Summary
Over the last three decades, knowledge about fundamental and clinical aspects of the ductus arteriosus has substantially improved, leading to considerable progress in the management of various cardiac diseases involving the ductus. The identification of the mechanisms regulating ductal patency led to design pharmacological drugs to achieve medical closure of PDA in premature infants, or inversely to maintain patency in neonates with duct-dependent congenital heart diseases. Concurrently, widespread availability of echocardiography has improved the detection of congenital PDA, resulting in earlier treatment. Closure of PDA, by either surgery or transcatheter techniques, can now be achieved safely, resulting in a decrease in the incidence of severe complications of PDA.
Résumé
Au cours des 30 dernières années, les connaissances des aspects fondamentaux et cliniques du canal artériel ont beaucoup progressé, conduisant à une amélioration de la prise en charge des pathologies cardiaques impliquant le canal artériel. L’identification des mécanismes régulant la perméabilité ductale a permis la mise au point de produits pharmacologiques entraînant une fermeture médicale du canal artériel chez le prématuré, ou au contraire maintenant la perméabilité ductale chez le nouveau-né atteint d’une cardiopathie ductodépendante. Simultanément, le développement de l’échocardiographie a amélioré la détection du canal artériel persistant congénital, permettant un traitement plus précoce. La fermeture du canal artériel, par chirurgie ou par cathétérisme interventionnel, peut maintenant être pratiquée avec un très faible risque, diminuant ainsi l’incidence des complications sévères du canal artériel persistant.
Anatomy
The ductus arteriosus is a large channel found normally in all mammalian foetuses, connecting the main pulmonary trunk with the left-sided descending aorta, about 5 to 10 mm distal to the origin of the left subclavian artery in a full-term infant. The length of the ductus arteriosus varies and its diameter is similar to that of the descending aorta.
Embryology
In normal cardiovascular development, the proximal portions of the sixth pair of embryonic aortic arches persist as the proximal branch pulmonary arteries and the distal portion of the left sixth arch persists as the ductus arteriosus, connecting the main pulmonary trunk with the left dorsal aorta. Normally, the distal right sixth arch degenerates.
Histology
The microscopic structure of the ductus arteriosus is quite different to that of the adjacent pulmonary trunk or aorta. Although the wall thickness of these vessels are similar, the media of the ductus arteriosus consists largely of smooth muscle cells, instead of the circumferentially arranged layers of elastic fibres composing the media of the aorta and the pulmonary artery. Contraction of these smooth muscle cells results in narrowing of the lumen and shortening of the ductus arteriosus.
Physiology
Function
In the foetus, gas exchange occurs in the placenta, and not in the lungs as after birth. There is thus need for only a small amount of blood in the lungs for nutritional and metabolic requirements, accounting for only 5 to 10% of the combined ventricular output (CVO), whereas the right ventricle ejects about 65% of CVO ( Fig. 1 ). The ductus arteriosus diverts a major proportion of the right ventricular output, i.e. about 55% of the CVO, away from the high-resistance pulmonary vascular bed to the low-resistance umbilical-placental circulation.
Regulation of the ductus
The ductus arteriosus is widely patent in the foetus. The factors considered as agents in maintaining ductal patency in the foetus include exposure to low partial pressure of oxygen (pO 2 ; 18 mmHg in the foetal lamb), circulating or locally produced prostaglandins, and local nitric oxide production.
Oxygen has been shown to constrict the ductus arteriosus in vitro and in vivo . In addition, responsiveness of the ductus arteriosus to oxygen increases with advancing gestation.
Vasodilator prostaglandins, especially prostaglandin E2 (PGE2), play a part in maintaining the patency of the ductus during foetal and neonatal life . Inhibition of prostaglandin synthesis, through inhibition of the enzyme cyclo-oxygenase, results in constriction of the foetal ductus. After birth, PGE2 is metabolized in the lungs and its concentration falls rapidly within 3 hours. Furthermore, prostaglandin-induced ductal dilation is developmentally regulated. The immature ductus produces more prostaglandin and is also more sensitive to the relaxant effect of PGE2 .
Finally, endothelial cells of the ductus produce nitric oxide, contributing to ductal patency.
Mechanisms of normal closure
In full-term infants, postnatal closure of the ductus is effected in two phases: smooth muscle constriction produces “functional” closure of the lumen of the ductus within 18 to 24 hours after birth; and “anatomical” occlusion of the lumen occurs over the next few days or weeks.
After delivery, there is an increase in arterial pO 2 , a drop in circulating PGE2 and a drop in blood pressure within the lumen of the ductus (caused by the drop in pulmonary vascular resistance). All these events promote constriction of the ductus. This initial functional constriction of the ductus arteriosus is responsible for its ultimate anatomical closure; the loss of luminal blood flow produces a zone of hypoxia in the muscle media of the ductus necessary for irreversible anatomical closure . This hypoxic zone is associated with local induction of smooth muscle cell death in the media and local production of hypoxia-inducible growth factors. These growth factors stimulate endothelial proliferation, leading to extensive neointimal thickening. In addition, the profound vessel wall hypoxia inhibits endogenous prostaglandin and nitric oxide production and prevents subsequent reopening. The endothelium proliferation results in fibrosis and permanent seal, producing a fibrous band known as the ligamentum arteriosum in 2 to 3 weeks.
