scholarly journals Molecular and Genetic Profiling for Precision Medicines in Pulmonary Arterial Hypertension

Cells ◽  
2021 ◽  
Vol 10 (3) ◽  
pp. 638
Author(s):  
Shahood Fazal ◽  
Malik Bisserier ◽  
Lahouaria Hadri
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Genetic Variants ◽  
High Throughput Sequencing ◽  
Molecular Genetic ◽  
Pulmonary Arteries ◽  
Pulmonary Vasculature ◽  
Common Genetic Variants ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a rare and chronic lung disease characterized by progressive occlusion of the small pulmonary arteries, which is associated with structural and functional alteration of the smooth muscle cells and endothelial cells within the pulmonary vasculature. Excessive vascular remodeling is, in part, responsible for high pulmonary vascular resistance and the mean pulmonary arterial pressure, increasing the transpulmonary gradient and the right ventricular “pressure overload”, which may result in right ventricular (RV) dysfunction and failure. Current technological advances in multi-omics approaches, high-throughput sequencing, and computational methods have provided valuable tools in molecular profiling and led to the identification of numerous genetic variants in PAH patients. In this review, we summarized the pathogenesis, classification, and current treatments of the PAH disease. Additionally, we outlined the latest next-generation sequencing technologies and the consequences of common genetic variants underlying PAH susceptibility and disease progression. Finally, we discuss the importance of molecular genetic testing for precision medicine in PAH and the future of genomic medicines, including gene-editing technologies and gene therapies, as emerging alternative approaches to overcome genetic disorders in PAH.

scholarly journals Steps forward in the treatment of pulmonary arterial hypertension: latest developments and clinical opportunities

2017 ◽  
Vol 8 (2-3) ◽  
pp. 47-64 ◽  
Author(s):  
Jessica B. Badlam ◽  
Todd M. Bull
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Soluble Guanylate Cyclase ◽  
Pulmonary Arteries ◽  
Right Heart Failure ◽  
Response To Treatment ◽  
Pulmonary Vasculature ◽  
Pulmonary Arterial ◽  
Efficacy Parameters

Pulmonary arterial hypertension (PAH) is a chronic disease that results in narrowing of the small pre-capillary pulmonary arteries leading to elevation of pulmonary artery pressure and pulmonary vascular resistance, subsequent right ventricular failure, and if unchecked, death. Advances in the treatment of PAH over the last two decades have markedly improved survival. These improvements reflect a combination of changes in treatments, improved patient care strategies, and varying disease phenotypes in the PAH population. Currently approved therapies for PAH are directed at the recognized abnormalities within the pulmonary vasculature and include endothelin receptor antagonists, phosphodiesterase-5 inhibitors, soluble guanylate cyclase stimulators, and prostacyclin pathway agents. Most of these drugs have been approved on the basis of short-term trials that mainly demonstrated improvements in exercise capacity. More recently, long-term, event-driven trials of novel drugs have been performed, demonstrating new efficacy parameters. There have also been exciting advances in the understanding of right heart failure pathophysiology in PAH that have the potential to inspire the development of right ventricular targeted therapy and continued discoveries in the heterogeneity of disease and response to treatment has great potential for developing more ‘personalized’ therapeutic options. In this article, we review the current available data regarding the management of PAH, with an emphasis on the pharmacologic therapies and discussion of novel therapeutic directions for the treatment of this fatal disease.

scholarly journals Hypoxia-inducible factors in human pulmonary arterial hypertension: a link to the intrinsic myeloid abnormalities

Blood ◽  
2011 ◽  
Vol 117 (13) ◽  
pp. 3485-3493 ◽  
Author(s):  
Samar Farha ◽  
Kewal Asosingh ◽  
Weiling Xu ◽  
Jacqueline Sharp ◽  
Deepa George ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Hypoxia Inducible Factor ◽  
Pulmonary Arteries ◽  
Disease Process ◽  
Pulmonary Vasculature ◽  
Normal Numbers ◽  
Pulmonary Arterial

AbstractPulmonary arterial hypertension (PAH) is a proliferative vasculopathy characterized by high circulating CD34+CD133+ proangiogenic progenitors, and endothelial cells that have pathologic expression of hypoxia-inducible factor 1 α (HIF-1α). Here, CD34+CD133+ progenitor cell numbers are shown to be higher in PAH bone marrow, blood, and pulmonary arteries than in healthy controls. The HIF-inducible myeloid-activating factors erythropoietin, stem cell factor (SCF), and hepatocyte growth factor (HGF) are also present at higher than normal levels in PAH blood, and related to disease severity. Primary endothelial cells harvested from human PAH lungs produce greater HGF and progenitor recruitment factor stromal-derived factor 1 α (SDF-1α) than control lung endothelial cells, and thus may contribute to bone marrow activation. Even though PAH patients had normal numbers of circulating blood elements, hematopoietic alterations in myeloid and erythroid lineages and reticulin fibrosis identified a subclinical myeloproliferative process. Unexpectedly, evaluation of bone marrow progenitors and reticulin in nonaffected family members of patients with familial PAH revealed similar myeloid abnormalities. Altogether, the results show that PAH is linked to myeloid abnormalities, some of which may be related to increased production of HIF-inducible factors by diseased pulmonary vasculature, but findings in nonaffected family suggest myeloid abnormalities may be intrinsic to the disease process.

