Various Forms Of Pulmonary Hypertension Research Articles

Long-standing response to calcium channel blocker therapy on patients with various types of pulmonary hypertension: a systematic review and meta analysis

Abstract Background It is widely acknowledged that the extended use of calcium channel blocker (CCBs) therapy in patients diagnosed with Idiopathic Pulmonary Arterial Hypertension (IPAH), Heritable Pulmonary Arterial Hypertension (HPAH), or Drug- or Toxin-Associated Pulmonary Arterial Hypertension (DPAH) who exhibit a positive acute vasoreactivity test (VdT+) provides benefits to patients. However, this practice is supported by a limited body of evidence in the scientific literature, mainly derived from expert consensus and/or small-scale studies, retrospective analyses, and registries, as per the European Society of Cardiology (ESC) guidelines. Objectives We performed a meta-analysis to evaluate the long-standing response to CCBs in patients diagnosed with various forms of pulmonary hypertension. Design We conducted searches in PubMed, Embase, and Cochrane to select both randomised and non-randomised studies. The primary outcomes of interest identified were Mean Pulmonary Artery Pressure (mPAP), 6-minute walk distance (6MWD), Cardiac Index (CI), Mean Right Atrial Pressure (mRAP), and Mixed venous oxygen saturation (SvO₂) measured at the beginning and end of the studies. Additionally, we performed subgroup analyses for all outcomes based on age groups: ≤18 years and >18 years. Statistical analysis was carried out using OpenMeta[Analyst] 12.11.14, and heterogeneity was assessed using I² statistics. Results We identified 7 non-randomised studies comprising a total of 131 patients with an average follow-up duration of 2.74 (1.3) years. The following are the mean values observed for individual outcomes: mPAP (33.1 mmHg; 95% CI [31.6, 34.6]; p < 0.001; I²=0%), 6MWD (470.1 m; 95% CI [452.6, 487.7]; I²=0%), Cardiac index (3.8 L/min/m²; 95% CI [3.6, 4.0]; I²=0%), mRAP (4.2 mmHg; 95% CI [3.6, 4.8]; I²=0%) and SvO₂ (73.9%; 95% CI [72.5, 75.3]; I²=0%) in patients with positive acute vasoreactivity test (VdT+) treated long-term with CCBs. Additionally, at study initiation, we found the following means: mPAP (51.2 mmHg; 95% CI [49.3, 53.0]; I²=0%), 6MWD (428.4 m; 95% CI [410.3, 446.6]; I²=0%), Cardiac index (2.8 L/min/m²; 95% CI [2.7, 2.9]; I²=0%), mRAP (6.4 mmHg; 95% CI [5.6, 7.2]; I²=0%), and SvO₂ (68.5%; 95% CI [66.5, 70.5]; I²=0%). Conclusion The findings from this meta-analysis suggest that in VdT+ patients, the means of certain haemodynamic parameters with long-standing use of CCBs are similar or nearly similar to those of patients without any subtype of PAH. These results align with current guidelines and reinforce their level of evidence.

Efficacy and safety of the Aria pulmonary endovascular device in pulmonary hypertension

Abstract Background and aims A common feature of various forms of pulmonary hypertension (PH) is progressive decline of pulmonary arterial compliance (CPA), which correlates with reduced survival. In this acute study, we evaluated feasibility, safety and hemodynamic performance of the Aria pulmonary endovascular device in patients with PH associated with left heart disease (PH-LHD) and chronic lung disease (PH-CLD). Methods 8 patients with PH-LHD and 10 patients with PH-CLD were included in this study. The device was placed in the main pulmonary artery via the right femoral vein and was connected by a catheter to a gas-filled reservoir outside the body. During systole, gas shifts from the balloon to the reservoir, leading to deflation of the balloon. In diastole, the gas returns from the reservoir to the balloon, leading to balloon inflation and enhancing diastolic blood flow to the distal pulmonary capillary bed. Hemodynamics were assessed at baseline, and again with device off, device on and device off. The primary safety endpoint was the incidence of serious adverse events through 30 days after the procedure. Results No complications or investigational device-related serious adverse events occurred. Device activation in PH-LHD and PH-CLD patients decreased pulmonary arterial pulse pressure by 5.6±4.2mmHg (-12%; p=0.003) and 4.2±2.2mmHg (-11%; p<0.001), increased CPA by 0.4±0.2mL/mmHg (+23%; p=0.004) and 0.4±0.3mL/mmHg (+25%; p=0.001), and increased RV-PV coupling by 0.24±0.18 (+40%; p=0.012) and 0.11±0.07 (+21%; p=0.001), respectively. Conclusions Temporary implantation of the Aria endovascular device was feasible and safe. Device activation resulted in acute improvement of CPA and RV-PV coupling.Figure

Pathology and pathobiology of pulmonary hypertension: current insights and future directions.

