Beyond the genome: challenges and potential for epigenetics-driven therapeutic approaches in pulmonary arterial hypertension

2020 ◽  
Vol 98 (6) ◽  
pp. 631-646
Author(s):  
Jessica Y. Hsu ◽  
Jennifer L. Major ◽  
Andrew S. Riching ◽  
Rwik Sen ◽  
Julie Pires da Silva ◽  
...  
Keyword(s):  
Cell Proliferation ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Mitochondrial Dynamics ◽  
Pulmonary Arteries ◽  
Therapeutic Approaches ◽  
Pulmonary Arterial ◽  
And Migration ◽  
Epigenetic Research

Pulmonary arterial hypertension (PAH) is a devastating disease of the cardiopulmonary system caused by the narrowing of the pulmonary arteries, leading to increased vascular resistance and pressure. This leads to right ventricle remodeling, dysfunction, and eventually, death. While conventional therapies have largely focused on targeting vasodilation, other pathological features of PAH including aberrant inflammation, mitochondrial dynamics, cell proliferation, and migration have not been well explored. Thus, despite some recent improvements in PAH treatment, the life expectancy and quality of life for patients with PAH remains poor. Showing many similarities to cancers, PAH is characterized by increased pulmonary arterial smooth muscle cell proliferation, decreased apoptotic signaling pathways, and changes in metabolism. The recent successes of therapies targeting epigenetic modifiers for the treatment of cancer has prompted epigenetic research in PAH, revealing many new potential therapeutic targets. In this minireview we discuss the emergence of epigenetic dysregulation in PAH and highlight epigenetic-targeting compounds that may be effective for the treatment of PAH.

Idiopathic pulmonary arterial hypertension

ESC CardioMed ◽  
2018 ◽  
pp. 2524-2527
Author(s):  
Carlos Jardim ◽  
Luciana K. Morinaga ◽  
Rogério Souza
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Pulmonary Arteries ◽  
Rare Condition ◽  
Idiopathic Pulmonary Arterial Hypertension ◽  
Trigger Factor ◽  
Ventricular Afterload ◽  
Pulmonary Arterial ◽  
Improvement In Survival

Idiopathic pulmonary arterial hypertension is a rare condition characterized by the progressive remodelling of the small pulmonary arteries, increasing right ventricular afterload and consequent failure, in the absence of an identifiable baseline condition or trigger factor. For this, an extensive diagnostic investigation is mandatory, together with invasive haemodynamic measurement, in order to ensure the elevation in the pulmonary artery pressure is associated with a pre-capillary pattern. Three main pathways have been associated with the pathophysiology of idiopathic pulmonary arterial hypertension: the endothelin, nitric oxide, and prostacyclin pathways. The development of specific therapies targeting these pathways has significantly improved survival in the last two decades. Although the disease remains as a relentlessly progressive condition, this improvement in survival was also accompanied by better functional capacity and quality of life, thus completely changing the daily life of patients.

Abstract 376: A Potential Role for TRAIL in the Pathogenesis of Pulmonary Arterial Hypertension

Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Allan Lawrie ◽  
Mark Southwood ◽  
Jay Suntharalingam ◽  
Sheila E Francis ◽  
David C Crossman ◽  
...  
Keyword(s):  
Gene Expression ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Transmembrane Protein ◽  
Pulmonary Arteries ◽  
Fold Increase ◽  
Vascular Lesions ◽  
Trail Receptors ◽  
Pulmonary Arterial ◽  
And Migration

