertension (PAH) is a deadly disease, characterized by increased vascular resistance, pulmonary arteriolar loss, and occlusive arterial remodeling, leading to eventual right heart failure. Evidence increasingly points to the pulmonary endothelium as a central actor in PAH. Endothelial cell apoptosis can result directly in distal lung arteriolar pruning and indirectly in the formation of complex and occlusive arterial lesions, reflecting an imbalance between endothelial injury and repair in the development and progression of PAH. Many of the mutations implicated in PAH are in genes, which are predominantly, or solely, expressed in endothelial cells, and the endothelium is a major target for therapeutic interventions to restore BMP signaling. We explore how arterial pruning can promote the emergence of occlusive arterial remodeling mediated by ongoing endothelial injury secondary to hemodynamic perturbation and pathological increases in luminal shear stress. The emerging role of endothelial cell senescence is discussed in the transition from reversible to irreversible arterial remodeling in advanced PAH, and we review the sometimes conflicting evidence that female sex hormones can both protect or promote vascular changes in disease. Finally, we explore the contribution of the endothelium to metabolic changes and the altered inflammatory and immune state in the PAH lung, focusing on the role of excessive TGFβ signaling. Given the complexity of the endothelial pathobiology of PAH, we anticipate that emerging technologies that allow the study of molecular events at a single cell level will provide answers to many of the questions raised in this review.

Prevalence of aortic stenosis and TAVR outcomes in patients with systemic sclerosis-associated pulmonary hypertension.

There is little known about performing transcatheter aortic valve replacement (TAVR) in patients with group 1 pulmonary arterial hypertension (PAH) on advanced pulmonary vasodilator therapy. Retrospective cohort study among 90 patients with systemic sclerosis‐associated pulmonary arterial hypertension and systemic sclerosis‐associated pulmonary hypertension (SSc‐PAH/PH) evaluated at a tertiary PH center. The SSc‐PAH/PH cohort was stratified by the presence or absence of aortic stenosis (AS) to identify differences in baseline characteristics, hemodynamics, and long‐term outcomes. Of the 90 SSc‐PAH/PH patients, 13 patients were diagnosed with AS at PH diagnosis and another 6 patients developed AS during the study period. The period prevalence of AS was 21.1% (19/90, 95% confidence interval: 13.2%–30.1%) of which 94.7% was mild (18/19) at diagnosis with mean age at AS diagnosis of 66.3 + 2.2 years. Among AS patients, 31.6% (6/19) progressed to severe AS, five of which underwent TAVR (median age: 70 years) while on advanced PAH therapy. One of the five TAVR patients developed worsening pulmonary hypertension post‐TAVR. The 5‐year survival rate for all AS patients from diagnosis date was 37.2%. There was a high prevalence of AS in this cohort of SSc‐PAH/PH patients, with mean age of onset younger than patients with nonbicuspid aortic valve stenosis. This is the largest series of SSc‐PAH/PH patients on advanced pulmonary vasodilator therapy who underwent TAVR with acceptable early outcomes.

Contribution of fatty acid oxidation to the pathogenesis of pulmonary hypertension.

Dysregulated metabolism characterizes both animal and human forms of pulmonary hypertension (PH). Enzymes involved in fatty acid metabolism have previously not been assessed in human pulmonary arteries affected by pulmonary arterial hypertension (PAH), and how inhibition of fatty acid oxidation (FAO) may attenuate PH remains unclear. Fatty acid metabolism gene transcription was quantified in laser-dissected pulmonary arteries from 10 explanted lungs with advanced PAH (5 idiopathic, 5 associated with systemic sclerosis), and 5 donors without lung diseases. Effects of oxfenicine, a FAO inhibitor, on female Sugen 5416-chronic hypoxia (SuHx) rats were studied in vivo using right heart catheterization, and ex vivo using perfused lungs and pulmonary artery ring segments. The impact of pharmacologic (oxfenicine) and genetic (carnitine palmitoyltransferase 1a heterozygosity) FAO suppression was additionally probed in mouse models of Schistosoma and hypoxia-induced PH. Potential mechanisms underlying FAO-induced PH pathogenesis were examined by quantifying ATP and mitochondrial mass in oxfenicine-treated SuHx pulmonary arterial cells, and by assessing pulmonary arterial macrophage infiltration with immunohistochemistry. We found upregulated pulmonary arterial transcription of 26 and 13 FAO genes in idiopathic and systemic sclerosis-associated PAH, respectively. In addition to promoting de-remodeling of pulmonary arteries in SuHx rats, oxfenicine attenuated endothelin-1-induced vasoconstriction. FAO inhibition also conferred modest benefit in the two mouse models of PH. Oxfenicine increased mitochondrial mass in cultured rat pulmonary arterial cells, and decreased the density of perivascular macrophage infiltration in pulmonary arteries of treated SuHx rats. In summary, FAO inhibition attenuated experimental PH, and may be beneficial in human PAH.

