Higher plasma fibroblast growth factor 23 levels are associated with a higher risk profile in pulmonary arterial hypertension

Metabolic abnormalities are proposed to contribute to pulmonary arterial as well as right ventricular remodelling in pulmonary arterial hypertension. Among the proposed abnormalities are altered glucose and lipid processing, mitochondrial malfunction, oxidative stress as well as vitamin D and iron abnormalities. In the present study, we investigated 11 metabolic plasma biomarkers, with the hypothesis that metabolic proteins may mirror disease severity in pulmonary arterial hypertension. Using proximity extension assays, plasma metabolic biomarkers were measured in 48 pulmonary arterial hypertension patients at diagnosis and, in 33 of them, at an early treatment follow-up, as well as in 16 healthy controls. Among the studied metabolic biomarkers, plasma fibroblast growth factor-23 ( p < 0.001), fibroblast growth factor-21 ( p < 0.001), fatty acid binding protein 4 ( p < 0.001) and lectin-like oxidised low-density lipoprotein receptor 1 ( p < 0.001) were increased and paraoxonase-3 was decreased ( p < 0.001) in pulmonary arterial hypertension at diagnosis versus controls. Fibroblast growth factor-23 showed the strongest correlations to studied clinical parameters and was therefore selected for further analyses. Fibroblast growth factor-23 correlated specifically to mean right atrial pressure ( r = 0.67, p < 0.001), six-min walking distance ( r = −0.66, p < 0.001), NT-proBNP ( r = 0.64, p < 0.001), venous oxygen saturation ( r = −0.61, p < 0.001), cardiac index ( r = −0.39, p < 0.007) and pulmonary vascular resistance ( r = 0.37, p < 0.01). Fibroblast growth factor-23 correlated moreover to ESC/ERS ( r = 0.72, p < 0.001) and the REVEAL risk score ( r = 0.61, p < 0.001). Comparing early treatment follow-up with baseline, fibroblast growth factor-23 decreased ( p < 0.02), with changes in fibroblast growth factor-23 correlating to changes in six-min walking distance ( r = −0.56, p < 0.003), venous oxygen saturation ( r = −0.46, p < 0.01), pulmonary vascular resistance ( r = 0.43, p < 0.02), mean right atrial pressure ( r = 0.38, p < 0.04) and cardiac index ( r = −0.39, p < 0.04). Elevated plasma fibroblast growth factor-23 levels at pulmonary arterial hypertension diagnosis were associated with worse haemodynamics and a higher risk profile, and were decreased after the administration of pulmonary arterial hypertension-specific treatment.

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Correlation Between Fibroblast Growth Factor-23 and Pulmonary Arterial Hypertension in Hemodialysis Patients

Iranian Journal of Kidney Diseases ◽

10.52547/ijkd.5940 ◽

2021 ◽

Vol 15 (4) ◽

Author(s):

Maryam Miri ◽

Mahnaz Ahmadi ◽

Mohsen Hatami

Keyword(s):

Growth Factor ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 23 ◽

Hemodialysis Patients ◽

Fibroblast Growth ◽

Pulmonary Arterial

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Elevated Basic Fibroblast Growth Factor Levels in Patients With Pulmonary Arterial Hypertension

CHEST Journal ◽

10.1378/chest.126.4.1255 ◽

2004 ◽

Vol 126 (4) ◽

pp. 1255-1261 ◽

Cited By ~ 56

Author(s):

Jacques I. Benisty ◽

Vallerie V. McLaughlin ◽

Michael J. Landzberg ◽

Jonathan D. Rich ◽

Jane W. Newburger ◽

...

Keyword(s):

Growth Factor ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Fibroblast Growth Factor ◽

Basic Fibroblast Growth Factor ◽

Fibroblast Growth ◽

Pulmonary Arterial

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FGF12 (Fibroblast Growth Factor 12) Inhibits Vascular Smooth Muscle Cell Remodeling in Pulmonary Arterial Hypertension

Hypertension ◽

10.1161/hypertensionaha.120.15068 ◽

2020 ◽

Vol 76 (6) ◽

pp. 1778-1786

Author(s):

Yeongju Yeo ◽

Eunhee S. Yi ◽

Jeong-Min Kim ◽

Eun-Kyung Jo ◽

Songyi Seo ◽

...

