The Roles of Immunity in the Prevention and Evolution of Pulmonary Arterial Hypertension

Nicolls, Mark R.; Voelkel, Norbert F.

doi:10.1164/rccm.201608-1630pp

Cited by 64 publications

(58 citation statements)

References 120 publications

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“…Predisposing conditions defining these clinical subtypes may produce heterogeneous inflammation due to patient-level variation in genetic factors, 28 metabolism, 29 sex hormones, 30 or endogenous anti-inflammatory responses. 31 Alternatively, all PAH predisposing conditions might elicit similar programmatic inflammation and vascular remodeling. If true, the heterogeneity we observed either (a) captured patient variability in the stage or rate of PAH pathogenesis, or (b) reflected confounding modulators like medications or comorbidities.…”

Section: Discussionmentioning

confidence: 99%

“…Inflammation has a multi-faceted and incompletely understood role in PAH vascular injury and remodeling that involves various signaling pathways, pleiotropic cytokines from multiple cellular sources that have canonical and non-canonical effects, complex local and distant cell-cell interactions, and impaired regulatory immune responses, which appear to perpetuate endothelial cell (EC) and smooth muscle cell (SMC) proliferation and cell phenotype shifts. 10,31 As an initial step toward disentangling cluster-specific pathobiology, we detected unique central cytokine signatures in each immune cluster using partial correlation network analysis. This approach has inferred biological relationships in several 'omics' domains.…”

Section: Discussionmentioning

confidence: 99%

“…Conversely, more patients in cluster 3 had six-minute walk distance >440 meters (51.4 vs 26.3%, p=0.039), NT-proBNP <300 pg/mL (61.0 vs 37.9%, p=0.046), and low or averagerisk REVEAL score (79.2 vs 55.2%, p=0.027). Echocardiographic right ventricular function was the most impaired in cluster 1 (Online Table VII), where fractional area change was significantly lower than cluster 3 (median 24% [21][22][23][24][25][26][27][28] vs 29% [25][26][27][28][29][30][31][32][33][34], p=0.028), and a greater percentage of patients had TAPSE 1.6 cm (53.8%) than in cluster 2 (32.2%, p=0.04) and cluster 3 (30.0%, p=0.04). Hemodynamic comparison (Online Table VIII and Figure XI) revealed that mPAP was more elevated in cluster 1 (52 mmHg [45][46][47][48][49][50][51][52][53][54][55][56][57][58][59][60]) than cluster 2 (46 mmHg [34-60], p=0.045) and cluster 3 (45 mmHg [35][36][37][38][39][40][41][42][43]…”

Section: Immune Clusters Have Different Clinical Risk Profilesmentioning

confidence: 99%

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Discovery of Distinct Immune Phenotypes Using Machine Learning in Pulmonary Arterial Hypertension

Sweatt

Hedlin

Balasubramanian

et al. 2019

Circulation Research

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153

116

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In December 2018, the average time from submission to first decision for all original research papers submitted to Circulation Research was 14.99 days. ABSTRACTRationale: Accumulating evidence implicates inflammation in pulmonary arterial hypertension (PAH) and therapies targeting immunity are under investigation, though it remains unknown if distinct immune phenotypes exist.Objective: Identify PAH immune phenotypes based on unsupervised analysis of blood proteomic profiles. Methods and Results:In a prospective observational study of Group 1 PAH patients evaluated at Stanford University (discovery cohort, n=281) and University of Sheffield (validation cohort, n=104) between 2008-2014, we measured a circulating proteomic panel of 48 cytokines, chemokines, and factors using multiplex immunoassay. Unsupervised machine learning (consensus clustering) was applied in both cohorts independently to classify patients into proteomic immune clusters, without guidance from clinical features. To identify central proteins in each cluster, we performed partial correlation network analysis. Clinical characteristics and outcomes were subsequently compared across clusters. Four PAH clusters with distinct proteomic immune profiles were identified in the discovery cohort. Cluster 2 (n=109) had low cytokine levels similar to controls. Other clusters had unique sets of upregulated proteins central to immune networks-cluster 1 (n=58)(TRAIL, CCL5, CCL7, CCL4, MIF), cluster 3 (n=77)(IL-12, IL-17, IL-10, IL-7, VEGF), and cluster 4 (n=37)(IL-8, IL-4, PDGF-, IL-6, CCL11). Demographics, PAH etiologies, comorbidities, and medications were similar across clusters. Non-invasive and hemodynamic surrogates of clinical risk identified cluster 1 as high-risk and cluster 3 as low-risk groups. Five-year transplant-free survival rates were unfavorable for cluster 1 (47.6%, CI 35.4-64.1%) and favorable for cluster 3 (82.4%, CI 72.0-94.3%)(across-cluster p<0.001). Findings were replicated in the validation cohort, where machine learning classified four immune clusters with comparable proteomic, clinical, and prognostic features.Conclusions: Blood cytokine profiles distinguish PAH immune phenotypes with differing clinical risk that are independent of World Health Organization Group 1 subtypes. These phenotypes could inform mechanistic studies of disease pathobiology and provide a framework to examine patient responses to emerging therapies targeting immunity. Nonstandard Abbreviations and Acronyms: CI confidence interval 95% EC pulmonary artery endothelial cell IQR interquartile range 25-75% K cluster number in unsupervised consensus clustering MFI median fluorescence intensity mPAP mean pulmonary arterial pressure NT-proBNP N-terminal pro b-type natriuretic peptide PAH pulmonary arterial hypertension PVDOMICS Pulmonary Vascular Disease Phenomics Program PVR pulmonary vascular resistance REVEAL Registry to Evaluate Early and Long-term PAH Disease Management SMC pulmonary artery smooth muscle cell SQL structured query language TAPSE tricuspid annular pla...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Immune Clusters Have Different Clinical Risk Profilesmentioning