Managing pulmonary arterial hypertension: how to select and facilitate successful transplantation.

Despite improvements in available medical therapies, pulmonary arterial hypertension (PAH) remains a progressive, ultimately fatal disorder. Lung transplantation is a viable treatment option for PAH patients with advanced disease. Recent guidelines from the International Society of Heart and Lung Transplantation (ISHLT) have updated recommendations regarding time of referral and listing for lung transplantation in PAH. The new guidelines emphasize earlier referral for transplant evaluation to ensure adequate time for proper evaluation and listing. They also incorporate objective risk stratification criteria to assist in decision-making regarding timing of referral and listing. With regards to the transplant procedure, bilateral lung transplantation has largely supplanted heart-lung transplantation as the procedure of choice for transplantation for advanced PAH. Exceptions to this include patients with PAH because of congenital heart disease and those with concurrent LV dysfunction. Use of mechanical support via venoarterial ECMO initiated before transplantation and continued into the early postoperative period is emerging as a standard of care and may help to reduce early posttransplant mortality in this population. There has been increased recognition of the importance of WHO Group 3 pulmonary hypertension. Many of the lessons learned from PAH may be applied when transplanting patients with severe WHO Group 3 pulmonary hypertension. Patients with PAH present unique challenges with regards to transplantation that require a therapeutic approach distinct from other lung disorders. Lung transplantations for PAH are high-risk endeavors best performed at centers with expertise in management of both PAH and extracorporeal support.

Prognostication Of Pulmonary Artery Pulsatility Index And Pulmonary Capillary Wedge Pressure In Patients Requiring Impella Support

<h3>Introduction</h3> Pulmonary Artery Pulsatility Index (PaPi) was initially described to identify patients at risk for right ventricular dysfunction after inferior wall myocardial infarctions. The formula has since been applied to patients with advanced heart failure and pulmonary arterial hypertension to predict adverse outcomes. However, there is a lack of data regarding the utility of PaPi in assessing outcomes in patients requiring Impella 2.5 and CP - temporary left ventricular support devices. <h3>Hypothesis</h3> Lower PaPi and higher PCWP will be associated with increased mortality after Impella placement. <h3>Methods</h3> All patients admitted to York Hospital requiring Impella support due to cardiogenic shock between January 1, 2018 and May 1, 2020 were included in this retrospective study. Baseline characteristics and in-hospital mortality months were compared for hemodynamic variables including pulmonary capillary wedge pressure (PCWP) and PaPi. These numbers were collected and analyzed after Impella placement, 24 hours later, and the day of removal using ANOVA, logistic regression, and Fisher's exact test. <h3>Results</h3> There were 32 patients who met inclusion criteria. At time of Impella implantation, the cohort had an average age of 67.6 + 9.9, ejection fraction of 24.62 + 13.09%, brain natriuretic peptide of 772.03 + 1103.8 pg/dL, and lactate of 4.634 + 4.194 mmol/L. The average duration of Impella support was 2.6875 + 1.89 days. Pulmonary artery pulsatility index was strongly associated with in-hospital mortality at values less than 1.2 after Impella placement (p = 0.0325) and on the day of removal (p = 0.0003). Increasing PCWP strongly correlated with in-hospital mortality after Impella placement (p = 0.0179) and on the day of removal (p = 0.0032). Neither PCWP nor PaPi correlated with mortality at 24 hours. <h3>Conclusions</h3> In patients requiring Impella support for cardiogenic shock, PaPi and PCWP are significant predictors of in-hospital mortality. These variables are strongly associated with mortality after Impella placement and on the day of removal. PaPi is a better predictor of poor outcomes at lower values, as values less than 1.2 strongly correlated with mortality. Increasing PCWP will invariably increase the value of PaPi due to the effects of PCWP on pulmonary artery capacitance. Patients with worsening left ventricular dysfunction will thus have higher values of PaPi. A lower PaPi may be an ominous sign in patients requiring mechanical support, but further studies should be done to further assess its prognostic role.

