[3H]iloprost and prostaglandin E2 compete for the same receptor site on cardiac sarcolemmal membranes.

We have previously demonstrated that high-affinity PGE receptors are present on purified cardiac sarcolemmal (SL) membrane from bovine heart (Lopaschuk et al. (1989) Circ. Res. 65, 538-545). In this study we determined whether PGI2 receptors are also present on the cardiac SL membrane. Due to the extreme lability of prostacyclin (PGI2) under physiological conditions, the PGI2 analogue, Iloprost was substituted for PGI2. 3H-Iloprost specifically bound to two sites on the SL membrane; one of high affinity (Kd = 0.3 nM, Bmax = 97.0 fmol/mg SL), and one of lower affinity (Kd = 20.6 nM, Bmax = 1589 fmol/mg SL). Competition studies demonstrated that the concentrations of PGE2 and PGE1 necessary to displace 50% of the specific binding of 20 nM [3H]Iloprost on cardiac SL were 15-fold lower than the concentrations of unlabelled Iloprost necessary to displace 50% of binding. In contrast, a 15-fold higher concentration of unlabelled Iloprost was needed to displaced 50% of specific binding of 2 nM [3H]PGE2 compared to the concentrations of PGE1 or PGE2 required to displace 50% of [3H]PGE2 binding. In summary, our results indicate that a prostacyclin receptor is present on the cardiac sarcolemmal membrane, and that PGI2 competes for the same receptor site as PGE2.

Solubilization and purification of the prostaglandin E2 receptor from cardiac sarcolemma.

A prostaglandin E2 (PGE2) receptor was solubilized and isolated from cardiac sarcolemma membranes. Its binding characteristics are almost identical to those of the membrane bound receptor. [3H]PGE2 binding to solubilized and membrane bound receptor was sensitive to elevated temperature and no binding was observed in the absence of NaCl. No significant effects of DTT, ATP, Mg2+, Ca2+ or of changes in buffer pH were observed on [3H]PGE2 binding to either solubilized or membrane-bound receptor. Unlabelled PGE1 displaced over 90% of [3H]PGE2 from the CHAPS-solubilized receptor. PGD2, PGI2, PGF2 alpha and 6-keto-PGF1 alpha were not effective in displacing [3H]PGE2 from the receptor. Scatchard analysis of [3H]PGE2 binding to CHAPS-solubilized receptor revealed the presence of two types of PGE2 binding sites with Kd of 0.33 +/- 0.05 nM and 3.00 +/- 0.27 nM and Bmax of 0.5 +/- 0.04 and 2.0 +/- 0.1 pmol/mg of protein. The functional PGE2 receptor was isolated from CHAPS-solubilized SL membrane using two independent methods: first by a WGA-Sepharose chromatography and second by sucrose gradient density centrifugation. Receptor isolated by these two methods bound [3H]PGE2. Unlabelled PGE1 and PGE2 displaced [3H]PGE2 from the purified receptor. Scatchard analysis of [3H]PGE2 binding to purified receptor revealed the presence of the two binding sites as observed for the membrane bound and CHAPS-solubilized receptor. SDS-polyacrylamide gel electrophoresis of the purified receptor fractions revealed the presence of a protein band of M(r) of approx. 100,000. This 100-kDa was photolabelled with [3H]azido-PGE2, a photoactive derivative of PGE2. We propose that this 100-kDa protein is a cardiac PGE2 receptor.

A novel method to maintain ductus arteriosus patency.

Survival of patients with certain ductal-dependent congenital heart diseases depends on continued patency of the ductus arteriosus or the surgical creation of an aortopulmonary shunt. The latter may be difficult in the presence of hypoplastic pulmonary arteries. Long-term prostaglandin therapy may be used to maintain ductal patency but is not without limitation and side effects. This experimental study describes a novel approach to maintain ductal patency with a stainless steel stent. Six newborn lambs less than or equal to 48-h old had a ductal stent placed during right heart catheterization. Two lambs less than 36-h old had a stent delivered by the arterial route. The stent was delivered and released at the target with relative ease and no incidence of embolization. Continued ductal patency up to 3 months was demonstrated by repeat cardiac catheterization and angiography, two-dimensional color Doppler echocardiography and postmortem examination. The experimental model provides a left to right shunt model in which the size may be increased as the animal grows. More important, a ductal stent could be used to maintain ductal blood flow in neonates and infants with ductal-dependent cardiac malformations, thereby avoiding a thoracotomy.