In recent years, major advances have been made in the understanding of the cellular and molecular mechanisms driving pulmonary vascular remodelling in various forms of pulmonary hypertension, including pulmonary arterial hypertension, pulmonary hypertension associated with left heart disease, pulmonary hypertension associated with chronic lung disease and hypoxia, and chronic thromboembolic pulmonary hypertension. However, the survival rates for these different forms of pulmonary hypertension remain unsatisfactory, underscoring the crucial need to more effectively translate innovative scientific knowledge into healthcare interventions. In these proceedings of the 7th World Symposium on Pulmonary Hypertension, we delve into recent developments in the field of pathology and pathophysiology, prioritising them while questioning their relevance to different subsets of pulmonary hypertension. In addition, we explore how the latest omics and other technological advances can help us better and more rapidly understand the myriad basic mechanisms contributing to the initiation and progression of pulmonary vascular remodelling. Finally, we discuss strategies aimed at improving patient care, optimising drug development, and providing essential support to advance research in this field.

Relationship of TAPSE Normalized by Right Ventricular Area With Pulmonary Compliance, Exercise Capacity, and Clinical Outcomes.

While tricuspid annular plane systolic excursion (TAPSE) captures the predominant longitudinal motion of the right ventricle (RV), it does not account for ventricular morphology and radial motion changes in various forms of pulmonary hypertension. This study aims to account for both longitudinal and radial motions by dividing TAPSE by RV area and to assess its clinical significance. We performed a retrospective analysis of 71 subjects with New York Heart Association class II to III dyspnea who underwent echocardiogram and invasive cardiopulmonary exercise testing (which defined 4 hemodynamic groups: control, isolated postcapillary pulmonary hypertension, combined postcapillary pulmonary hypertension, and pulmonary arterial hypertension). On the echocardiogram, TAPSE was divided by RV area in diastole (TAPSE/RVA-D) and systole (TAPSE/RVA-S). Analyses included correlations (Pearson and linear regression), receiver operating characteristic, and survival curves. On linear regression analysis, TAPSE/RVA metrics (versus TAPSE) had a stronger correlation with pulmonary artery compliance (r=0.48-0.54 versus 0.38) and peak VO2 percentage predicted (0.23-0.30 versus 0.18). Based on the receiver operating characteristic analysis, pulmonary artery compliance ≥3 mL/mm Hg was identified by TAPSE/RVA-D with an under the curve (AUC) of 0.79 (optimal cutoff ≥1.1) and by TAPSE/RVA-S with an AUC of 0.83 (optimal cutoff ≥1.5), but by TAPSE with only an AUC of 0.67. Similarly, to identify peak VO2 <50% predicted, AUC of 0.66 for TAPSE/RVA-D and AUC of 0.65 for TAPSE/RVA-S. Death or cardiovascular hospitalization at 12 months was associated with TAPSE/RVA-D ≥1.1 (HR, 0.38 [95% CI, 0.11-0.56]) and TAPSE/RVA-S ≥1.5 (HR, 0.44 [95% CI, 0.16-0.78]), while TAPSE was not associated with adverse outcomes (HR, 0.99 [95% CI, 0.53-1.94]). Among 31 subjects with available cardiac magnetic resonance imaging, RV ejection fraction was better correlated with novel metrics (TAPSE/RVA-D r=0.378 and TAPSE/RVA-S r=0.328) than TAPSE (r=0.082). In a broad cohort with suspected pulmonary hypertension, TAPSE divided by RV area was superior to TAPSE alone in correlations with pulmonary compliance and exercise capacity. As a prognostic marker of right heart function, TAPSE/RVA-D <1.1 and TAPSE/RVA-S <1.5 predicted adverse cardiovascular outcomes.

Efficacy and safety of the Aria pulmonary endovascular device in pulmonary hypertension.