Pulmonary arterial hypertension (PAH) is a life threatening disease characterised by the narrowing and occlusion of small pulmonary arteries. Endothelial cell (EC) loss, and increased proliferation and migration of pulmonary artery smooth muscle cells (PA-SMC) are strongly implicated in disease pathogenesis. Tumor necrosis factor (TNF)-Related Apoptosis-Inducing Ligand (TRAIL) induces EC apoptosis and SMC migration, consistent with an important role in vascular biology. TRAIL is a type II TNF family transmembrane protein, whose extracellular domain can be proteolytically cleaved from the cell surface to act as a soluble cytokine (sTRAIL) capable of binding to five TRAIL receptors, (TRAIL-R1– 4) and osteoprotegerin (OPG). We hypothesised that TRAIL expression is increased in PAH and that this contributes to the excessive migration of PA-SMC that characterises this condition. TRAIL gene expression was studied in microarrays of PA-SMC RNA isolated from idiopathic PAH (IPAH) patients, and from the lungs of monocrotaline-treated (Mct) rats. Immunohistochemistry was performed to localise TRAIL in both human and rat lung sections. To investigate the functional effects of TRAIL in PA-SMC, human PA-SMC were incubated with recombinant human TRAIL (1–50 ng/ml) for 5h and migration assessed by transwell assay. TRAIL gene expression was 10-fold higher in PA-SMC from IPAH patients compared to controls. Moreover, strong TRAIL immunoreactivity was observed in pulmonary vascular lesions from IPAH patients but not in vessels from patients undergoing lobectomy for lung carcinoma. In the Mct-rat model of PAH we found a 20-fold increase in TRAIL gene expression and a 2-fold increase in protein from whole lung extracts. Immunohistochemistry revealed strong TRAIL immunoreactivity within the muscularised pulmonary arteries of Mct-treated but not saline-treated control rats. Recombinant TRAIL was found to induce a dose dependent (maximum 3 fold) increase in migration of human PA-SMC compared with cells incubated with 0.1% serum alone. These data suggest that TRAIL may be an important molecule in the pathogenesis of PAH. Further studies to elucidate the regulation and function of this molecule in PAH are warranted.

Depression: Beyond Description As an Important Comorbidity in Pulmonary Arterial Hypertension—The Next Steps

2012 ◽  
Vol 10 (4) ◽  
pp. 227-232 ◽  
Author(s):  
Deborah H. McCollister ◽  
Philippe Weintraub ◽  
David B. Badesch
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Important Determinant ◽  
Provider Education ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Broad Array ◽  
Pulmonary Arterial

The recent identification of depression as an important comorbidity in pulmonary arterial hypertension (PAH)12 is leading to a broad array of efforts to further refine our understanding of this disorder, enhance patient and provider education about it, and encourage prompt recognition, appropriate diagnosis, and treatment of affected individuals. We will provide an update on the nature and extent of the problem, and describe ongoing and future efforts to address this very important determinant of quality of life and possible long-term outcome in patients with PAH.

scholarly journals Strategies for the management of pulmonary arterial hypertension in patients with congenital heart disease

2020 ◽  
Vol 4 (S1) ◽  
Author(s):  
Nathalie Liew ◽  
Zoya Rashid ◽  
Robert Tulloh
Keyword(s):  
Congenital Heart Disease ◽  
Heart Disease ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Congenital Heart ◽  
Standard Management ◽  
Advanced Therapies ◽  
Pulmonary Arterial ◽  
The Uk

Abstract Background Pulmonary hypertension (PH) is commonly seen in adults who have congenital heart disease (CHD). Therapy is available for pulmonary arterial hypertension (PAH) and has greatly benefitted many patients with PAH related to CHD (PAH-CHD) over the last 15 years, with evidence of improved quality of life and prognosis in those with Eisenmenger syndrome and repaired PAH-CHD. In this review, we describe the standard management and advanced therapies for PAH, which are available in specialist PH centres around the UK and Ireland, and how these are used in PAH-CHD. Decisions around the choice of therapy are governed by commissioning and available evidence. Conclusion We explain the different pathways for action and the variety of medications now at our disposal to help this important group of patients.

