Different Forms Of Pulmonary Hypertension Research Articles

A comprehensive map of proteoglycan expression and deposition in the pulmonary arterial wall in health and pulmonary hypertension.

Changes in the extracellular matrix of pulmonary arteries (PAs) are a key aspect of vascular remodelling in pulmonary hypertension (PH). Yet, our understanding of the alterations affecting the proteoglycan (PG) family remains limited. We sought to investigate the expression and spatial distribution of major vascular PGs in PAs from healthy individuals and various PH groups (chronic obstructive pulmonary disease: PH-COPD, pulmonary fibrosis: PH-PF, idiopathic: IPAH). PG regulation, deposition, and synthesis were notably heightened in IPAH, followed by PH-PF, with minor alterations in PH-COPD. Single-cell analysis unveiled cell-type and disease-specific PG regulation. Agrin expression, a basement membrane PG, was increased in IPAH, with PA endothelial cells (PAECs) identified as a major source. PA smooth muscle cells (PASMCs) mainly produced large-PGs, aggrecan and versican, and small-leucine-like proteoglycan (SLRP) biglycan, while the major PGs produced by adventitial fibroblasts were SLRP decorin and lumican. In IPAH and PF-PH, the neointima-forming PASMC population increased the expression of all investigated large-PGs and SLRPs, except fibroblast-predominant DCN. Expression of lumican, versican, and biglycan also positively correlated with collagen 1α1/1α2 expression in PASMCs of IPAH and PH-PF patients. We demonstrated that TGF-β regulates versican and biglycan expression, indicating their contribution to vessel fibrosis in IPAH and PF-PH. We furthermore show that certain circulating PG levels display a disease-dependent pattern, with increased decorin and lumican across all patient groups, while versican was elevated in PH-COPD and IPAH and biglycan reduced in IPAH. These findings suggest unique compartment-specific PG regulation in different forms of PH, indicating distinct pathological processes.

Nailfold capillaroscopy and candidate-biomarker levels in systemic sclerosis-associated pulmonary hypertension: A cross-sectional study.

Pulmonary hypertension is one of the leading causes of death in systemic sclerosis. Early detection and treatment of pulmonary hypertension in systemic sclerosis is crucial. Nailfold capillaroscopy microscopy, vascular autoantibodies AT1R and ETAR, and several candidate-biomarkers have the potential to serve as noninvasive tools to identify systemic sclerosis patients at risk for developing pulmonary hypertension. Here, we explore the classifying potential of nailfold capillaroscopy microscopy characteristics and serum levels of selected candidate-biomarkers in a sample of systemic sclerosis patients with and without different forms of pulmonary hypertension. A total of 81 consecutive systemic sclerosis patients were included, 40 with systemic sclerosis pulmonary hypertension and 41 with no pulmonary hypertension. In each group, quantitative and qualitative nailfold capillaroscopy microscopy characteristics, vascular autoantibodies AT1R and ETAR, and serum levels of 24 soluble serum factors were determined. For evaluation of the nailfold capillaroscopy microscopy characteristics, linear regression analysis accounting for age, sex, and diffusing capacity of the lungs for carbon monoxide percentage predicted was used. Autoantibodies and soluble serum factor levels were compared using two-sample t test with equal variances. No statistically significant differences were observed in quantitative or qualitative nailfold capillaroscopy microscopy characteristics, or vascular autoantibody ETAR and AT1R titer between systemic sclerosis-pulmonary hypertension and systemic sclerosis-no pulmonary hypertension. In contrast, several serum levels of soluble factors differed between groups: Endostatin, sVCAM, and VEGFD were increased, and CXCL4, sVEGFR2, and PDGF-AB/BB were decreased in systemic sclerosis-pulmonary hypertension. Random forest classification identified Endostatin and CXCL4 as the most predictive classifiers to distinguish systemic sclerosispulmonary hypertension from systemic sclerosis-no pulmonary hypertension. This study shows the potential for several soluble serum factors to distinguish systemic sclerosis-pulmonary hypertension from systemic sclerosis-no pulmonary hypertension. We found no classifying potential for qualitative or quantitative nailfold capillaroscopy microscopy characteristics, or vascular autoantibodies.

Pulmonary artery compliance in different forms of pulmonary hypertension

ObjectivePulmonary artery compliance (PAC), estimated as stroke volume (SV) divided by pulmonary artery pulse pressure (PP), may be a predictor of survival in pulmonary arterial hypertension (PAH). Resistance–compliance (RC) time,...