A common feature of various forms of pulmonary hypertension (PH) is progressive decline of pulmonary arterial compliance (CPA), which correlates with reduced survival. In this acute study, we evaluated feasibility, safety and haemodynamic performance of the Aria pulmonary endovascular device in patients with PH associated with left heart disease (PH-LHD) and chronic lung disease (PH-CLD). Eight patients with PH-LHD and 10 patients with PH-CLD were included in this study. The device was placed in the main pulmonary artery via the right femoral vein and was connected by a catheter to a gas-filled reservoir outside the body. During systole, gas shifts from the balloon to the reservoir, leading to deflation of the balloon. In diastole, the gas returns from the reservoir to the balloon, leading to balloon inflation and enhancing diastolic blood flow to the distal pulmonary capillary bed. Haemodynamics were assessed at baseline, and again with device off, device on and device off. The primary safety endpoint was the incidence of serious adverse events through 30 days after the procedure. No complications or investigational device-related serious adverse events occurred. Device activation in PH-LHD and PH-CLD patients decreased pulmonary arterial pulse pressure by 5.6 ± 4.2 mmHg (-12%; p = 0.003) and 4.2 ± 2.2 mmHg (-11%; p < 0.001), increased CPA by 0.4 ± 0.2 ml/mmHg (+23%; p = 0.004) and 0.4 ± 0.3 ml/mmHg (+25%; p = 0.001), and increased right ventricular-to-pulmonary vascular (RV-PV) coupling by 0.24 ± 0.18 (+40%; p = 0.012) and 0.11 ± 0.07 (+21%; p = 0.001), respectively. Temporary implantation of the Aria endovascular device was feasible and safe. Device activation resulted in acute improvement of CPA and RV-PV coupling.

Connective tissue disease-associated pulmonary hypertension: A comprehensive review.

Connective tissue diseases (CTDs) can be associated with various forms of pulmonary hypertension, including pulmonary arterial hypertension (PAH), pulmonary veno-occlusive disease, pulmonary venous hypertension, interstitial lung disease-associated pulmonary hypertension, chronic thromboembolic pulmonary hypertension, and sometimes a combination of several processes. The prevalence of PAH varies among the different CTDs, with systemic sclerosis (SSc) having the highest at 8%-12%. The most recent European Society of Cardiology/European Respiratory Societyguidelines recommend routine annual screening for PAH in SSc and CTDs with SSc features. As CTDs can be associated with a myriad of presentations of pulmonary hypertension, a thorough evaluation to include a right heart catheterization to clearly delineate the hemodynamic profile is essential in developing an appropriate treatment plan. Treatment strategies will depend on the predominant phenotype of pulmonary vasculopathy. In general, management approach to CTD-PAH mirrors that of idiopathic PAH. Despite this, outcomes of CTD-PAH are inferior to those of idiopathic PAH, with those of SSc-PAH being particularly poor. Reasons for this may include extrapulmonary manifestations of CTDs, including renal disease and gastrointestinal involvement, concurrent interstitial lung disease, and differences in the innate response of the right ventricle to increased pulmonary vascular resistance. Early referral for lung transplant evaluation of patients with CTD-PAH, particularly SSc-PAH, is recommended. It is hoped that in the near future, additional therapies may be added to the armamentarium of effective treatments for CTD-PAH. Ultimately, a better understanding of the pathogenesis of CTD-PAH will be required to develop targeted therapies for this morbid condition.

Chitinase 3 like 1 contributes to the development of pulmonary vascular remodeling in pulmonary hypertension.

Chitinase 3 like 1 (CHI3L1) is the prototypic chitinase-like protein mediating inflammation, cell proliferation, and tissue remodeling. Limited data suggest CHI3L1 is elevated in human pulmonary arterial hypertension (PAH) and is associated with disease severity. Despite its importance as a regulator of injury/repair responses, the relationship between CHI3L1 and pulmonary vascular remodeling is not well understood. We hypothesize that CHI3L1 and its signaling pathways contribute to the vascular remodeling responses that occur in pulmonary hypertension (PH). We examined the relationship of plasma CHI3L1 levels and severity of PH in patients with various forms of PH, including group 1 PAH and group 3 PH, and found that circulating levels of serum CHI3L1 were associated with worse hemodynamics and correlated directly with mean pulmonary artery pressure and pulmonary vascular resistance. We also used transgenic mice with constitutive knockout and inducible overexpression of CHI3L1 to examine its role in hypoxia-, monocrotaline-, and bleomycin-induced models of pulmonary vascular disease. In all 3 mouse models of pulmonary vascular disease, pulmonary hypertensive responses were mitigated in CHI3L1-null mice and accentuated in transgenic mice that overexpress CHI3L1. Finally, CHI3L1 alone was sufficient to induce pulmonary arterial smooth muscle cell proliferation, inhibit pulmonary vascular endothelial cell apoptosis, induce the loss of endothelial barrier function, and induce endothelial-mesenchymal transition. These findings demonstrate that CHI3L1 and its receptors play an integral role in pulmonary vascular disease pathobiology and may offer a target for the treatment of PAH and PH associated with fibrotic lung disease.

