Authors
Thomas Doyle, MD
Ann Kavanaugh-McHugh, MD
Thomas P Graham, Jr, MD
Section Editors
Heidi M Connolly, MD
John Triedman, MD
Deputy Editor
Melanie S Kim, MD



INTRODUCTION — The ductus arteriosus (DA) is a fetal vascular connection between the main pulmonary artery and the aorta (figure 1) that diverts blood away from the pulmonary bed. After birth, the DA undergoes active constriction and eventual obliteration. A patent ductus arteriosus (PDA) occurs when the DA fails to completely close postnatally. (See "Physiologic transition from intrauterine to extrauterine life".)

The clinical manifestations and diagnosis of PDA in full term infants, older children, and adults will be reviewed here. PDA in the premature infant, and the management of PDA are discussed separately. (See "Patent ductus arteriosus in premature infants" and "Management of patent ductus arteriosus".)

DUCTAL EMBRYOLOGY AND ANATOMY — The DA is thought to derive from the embryonic left sixth aortic arch (figure 2 and picture 1). In the typical left aortic arch, the aortic end of the DA arises distal to the left subclavian artery and the pulmonary end inserts at the junction of the main and left pulmonary arteries.

The anatomy is more varied in the presence of a right aortic arch. Most commonly, the DA arises from the left innominate artery and inserts into the region of the proximal left pulmonary artery [1]. Less frequently, the DA arises distal to the right subclavian artery and inserts near the proximal right pulmonary artery. In rare instances, there is a bilateral DA, usually in the presence of other complex congenital cardiovascular anomalies.

Regardless of the aortic arch orientation, the vascular structures remain anterior to the trachea and esophagus, and there is no vascular ring. One exception to this general rule occurs when there is a right aortic arch with an aberrant left subclavian artery (called RALL). In this setting, the DA typically arises from the aberrant subclavian artery and inserts into the proximal left pulmonary artery. This creates a vascular ring with the aorta anterior to and rightward of the trachea and esophagus; the aberrant subclavian artery is posterio,r and the DA is along the left side, connecting the subclavian to the pulmonary artery. (See "Vascular rings", section on RALL.)

Histologically, ductal tissue differs from that of the adjacent aorta and pulmonary artery. The intima of the ductus is thicker, and the media contains more smooth muscle fibers arranged in a characteristic spiral fashion [2]. The DA may take a variety of shapes and forms. The Krichenko classification describes the angiographic appearance of the patent ductus, including several subtypes broadly defined as [3]:

* Type A: Conical with the narrowest portion at the PA side
* Type B: Short with narrowing at the aortic insertion
* Type C: Tubular without constriction
* Type D: Tubular with multiple constrictions
* Type E: Bizarre, with an elongated, conical appearance and multiple constrictions

This classification scheme does not include the reverse-oriented ductus, which is commonly associated with congenital heart disease.

FETAL AND TRANSITIONAL DUCTAL CIRCULATION — In the fetus, the right ventricle accommodates approximately 60 percent of the total cardiac output [4]. The pulmonary vasculature constricted, resulting in a high vascular resistance within the pulmonary bed. In contrast, the placenta creates a very low resistance bed arising from the aorta, and systemic vascular resistance is low. As a result, the majority of blood exiting from the right ventricle passes right-to-left across the DA into the descending aorta and on to the placenta. (See "Physiologic transition from intrauterine to extrauterine life", section on 'Fetus'.)

In the fetus, the DA is large, with a diameter approximating that of the descending aorta. With the onset of respiration after delivery, the lungs expand and the systemic oxygen saturation rises, resulting in pulmonary vasodilatation and a drop in pulmonary vascular resistance. At the same time, systemic resistance rises with placental removal after cutting the umbilical cord. These factors lead to a sudden reversal of blood flow in the DA from right-to-left to left-to-right. (See "Physiologic transition from intrauterine to extrauterine life", section on 'Transition at delivery'.)

