Diagnosis and Pathophysiological Mechanisms of Group 3 Hypoxia-Induced Pulmonary Hypertension
- 93 Downloads
Purpose of review
Group 3 hypoxia-induced pulmonary hypertension (PH) is an important and increasingly diagnosed condition in both the pediatric and adult population. The majority of pulmonary hypertension studies to date and all three classes of drug therapies were designed to focus on group 1 PH. There is a clear unmet medical need for understanding the molecular mechanisms of group 3 PH and a need for novel non-invasive methods of assessing PH in neonates.
Several growth factors are expressed in patients and in animal models of group 3 PH and are thought to contribute to the pathophysiology of this disease. Here, we review some of the findings on the roles of vascular endothelial growth factor A (VEGFA), platelet-derived growth factor B (PDGFB), transforming growth factor-beta (TGFB1), and fibroblast growth factors (FGF) in PH. Additionally, we discuss novel uses of echocardiographic parameters in assessing right ventricular form and function.
FGF2, TGFB, PDGFB, and VEGFA may serve as biomarkers in group 3 PH along with echocardiographic methods to diagnose and follow right ventricle function. FGFs and VEGFs may also function in the pathophysiology of group 3 PH.
KeywordsPulmonary hypertension Hypoxia Group 3 pulmonary hypertension Echocardiography Right ventricle Fibroblast growth factors
Compliance with Ethical Standards
Conflict of Interest
Kel Vin Woo declares no potential conflicts of interest.
David M. Ornitz reports a grant from the NIH.
Gautam K. Singh is a section editor for Current Treatment Options in Cardiovascular Medicine.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
References and Recommended Reading
Papers of particular interest, published recently, have been highlighted as: • Of importance
- 7.• Mourani PM, Sontag MK, Younoszai A, Miller JI, Kinsella JP, Baker CD, et al. Early pulmonary vascular disease in preterm infants at risk for bronchopulmonary dysplasia. Am J Respir Crit Care Med. 2015;191(1):87–95. This is an important investigation that assessed the utility of echocardiography to identify preterm infants developing pulmonary vascular disease. Early echocardiograms may be useful in identifying patients at risk for BPD and PH.PubMedPubMedCentralGoogle Scholar
- 15.Pacileo G, Calabro P, Limongelli G, Verrengia M, Di Salvo G, Russo GM, et al. Feasibility and usefulness of right ventricular ultrasonic tissue characterization with integrated backscatter in patients with unsuccessfully operatively “repaired” tetralogy of Fallot. Am J Cardiol. 2002;90(6):669–71.PubMedGoogle Scholar
- 25.Matias C, Isla LP, Vasconcelos M, Almeria C, Rodrigo JL, Serra V, et al. Speckle-tracking-derived strain and strain-rate analysis: a technique for the evaluation of early alterations in right ventricle systolic function in patients with systemic sclerosis and normal pulmonary artery pressure. J Cardiovasc Med (Hagerstown). 2009;10(2):129–34.Google Scholar
- 26.• Levy PT, El-Khuffash A, Patel MD, Breatnach CR, James AT, Sanchez AA, et al. Maturational patterns of systolic ventricular deformation mechanics by two-dimensional speckle-tracking echocardiography in preterm infants over the first year of age. J Am Soc Echocardiogr. 2017;30(7):685–98 e1. This investigation uses 2DSTE in a large cohort of ELGAN from birth. BPD and PH negatively impact RV strain throughout the first year of life. Deformation imaging by 2DSTE may be used early to identify impending cardiovascular compromise, and guide early intervention.PubMedPubMedCentralGoogle Scholar
- 35.Sengupta PP, Khandheria BK, Korinek J, Jahangir A, Yoshifuku S, Milosevic I, et al. Left ventricular isovolumic flow sequence during sinus and paced rhythms: new insights from use of high-resolution Doppler and ultrasonic digital particle imaging velocimetry. J Am Coll Cardiol. 2007;49(8):899–908.PubMedGoogle Scholar
- 36.Faludi R, Szulik M, D'Hooge J, Herijgers P, Rademakers F, Pedrizzetti G, et al. Left ventricular flow patterns in healthy subjects and patients with prosthetic mitral valves: an in vivo study using echocardiographic particle image velocimetry. J Thorac Cardiovasc Surg. 2010;139(6):1501–10.PubMedGoogle Scholar
- 37.Idiopathic Pulmonary Fibrosis Clinical Research N, Zisman DA, Schwarz M, Anstrom KJ, Collard HR, Flaherty KR, et al. A controlled trial of sildenafil in advanced idiopathic pulmonary fibrosis. N Engl J Med. 2010;363(7):620–8.Google Scholar
- 39.Bayer terminates phase II study with riociguat in patients with pulmonary hypertension associated with idiopathic interstitial pneumonias [press release]. 2016.Google Scholar
- 45.Gilbane AJ, Derrett-Smith E, Trinder SL, Good RB, Pearce A, Denton CP, et al. Impaired bone morphogenetic protein receptor II signaling in a transforming growth factor-beta-dependent mouse model of pulmonary hypertension and in systemic sclerosis. Am J Respir Crit Care Med. 2015;191(6):665–77.PubMedGoogle Scholar
- 46.Liu Y, Cao Y, Sun S, Zhu J, Gao S, Pang J, et al. Transforming growth factor-beta1 upregulation triggers pulmonary artery smooth muscle cell proliferation and apoptosis imbalance in rats with hypoxic pulmonary hypertension via the PTEN/AKT pathways. Int J Biochem Cell Biol. 2016;77(Pt A):141–54.PubMedGoogle Scholar
- 53.Taraseviciene-Stewart L, Kasahara Y, Alger L, Hirth P, Mc Mahon G, Waltenberger J, et al. Inhibition of the VEGF receptor 2 combined with chronic hypoxia causes cell death-dependent pulmonary endothelial cell proliferation and severe pulmonary hypertension. FASEB J. 2001;15(2):427–38.PubMedGoogle Scholar