Beta3-adrenergic stimulation restores endothelial mitochondrial dynamics and prevents pulmonary arterial hypertension

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
E Oliver ◽  
S.F Rocha ◽  
M Spaczynska ◽  
D.V Lalama ◽  
M Gomez ◽  
...  
Keyword(s):  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Therapeutic Strategy ◽  
Mitochondrial Dynamics ◽  
Systolic Pressure ◽  
Funding Source ◽  
Pulmonary Arterial

Abstract Background Endothelial dysfunction is one of the most important hallmarks of pulmonary arterial hypertension (PAH). This leads to anomalous production of vasoactive mediators that are responsible for a higher vascular tone and a subsequent increase in pulmonary artery pressure (PAP), and to an increased vascular permeability that favors perivascular inflammation and remodeling, thus worsening the disease. Therefore, preservation of the endothelial barrier could become a relevant therapeutic strategy. Purpose In previous studies, others and we have suggested the pharmacological activation of the β3-adrenergic receptor (AR) as a potential therapeutic strategy for pulmonary hypertension (PH) due to left heart disease. However, its potential use in other forms of PH remain unclear. The aim of the present study was to elucidate whether the β3-AR agonist mirabegron could preserve pulmonary endothelium function and be a potential new therapy in PAH. Methods For this purpose, we have evaluated the effect of mirabegron (2 and 10 mg/kg·day) in different animal models, including the monocrotaline and the hypoxia-induced PAH models in rats and mice, respectively. Additionally, we have used a transgenic mouse model with endothelial overexpression of human β3-AR in a knockout background, and performed in vitro experiments with human pulmonary artery endothelial cells (HPAECs) for mechanistic experiments. Results Our results show a dose dependent effect of mirabegron in reducing mean PAP and Right Ventricular Systolic Pressure in both mice and rats. In addition, the use of transgenic mice has allowed us to determine that pulmonary endothelial cells are key mediators of the beneficial role of β3-AR pathway in ameliorating PAH. Mechanistically, we have shown in vitro that activation of β3-AR with mirabegron protects HPAECs from hypoxia-induced ROS production and mitochondrial fragmentation by restoring mitochondrial fission/fusion dynamics. Conclusions This protective effect of mirabegron would lead to endothelium integrity and preserved pulmonary endothelial function, which are necessary for a correct vasodilation, avoiding increased permeability and remodeling. Altogether, the current study demonstrates a beneficial effect of the β3-AR agonist mirabegron that could open new therapeutic avenues in PAH. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): Programa de Atracciόn de Talento, Comunidad de Madrid

scholarly journals EXPRESS: Association of daily physical activity with psychosocial aspects and functional capacity in patients with Pulmonary Arterial Hypertension: a cross-sectional study

2021 ◽  
pp. 204589402199995
Author(s):  
Layse Nakazato Lima ◽  
Felipe Mendes ◽  
Ilma Paschoal ◽  
Daniela Oliveira ◽  
Marcos Mello Moreira ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Physical Activity ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Functional Capacity ◽  
Daily Physical Activity ◽  
Cross Sectional ◽  
Pulmonary Arterial ◽  
The Mean

Pulmonary arterial hypertension (PAH) impairs exercise tolerance and daily physical activity (PA). Aside from the hemodynamic limitations, physical, cognitive and emotional factors may play a relevant and as yet unexplored role. We investigated whether there is an association between the PA level and psychological disorders, health-related quality of life, and daily activities. We also searched for an association of the PA level with clinical factors and functional capacity. This was an analytical, cross-sectional, observational study conducted in a Brazilian University Hospital. Twenty stable PAH subjects wore an accelerometer for a week and completed an activity diary. They answered the quality of life questionnaire (SF-36), as well as the anxiety and depression scale (HADS), and the Manchester Respiratory Activities of Daily Living questionnaire (MRADL). Transthoracic echocardiography, the 6-Minute walk test (6MWT), the 1-minute sit-to-stand test (STST), and spirometry were performed. For statistical analysis we used Chi-square tests or Fisher's test as appropriate and the Mann-Whitney test to compare numerical values between two groups. The relationship between the parameters was assessed using the Spearman correlation test. The mean age was 44.3 years, 80% were women, 80% had idiopathic PAH, and 20% had connective tissue disease . The mean daily step count was 4,280 ± 2,351, and the mean activity time was 41.6 ± 19.3 minutes. The distance covered (6MWT) was 451.5 m, and the number of movements (1-STST) was 23.8. Thirty percent scored positive for anxiety, and 15% for depression (HADS). There was a significant correlation between accelerometer data and walking distance (6MWT), number of movements (1-STST), level of daily physical activity (MRADL), and depression symptoms. Our findings support the hypothesis that other aspects beyond physical and hemodynamic ones might impact the daily physical activity of patients with PAH.