Pulsed Doppler echocardiographic assessment of extraparenchymal pulmonary vein flow.

Extraparenchymal pulmonary vein flow profiles were assessed by pulsed Doppler echocardiography in three groups of patients. Group I comprised 41 normal patients. Group II comprised 16 patients, 10 of whom had nonpulsatile pulmonary artery flow (5 with a right atrium to pulmonary artery Fontan procedure and 5 with a Glenn shunt). Six patients with pulsatile pulmonary artery flow had simultaneous Doppler and left atrial pressure measurements during cardiac catheterization. Group III comprised one patient with pulmonary vein obstruction, six with a large left to right shunt at ventricular level and two with pulmonary vascular disease. In Group I, biphasic forward pulmonary vein flow occurring during ventricular systole and diastole was observed in 26 subjects, 15 others had triphasic flow. In those with triphasic flow, the ventricular systolic component was divided into early and late. Reversed flow in the pulmonary veins during atrial systole was seen in 36 of the 41 subjects. The flow pattern in Group II was identical irrespective of the presence of pulsatile or nonpulsatile flow. The two periods of ventricular systolic flow occurred during the a to c and c to x descent, with the ventricular diastolic flow occurring during the y descent. Variations in waveform were mirrored in the left atrial pressure. Neither increased nor decreased pulmonary artery flow substantially altered the pattern. Pulmonary vein obstruction produced a distinctive pattern of high velocity turbulent flow. This technique demonstrates that extraparenchymal pulmonary vein flow is dependent on left atrial pressure events. It has major potential applications in patients who are prone to develop pulmonary vein obstruction.

Photolabelling of the prostaglandin E2 receptor in cardiac sarcolemmal vesicles.

A [3H]azidophenacyl ester of PGE2 ([3H]azido-PGE2) was synthesized and used to photoaffinity label the protein component of the high affinity PGE2 binding site in cardiac sarcolemma membrane. Photolysis of the isolated cardiac sarcolemmal vesicles in the presence of [3H]azido-PGE2 resulted in the covalent labelling of a protein component that migrated on sodium dodecyl sulfate-polyacrylamide gels with an apparent molecular weight of 100,000. Incorporation of the [3H]azido-PGE2 did not occur in the absence of photolysis. The photolabelling of the 100-kDa protein by [3H]azido-PGE2 was inhibited by excess unlabelled PGE2 and azido-PGE2. Specific binding of [3H]azido-PGE2 was displaced by excess unlabelled PGE2 or azido-PGE2, but not PGF2 alpha, 6-keto-PGF1 alpha or PGD2. These results indicate that the 100-kDa photoaffinity labelled [3H]azido-PGE2 binding protein contains the binding site for PGE2 in isolated cardiac sarcolemma membranes.

Cancer mortality following cardiac catheterization: a preliminary follow-up study on 4,891 irradiated children.

A retrospective cohort study was conducted on the risk of radiation-induced cancer mortality following cardiac catheterization. The study included 4,891 children with congenital heart disease who were assessed by cardiac catheterization during 1946 to 1968 at The Hospital for Sick Children, Toronto. The cohort was matched against the Ontario cancer death file from 1950 to 1975. The average period of follow-up was 13 years and more than 66,000 person-years have been accrued from the cohort. No deaths from breast cancer or thyroid cancer were identified. Five cancer deaths were observed and compared with 4.8 expected deaths based on Ontario cancer death rates. The five cancer deaths resulted from three leukemias, one Wilms' tumor, and one unspecified nervous system tumor. The preliminary findings did not demonstrate a significant leukemia risk arising from diagnostic cardiac catheterizations. Continued follow-up of this cohort is required to evaluate the risk of breast and thyroid cancers which can occur more than 20 years following radiation exposure.

Determination of left ventricular diastolic chamber stiffness and myocardial stiffness in patients with congenital heart disease.

