Showing papers on "Pulmonary hypertension published in 2023"
TL;DR: Sotatercept as discussed by the authors is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension, which is a progressive disease involving proliferative remodeling of the pulmonary vessels.
Abstract: Pulmonary arterial hypertension is a progressive disease involving proliferative remodeling of the pulmonary vessels. Despite therapeutic advances, the disease-associated morbidity and mortality remain high. Sotatercept is a fusion protein that traps activins and growth differentiation factors involved in pulmonary arterial hypertension. We conducted a multicenter, double-blind, phase 3 trial in which adults with pulmonary arterial hypertension (World Health Organization [WHO] functional class II or III) who were receiving stable background therapy were randomly assigned in a 1:1 ratio to receive subcutaneous sotatercept (starting dose, 0.3 mg per kilogram of body weight; target dose, 0.7 mg per kilogram) or placebo every 3 weeks. The primary end point was the change from baseline at week 24 in the 6-minute walk distance. Nine secondary end points, tested hierarchically in the following order, were multicomponent improvement, change in pulmonary vascular resistance, change in N-terminal pro–B-type natriuretic peptide level, improvement in WHO functional class, time to death or clinical worsening, French risk score, and changes in the Pulmonary Arterial Hypertension–Symptoms and Impact (PAH-SYMPACT) Physical Impacts, Cardiopulmonary Symptoms, and Cognitive–Emotional Impacts domain scores; all were assessed at week 24 except time to death or clinical worsening, which was assessed when the last patient completed the week 24 visit. A total of 163 patients were assigned to receive sotatercept and 160 to receive placebo. The median change from baseline at week 24 in the 6-minute walk distance was 34.4 m (95% confidence interval [CI], 33.0 to 35.5) in the sotatercept group and 1.0 m (95% CI, −0.3 to 3.5) in the placebo group. The Hodges–Lehmann estimate of the difference between the sotatercept and placebo groups in the change from baseline at week 24 in the 6-minute walk distance was 40.8 m (95% CI, 27.5 to 54.1; P<0.001). The first eight secondary end points were significantly improved with sotatercept as compared with placebo, whereas the PAH-SYMPACT Cognitive–Emotional Impacts domain score was not. Adverse events that occurred more frequently with sotatercept than with placebo included epistaxis, dizziness, telangiectasia, increased hemoglobin levels, thrombocytopenia, and increased blood pressure. In patients with pulmonary arterial hypertension who were receiving stable background therapy, sotatercept resulted in a greater improvement in exercise capacity (as assessed by the 6-minute walk test) than placebo. (Funded by Acceleron Pharma, a subsidiary of MSD; STELLAR ClinicalTrials.gov number, NCT04576988.)
272 citations
TL;DR: The definition of pulmonary hypertension (PH) has changed recently based on contemporary outcome data and to focus on early disease detection as mentioned in this paper , which is important because delay to diagnosis of PH is common and linked to elevated morbidity and shortened lifespan.
Abstract: The definition of pulmonary hypertension (PH) has changed recently based, in part, on contemporary outcome data and to focus on early disease detection. Now, PH includes patients with mean pulmonary artery pressure >20 mm Hg measured by right heart catheterization. In contrast to the classical era, pulmonary vascular resistance >2.0 Wood units is also used for diagnosis and prognostication. These lowered thresholds aim to identify patients early in the disease course, which is important because delay to diagnosis of PH is common and linked to elevated morbidity and shortened lifespan. This clinical primer highlights key changes in diagnosis and approach to PH management, focusing on concepts that are likely to be encountered frequently in general practice. Specifically, this includes hemodynamic assessment of at-risk patients, pharmacotherapeutic management of pulmonary arterial hypertension, approach to PH in patients with heart failure with preserved ejection fraction, and newly established indications for early referral to PH centers to prompt comanagement of patients with pulmonary vascular disease experts.
69 citations
TL;DR: In this paper , the role of senescent cells in pulmonary hypertension was investigated in mice with pulmonary arterial hypertension and their role in proliferative disorders, including cancer, using luminescence imaging in p16-luciferase (p16LUC+) knock-in mice.
