Non-functional capillary modulates the honeymoon period in congenital diaphragmatic hernia

Congenital diaphragmatic hernia (CDH) results in lung hypoplasia and vascular remodeling with persistent pulmonary hypertension with significant mortality and morbidity. While only the analysis of the ‘’functional’’ gas-exchange capillary with diverging findings has been published, our aim was to investigate the role of the morphologically non-functional capillaries—those that are not in direct contact with neighboring pneumocytes and do not participate in gas exchange— to the pathophysiological cascade culminating in the end of the honeymoon period in CDH. CDH was induced in rats and rabbits, mimicking the first and second hit, respectively. FFPE samples from human CDH autopsy cases were collected. Morphometric analysis of capillary and artery was performed for all cases. Morphometric analysis revealed a significant increase in non-functional capillaries in CDH animal models vs. control and human CDH vs. normal lungs. Higher capillary density correlated with later mortality. Significant changes in the pulmonary vasculature’s adventitial layer, especially in smaller arteries, were noted, along with marked adventitial thickening. These alterations were correlated with the loss of elastic recoil and wave amplitude, leading to progressive deterioration of the PaO 2 /FiO 2 ratio, pulmonary congestion and mortality. The proliferation of non-functional capillaries plays a pivotal role in CDH pathogenesis and is associated with later mortality. Concurrently, aberrant vascular remodeling is linked to the maintenance of pulmonary hypertension during the honeymoon period. These findings suggest that pulmonary hypertension may play a compensatory role in CDH by limiting overload of the non-functional capillary network. The use of vasodilators and vasoactive drugs should be approached with caution. Further hemodynamic and therapeutic investigations are warranted to validate these findings and explore potential treatment strategies.