Left ventricular diastolic indexes were derived in 13 patients aged 5 to 21 years. Three had a normal heart, three had lesions causing volume overload and seven had coarctation of the aorta, including one whose main lesion was severe endocardial fibroelastosis. At cardiac catheterization simultaneous high fidelity pressure (P) and left ventricular volume (V) measurements were obtained and several points in one diastolic cycle taken. With use of a monoexponential formula (P = aebv) for P versus V, dP/dv and the operant chamber stiffness b were obtained. Similarly, with use of sigma = alpha e beta epsilon, d sigma/d epsilon, elastic stiffness (E) and the muscle stiffness constant KE were obtained. Values for b were 0.0273 +/- 0.0065 in normal subjects, 0.017 +/- 0.0043 in those with volume overload, 0.0369 +/- 0.0173 in those with coarctation (without endocardial fibroelastosis) and 0.0192 in the child with endocardial fibroelastosis. The plot of P versus V for coarctation was to the left and steeper than normal and the patients with volume overload had a flattened rightward curve, whereas the curve for those with endocardial fibroelastosis was extremely rightward. The stress-radii curves of the normal subjects and those with coarctation were similar whereas the curves for patients with volume overload and endocardial fibroelastosis were rightward of normal. The value for KE was 8.92 +/- 0.87 for the normal subjects, 8.26 +/- 0.75 for those with volume overload, 9.2 +/- 2.5 for those with coarctation and 22.75 for those with endocardial fibroelastosis. Thus, the pressure-loaded ventricle is stiffer than the normal, which in turn, is stiffer than the volume-loaded ventricle. This response, due to hypertrophy, appears to be appropriate in that diastolic stress was normalized and muscle stiffness was not increased except in the patient with endocardial fibroelastosis.

Residual hypertension after coarctectomy in children.

Coarctectomy in 190 children aged over 1 year to 15 years at operation produced a significant reduction in blood pressure for the group as a whole. Forty-nine patients (24 percent) remained hypertensive. Postoperative hypertension was unexplained in 29 (15 percent) of the 190 patients, and coarctation persisted or recurred in 20 (11 percent). For patients operated on between the ages of 4 and 15 years the earlier the age of operation, the greater the reduction in the blood pressure index: (measured blood pressure/normal mean systolic [or diastolic] blood pressure for age) X 100.

Double outlet right ventricle: clinical spectrum and prognosis.

Patients with double outlet right ventricle can be separated into four distinct groups. In the largest (Group III), patients have a subaortic ventricular septal defect and pulmonary stenosis and clinically resemble patients with tetralogy of Fallot. In the next largest group (Group I), patients have a subpulmonry ventricular septal defect and no pulmonary stenosis and clinically resemble children with D-transposition of the great arteries and a ventricular septal defect. These patients have a high rate of coarctation of the aorta leading to early congestive heart failure, and their overall prognosis is poor. In the next largest group (Group II), patients have a subaortic ventricular septal defect and no pulmonary stenosis. Their presentation is similar to that of children with a large ventricular septal defect and pulmonary hypertension. In the smallest group (Group IV), the ventricular septal defect is uncommitted. Survivors in this group also clinically resemble children with a large ventricular septal defect and pulmonary hypertension. When present, coarctation of the aorta and severe mitral valve abnormalities greatly influence the prognosis in double outlet right ventricle. Although the prevalence of associated cardiac abnormalities is large, asplenia, polysplenia, chromosomal abnormalities and other congenital noncardiac abnormalities occur in only 12.5% of patients with double outlet right ventricle.

Role of the renin-angiotensin-aldosterone system in hypertensive children with coarctation of the aorta.

To investigate the role of the renin-angiotensin-aldosterone system as a cause of hypertension, 20 hypertensive patients with coarctation of the aorta were studied during normal and low sodium intake and after diuresis with flurosemide. Eight patients with essential hypertension and 13 control subjects were similarly studied. Plasma renin activity values in patients with coarctation were similar to those in patients with essential hypertension and in control patients during normal and low sodium diets. However, after the administration of furosemide, plasma renin activity values were significantly higher in the patients with coarctation than in the other two groups (P less than 0.005 and less than 0.01, respectively). The values for urinary aldosterone, plasma volume and extracell fluid volume (bromide space) were increased in patients with coarctation during both normal and low sodium intake. These renin and aldosterone responses and body fluid spaces in patients with coarctation suggest that their hypertension resembles a one-kidney Goldblatt model. The data help to better define the role of the renin-angiotensin-aldosterone system in the hypertension of coarctation and thus may help guide the clinician in therapeutic interventions.

Survival after systemic to pulmonary arterial shunts in infants less than 30 days old with obstructive lesions of the right heart chambers.