scholarly journals Pulmonary Pulse Wave Transit Time is Associated with Right Ventricular–Pulmonary Artery Coupling in Pulmonary Arterial Hypertension

2016 ◽  
Vol 6 (4) ◽  
pp. 576-585 ◽  
Author(s):  
Kurt W. Prins ◽  
E. Kenneth Weir ◽  
Stephen L. Archer ◽  
Jeremy Markowitz ◽  
Lauren Rose ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Pulmonary Artery ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Transit Time ◽  
Pulse Wave ◽  
Pulmonary Vasculature ◽  
Pulmonary Vascular Disease ◽  
Pulse Wave Transit Time ◽  
Pulmonary Arterial

Pulmonary pulse wave transit time (pPTT), defined as the time for the systolic pressure pulse wave to travel from the pulmonary valve to the pulmonary veins, has been reported to be reduced in pulmonary arterial hypertension (PAH); however, the underlying mechanism of reduced pPTT is unknown. Here, we investigate the hypothesis that abbreviated pPTT in PAH results from impaired right ventricular–pulmonary artery (RV-PA) coupling. We quantified pPTT using pulsed-wave Doppler ultrasound from 10 healthy age- and sex-matched controls and 36 patients with PAH. pPTT was reduced in patients with PAH compared with controls. Univariate analysis revealed the following significant predictors of reduced pPTT: age, right ventricular fractional area change (RV FAC), tricuspid annular plane excursion (TAPSE), pulmonary arterial pressures (PAP), diastolic pulmonary gradient, transpulmonary gradient, pulmonary vascular resistance, and RV-PA coupling (defined as RV FAC/mean PAP or TAPSE/mean PAP). Although the correlations between pPTT and invasive markers of pulmonary vascular disease were modest, RV FAC ( r = 0.64, P < 0.0001), TAPSE ( r = 0.67, P < 0.0001), and RV-PA coupling (RV FAC/mean PAP: r = 0.72, P < 0.0001; TAPSE/mean PAP: r = 0.74, P < 0.0001) had the strongest relationships with pPTT. On multivariable analysis, only RV FAC, TAPSE, and RV-PA coupling were independent predictors of pPTT. We conclude that shortening of pPTT in patients with PAH results from altered RV-PA coupling, probably occurring as a result of reduced pulmonary arterial compliance. Thus, pPTT allows noninvasive determination of the status of both the pulmonary vasculature and the response of the RV in patients with PAH, thereby allowing monitoring of disease progression and regression.

scholarly journals The Molecular Genetics and Cellular Mechanisms Underlying Pulmonary Arterial Hypertension

Scientifica ◽  
2012 ◽  
Vol 2012 ◽  
pp. 1-17 ◽  
Author(s):  
Rajiv D. Machado
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Treatment Options ◽  
Molecular Genetic ◽  
Pulmonary Arteries ◽  
Rapid Identification ◽  
Cellular Mechanisms ◽  
Systemic Involvement ◽  
Pulmonary Arterial ◽  
The Impact

Pulmonary arterial hypertension (PAH) is an incurable disorder clinically characterised by a sustained elevation of mean arterial pressure in the absence of systemic involvement. As the adult circulation is a low pressure, low resistance system, PAH represents a reversal to a foetal state. The small pulmonary arteries of patients exhibit luminal occlusion resultant from the uncontrolled growth of endothelial and smooth muscle cells. This vascular remodelling is comprised of hallmark defects, most notably the plexiform lesion. PAH may be familial in nature but the majority of patients present with spontaneous disease or PAH associated with other complications. In this paper, the molecular genetic basis of the disorder is discussed in detail ranging from the original identification of the major genetic contributant to PAH and moving on to current next-generation technologies that have led to the rapid identification of additional genetic risk factors. The impact of identified mutations on the cell is examined, particularly, the determination of pathways disrupted in disease and critical to pulmonary vascular maintenance. Finally, the application of research in this area to the design and development of novel treatment options for patients is addressed along with the future directions PAH research is progressing towards.