Clinical phenotyping of plasma thrombospondin-2 reveals relationship to right ventricular structure and function in pulmonary hypertension.

Converging evidence from proteogenomic analyses prioritises thrombospondin-2 (TSP2) as a potential biomarker for idiopathic or heritable pulmonary arterial hypertension (PAH). We aimed to assess TSP2 levels in different forms of pulmonary hypertension (PH) and to define its clinical phenotype. Absolute concentrations of TSP2 were quantified in plasma samples from a prospective single-centre cohort study including 196 patients with different forms of PH and 16 disease controls (suspected PH, but normal resting pulmonary haemodynamics). In an unbiased approach, TSP2 levels were related to 152 clinical variables. Concentrations of TSP2 were increased in patients with PH versus disease controls (p<0.001 for group comparison). The discriminatory ability of TSP2 levels to distinguish between patients and controls was superior to that of N-terminal pro-brain natriuretic peptide (p=0.0023 for comparison of areas under the curve). Elevation of TSP2 levels was consistently found in subcategories of PAH, in PH due to lung disease and due to left heart disease. Phenotypically, TSP2 levels were robustly related to echocardiographic markers that indicate the right ventricular (RV) response to chronically increased afterload with increased levels in patients with impaired systolic function and ventriculoarterial uncoupling. Focusing on PAH, increased TSP2 levels were able to distinguish between adaptive and maladaptive RV phenotypes (area under the curve 0.87, 95% CI 0.76-0.98). The study indicates that plasma TSP2 levels inform on the presence of PH and associate with clinically relevant RV phenotypes in the setting of increased afterload, which may provide insight into processes of RV adaptability.

Evaluation of heart rate variability in patients with different forms of pulmonary hypertension

Pulmonary hypertension (PH) is a severe pathology of the cardiovascular system with extremely poor prognosis, if unreated. Early diagnosis of PH is difficult, due to the absence pathognomonic symptoms, and at the initial stage the disease may be asymptomatic. An increase in pulmonary vascular resistance and pressure in the pulmonary artery cause severe dysfunction of the right ventricle, which affects the functional status of patients. The assessment of heart rate variability (HRV) parameters is used to predict the increased risk of sudden death in various diseases of the cardiovascular system and the functional status of the body. HRV is mainly regulated by the sympathetic and parasympathetic divisions of the autonomic nervous system. It is noted that pulmonary arterial hypertension is associated with increasing of sympathetic activity. The review, based on the analysis of the pathophysiological mechanisms of pulmonary arterial hypertension and chronic thromboembolic PH, presents the results of studies assessing the time and spectral parameters of HRV in patients with PH of various etiologies.

An expert opinion of the Polish Cardiac Society Working Group on Pulmonary Circulation and the Polish Society for Rheumatology on the diagnosis and treatment of pulmonary hypertension in patients with connective tissue disease.

Systemic connective tissue diseases (CTDs) comprise a large group of diseases that are auto-immune in nature and characterized by the involvement of multiple systems and organs. Pul-monary hypertension (PH) of various etiologies may develop in the course of CTD, including pulmonary arterial hypertension (PAH), PH secondary to the lung disease, postcapillary PH in the course of left heart disease, and chronic thromboembolic pulmonary hypertension (CTEPH). In addition, the different forms of PH may coexist with each other. Among patients with CTD, PAH occurs most commonly in those with systemic sclerosis, where it affects ap-proximately 8%-12% of patients. The prognosis in patients with untreated PAH is very poor. It is particularly important to identify the high-risk CTD-PAH population and to perform effi-cient and accurate diagnostics so that targeted therapy of the pulmonary arteries can be intro-duced. Echocardiography is used to screen for PH, but clinical and echocardiographic suspicion of PH always requires confirmation by right heart catheterization. Confirmation of PAH ena-bles the initiation of life-prolonging pharmacological treatment in this group of patients, which should be administered in referral centers. Drugs available for pharmacological management include endothelin receptor antagonists, phosphodiesterase-5 inhibitors, and prostacyclins.

