IJCA-18057; No of Pages 6 International Journal of Cardiology xxx (2014) xxx–xxx
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Blood biomarkers and their potential role in pulmonary arterial hypertension associated with congenital heart disease. A systematic review☆ George Giannakoulas a,b,⁎, Sophia-Anastasia Mouratoglou a, Michael A. Gatzoulis b, Haralambos Karvounis a a b
First Cardiology Department, AHEPA Hospital, Aristotle University of Thessaloniki, St. Kyriakidi 1, 54636, Thessaloniki, Greece Royal Brompton Biomedical Research Unit NIHR, National Heart and Lung Institute, Imperial College, London, United Kingdom
a r t i c l e
i n f o
Article history: Received 28 January 2014 Accepted 13 April 2014 Available online xxxx Keywords: Congenital heart disease Pulmonary hypertension Endothelial dysfunction Brain natriuretic peptide Asymmetric dimethylarginine Vascular endothelial growth factor
a b s t r a c t Background: The development of pulmonary arterial hypertension (PAH) in patients with congenital heart disease (CHD) is multifactorial with a number of biomarkers serving as mediators of neurohormonal activation [B-type natriuretic peptide (BNP) and its N-terminal-pro-fragment (NT-proBNP)], endothelial dysfunction [asymmetric dimethylarginine (ADMA)] and cellular proliferation [vascular endothelial growth factor (VEGF)]. Methods: We systematically reviewed the literature for trials studying the role of these biomarkers in the clinical evaluation, prognosis and management of patients with PAH related to CHD (CHD–PAH). Results: Twenty-six studies were included in the systematic review, involving a total of 1113 patients with CHD– PAH. These patients had higher BNP, NT-proBNP and ADMA levels and higher VEGF expression when compared with healthy controls. Baseline and serial values of plasma levels of natriuretic peptides were shown to be significant predictors of survival. ADMA concentration was elevated in patients with CHD–PAH when compared with patients with simple CHD without PAH, whereas VEGF expression was particularly high in patients with CHD and persistent PAH after corrective surgery of the underlying heart disease. Conclusion: Right heart dysfunction, endothelial inflammation and proliferation are mirrored by plasma levels of the corresponding biomarkers among patients with CHD–PAH. There is early evidence to suggest that natriuretic peptides, in particular, may be a simple and effective tool for determining prognosis and timing for therapeutic interventions in patients with CHD–PAH. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Pulmonary arterial hypertension (PAH) is a relatively common complication in patients with congenital heart disease (CHD), affecting both disease progression and prognosis. Increased proliferation and migration of pulmonary vascular smooth cells are considered to be the pathophysiological keystones in all forms of PAH [1]. Additionally, neurohormonal activation and endothelial dysfunction are also important pathogenic features in PAH associated with CHD (CHD–PAH) [2]. To this extent, some biomarkers have been identified to play an important role in the pathophysiology of CHD–PAH, serving as mediators of neurohormonal activation [B-type natriuretic peptide (BNP) and its N-terminal-pro-fragment (NT-proBNP)], endothelial dysfunction
☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: First Cardiology Department, AHEPA University Hospital, St. Kyriakidi 1, 54636, Thessaloniki, Greece. Tel./fax: +30 2310400304. E-mail address: [email protected] (G. Giannakoulas).
[asymmetric dimethylarginine (ADMA)], and cell proliferation [vascular endothelial growth factor (VEGF)]. Numerous biomarkers have been shown to carry prognostic significance in idiopathic PAH and to correlate with other predictors of outcome. As CHD–PAH differs significantly to other types of PAH in terms of cardiac physiology and prognosis, it is indeed a worthwhile endeavor reviewing the evidence related to this expanding group of patients. In the present systematic review, we sought to evaluate the literature on the role of BNP/NT-proBNP, ADMA, and VEGF in the diagnosis, clinical management and prognosis of patients with CHD–PAH. 2. Methods 2.1. Search strategy Eligible studies were identified through literature search in the electronic databases MEDLINE and EMBASE with the use of various combinations of MeSH and non-MeSH terms, with focus on pulmonary hypertension associated with congenital heart disease. The following Medical Subject Headings and text key words were used: “cardiac or heart defects, congenital,” “heart defects, congenital” and “pulmonary hypertension, arterial” and “natriuretic peptide, brain” and/or “pro-brain natriuretic peptide” and/or “dimethylarginine, asymmetric” and/or “endothelial growth factor, vascular.” The
http://dx.doi.org/10.1016/j.ijcard.2014.04.156 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Giannakoulas G, et al, Blood biomarkers and their potential role in pulmonary arterial hypertension associated with congenital heart disease. A
Contents lists available at ScienceDirect