Abstract: Senescent cells (SCs) are involved in proliferative disorders, but their role in pulmonary hypertension remains undefined. We investigated SCs in patients with pulmonary arterial hypertension and the role of SCs in animal pulmonary hypertension models.We investigated senescence (p16, p21) and DNA damage (γ-H2AX, 53BP1) markers in patients with pulmonary arterial hypertension and murine models. We monitored p16 activation by luminescence imaging in p16-luciferase (p16LUC/+) knock-in mice. SC clearance was obtained by a suicide gene (p16 promoter-driven killer gene construct in p16-ATTAC mice), senolytic drugs (ABT263 and cell-permeable FOXO4-p53 interfering peptide [FOXO4-DRI]), and p16 inactivation in p16LUC/LUC mice. We investigated pulmonary hypertension in mice exposed to normoxia, chronic hypoxia, or hypoxia+Sugen, mice overexpressing the serotonin transporter (SM22-5-HTT+), and rats given monocrotaline.Patients with pulmonary arterial hypertension compared with controls exhibited high lung p16, p21, and γ-H2AX protein levels, with abundant vascular cells costained for p16, γ-H2AX, and 53BP1. Hypoxia increased thoracic bioluminescence in p16LUC/+ mice. In wild-type mice, hypoxia increased lung levels of senescence and DNA-damage markers, senescence-associated secretory phenotype components, and p16 staining of pulmonary endothelial cells (P-ECs, 30% of lung SCs in normoxia), and pulmonary artery smooth muscle cells. SC elimination by suicide gene or ABT263 increased the right ventricular systolic pressure and hypertrophy index, increased vessel remodeling (higher dividing proliferating cell nuclear antigen-stained vascular cell counts during both normoxia and hypoxia), and markedly decreased lung P-ECs. Pulmonary hemodynamic alterations and lung P-EC loss occurred in older p16LUC/LUC mice, wild-type mice exposed to Sugen or hypoxia+Sugen, and SM22-5-HTT+ mice given either ABT263 or FOXO4-DRI, compared with relevant controls. The severity of monocrotaline-induced pulmonary hypertension in rats was decreased slightly by ABT263 for 1 week but was aggravated at 3 weeks, with loss of P-ECs.Elimination of senescent P-ECs by senolytic interventions may worsen pulmonary hemodynamics. These results invite consideration of the potential impact on pulmonary vessels of strategies aimed at controlling cell senescence in various contexts.
60 citations
TL;DR: Pulmonary arterial hypertension is a progressive and often fatal cardiopulmonary condition characterised by increased pulmonary arterial pressure, structural changes in the pulmonary circulation, and the formation of vaso-occlusive lesions as discussed by the authors .
Abstract: Pulmonary hypertension is a progressive and often fatal cardiopulmonary condition characterised by increased pulmonary arterial pressure, structural changes in the pulmonary circulation, and the formation of vaso-occlusive lesions. These changes lead to increased right ventricular afterload, which often progresses to maladaptive right ventricular remodelling and eventually death. Pulmonary arterial hypertension represents one of the most severe and best studied types of pulmonary hypertension and is consistently targeted by drug treatments. The underlying molecular pathogenesis of pulmonary hypertension is a complex and multifactorial process, but can be characterised by several hallmarks: inflammation, impaired angiogenesis, metabolic alterations, genetic or epigenetic abnormalities, influence of sex and sex hormones, and abnormalities in the right ventricle. Current treatments for pulmonary arterial hypertension and some other types of pulmonary hypertension target pathways involved in the control of pulmonary vascular tone and proliferation; however, these treatments have limited efficacy on patient outcomes. This review describes key features of pulmonary hypertension, discusses current and emerging therapeutic interventions, and points to future directions for research and patient care. Because most progress in the specialty has been made in pulmonary arterial hypertension, this review focuses on this type of pulmonary hypertension. The review highlights key pathophysiological concepts and emerging therapeutic directions, targeting inflammation, cellular metabolism, genetics and epigenetics, sex hormone signalling, bone morphogenetic protein signalling, and inhibition of tyrosine kinase receptors.
51 citations
TL;DR: Pulmonary hypertension (PH) review summarizes recent advances in pathogenetic mechanisms, epidemiology, diagnosis, and treatment. It includes key basic, translational, and clinical reports, emphasizing findings that build on current state-of-the-art research.
Abstract: Major advances in pulmonary arterial hypertension, pulmonary hypertension (PH) associated with lung disease, and chronic thromboembolic PH cast new light on the pathogenetic mechanisms, epidemiology, diagnostic approach, and therapeutic armamentarium for pulmonary vascular disease. Here, we summarize key basic, translational, and clinical PH reports, emphasizing findings that build on current state-of-the-art research. This review includes cutting-edge progress in translational pulmonary vascular biology, with a guide to the diagnosis of patients in clinical practice, incorporating recent PH definition revisions that continue emphasis on early detection of disease. PH management is reviewed including an overview of the evolving considerations for the approach to treatment of PH in patients with cardiopulmonary comorbidities, as well as a discussion of the groundbreaking sotatercept data for the treatment of pulmonary arterial hypertension.
49 citations
TL;DR: In this article , the authors describe the various pulmonary hypertension groups and subgroups associated with congenital heart disease, elucidate medical and surgical management considerations, highlight disparities within this population, and identify gaps and future research needs of patients with pulmonary hypertension associated with Congenital Heart Disease.
