There is a basic difference between pulmonary arterial hypertension (PAH) in adults and in children. In the former case, there are a wide range of causes that contribute to development of PAH, including thromoembolism, vascular obstruction, pulmonary insufficiency, alveolar hypoventilation, chronic lung disease, and other associated comorbidities (e.g.: systemic, metabolic and hematologic disorders) among others.
However, regarding the development of neonatal and pediatric PAH, there is one primary root cause for the onset of the condition: the impaired or incomplete transition and development of pulmonary circulation during the transformation from fetal to postnatal life. This stunted development can either lead to development of PAH in children or at a later stage, such as in adulthood, and gradually leads to development of adverse lung conditions like hypoxia, hyperemia, and inflammation.
Impaired pulmonary transition leads to improper distention of the lungs, faulty exchange of gases, improper development of lung vasculature, and differentiation of distal space chambers. Though some of the common predisposing factors include bronchopulmonary dysplasia (BPD: a chronic neonatal lung condition caused as a result of mechanical ventilation or treatment with an external source of oxygen supply) or congenital heart disease (CHD), reduced production of vasodilators (eg: nitric oxide) or increased production of vasoconstrictors (eg: endothelin and serotonin) and use of anti-depressants during the thrid trimester of pregnancy among others, new insights have shed light to possibilities like abnormal epithelial and endothelial wound repair and genetic mutations as causes behind the pathogenesis of PAH.
Injury caused to endothelial cells might lead to excess accumulation of fibroblasts, which in turn cause accumulation of extracellular matrix, leading to fibrosis, which is another predisposing factor for development of PAH.
Another possibility that researchers have recently suggested as a cause of PAH in newborns and children is faulty angiogenesis (formation of blood vessels), which leads to reduced vascular density, creating pressure on the right ventricle due to improper flow of blood and oxygen, leading to PAH. Hemodynamic stress, impaired mitochondrial metabolism and increase in the levels of sodium and potassium are also predisposing factors.
Circulating endothelial cells and endothelial progenitor cells have also been concluded to have severely affected PAH in children.
Though most of the contributing factors behind pediatric PAH remain unknown, increasing, researchers believe that genetic predisposition plays a major role in why pulmonary circulation development becomes stunted. For instance, mutations in the gene BMPR2 might lead to imbalance in the formation of arterial and vascular cells, since the same is involved in apoptosis and proliferation of endothelial cells. This might lead to improper vasculogenesis or angiogenesis, ultimately causing PAH. Another mutation in the gene, ALK-1, has been linked to the formation of hemorrhagic aggregation of arterioles, capillaries and venules, which leads to venous hypertension and eventually PAH. It is worth noting that both of these genes have their binding ligands as members of the transforming growth factor-beta (TGF-Beta) family, which makes the latter a potential therapeutic target.
New Perspectives On Treatment For Pediatric Pulmonary Hypertension
As far as treatment options are concerned, the premier class of drugs used to treat PAH in adults as well as children include Endothelin Receptor Antagonists (ERA), phosphodiesterase-5 inhibitors (PDE-5 inhibitors) and prostacyclin analogs, all of which have vasodilatory effects. However, the intensity and pathway of dosage in children and adults vary due to tolerance issues and possibilities of side-effects. Though mono therapy (treatment using only one of these above-mentioned therapies) with each of the above class of drugs traditionally has been the conventional method for treating pediatric PH, recent research has emphasized the use of combination therapy to effectively target the condition. Some novel therapies that are currently under investigation by researchers include blockage of platelet-derived growth factor receptors, soluble guanylate cyclase activators, statins, and serotonin signaling molecules.
It is also worth noting that despite ongoing research, the available treatment options only include short-term treatment strategies. Targeting the pathophysiological pathways thus might prove to be just the option which would treat the condition at its root cause.
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