Pathogenic Role of mTORC1 and mTORC2 in Pulmonary Hypertension.

Concentric lung vascular wall thickening due to enhanced proliferation of pulmonary arterial smooth muscle cells is an important pathological cause for the elevated pulmonary vascular resistance reported in patients with pulmonary arterial hypertension. We identified a differential role of mammalian target of rapamycin (mTOR) complex 1 and complex 2, two functionally distinct mTOR complexes, in the development of pulmonary hypertension (PH). Inhibition of mTOR complex 1 attenuated the development of PH; however, inhibition of mTOR complex 2 caused spontaneous PH, potentially due to up-regulation of platelet-derived growth factor receptors in pulmonary arterial smooth muscle cells, and compromised the therapeutic effect of the mTOR inhibitors on PH. In addition, we describe a promising therapeutic strategy using combination treatment with the mTOR inhibitors and the platelet-derived growth factor receptor inhibitors on PH and right ventricular hypertrophy. The data from this study provide an important mechanism-based perspective for developing novel therapies for patients with pulmonary arterial hypertension and right heart failure

Biological heterogeneity in idiopathic pulmonary arterial hypertension identified through unsupervised transcriptomic profiling of whole blood

Idiopathic pulmonary arterial hypertension (IPAH) is a rare but fatal disease diagnosed by right heart catheterisation and the exclusion of other forms of pulmonary arterial hypertension, producing a heterogeneous population with varied treatment response. Here we show unsupervised machine learning identification of three major patient subgroups that account for 92% of the cohort, each with unique whole blood transcriptomic and clinical feature signatures. These subgroups are associated with poor, moderate, and good prognosis. The poor prognosis subgroup is associated with upregulation of the ALAS2 and downregulation of several immunoglobulin genes, while the good prognosis subgroup is defined by upregulation of the bone morphogenetic protein signalling regulator NOG, and the C/C variant of HLA-DPA1/DPB1 (independently associated with survival). These findings independently validated provide evidence for the existence of 3 major subgroups (endophenotypes) within the IPAH classification, could improve risk stratification and provide molecular insights into the pathogenesis of IPAH

An Advanced Protocol-Driven Transition from Parenteral Prostanoids to Inhaled Trepostinil in Pulmonary Arterial Hypertension

Patients with pulmonary arterial hypertension (PAH) often require parenteral prostanoids to improve symptoms and signs of PAH. Complications of parenteral prostanoids-such as catheter-related infections and intolerable adverse effects-may develop, prompting transition to inhaled prostanoids. We report a prospective, protocol-driven transition from parenteral prostanoids to inhaled prostanoids with monitoring of exercise gas exchange and acute hemodynamics. Three PAH centers recruited patients transitioning from parenteral prostanoids to inhaled trepostinil. Rigid inclusion criteria were used, including parenteral prostanoid dose < 30 ng/kg/min, New York Heart Association functional class (FC) < 3, and pulmonary vascular resistance (PVR) < 6 Wood units. Of the 9 patients meeting initial inclusion criteria, 3 were excluded. In the remaining patients, the parenteral prostanoid was reduced and the inhaled prostanoid was increased over 24-36 hours with continuous hemodynamic monitoring. Exercise capacity and FC were measured at baseline and weeks 1, 4, and 12. All patients were successfully weaned from parenteral prostanoids. An acute PVR decrease was seen with most inhaled prostanoid doses, but PVR varied throughout the transition. Patients tolerated inhaled prostanoids for 9-12 breaths 4 times a day with no treatment-limiting adverse events. At week 12, FC was unchanged, and all patients continued to receive inhaled prostanoids without serious adverse events or additional PAH therapy. In 5 of 6 patients, 6-minute walk distance and peak VO2 were within 10% of baseline. Using a strict transition protocol and rigid patient selection criteria, the parenteral prostanoid to inhaled prostanoid transition appeared safe and well tolerated and did not result in clinical deterioration over 12 weeks. Hemodynamic variability noted acutely during transition in our study did not adversely affect successful transition.United Therapeutics Corporation, Research Triangle Park, North CarolinaFirst Published January 23, 2017; 12 month embargo.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

An Advanced Protocol-Driven Transition from Parenteral Prostanoids to Inhaled Trepostinil in Pulmonary Arterial Hypertension