Transition from Parenteral to Oral Prostacyclin Agents in Pulmonary Arterial Hypertension in Ambulatory Care Setting: A Tertiary Care Institutional Experience

<h3>Purpose</h3> Prostacyclins are used to treat advanced pulmonary arterial hypertension as continuous intravenous or subcutaneous infusions. In the right clinical setting, parenteral Prostacyclins can be transitioned to newer oral Prostacyclins. There is a dearth of published guidance for this transition and is limited to inpatient setting. We present our experience with transitioning patients with WHO group 1 pulmonary arterial hypertension from parenteral Treprostinil to oral Treprostinil in the outpatient setting. <h3>Methods</h3> 6 patients with WHO group 1 pulmonary arterial hypertension on stable doses of intravenous or subcutaneous Treprostinil for at least 6 months were transitioned to oral Treprostinil as per published protocol albeit at a slower rate of transition at 6 ng/kg/min per day <h3>Results</h3> All the 6 patients were successfully transitioned from Parenteral Treprostinil to oral Treprostinil and 4 remain on oral therapy for 1- 4 years. The reasons for transition include complications of central line, side effects related to parenteral Prostacyclins and personal preference. Two patients deteriorated over 6-12 months after the transition requiring transition back to parenteral Treprostinil. No deterioration in PAH was noted during the transition. High 6 MWD, High WHO FC (1/2) and normal RV function on parenteral Prostacyclins are associated with successful results. <h3>Conclusion</h3> In the right clinical setting, patients can be successfully transitioned from parenteral Treprostinil to oral Treprostinil and this can be accomplished safely in the outpatient setting.

PH Roundtable: Genetics and Pulmonary Hypertension

PH Roundtable: Genetics and Pulmonary Hypertension

The Right Ventricular-Pulmonary Arterial Coupling and Diastolic Function Response to Therapy in Pulmonary Arterial Hypertension

Multiparametric risk assessment is used in pulmonary arterial hypertension (PAH) to target therapy. However, this strategy is imperfect because most patients remain at intermediate or high risk after initial treatment, with low risk being the goal. Metrics of right ventricular (RV) adaptation are promising tools that may help refine our therapeutic strategy. Does RV adaptation predict therapeutic response over time? We evaluated 52 incident treatment-naive patients with advanced PAH by catheterization and cardiac imaging longitudinally at baseline, follow-up 1 (∼3months), and follow-up 2 (∼18months). All patients received goal-directed therapy with parenteral treprostinil and/or combination therapy with treatment escalation if functional class I or II was not achieved. On the basis of their therapeutic response, patients were evaluated at follow-up 1 as nonresponders (died) or as responders, and again at follow-up 2 as super-responders (low risk) or partial responders (high/intermediate risk). Multiparametric risk was based on a simplified European Respiratory Society/European Society of Cardiology guideline score. RV adaptation was evaluated with the single-beat coupling ratio (Ees/Ea) and diastolic function with diastolic elastance (Eed). Data are expressed as mean ± SD or as OR (95%CI). Nine patients (17%) were nonresponders. PAH-directed therapy improved the European Respiratory Society low-risk score from 1 (2%) at baseline to 23 (55%) at follow-up 2. Ees/Ea at presentation was nonsignificantly higher in responders (0.9 ± 0.4) vsnonresponders (0.6 ± 0.4; P= .09) but could not be used to predict super-responder status at follow-up 2 (OR, 1.40 [95%CI, 0.28-7.0]; P= .84). Baseline RV ejection fraction and change in Eed were successfully used to predict super-responder status at follow-up 2 (OR, 1.15 [95%CI, 1.0-1.27]; P= .009 and OR, 0.29 [95%CI, 0.86-0.96]; P= .04, respectively). In patients with advanced PAH, RV-pulmonary arterial coupling could not discriminate irreversible RV failure (nonresponders) at presentation but showed a late trend to improvement by follow-up 2. Early change in Eed and baseline RV ejection fraction were the best predictors of therapeutic response.

