Prognostic Significance of Proteomics-Discovered Circulating Inflammatory Biomarkers in Patients With Pulmonary Arterial Hypertension.

BACKGROUND: Pulmonary arterial hypertension (PAH) ultimately leads to right ventricular failure and premature death. The identification of circulating biomarkers with prognostic utility is considered a priority. As chronic inflammation is recognized as key pathogenic driver, we sought to identify inflammation-related circulating proteins that add incremental value to current risk stratification models for long-term survival in patients with PAH. METHODS AND RESULTS: Plasma levels of 384 inflammatory proteins were measured with the proximity extension assay technology in patients with PAH (n=60) and controls with normal hemodynamics (n=28). Among these, 51 analytes were significantly overexpressed in the plasma of patients with PAH compared with controls. Cox proportional hazard analyses and C-statistics were performed to assess the prognostic value and the incremental prognostic value of differentially expressed proteins. A panel of 6 proteins (CRIM1 [cysteine rich transmembrane bone morphogenetic protein regulator 1], HGF [hepatocyte growth factor], FSTL3 [follistatin-like 3], PLAUR [plasminogen activator, urokinase receptor], CLSTN2 [calsyntenin 2], SPON1 [spondin 1]) were independently associated with death/lung transplantation at the time of PAH diagnosis after adjustment for the 2015 European Society of Cardiology/European Respiratory Society guidelines, the REVEAL (Registry to Evaluate Early and Long-Term PAH Disease Management) 2.0 risk scores, and the refined 4-strata risk assessment. CRIM1, PLAUR, FSTL3, and SPON1 showed incremental prognostic value on top of the predictive models. As determined by Western blot, FSTL3 and SPON1 were significantly upregulated in the right ventricle of patients with PAH and animal models (monocrotaline-injected and pulmonary artery banding-subjected rats). CONCLUSIONS: In addition to revealing new actors likely involved in cardiopulmonary remodeling in PAH, our screening identified promising circulating biomarkers to improve risk prediction in PAH, which should be externally confirmed.

Myeloproliferative Diseases as Possible Risk Factor for Development of Chronic Thromboembolic Pulmonary Hypertension-A Genetic Study.

Chronic thromboembolic pulmonary hypertension (CTEPH) is a rare disease which is often caused by recurrent emboli. These are also frequently found in patients with myeloproliferative diseases. While myeloproliferative diseases can be caused by gene defects, the genetic predisposition to CTEPH is largely unexplored. Therefore, the objective of this study was to analyse these genes and further genes involved in pulmonary hypertension in CTEPH patients. A systematic screening was conducted for pathogenic variants using a gene panel based on next generation sequencing. CTEPH was diagnosed according to current guidelines. In this study, out of 40 CTEPH patients 4 (10%) carried pathogenic variants. One patient had a nonsense variant (c.2071A>T p.Lys691*) in the BMPR2 gene and three further patients carried the same pathogenic variant (missense variant, c.1849G>T p.Val617Phe) in the Janus kinase 2 (JAK2) gene. The latter led to a myeloproliferative disease in each patient. The prevalence of this JAK2 variant was significantly higher than expected (p < 0.0001). CTEPH patients may have a genetic predisposition more often than previously thought. The predisposition for myeloproliferative diseases could be an additional risk factor for CTEPH development. Thus, clinical screening for myeloproliferative diseases and genetic testing may be considered also for CTEPH patients.

MiR-23a regulates the proliferation and migration of human pulmonary artery smooth muscle cells (HPASMCs) through targeting BMPR2/Smad1 signaling.

Pulmonary arterial hypertension (PAH) associated with congenital heart disease (CHD) (PAH-CHD) is a severe and progressive disease with a poor prognosis. MiR-23a, a member of miR-23a/24/27a cluster, has been reported to function as an important player in PAH. However, the detailed functions and molecular mechanisms of miR-23a in PAH-CHD are still not fully elucidated. Due to hypoxia is an important stimulus for pulmonary artery smooth muscle cells (PASMCs) proliferation and vascular remodeling, we assessed the expression and functions of miR-23a in hypoxia-induced HPASMCs. qRT-PCR assay revealed that miR-23a level was upregulated in plasma of PAH-CHD patients and hypoxia-induced HPASMCs. Loss-of-function experiments demonstrated that miR-23a depletion suppressed hypoxia-induced proliferation and migration in HPASMCs. Dual-luciferase reporter assay verified that bone morphogenetic protein receptor type 2 (BMPR2) was a direct target of miR-23a. Moreover, BMPR2 level was downregulated in plasma of PAH-CHD patients and hypoxia-induced HPASMCs. Additionally, BMPR2-mediated suppression on proliferation and migration of hypoxia-induced HPASMCs was abrogated by miR-23a overexpression. Furthermore, miR-23a directly affected BMPR2/Smad1 signaling in hypoxia-induced HPASMCs. In conclusion, miR-23a facilitated cell proliferation and migration by targeting BMPR2/Smad1 signaling in hypoxia-induced HPASMCs, providing a potential therapeutic target for PAH treatment.

Transcriptional up-regulation of BMP-4 and BMPR-II genes in the peripheral blood of breast cancer patients: A pilot study.

