Arterial Duct: Its Persistence and Its Patency

Arterial Duct and Its Normal Closure

Patency is maintained by the relatively low fetal oxygen tension and cyclooxygenase-mediated products of arachidonic acid metabolism, primarily prostaglandin and prostacyclin, whose levels are high because of production by the placenta and decreased metabolism in the fetal lungs. Produced both locally, in ductal tissue, and circulating, these mediators cause vasodilation through interaction with prostanoid receptors.

In the fetus, and in the neonate prior to its closure, the arterial duct is a short and wide vessel of variable length. It connects the pulmonary arteries to the lesser curve of the arch of the aorta, terminating at the point of transition from the isthmus to the descending aorta, distal to the origin of the left subclavian artery ( Fig. 41.3 ).

Prior to birth, the duct is very much the direct continuation of the pulmonary trunk, with the left and right pulmonary arteries taking origin as smaller branches from the trunk. Posteriorly, the duct is related posteriorly to the left main bronchus, while anteriorly it is crossed by the vagus nerve. This gives off the left recurrent laryngeal nerve, which encircles the duct before ascending behind the aortic arch into the neck ( Fig. 41.4 ).

The pulmonary arterial end of the vessel is covered by a reflection of the pericardium.

In terms of its microscopic structure, the duct is a muscular artery endowed with an intima, media, and adventitia, differing markedly from the adjacent pulmonary trunk and aorta ( Fig. 41.5 ).

The media of the aorta is composed mainly of circumferentially arranged elastic fibers, whereas the media of the duct consists largely of spirally arranged smooth muscle cells, some with circular and others with longitudinal orientation, with an increased content of hyaluronic acid. The intimal layers are thicker than those of the adjoining vessels and contain increased amounts of mucoid substance. In the newborn, the tissues are rather loosely arranged, with a well-defined internal elastic lamina that may be single or focally duplicated, with small interruptions encountered regularly. No collagen is seen in the media by light microscopy, but abundant material that strains positively for acid mucopolysaccharides is observed between the muscle and the elastic laminas. Electron microscopy reveals fine collagen fibrils lying between adjacent lamellas of smooth muscle cells and elastin. During the second half of gestation, the smooth muscle cells show decreasing evidence of secretory activity, and increasing maturation of their contractile elements.

It is known that vessels cannot close by isolated contraction of circularly arranged muscle, so coincident shortening of the less abundant longitudinally arranged muscle fibers is critical to effective closure. The duct is innervated mostly by adrenergic fibers, supplying largely the adventitia and outer media, with cholinergic fibers being extremely sparse or totally absent. Vessels are also found in its walls that may have a role in fueling contraction at birth. Some degree of hyperemia of these vessels is common in newborn infants.

There is controversy with regard to the structure of the intimal layers during fetal life. Eccentrically placed intimal cushions, or mounds composed of smooth muscle and elastic tissue, have been described by many authors, with suggestions made that the formation of these mounds precedes normal ductal closure subsequent to birth. However, it is questionable whether the intimal cushions are produced during normal fetal maturation. When account is taken of the high flow of blood through the fetal duct, it is difficult to conceive that prominent protrusions of intima into the lumen could exist without inducing turbulent flow and a bruit. No such bruit is heard in the undisturbed ducts of fetal lambs at term. Furthermore, in many of the studies suggesting the presence of intimal cushions, the tissues have usually been subjected to one or more perturbations, such as relatively slow fixation, mechanical stimulation, or cessation of circulation with loss of intraluminal distending pressure. On this basis, the existence of intimal cushions as prenatal structures has been challenged. In a series of experiments, Hornblad and colleagues showed that, independent of the degree of closure, the lumen of the duct remained round, was without deformation, and showed no evidence of formation of mounds. Wall thickness increased at the time of closure, while the internal elastic lamina became corrugated, especially in the midportion of the vessels. A decrease in the lumen was associated with accumulation of endothelial cells within the lumen. They concluded that closure was aided by passive central displacement of endothelial and inner medial cells but that no part of the medial layer was prepared prenatally for this process. These findings endorsed earlier studies in the human, which suggested that the cushions appeared as a normal reparative reaction to distending forces during fetal life.