Abstract: Patients with pulmonary hypertension associated with congenital heart disease make up an increasing proportion of the total pulmonary hypertension population who bring with them added complexity because of underlying anatomical and hemodynamic abnormalities. Currently, no consensus recommendations are available on how to best manage this group of patients for either the primary cardiologist or pulmonary hypertension subspecialist, including timing of referral. The purposes of this document are (1) to describe the various pulmonary hypertension groups and subgroups associated with congenital heart disease, (2) to describe imaging modalities used in patient evaluation, (3) to elucidate medical and surgical management considerations, (4) to highlight disparities within this population, and (5) to identify gaps and future research needs of patients with pulmonary hypertension associated with congenital heart disease.
46 citations
TL;DR: In this paper , the authors provide guidance on the evaluation and management of pulmonary hypertension in patients undergoing noncardiac surgery, and highlight the paucity of evidence to support perioperative pulmonary hypertension management and identifies areas of uncertainty and opportunities for future investigation.
Abstract: Pulmonary hypertension, defined as an elevation in blood pressure in the pulmonary arteries, is associated with an increased risk of death. The prevalence of pulmonary hypertension is increasing, with an aging population, a rising prevalence of heart and lung disease, and improved pulmonary hypertension survival with targeted therapies. Patients with pulmonary hypertension frequently require noncardiac surgery, although pulmonary hypertension is associated with excess perioperative morbidity and death. This scientific statement provides guidance on the evaluation and management of pulmonary hypertension in patients undergoing noncardiac surgery. We advocate for a multistep process focused on (1) classification of pulmonary hypertension group to define the underlying pathology; (2) preoperative risk assessment that will guide surgical decision-making; (3) pulmonary hypertension optimization before surgery to reduce perioperative risk; (4) intraoperative management of pulmonary hypertension to avoid right ventricular dysfunction and to maintain cardiac output; and (5) postoperative management of pulmonary hypertension to ensure recovery from surgery. Last, this scientific statement highlights the paucity of evidence to support perioperative pulmonary hypertension management and identifies areas of uncertainty and opportunities for future investigation.
43 citations
39 citations
TL;DR: A review of published mechanisms linking metabolic abnormalities with dysfunctional BMPR2 (bone morphogenetic protein receptor 2) signaling and their relevance to pulmonary arterial hypertension pathogenesis and the development of potential therapeutic strategies is presented in this paper .
Abstract: Pulmonary arterial hypertension forms the first and most severe of the 5 categories of pulmonary hypertension. Disease pathogenesis is driven by progressive remodeling of peripheral pulmonary arteries, caused by the excessive proliferation of vascular wall cells, including endothelial cells, smooth muscle cells and fibroblasts, and perivascular inflammation. Compelling evidence from animal models suggests endothelial cell dysfunction is a key initial trigger of pulmonary vascular remodeling, which is characterised by hyperproliferation and early apoptosis followed by enrichment of apoptosis-resistant populations. Dysfunctional pulmonary arterial endothelial cells lose their ability to produce vasodilatory mediators, together leading to augmented pulmonary arterial smooth muscle cell responses, increased pulmonary vascular pressures and right ventricular afterload, and progressive right ventricular hypertrophy and heart failure. It is recognized that a range of abnormal cellular molecular signatures underpin the pathophysiology of pulmonary arterial hypertension and are enhanced by loss-of-function mutations in the BMPR2 gene, the most common genetic cause of pulmonary arterial hypertension and associated with worse disease prognosis. Widespread metabolic abnormalities are observed in the heart, pulmonary vasculature, and systemic tissues, and may underpin heterogeneity in responsivity to treatment. Metabolic abnormalities include hyperglycolytic reprogramming, mitochondrial dysfunction, aberrant polyamine and sphingosine metabolism, reduced insulin sensitivity, and defective iron handling. This review critically discusses published mechanisms linking metabolic abnormalities with dysfunctional BMPR2 (bone morphogenetic protein receptor 2) signaling; hypothesized mechanistic links requiring further validation; and their relevance to pulmonary arterial hypertension pathogenesis and the development of potential therapeutic strategies.
36 citations
TL;DR: In this paper , the authors investigated the difference in long-term prognosis between atrial functional tricuspid regurgitation (AFTR) and VFTR, and found that patients with AFTR had significantly better survival as compared with patients with VfTR, independently of other clinical and echocardiographic characteristics.
Abstract: AIMS
Atrial functional tricuspid regurgitation (AFTR) has shown distinctive pathophysiological and anatomical differences compared with ventricular functional tricuspid regurgitation (VFTR) with potential implications for interventions. However, little is known about the difference in long-term prognosis between these two FTR-aetiologies, which was investigated in the current study.