Avalanches in cardiology.

Sudden cardiac death (SCD) accounts for 15%–60% of mortality in patients with heart disease. Generally, this has been attributed to ventricular tachyarrhythmia. However, ventricular tachyarrhythmia has been documented or strongly suspected on clinical grounds in a relatively small proportion of SCD patients (8%–50%). Attempted prophylaxis of SCD by implantation of cardioverter-defibrillator is associated with variable success in different subsets of high-risk cardiac patients (30%–70%). A significant number of SCD, therefore, appear to be due to catastrophic circulatory failure. Multiple interdependent compensatory mechanisms help to maintain circulation in advanced cardiac disease. Rapid, unexpected, and massive breakdown of the compensated state can be precipitated by small and often imperceptible triggers. The initial critical but stable state followed by rapid circulatory failure and death has been considered to be analogous to snow avalanches. It is typically described in patients with left ventricular (LV) dysfunction (ischemic or nonischemic). It is now recognized that SCD can also happen in conditions where the right ventricle (RV) takes the brunt of the hemodynamic load. Advanced pulmonary arterial hypertension and operated patients of tetralogy of Fallot with pulmonary regurgitation are of particular interest to pediatric cardiologists. A large amount of data is available on LV changes and mechanics, while relatively little information is available on the mechanisms of RV adaptation to increased load and RV failure. Whether the triggers and the decompensatory processes are similar for the two ventricles is a moot point. This article highlights the currently available knowledge on the pathophysiology of SCD in RV overload states, with special reference to RV adaptive and decompensatory mechanisms, and therapeutic measures that can potentially interrupt the vicious downward course (cardiac avalanches).

Periprocedural safety and outcome after pump implantation for intravenous treprostinil administration in patients with pulmonary arterial hypertension

MethodsIn this retrospective observational study, we analyzed all patients with pulmonary arterial hypertension undergoing LenusPro® pump implantation between November 2013 and October 2019 at our center. Periprocedural safety was assessed by describing all complications that occurred within 28 days after surgery; complications that occurred later were described to assess long-term safety. Clinical outcomes were measured by comparison of clinical parameters and echocardiographic measurements of right ventricular function from baseline to 6-months-follow-up.ResultsFifty-four patients underwent LenusPro® pump implantation for intravenous treprostinil treatment during the investigation period. Periprocedural complications occurred in 5 patients; the only anesthesia-related complication (right heart failure with recovery after prolonged intensive care and death in the further course) occurred in the only patient who underwent general anesthesia. All other patients underwent local anesthesia with or without short-acting (analgo-) sedation. Eighteen long-term complications occurred in 15 patients, most notably pump pocket or catheter related problems. Transplant-free survival rates at 1, 2, and 3 years were 77 %, 56 %, and 48 %, respectively.ConclusionsSubcutaneous pump implantation under local anesthesia and conscious analgosedation while avoiding intubation and mechanical ventilation is feasible in patients with advanced PAH. Controlled studies are needed to determine the safest anesthetic approach for this procedure.Background/ObjectivesIntravenous treprostinil treatment via a fully implantable pump is a treatment option for patients with advanced pulmonary arterial hypertension. However, there is no consensus on the preferred anesthetic approach for the implantation procedure. Primary objective was to assess periprocedural safety with particular attention to feasibility of local anesthesia and conscious analgosedation instead of general anesthesia. Long-term safety and clinical outcomes were secondary endpoints.

Off-label use of PAH-targeted medications approved for adults and their financial coverage by health insurances are vital for children with pulmonary hypertension.