At birth, the vessel unequivocally constricts. The intimal thickenings, or cushions, become irregular ridges protruding into the lumen, running mainly lengthwise. By their extrusion, they exert traction on the media, causing disorganization and formation of mucoid lakes (see Fig. 41.5 ). Anatomic obliteration follows functional closure. The process begins with necrosis of the inner wall, followed by the formation of dense fibrous tissue. The lumen is progressively obliterated by a process of fibrosis, probably representing organization of mural or occlusive thrombus. Eventually, the duct becomes converted into a fibrous strand, the arterial ligament, which may become calcified. Anatomic obliteration may take several weeks to complete. Approximately two-thirds of ducts are normally obliterated by the age of 2 weeks and almost all by 1 year.

Persistently Patent Arterial Duct

As stated earlier, in normal circumstances all ducts should be converted to an arterial ligament within the first year of life, with two-thirds closing in the initial 2 weeks. However, some ducts never close. These are the channels best described as showing persistent patency. Gittenberger-de-Groot found the internal elastic lamina to be intact in some, but not all, of the persistently patent ducts studied histologically, along with a sparsity of intimal cushions ( Fig. 41.6 ). Bakker had noted similar findings, describing them in terms of “aortification.”

The duct, if persisting as a patent structure, joins the pulmonary arteries to the descending aorta in the fashion seen in the neonate ( Fig. 41.7 ). The channel itself can vary markedly in its width ( Fig. 41.8 ).

The duct can also vary considerably in its shape. Study of a large number of angiograms from patients with persistently patent ducts undergoing interventional closure at the Hospital for Sick Children, Toronto, showed that the most frequent pattern was to find a constriction at the pulmonary end of the duct. This pattern was seen in two-thirds of cases. In just less than 20%, a constriction was found at the aortic end of the duct, and in just less than 10% the lumen was unrestricted. In just less than 5%, there was a constriction at both ends, and the remaining patients showed bizarre patterns not lending themselves to classification ( Fig. 41.9 ). Unique to the premature infant, the duct is elongated and unrestrictive, with a slight cranial angulation followed by a caudal turn as it connects to the pulmonary artery.

In the past, persistently patent arterial ducts were often the nidus for infectious endocarditis, but this complication is now extremely rare in developed countries. Ducts could also become aneurysmal and elongated ( Fig. 41.10 ), but this is also now a rare finding, as is ductal rupture.

Epidemiology

The factors responsible for persistent ductal patency beyond the first days of life are not fully understood. An increased incidence is seen in the premature neonate due to physiologic factors more related to prematurity rather than an inherent abnormality of the duct. In infants born at term, persistent patency occurs sporadically, but there is increasing evidence that genetic factors, or prenatal infection, play a role in many children. The estimated incidence lies between 1 in 2000 and 1 in 5000 live births. Persistent patency of the duct accounts for approximately 12% of all congenital cardiac malformations. The most extensive study from a relatively homogeneous population was that performed by Carlgren, when he charted the incidence of congenital cardiac disease to children born in the Swedish City of Gothenburg. Persistent ductal patency was the third most common lesion identified, representing approximately 0.04% of live births. If children with the so-called silent duct are included, found incidentally by echocardiography performed for another reason, the incidence may be as high as 1 in 500. A significantly higher incidence of ductal patency is also seen in infants born with low weight, patency being found in almost half of infants weighing less than 1750 g at birth, and up to 80% of those weighing less than 1200 g (see also Chapter 15 ).

Genetic Factors

Unlike premature infants, as noted earlier, where persistent ductal patency is more often due to developmental immaturity, in the infant born at term there is likely a structural abnormality. There is also an increased frequency in several genetic syndromes, such as those with defined chromosomal aberrations, examples being trisomy 21, 14q- and 4p- syndromes, the Rubinstein-Taybi and CHARGE syndromes, single-gene mutations such as Carpenter and Holt-Oram syndromes, and X-linked mutations such as incontinentia pigmenti. Although most cases of persistent patency are sporadic, many are also believed to be due to a multifactorial inheritance pattern, with a genetic predisposition and an environmental trigger that occurs at a vulnerable time. Females predominate in a ratio of greater than 2 to 1. The mode of inheritance appears to be autosomal recessive with incomplete penetrance. In a family having one sibling with a patent duct, there is approximately a 3% chance of a persistent duct in a subsequent offspring and a higher risk to the offspring given one affected parent, some 45 times greater than the that for the general population. The risk to further children in sibships where two children have been affected is probably in the order of 10% and increases with each affected child.