Effect of Pulmonary Arterial Hypertension-Specific Therapies on Health-Related Quality of Life

CHEST Journal ◽  
2014 ◽  
Vol 146 (3) ◽  
pp. 686-708 ◽  
Author(s):  
Gilles Rival ◽  
Yves Lacasse ◽  
Sylvie Martin ◽  
Sébastien Bonnet ◽  
Steeve Provencher
Keyword(s):  
Quality Of Life ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Health Related Quality ◽  
Related Quality ◽  
Health Related ◽  
Pulmonary Arterial

scholarly journals A prescribed walking regimen plus arginine supplementation improves function and quality of life for patients with pulmonary arterial hypertension: a pilot study

2017 ◽  
Vol 8 (1) ◽  
pp. 204589321774396 ◽  
Author(s):  
Mary Beth Brown ◽  
Attie Kempf ◽  
Catherine M. Collins ◽  
Gary M. Long ◽  
Matthew Owens ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Current Evidence ◽  
Proof Of Concept ◽  
Concept Study ◽  
Sf 36 ◽  
Pulmonary Arterial ◽  
Arginine Supplementation

Current evidence suggests that exercise training is beneficial in pulmonary arterial hypertension (PAH). Unfortunately, the standard supervised, hospital-based programs limit patient accessibility to this important intervention. Our proof-of-concept study aimed to provide insight into the usefulness of a prescribed walking regimen along with arginine supplementation to improve outcomes for patients with PAH. Twelve PAH patients (all women) in New York Heart Association (NYHA) functional class (FC) II (n = 7) or III (n = 5) and in stable condition for ≥ 3 months were enrolled. Patients performed home- and fitness-center- based walking at 65–75% heart rate (HR) reserve for 45 min, six sessions/week for 12 weeks. Concomitant L-arginine supplementation (6000 mg/day) was provided to maximize beneficial endothelial training adaptations. Cardiopulmonary exercise testing, 6-min walk testing (6MWT), echocardiography, laboratory studies, and quality of life (QoL) survey (SF-36) were performed at baseline and 12 weeks. Eleven patients completed the study (72 session adherence rate = 96 ± 3%). Objective improvement was demonstrated by the 6MWT distance (increased by 40 ± 13 m, P = 0.01), VO2max (increased by 2 ± 0.7 mL/kg/min, P = 0.02), time-to-VO2max (increased by 2.5 ± 0.6 min, P = 0.001), VO2 at anaerobic threshold (increased by 1.3 ± 0.5 mL/kg/min, P = 0.04), HR recovery (reduced by 68 ± 23% in slope, P = 0.01), and SF-36 subscales of Physical Functioning and Energy/Fatigue (increased by 70 ± 34% and 74 ± 34%, respectively, P < 0.05). No adverse events occurred, and right ventricular function and brain natriuretic peptide levels remained stable, suggesting safety of the intervention. This proof-of-concept study indicates that a simple walking regimen with arginine supplementation is a safe and efficacious intervention for clinically stable PAH patients, with gains in objective function and QoL measures. Further investigation in a randomized controlled trial is warranted.

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