Ninety-seven infants less than 30 days old with obstructive lesions of the right heart chambers underwent palliative surgery from 1950 through 1972. The diagnosis was made at cardiac catheterization and confirmed at operation or subsequent autopsy. Because of unavailability of complete preoperative studies and sufficient blood gas data, 36 patients presenting between 1950 and 1965 (Group I) were analyzed for surgical risk only. In 61 patients who underwent palliative procedures between 1966 and 1972 (Group II) a more detailed analysis was done. In this group, 31 had a Potts shunt, 29 a Waterston shunt and 1 a Blalock-Taussig shunt. The most frequently encountered malformation was severe tetralogy of Fallot (30 percent) with or without pulmonary atresia, followed by pulmonary atresia with intact ventricular septum (25 percent). The overall surgical mortality rate in patients seen after 1965 (Group II) was 34 percent compared with the 78 percent mortality rate in patients seen earlier (Group I). The surgical mortality in infants operated on during the 1st week of life was double that of those operated on in the 2nd through 4th weeks. Survivors were compared with nonsurvivors for timing of surgery, age at presentation and clinical profile. Only two significant differences were found. Preoperative continuous murmurs were more common in those who survived operation (13 of 40 patients) than in those who died (2 of 21). Arterial pH during cardiac catheterization was the best predictor of subsequent survival, nonsurvivors having significantly greater metabolic acidosis. Palliation of these severe lesions still carries a high mortality rate to which must be added the risk of subsequent repair. Our data suggest that primary repair is to be preferred if it can be undertaken with a risk approximating that of palliative procedures.

Hemodynamic responses to supine exercise in children with left-sided cardiac disease.

Exercise, a physiologic stress, has been used in adults to unmask abnormalities of left ventricular hemodynamics not detectable at rest. Similar data in children are not available. An evaluation was made of the feasibility, safety and value of a graded upright and supine ergometer stress test to assess exercise hemodynamics during cardiac catheterization in 21 children with left-sided cardiac disease. The catheterization technique involved the simultaneous recording of intracardiac and great vessel pressures, thermodilution cardiac index and M mode echocardiograms of the left ventricular cavity. The method appears practical and safe. Although hemodynamic responses varied among clinical groups, the lack of control data currently prevents assessment of the value of this technique for long-term management.

Right ventricular ejection fraction and volumes after mustard repair: correlation of two dimensional echocardiograms and cineangiograms.

The right ventricular ejection fractions derived from two dimensional echocardiograms and cineangiograms were compared in 24 children. All patients (aged 2.1 to 16 years) had undergone Mustard repair for transposition of the great arteries 1 to 12 years earlier. The correlation of the two methods was excellent (r = 0.977), confirming the usefulness of echocardiography for deriving ejection fraction. The volume components of the ejection fraction were less well estimated from the echocardiograms, but the ratios of end-diastolic to end-systolic volumes estimated from each method were similar.

Thallium-201 myocardial imaging in anomalous left coronary artery arising from the pulmonary artery. Applications before and after medical and surgical treatment.

Thallium-201 myocardial imaging was performed on six patients with an anomalous left coronary artery arising from the pulmonary artery. Initial images in three children (aged 4 months, 12 months and 2 1/2 years, respectively) demonstrated anterolateral perfusion defects in agreement with the electrocardiographic localization of infarction. Repeat imaging in two patients 2 to 3 months later, after clinical improvement with anticongestive therapy, demonstrated a reduction in the perfusion defect. In 3 other patients (aged 16, 16 and 20 years, respectively) thallium-201 scans performed during exercise stress demonstrated normal myocardial perfusion 7 to 15 years after operation (ligation of anomalous left coronary in two, ligation plus bypass graft in one). Thallium-201 imaging appears to be helpful in monitoring changes in myocardial perfusion before and after medical or surgical treatment of an anomalous left coronary artery, and may shed light on the pathophysiology of the defect. A possible practical limitation of thallium-201 imaging in this condition is the difficulty of imaging subendocardial infarction.

Radionuclide angiographic evaluation of ventricular function in isolated congenitally corrected transposition of the great arteries.