Infection and Environmental Factors

Maternal rubella during the first trimester of pregnancy, particularly in the first 4 weeks, is associated with a high incidence of a persistently patent arterial duct. The histology resembles that of a very immature duct, with an extensive subendothelial elastic lamina, thought to retard anatomic sealing. Additional environmental factors have been reported associated with persistence, such as in fetal valproate syndrome, or after thalidomide. A patent arterial duct may be more likely to be found in infants born at high altitude.

Pathophysiology

Persistent patency results in shunting of blood from one side of the circulation to the other, the volume of flow depending on the length and internal diameter of the duct and on the systemic and pulmonary vascular resistances. Because pulmonary resistance is usually much lower than systemic, the flow is from the aorta to the pulmonary trunk. Hence flow to the lungs is increased, resulting in left atrial and left ventricular volume overload. If the duct is widely patent, flow depends entirely on the ratio of resistances. Right ventricular failure may occur in the presence of a large duct with pulmonary hypertension or pulmonary edema, and an elevated left atrial pressure. In most patients, the duct is partially constricted and the major factor limiting flow. Under these conditions, pulmonary arterial pressure is normal or only mildly elevated. Symptoms and clinical findings are largely determined by the magnitude of the shunt.

Clinical Features

Most patients are asymptomatic, the lesion recognized with detection of the characteristic murmur. Occasionally, there may be a history of prematurity or asphyxia during birth. Children with large shunts may fail to thrive, experience difficulty with feeding during infancy, and frequently suffer recurrent infections of the upper respiratory tract. Occasionally, congestive heart failure develops.

Physical Examination

There is retarded growth in approximately one-third of children. They are acyanotic in the absence of complicating factors. The peripheral pulses are easily palpable, with a rapid upstroke and decay. There is a widened pulse pressure, with lowering of the diastolic component. Arterial pulsation in the neck may be prominent in those with large shunts. The precordial examination reveals an active cardiac impulse, with the forceful cardiac apex displaced to the left. When the shunt is small, the only abnormal finding may be the murmur. The continuous, or “machinery,” murmur of the uncomplicated persistent duct is best heard in the left infraclavicular area, although it is occasionally maximal at the third left interspace. Gibson's description of the murmur as quoted by Tynan :

It begins quite obviously after the commencement of the first sound. It is continued during the latter part of that sound and the whole of the short pause. It persists throughout the second sound and dies away gradually during the long pause. The murmur is distinctly rough and thrilling in its character. It begins, however, somewhat softly, and increases in intensity to reach its acme just about, or immediately after, the incidence of the second sound, and from that point wanes until its termination. The second sound can be heard to be loud and clanging and when carefully analyzed it is the pulmonary part of that sound which is accentuated.

Turbulent flow through the duct itself causes the murmur. Additional murmurs may be present due to increased flow across the aortic valve, producing an ejection systolic sound, and across the mitral valve, giving a diastolic murmur with loud onset. The systolic component of the continuous murmur may be transmitted into the neck, may be associated with a thrill in the second left intercostal space, or may increase in intensity during inspiration due to a fall in pulmonary vascular resistance. Many patients with loud continuous murmurs also have multiple “clanging” sounds. These are relatively localized to the pulmonary area and are most frequent in the second half of systole, corresponding to the period of peak flow within the duct. Neill and Mounsey attributed these sounds to the turbulence caused by the “head on” collision of opposed flow from the duct and the right ventricle and named them eddy sounds. These auscultatory findings are only for an uncomplicated persistent duct in a child. It should be remembered that these features may differ in infancy or be altered by the development of complications.

Investigations