Beyond Thrombosis: the Role of Platelets in Pulmonary Hypertension

Pulmonary Hypertension (PH) is a multifactorial and lethal disease, characterised by elevated pulmonary arterial pressure and progressive right heart failure. PH pathobiology rests on four pillars: vascular remodelling, vasoconstriction, inflammation and thrombosis. While vascular and inflammatory cells have been the focus of PH research over the past decades, platelets have received relatively less attention, despite their associations with key pathophysiological processes of the disease. Platelets contain a wide range of vasoactive, inflammatory and pro-thrombotic mediators, likely to promote PH development and progression. There is currently no cure for PH, and platelet-associated pathways may help identify new therapeutic strategies. This review summarises available evidence on the role of platelets in different forms of PH, and comments on the current state of platelet-targeting therapies. It also describes the latest advances in the in vitro technologies that enable exploration of platelet function under dynamic and physiologically relevant conditions. Doi: 10.28991/SciMedJ-2020-0204-7 Full Text: PDF

Use of Anticoagulants in Patients with Pulmonary Hypertension.

Since the earliest works on the understanding of different forms of pulmonary hypertension, thrombosis has been involved in the pathophysiology of the disease, both in pulmonary arterial hypertension (PAH) and in chronic thromboembolic pulmonary hypertension (CTEPH). Autopsy and then pathophysiological data paved the way for the use of anticoagulants as a treatment for PAH and CTEPH. In PAH their role has diminished with the advent of specific targeted therapies, but they are still prescribed in more than half of PAH patients, because of concomitant venous thromboembolism or atrial fibrillation. In CTEPH long-term anticoagulant therapy is the cornerstone of the management. The recent development of direct oral anticoagulants (DOACs) raises the question of the best anticoagulation strategy, both in patients with PAH and in patients with CTEPH. In this review, we present an overview of the history of anticoagulants in the management of patients suffering from PAH or CTEPH, an update of the available data on the underlying rationale of their use in these subjects, an alert on the potential risks of using DOACs in these poorly explored situations, and the setting up of dedicated trials to evaluate the best anticoagulant treatment strategies in patients suffering from PAH or CTEPH.

MANAGEMENT OF PATIENTS WITH PULMONARY ARTERIAL HYPERTENSION IN THE PANDEMIC OF A NEW CORONAVIRUS INFECTION

The pandemic of a new coronavirus infection – COVID-19 («Coronavirus disease 2019») has changed the routine management of patients with pulmonary arterial hypertension (PAH). Like patients with other chronic cardiovascular diseases, PAH patients are not at higher risk of a new coronavirus infection. However, in the current epidemiological situation, the problems of managing high-risk groups are sharply indicated, in which the severe course of COVID-19 with a higher lethality is more often noted. Undoubtedly, рatients with different forms of pulmonary hypertension belong to the high-risk group, considering both the presence of severe lifethreatening cardiovascular pathology and background pathology in cases of the associated forms of the disease.At the same time, the first foreign experience indicates a rather low incidence and relatively favorable course of COVID-19 in PAH, which allows to formulate a number of hypotheses that will be confirmed or rejected in the near future. The unique problems of managing patients with PAH are those associated with changes in generally accepted standards of medical care and patient routing, which is especially important for patients receiving PAH-specific drugs. The problems of a complex assessment of the risk of possible infection in the event of hospitalization or an outpatient visit of patients on the one hand, and on the other, the risk of PAH progression with a delay in starting treatment, are a dilemma that requires an individual solution. Based on an analysis of current data, this review summarizes the main approaches to managing patients with PAH in the current epidemiological situation.

The global view.

To understand the global distribution of different forms of pulmonary hypertension. Different registries have explored the epidemiological characteristics of pulmonary hypertension. Interestingly, there is a clear difference in the prevalence of different forms of pulmonary hypertension in developed regions in comparison with less developed countries. This finding suggests not only that extrapolation of data should be avoided but also that the known prevalence of pulmonary hypertension might be underestimated. Pulmonary hypertension might be more prevalent than what is currently believed. Specific forms of pulmonary hypertension distributed worldwide might characterize an unrecognized burden that still have to be properly approached. This highlights the heterogeneity of pulmonary hypertension around the world. It is clear that more epidemiological data are still needed as well as studies addressing management alternatives in these specific regions.

Enhanced circulating levels of CD3 cells-derived extracellular vesicles in different forms of pulmonary hypertension.

It has been shown previously that increased circulating endothelial cells-derived extracellular vesicles represent an important pathological attribute of pulmonary hypertension. Although it is a well-known fact that inflammatory cells may also release extracellular vesicles, and pulmonary hypertension is a disease associated with abnormal inflammation, there is no profound knowledge with regard to the role of inflammatory cells-derived extracellular vesicles. Therefore, our study demonstrated that circulating levels of extracellular vesicles derived from T-cells are enhanced in various pulmonary hypertension forms and that endothelial cells-derived extracellular vesicles may have distinctive profiles in different clinical subgroups of pulmonary hypertension, which still remains as a poorly treatable and life-threatening disorder.

