Pulmonary arterial hypertension in congenital heart disease: translational opportunities to study the reversibility of pulmonary vascular disease

Abstract

Pulmonary arterial hypertension (PAH) is a progressive and lethal pulmonary vascular disease (PVD). Although in recent years outcome has improved by new treatments that delay disease progression, a cure has not yet been achieved. In PAH associated with congenital heart disease (CHD), remodeling of the pulmonary vasculature reaches an irreversible phenotype similar to all forms of end-stage PAH. In PAH-CHD, however, also an early stage is recognised, which can be completely reversible. This reversible phase has never been recognised in other forms of PAH, most likely because these patients are only diagnosed once advanced disease has developed. We propose that the clinical model of PAH-CHD, with an early reversible and advanced irreversible stage, offers unique opportunities to study pathophysiological and molecular mechanisms that orchestrate the transition from reversible medial hypertrophy into irreversible plexiform lesions. Comprehension of these mechanisms is not only pivotal in clinical assessment of disease progression and operability of patients with PAH-CHD; specific targeting of these mechanisms may also lead to pharmacological interventions that transform 'irreversible' plexiform lesions into a reversible PVD: one that is amenable for a cure. In recent years, significant steps have been made in the strive to 'reverse the irreversible'. This review provides an overview of current clinical and experimental knowledge on the reversibility of PAH, focussing on flow-associated mechanisms, and the near-future potential to advance this field.

Assessment of reversibility in pulmonary arterial hypertension and congenital heart disease

“…Non-restrictive, post-tricuspid shunts such as a ventricular septal defect (high flow/high pressure) induce advanced PAH-remodelling frequently and rapidly, usually within a few years. In contrast, pretricuspid high flow/normal pressure lesions like atrial septal defects induce advanced remodelling only in 5%–10% of the patients and generally only after two to four decades 2. Increased flow, especially in combination with increased pressure, disturb blood flow throughout the PA tree,6 leading to upregulation of flow-sensitive genes via mechanotransduction, such as early growth response-19 or p53 10.…”

“…Increased flow, especially in combination with increased pressure, disturb blood flow throughout the PA tree,6 leading to upregulation of flow-sensitive genes via mechanotransduction, such as early growth response-19 or p53 10. These in turn induce pro-apoptotic, pro-proliferative and inflammatory signalling2 and cause endothelial dysfunction. Morphological changes in cell surface, swelling and cohesion of ECs are one of the first structural changes visible,11 followed by neomuscularisation of the normally non-muscularised acinar arterioles and medial hypertrophy of pre-acinar arteries 7.…”

“…These recommendations however, are predominantly based on expert opinion and are hardly supported by data. In fact, in PAH-CHD, no prospective studies have yet identified reliable haemodynamic cut-offs that predict reversal of pulmonary vascular disease and normalisation of haemodynamics after cardiac correction 2. Available retrospective studies are seriously hampered by selection bias, lack of preoperative characteristics or incomplete follow-up.…”

“…The assessment of vascular morphology via lung biopsy has long been considered the gold standard for phenotyping pulmonary vascular disease 2. In patients with PAH-CHD, a lung biopsy showing neointimal fibrosis and plexiform lesions predicts progression, also after shunt closure, whereas isolated medial hypertrophy and mild intimal proliferation are likely, but not sure, to improve 3 23.…”

Outcome of congenital heart disease with modern cardiac care

“…7 Atrial septal defects are among the most common congenital heart defects. Although the lesion can be closed nowadays with interventional or surgical techniques, timing and indication for such procedures to prevent pulmonary hypertension, 8 right heart failure, 3 and premature death is still debated. Camilla Nyboe and colleagues from the Aarhus University Hospital in Denmark address this issue in their paper entitled 'Long-term mortality in patients with atrial septal defect: a nationwide cohort-study'.…”