Patency of the ductus — The fetal DA is kept patent by low arterial oxygen content and circulating prostaglandin E2 (PGE2), which is produced in part by the placenta [5]. PGE2 appears to be mediated by its COX-2 isoform, since constriction of the fetal DA in mice is induced by selective COX-2 inhibitors but not selective COX-1 inhibitors [6]. The rationale for the administration of nonsteroidal anti-inflammatory drugs in the treatment of PDA in preterm infants is based upon the role of PGE2 in maintaining DA patency. (See "Patent ductus arteriosus in premature infants", section on 'Indomethacin'.)

Ductal constriction — At birth, the rise in systemic arterial oxygen tension and a decrease in circulating PGE2 levels trigger ductal constriction.

* Although the mechanism that causes active ductal constriction is not known, gene transfer studies suggest that an oxygen-sensitive potassium channel mediates DA constriction [7].
* After delivery, circulating PGE2 levels fall because of reduced production following removal of the placenta, and increased PGE2 clearance due to increase in circulating levels of prostaglandin dehydrogenase [6,8]. Removal of the strong vasodilatory effect of PGE2 is sensed by the PGE2 receptor (EP4) and promotes further constriction of the ductus [9,10].

Constriction of the DA usually results in functional hemodynamic closure within 10 to 15 hours after delivery [11]. Closure begins at the pulmonary end of the DA and proceeds toward the aortic end [12], and is usually completed by two to three weeks of age. Following initial constriction, a series of histologic changes result in obliteration of the ductus and conversion into the ligamentum arteriosum [12]. It appears that these changes do not occur in a PDA, suggesting distinct anatomic differences in the DA tissue [12].

INCIDENCE OF PDA — The incidence of PDA has increased dramatically over the last two decades. This is due to the improved survival rate of premature infants, because the incidence of PDA significantly increases in infants born before 30 weeks gestation. The effect of prematurity on the incidence of PDA is discussed separately. (See "Patent ductus arteriosus in premature infants", section on 'Delayed closure'.)

The reported incidence of an isolated PDA among term infants ranges from 0.03 to 0.08 percent [13]. In a population-based study of 400,000 term infants born in Atlanta from 1998 to 2005, the reported incidence of PDA was 2.9 per 10,000 live births [14]. In this study, the diagnosis was defined as a PDA persisting up to or beyond six weeks after delivery in infants with a gestational age at or greater than 36 weeks, and excluded patients with obligatory shunt lesions due to complex congenital heart disease (CHD) or those who received prostaglandin therapy.

There is a female predominance for PDA with a 2:1 female to male ratio in most case series of term infants [14,15]. The incidence of PDA is also greater in infants born at high altitude compared to those born at sea level [8], and in infants with congenital rubella. (See "Overview of TORCH infections", section on 'Rubella'.)

PDA may present with other congenital heart lesions, especially those associated with hypoxemia. PDA should be considered when the clinical features of left-to-right shunt seem out of proportion to the particular lesion being considered.

Genetic factors — It is likely that genetic factors contribute to some cases of PDA. Siblings of patients with PDA have an increased frequency of this abnormality (2 to 4 percent) [16]. PDA occasionally occurs in many members of multiple generations of a family, making simple autosomal dominant inheritance likely in these families [17].

In Char syndrome, for example, family members have PDA, unusual facial features, and an abnormal fifth digit of the hand [18]. A gene for this syndrome has been mapped to chromosome 6p12-p21 [19] and is caused by defects in TFAP2B proteins, encoding a neural crest-related transcription factor [20]

CLINICAL MANIFESTATIONS — The clinical manifestations of a PDA are determined by the degree of left-to-right shunting, which is dependent upon the size and length of the PDA, and the difference between pulmonary and systemic vascular resistances.

The hemodynamic consequences of the PDAs can be categorized by the degree of left-to-right shunting based upon the pulmonary to systemic flow ratio (Qp:Qs) [21].