The pathology of the pulmonary vasculature in various forms of pulmonary hypertension [reproduced from G Ital Cardiol 1975;5:1-7]

The pathology of the pulmonary vasculature in various forms of pulmonary hypertension [reproduced from G Ital Cardiol 1975;5:1-7]

HEALTH-RELATED QUALITY OF LIFE ACROSS THE SPECTRUM OF PULMONARY HYPERTENSION IN PVDOMICS

SESSION TITLE: Pulmonary Vascular Disease Posters SESSION TYPE: Original Investigation Posters PRESENTED ON: October 18-21, 2020 PURPOSE: Health related quality of life (HRQOL) is frequently impaired and predictive of survival in pulmonary arterial hypertension (PAH). However, little is known about HRQOL in other forms of pulmonary hypertension (PH). PVDOMICS (Redefining Pulmonary Hypertension through Pulmonary Vascular Disease Phenomics) is a NIH-sponsored, multi-center, observational study of patients with PH and those at-risk for PH. Using this large cohort of patients with various forms of PH, we sought to characterize HRQOL across groups of the World Symposium on Pulmonary Hypertension (WSPH) classification system. METHODS: Enrollees underwent cardiac imaging, pulmonary function testing, six-minute walk testing (6MWT), and right heart catheterization. HRQOL was assessed using emPHasis-10 (e-10), Medical Outcomes Survey Short Form-36 (SF-36; physical component (PCS) and mental component (MCS)), and Minnesota Living with Heart Failure Questionnaire (MLHF). HRQOL measures were summarized as means (SD) and were compared between WSPH groups using ANOVA and t-tests. Pearson’s correlation assessed the relationship between HRQOL and demographic, physiologic, and imaging characteristics. RESULTS: Of the 763 subjects enrolled, 372 were in Group 1, 145 in Group 2, 160 in Group 3, 58 in Group 4, and 28 in Group 5. Age and sex significantly differed between groups; most subjects were white (n=580, 78%) and had moderate functional impairment by 6MWT (mean 350±134 m). Hemodynamics showed mild to moderate severity PH. Overall, HRQOL was severely depressed and differed significantly across WSPH groups except for the MCS score of the SF-36. When compared to Group 1, Group 2 subjects had significantly worse e-10 (28.1(11.5) vs. 23.5(12.9), p=0.002), PCS (32.5(7.9) vs. 38.5(10.1), p<0.001), and MLHF (50.2(26.2) vs. 39.9(28.2), p=0.003). Group 3 subjects had worse e-10 (30.1(11.6) vs. 23.5(12.9), p<0.001) and PCS (32.9(8.7) vs. 38.5(10.1), p<0.001) compared to Group 1. There were no significant differences in HRQOL noted between Group 1 and Group 4 or 5 patients. There were weak but statistically significant associations between HRQOL measures and hemodynamics in Group 1 and Group 3, but not in Groups 2,4, or 5. Overall, there were modest correlations between HRQOL measures and 6MWT that were strongest in Group 1. CONCLUSIONS: HRQOL is depressed across the spectrum of PH. Group 2 and Group 3 patients have worse HRQOL than Group 1 patients despite less severe PH. HRQOL does not strongly associate with hemodynamic perturbations but is modestly associated with 6MWT. These data suggest that the impact of PH on HRQOL is not related to hemodynamic severity and differs between PH groups. CLINICAL IMPLICATIONS: HRQOL differs between PH groups and appears independent from hemodynamic severity, suggesting current assessment of disease severity by hemodynamic metrics may underestimate disease impact from the patient’s perspective DISCLOSURES: No relevant relationships by Aparna Balasubramanian, source=Web Response No relevant relationships by Erika Berman Rosenzweig, source=Web Response Advisory Committee Member relationship with Liquidia Please note: $1001 - $5000 Added 03/19/2020 by Robert Frantz, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Altavant Please note: $1001 - $5000 Added 03/19/2020 by Robert Frantz, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Actelion Please note: $5001 - $20000 Added 07/16/2020 by Robert Frantz, source=Web Response, value=Consulting fee No relevant relationships by Paul Hassoun, source=Web Response Advisory Committee Member relationship with bayer Please note: $1001 - $5000 Added 04/14/2020 by Anna Hemnes, source=Web Response, value=Consulting fee Advisory Committee Member relationship with Complexa Please note: $1-$1000 Added 04/14/2020 by Anna Hemnes, source=Web Response, value=Consulting fee Advisory Committee Member relationship with United Therapeutics Please note: $1001 - $5000 Added 04/14/2020 by Anna Hemnes, source=Web Response, value=Consulting fee Advisory Committee Member relationship with actelion Please note: $1001 - $5000 Added 04/14/2020 by Anna Hemnes, source=Web Response, value=Consulting fee Scientific Medical Advisor relationship with PHPreMedicine Please note: $1-$1000 Added 04/14/2020 by Anna Hemnes, source=Web Response, value=Ownership interest no disclosure on file for Evelyn Horn; My spouse/partner as a Consultant relationship with Cellectis Please note: >$100000 Added 05/28/2020 by Jane Leopold, source=Web Response, value=Consulting fee Clinical Trial Steering Committee relationship with Actelion Please note: $1001 - $5000 Added 05/27/2020 by Stephen Mathai, source=Web Response, value=Consulting fee Consultant relationship with Liquidia Please note: $1001 - $5000 Added 05/27/2020 by Stephen Mathai, source=Web Response, value=Consulting fee Consultant relationship with United Therapeutics Please note: $1001 - $5000 Added 05/27/2020 by Stephen Mathai, source=Web Response, value=Consulting fee My spouse/partner as a Consultant relationship with GSK Please note: $1001 - $5000 Added 05/27/2020 by Stephen Mathai, source=Web Response, value=Consulting fee My spouse/partner as a Consultant relationship with Celegene Please note: $1001 - $5000 Added 05/27/2020 by Stephen Mathai, source=Web Response, value=Consulting fee My spouse/partner as a Royalty relationship with Up To Date Please note: $1001 - $5000 Added 05/27/2020 by Stephen Mathai, source=Web Response, value=Royalty no disclosure on file for Franz Rischard