Keyword(s):

Smooth Muscle ◽

Growth Factor ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Fibroblast Growth Factor ◽

Vascular Remodeling ◽

Fibroblast Growth ◽

Pulmonary Vascular Remodeling ◽

Phenotype Switch ◽

Pulmonary Arterial

Loss of BMP (bone morphogenic protein) signaling induces a phenotype switch of pulmonary arterial smooth muscle cells (PASMCs), which is the pathological basis of pulmonary vascular remodeling in pulmonary arterial hypertension (PAH). Here, we identified FGF12 (fibroblast growth factor 12) as a novel regulator of the BMP-induced phenotype change in PASMCs and elucidated its role in pulmonary vascular remodeling during PAH development. Using murine models of PAH and lung specimens of patients with PAH, we observed that FGF12 expression was significantly reduced in PASMCs. In human PASMCs, FGF12 expression was increased by canonical BMP signaling. FGF12 knockdown blocked the antiproliferative and prodifferentiation effect of BMP on human PASMCs, suggesting that FGF12 is required for the BMP-mediated acquisition of the quiescent and differentiated PASMC phenotype. Mechanistically, FGF12 regulated the BMP-induced phenotype change by inducing MEF2a (myocyte enhancer factor 2a) phosphorylation via p38MAPK signaling, thereby modulating the expression of MEF2a target genes involved in cell proliferation and differentiation. Furthermore, we observed that TG (transgenic) mice with smooth muscle cell–specific FGF12 overexpression were protected from chronic hypoxia–induced PAH development, pulmonary vascular remodeling, and right ventricular hypertrophy. Consistent with the in vitro data using human PASMCs, FGF12 TG mice showed increased MEF2a phosphorylation and a substantial change in MEF2a target gene expression, compared with the WT (wild type) controls. Overall, our findings demonstrate a novel BMP/FGF12/MEF2a pathway regulating the PASMC phenotype switch and suggest FGF12 as a potential target for the development of therapeutics for ameliorating pulmonary vascular remodeling in PAH.

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Correlations between basic fibroblast growth factor (bFGF), vascular endothelial growth factor (VEGF), and clinical features of pulmonary arterial hypertension (PAH)

The Journal of Heart and Lung Transplantation ◽

10.1016/s1053-2498(01)00724-0 ◽

2002 ◽

Vol 21 (1) ◽

pp. 159

Author(s):

J.D Rich ◽

J Benisty ◽

V.V McLaughlin ◽

J Folkman ◽

S Rich

Keyword(s):

Vascular Endothelial Growth Factor ◽

Growth Factor ◽

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Fibroblast Growth Factor ◽

Clinical Features ◽

Vascular Endothelial ◽

Fibroblast Growth ◽

Pulmonary Arterial ◽

Endothelial Growth Factor

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Single-center prognostic validation of the risk assessment of the 2015 ESC/ERS guidelines in patients with pulmonary arterial hypertension in Japan

Canadian Journal of Physiology and Pharmacology ◽

10.1139/cjpp-2019-0640 ◽

2020 ◽

Vol 98 (9) ◽

pp. 653-658 ◽

Cited By ~ 1

Author(s):

Ryo Imai ◽

Shiro Adachi ◽

Masahiro Yoshida ◽

Shigetake Shimokata ◽

Yoshihisa Nakano ◽

...

Keyword(s):

Risk Assessment ◽

Pulmonary Arterial Hypertension ◽

High Risk ◽

Arterial Hypertension ◽

Risk Group ◽

Low Risk ◽

World Health ◽

Right Atrial ◽

Walking Distance ◽

Pulmonary Arterial

The 2015 European Society of Cardiology/European Respiratory Society guidelines for the diagnosis and treatment of pulmonary hypertension include a multidimensional risk assessment for patients with pulmonary arterial hypertension (PAH). However, prognostic validations of this risk assessment are limited, especially outside Europe. Here, we validated the risk assessment strategy in PAH patients in our institution in Japan. Eighty consecutive PAH patients who underwent right heart catheterization between November 2006 and December 2018 were analyzed. Patients were classified as low, intermediate, or high risk by using a simplified version of the risk assessment that included seven variables: World Health Organization functional class, 6-min walking distance, peak oxygen consumption, brain natriuretic peptide, right atrial pressure, mixed venous oxygen saturation, and cardiac index. The high-risk group showed significantly higher mortality than the low- or intermediate-risk group at baseline (P < 0.001 for both comparisons), and the mortalities in the intermediate- and low-risk groups were both low (P = 0.989). At follow-up, patients who improved to or maintained a low-risk status showed better survival than those who did not (P = 0.041). Our data suggest that this risk assessment can predict higher mortality risk and long-term survival in PAH patients in Japan.

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Response of fibroblast growth factor 23 to volume interventions in arterial hypertension and diabetic nephropathy

Medicine ◽

10.1097/md.0000000000005003 ◽

2016 ◽

Vol 95 (46) ◽

pp. e5003 ◽

Cited By ~ 6

Author(s):

Jelmer K. Humalda ◽

Sarah Seiler-Muler ◽

Arjan J. Kwakernaak ◽

Marc G. Vervloet ◽

Gerjan Navis ◽

...

