Lung Function, Inflammation, and Endothelin‐1 in Congenital Heart Disease–Associated Pulmonary Arterial Hypertension

Low, Andrew; George, Sarah J.; Howard, Luke; Bell, Nicholas; Millar, Ann; Tulloh, Robert

doi:10.1161/jaha.117.007249

Cited by 17 publications

(17 citation statements)

References 53 publications

(113 reference statements)

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“…Inflammatory biomarkers might be useful as diagnostic and prognostic tools in PAH and CTEPH [21,32,42,80,[94][95][96][97][98][99][100][101][102]; these are highlighted in Table 1. Inflammatory cytokines and chemokines can contribute directly to the recruitment of immune cells, the activation and proliferation of PASMCs, and endothelial dysfunction.…”

Section: Inflammatory Diagnostic and Prognostic Biomarkers In Pah Andmentioning

confidence: 99%

Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective

Koudstaal

Boomars

Kool

2020

JCM

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Pulmonary hypertension (PH) is a debilitating progressive disease characterized by increased pulmonary arterial pressures, leading to right ventricular (RV) failure, heart failure and, eventually, death. Based on the underlying conditions, PH patients can be subdivided into the following five groups: (1) pulmonary arterial hypertension (PAH), (2) PH due to left heart disease, (3) PH due to lung disease, (4) chronic thromboembolic PH (CTEPH), and (5) PH with unclear and/or multifactorial mechanisms. Currently, even with PAH-specific drug treatment, prognosis for PAH and CTEPH patients remains poor, with mean five-year survival rates of 57%–59% and 53%–69% for PAH and inoperable CTEPH, respectively. Therefore, more insight into the pathogenesis of PAH and CTEPH is highly needed, so that new therapeutic strategies can be developed. Recent studies have shown increased presence and activation of innate and adaptive immune cells in both PAH and CTEPH patients. Moreover, extensive biomarker research revealed that many inflammatory and immune markers correlate with the hemodynamics and/or prognosis of PAH and CTEPH patients. Increased evidence of the pathological role of immune cells in innate and adaptive immunity has led to many promising pre-clinical interventional studies which, in turn, are leading to innovative clinical trials which are currently being performed. A combination of immunomodulatory therapies might be required besides current treatment based on vasodilatation alone, to establish an effective treatment and prevention of progression for this disease. In this review, we describe the recent progress on our understanding of the involvement of the individual cell types of the immune system in PH. We summarize the accumulating body of evidence for inflammation and immunity in the pathogenesis of PH, as well as the use of inflammatory biomarkers and immunomodulatory therapy in PAH and CTEPH.

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Section: Inflammatory Diagnostic and Prognostic Biomarkers In Pah Andmentioning

confidence: 99%

Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective

Koudstaal

Boomars

Kool

2020

JCM

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“…The cause of airway obstruction in ES seems to be multifactorial: loss of elastic recoil at low lung volumes, intrinsic narrowing or obliteration of small airways, effect of vasoactive and inflammatory mediators and mechanical encroachment of dilated vessels. 10,11,15,[20][21][22][23] Increased serum endothelin-1 level is correlated with airway obstruction in CHD-associated PAH. 11 Airflow obstruction in PH may be due to compression of the mainstem bronchi by dilated pulmonary arteries.…”

Section: Discussionmentioning

confidence: 99%

“…10,11,15,[20][21][22][23] Increased serum endothelin-1 level is correlated with airway obstruction in CHD-associated PAH. 11 Airflow obstruction in PH may be due to compression of the mainstem bronchi by dilated pulmonary arteries. [21][22][23] Unfortunately, we cannot confirm this hypothesis because in our study, bronchial compression on CT did not differ in the obstruction and non-obstruction groups (Fig.…”

Section: Discussionmentioning

confidence: 99%

“…8 The diagnosis of chronic obstructive pulmonary disease (COPD) in patients with HF might be challenging, because both conditions may overlap. [9][10][11] There is a controversy about changes in lung function in pulmonary hypertension (PH), especially in patients with ES, because the precise mechanisms that contribute to abnormal changes of lung function are not clearly known, probably are multifactorial and variable, depending on the underlying CHD. 12,13 The aim of the study was to determine the relationship between lung function and disease severity (including HF markers and associated CHD) and to analyse the possible causes of airflow obstruction in patients with ES.…”