Clinical and Instrumental Characteristics of Newly Diagnosed Patients with Various Forms of Pulmonary Hypertension according to the Russian National Registry.

Aim To study demographic and clinical characteristics and to give a comparative description of the functional and hemodynamic status, profile of concomitant pathology in patients with various forms of pulmonary arterial hypertension (PAH), and chronic thromboembolic pulmonary hypertension (CTEPH) according to the Russian National Registry. Methods During the period from January 01, 2012, till January 01, 2019, 1105 patients aged >18 years with verified diagnosis of PAH and CTEPH, who were subsequently observed at 15 PH expert centers of the Russian Federation in the 52 provinces, are included in the Russian registry on the basis of the Federal State Budgetary Institution of Cardiology of the Ministry of Healthcare of Russia. All newly diagnosed patients (n = 727) were entered into the registry database (NCT03707561). A comparative analysis of demographic and clinical characteristics, profile of concomitant pathology, and parameters of a comprehensive examination of patients was performed. Results Among newly diagnosed patients, 67% had PAH and 28.3% had CTEPH. In the PAH group, 40.9% of patients had idiopathic arterial PAH (IPAH), 36.6% had PAH associated with simple congenital heart disease (PAH-CHD), 19.3% had PAH associated with systemic connective tissue disease (PAH-CTD), 1.8% had portal pulmonary hypertension (PoPH), 0.6% had PAH associated with HIV infection (PAH-HIV), 0.4% had heritable PAH (HPAH), and 0.4% had drug/toxin-induced PAH. At the time of diagnosis, PAH patients were younger than patients with CTEPH (45.2 ± 14.9; 52.6 ± 15.3 years, respectively) (p < 0.05). At the time of diagnosis, 71% PAH and 77% CTEPH patients had WHO FC III/IV. Mean (±SD) 6MWD was significantly less in CTEPH vs. the PAH group 331.3 ± 110.3 vs. 361.8 ± 135.7 m (p = 0.0006). Echo data showed a comparable sPAP between groups; CTEPH population had a more pronounced increase in the area of the right atrium (SRA) (24 [20; 32] cm2 and 19 [15; 26] cm2, respectively), and a significant decrease in FAC (24.7 [22, 4; 29.0] and 29.0 [23.0; 31.0] %, respectively) as compared to the PAH group. RHC showed a comparable increase of sPAP and mPAP in PAH and CTEPH groups. 15.2% of patients with IPAH and HPAH demonstrated positive results in the acute vasoreactivity testing. CTEPH patients were more often obese and suffered from arterial hypertension and right heart failure. Deep venous thrombosis was significantly more often observed in patients with CTEPH (53%). The most common concomitant pathology was erosive-ulcerative lesion of the stomach/duodenum, less often of the esophagus (23.5% and 44.5%, respectively). Conclusion According to the Russian registry in patients with PAH and IPAH, the diagnosis is established at a younger age in comparison with the European registries. CTEPH patients are characterized by more severe functional status, pronounced signs of right heart failure taking into account the older age and the spectrum of comorbid pathology, which limits the possibility of surgical treatment. An increase in the number of expert centers participating in the registry is the key to improving early diagnosis of PH and optimal follow-up according to common standards in order to timely optimize therapy and reduce mortality of patients.