Keyword(s):

Diabetic Nephropathy ◽

Growth Factor ◽

Arterial Hypertension ◽

Fibroblast Growth Factor ◽

Fibroblast Growth Factor 23 ◽

Fibroblast Growth

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First-in-child use of the oral selective prostacyclin IP receptor agonist selexipag in pulmonary arterial hypertension

Pulmonary Circulation ◽

10.1177/2045893217703369 ◽

2017 ◽

Vol 7 (2) ◽

pp. 551-554 ◽

Cited By ~ 17

Author(s):

Lianne M. Geerdink ◽

Harald Bertram ◽

Georg Hansmann

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Right Ventricular ◽

Receptor Agonist ◽

Diastolic Pressure ◽

Functional Class ◽

Right Atrial ◽

Walking Distance ◽

Off Label ◽

Pulmonary Arterial

Pulmonary arterial hypertension (PAH) is a complex disease with a poor prognosis. Selexipag is a selective prostacyclin receptor agonist with vasodilatory, anti-proliferative, anti-inflammatory, and pro-angiogenic properties. However, no clinical data on its therapeutic use in children with PAH are currently available. Here, we report the case of a 12-year-old girl who presented in World Health Organization (WHO) functional class III and right ventricular (RV) failure with recurrent syncope, dizziness, and progressive fatigue for two years. Cardiac catheterization revealed severe precapillary PAH: mean right atrial pressure (RAP) = 10–13 mmHg, right ventricular end-diastolic pressure (RVEDP) = 13 mmHg, left ventricular end-diastolic pressure (LVEDP) = 7 mmHg, mean pulmonary arterial pressure (PAP) = 81 mmHg, and mean aorta ascendens pressure = 89 mmHg. The pulmonary vascular resistance index (PVRi) was 25.2 WU × m2. An oral combination therapy was started with a phosphodiesterase type 5 inhibitor (sildenafil 3 × 20 mg) and an endothelin-1 receptor antagonist (bosentan 2 × 62.5 mg). No significant clinical/hemodynamic improvement was seen after nine months of dual therapy, so that the patient was transferred to our institution. We agreed upon the off-label add-on use of oral selexipag. Within ten days, we up-titrated selexipag to a final (max. adult) dose of 1600 mcg twice daily. After six months, the patient had: (1) decrease in PVR index, pulmonary artery acceleration time, RAP, RVEDP, right atrial/RV size; (2) re-gain of vasoreactivity; and (3) improvement of cardiac index, 6-minute walking distance, functional class, body weight, and CAMPHOR score. Our encouraging results suggest the consideration of off-label use of oral selexipag in children with severe PAH, preferably in a protocol-driven prospective study.

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Association between cytokines and functional, hemodynamic parameters, and clinical outcomes in pulmonary arterial hypertension

Pulmonary Circulation ◽

10.1177/2045894018794051 ◽

2018 ◽

Vol 8 (3) ◽

pp. 204589401879405 ◽

Cited By ~ 3

Author(s):

Aditya A. Joshi ◽

Ryan Davey ◽

Youlan Rao ◽

Kai Shen ◽

Raymond L. Benza ◽

...

Keyword(s):

Pulmonary Arterial Hypertension ◽

Arterial Hypertension ◽

Clinical Outcomes ◽

Functional Class ◽

Right Atrial ◽

Walking Distance ◽

Hemodynamic Parameters ◽

Risk Of Death ◽

Cytokine Levels ◽

Pulmonary Arterial

To assess the relationship of cytokines with functional and clinical outcomes in pulmonary arterial hypertension (PAH). Endothelial dysfunction and vascular inflammation are characteristic of PAH. We investigated whether markers of angiogenesis and inflammation associated with functional, hemodynamic parameters, and clinical outcomes in PAH. PAH patients (n = 206) were pooled from two clinical trials: TRUST-1 and FREEDOM-C2. Baseline and post-treatment cytokine levels were correlated to baseline clinical and hemodynamic parameters, were assessed in clinical subgroups, and were associated with clinical outcomes. In 206 patients (mean age = 48 years; 74% women) with WHO group-1 PAH, most cytokine levels were higher in those with 6-min walking distance (6MWD) < median (335 m) vs. those above median, including Ang-1 (11.9 ± 10.1 vs. 5.9 ± 6.0 ng/mL), Ang-2 (14.3 ± 11.8 vs. 12.2 ± 11.2 ng/mL), and MMP-9 (221 ± 262.3 vs. 119 ± 171 ng/mL). Baseline 6MWD inversely correlated with Ang-1 (r = −0.27, P < 0.0001), Ang-2 (r = −0.20, P = 0.004), and MMP-9 (r = −0.27, P < 0.0001). MMP-9 levels differed significantly by NYHA functional class ( P = 0.001) suggesting an association between MMP-9 and subjective PAH severity. Mean Ang-2 levels were higher in those with baseline right atrial pressure (RAP) > 15 mmHg compared to those with RAP < 15 mmHg (23,841 vs. 11,020 pg/mL). Baseline RAP was associated with change in MMP-9 levels (r = −0.53, P = 0.03). Finally, baseline Ang-1, VEGF and MMP-9 levels were associated with risk of death and hospitalization at 16-week follow-up. Inflammatory cytokines and vascular angiogenesis markers are associated with baseline functional, hemodynamic parameters in PAH, and predict death and hospitalization. Larger prospective studies are needed to confirm the utility of cytokines in PAH.

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