* Small — Qp:Qs <1.5 to 1
* Moderate — Qp:Qs between 1.5 and 2.2 to 1
* Large — Qp:Qs >2.2 to 1

The clinical findings for the full term infant, older children, and adults based upon the size of PDA are discussed in the next sections. The clinical manifestations of PDA in preterm infants are discussed separately. (See "Patent ductus arteriosus in premature infants".)

Small PDA — A small PDA (Qp:Qs <1.5 to 1) that restricts excessive blood flow into the lungs may go undetected, and the patient will have no identifiable symptoms. These patients are commonly identified incidentally by the detection of the characteristic continuous flow murmur noted during a routine primary care visit or by a finding of a PDA on a diagnostic study (eg, computed tomography or echocardiography) performed for other medical conditions [22].

In patients with a small PDA, the physical examination reveals normal precordial activity, and normal first and second heart sounds. Pulses are normal or only mildly accentuated. The respiratory examination also is unremarkable, and there is no evidence of cyanosis.

A murmur is commonly present, and its characteristics vary between the neonate and older patients because of changes in the relative differences between pulmonary and systemic vascular resistances.

* In the newborn, aortic systolic pressure is greater than pulmonary systolic pressure, but this gradient may not be present during diastole. As a result, the murmur may be confined to systole.
* Pulmonary artery pressure falls after the newborn period. As a result, aortic pressure is higher than pulmonary artery pressure during both systole and diastole, producing continuous flow through the ductus and a characteristic continuous murmur (Gibson's murmur or machinery murmur). The murmur is grade 3/6 or less and is heard best in the left infraclavicular region. The intensity of the murmur is maximal immediately before and after the second heart sound (S2) and is not affected by position (algorithm 1). (See "Auscultation of cardiac murmurs", section on 'Patent ductus arteriosus'.)

Infective endarteritis is an uncommon presentation and complication of small PDAs. It appears to occur more frequently in patients in developing countries. In one case series of 14 Pakistani patients, fever was the presenting symptom and the presence of a heart murmur was detected upon physical examination in all patients [23]. The diagnosis of PDA was confirmed by echocardiography and vegetations were detected in 12 of the 14 patients.

Moderate PDA — Patients with moderate size PDAs (Qp:Qs between 1.5 and 2.2 to 1) may present with exercise intolerance. In these patients, the moderate left-to-right shunt increases the volume load on the left atrium and ventricle, which results in left ventricular dilation and dysfunction.

The characteristic continuous murmur (usually grade 2 or 3, occasionally grade 4) in the left infraclavicular area, which is louder than that associated with a small PDA, is typically accompanied by a wide systemic pulse pressure and signs of left ventricular overload, such as a displaced left ventricular apex.

Large PDA — A large PDA (Qp:Qs >2.2 to 1) initially causes left ventricular overload. Over time, there may be a progressive rise in pulmonary artery pressures, which in the uncorrected patient, may lead to irreversible pulmonary vascular changes. With sufficiently increased pulmonary vascular resistance, flow reverses to a right-to-left shunt and over time, these patients develop cyanotic heart disease (ie, Eisenmenger syndrome). (See "Evaluation and prognosis of Eisenmenger syndrome".)

In the infant, a large PDA may present with signs of heart failure, including failure to thrive, poor feeding, and respiratory distress. The older child may present with shortness of breath or easy fatigability.

In the uncorrected adult, a large PDA may present with a short systolic ejection murmur, and features of Eisenmenger syndrome including cyanosis and clubbing. Patients with PDA and Eisenmenger syndrome typically have cyanosis and clubbing that is more pronounced in the lower extremities (ie, differential cyanosis) because the ductus typically delivers unoxygenated blood distal to the left subclavian artery.

In the patient with a left-to-right shunt, precordial palpation reveals a dynamic left ventricular impulse and a thrill, and the pulses are bounding with a wide pulse pressure due to runoff into the pulmonary bed. On auscultation, S1 is normal, S2 may be split with an accentuated pulmonary component, and eddy sounds may be heard in late systole and early diastole. A grade 4/6 continuous murmur is heard in the left infraclavicular region. An apical diastolic rumble induced by increased flow across the mitral valve may be present, preceded by a third heart sound.

