Patent Ductus Arteriosus: A Contemporary Perspective for the Pediatric and Adult Cardiac Care Provider

Abstract

The burden of patent ductus arteriosus (PDA) continues to be significant. In view of marked differences in preterm infants versus more mature, term counterparts (viewed on a continuum with adolescent and adult patients), mechanisms regulating ductal patency, genetic contributions, clinical consequences, and diagnostic and treatment thresholds are discussed separately, when appropriate. Among both preterm infants and older children and adults, a range of hemodynamic profiles highlighting the markedly variable consequences of the PDA are provided. In most contemporary settings, transcatheter closure is preferable over surgical ligation, but data on longer-term outcomes, particularly among preterm infants, are lacking. The present review provides recommendations to identify gaps in PDA diagnosis, management, and treatment on which subsequent research can be developed. Ultimately, the combination of refined diagnostic thresholds and expanded treatment options provides the best opportunities to address the burden of PDA. Although fundamental gaps remain unanswered, the present review provides pediatric and adult cardiac care providers with a contemporary framework in PDA care to support the practice of evidence-based medicine.

Keywords: patent ductus arteriosus; pediatric cardiology; treatment.

Figure 1. Schematic of embryonic aortic arch system.

The 6 pairs of embryonic aortic arches are shown (left‐sided arches are numbered). Broken‐lines represent portions that involute in normal development. The distal left sixth embryonic arch normally persists and becomes the PDA, bridging the left pulmonary artery to the proximal descending aorta. The right distal sixth arch normally involutes, as does the eighth segment of the right dorsal aorta (*), which results in a leftward aortic arch. PDA indicates patent ductus arteriosus; LCA, left carotid artery; LSCA, left subclavian artery; RCA, right carotid artery; and RSCA, right subclavian artery. Reproduced from Schneider and Moore [ ⁴ ] with permission. Copyright ©2006, American Heart Association, Inc.

Figure 2. Variations in patent ductus arteriosus (PDA) configuration.

Illustration of multiple configuration of PDAs: type a (“conical”) ductus, with defined aortic ampulla and constriction near the pulmonary artery (PA) end; type b (“window”) ductus, with short length and constriction at the aortic end (wide PA end); type c (“tubular”) ductus, without constrictions at the aortic or pulmonary ends; type d (“saccular”) ductus, with constricted aortic and pulmonary ends and a wide center; type e (“elongated”) ductus, which is narrow with a constricted pulmonary end; and type f (“fetal”) ductus, which is found largely in premature infants and is long, wide, and tortuous. AO indicates aorta.

Figure 3. Molecular pathways involved in intrauterine ductus arteriosus (DA) relaxation (A) and molecular pathways involved in postnatal DA constriction (B).

A, Endothelial NO synthase (eNOS)–derived NO, CO, and atrial natriuretic peptide (ANP) initiate the cGMP signaling cascade by activating membrane‐bound or soluble guanylate cyclase (sGC). cGMP subsequently activates protein kinase G (PKG), which decreases the intracellular calcium concentration by inhibiting voltage‐dependent calcium channels (VDCCs) and promoting calcium uptake into the sarcoplasmic reticulum. PKG also activates voltage‐gated potassium channel (K_v), ATP‐gated potassium channel (K_ATP), and large conductance calcium‐activated potassium channel (BK_Ca), which trigger potassium efflux and membrane hyperpolarization, resulting in VDCC inhibition. In addition, prostaglandin E₂ (PGE₂), working through the prostaglandin E₂ receptor 4 (EP₄), activates adenylyl cyclase. Adenosine also activates adenylyl cyclase, which, in turn, activates the cAMP/protein kinase A (PKA) signaling cascade. PKA activates K_v, K_ATP, and BK_Ca and inhibits myosin light chain kinase (MLCK), which subsequently reduces phosphorylation of myosin light chains (MLCs), thereby preventing vasoconstriction. B, Increased O₂ tension increases the concentration of intracellular calcium via several pathways. First, O₂ stimulates mitochondrial production of ATP and H₂O₂, which inhibit vasodilating K_ATP and K_v. H₂O₂ also activates the ras homologous protein (Rho)/rho‐associated protein kinase (ROCK) cascade, which promotes constriction by inhibiting MLC phosphatase (MLCP)–mediated MLC dephosphorylation. In addition, O₂ upregulates the production of 8‐iso‐prostaglandin F2α (8‐iso‐PGF2α), which signals through thromboxane receptor (TR) to activate Rho/ROCK and inositol trisphosphate (IP₃) signaling cascades. Furthermore, O₂ promotes constriction by cytochrome P450 (CYP450)–mediated binding of endothelin‐1 (ET‐1) to endothelin receptor A (ET_A), which subsequently activates the IP₃ pathway. Similarly, glutamate activates IP₃ signaling via noradrenaline (NA) production. Once activated, IP₃ then binds to IP₃ receptor (IP₃R) on the sarcoplasmic reticulum, causing movement of calcium into the cytoplasm. Intracellular calcium concentrations are also regulated by transient receptor potential melastatin‐3 channel (TRPM3), which becomes activated under hypo‐osmotic conditions. Accumulation of intracellular calcium facilitates activation of MLCK, which phosphorylates MLC, allowing for myosin and actin interaction and subsequent muscle contraction. [Ca²⁺]i indicates concentration of intracellular calcium; and [Ca²⁺]SR, concentration of calcium in the sarcoplasmic reticulum.