METHODS AND RESULTS
Patients with severe FTR were divided into two aetiologies, based on echocardiography: AFTR and VFTR. VFTR was further subdivided into (i) left-sided cardiac disease; (ii) pulmonary hypertension; and (iii) right ventricular dysfunction. Long-term mortality rates were compared and independent associates of all-cause mortality were investigated.A total of 1037 patients with severe FTR were included, of which 129 patients (23%) were classified as AFTR and compared with 425 patients (78%) classified as VFTR and in sinus rhythm. Of the 425 VFTR patients, 340 patients (61%) had left-sided cardiac disease, 37 patients (7%) had pulmonary hypertension, and 48 patients (9%) had right ventricular dysfunction. Cumulative 10-year survival rates were significantly better for patients with AFTR (78%) compared with VFTR (46%, log-rank P < 0.001). On multivariable Cox regression analysis, VFTR as well as all VFTR subtypes were independently associated with worse overall survival compared with AFTR (HR: 2.292, P < 0.001 for VFTR).
CONCLUSION
Patients with AFTR had significantly better survival as compared with patients with VFTR, as well as all VFTR subtypes, independently of other clinical and echocardiographic characteristics.
35 citations
TL;DR: In this paper , single-cell RNA sequencing of tissue removed at the time of pulmonary endarterectomy surgery from five patients to identify the multiple cell types that constitute CTEPH thrombusy and to study their dysfunction.
Abstract: Rationale: Chronic thromboembolic pulmonary hypertension (CTEPH) is a sequela of acute pulmonary embolism (PE) in which the PE remodels into a chronic scar in the pulmonary arteries. This results in vascular obstruction, pulmonary microvasculopathy, and pulmonary hypertension. Objectives: Our current understanding of CTEPH pathobiology is primarily derived from cell-based studies limited by the use of specific cell markers or phenotypic modulation in cell culture. Therefore, our main objective was to identify the multiple cell types that constitute CTEPH thrombusy and to study their dysfunction. Methods: Here we used single-cell RNA sequencing of tissue removed at the time of pulmonary endarterectomy surgery from five patients to identify the multiple cell types. Using in vitro assays, we analyzed differences in phenotype between CTEPH thrombus and healthy pulmonary vascular cells. We studied potential therapeutic targets in cells isolated from CTEPH thrombus. Measurements and Main Results: Single-cell RNA sequencing identified multiple cell types, including macrophages, T cells, and smooth muscle cells (SMCs), that constitute CTEPH thrombus. Notably, multiple macrophage subclusters were identified but broadly split into two categories, with the larger group characterized by an upregulation of inflammatory signaling predicted to promote pulmonary vascular remodeling. CD4+ and CD8+ T cells were identified and likely contribute to chronic inflammation in CTEPH. SMCs were a heterogeneous population, with a cluster of myofibroblasts that express markers of fibrosis and are predicted to arise from other SMC clusters based on pseudotime analysis. Additionally, cultured endothelial, smooth muscle, and myofibroblast cells isolated from CTEPH fibrothrombotic material have distinct phenotypes from control cells with regard to angiogenic potential and rates of proliferation and apoptosis. Last, our analysis identified PAR1 (protease-activated receptor 1) as a potential therapeutic target that links thrombosis to chronic PE in CTEPH, with PAR1 inhibition decreasing SMC and myofibroblast proliferation and migration. Conclusions: These findings suggest a model for CTEPH similar to atherosclerosis, with chronic inflammation promoted by macrophages and T cells driving vascular remodeling through SMC modulation, and suggest new approaches for pharmacologically targeting this disease.
TL;DR: In this article , the authors evaluated the predictive power of a surrogate of right ventricle (RV) to pulmonary artery (PA) coupling obtained using RV volumes measured by three-dimensional echocardiography.
Abstract: Aims Echocardiographic surrogates of right ventricle (RV) to pulmonary artery (PA) coupling have been reported to be associated with outcomes in secondary tricuspid regurgitation (STR). However, pulmonary artery systolic pressure (PASP) is difficult to estimate using echocardiography in patients with severe STR. The aim of the present study was to evaluate the predictive power of a surrogate of RV/PA coupling obtained using RV volumes measured by three-dimensional echocardiography (3DE). Methods and results We included 180 patients (73±13 years, 61% women) with moderate or severe STR. At a median follow-up of 24 months (IQR: 2-48), 72 patients (40%) reached the composite endpoint of death from any cause and heart failure (HF) hospitalization. We computed RV-PA coupling as the ratio between RV forward stroke volume (SV) [i.e., RV stroke volume (SV) - regurgitant volume] and RV end-systolic volume (ESV). RV forward SV/ESV was significantly more related to the composite endpoint than RVEF (AUC 0.85[95%CI 0.78-0.93] vs. 0.73 [95%CI 0.64-0.83], respectively; p= 0.03). A value of 0.40 was found as the best correlated with outcome. At multivariate Cox-regression, RV forward SV/ESV, TAPSE/PASP, and RVFWLS/PASP were all independently associated with the occurrence of the composite endpoint when added to a group of parameters including STR severity (severe vs moderate), atrial fibrillation, pulmonary arterial hypertension, right atrial volume, RV end-diastolic volume, and RV free-wall longitudinal strain. RV forward SV/ESV<0.40 carried higher related risk than RVFWLS/PASP<-0.42 %/mmHg, and TAPSE/PASP<0.36 mm/mmHg (HR 3.36, CI 95% 1.49-7.56, P <0.01 vs HR 3.1, CI95% 1.26-7.84, P=0.01 and HR 2.69, CI9% 1.29-5.58, P=0.01, respectively). RV ejection fraction did not correlate independently with prognosis when added to the same group of variables. Conclusions RV forward SV/ESV is associated with the risk of death and HF hospitalization in patients with STR.