Pulmonary arterial hypertension in systemic sclerosis: Diagnosis and treatment according to the European Society of Cardiology and European Respiratory Society 2015 guidelines.

Scleroderma (systemic sclerosis) is an autoimmune connective tissue disease which presents endothelial dysfunction and fibroblast dysregulation, resulting in vascular and fibrotic disorders. Pulmonary hypertension is frequent in patients with systemic sclerosis: the natural evolution of the disease can induce the development of different forms of pulmonary hypertension, representing one of the main causes of death. Among the different forms of pulmonary hypertension in systemic sclerosis, pulmonary arterial hypertension is the most frequent one (rate of occurrence is estimated between 7% and 12%). This pulmonary vascular complication should be treated with a combination of drugs that is able to counteract endothelial dysfunction, antagonizing the endothelin-1 system and replacing prostaglandin I2 and nitric oxide activity. A correct diagnosis is mandatory, because it is possible only for pulmonary arterial hypertension to use specific drugs that are able to control the symptomatic condition and the evolution of the disease. According to the most recent guidelines, for the patients with systemic sclerosis, also without pulmonary hypertension symptoms, echocardiography screening for the detection of pulmonary hypertension is recommended. Pulmonary arterial hypertension screening programs in systemic sclerosis patients is able to identify milder forms of the disease, allowing earlier management and better long-term outcome.

Arrhythmias in Patients With Pulmonary Hypertension; A Narrative Review of the Current Literature

Incidence and prognostic relevance of supraventricular arrhythmias were evaluated in nine studies. These studies investigated patients with different forms of pulmonary hypertension. Supraventricular arrhythmias were more often found in patients with group two pulmonary hypertension. Common findings in these patients were elevated right atrial pressure and diameters and reduced tricuspid annular plane systolic excursion (TAPSE). Elevations in other parameters like systolic pulmonary arterial pressure, mean pulmonary arterial pressure, and pulmonary vascular resistance (PVR) were inconsistent. Most of the patients with arrhythmias suffered symptoms and improved after sinus rhythm (SR) was restored. The prognostic relevance of non-sustained ventricular tachycardia was evaluated in only one study. Non-sustained ventricular tachycardia does not seem to be prognostically relevant. Extending Holter electrocardiogram (ECG) monitoring over 24 hours up to 72 hours raises the detection rate of arrhythmias. Ablation of arrhythmias, especially atrial flutter and atrioventricular node reentry tachycardia, is feasible and safe in these patients.

From molecules to patients: exploring the therapeutic role of soluble guanylate cyclase stimulators.

Nitric oxide (NO) signaling represents one of the major regulatory pathways for cardiovascular function. After the discovery of NO, awarded with the Nobel Prize in 1998, this signaling cascade was stepwise clarified. We now have a good understanding of NO production and NO downstream targets such as the soluble guanylyl cyclases (sGCs) which catalyze cGMP production. Based on the important role of NO-signaling in the cardiovascular system, intense research and development efforts are currently ongoing to fully exploit the therapeutic potential of cGMP increase. Recently, NO-independent stimulators of sGC (sGC stimulators) were discovered and characterized. This new compound class has a unique mode of action, directly binding to sGC and triggering cGMP production. The first sGC stimulator made available to patients is riociguat, which was approved in 2013 for the treatment of different forms of pulmonary hypertension (PH). Besides riociguat, other sGC stimulators are in clinical development, with vericiguat in phase 3 clinical development for the treatment of chronic heart failure (HF). Based on the broad impact of NO/cGMP signaling, sGC stimulators could have an even broader therapeutic potential beyond PH and HF. Within this review, the NO/sGC/cGMP/PKG/PDE-signaling cascade and the major pharmacological intervention sites are described. In addition, the discovery and mode of action of sGC stimulators and the clinical development in PH and HF is covered. Finally, the preclinical and clinical evidence and treatment approaches for sGC stimulators beyond these indications and the cardiovascular disease space, like in fibrotic diseases as in systemic sclerosis (SSc), are reviewed.