Pulmonary hypertension (PH), and especially pulmonary arterial hypertension (PAH), are chronic, progressive, and fatal conditions for which - apart from bilateral lung transplantation - there is currently no cure. However, recently developed, so-called "targeted" ("advanced") PAH medications, are now approved for adult PAH, and have improved quality of life and survival of affected children and adults. In 2020, two prospective pediatric observational studies on add-on macitentan and selexipag, respectively, have been published. Due the lack of approved pediatric PAH-medications, the well-founded rationale for combination therapy in childhood, and the absence of serious adverse effects, advanced pharmacotherapy should not be withheld from young PH patients. Such an "off-label use" of PAH-targeted medications in children with PH, and its financial reimbursement by health insurances, are urgently needed. The decision on the specific, vasoactive pharmacotherapy should be made by a PH expert with sufficient experience in the diagnosis and treatment of children with PH - followed by close out-patient monitoring. Combination pharmacotherapy should include the option of combining drugs of all substance classes (phosphodiesterase inhibitors, soluble guanylate cyclase stimulators, endothelin receptor antagonists, drugs targeting prostacyclin pathways, and calcium channel blockers in select cases) - including "off-label, pediatric drug formulations". Neither the lack of approval for modern PAH drugs directed against PAH nor the limited evidence-based study data available for children, should preclude PH expert centers to offer these therapies early and in combination to young patients with progressive PH, in order to improve exercise capacity, quality of life, and survival.

Ambulatory prostanoid therapy: safe reduction in duration of inpatient training.

IV prostanoid therapy for advanced pulmonary arterial hypertension requires lifelong, continuous infusion, and extensive self-care. The inpatient training pathway (ITP) ensures patient competency but can be psychologically and physically demanding. Therefore, an alternative Elective Prostanoid Admission Pathway (EPAP) was developed.Compare clinical outcomes and patient experiences for patients following the EPAP vs. the ITP. From 2013, clinically stable patients were trained via the EPAP, which consisted of pre-admission including an outpatient training day, followed by inpatient training. The EPAP patients were followed-up face-to-face/via telephone and could access a Clinical Nurse Specialist-led telephone service between appointments. Very high-risk patients were trained via the ITP, which consisted of pre-therapy counselling and daily ward-based training. Prior to 2013, patients followed the ITP pathway irrespective of clinical status. All were enrolled into the 'IV buddy' scheme and retrospectively asked to complete patient experience surveys. Among EPAP (n = 24) and ITP (n = 54) patients, 17% and 33% discontinued therapy, respectively. Among all, frequent challenges to treatment initiation were: dexterity (43%) and body image (27%). Elective Prostanoid Admission Pathway use reduced inpatient stay duration by 8 days per patient and infection rates remained low. Patient experience surveys [n = 17 (EPAP), n = 10 (ITP)] showed equal patient satisfaction between groups, but the incidence of side effects was numerically lower in EPAP patients, who also reported home practice and having access to the 'IV buddy' scheme as 'very useful' [12/14 (86%) and 10/13 (77%), respectively]. Elective Prostanoid Admission Pathway implementation improved patient outcomes and has the potential for application to other clinical scenarios where patient self-management is required.

Study of the effect of Occlutech Atrial Flow Regulator on symptoms, hemodynamics, and echocardiographic parameters in advanced pulmonary arterial hypertension.

Optimal sized balloon atrial septostomy improves hemodynamics in advanced pulmonary arterial hypertension. Occlutech Atrial Flow Regulator is designed to provide an atrial septal fenestration diameter titrated according to the age and right atrial pressures. This observational study analyzed symptoms, exercise distance, oxygen saturations, hemodynamics and echocardiographic parameters after Atrial Flow Regulator implantation in patients with syncope or right-heart failure. Patients with high-risk predictors of mortality during septostomy were scrutinized. Thirty-nine patients (9 children) with syncope (34/39) or right-heart failure (27/39) underwent Atrial Flow Regulator implantation without procedural complications. Six-minute walk distance increased from 310 ± 158.2 to 376.4 ± 182.6 m, none developed syncope. Oxygen saturations reduced from 96.4 ± 6.4% to 92 ± 4.9% at rest and further to 80.3 ± 5.9% on exercise. Right atrial pressures reduced from 9.4 ± 5 (2–27) mmHg to 6.9 ± 2.6 (1–12) mmHg, while cardiac index increased from 2.4 ± 0.8 (0.98–4.3) to 3 ± 1 (1.1–5.3) L/min/m2 and systemic oxygen transport increased from 546.1 ± 157.9 (256.2–910.5) to 637.2 ± 191.1 (301.3–1020.2) ml/min. Echocardiographic improvement included significant reduction of pericardial effusion and inferior caval congestion at a median follow-up of 37 months. Overall survival improved except two early and one late deaths in high-risk patients. Five of seven patients with advanced disease and key hemodynamic predictors of mortality survived. Acute hemodynamic benefits in pulmonary arterial hypertension after Atrial Flow Regulator were improved cardiac output, systemic oxygen transport, and reduced right atrial pressures. Improvement of symptoms especially syncope, exercise duration, and right ventricular systolic function as well as device patency were sustained on mid-term follow-up. Implantation was safe in all including young children without procedural complications. Mortality was noted only in patients who had high-risk predictors and patients at advanced stage of the disease.

