scholarly journals Smouldering fire or conflagration? An illustrated update on the concept of inflammation in pulmonary arterial hypertension

2021 ◽  
Vol 30 (162) ◽  
pp. 210161
Author(s):  
Frédéric Perros ◽  
Marc Humbert ◽  
Peter Dorfmüller
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Rare Condition ◽  
Progressive Increase ◽  
Pulmonary Vasculature ◽  
Ventricular Failure ◽  
Myocardial Remodelling ◽  
Pulmonary Arterial ◽  
The Right

Pulmonary arterial hypertension (PAH) is a rare condition that is characterised by a progressive increase of pulmonary vascular resistances that leads to right ventricular failure and death, if untreated. The underlying narrowing of the pulmonary vasculature relies on several independent and interdependent biological pathways, such as genetic predisposition and epigenetic changes, imbalance of vasodilating and vasoconstrictive mediators, as well as dysimmunity and inflammation that will trigger endothelial dysfunction, smooth muscle cell proliferation, fibroblast activation and collagen deposition. Progressive constriction of the pulmonary vasculature, in turn, initiates and sustains hypertrophic and maladaptive myocardial remodelling of the right ventricle. In this review, we focus on the role of inflammation and dysimmunity in PAH which is generally accepted today, although existing PAH-specific medical therapies still lack targeted immune-modulating approaches.

scholarly journals Echocardiography in Pulmonary Arterial Hypertension: Is It Time to Reconsider Its Prognostic Utility?

2021 ◽  
Vol 10 (13) ◽  
pp. 2826
Author(s):  
Ioannis T. Farmakis ◽  
Eftychia Demerouti ◽  
Panagiotis Karyofyllis ◽  
George Karatasakis ◽  
Maria Stratinaki ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Heart Failure ◽  
Pulmonary Vasculature ◽  
Right Heart ◽  
Prognostic Utility ◽  
Pulmonary Arterial ◽  
Prognostic Implications ◽  
The Right

Pulmonary arterial hypertension (PAH) is characterized by an insult in the pulmonary vasculature, with subsequent right ventricular (RV) adaptation to the increased afterload that ultimately leads to RV failure. The awareness of the importance of RV function in PAH has increased considerably because right heart failure is the predominant cause of death in PAH patients. Given its wide availability and reduced cost, echocardiography is of paramount importance in the evaluation of the right heart in PAH. Several echocardiographic parameters have been shown to have prognostic implications in PAH; however, the role of echocardiography in the risk assessment of the PAH patient is limited under the current guidelines. This review discusses the echocardiographic evaluation of the RV in PAH and during therapy, and its prognostic implications, as well as the potential significant role of repeated echocardiographic assessment in the follow-up of patients with PAH.

scholarly journals The pathophysiological role of novel pulmonary arterial hypertension gene SOX17

2021 ◽  
pp. 2004172
Author(s):  
Yukyee Wu ◽  
John Wharton ◽  
Rachel Walters ◽  
Eleni Vasilaki ◽  
Jurjan Aman ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Dominant Mode ◽  
Pulmonary Vasculature ◽  
Incomplete Penetrance ◽  
Pathophysiological Role ◽  
Sequencing Studies ◽  
Pulmonary Arterial ◽  
The Right

Pulmonary arterial hypertension (PAH) is a progressive disease predominantly targeting pre-capillary blood vessels. Adverse structural re-modelling and increased pulmonary vascular resistance result in cardiac hypertrophy and ultimately failure of the right ventricle. Recent whole genome and exome sequencing studies have identified SOX17 as a novel risk gene in PAH, with a dominant mode of inheritance and incomplete penetrance. Rare deleterious variants in the gene and more common variants in upstream enhancer sites have both been associated with the disease and a deficiency of SOX17 expression may predispose to PAH. This review aims to consolidate the evidence linking genetic variants in SOX17 to PAH and explores the numerous targets and effects of the transcription factor, focussing on the pulmonary vasculature and the pathobiology of PAH.