scholarly journals Gender, Sex Hormones, and Pulmonary Arterial Hypertension

2011 ◽  
Vol 10 (3) ◽  
pp. 160-166 ◽  
Author(s):  
Eric D. Austin
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Animal Studies ◽  
Pulmonary Arteries ◽  
Connective Tissue Diseases ◽  
World Health ◽  
Pulmonary Vasculature ◽  
Diverse Range ◽  
Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a progressive disease characterized by pulmonary vascular remodeling of the distal pulmonary vasculature, ultimately leading to destruction and loss of the smallest pulmonary arteries.1 The ensuing syndrome of PAH is clinically characterized by reduced pulmonary arterial circulatory flow, resulting in increased pulmonary vascular resistance, which ultimately results in failure of the right heart.2 In both children and adults, PAH presents as a primary disease or in association with a diverse range of diseases such as connective tissue diseases, portal hypertension, and congenital heart disease.3 Nearly all forms of World Health Organization (WHO) Group 1 PAH demonstrate a skewed gender ratio with significantly more females diagnosed with PAH than males.4–6 While the mechanistic details behind the female predominance remain unclear, this gender discrepancy may represent an opportunity for advanced biologic understanding and future therapeutic development. This article will briefly discuss the intersection of human, in vitro, and animal studies of PAH, and highlight the conflicting data that others have discussed and elegantly elaborated upon as the “estrogen paradox” in PAH.7–9

scholarly journals Common genetic variants in pulmonary arterial hypertension

2019 ◽  
Vol 7 (3) ◽  
pp. 190-191 ◽  
Author(s):  
Sue Gu ◽  
Rahul Kumar ◽  
Michael H Lee ◽  
Claudia Mickael ◽  
Brian B Graham
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Genetic Variants ◽  
Common Genetic Variants ◽  
Pulmonary Arterial

scholarly journals Patient-Specific Computational Analysis of Hemodynamics and Wall Mechanics and Their Interactions in Pulmonary Arterial Hypertension

2021 ◽  
Vol 8 ◽  
Author(s):  
Byron A. Zambrano ◽  
Nathan McLean ◽  
Xiaodan Zhao ◽  
Ju-Le Tan ◽  
Liang Zhong ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Pulmonary Arteries ◽  
Patient Specific ◽  
Pulmonary Vasculature ◽  
Control Group ◽  
Regurgitant Flow ◽  
Wall Stiffness ◽  
Wall Deformation ◽  
Pulmonary Arterial

Vascular wall stiffness and hemodynamic parameters are potential biomechanical markers for detecting pulmonary arterial hypertension (PAH). Previous computational analyses, however, have not considered the interaction between blood flow and wall deformation. Here, we applied an established computational framework that utilizes patient-specific measurements of hemodynamics and wall deformation to analyze the coupled fluid–vessel wall interaction in the proximal pulmonary arteries (PA) of six PAH patients and five control subjects. Specifically, we quantified the linearized stiffness (E), relative area change (RAC), diastolic diameter (D), regurgitant flow, and time-averaged wall shear stress (TAWSS) of the proximal PA, as well as the total arterial resistance (Rt) and compliance (Ct) at the distal pulmonary vasculature. Results found that the average proximal PA was stiffer [median: 297 kPa, interquartile range (IQR): 202 kPa vs. median: 75 kPa, IQR: 5 kPa; P = 0.007] with a larger diameter (median: 32 mm, IQR: 5.25 mm vs. median: 25 mm, IQR: 2 mm; P = 0.015) and a reduced RAC (median: 0.22, IQR: 0.10 vs. median: 0.42, IQR: 0.04; P = 0.004) in PAH compared to our control group. Also, higher total resistance (Rt; median: 6.89 mmHg × min/l, IQR: 2.16 mmHg × min/l vs. median: 3.99 mmHg × min/l, IQR: 1.15 mmHg × min/l; P = 0.002) and lower total compliance (Ct; median: 0.13 ml/mmHg, IQR: 0.15 ml/mmHg vs. median: 0.85 ml/mmHg, IQR: 0.51 ml/mmHg; P = 0.041) were observed in the PAH group. Furthermore, lower TAWSS values were seen at the main PA arteries (MPAs) of PAH patients (median: 0.81 Pa, IQR: 0.47 Pa vs. median: 1.56 Pa, IQR: 0.89 Pa; P = 0.026) compared to controls. Correlation analysis within the PAH group found that E was directly correlated to the PA regurgitant flow (r = 0.84, P = 0.018) and inversely related to TAWSS (r = −0.72, P = 0.051). Results suggest that the estimated elastic modulus E may be closely related to PAH hemodynamic changes in pulmonary arteries.

scholarly journals Resveratrol Protects Against Pulmonary Arterial Hypertension in Rats via Activation of Silent Information Regulator 1