As mentioned above, adult patients with PDA may have a short systolic ejection murmur because the diastolic run-off into the pulmonary circulation is decreased due to increasing pulmonary vascular resistance. With increasing pulmonary vascular resistance, patients may develop pulmonary hypertension. (See 'Pulmonary hypertension' below.)

DIAGNOSIS — The diagnosis of PDA is usually based upon its characteristic clinical findings and typically confirmed by echocardiography. The chest x-ray and the electrocardiogram may be helpful but are less sensitive and specific than echocardiography. Cardiac catheterization and angiography are generally only necessary when percutaneous therapy is being considered or in the context of more complex congenital heart disease.

Echocardiography — A complete echocardiographic evaluation of a PDA includes anatomic confirmation by two-dimensional imaging, and Doppler echocardiography hemodynamic assessment including the degree of shunting and pulmonary artery pressure [24,25].

Two-dimensional echocardiography — The PDA can be imaged in many views using two-dimensional imaging and superimposed Doppler color flow mapping [24,25]. Most commonly, the ductus is imaged in the parasternal and suprasternal notch views.

* Parasternal view — In the high parasternal short axis view, with the transducer oriented leftward toward the pulmonary artery bifurcation, the ductus can be imaged coursing between the pulmonary artery and the descending aorta (figure 3A-B). In this view, the ductus can be seen arising from the anterior aspect of the descending aorta, which is viewed in cross section. The patent ductus enters the pulmonary artery near the origin of the left pulmonary artery.
* Suprasternal view — In the suprasternal notch window, the ductus arises from the descending aorta at the level of the left subclavian artery, and courses anteriorly to join the pulmonary artery (figure 4). Moving the transducer just laterally and inferiorly to an infraclavicular position, and rotating clockwise, permits further imaging of the ductus and its relationship to the branch pulmonary arteries and descending aorta (figure 5).

In patients with a right aortic arch, the ductus usually arises from the left brachiocephalic vessels instead of the descending aorta and can be followed caudally to its insertion on the pulmonary artery in the suprasternal view.

The presence of a PDA may mask an aortic coarctation, since the ductus augments the left aortic arch at its origin. The presence of a bicuspid aortic valve, hypoplasia of the aortic isthmus, or a posterior shelf should alert the echocardiographer to the possible presence of a coexistent coarctation. (See "Pathophysiology and clinical features of valvular aortic stenosis in adults".)

Two-dimensional imaging may give important qualitative information regarding the hemodynamic significance of a PDA. Left atrial and ventricular dilation are seen in the presence of a large left-to-right shunt.

Doppler color flow — Doppler color flow mapping can supplement imaging of the PDA, which is most commonly seen as a retrograde color flow jet in the pulmonary artery (figure 3A-B and figure 4). This jet usually occurs along the leftward aspect of the pulmonary artery but may be directed into the center or more rightward (figure 6). In patients with normal pulmonary artery pressure, the high velocity turbulent flow is easily seen in both systole and diastole. In patients with high pulmonary vascular resistance, the retrograde jet may be visible only in diastole.

Color flow mapping is particularly helpful in the setting of a small PDA that may be difficult to identify by two-dimensional imaging, especially in adults in whom resolution is more limited than in infants and small children. Determination of the origin of the retrograde flow into the pulmonary artery using two-dimensional imaging as well as color flow mapping is crucial to avoid confusion of the patent ductus with other aortopulmonary shunts, such as collateral vessels, coronary artery fistulae, or an aortopulmonary window. (See 'Differential diagnosis' below.)

Doppler echocardiography — Doppler echocardiography can estimate the degree of left-to right shunt and assess the pulmonary artery pressure. In the setting of a large left-to-right shunt at the DA, continuous runoff can be seen in the branch pulmonary arteries and in the aorta proximal to the PDA by pulsed Doppler (figure 7). Distal to the origin of the PDA, diastolic retrograde flow can be demonstrated corresponding to the runoff into the pulmonary artery (figure 8A-B) [26].