scholarly journals Targeting HIF2α-ARNT hetero-dimerisation as a novel therapeutic strategy for Pulmonary Arterial Hypertension

2020 ◽  
pp. 1902061
Author(s):  
David Macias ◽  
Stephen Moore ◽  
Alexi Crosby ◽  
Mark Southwood ◽  
Xinlin Du ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Target Genes ◽  
Right Heart Failure ◽  
Pulmonary Vasculature ◽  
Pulmonary Arterial ◽  
The Impact

Pulmonary Arterial Hypertension (PAH) is a destructive disease of the pulmonary vasculature often leading to right heart failure and death. Current therapeutic intervention strategies only slow disease progression. The role of aberrant HIF2α stability and function in the initiation and development of pulmonary hypertension (PH) has been an area of intense interest for nearly two decades.Here we determine the effect of a novel HIF2α inhibitor (PT2567) on PH disease initiation and progression, using two pre-clinical models of PH. Haemodynamic measurements were performed followed by collection of heart, lung and blood for pathological, gene expression and biochemical analysis. Blood outgrowth endothelial cells from IPAH patients were used to determine the impact of HIF2α-inhibition on endothelial function.Global inhibition of HIF2a reduced pulmonary vascular haemodynamics and pulmonary vascular remodelling in both su5416/hypoxia prevention and intervention models. PT2567 intervention reduced the expression of PH associated target genes in both lung and cardiac tissues and restored plasma nitrite concentration. Treatment of monocrotaline exposed rodents with PT2567 reduced the impact on cardiovascular haemodynamics and promoted a survival advantage. In vitro, loss of HIF2α signalling in human pulmonary arterial endothelial cells suppresses target genes associated with inflammation, and PT2567 reduced the hyper-proliferative phenotype and over-active arginase activity in blood outgrowth endothelial cells from IPAH patients. These data suggest that targeting HIF2α hetero-dimerisation with an orally bioavailable compound could offer a new therapeutic approach for PAH. Future studies are required to determine the role of HIF in the heterogeneous PAH population.

scholarly journals Non-parenteral Therapy for Pulmonary Arterial Hypertension: A Review of Efficacy, Tolerability and Factors Related to Patient Adherence

2011 ◽  
Vol 3 ◽  
pp. CMT.S2689
Author(s):  
Geoff Strange ◽  
Christianne Manterfield ◽  
Trudi Miller ◽  
Annette Pidoux ◽  
Karen Brown ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Patient Adherence ◽  
Multidisciplinary Care ◽  
Premature Death ◽  
Progressive Increase ◽  
Effective Manner ◽  
History Of ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is defined as a group of diseases characterized by a progressive increase in pulmonary vascular resistance (PVR) leading to right ventricular failure and premature death. Untreated, it is a potentially devastating disease. However, the past decade has seen remarkable improvements in our understanding of the pathology associated with the condition and the development of multiple PAH-specific therapies with the ability to alter the natural history of the disease. These new advances provide a significant opportunity for practitioners to detect and treat patients with PAH in a timely and effective manner, thereby improving overall mortality, morbidity, and quality of life associated with this disease. The aim of this review is two-fold: firstly to review the evidence for efficacy and safety of non-parenteral PAH therapies and to discuss treatment selection based on clinically meaningful differences among the approved therapies, such as the potential for serious drug-drug interactions, convenience of dosing schedules, and rates of limiting side effects. Secondly, the central role of the PAH clinical nurse in the multidisciplinary care of patients with PAH will be discussed, together with issues relating to adherence and interventions to enhance patient compliance.