Section: Introductionmentioning

confidence: 99%

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Insights to correlations and discrepancies between impaired lung function and heart failure in Eisenmenger patients

et al. 2020

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Impaired lung function and spirometric signs of airway obstruction without common risk factors for chronic obstructive pulmonary disease could be found in patients with Eisenmenger syndrome. This study aimed to analyse the association between lung function parameters and disease severity (including heart failure markers, associated congenital heart defect) as well as the possible reasons for airflow obstruction in Eisenmenger syndrome. The data of 25 patients with Eisenmenger syndrome were retrospectively evaluated. The patients were divided into groups according to airflow obstruction and a type of congenital heart defect. Airflow obstruction was found in nearly third (32%) of our cases and was associated with older age and worse survival. No relation was found between airway obstruction, B-type natriuretic peptide level, complexity of congenital heart defect and bronchial compression. Most of the patients (88%) had gas diffusion abnormalities. A weak negative correlation was noticed between gas diffusion (diffusing capacity of the lung for carbon monoxide) and B-type natriuretic peptide level (r = −0.437, p = 0.033). Increased residual volume was associated with higher mortality (p = 0.047 and p = 0.021, respectively). A link between B-type natriuretic peptide and lung diffusion, but not airway obstruction, was found. Further research and larger multicentre studies are needed to evaluate the importance of pulmonary function parameters and mechanisms of airflow obstruction in Eisenmenger syndrome.

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“…This is significant because PAH is characterized by progressive inflammation and vessel wall remodelling leading to increased vasoconstriction and increased pulmonary artery resistance. 26,27…”

Section: Discussionmentioning

confidence: 99%

Chronic dosing with metformin plus bosentan decreases in vitro pulmonary artery contraction from isolated arteries in adults with pulmonary hypertension

Liao

Zheng

et al. 2019

J Cardiovasc Thorac Res

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Introduction: Pulmonary arterial hypertension (PAH) specific drug therapy using bosentan has significantly improved quality of life and survival, although PAH is still an incurable disease. Recent studies suggest metformin may have additional treatment benefits in PAH. We therefore investigated in vitro pulmonary artery reactivity after combination therapy of bosentan and metformin in PAH patients as compared with bosentan monotherapy in a prospective, randomized study. Methods: Adult patients with PAH associated with congenital heart defects (PAH-CHD) were randomised to receive bosentan (initially at 62.5 mg twice daily for 4 weeks and then 125 mg twice daily) for 3 months with or without the combination treatment of metformin (500 mg twice daily). Vessel reactivity of isolated pulmonary arteries was examined using a wire myograph. Results: Phenylephrine (PE)-induced contractions of arteries in patients received combination therapy were significantly attenuated at concentrations of 3 × 10-7 M, 10-6 M and 3 × 10-6 M, compared to those received bosentan monotherapy. After denudation, PE-induced contractions at concentrations of 3 × 10-6 M and 10-5 M were significantly decreased in the combination therapy group. AMP-activated protein kinase (AMPK) inhibitor compound C abrogated the inhibitory effects of metformin on PE-induced contractility. AMPK and eNOS phosphorylation in the pulmonary arteries of patients treated with combination therapy was increased compared to monotherapy (P < 0.05). Conclusion: Adding metformin to bosentan therapy in patients with PAH-CHD decreased in vitro pulmonary artery contraction induced by PE, which is possibly related to increased AMPK phosphorylation.

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Lung Function, Inflammation, and Endothelin‐1 in Congenital Heart Disease–Associated Pulmonary Arterial Hypertension

Cited by 17 publications

References 53 publications

Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective

Pulmonary Arterial Hypertension and Chronic Thromboembolic Pulmonary Hypertension: An Immunological Perspective

Insights to correlations and discrepancies between impaired lung function and heart failure in Eisenmenger patients

Chronic dosing with metformin plus bosentan decreases in vitro pulmonary artery contraction from isolated arteries in adults with pulmonary hypertension

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