Pulmonary to systemic flow ratio (Qp:Qs) can be estimated echocardiographically using the area of the left and right ventricular outflow tracts, and Doppler-derived velocity and flow data. Paradoxically, in the setting of the patent ductus arteriosus, the systemic blood flow is calculated by using the area of the right ventricular and pulmonary outflow tracts and velocity time integrals, and the pulmonary blood flow is calculated utilizing the aortic outflow tract area and velocity time integral. However, the ductal jet frequently distorts the antegrade pulmonary flow signal; as a result, this measurement is not usually helpful [24].

Doppler information derived directly from the ductus is helpful in assessing pulmonary artery pressure. When the pulmonary artery pressure is lower than systemic arterial pressure, there is continuous left-to-right shunting demonstrated by both color flow mapping and pulsed Doppler interrogation. The velocity of flow across the ductus, measured by either pulsed or continuous wave Doppler, can be translated into the gradient between the aorta and the pulmonary artery using the modified Bernoulli equation (figure 9). This Doppler-derived gradient correlates with gradients measured at catheterization and can be subtracted from the cuff pressure to estimate pulmonary artery pressure.

Information regarding right ventricular and pulmonary artery pressure may also be derived by determination of tricuspid regurgitation velocity and, qualitatively, by ventricular septal configuration.

As with any Doppler-derived measurement, care must be taken to minimize the angle between the Doppler interrogation and the direction of flow in the ductus. The length and shape of the ductus may influence the accuracy of gradient estimates using the Bernoulli equation; longer and more "tunnel" like structures are less reliably evaluated using this equation [25].

When the pulmonary artery pressure is equal to systemic pressure, pulsed Doppler within the ductus demonstrates systolic right-to-left shunting, with diastolic left-to-right flow within the vessel (figure 10). The finding of systolic right-to-left flow within the ductus may be confused with normal antegrade systolic flow in the left pulmonary artery if the sample volume is not placed within the ductus. In rare cases of arch abnormalities and pulmonary hypertension, right-to-left shunting may be seen throughout the cardiac cycle [27,28].

Transesophageal echocardiography can be used for identification of a PDA, but the PDA may be difficult to visualize using this technique.

M-mode echocardiography — Although M-mode echocardiography may reveal findings suggesting a left-to-right shunt, it is not diagnostic for a PDA. A ratio of left atrial-to-aortic diameter greater than 1.3:1 is usually associated with significant left-to-right shunting.

Other diagnostic tests

Chest radiograph — The findings on chest radiography vary with the size of the ductus and the degree of left-to-right shunting. In patients with a small PDA (ie, restrictive), the chest radiograph is normal.

The earliest radiographic finding usually is a prominent main pulmonary artery segment blending with a prominent aortic knob along the upper left heart border. In patients with moderate size PDAs, the heart is slightly enlarged and the pulmonary vascular markings are increased. In patients with a large PDA, these features become more pronounced with enlargement of the left ventricle and atrium, and increased pulmonary vascular markings.

Electrocardiogram — The electrocardiogram (ECG) is often normal in patients with a small PDA. In contrast, a large PDA with a large left-to-right shunt typically produces ECG findings of biventricular hypertrophy and a left atrial abnormality. With longstanding pulmonary hypertension, the ductus shunt is reversed and signs of right ventricular hypertrophy predominate. (See "ECG tutorial: Chamber enlargement and hypertrophy".)

DIFFERENTIAL DIAGNOSIS — A PDA can usually be distinguished from other causes of continuous murmurs by the physical examination [29] and be completely differentiated by echocardiography.