TL;DR: A review of the current evidence on the pathogenesis, recognized patterns, and useful diagnostic tools to detect pulmonary hypertension in interstitial lung disease (ILD) is presented in this article , where the authors propose a set of recommendations for future studies that might enable the recognition of new phenotypes.
Abstract: Abstract Pulmonary hypertension (PH) is a frequent complication of interstitial lung disease (ILD). Although PH has mostly been described in idiopathic pulmonary fibrosis, it can manifest in association with many other forms of ILD. Associated pathogenetic mechanisms are complex and incompletely understood but there is evidence of disruption of molecular and genetic pathways, with panvascular histopathologic changes, multiple pathophysiologic sequelae, and profound clinical ramifications. While there are some recognized clinical phenotypes such as combined pulmonary fibrosis and emphysema and some possible phenotypes such as connective tissue disease associated with ILD and PH, the identification of further phenotypes of PH in ILD has thus far proven elusive. This statement reviews the current evidence on the pathogenesis, recognized patterns, and useful diagnostic tools to detect phenotypes of PH in ILD. Distinct phenotypes warrant recognition if they are characterized through either a distinct presentation, clinical course, or treatment response. Furthermore, we propose a set of recommendations for future studies that might enable the recognition of new phenotypes.
TL;DR: In this article , the authors studied whether key members of the activin pathway could be used as biomarkers for pulmonary arterial hypertension (PAH) in patients with newly diagnosed idiopathic, heritable, or anorexigen-associated PAH.
Abstract: Activins are novel therapeutic targets in pulmonary arterial hypertension (PAH). We therefore studied whether key members of the activin pathway could be used as PAH biomarkers.Serum levels of activin A, activin B, α-subunit of inhibin A and B proteins, and the antagonists follistatin and follistatin-like 3 (FSTL3) were measured in controls and in patients with newly diagnosed idiopathic, heritable, or anorexigen-associated PAH (n=80) at baseline and 3 to 4 months after treatment initiation. The primary outcome was death or lung transplantation. Expression patterns of the inhibin subunits, follistatin, FSTL3, Bambi, Cripto, and the activin receptors type I (ALK), type II (ACTRII), and betaglycan were analyzed in PAH and control lung tissues.Death or lung transplantation occurred in 26 of 80 patients (32.5%) over a median follow-up of 69 (interquartile range, 50-81) months. Both baseline (hazard ratio, 1.001 [95% CI, 1.000-1.001]; P=0.037 and 1.263 [95% CI, 1.049-1.520]; P=0.014, respectively) and follow-up (hazard ratio, 1.003 [95% CI, 1.001-1.005]; P=0.001 and 1.365 [95% CI, 1.185-1.573]; P<0.001, respectively) serum levels of activin A and FSTL3 were associated with transplant-free survival in a model adjusted for age and sex. Thresholds determined by receiver operating characteristic analyses were 393 pg/mL for activin A and 16.6 ng/mL for FSTL3. When adjusted with New York Heart Association functional class, 6-minute walk distance, and N-terminal pro-B-type natriuretic peptide, the hazard ratios for transplant-free survival for baseline activin A <393 pg/mL and FSTL3 <16.6 ng/mL were, respectively, 0.14 (95% CI, 0.03-0.61; P=0.009) and 0.17 (95% CI, 0.06-0.45; P<0.001), and for follow-up measures, 0.23 (95% CI, 0.07-0.78; P=0.019) and 0.27 (95% CI, 0.09-0.78, P=0.015), respectively. Prognostic values of activin A and FSTL3 were confirmed in an independent external validation cohort. Histological analyses showed a nuclear accumulation of the phosphorylated form of Smad2/3, higher immunoreactivities for ACTRIIB, ALK2, ALK4, ALK5, ALK7, Cripto, and FSTL3 in vascular endothelial and smooth muscle layers, and lower immunostaining for inhibin-α and follistatin.These findings offer new insights into the activin signaling system in PAH and show that activin A and FSTL3 are prognostic biomarkers for PAH.
TL;DR: In this paper , the authors investigated prevalence and prognostic implications of elevated left ventricular filling pressures (LVFP) in chronic thromboembolic pulmonary hypertension (CTEPH), which is characterized by obstruction of major pulmonary arteries with organized thrombi.