Patients with pulmonary arterial hypertension (PAH) often require parenteral prostanoids to improve symptoms and signs of PAH. Complications of parenteral prostanoids-such as catheter-related infections and intolerable adverse effects-may develop, prompting transition to inhaled prostanoids. We report a prospective, protocol-driven transition from parenteral prostanoids to inhaled prostanoids with monitoring of exercise gas exchange and acute hemodynamics. Three PAH centers recruited patients transitioning from parenteral prostanoids to inhaled trepostinil. Rigid inclusion criteria were used, including parenteral prostanoid dose < 30 ng/kg/min, New York Heart Association functional class (FC) < 3, and pulmonary vascular resistance (PVR) < 6 Wood units. Of the 9 patients meeting initial inclusion criteria, 3 were excluded. In the remaining patients, the parenteral prostanoid was reduced and the inhaled prostanoid was increased over 24-36 hours with continuous hemodynamic monitoring. Exercise capacity and FC were measured at baseline and weeks 1, 4, and 12. All patients were successfully weaned from parenteral prostanoids. An acute PVR decrease was seen with most inhaled prostanoid doses, but PVR varied throughout the transition. Patients tolerated inhaled prostanoids for 9-12 breaths 4 times a day with no treatment-limiting adverse events. At week 12, FC was unchanged, and all patients continued to receive inhaled prostanoids without serious adverse events or additional PAH therapy. In 5 of 6 patients, 6-minute walk distance and peak VO2 were within 10% of baseline. Using a strict transition protocol and rigid patient selection criteria, the parenteral prostanoid to inhaled prostanoid transition appeared safe and well tolerated and did not result in clinical deterioration over 12 weeks. Hemodynamic variability noted acutely during transition in our study did not adversely affect successful transition.United Therapeutics Corporation, Research Triangle Park, North CarolinaFirst Published January 23, 2017; 12 month embargo.This item from the UA Faculty Publications collection is made available by the University of Arizona with support from the University of Arizona Libraries. If you have questions, please contact us at [email protected]

Simple functional imaging of the right ventricle in pulmonary hypertension: Can right ventricular ejection fraction be improved?

SCOPUS: ar.jinfo:eu-repo/semantics/publishe

Pulmonary circulatory – right ventricular uncoupling: New insights into pulmonary hypertension pathophysiology

The pulmonary circulatory – right ventricular uncoupling is a key pathophysiological feature of pulmonary hypertension. Uncoupling develops when the ventricular contractility is not matched to its afterload due to a discordant response of the RV to increased afterload, or to an impaired right ventricular function. In this chapter we reported the methods which were developed to quantify the right ventricular –pulmonary artery (RV-PA) coupling in patients with PH and in experimental models of PH. The RV pressure-volume loop analysis are the gold standard to quantify RV-PA coupling metrics but more simple and less invasive methods were developed. We also reported how the RV-PA coupling metrics may be used to improve the phenotyping of patients and experimental models with PH. RV-PA coupling was also used to quantify the pharmacological effects of treatments in animal models with PH and to improve the understanding of the pathophysiological differences in different PH types. In recent studies, RV-PA coupling quantification with imaging methods showed interesting application to prognosis stratification of patients with PH.SCOPUS: ch.binfo:eu-repo/semantics/publishe

iCPET Calculator: A Web‐Based Application to Standardize the Calculation of Alpha Distensibility in Patients With Pulmonary Arterial Hypertension

Background Pulmonary vascular distensibility associates with right ventricular function and clinical outcomes in patients with unexplained dyspnea and pulmonary hypertension. Alpha distensibility coefficient is determined from a nonlinear fit to multipoint pressure‐flow plots. Study aims were to (1) create and test a user‐friendly tool to standardize analysis of exercise hemodynamics including distensibility, and (2) investigate changes in distensibility following treatment in patients with pulmonary arterial hypertension. Methods and Results Participants with an exercise right heart catherization were retrospectively identified from the University of Arizona Pulmonary Hypertension (UA PH) registry and split into a pulmonary arterial hypertension group, a comparator group, and a control group. Right ventricular function was quantified using the coupling ratio and diastolic stiffness. Prototypes of the invasive cardiopulmonary exercise testing (iCPET) calculator were developed using Matlab, Python, and RShiny to analyze exercise hemodynamics and alpha distensibility coefficient, α (%/mm Hg) from multipoint pressure flow plots. Interclass correlation coefficients were calculated for interplatform and interobserver variability in alpha. No significant bias in the intraplatform (Matlab versus RShiny; intraclass correlation coefficient: 0.996) or interobserver (intraclass correlation coefficient: 0.982) comparison of alpha values. Afterload significantly decreased (P<0.05) with no change in alpha distensibility in the pulmonary arterial hypertension group at follow‐up. The comparator group had no change in pressure, resistance or alpha distensibility. There were no significant changes in RV diastolic stiffness at follow‐up. Conclusions The interactive user interface in the iCPET calculator allows exploration of alpha distensibility using standardized methods. No significant change in alpha distensibility at follow‐up suggests that alpha may be less modifiable in patients with long‐standing pulmonary arterial hypertension