Pathobiology of pulmonary hypertension in infants and children

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Abstract

Pulmonary vascular disease occurs as a rare primary disorder and a common, frequently major complication of many disease states. But we still cannot define the stimuli and signal transduction pathways which instigate and perpetuate the disease state, and therefore our treatment strategies are reactive, nor proactive. Observational studies on patients with pulmonary hypertension of different aetiologies have identified potentially important structural and functional abnormalities, but whether these are a cause or a consequence of the disease process remains to be determined. Recent genetic studies indicate, for the first time, a primary abnormality in the regulation of pulmonary vascular remodelling in a sub-set of patients with pulmonary hypertension. The aim of research in pathobiology is to discover the molecular mechanisms responsible for the complex vascular changes associated with pulmonary hypertension and in doing so, improve treatment strategies.

Introduction

Pulmonary vascular disease occurs as a rare primary disorder and a common, frequently major complication of many disease states. The pathogenesis may appear self evident, as in the endothelial dysfunction characteristic of pulmonary hypertensive congenital heart disease and the vasoconstriction of chronic hypoxia, but we still cannot define the stimuli and signal transduction pathways, which instigate and perpetuate the disease state in the common forms of sustained pulmonary hypertension. Hence our treatment strategies are reactive, not proactive. The aim of research in pathobiology is to discover the molecular mechanisms responsible for the complex vascular changes associated with pulmonary hypertension and, in doing so, improve treatment strategies. Research activity is intense and accelerating rapidly. In 1997, a locus for familial primary pulmonary hypertension (FPPH) was mapped to chromosome 2q 31–32 [1]. In September 2000, a mutation in the gene encoding a TGF-β type II receptor was identified in FPPH [2]. This indicates for the first time, a primary abnormality in the regulation of pulmonary vascular remodelling in a sub-set of patients with pulmonary hypertension.

Observational studies on patients with pulmonary hypertension of different aetiologies have identified potentially important structural and functional abnormalities, but whether these are a cause or consequence of the disease process remains to be determined. Such abnormalities include an imbalance between vasodilator and vasoconstrictor mediators, defects in the potassium channels of resistance artery smooth muscle cells, and increased synthesis of inflammatory mediators, which cause vasoconstriction and enhanced cell growth (Fig. 1). The previous paper by Rabinovitch emphasised recent insights into vessel wall remodelling, the phenotypic changes in endothelial and smooth muscle cells, apoptosis and the role of metalloproteinases in matrix turnover. This chapter addresses the pathobiology of pulmonary vascular disease. In those children whose pulmonary vasculature is exposed to haemodynamic stress, hypoxia and other insults, and in infants with persistent pulmonary hypertension of the newborn (PPHN), work on the pathobiology is followed by an account of the experimental studies, which enhance our understanding of the human condition.

Section snippets

Primary pulmonary hypertension

The recent WHO Nomenclature and Classification of pulmonary hypertension 1998 [3] defined primary pulmonary hypertension as sporadic and familial. Most instances are sporadic, but 6% are familial [4].

The human condition

In children with pulmonary hypertensive congenital heart disease endothelial microfilament disarray is seen in early infancy, and the cells become partially detached from the basement membrane, although the cell sheet may still be continuous [39] (Fig. 5). Endothelial dysfunction is present early, in young children who are potentially operable (Fig. 5). The relaxant response to acetylcholine is impaired when the pulmonary blood flow is increased, even with little increase in pressure, and

Recovery from pulmonary arterial hypertension

In the normal lung experimental studies indicate that the various signal transduction pathways involved in endothelium-dependent relaxation and vasoconstriction, mature at different rates during the first weeks of life, and mature more rapidly in some vascular segments than others. Absent or poor endothelium-dependent relaxation at birth is not a feature of all segments of the pulmonary vasculature, as is often supposed. From a therapeutic perspective, it is probably extremely important to note

Pulmonary venous hypertension

Congenital heart disease is the commonest cause of pulmonary venous hypertension in childhood, caused by obstructed total anomalous pulmonary venous return, left heart obstruction, or severe left ventricular failure. The lungs of those born with severe left heart inflow obstruction show pronounced thickening of the walls of those arteries and veins, extensive perivascular deposition of connective tissue and thickening of the capillary basement membrane at birth reflecting intra-uterine damage.

A vision for the future

Our present understanding of the pathobiology of pulmonary vascular disease is patchy. The ultimate objective is to understand:

  • •

    the genetic basis of sporadic primary pulmonary hypertension and ‘genetic susceptibility’ to react excessively to stimuli associated with the development of secondary pulmonary hypertension;

  • •

    adaptation of the pulmonary vasculature to extrauterine life and the extent to which sub-clinical impairment may prejudice the circulation in adult life;

  • •

    the cascades of molecular

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