TL;DR: Pulmonary vascular remodeling consists of the proliferation and phenotypic transformation of pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs), as well as complex interactions involving external layer pulmonary artery fibroblasts (PAFs) and extracellular matrix (ECM) as mentioned in this paper .
Abstract: Pulmonary vascular remodeling is the critical structural alteration and pathological feature in pulmonary hypertension (PH) and involves changes in the intima, media and adventitia. Pulmonary vascular remodeling consists of the proliferation and phenotypic transformation of pulmonary artery endothelial cells (PAECs) and pulmonary artery smooth muscle cells (PASMCs) of the middle membranous pulmonary artery, as well as complex interactions involving external layer pulmonary artery fibroblasts (PAFs) and extracellular matrix (ECM). Inflammatory mechanisms, apoptosis and other factors in the vascular wall are influenced by different mechanisms that likely act in concert to drive disease progression. This article reviews these pathological changes and highlights some pathogenetic mechanisms involved in the remodeling process.
TL;DR: The early diagnosis of chronic thromboembolic pulmonary hypertension (CTEPH) is a severe late complication of acute pulmonary embolism (PE), and the earlier CTEPH is diagnosed, the better the prognosis of patients, including survival and quality of life as mentioned in this paper .
Abstract: Chronic thromboembolic pulmonary hypertension (CTEPH) is a severe late complication of acute pulmonary embolism (PE) [1, 2]. The earlier CTEPH is diagnosed, the better the prognosis of CTEPH patients is, including survival and quality of life [2–4]. Footnotes This manuscript has recently been accepted for publication in the European Respiratory Journal . It is published here in its accepted form prior to copyediting and typesetting by our production team. After these production processes are complete and the authors have approved the resulting proofs, the article will move to the latest issue of the ERJ online. Please open or download the PDF to view this article. Conflict of Interest: All authors have nothing to disclose.
TL;DR: In this paper , treprostinil was associated with improved tricuspid annular plane systolic excursion Z-score and speckle tracking echocardiography (global longitudinal and free wall strain).
TL;DR: In this paper , the authors evaluated the predictive role of tricuspid annular plane systolic excursion/systolic pulmonary artery pressure (TAPSE/sPAP) ratio for pulmonary hypertension diagnosis and mortality in the European Scleroderma Trials and Research (EUSTAR) cohort.
TL;DR: A review of the role of genetics, dysregulation of growth factors, inflammatory pathways, mitochondrial dysfunction, DNA damage, sex hormones, neurohormonal pathways, and iron deficiency in the pathogenesis of pulmonary arterial hypertension can be found in this paper .
Abstract: Pulmonary arterial hypertension is a chronic, progressive disorder of the pulmonary vasculature with associated pulmonary and cardiac remodeling. PAH was a uniformly fatal disease until the late 1970s, but with the advent of targeted therapies, the life expectancy of patients with PAH has now considerably improved. Despite these advances, PAH inevitably remains a progressive disease with significant morbidity and mortality. Thus, there is still an unmet need for the development of new drugs and other interventional therapies for the treatment of PAH. One shortcoming of currently approved vasodilator therapies is that they do not target or reverse the underlying pathogenesis of the disease process itself. A large body of evidence has evolved in the past two decades clarifying the role of genetics, dysregulation of growth factors, inflammatory pathways, mitochondrial dysfunction, DNA damage, sex hormones, neurohormonal pathways, and iron deficiency in the pathogenesis of PAH. This review focuses on newer targets and drugs that modify these pathways as well as novel interventional therapies in PAH.
TL;DR: In this article , the authors highlight a key event in early stages of PAH progression, namely, the occurrence of pulmonary arterial smooth muscle cell (PASMC) phenotypic switching.
TL;DR: In this paper , the effect of pulmonary hypertension on right ventricular (RV) afterload is defined by elevation of pulmonary artery (PA) pressure or pulmonary vascular resistance (PVR), which expresses opposition of the PA to pulsatile blood flow.
Abstract: The effect of pulmonary hypertension (PH) on right ventricular (RV) afterload is commonly defined by elevation of pulmonary artery (PA) pressure or pulmonary vascular resistance (PVR). In humans however, one‐third to half of the hydraulic power in the PA is contained in pulsatile components of flow. Pulmonary impedance (Zc) expresses opposition of the PA to pulsatile blood flow. We evaluate pulmonary Zc relationships according to PH classification using a cardiac magnetic resonance (CMR)/right heart catheterization (RHC) method.
TL;DR: In this article , the authors investigated the association between Trusid Regurgitation (TR) and mortality and the interaction with pulmonary hypertension (PH) in patients admitted for acute chronic heart failure.