Alpha-2-Antiplasmin : A Fibrinolytic Peptide, could be a Potential Biomarker for Diagnosis of High Altitude Induced Pulmonary Hypertension

&lt;p class="p1"&gt;Prolonged exposure to high altitude is known to cause pulmonary vascular remodeling and pulmonary hypertension. Despite the advancements in diagnostics of pulmonary hypertension (PH), a potential biomarker for early diagnosis of PH progression is still lacking. High altitude induced pulmonary hypertension (HAPH) is great concern in mountain regions across the world. Early diagnosis and monitoring the disease progression are critical for therapeutic decisions. A fibrinolytic peptide, alpha-2-antiplasmin (α2AP) is known to cause tissue and vascular remodeling. Recently, elevated levels of α2AP were reported in different forms of PH; however its role in high altitude induced pulmonary hypertension is not yet known. To assess whether α-2AP can be used as diagnostic marker for HAPH, a cross sectional study was carried out on 100 healthy male Indian army soldiers who were posted to high altitude (14,800 ft to 18,700 ft) for a prolonged period of 6 to 8 months. We used 2D Echocardiography to screen the pulmonary arterial systolic pressure (PASP) and semi-quantitatively ELISA method for estimation of α-2AP in plasma. We found 34 out of 100 subjects have elevated PASP upon immediate screening after de-induction to moderate altitude of 10,000 ft. Age matched 17 subjects with elevated PASP were assessed for plasma levels of α-2AP in comparison to subjects with normal PASP, but posted to same altitude for same duration of time. Here for the first time we demonstrated an increase in plasma level of α-2AP was positively correlated with hypoxia induced elevated pulmonary arterial pressure. However, additional comprehensive investigations are warranted with large sample size to confirm our findings and explore the use of α2AP as potential diagnostic marker for monitoring progression of HAPH.&lt;span class="Apple-converted-space"&gt; &lt;/span&gt;&lt;/p&gt;

Pathology and Pathobiology of Pulmonary Hypertension.

Pulmonary hypertension (PH) is a hemodynamic state defined by a mean pulmonary artery pressure ≥ 25 mm Hg during resting right heart catheterization. PH can result from precapillary (arterial) or postcapillary (venous) pathophysiological mechanisms. Interestingly, recent PH pathology has shown that pulmonary arterial or pulmonary venous remodelling are rarely independent phenomena, but frequently occur in combined fashion in lungs from patients suffering from different forms of PH, including pulmonary arterial hypertension (PAH). In PAH, it is now becoming clear that aberrant signals present in vessel wall microenvironment, which is largely orchestrated by dysfunctional pulmonary endothelial cells, are key contributors of the pulmonary vascular remodeling process, fostering proliferation, and survival and migration of resident pulmonary vascular cells such as smooth muscle cells, myofibroblasts, and pericytes. In addition, both genetic and environmental factors are also critical in the development of pulmonary vascular inflammation and chronic impairment of the pulmonary endothelium. This article outlines the current understanding of this disease from the point of view of pathology and pathobiology.

Clinical and prognostic value of endothelin-1 and big endothelin-1 expression in children with pulmonary hypertension

ObjectivePulmonary arterial hypertension is known to be associated with increased expression of endothelin (ET)-1 and its precursor big ET-1. Therefore, we hypothesised that in children with pulmonary hypertension (PH) altered...

The clinical development of sGC modulators, riociguat and vericiguat

Clinical background The NO – sGC – cyclic GMP pathway is a key pathway to regulate vascular tone. Its stimulation leads to vasodilatation; NO deficiency leads to vasoconstriction, inflammation and fibrotic remodelling. Riociguat and vericiguat are two representatives of modulators of the soluble guanylate cyclase and are able to increase cyclic GMP even in conditions of NO deficiency. Riociguat, a first lead sGC stimulator, was developed in two different forms of pulmonary hypertension (PH). PH is a rare, severe disease which untreated has a high morbidity and mortality. It is characterized by endothelial dysfunction, NO deficiency, vascular remodelling and results and devastating increases of the mean pulmonary artery pressure above 25 mm Hg. This condition leads to right heart failure, is associated with impaired exercise capacity and death. Riociguat has been successfully developed in two different forms of PH, pulmonary arterial hypertension (PAH, WHO group 1), and chronic thromboembolic pulmonary hypertension (CTEPH, WHO group 4). It was shown to significantly improve exercise capacity, time to clinical worsening, and also led to meaningful hemodynamic improvements. Riociguat (Trade name: Adempas) is now the first approved medical treatment for patients with CTEPH who are not eligible to undergo surgery, or who have residual disease after pulmonary endarterectomy. Riociguat's ongoing clinical development program includes PH-IIP and diffuse cutaneous sclerodermia, as well as an exploratory study in cystic fibrosis. Vericiguat is currently in late stage clinical development for the treatment of heart failure with reduced and also with preserved ejection fraction (HFrEF and HFpEF). Data from the LEPHT trial with riociguat in patients with PH due to left heart disease hint to the usefulness of sGC modulation in patients with heart failure. The SOCRATRES program studies the efficacy and safety of vericiguat in patients with HFrEF and HFpEF and assesses its effect on ventricular decongestion, as measured by the biomarker NT-pro BNP, and left atrial size. Results of that program will be reported later this year.