confidence: 99%

See 1 more Smart Citation

Discovery of Distinct Immune Phenotypes Using Machine Learning in Pulmonary Arterial Hypertension

Sweatt

Hedlin

Balasubramanian

et al. 2019

Circulation Research

Self Cite

153

116

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“…A growing body of evidence has implicated inflammation and altered immunity in the pathogenesis of PAH [190][191][192]. In PAH patients, the size of perivascular inflammatory and immune cell infiltrates correlates with intima + media remodeling and pulmonary artery pressure [193], and abnormally elevated levels of circulating proinflammatory cytokines are predictive of worse outcomes [194,195].…”

Section: Inflammation Immunity and Estradiol Metabolism In Pahmentioning

confidence: 99%

Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension

Tofovic

Jackson

2019

IJMS

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Pulmonary arterial hypertension (PAH) is a debilitating and progressive disease that predominantly develops in women. Over the past 15 years, cumulating evidence has pointed toward dysregulated metabolism of sex hormones in animal models and patients with PAH. 17β-estradiol (E2) is metabolized at positions C2, C4, and C16, which leads to the formation of metabolites with different biological/estrogenic activity. Since the first report that 2-methoxyestradiol, a major non-estrogenic metabolite of E2, attenuates the development and progression of experimental pulmonary hypertension (PH), it has become increasingly clear that E2, E2 precursors, and E2 metabolites exhibit both protective and detrimental effects in PH. Furthermore, both experimental and clinical data suggest that E2 has divergent effects in the pulmonary vasculature versus right ventricle (estrogen paradox in PAH). The estrogen paradox is of significant clinical relevance for understanding the development, progression, and prognosis of PAH. This review updates experimental and clinical findings and provides insights into: (1) the potential impacts that pathways of estradiol metabolism (EMet) may have in PAH; (2) the beneficial and adverse effects of estrogens and their precursors/metabolites in experimental PH and human PAH; (3) the co-morbidities and pathological conditions that may alter EMet and influence the development/progression of PAH; (4) the relevance of the intracrinology of sex hormones to vascular remodeling in PAH; and (5) the advantages/disadvantages of different approaches to modulate EMet in PAH. Finally, we propose the three-tier-estrogen effects in PAH concept, which may offer reconciliation of the opposing effects of E2 in PAH and may provide a better understanding of the complex mechanisms by which EMet affects the pulmonary circulation–right ventricular interaction in PAH.

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“…29 This is not surprising, as it is well documented that multiple inflammatory mediators induce pulmonary vascular remodeling in a variety of PH models. 30,31 For example, IL-6 and IL-13 induce migration of pulmonary smooth muscle cells, thus contributing to pulmonary vascular remodeling. 23, [32][33][34] Transforming growth factor (TGF)-β signaling seems to be particularly important in driving vascular remodeling.…”

Section: Pathophysiology Of Pulmonary Vascular Disease Due To Schistomentioning

confidence: 99%

Pulmonary Vascular Diseases Secondary to Schistosomiasis

Butrous

2017

Advances in Pulmonary Hypertension

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Schistosomiasis is the most common parasitic disease associated with pulmonary arterial hypertension (PAH). It induces remodeling via complex inflammatory processes produced by the parasite eggs. Changes in the pulmonary vasculature after Schistosoma infection are common, but may not always be associated with a clinical manifestation of PAH. Those patients who presented with PAH show clinical signs and symptoms that are not distinguishable from other forms of PAH.

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The Roles of Immunity in the Prevention and Evolution of Pulmonary Arterial Hypertension

Cited by 64 publications

References 120 publications

Discovery of Distinct Immune Phenotypes Using Machine Learning in Pulmonary Arterial Hypertension

Discovery of Distinct Immune Phenotypes Using Machine Learning in Pulmonary Arterial Hypertension

Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension

Pulmonary Vascular Diseases Secondary to Schistosomiasis

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