International Journal of Cardiology journal homepage: www.elsevier.com/locate/ijcard
Blood biomarkers and their potential role in pulmonary arterial hypertension associated with congenital heart disease. A systematic review☆ George Giannakoulas a,b,⁎, Sophia-Anastasia Mouratoglou a, Michael A. Gatzoulis b, Haralambos Karvounis a a b
First Cardiology Department, AHEPA Hospital, Aristotle University of Thessaloniki, St. Kyriakidi 1, 54636, Thessaloniki, Greece Royal Brompton Biomedical Research Unit NIHR, National Heart and Lung Institute, Imperial College, London, United Kingdom
a r t i c l e
i n f o
Article history: Received 28 January 2014 Accepted 13 April 2014 Available online xxxx Keywords: Congenital heart disease Pulmonary hypertension Endothelial dysfunction Brain natriuretic peptide Asymmetric dimethylarginine Vascular endothelial growth factor
a b s t r a c t Background: The development of pulmonary arterial hypertension (PAH) in patients with congenital heart disease (CHD) is multifactorial with a number of biomarkers serving as mediators of neurohormonal activation [B-type natriuretic peptide (BNP) and its N-terminal-pro-fragment (NT-proBNP)], endothelial dysfunction [asymmetric dimethylarginine (ADMA)] and cellular proliferation [vascular endothelial growth factor (VEGF)]. Methods: We systematically reviewed the literature for trials studying the role of these biomarkers in the clinical evaluation, prognosis and management of patients with PAH related to CHD (CHD–PAH). Results: Twenty-six studies were included in the systematic review, involving a total of 1113 patients with CHD– PAH. These patients had higher BNP, NT-proBNP and ADMA levels and higher VEGF expression when compared with healthy controls. Baseline and serial values of plasma levels of natriuretic peptides were shown to be significant predictors of survival. ADMA concentration was elevated in patients with CHD–PAH when compared with patients with simple CHD without PAH, whereas VEGF expression was particularly high in patients with CHD and persistent PAH after corrective surgery of the underlying heart disease. Conclusion: Right heart dysfunction, endothelial inflammation and proliferation are mirrored by plasma levels of the corresponding biomarkers among patients with CHD–PAH. There is early evidence to suggest that natriuretic peptides, in particular, may be a simple and effective tool for determining prognosis and timing for therapeutic interventions in patients with CHD–PAH. © 2014 Elsevier Ireland Ltd. All rights reserved.
1. Introduction Pulmonary arterial hypertension (PAH) is a relatively common complication in patients with congenital heart disease (CHD), affecting both disease progression and prognosis. Increased proliferation and migration of pulmonary vascular smooth cells are considered to be the pathophysiological keystones in all forms of PAH [1]. Additionally, neurohormonal activation and endothelial dysfunction are also important pathogenic features in PAH associated with CHD (CHD–PAH) [2]. To this extent, some biomarkers have been identified to play an important role in the pathophysiology of CHD–PAH, serving as mediators of neurohormonal activation [B-type natriuretic peptide (BNP) and its N-terminal-pro-fragment (NT-proBNP)], endothelial dysfunction
☆ All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation. ⁎ Corresponding author at: First Cardiology Department, AHEPA University Hospital, St. Kyriakidi 1, 54636, Thessaloniki, Greece. Tel./fax: +30 2310400304. E-mail address: [email protected] (G. Giannakoulas).
[asymmetric dimethylarginine (ADMA)], and cell proliferation [vascular endothelial growth factor (VEGF)]. Numerous biomarkers have been shown to carry prognostic significance in idiopathic PAH and to correlate with other predictors of outcome. As CHD–PAH differs significantly to other types of PAH in terms of cardiac physiology and prognosis, it is indeed a worthwhile endeavor reviewing the evidence related to this expanding group of patients. In the present systematic review, we sought to evaluate the literature on the role of BNP/NT-proBNP, ADMA, and VEGF in the diagnosis, clinical management and prognosis of patients with CHD–PAH. 2. Methods 2.1. Search strategy Eligible studies were identified through literature search in the electronic databases MEDLINE and EMBASE with the use of various combinations of MeSH and non-MeSH terms, with focus on pulmonary hypertension associated with congenital heart disease. The following Medical Subject Headings and text key words were used: “cardiac or heart defects, congenital,” “heart defects, congenital” and “pulmonary hypertension, arterial” and “natriuretic peptide, brain” and/or “pro-brain natriuretic peptide” and/or “dimethylarginine, asymmetric” and/or “endothelial growth factor, vascular.” The
http://dx.doi.org/10.1016/j.ijcard.2014.04.156 0167-5273/© 2014 Elsevier Ireland Ltd. All rights reserved.
Please cite this article as: Giannakoulas G, et al, Blood biomarkers and their potential role in pulmonary arterial hypertension associated with congenital heart disease. A