Abstract: Tricuspid regurgitation (TR) is common in chronic heart failure (HF) and is associated with negative prognosis. However, evidence on prognostic implications of TR in acute HF is lacking. We sought to investigate the association between TR and mortality and the interaction with pulmonary hypertension (PH) in patients admitted for acute HF.We enrolled 1176 consecutive patients with a primary diagnosis of acute HF and with available noninvasive estimation of TR and pulmonary arterial systolic pressure.Moderate-severe TR was present in 352 patients (29.9%) and was associated with older age and more comorbidities. The prevalence of PH (ie, pulmonary arterial systolic pressure >40 mm Hg), right ventricular dysfunction, and mitral regurgitation was higher in moderate-severe TR. At 1 year, 184 (15.6%) patients died. Moderate-severe TR was associated with higher 1-year mortality risk after adjustment for other echocardiographic parameters (pulmonary arterial systolic pressure, left ventricle ejection fraction, right ventricular dysfunction, mitral regurgitation, left and right atrial indexed volumes; hazard ratio, 1.718; P=0.009), and the association with outcome was maintained when clinical variables (eg, natriuretic peptides, serum creatinine and urea, systolic blood pressure, atrial fibrillation) were added to the multivariable model (hazard ratio, 1.761; P=0.024). The association between moderate-severe TR and outcome was consistent in patients with versus without PH, with versus without right ventricular dysfunction, and with versus without left ventricle ejection fraction <50%. Patients with coexistent moderate-severe TR and PH had 3-fold higher 1-year mortality risk compared with patients with no TR or PH (hazard ratio, 3.024; P<0.001).In patients hospitalized for acute HF, the severity of TR is associated with 1-year survival, regardless of the presence of PH. The coexistence of moderate-severe TR and estimated PH was associated with a further increase in mortality risk. Our data must be interpreted in the context of potential underestimation of pulmonary arterial systolic pressure in patients with severe TR.
TL;DR: In this paper , the role of ENO1-caused endothelial and mitochondrial dysfunctions in Group 3 pulmonary hypertension remain unexplored; however, the roles of the glycolytic protein and its role in the pathogenesis of pulmonary hypertension through acting smooth muscle cells are unexplored.
Abstract: It has been shown that glycolytic protein ENO1 (alpha-enolase) contributes to the pathogenesis of pulmonary hypertension through acting smooth muscle cells; however, the roles of ENO1-caused endothelial and mitochondrial dysfunctions in Group 3 pulmonary hypertension remain unexplored.PCR array and RNA sequencing were used to screen and decipher the differential gene expression by hypoxia-treated human pulmonary artery endothelial cells. Techniques of small-interfering RNA, specific inhibitor and plasmids carrying gene of ENO1, interventions with specific inhibitor and AAV-ENO1 delivery were employed to explore the role of ENO1 in hypoxic pulmonary hypertension in vitro and in vivo, respectively. Assays for cell proliferation, angiogenesis, and adhesion were employed to analyze cell behaviors, while seahorse analysis was used to measure mitochondrial function of human pulmonary artery endothelial cells.PCR array data showed that ENO1 expression increased in human pulmonary artery endothelial cells exposed to hypoxia, as well as in lung tissues from patients with chronic obstructive lung disease-associated pulmonary hypertension and murine model of hypoxic pulmonary hypertension. Inhibition of ENO1 restored the hypoxia-induced endothelial dysfunction, including excessive proliferation, angiogenesis, and adhesion, while overexpression of ENO1 promotes these disorders of human pulmonary artery endothelial cells. RNA-seq showed that ENO1 targets mitochondrion-related genes and PI3K-Akt signaling pathway, which were validated in vitro and in vivo. Mice treated with ENO1 inhibitor exhibited ameliorated pulmonary hypertension and improved right ventricular failure induced by hypoxia. A reversal effect was observed in mice exposed to hypoxia and inhaled adeno-associated virus overexpressing ENO1.These results indicate that hypoxic pulmonary hypertension is associated with an increased level of ENO1 and that targeting ENO1 might reduce experimental hypoxic pulmonary hypertension by improving endothelial and mitochondrial dysfunction via PI3K-Akt-mTOR signaling pathway.
TL;DR: In this article , the authors conducted a matched case-control study of extremely preterm infants from 22 weeks 0 days to 28 weeks 6 days born between 2018 and 2020 at the University of Alabama at Birmingham.