Figure 4. Ductal size and shunt direction evaluation (A) and ductal shunt volume evaluation (B).

A, Echocardiographic verification of patent ductus arteriosus (PDA) presence, with PDA size and shunt direction assessment. a, Color flow of PDA. b, Pulsatile pattern with left‐to‐right low‐velocity flow with wide differential between systole and diastole. c, Restrictive pattern with higher velocity in both systole and diastole. d, Bidirectional pattern with right‐to‐left ductal flow during systole. B, Echocardiographic examination of left atrial and left ventricular enlargement and quantification of ductal impact on cardiac performance. a, Dilated left atrium (A) and ventricle (V). b, M‐mode measurement, demonstrating a dilated left atrium indexed to the aortic diameter. c, Elevated and pulsatile pulmonary venous flow, demonstrating high pulmonary venous diastolic flow. d, Shortened isovolumetric relaxation time. e, Transmitral flow, demonstrating an early/atrial flow ratio of 1. f, Reversal of diastolic flow in the postductal descending thoracic aorta. IVRT indicates isovolumetric relaxation time; LA:Ao, left atrial diameter to aortic root diameter ratio; MPA, main pulmonary artery; MV E/A, mitral valve early/atrial flow ratio; and PV D, pulmonary vein diastolic velocity.

Figure 5. American Heart Association guideline for management of noninfant patients with hemodynamically significant patent ductus arteriosus (HSPDA).

Flowchart and guideline for the management of older patients and adults with HSPDA. Adapted from and based on recommendations in Stout et al. ECHO indicates echocardiography; IE, infective endocarditis; PASP, pulmonary arterial systolic pressure; PH, pulmonary hypertension; and PVR, pulmonary vascular resistance.

Figure 6. Percutaneous patent ductus arteriosus (PDA) closure (A) and intraprocedural imaging of percutaneous PDA closure (B).

A, Illustration of percutaneous device release for closure of a PDA. An end hole catheter is used to cross the tricuspid valve into the right ventricle (RV), then a soft, floppy‐tipped wire is advanced across the PDA and into the descending aorta (DAO) (data not shown). At this point, the catheter in the right ventricle is removed over the wire, and a delivery catheter is advanced over the wire through the venous sheath into the PDA and descending aorta (data not shown). The device is advanced to the tip of the catheter (a). The device is deployed under fluoroscopic and transthoracic echocardiography guidance within the PDA with careful attention to avoid device protrusion into the aorta or pulmonary artery (b). When position is satisfactory, the device is released from the delivery cable (c). B, Radiographs illustrating steps and final result of a percutaneous PDA closure procedure. a, Following femoral vein access, a 4F catheter is introduced and advanced to the RV under fluoroscopic guidance, wherein a floppy‐tipped wire is guided via this catheter through the PDA and into the descending aorta, after which a 4F delivery catheter is exchanged. b, An angiogram is obtained for configuration and dimensional data of the PDA, which permits selection of the most appropriate device for closure. c, The device is then advanced through the delivery catheter and deployed, but not fully released. d, Additional echocardiographic imaging is obtained to confirm placement of the device. e, Additional angiographic imaging to evaluate for aortic or left pulmonary obstruction attributable to the device. f, Device is released; additional imaging to evaluate postrelease positioning and stability, residual shunting, and other clinical parameters (eg, presence of new or increased tricuspid valve regurgitation) may be warranted. Reproduced from Barcroft et al with permission. Copyright ©2022 Elsevier. LPA indicates left pulmonary artery; and MPA, main pulmonary artery.