Platelet activation contributes to hypoxia-induced inflammation.

Inflammation is central to the pathogenesis of pulmonary vascular remodeling and pulmonary hypertension (PH). Inflammation precedes remodeling in preclinical models, thus supporting the concept that changes in immunity drive remodeling in PH. Platelets are recognized as mediators of inflammation, but whether platelets contribute to hypoxia-driven inflammation has not been studied. We utilized a murine hypoxia model to test the hypothesis that platelets drive hypoxia-induced inflammation. We evaluated male and female 9-wk-old normoxic and hypoxic mice and in selected experiments included hypoxic thrombocytopenic mice. Thrombocytopenic mice were generated with an anti-GP1bα rat IgG antibody. We also performed immunostaining of lung sections from failed donor controls and patients with idiopathic pulmonary arterial hypertension. We found that platelets are increased in the lungs of hypoxic mice and hypoxia induces platelet activation. Platelet depletion prevents hypoxia-driven increases in the proinflammatory chemokines CXCL4 and CCL5 and attenuates hypoxia-induced increase in plasma CSF-2. Pulmonary interstitial macrophages are increased in the lungs of hypoxic mice; this increase is prevented in thrombocytopenic mice. To determine the potential relevance to human disease, lung sections from donors and patients with advanced idiopathic pulmonary arterial hypertension (iPAH) were immunostained for the platelet-specific protein CD41. We observed iPAH lungs had a two-fold increase in CD41, compared with controls. Our data provide evidence that the platelet count is increased in the lungs and activated in mice with hypoxia-induced inflammation and provides rationale for the further study of the potential contribution of platelets to inflammatory mediated vascular remodeling and PH.

Abstract 13082: The Impact of Specific Therapy on Glucose Metabolism in Pulmonary Arterial Hypertension Patients - Follow Up Study

Introduction: Right ventricular (RV) function is a major determinant of survival in patients with pulmonary arterial hypertension (PAH). In our previous study, we confirmed that increased RV fluorodeoxyglucose (FDG) uptake in positron emission tomography (PET) (presented as higher ratio of FDG uptake of RV to LV) was associated with progressive RV dysfunction and preceded hemodynamic and clinical deterioration in PAH patients. Now, we obtained second PET/MRI assessments of the study group after 2-years of PAH-targeted treatment. Hypothesis: Altered cardiac glucose uptake in severe PAH patients may change after PAH specific treatment. Methods: Twenty-eight PAH patients (51.32±15.91 years) had simultaneous PET/MRI scans performed during baseline visit. Second PET/MRI assessments were done after 2 years in the group of twenty patients (four deaths, four patients did not agree to perform additional scans). Results: After follow-up period, we observed significant change of MRI-derived RV ejection fraction (45±10% to 51.2±12.7%, p=0.03), and improvement in hemodynamic parameters obtained from right heart catheterization e.g. mean pulmonary artery pressure, mPAP (48.5±17.2 to 41.8±17.1 mmHg, p=0.01) and pulmonary vascular resistance, PVR (8.7±5.3 to 7.0±4.2 WU, p=0.04). Follow-up SUVRV/SUVLV ratio was lower than baseline (0.84±0.57 vs 1.02±0.75, p=0.05) and significantly correlated with follow-up RV hemodynamic parameters confirming relationship between RV function and metabolic alterations. Interestingly, patients who had improvement in SUVRV/SUVLV (lower follow-up value than baseline, n=11) had significantly higher mPAP at baseline visit (58.9±18.7 vs 40.3±11.8 mmHg, p=0.02), suggesting that RV FDG accumulation in advanced PAH may decrease after the specific PAH-treatment in accordance with the degree of reduction in the pulmonary vascular resistance. Conclusions: Impaired RV function is associated with increased glucose uptake of RV myocytes estimated by FDG PET in PAH patients. Targeted treatment may improve RV function and thus affect previously altered cardiac glucose uptake.