BACKGROUND: Bone morphogenetic proteins (BMPs) belong to the transforming growth factor beta (TGF-ß) super family, which are primarily known for their inherent role in osteogenesis and ontogenesis. Accumulating evidence suggests the regulatory role of BMP-4 in cellular proliferation, apoptosis, differentiation and thus a possible oncogenic role. OBJECTIVE: Variable cellular expression and in vitro functional assays are indicative of the involvement of BMP related signaling in Breast cancer (BC). The differential expression of BMP-4 in the peripheral blood of BC patients may therefore be considered as a potential biomarker. Therefore, this study aimed to evaluate transcriptional expression of BMP-4 and its cognate receptor BMPR-II in the peripheral blood from the BC patients in relation to the healthy individuals. METHODS: The expression pattern of BMP-4 and BMPR-II was analyzed in the blood of breast cancer patients (n = 22) and healthy controls (n = 22) through Semi Quantitative Reverse transcription Polymerase chain reaction. RESULTS: An up-regulated expression of BMP-4 and BMPR-II was observed in the peripheral blood of breast cancer patients especially in the advanced-stage of the disease. Moreover, BMP-4 and BMPR-II expressions were found to be correlated. CONCLUSION: The current preliminary results based on the transcriptional analysis suggest the prospective use of BMP4 as a biomarker, however further validation is required.

Elevation of plasma cell-free hemoglobin in pulmonary arterial hypertension.

BACKGROUND: Cell-free hemoglobin (CFH) is a potent nitric oxide scavenger associated with poor outcomes in several diseases. Pulmonary arterial hypertension (PAH) is characterized by reduced nitric oxide availability. We hypothesized that CFH would be elevated in PAH and would associate with hemodynamics and clinical outcomes. METHODS: We measured CFH in 200 consecutively evaluated patients with PAH, 16 unaffected bone morphogenetic receptor protein type 2 (BMPR2) mutation carriers, 19 healthy subjects, and 29 patients with pulmonary venous hypertension (PVH). CFH values were tested for association with hemodynamics, time to hospitalization, and death. RESULTS: CFH was elevated in patients with PAH and BMPR2 carriers compared with healthy subjects and patients with PVH (P ≤ .01 all comparisons). There were no differences in CFH across PAH subtypes. CFH modestly correlated with mean pulmonary artery pressure (ρ = 0.16, P = .03) and pulmonary vascular resistance (ρ = 0.21, P = .01) and inversely with cardiac index (ρ = -0.18, P = .02) in patients with PAH. CFH was not associated with hemodynamic response to nitric oxide or death. Patients with the highest CFH levels had increased risk of PAH-related hospitalization when adjusted for age, sex, and PAH cause (hazard ratio, 1.69; 95% CI ,1.08-2.66; P = .02). CONCLUSIONS: CFH is elevated in patients with PAH and BMPR2 carriers compared with healthy subjects and patients with PVH. Elevated CFH levels are independently associated with an increased risk of hospitalization. Further study is required to understand the mechanism of CFH elevation and the potential pathologic contribution of CFH in PAH.

Marcadores biológicos. Utilidad para el control del paciente con hipertensión pulmonar / Biological markers. Utility in the management of patients with pulmonary hypertension

Se entiende como marcador biológico cualquier característica que puede ser objetivamente medida y evaluada como indicadora de un proceso biológico normal, un proceso patogénico o una respuesta farmacológica a una intervención terapéutica. En el terreno de la hipertensión arterial pulmonar (HAP), además de los marcadores habituales (hemodinámicos y funcionales), se cuenta con un número creciente de biomarcadores que permiten un acercamiento cada vez más completo al conocimiento de la susceptibilidad y al establecimiento del diagnóstico, pronóstico y respuesta al tratamiento. Estos marcadores pueden ser tanto constitutivos (genéticos) como reactivos a la enfermedad (relacionados con el fallo ventricular derecho, como BMP/NT-proBNP, con la disfunción endotelial, como la endotelina-1, o con la inflamación, como determinadas citocinas y quimiocinas). Los nuevos descubrimientos en genómica y proteómica permiten augurar avances fundamentales en este campo (AU)

A biological marker can be defined as any substance that can be objectively measured and evaluated as an indicator of a normal biological process, a pathogenic process or pharmacological responses to a therapeutic intervention. In pulmonary hypertension (PH), in addition to routine markers (hemodynamic and functional), there are a growing number of biomarkers that allow an increasingly comprehensive approach to knowledge of susceptibility to this disease and to diagnosis, prognosis and treatment response. These markers can be both constitutive (genetic) and disease-related (related to right ventricular failure, such as BMP/NT-proBNP, endothelial dysfunction, such as endothelin-1, or inflammation, such as certain cytokines and chemokines). Novel insights in genomics and proteomics may allow major advances in this field (AU)

[Biological markers. Utility in the management of patients with pulmonary hypertension]. / Marcadores biológicos. Utilidad para el control del paciente con hipertensión pulmonar.

A biological marker can be defined as any substance that can be objectively measured and evaluated as an indicator of a normal biological process, a pathogenic process or pharmacological responses to a therapeutic intervention. In pulmonary hypertension (PH), in addition to routine markers (hemodynamic and functional), there are a growing number of biomarkers that allow an increasingly comprehensive approach to knowledge of susceptibility to this disease and to diagnosis, prognosis and treatment response. These markers can be both constitutive (genetic) and disease-related (related to right ventricular failure, such as BMP/NT-proBNP, endothelial dysfunction, such as endothelin-1, or inflammation, such as certain cytokines and chemokines). Novel insights in genomics and proteomics may allow major advances in this field.