Distinct Forms of Pulmonary Hypertension Complicate Hereditary Hemorrhagic Telangiectasia

Pulmonary hypertension (PH) associated with hereditary hemorrhagic telangiectasia (HHT) occurs most commonly as a consequence of high-output heart failure related to excessive shunting through visceral vascular malformations. A smaller number of HHT patients develop a form of heritable pulmonary arterial hypertension, characterized by an elevated pulmonary vascular resistance with normal left heart filling pressures. In this review, we will discuss the clinical manifestations of HHT in general, the pathophysiology behind the different forms of PH associated with HHT, and the clinical care of the HHT patient with PH.

New Thematic Series

HomeCirculationVol. 130, No. 20New Thematic Series Free AccessResearch ArticlePDF/EPUBAboutView PDFView EPUBSections ToolsAdd to favoritesDownload citationsTrack citationsPermissions ShareShare onFacebookTwitterLinked InMendeleyReddit Jump toFree AccessResearch ArticlePDF/EPUBNew Thematic SeriesRecent Advances in Pulmonary Hypertension Jane A. Leopold, MD and Bradley A. Maron, MD Jane A. LeopoldJane A. Leopold Co-Series Editors Search for more papers by this author and Bradley A. MaronBradley A. Maron Co-Series Editors Search for more papers by this author Originally published11 Nov 2014https://doi.org/10.1161/CIRCULATIONAHA.114.013548Circulation. 2014;130:1771Pulmonary hypertension is associated with a high degree of morbidity and mortality in patients with World Health Organization Group 1 pulmonary hypertension (pulmonary artery hypertension) as well as Groups 2 to 5 pulmonary hypertension (pulmonary hypertension attributable to left heart disease, lung disease, thromboembolic disease, and miscellaneous causes, respectively). Historically, the underlying cause of pulmonary hypertension coupled with a defining hemodynamic profile has been used for the clinical classification of patients into different groups, in part, to facilitate management. Over the past several years, advances in the field have increased our understanding of the pathobiology, clinical course, and treatment outcomes for patients with pulmonary hypertension. Along these lines, recent findings from randomized, clinical trials have demonstrated efficacy of novel therapeutics and expanded treatment options for this important cardiopulmonary disease.In this thematic series in Circulation on Recent Advances in Pulmonary Hypertension, a group of experts will discuss progress in the field and remaining controversies that are likely to have broad applicability to patients with different forms of pulmonary hypertension. The topics reviewed will cover practical considerations in the care of patients with pulmonary hypertension, such as clinical diagnosis, therapeutic interventions, use of noninvasive imaging to evaluate pulmonary vascular-right ventricular function, and the role of mechanical support for the failing right ventricle. Next, select populations of patients with pulmonary hypertension who clinicians may encounter in practice will be discussed, including patients with congenital heart disease, human immunodeficiency virus, or those who develop pulmonary hypertension as a consequence of exposure to high altitude. The series will also provide a focused review of current end points used in clinical trials and their attendant limitations as a consideration for how to interpret findings from previous studies as well as design future trials in this field. Finally, recent translational advances with clinical implications for patients with pulmonary hypertension in the areas of cellular metabolism, neurohumoral signaling, and sex hormones will be reviewed. Together, the reviews in this series aim to provide the reader with a state-of-the art view of diagnostic modalities and therapeutic interventions as well as an introduction to new frontiers in the care of patients afflicted with this heterogeneous and complex disease. Previous Back to top Next FiguresReferencesRelatedDetails November 11, 2014Vol 130, Issue 20 Advertisement Article InformationMetrics © 2014 American Heart Association, Inc.https://doi.org/10.1161/CIRCULATIONAHA.114.013548 Originally publishedNovember 11, 2014 PDF download Advertisement SubjectsHeart Failure