* A venous hum is more often located on the right side, and changes with position and local compression.
* Murmurs of systemic arteriovenous fistulas are in extracardiac locations.
* Murmurs of coronary artery fistulas are most often located over the lower precordium.
* Aortopulmonary window often has only a systolic murmur.
* Aortic stenosis or ventricular septal defect with aortic regurgitation are characterized by systolic and diastolic murmurs rather than continuous murmurs.
* The murmur of a ruptured sinus of Valsalva aneurysm is typically a new murmur loudest at the second left interspace.

COMPLICATIONS — Individuals with PDA have increased morbidity and mortality, primarily due to heart failure and rarely infective endocarditis [30]. Pulmonary vascular disease is an uncommon problem.

Heart failure — If untreated, a large PDA can cause significant cardiac volume overload resulting in heart failure. This most commonly occurs in the young infant and in elderly patients, whose left atrial and ventricular function have been impaired due to the effects of chronic volume workload. In the elderly, heart failure is often associated with atrial fibrillation.

Infants with heart failure will present with failure to thrive, poor feeding, and respiratory distress. Initial management includes digoxin and diuretic therapy, until they are candidates for device or surgical closure. (See "Management of patent ductus arteriosus".)

Infective endocarditis — A PDA carries a moderate risk of infective endocarditis (IE). When IE does occur, the vegetations usually accumulate at the pulmonary end of the PDA and shower the lungs with septic emboli. IE is an indication for PDA closure based upon the American College of Cardiology/American Heart Association 2008 guidelines for the management of adults with congenital heart disease [31]. (See "Epidemiology, risk factors and microbiology of infective endocarditis".)

Antibiotic prophylaxis is not recommended in patients with unrepaired PDA, unless it is complicated by pulmonary hypertension/Eisenmenger syndrome resulting in cyanosis, then antibiotic prophylaxis is indicated. (See "Antimicrobial prophylaxis for bacterial endocarditis".)

Antibiotic prophylaxis is recommended during the first six months after repair with prosthetic material or device. Prophylaxis is recommend if there is a residual defect adjacent to the site of repair

As a result of surgical repair, IE is now a rare complication of PDA [32-34]. In a population-based registry in Oregon, for example, no child with a surgically corrected PDA developed IE at up to 25-year follow-up [33]. (See "Antimicrobial prophylaxis for bacterial endocarditis".)

Pulmonary hypertension — An isolated large PDA, as with any large left-to-right shunt, is a risk factor for irreversible pulmonary vascular disease. (See "Overview of pulmonary hypertension" and "Pathogenesis of pulmonary hypertension".)

In such patients, the classic physical findings of a patent ductus are no longer present, and are replaced by signs of pulmonary hypertension. The continuous murmur vanishes, precordial palpation reveals a right ventricular impulse, and auscultation reveals a pulmonary ejection sound, a loud single second heart sound, and, in some cases, a Graham Steel murmur. The Graham-Steel murmur of pulmonic regurgitation and hypertension is high-pitched and "blowing." It begins with an accentuated P2 of S2 and can be of variable duration. (See "Auscultation of cardiac murmurs", section on Pulmonary regurgitation.) Pulmonary vascular disease may lead to right-to left shunting. This will deliver unoxygenated blood into the descending aorta distal to the left subclavian artery, leading to cyanosis and clubbing in the lower extremities (ie, Eisenmenger syndrome). (See "Evaluation and prognosis of Eisenmenger syndrome".)

A PDA appears to be a relatively common cause of pulmonary artery hypertension of unknown cause in adolescents and adults. In one series of 24 such patients, 16 had a left-to-right shunt (atrial septal defect in eight, PDA in six, and ventricular septal defect in two) [35]. In this series, these lesions were best detected by transesophageal echocardiography.

SUMMARY AND RECOMMENDATIONS — The ductus arteriosus (DA) is a fetal vascular connection between the main pulmonary artery and the aorta that normally closes soon after birth (figure 1). (See 'Ductal embryology and anatomy' above and 'Fetal and transitional ductal circulation' above.)