Novel Molecular Mechanisms of Pulmonary Hypertension: A Search for Biomarkers and Novel Drug Targets-From Bench to Bed Site.

Pulmonary hypertension (PH) is defined as increased mean pulmonary artery pressure (mPAP) above 25 mmHg, measured at rest by right heart catheterization. The exact global prevalence of PH is difficult to estimate, mainly due to the complex aetiology, and its spread may be underestimated. To date, numerous studies on the aetiology and pathophysiology of PH at molecular level were conducted. Simultaneously, some clinical studies have shown potential usefulness of well-known and widely recognized cardiovascular biomarkers, but their potential clinical usefulness in diagnosis and management of PH is poor due to their low specificity accompanied with numerous other cardiovascular comorbidities of PH subjects. On the other hand, a large body of basic research-based studies provides us with novel molecular pathomechanisms, biomarkers, and drug targets, according to the evidence-based medicine principles. Unfortunately, the simple implementation of these results to clinical practice is impossible due to a large heterogeneity of the PH pathophysiology, where the clinical symptoms constitute only a common denominator and a final result of numerous crosstalking metabolic pathways. Therefore, future studies, based mostly on translational medicine, are needed in order to both organize better the pathophysiological classification of various forms of PH and define precisely the optimal diagnostic markers and therapeutic targets in particular forms of PH. This review paper summarizes the current state of the art regarding the molecular background of PH with respect to its current classification. Novel therapeutic strategies and potential biomarkers are discussed with respect to their limitations in use in common clinical practice.

Socio-economic burden of pulmonary hypertension: relevance of assessment in Russia and the world

Pulmonary hypertension (PH) is a progressive disease which is characterized with the increase of pulmonary artery pressure and pulmonary vascular resistance. Such condition leads to right ventricular heart failure and premature death of patients. Pulmonary arterial hypertension (PAH) has the status of an orphan disease. However in Russia only idiopathic PH is included in the list of 24 life-threatening and chronic progressive rare diseases, while other forms of PH are not in it. Inclusion in this list guarantees drug provision for patients at the expense of the regional budget, while patients with other forms of PH can rely on free medication only if they have a disability. The lack of criteria for revising this list as well as the imperfection of legal regulation in the field of drug support for orphan diseases leads to high disability, a significant decrease in the duration and quality of life of patients with PH. As part of a multicriteria approach, a clinical and economic analysis of the disease burden can be one of the tools for policy development and decision-making on the distribution of funding in the healthcare. The article provides a review of the economic burden of various forms of PH in the world.

An Hb-mediated circulating macrophage contributing to pulmonary vascular remodeling in sickle cell disease.