2017 ◽  
Vol 42 (1) ◽  
pp. 55-67 ◽  
Author(s):  
Lei Yu ◽  
Yingfeng Tu ◽  
Xueling Jia ◽  
Kun Fang ◽  
Li Liu ◽  
...  
Keyword(s):  
Pulmonary Arterial Hypertension ◽  
Protein Expression ◽  
Arterial Hypertension ◽  
Right Ventricular ◽  
Systolic Pressure ◽  
Pulmonary Vasculature ◽  
Dependent Manner ◽  
Silent Information Regulator 1 ◽  
Pulmonary Arterial

Background/Objectives: The polyphenol resveratrol (Rev) has been found to exhibit various beneficial effects including prevention of pulmonary arterial hypertension (PAH). The present study was designed to investigate the action and potential mechanism of Rev on PAH, focusing on the role of SIRT1 (Silent Information Regulator 1) in apoptosis of pulmonary artery smooth muscle cells (PASMCs). Methods: PAH rats were established by exposure to hypoxia for 21 days. Rev and SRT1720 (a selective SIRT1 activator) were used to reverse PAH by gavaging rats. PASMCs were confronted with hypoxia for 24 h or 48 h and were then treated with Rev or SRT1720 in vitro. Western blot was performed to detect the protein expression of SIRT1. CCK-8 and scratch wound experiments were carried out to verify cell proliferation. In addition, the TUNEL positive assay and flow cytometry assay were used to measure PASMC apoptosis. Mitochondrial permeability transition (mPT) was identified by confocal microscopy. Right ventricular systolic pressure (RVSP) was determined with a Gould pressure transducer, and right ventricular hypertrophy (RVH) was determined by weighing the cardiac muscle. Results: We demonstrated that Rev could reverse the remodelling of the pulmonary vasculature, thus contributing to alleviating the severity of PAH. Down-regulation of SIRT1 was observed in PAH, but administration of Rev had no obvious effect on the protein expression of SIRT1. In addition, Rev could induce mitochondrial swelling and nuclear pyknosis, leading to small, dense, and dysmorphic mitochondria in rats exposed to hypoxia alone. Rev treatment inhibited PASMC proliferation in a dose-dependent manner in vitro. Incubation with SRT1720, a specific activator of SIRT1, significantly retarded PASMC proliferation and promoted PASMC apoptosis in vitro. The mechanism could be associated with inducing mPT damage in PASMCs. Rev and SRT1720 treatment mitigated RVSP and reduced RVH. Conclusion: Rev produced a beneficial effect partially by enhancing the activation of SIRT1, thus improving RVSP and reducing RVH. SIRT1 activation increased PASMC apoptosis by inducing mPT dysfunction, which might be a novel future strategy for the treatment of PAH.

scholarly journals Single-cell transcriptomic profile of human pulmonary artery endothelial cells in health and pulmonary arterial hypertension

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
Kewal Asosingh ◽  
Suzy Comhair ◽  
Lori Mavrakis ◽  
Weiling Xu ◽  
Dean Horton ◽  
...  
Keyword(s):  
Gene Expression ◽  
Endothelial Cells ◽  
Pulmonary Arterial Hypertension ◽  
Arterial Hypertension ◽  
Single Cell ◽  
Pulmonary Arteries ◽  
Cellular Heterogeneity ◽  
Pulmonary Vasculature ◽  
Cell Functions ◽  
Pulmonary Arterial

AbstractPulmonary arterial hypertension (PAH) is an insidious disease characterized by severe remodeling of the pulmonary vasculature caused in part by pathologic changes of endothelial cell functions. Although heterogeneity of endothelial cells across various vascular beds is well known, the diversity among endothelial cells in the healthy pulmonary vascular bed and the pathologic diversity among pulmonary arterial endothelial cells (PAEC) in PAH is unknown and previously unexplored. Here single-cell RNA sequencing technology was used to decipher the cellular heterogeneity among PAEC in the human pulmonary arteries isolated from explanted lungs from three patients with PAH undergoing lung transplantation and three healthy donor lungs not utilized for transplantation. Datasets of 36,368 PAH individual endothelial cells and 36,086 healthy cells were analyzed using the SeqGeq bioinformatics program. Total population differential gene expression analyses identified 629 differentially expressed genes between PAH and controls. Gene Ontology and Canonical Ingenuity analysis revealed pathways that are known to be involved in pathogenesis, as well as unique new pathways. At the individual cell level, dimensionality reduction followed by density based clustering revealed the presence of eight unique PAEC clusters that were typified by proliferative, angiogenic or quiescent phenotypes. While control and PAH harbored many similar subgroups of endothelial cells, PAH had greater proportions of angiogenic and proliferative subsets. These findings identify that only specific subgroups of PAH PAEC have gene expression different than healthy PAEC, and suggest these subpopulations lead to the pathologic functions leading to remodeling.

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