* The incidence of patent ductus arteriosus (PDA), failure of the DA to completely close postnatally, has risen over the last two decades due to the improved survival rate of premature infants below 30 weeks gestation who are at increased risk for PDA. In term infants, the reported incidence of an isolated PDA ranges from 0.03 to 0.08 percent. (See 'Incidence of PDA' above.)

* The clinical manifestations of a PDA are determined by the degree of left-to-right shunting, which is dependent upon the size and length of the PDA, and the difference between pulmonary and systemic vascular resistances. (See 'Clinical manifestations' above.)

- Patients with a small PDA are generally asymptomatic and are detected incidentally during routine primary care visits or testing for other conditions.

- Symptoms vary in patients with moderate and large PDAs depending upon the size of the shunt. Symptoms may range from exertional dyspnea to heart failure.

- Adults with uncorrected large PDAs may develop pulmonary vascular disease, which may result in a right-to-left shunt and cyanosis (ie, Eisenmenger syndrome).

* The diagnosis of PDA is usually based upon its characteristic clinical findings and typically confirmed by echocardiography. (See 'Diagnosis' above.)

* Complications of PDA include heart failure, infective endocarditis, and pulmonary hypertension. Antibiotic prophylaxis is not recommended in patients with unrepaired PDA unless they have developed Eisenmenger syndrome. (See 'Complications' above.)