Eight asymptomatic patients (mean age 19 years, range 7 to 32) with congenitally corrected transposition of the great arteries (CCTGA) underwent equilibrium gated radionuclide angiocardiography at rest and during supine bicycle exercise to assess systemic (morphologic right) and pulmonary (morphologic left) ventricular function. Five patients had normal intracardiac hemodynamic values, 2 had trivial atrioventricular valve regurgitation and 1 patient had trivial pulmonary ventricular outflow tract obstruction. Average exercise duration was 11 +/- 1 minute, with limitation due only to fatigue. At peak exercise, heart rate increased 225% and systolic blood pressure 152% over the rest value. Pulmonary ventricular ejection fraction at rest was 51 +/- 3% (mean +/- standard error of the mean); it did not change significantly at peak stress, 53 +/- 2%. Systemic ventricular ejection fraction was 48 +/- 4% at rest and increased to 64 +/- 4% at peak exercise (p less than 0.01). Count-based volume changes for the pulmonary chamber showed no significant change in end-diastolic or systolic counts at peak exercise (109 +/- 8% and 106 +/- 9% of rest value, respectively). However, end-diastolic counts decreased 13% (87 +/- 3% of rest value) and end-systolic counts 34% (62 +/- 7% of rest value) at peak exercise in the systemic ventricle. These data suggest normal systemic and impaired pulmonary ventricular function in patients with congenitally corrected transposition of the great arteries unaccompanied by significant associated lesions. These findings have important clinical implications in the setting of complex congenital heart disease in patients in whom a morphologic right ventricle functions as the systemic pumping chamber. Despite the pulmonary ventricular dysfunction, symptoms were not apparent at rest or during exercise.

Combined noninvasive assessment of the patent ductus arteriosus in the preterm infant before and after indomethacin treatment.

Fifteen preterm infants who weighed 0.7 to 2.0 kg and had clinical evidence of a patent ductus arteriosus (PDA) were studied by combined 2-dimensional and Doppler echocardiography before and after the administration of indomethacin. In 10 patients the PDA was widely patent at the time of the study and in 5 the lumen was narrow. In this latter group, the PDA was narrow at the pulmonary artery end in 2 patients, in the middle in 2 patients and at the aortic end and the middle in 1 patient. After the administration of intravenous indomethacin, the PDA closed completely in 12 patients and constricted in 3. The patterns of closure could be documented in those in whom serial studies were performed. In 3 patients, closure occurred after a single dose of indomethacin, in 3 after 2 doses and in the rest after a full course of 3 doses. Doppler interrogation at the aortic and pulmonary artery end of the PDA demonstrated the shunting patterns and provided a reliable assessment of patency after the ductal lumen was outside the range of lateral resolution following constriction. In no case did the PDA reopen after the course of indomethacin. This combined approach is a reliable method of assessing a PDA before and after a course of indomethacin. It should provide the means to answer many of the questions regarding the effect of various manipulations on the PDA in the preterm infant.

Bilateral ductus arteriosus (or remnant): an analysis of 27 patients.

Bilateral ductus arteriosus (DA) was clinically recognized in 27 patients studied angiographically from 1963 through May 1983. Distal bilateral DA origin of non-confluent pulmonary arteries was identified in 15 patients, ectopic or distal ductal origin of 1 pulmonary artery in 9 patients (5 without evidence of intracardiac disease) and isolation of the left subclavian artery in 3 (all 3 of whom had a right aortic arch). Other conditions reported to be associated with bilateral DA include interruption of the aortic arch with isolation of a subclavian artery, aortic atresia with interruption of the aortic arch in which bilateral DA supports the entire systemic circulation, bilateral DA complicating forms of congenitally malformed hearts other than those just stated, and, rarely, bilateral DA in isolation. Understanding the symmetric or paired nature of the primitive aortic arch system in the developing human heart facilitates recognition of the patterns of fourth and sixth arch anomalies seen with bilateral DA.

The role of nitric oxide in cardiac depression induced by interleukin-1 beta and tumour necrosis factor-alpha.