Abstract: Rationale: Bedside biomarkers that allow early identification of infants with bronchopulmonary dysplasia-associated pulmonary hypertension (BPD-PH) are critically important, given the higher risk of death in these infants. Objectives: We hypothesized that infants with BPD-PH have patterns of intermittent hypoxemia (IH) that differ from infants with BPD without PH. Methods: We conducted a matched case-control study of extremely preterm infants from 22 weeks 0 days to 28 weeks 6 days born between 2018 and 2020 at the University of Alabama at Birmingham. BPD-PH status was determined using echocardiographic data performed after postnatal Day 28. Physiologic data were compared between infants with BPD-PH (cases) and BPD alone (control subjects). Receiver operating characteristic (ROC) analysis estimated the predictive ability of cumulative hypoxemia, desaturation frequency, and duration of intermittent hypoxemic events in the week preceding echocardiography to discriminate between cases and control subjects. Measurements and Main Results: Forty infants with BPD-PH were compared with 40 infants with BPD alone. Infants with and without PH had a similar frequency of IH events, but infants with PH had more prolonged hypoxemic events for desaturations below 80% (7 s vs. 6 s; P = 0.03) and 70% (105 s vs. 58 s; P = 0.008). Among infants with BPD-PH, infants who died had longer hypoxemic events below 70% (145 s vs. 72 s; P = 0.01). Using the duration of hypoxemic events below 70%, the areas under the ROC curves for diagnosis of BPD-PH and death in BPD-PH infants were 0.71 and 0.77, respectively. Conclusions: Longer duration of intermittent hypoxemic events was associated both with a diagnosis of BPD-PH and with death among infants with BPD-PH.
TL;DR: In this paper , the authors characterize the pathophysiology of disproportionate exercise-induced pulmonary hypertension in relation to CO and its prognostic impact in patients with preserved ejection fraction (HFpEF).
Abstract: Pulmonary hypertension (PH) and pulmonary vascular remodelling are common in patients with heart failure with preserved ejection fraction (HFpEF). Many patients with HFpEF demonstrate an abnormal pulmonary haemodynamic response to exercise that is not identifiable at rest. This can be estimated non‐invasively by the mean pulmonary artery pressure–cardiac output relationship (mPAP/CO slope). We sought to characterize the pathophysiology of disproportionate exercise‐induced PH in relation to CO (DEi‐PH) and its prognostic impact in patients with HFpEF.
TL;DR: In this article , a risk score based on common echocardiographic parameters risk-stratify patients with pulmonary arterial hypertension (PAH) was derived using retrospective echology data from 2,400 adults with PAH enrolled in the REVEAL registry database.
TL;DR: In this paper , the authors proposed an early diagnosis of Systemic Lupus Erythematosus (SLE) related pulmonary hypertension and identification of the underlying pathogenetic mechanisms, in order to prevent irreversible pulmonary vascular damage.
Abstract: Pulmonary Hypertension (PH) is a common manifestation in patients with Systemic Lupus Erythematosus (SLE) and varies from asymptomatic to life-threatening disease. PH can result not only from immune system dysregulation, but also from various conditions, including cardiorespiratory disorders and thromboembolic diseases. Most commonly, SLE-related PH presents with non-specific symptoms, such as progressive dyspnea on exertion, generalized fatigue and weakness and eventually dyspnea at rest. Prompt diagnosis of SLE-related PH and early identification of the underlying pathogenetic mechanisms is demanded in order to introduce targeted therapy to prevent irreversible pulmonary vascular damage. In most cases the management of PH in SLE patients is similar to idiopathic pulmonary arterial hypertension (PAH). Furthermore, specific diagnostic tools like biomarkers or screening protocols, to establish early diagnosis seem to be not available yet. Although, the survival rates for patients with SLE-related PH vary between studies, it is evident that PH presence negatively affects the survival of SLE patients.
TL;DR: In this article , the authors developed a computer aided diagnosis, which based on single cycle with multiple features, for detecting pulmonary hypertension associated with congenital heart disease (CHD-PAH) is a serious heart disease and often associated with severe disability and death.
TL;DR: In this paper , the authors quantified the RV free wall myoarchitecture using generalized Q-space imaging and tractography analyses and developed a model to predict RV wall strains.
Abstract: Global indices of right ventricle (RV) function provide limited insights into mechanisms underlying RV remodeling in pulmonary hypertension (PH). While RV myocardial architectural remodeling has been observed in PH, its effect on RV adaptation is poorly understood.Hemodynamic assessments were performed in 2 rodent models of PH. RV free wall myoarchitecture was quantified using generalized Q-space imaging and tractography analyses. Computational models were developed to predict RV wall strains. Data from animal studies were analyzed to determine the correlations between hemodynamic measurements, RV strains, and structural measures.In contrast to the PH rats with severe RV maladaptation, PH rats with mild RV maladaptation showed a decrease in helical range of fiber orientation in the RV free wall (139º versus 97º; P=0.029), preserved global circumferential strain, and exhibited less reduction in right ventricular-pulmonary arterial coupling (0.029 versus 0.017 mm/mm Hg; P=0.037). Helical range correlated positively with coupling (P=0.036) and stroke volume index (P<0.01). Coupling correlated with global circumferential strain (P<0.01) and global radial strain (P<0.01) but not global longitudinal strain.Data analysis suggests that adaptive RV architectural remodeling could improve RV function in PH. Our findings suggest the need to assess RV architecture within routine screenings of PH patients to improve our understanding of its prognostic and therapeutic significance in PH.