REFERENCES

1. Knight, L, Edwards, JE. Right aortic arch. Types and associated cardiac anomalies. Circulation 1974; 50:1047.
2. Allen, HD, Driscoll, DJ, Shaddy, RE, Feltes, T. Moss and Adams' heart disease in infants, children, and adolescents: including the fetus and young adult, 7th ed, Lippincott Williams and Wilkins, Philadelphia, PA, 2007.
3. Krichenko, A, Benson, LN, Burrows, P, et al. Angiographic classification of the isolated, persistently patent ductus arteriosus and implications for percutaneous catheter occlusion. Am J Cardiol 1989; 63:877.
4. Rudolph, AM. The changes in the circulation after birth. Their importance in congenital heart disease. Circulation 1970; 41:343.
5. Smith, GC. The pharmacology of the ductus arteriosus. Pharmacol Rev 1998; 50:35.
6. Loftin, CD, Trivedi, DB, Langenbach, R. Cyclooxygenase-1-selective inhibition prolongs gestation in mice without adverse effects on the ductus arteriosus. J Clin Invest 2002; 110:549.
7. Thebaud, B, Michelakis, ED, Wu, XC, et al. Oxygen-sensitive Kv channel gene transfer confers oxygen responsiveness to preterm rabbit and remodeled human ductus arteriosus: implications for infants with patent ductus arteriosus. Circulation 2004; 110:1372.
8. Coggins, KG, Latour, A, Nguyen, MS, et al. Metabolism of PGE2 by prostaglandin dehydrogenase is essential for remodeling the ductus arteriosus. Nat Med 2002; 8:91.
9. Nguyen, M, Camenisch, T, Snouwaert, JN, et al. The prostaglandin receptor EP4 triggers remodelling of the cardiovascular system at birth. Nature 1997; 390:78.
10. Segi, E, Sugimoto, Y, Yamasaki, A, et al. Patent ductus arteriosus and neonatal death in prostaglandin receptor EP4-deficient mice. Biochem Biophys Res Commun 1998; 246:7.
11. Heymann, MA, Rudolph, AM. Control of the ductus arteriosus. Physiol Rev 1975; 55:62.
12. Gittenberger-de Groot, AC, Strengers, JL, Mentink, M, et al. Histologic studies on normal and persistent ductus arteriosus in the dog. J Am Coll Cardiol 1985; 6:394.
13. Hoffman, JI, Kaplan, S. The incidence of congenital heart disease. J Am Coll Cardiol 2002; 39:1890.
14. Reller, MD, Strickland, MJ, Riehle-Colarusso, T, et al. Prevalence of congenital heart defects in metropolitan Atlanta, 1998-2005. J Pediatr 2008; 153:807.
15. RECORD, RG, McKEOWN, T. Observations relating to the aetiology of patent ductus arteriosus. Br Heart J 1953; 15:376.
16. Nora, JJ. Multifactorial inheritance hypothesis for the etiology of congenital heart diseases. The genetic-environmental interaction. Circulation 1968; 38:604.
17. Davidson, HR. A large family with patent ductus arteriosus and unusual face. J Med Genet 1993; 30:503.
18. Char, F. Peculiar facies with short philtrum, duck-bill lips, ptosis and low-set ears-a new syndrome? Birth Defects Orig Artic Ser 1978; 14:303.
19. Satoda M, et al. Char syndrome, an inherited disorder with patent ductus arteriosus, maps to chromosome 6p12-p21. Circulation 1999; 99:3036.
20. Satoda, M, Zhao, F, Diaz, GA, et al. Mutations in TFAP2B cause char syndrome, a familial form of patent ductus arteriosus. Nat Genet 2000; 25:42.
21. Webb, GD, Smallhorn, FJ, Terrien, J, Redington, AN. Congenital heart disease. In: Braunwalds' Heart Disease, 8th ed, Libby P, Bonow, RO, Mann, DL, Zipes, DP (eds), Philadelphia, 2008. p. 1561.
22. Goitein, O, Fuhrman, CR, Lacomis, JM. Incidental finding on MDCT of patent ductus arteriosus: use of CT and MRI to assess clinical importance. AJR Am J Roentgenol 2005; 184:1924.
23. Sadiq, M, Latif, F, Ur-Rehman, A. Analysis of infective endarteritis in patent ductus arteriosus. Am J Cardiol 2004; 93:513.
24. Silverman, NH. Pediatric Echocardiography. Williams & Wilkins, Baltimore 1993. p.173.
25. Snider, AR, Serwer, GA, Ritter, SB. Echocardiography in Pediatric Heart Disease. Mosby-Year Book, St. Louis 1977. p.455.
26. Serwer, GA, Armstrong, BE, Anderson, PA. Noninvasive detection of retrograde descending aortic flow in infants using continuous wave Doppler ultrasonography. Implications for diagnosis of aortic run-off lesions. J Pediatr 1980; 97:394.
27. Cloez, JL, Isaaz, K, Pernot, C. Pulsed Doppler flow characteristics of ductus arteriosus in infants with associated congenital anomalies of the heart or great arteries. Am J Cardiol 1986; 57:845.
28. Hiraishi, S, Horiguchi, Y, Misawa, H, et al. Noninvasive Doppler echocardiographic evaluation of shunt flow dynamics of the ductus arteriosus. Circulation 1987; 75:1146.
29. Mullins, CE. Patent ductus arteriosus. In: The Science and Practice of Pediatric Cardiology, Garson, A, Bricker, JT, McNamara, DG (Eds), Lea & Febiger, Philadelphia 1990. p.1055.
30. Campbell, M. Natural history of persistent ductus arteriosus. Br Heart J 1968; 30:4.
31. Warnes, CA, Williams, RG, Bashore, TM, et al. ACC/AHA 2008 Guidelines for the Management of Adults with Congenital Heart Disease: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (writing committee to develop guidelines on the management of adults with congenital heart disease). Circulation 2008; 118:e714.
32. Thilen, U, Astrom-Olsson, K. Does the risk of infective endarteritis justify routine patent ductus arteriosus closure? Eur Heart J 1997; 18:503.
33. Morris, CD, Reller, MD, Menashe, VD. Thirty-year incidence of infective endocarditis after surgery for congenital heart defect. JAMA 1998; 279:599.
34. Lankipalli, RS, Lax, K, Keane, MG, et al. Images in cardiovascular medicine. Infected patent ductus arteriosus. Circulation 2005; 112:e364.
35. Chen, WJ, Chen, JJ, Lin, SC, et al. Detection of cardiovascular shunts by transesophageal echocardiography in patients with pulmonary hypertension of unexplained cause. Chest 1995; 107:8.