1. Myocardial dysfunction during septic shock is associated with enhanced production of cytokines such as interleukin-1 beta (IL-1 beta) and tumour necrosis factor-alpha (TNF-alpha). These cytokines depress cardiac mechanical function by a mechanism which is not well defined. 2. Bacterial endotoxin or cytokines cause the expression of Ca(2+)-independent nitric oxide (NO) synthase in cardiac myocytes, vascular endothelial cells and endocardial endothelial cells, causing enhanced production of NO. As NO has negative inotropic actions on cardiac muscle, we tested the sum effects of IL-1 beta plus TNF-alpha in the intact heart to determine whether enhanced expression of NO synthase activity in the cells that comprise the heart is involved in cardiac depression associated with cytokine stimulation. 3. Rat isolated working hearts perfused with IL-1 beta plus TNF-alpha showed a markedly greater depression in contractile function, measured as cardiac work, after 2 h of perfusion compared with time-matched control hearts. The depressant action of IL-1 beta plus TNF-alpha was first apparent after 1 h of perfusion; no early (15 min) cardiac depressant actions were seen. 4. The competitive inhibitor of Ca(2+)-dependent and Ca(2+)-independent NO synthases, NG-nitro-L-arginine methyl ester (L-NAME, 3 microM) when given concurrently with IL-1 beta plus TNF-alpha prevented the loss in contractile function such that these hearts after 2 h of perfusion had similar function to time-matched controls. L-NAME did not acutely reverse the loss of contractile function in hearts exposed for 2 h to IL-1 beta plus TNF-alpha. The protective action of L-NAME in the presence of cytokines was concentration-dependent and was not seen at a higher concentration (10 micro M) due to the significant reduction in coronary flow observed at this concentration.5. In contrast, when L-NAME (3 micro M) was given in the absence of IL-l beta plus TNF-alpha it depressed contractile function over the 2 h perfusion period by significantly reducing coronary flow.6. Inhibition of protein synthesis with cycloheximide (Cx) abolished the loss in function that occurred over 2h in both control and IL-1 beta plus TNF-a-treated hearts.7. Inducible, Ca2+-independent NO synthase activity was not observed in freshly isolated hearts but was observed in control hearts perfused for 2 h in vitro and was doubled in hearts perfused with IL-1 beta plus TNF-a. Cx prevented the expression of Ca2+-independent NO synthase in both control and cytokine-treated hearts.8. In summary, these results suggest that the depression of myocardial function by IL-l beta plus TNF-alpha is mediated, at least in part, by induction of Ca2+-independent NO synthase activity in the heart.

The response of the isolated ductus arteriosus to transmural stimulation and drugs.

1 Responses of isolated ductus arteriosus preparations from near term guinea-pigs and lambs to transmural electrical stimulation and drugs were studied in a low oxygen medium (Po(2) 19 to 28 mmHg).2 Acetylcholine and noradrenaline contracted both vessels in a dose-dependent manner, their threshold being between 10(-8) and 10(-7) M. Transmural stimulation (pulse width 0.2 to 0.6 ms, typically 20 Hz) also contracted the vessels.3 Atropine and phentolamine or dibenzyline selectively blocked responses to acetylcholine and noradrenaline, respectively.4 In the guinea-pig ductus, part of the response to transmural stimulation was due to activation of intrinsic adrenergic nerves since the responses were reduced by alpha-adrenoceptor antagonists, bretylium or prior reserpine treatment, but not by atropine. The response of the lamp ductus to transmural stimulation varied greatly in magnitude and was inconsistently affected by alpha-adrenoceptor blocking drugs.5 There was no evidence that transmural stimulation activated cholinergic nerves in either species.6 After inactivation of alpha-adrenoceptors with dibenzyline, noradrenaline caused a beta-adrenoceptor-mediated relaxation. Both this effect and isoprenaline-mediated relaxation were blocked by propranolol. beta-Adrenoceptor activity was more prominent in the ductus of the guinea-pig than of the lamb.7 Raising the Po(2) from 19-28 to 92-98 mmHg increased the response of the guinea-pig ductus to transmural stimulation suggesting that, in this species, physiological elevation of oxygen tension at birth may increase transmitter release from intrinsic adrenergic nerves. Whether this mechanism would contribute to ductus closure remains an open question.8 We postulate that beta-adrenoceptor-mediated relaxation has a role in maintaining ductus patency in the guinea-pig foetus.

The morphology of the human newborn ductus arteriosus: a reappraisal of its structure and closure with special reference to prostaglandin E1 therapy.

The ductus arteriosus was examined in 103 fetuses and infants to define the normal structure, development, and morphologic features of the functional and anatomic phases of ductal closure. New contributions include ultrastructural observations and the light microscopic definition of the junctional regions of the ductus with the pulmonary artery and aorta. Observations relating to ductal closure include hyperemia of the ductal vasa vasorum, the presence of longitudinal muscle bands in the inner media, necrosis of the inner ductal wall, and organization of intraluminal thrombi. We found that a ductus arteriosus that fails to close normally is liable to show morphologic lesions, including intimal fibrinous deposits, medial hemorrhages, and dissecting aneurysms. The findings were used comparatively to investigate whether prostaglandin E1 infusion, given to maintain ductal patency in 7 infants with ductus dependent congenital heart disease, was associated with specific morphologic features. We could not delineate specific changes attributable to its use.