scholarly journals Exercise Intolerance in Pulmonary Arterial Hypertension

2012 ◽  
Vol 2012 ◽  
pp. 1-10 ◽  
Author(s):  
Robin M. Fowler ◽  
Kevin R. Gain ◽  
Eli Gabbay
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Functional Limitation ◽  
Cardiopulmonary Exercise Test ◽  
Exercise Intolerance ◽  
Exercise Limitation ◽  
Pulmonary Arterial ◽  
The Right ◽  
The Relationship

Pulmonary arterial hypertension (PAH) is associated with symptoms of dyspnea and fatigue, which contribute to exercise limitation. The origins and significance of dyspnea and fatigue in PAH are not completely understood. This has created uncertainly among healthcare professionals regarding acceptable levels of these symptoms, on exertion, for patients with PAH. Dysfunction of the right ventricle (RV) contributes to functional limitation and mortality in PAH; however, the role of the RV in eliciting dyspnea and fatigue has not been thoroughly examined. This paper explores the contribution of the RV and systemic and peripheral abnormalities to exercise limitation and symptoms in PAH. Further, it explores the relationship between exercise abnormalities and symptoms, the utility of the cardiopulmonary exercise test in identifying RV dysfunction, and offers suggestions for further research.

scholarly journals EXPRESS: Platelets, extracellular vesicles & coagulation in pulmonary arterial hypertension

2021 ◽  
pp. 204589402110210
Author(s):  
Sarah Cullivan ◽  
Claire A Murphy ◽  
Luisa Weiss ◽  
Shane P Comer ◽  
Barry Kevane ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Therapeutic Interventions ◽  
Pulmonary Vasculature ◽  
Future Research ◽  
Regulatory Pathways ◽  
Paracrine Signalling ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a rare disease of the pulmonary vasculature, characterised pathologically by proliferation, remodelling and thrombosis in situ. Unfortunately, existing therapeutic interventions do not reverse these findings and the disease continues to result in significant morbidity and premature mortality. A number of haematological derangements have been described in PAH which may provide insights into the pathobiology of the disease and also provide opportunities to target new therapeutic pathways. These include quantitative and qualitative platelet abnormalities, such as thrombocytopaenia, increased mean platelet volume (MPV) and altered platelet bioenergetics. Furthermore, a hypercoagulable state and aberrant negative regulatory pathways can be observed, which could contribute to thrombosis in situ in distal pulmonary arteries and arterioles. Finally, there is increasing interest in the role of extracellular vesicle (EV) autocrine and paracrine signalling in PAH, and their potential utility as biomarkers and novel therapeutic targets. This review focuses on the potential role of platelets, EVs and coagulation pathways in the pathobiology of PAH. We highlight important unanswered clinical questions and the implications of these observations for future research and PAH directed therapies.

scholarly journals Consensus or Controversy: Do Recent Advances Shift the Debate for the Use of Echocardiography Versus Cardiac Magnetic Resonance Imaging of the Right Ventricle in Pulmonary Arterial Hypertension?

2015 ◽  
Vol 14 (1) ◽  
pp. 28-36
Author(s):  
Amresh Raina ◽  
Benjamin Freed
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Right Ventricle ◽  
Arterial Hypertension ◽  
Surrogate Endpoint ◽  
Pulmonary Vasculature ◽  
Technological Advances ◽  
The Status ◽  
Pulmonary Arterial ◽  
The Right ◽  
Insight Into

Pulmonary arterial hypertension (PAH) is a progressive, often lethal condition originating in the pulmonary arteriolar tree. It is typically manifested in stereotypical changes in the right ventricle (RV). RV dysfunction is an important mediator of patient symptoms in PAH, and RV failure is the most common cause of mortality in PAH patients. Because of the physiologic importance of the RV, RV imaging is critical in the initial diagnostic evaluation and serial assessment of PAH patients, and can provide indirect insight into the status of the disease at the level of the pulmonary vasculature. This article will focus on whether technological advances in imaging have shifted the debate toward which modality is optimal both for routine clinical practice and for a possible surrogate endpoint in PAH clinical trials.

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