Patent ductus arteriosus
Epidemiology – risk factors
The incidence of PDA in term infants is about 1 in 2000 births, accounting for 5 to 10% of all congenital heart disease. The female to male ratio is ∼2:1.
In contrast to premature infants, in whom PDA is due to developmental immaturity, PDA in term infants results from a significant structural abnormality. It occurs with increased frequency in several genetic syndromes, including chromosomal aberrations and single gene mutations. Although most cases of PDA are seemingly sporadic, many are believed to be due to multifactorial inheritance, with the requirement of genetic predisposition and an environmental trigger that occurs at a vulnerable time . The genetic mechanisms of PDA in some patients may be autosomal recessive inheritance with incomplete penetrance . The precise mechanisms of how these genetic abnormalities result in PDA are not clear. Genetic studies suggest that the abnormalities in Char syndrome (an inherited disorder with PDA) result from derangement of neural crest derivatives .
In addition to these genetic factors, infection and environmental factors, such as congenital rubella, may play a role.
Aetiology
In a breed of dogs with hereditary PDA, the media of the ductus has an abnormal structure, with smooth muscle cells partly replaced by collagen and elastic fibres . In this animal model, the endothelial cells fail to separate normally from the internal elastic lamina. These histological features resemble those of the PDA in humans, suggesting a similar pathogenesis.
Pathophysiology
The haemodynamic impact of PDA depends on the magnitude of the left-to-right shunting, determined by the size of the ductus and the relationship between systemic and pulmonary vascular resistance (PVR), and on left ventricular performance. After birth, the rise in systemic vascular resistance and the fall in PVR results in left-to-right shunting, increasing over the first weeks of life. Left-to-right shunting through the ductus results in pulmonary overcirculation and left ventricular overload. Increased pulmonary blood flow leads to increased pulmonary fluid volume, decreased lung compliance and increased work of breathing. Although uncommon, pulmonary oedema may occur.
Increased flow returning to the left heart results in left ventricular overload. The left ventricle is able to handle the increased volume load up to a shunting of 50% of its output. Above that limit, left ventricular failure may occur.
In the long term, pulmonary hypertension resulting from pulmonary overcirculation may induce progressive morphological changes in the pulmonary vasculature. These changes, including arteriolar medial hypertrophy, intimal proliferation and eventual obliteration of pulmonary arterioles and capillaries, lead to increased PVR. This form of pulmonary hypertension as a consequence of left-to-right shunt is called Eisenmenger’s syndrome. When PVR exceeds systemic vascular resistance, ductal shunting is reversed and becomes right-to-left.
Clinical manifestations
The clinical picture varies depending on the magnitude of the shunting. In the most severe forms, infants with a moderate or large PDA will present with progressive congestive heart failure, often within 8 to 10 weeks after birth. Most patients with small to moderate left-to-right shunt compensate well throughout childhood, but may finally develop congestive heart failure secondary to chronic volume overload in adulthood, starting in the third decade. Some patients with a small ductus may remain completely asymptomatic. In those patients, PDA is usually diagnosed during evaluation of a heart murmur. Since the introduction of echocardiography, very small ductus, referred to as “silent” ductus, may be detected incidentally by an echocardiogram performed for another purpose.
Physical examination findings also vary. Typically, a continuous murmur is heard, located at the upper left sternal border, referred to as a “machinery” murmur. It radiates down the left side of the sternum and into the back, and a thrill may be present. If the shunt is moderate or large, the pulse is rapid and bounding and pulse pressure is increased. Hepatomegaly is usually noted.
In the severe forms presenting during infancy, the symptoms of cardiac failure will gradually subside after 3 to 6 months, as pulmonary vascular resistance increases. The time course of subsequent changes varies between 2 to 3 years and late adolescence or even early adult life. In the late stages of Eisenmenger’s syndrome, the patients are cyanotic and may have differential cyanosis, more marked with exertion. There is no murmur during systole or diastole because shunting is minimal. Auscultation may reveal a diastolic murmur of pulmonary regurgitation and/or a holosystolic murmur from tricuspid regurgitation. The intensity of the pulmonic component of the second heart sound is increased.
Electrocardiogram
The electrocardiogram shows left ventricular hypertrophy and left atrial enlargement in patients with moderate or large PDA. In patients with smaller shunts, the electrocardiogram is usually normal. In advanced stages (Eisenmenger’s syndrome), the electrocardiogram shows nonspecific signs of pulmonary hypertension.
Echocardiogram
The echocardiogram is the procedure of choice to confirm the diagnosis, evaluate the impact of a PDA, and assess the presence of associated lesions ( Fig. 2 A ). The ductus can be imaged throughout its length using a high left parasternal view, allowing evaluation of ductal size and geometry. M-mode studies provide an assessment of left atrial and ventricular size, which gives some idea of the magnitude of the shunt. In patients with moderate or large PDA, the left atrium and left ventricle are enlarged, whereas they are normal in patients with smaller PDA. A left atrium/aorta ratio > 2 is considered to be a reliable marker of a haemodynamically significant ductal shunt.