Circulating macrophages recruited to the lung contribute to pulmonary vascular remodeling in various forms of pulmonary hypertension (PH). In this study we investigated a macrophage phenotype characterized by intracellular iron accumulation and expression of antioxidant (HO-1), vasoactive (ET-1), and proinflammatory (IL-6) mediators observed in the lung tissue of deceased sickle cell disease (SCD) patients with diagnosed PH. To this end, we evaluated an established rat model of group 5 PH that is simultaneously exposed to free hemoglobin (Hb) and hypobaric hypoxia (HX). Here, we tested the hypothesis that pulmonary vascular remodeling observed in human SCD with concomitant PH could be replicated and mechanistically driven in our rat model by a similar macrophage phenotype with iron accumulation and expression of a similar mixture of antioxidant (HO-1), vasoactive (ET-1), and inflammatory (IL-6) proteins. Our data suggest phenotypic similarities between pulmonary perivascular macrophages in our rat model and human SCD with PH, indicating a potentially novel maladaptive immune response to concomitant bouts of Hb and HX exposure. Moreover, by knocking out circulating macrophages with gadolinium trichloride (GdCl3), the response to combined Hb and hypobaric HX was significantly attenuated in rats, suggesting a critical role for macrophages in the exacerbation of SCD PH.

An insider view on the World Symposium on Pulmonary Hypertension

An insider view on the World Symposium on Pulmonary Hypertension

Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives.

Clinical and translational research has played a major role in advancing our understanding of pulmonary hypertension (PH), including pulmonary arterial hypertension and other forms of PH with severe vascular remodelling (e.g. chronic thromboembolic PH and pulmonary veno-occlusive disease). However, PH remains an incurable condition with a high mortality rate, underscoring the need for a better transfer of novel scientific knowledge into healthcare interventions. Herein, we review recent findings in pathology (with the questioning of the strict morphological categorisation of various forms of PH into pre- or post-capillary involvement of pulmonary vessels) and cellular mechanisms contributing to the onset and progression of pulmonary vascular remodelling associated with various forms of PH. We also discuss ways to improve management and to support and optimise drug development in this research field.

Redox Biology of Right-Sided Heart Failure.

Right-sided heart failure is the major cause of death among patients who suffer from various forms of pulmonary hypertension and congenital heart disease. The right ventricle (RV) and left ventricle (LV) originate from different progenitor cells and function against very different blood pressures. However, differences between the RV and LV formed after birth have not been well defined. Work from our laboratory and others has accumulated evidence that redox signaling, oxidative stress and antioxidant regulation are important components that define the RV/LV differences. The present article summarizes the progress in understanding the roles of redox biology in the RV chamber-specificity. Understanding the mechanisms of RV/LV differences should help develop selective therapeutic strategies to help patients who are susceptible to and suffering from right-sided heart failure. Modulations of redox biology may provide effective therapeutic avenues for these conditions.

Strengths and weaknesses of echocardiography for the diagnosis of pulmonary hypertension

Doppler echocardiography is extensively used in clinical practice for the screening and detection of pulmonary hypertension (PH). It allows for accurate estimates of pulmonary artery pressures, but with moderate precision, which explains why it is more appropriate for population studies than for definitive diagnosis of PH in individual patients. Moreover, echocardiography allows one to distinguish different patterns of right ventricular remodelling in various forms of PH and enables clinically satisfactory differentiation between pre- and post-capillary PH.This article will review the methods for evaluating PH by echocardiography, while also providing an insight into specific strengths and weaknesses.

Roles for the CX3CL1/CX3CR1 and CCL2/CCR2 Chemokine Systems in Hypoxic Pulmonary Hypertension.

Monocytes/macrophages are major effectors of lung inflammation associated with various forms of pulmonary hypertension (PH). Interactions between the CCL2/CCR2 and CX3CL1/CX3CR1 chemokine systems that guide phagocyte infiltration are incompletely understood. Our objective was to explore the individual and combined actions of CCL2/CCR2 and CX3CL1/CX3CR1 in hypoxia-induced PH in mice; particularly their roles in monocyte trafficking, macrophage polarization, and pulmonary vascular remodeling. The development of hypoxia-induced PH was associated with marked increases in lung levels of CX3CR1, CCR2, and their respective ligands, CX3CL1 and CCL2. Flow cytometry revealed that both inflammatory Ly6Chi and resident Ly6Clo monocyte subsets exhibited sustained increases in blood and a transient peak in lung tissue, and that lung perivascular and alveolar macrophage counts showed sustained elevations. CX3CR1-/- mice were protected against hypoxic PH compared with wild-type mice, whereas CCL2-/- mice and double CX3CR1-/-/CCL2-/- mice exhibited similar PH severity, as did wild-type mice. The protective effects of CX3CR1 deficiency occurred concomitantly with increases in lung monocyte and macrophage counts and with a change from M2 to M1 macrophage polarization that markedly diminished the ability of conditioned media to induce pulmonary artery smooth muscle cell (PA-SMC) proliferation, which was partly dependent on CX3CL1 secretion. Results in mice given the CX3CR1 inhibitor F1 were similar to those in CX3CR1-/- mice. In conclusion, CX3CR1 deficiency protects against hypoxia-induced PH by modulating monocyte recruitment, macrophage polarization, and PA-SMC cell proliferation. Targeting CX3CR1 may hold promise for treating PH.

