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The heart of the matter: a vascular hypothesis for bronchopulmonary dysplasia

The smaller the baby, the sicker they are likely to be in both the immediate newborn period as well as later in life. Infants with the greatest risk of morbidity and mortality are therefore those who grew poorly during fetal life and who deliver preterm (<37 weeks gestational age). As the capacity of our perinatal services continue to grow, and survival rates of extremely preterm infants continue to rise, it is imperative that biomedical research focuses on improving morbidity as well as reducing mortality rates. Similarly, it is now abundantly clear that the (mal)adaptations that occur in perinatal life to enable these preterm and, or, growth restricted babies to survive have implications for health and wellbeing that extend well beyond the newborn period. Detailed physiological studies, such as that undertaken by Sehgal and his colleagues 2019, published in this issue of The Journal of Physiology, need to sit alongside appropriate animal and interventional studies such that clinical and basic science work synergistically to improve outcomes for the most vulnerable of our patients. Fetal growth restriction (FGR) is most commonly the manifestation of utero-placental dysfunction. The fetus is deprived of oxygen/nutrients and fails to grow according to its genetic potential. Experimental and clinical studies have consistently demonstrated fetal vascular remodelling in FGR that persists in postnatal life. Similarly, human clinical studies have demonstrated altered systemic cardiovascular structure and function in those born preterm, especially if also FGR. However, the full impact of FGR on pulmonary vascular characteristics in those born preterm, and its implications for respiratory function, is less well characterised. Fetal lung development takes place in an environment where the low resistance placenta and not the lung functions as the organ of gas exchange, and fetal cardiac output is primarily shunted via the ductus arteriosus (DA) through to the systemic circulation, bypassing the pulmonary circulation altogether. Following birth, the DA closes and the bulk of cardiac output is directed to the lungs which must now function as the organ of gas exchange and are subject to far higher oxygen concentrations than a fetus at a comparable post-conception age. It is therefore unsurprising that for the preterm infant the myriad of complex interconnecting developmental processes necessary for normal lung development are disrupted. Bronchopulmonary dysplasia (BPD) is one of the commonest serious preterm-associated morbidities (Collins et al. 2017) and describes a clinical endpoint (requirement for oxygen supplementation and/or respiratory support at 36 weeks corrected postnatal age), irrespective of the antecedent causal factors. The lungs of affected infants show disruption of the alveolar units themselves as well as the supporting microvasculature. Infants who develop BPD spend longer in hospital and are at greater risk of developing asthma in childhood and emphysema-like illnesses as an adult. To put this in context, globally, preterm birth affects around 15 million infants each year (March of Dimes, PMNCH, Save the Children, WHO, 2012) and up to a third of these infants are also FGR. The lower the gestational age at birth, the greater the risk of FGR and the greater the risk of developing BPD. Despite these significant individual and socio-economic burdens imposed by BPD, we currently have no targeted therapies to mitigate or prevent its development, or to treat it once established. Although clearly a multi-factorial process, much of the current thinking about BPD reflects the pro-inflammatory mileau that preterm infants are exposed to in both antenatal as well as postnatal life. However, this does not fully explain the heightened vulnerability of preterm FGR infants. In this paper Sehgal and colleagues 2019 revisit the notion that abnormal pulmonary vascular morphology and function (Abman, 2001) may underpin the BPD and therefore explain the risk amplification seen in growth restricted infants. In experimental FGR there is good evidence that systemic vascular biomechanics are altered leading to increased arterial wall stiffness (Dodson et al. 2017) and that altered pulmonary vascular structure and function negatively impact the normal trajectory of pulmonary alveolarisation. The authors used non-invasive echocardiographic techniques to study a group of FGR and normally grown preterm infants in the early postnatal period. Crucially, the DA was functionally closed in all infants, participants were well matched for gestational age and no infants had clinically relevant pulmonary hypertension. Those infants with FGR had evidence of structural and functional changes within the pulmonary vasculature: a thicker, less distensible right main pulmonary artery and evidence of reduced cardiac performance. They argue that these changes allow excessive distal propagation of pressure oscillations in the pulmonary vasculature, leading to disruption of angiogenesis within the pulmonary microvasculature, pulmonary interstitial oedema and thus impaired alveolar growth. However, it remains to be seen whether these early measures of pulmonary vascular dysfunction predict the development and/or severity of later BPD. Nonetheless, characterisation of these changes within a high-risk group of infants raises intriguing questions about the need for early targeted therapy to improve pulmonary vascular performance. Current therapeutic strategies are limited to respiratory interventions designed to keep peripheral oxygen saturations within pre-determined thresholds, and treatment of gross pulmonary hypertension, typically a late manifestation of BPD, with pulmonary vasodilators such as inhaled nitric oxide (iNO) or Sildenafil. If the vascular hypothesis holds true, interventions to improve pulmonary vascular function and therefore optimise alveolar development might mitigate the risk of BPD and transform respiratory health for those born preterm, especially those with FRG.