Mass Effect Alone May Not Explain Pulmonary Vascular Pathology in Severe Congenital Diaphragmatic Hernia

Abstract

Congenital diaphragmatic hernia (CDH) and congenital pulmonary airway malformation (CPAM) are diseases in which chest-occupying lesions can result in severe pulmonary hypoplasia. However, significant postnatal mortality due to pulmonary hypertension (PH) is more often seen in patients with CDH. We analyzed prenatal echocardiographic parameters of pulmonary vascular pathology in these groups to understand whether PH in patients with CDH is secondary to a mass effect or to underlying disease. We analyzed pre- and postnatal characteristics of 26 patients with severe CDH and 23 patients with severe CPAM from 2009 to 2012. Severe mediastinal compression, indicated by a low cardiothoracic ratio, was evident in both groups. However, fetuses with severe CDH had smaller pulmonary arteries bilaterally and higher pulsatility indices in the ipsilateral lung than those with severe CPAM. Prenatal modified McGoon indices were significantly lower in patients with CDH versus CPAM. Consistent with these prenatal measurements, postnatal PH was seen more frequently in patients with CDH compared to CPAM. Patients with severe CDH have prenatal evidence of pulmonary vascular remodeling compared to patients with severe CPAM. These results suggest a multifactorial origin for PH in CDH and support the idea of using prenatal medical therapies to promote vascular remodeling in these patients.

PBX transcription factors drive pulmonary vascular adaptation to birth

“…Using this approach, we found that, All infants with CDH have some degree of mechanical compression of the lung that contributes to PH after birth. This direct, causal relationship has been challenged, for example, in cases of congenital pulmonary airway malformation (CPAM), in which mechanical compression of the lung does not lead to elevated PVR (12). Our findings from the lung mesenchymal deletion of Pbx1/2 demonstrate for the first time to our knowledge that molecular defects intrinsic to the lung are sufficient to cause PH independently of the diaphragmatic defect and mechanical compression.…”

“…However, the severity of lung hypoplasia and PH and the rate of mortality in patients with CDH exceed what is observed in infants with other malformations, such as congenital pulmonary airway malformation or omphalocele, which similarly compromise lung development due to mechanical compression (12,13). These findings raise the possibility that there may be diaphragm-independent causes of lung abnormalities in CDH.…”

Congenital diaphragmatic hernias: from genes to mechanisms to therapies

“…In support of the dual-hit hypothesis, there is increasing evidence that some CDH patients have primary defects of the lung and pulmonary vasculature. A recent study of CDH patients with lesions that cause decreased thoracic space in the developing fetus demonstrated that, in comparison to patients with congenital pulmonary airway malformation, whose lungs are distorted by cysts that develop within the tissue, CDH patients have more severe lung and pulmonary vascular defects ( Derderian et al, 2016 ). This finding suggests that mechanical compression alone is not solely responsible for the lung and pulmonary vascular defects seen in this disorder.…”

Fetal lung transcriptome patterns in an ex vivo compression model of diaphragmatic hernia

“…9 Second, other space-occupying lesions because of which there is extrinsic mass effect on the early fetal lung (e.g., congenital lung malformations) do not typically result in significant lung hypoplasia and pulmonary hypertension at birth. 10 Finally, teratogenic rodent models of CDH point toward primary aberrations of retinoic acid signaling within the mesenchyme itself as a causative factor in CDH. 11,12 Given these observations, we sought to better understand the relative contribution of mechanical forces in the CDH lung by exploring lung development in the nitrofen rat model using a novel ex vivo mechanical compression microdevice.…”