Pulmonary hypertension and pregnancy outcomes: data from the Registry Of Pregnancy and Cardiac Disease (ROPAC) of the European Society of Cardiology.

To describe the outcomes of pregnancy in women with pulmonary hypertension. In 2007 the European Registry on Pregnancy and Heart Disease was initiated by the European Society of Cardiology. Consecutive patients with all forms of cardiovascular disease, presenting with pregnancy, were enrolled with the aim of investigating the pregnancy outcomes. This subgroup of the cohort included 151 women with pulmonary hypertension (PH) either diagnosed by right heart catheterization or diagnosed as possible PH by echocardiographic signs, with 26% having pulmonary arterial hypertension (PAH), in three subgroups: idiopathic (iPAH), associated with congenital heart disease (CHD-PAH), or associated with other disease (oPAH), and 74% having PH caused by left heart disease (LHD-PH, n = 112). Maternal mean age was 29.2 ± 5.6 years and 37% were nulliparous. Right ventricular systolic pressure was <50 mmHg in 59.6% of patients, 50-70 mmHg in 28.5% and >70 mmHg in 11.9%. In more than 75% of patients, the diagnosis of PH had been made before pregnancy. Maternal death up to 1 week after delivery occurred in five patients (3.3%), with another two out of 78 patients who presented for follow-up (2.6%), dying within 6 months after delivery. The highest mortality was found in iPAH (3/7, 43%). During pregnancy, heart failure occurred in 27%. Caesarean section was performed in 63.4% (23.9% as emergency). Therapeutic abortion was performed in 4.0%. Complications included miscarriage (5.6%), fetal mortality (2%), premature delivery (21.7%), low birth weight (19.0%), and neonatal mortality (0.7%). Mortality in this group of patients with various forms of PH was lower than previously reported as specialized care during pregnancy and delivery was available. However, maternal and fetal mortality remains prohibitively high in women with iPAH, although this conclusion is restricted by limited numbers. Early advice on contraception, pregnancy risk and fetal outcome remains paramount.

The causes, treatment, and outcome of pulmonary hypertension in Africa: Insights from the Pan African Pulmonary Hypertension Cohort (PAPUCO) Registry

BackgroundEpidemiology, aetiology, management and outcome data for various forms of pulmonary hypertension (PH) in Africa are scarce. MethodsA prospective, multinational cohort registry of 220 consecutive patients (97% of African descent) from 9 specialist centres in 4 African countries. The antecedents, characteristics and management of newly diagnosed PH plus 6-month survival were studied. ResultsThere were 209 adults (median age 48years [IQR 35, 64]) and 11 children (age range 1 to 17years). Most adults had advanced disease - 66% WHO Functional Class III-IV, median 6-minute walk test distance of 252m (IQR 120, 350) and median right ventricular systolic pressure 58mmHg (IQR 49, 74). Adults comprised 16% pulmonary arterial hypertension, 69% PH due to left heart disease, 11% PH due to lung disease and/or hypoxia, 2% chronic thromboembolic pulmonary hypertension, and 2% PH with unclear multifactorial mechanism. At 6-months, 21% of adults with follow-up data had died. On an adjusted basis (independent of sub-groups) mortality was associated with increasing functional impairment (p=0.021 overall - WHO Class IV versus I, OR 1.68 [95% CI 0.13, 4.36]) and presence of combined right atrial and ventricular hypertrophy (46% - OR 2.88, 95% CI 1.45, 5.72). Children commonly presented with dyspnoea, fatigue, cough, and palpitations with six and three children, respectively diagnosed with concurrent PH associated congenital heart disease and left heart disease. ConclusionsThese data provide new insights into PH from an African perspective, with clear opportunities to improve its prevention, treatment and outcomes. Trial RegistrationClinicalTrials.gov (NCT02265887).